Pyridazine and pyridazinone derivatives as potent and selective factor XIa inhibitors

Article abstract of DOI:10.1016/j.bmcl.2018.02.049

Pyridazine and pyridazinone derivatives were designed and synthesized as coagulation factor XIa inhibitors. Potent and selective inhibitors with single digit nanomolar affinity for factor XIa were discovered. Selected inhibitors demonstrated moderate oral bioavailability.

Full text of DOI:10.1016/j.bmcl.2018.02.049

Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Pyridazine and pyridazinone derivatives as potent and selective factor
XIa inhibitors
a
a
a
b
b
c
Zilun Hu a, , Cailan Wang , Wei Han , Karen A. Rossi , Jeffrey M. Bozarth , Yiming Wu , Steven Sheriff ,
⇑
Joseph E. Myers Jr. c, Joseph M. Luettgen b, Dietmar A. Seiffert c, Ruth R. Wexler a, Mimi L. Quan a
a Bristol-Myers Squibb Company, Research and Development, 350 Carter Road, Hopewell, NJ 08540, United States
b Bristol-Myers Squibb Company, Research and Development, 311 Pennington-Rocky Hill Road, Pennington, NJ 08543, United States
c Bristol-Myers Squibb Company, Research and Development, US Rt. 206 & Province Line Road, Princeton, NJ 08540, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Pyridazine and pyridazinone derivatives were designed and synthesized as coagulation factor XIa inhibi-
tors. Potent and selective inhibitors with single digit nanomolar affinity for factor XIa were discovered.
Selected inhibitors demonstrated moderate oral bioavailability.
Received 2 January 2018
Revised 22 February 2018
Accepted 26 February 2018
Available online xxxx
Ó 2018 Elsevier Ltd. All rights reserved.
Keywords:
Factor XIa inhibitors
FXIa
Thrombosis
Pyridazine
Pyridazinone
Introduction
chlorophenyltetrazole acrylamide P1 group had a FXIa Ki of 2.7
nM in the FXIa enzyme binding assay, and had in vitro anticoagu-
Evidence supports the hypothesis that factor XIa (FXIa) is a valid
target for anticoagulation therapy with the promise of an increased
net clinical benefit compared to currently available anticoagu-
lants.1–3 Preclinical, clinical,1,3 and genetic4 data indicates that
inhibition of the intrinsic coagulation cascade FXIa is efficacious
in preventing thrombosis while maintaining hemostasis. A recent
clinical study showed that reducing FXI levels specifically by an
antisense oligonucleotide in patients undergoing elective knee
arthroplasty was an effective method for postoperative venous
thromboembolism prevention and appeared to be safe with
respect to the risk of bleeding.5 Preclinical proof of concept studies
demonstrated robust antithrombotic efficacy with minimal bleed-
ing liability were reported by our group based on a series of small
molecule, active site directed FXIa inhibitors.1,6,7
lant activity with an EC1.5x of 5.3 lM in the activated partial
thromboplastin time (aPTT)8 clotting assay. However no oral
bioavailability was observed for 1 in a dog pharmacokinetic study.9
Promising oral bioavailability was observed for the phenyl pyridine
and pyrimidine series by following the strategy of reducing the
number of H-bond donors in the chemotype.11 For example, pyri-
dine 2 demonstrated improved bioavailability. Unfortunately these
analogs were less potent than 1 in FXIa binding and aPTT clotting
assays.12 In the search for potent and orally bioavailable FXIa inhi-
bitors, we explored and evaluated the pyridazine derived analogs
(Fig. 1, A and B) based on their structural similarity to the imida-
zole and pyridine scaffolds, but with reduced basicity (See Fig. 2.).
The pyridazine regioisomers 3 and 4 were synthesized to com-
pare with 2. Table 1 shows the FXIa affinity (Ki) and in vitro anti-
Researchers of our group have reported several series of FXIa
inhibitors. The chemotypes include phenyl imidazoles,8–10 phenyl
pyridines,11 dipeptides12 and recently macrocycles13 that are
potent and selective FXIa inhibitors. One of the challenges with
these series has been in achieving sufficient oral bioavailability.
As shown in Fig. 1, the imidazole inhibitor 1 with a neutral
coagulant clotting potency (aPTT EC1.5x) for both analogs.
Compounds 3 and 4 demonstrated potency comparable to the imi-
dazole analogs9 and better than the pyridine analog 211 in the FXIa
Ki and aPTT assays. The regioisomer of 4,6-disubstituted pyridazine
analog (4, FXIa Ki = 4.1 nM) was similar in binding potency to the
3,5-disubstituted pyridazine analog (3, Ki = 7.0 nM), while analog
4 exhibited better aPTT potency with an aPTT EC1.5x of 3.5
3 (aPTT EC1.5x = 14 M).
lM than
l
⇑
Corresponding author.
E-mail address: zilun.hu@bms.com (Z. Hu).
https://doi.org/10.1016/j.bmcl.2018.02.049
0960-894X/Ó 2018 Elsevier Ltd. All rights reserved.
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Z. Hu et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
Table 1
Phenyl pyridazine FXIa inhibitors
Compd
Core
FXIa Kia(nM)
aPTTbEC1.5x
14
(lM)
3
7.0
4
4.1
3.5
a
Ki values were obtained from purified human enzyme at 25 °C and were
averaged from multiple determinations (n ꢀ 2), as described in reference 8.
bActivated partial thromboplastin time (aPTT) in vitro clotting assay was performed
in human plasma as described in reference 8
Figure 1. Pyridazine based FXIa inhibitors.
provided analogs 14 and 15, which maintained the FXIa Ki potency
(Table 3). However, these modifications led to no significant
improvement in HLM stability (20 and 12 min in T1/2 for 14 and
15 versus 8.6 min for 9). The 4-pyridine analog (16) demonstrated
improvement in aPTT, however showed decreased HLM stability
(T1/2 2.8 min). Selected saturated heterocyclic analogs were also
evaluated. The piperidine analog 17 demonstrated weaker potency
compared with 9.
A number of substituted pyridazine and pyridazinone analogs
were evaluated to probe the effect on potency and metabolic sta-
bility (infra), and their potencies are listed in Table 2. The two pyri-
dazinone regioisomers 5 and 6 (racemic) showed similar Ki values
(10 and 22 nM) and aPTT EC1.5x (11 and 19 lM). Methyl substitu-
tion at the C3 (7) and C6 (8) positions also demonstrated similar
potency (6.1 and 10 nM). The chlorine substitution analog at the
C6 position (9) also had comparable FXIa binding (Ki = 9.6 nM)
Further SAR at the P10 led to the exploration of aspartic acid
derivatives based on our perviously described research that the
amide carbonyl made a hydrogen bond to Leu 41 of FXIa, which
enhanced binding potency.10 The introduction of aspartic amide
oriented the substituent towards both the S10 and S2 pockets,
and was different from the benzyl group which projected solely
into the S10 pocket. As shown in Table 3, the hydroxypyrrolidine
amide analog 18 was more potent than 17.
and clotting (aPTT EC1.5x = 9.3 lM) potencies to the C6 unsubsti-
tuted analog (3). The analog with the C3 chloro (10) was discovered
to have improved potency (FXIa Ki = 1.9 nM and aPTT EC1.5x = 2.2
lM). Besides the methyl and chloro groups, methyl ether (11) and
the methyl amide (13) analogs at the C6-position of the 3,5-disub-
stituted pyridazine were found to be less potent (FXIa Ki = 36 and
31 nM, respectively), while the carboxylic acid analog (12) retained
FXIa potency with a Ki 11 nM.
Further improved FXIa binding and aPTT potencies were
observed when the same P10/P2 group was combined with
the C3- chloropyridazine core (19, FXI Ki 6.6 nM and aPTT EC1.5x
A metabolite identification study of compounds 3 and 4 indi-
cated that the P10 phenyl group presented as a soft spot in human
liver microsomes (HLM). Fluorination of the P10 phenyl group
Figure 2. X-ray crystal structure of analog 17 bound to FXIa. The red spheres depict water molecules, the dotted lines depict hydrogen bonds, and ethylene diol is an artifact
of the flash-cooling procedure. PDB ID: 6C0S.
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Z. Hu et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
3
Table 2
1.6
l
M). The methylpiperazine amide 20 demonstrated an antico-
M.
Substitutions on pyridazin(on)e
agulant activity of aPTT EC1.5x 0.9
l
The crystal structure of compound 17 bound to the active site of
FXIa was obtained at 2.35 Å resolution. This ligand shows previ-
ously observed interactions in the S1 and S20 sites,9–11 but also
shows lipophilic interactions that lie between the S10 and S2 pock-
ets. The chlorophenyl tetrazole binds deep in the S1 pocket near
Tyr228 and the acrylamide orients the carbonyl into the oxyanion
hole formed by backbone residues Gly193, Asp194 and Ser195.
One nitrogen of the chloropyridazine makes a hydrogen bond
through an ethylene diol solvent molecule and a series of con-
served waters to the backbone carbonyl of Ser214. As seen in pre-
ceding crystal structures of this chemotype,9–11 the phenyl
carbamate binds in the S20 pocket, The aniline NH makes a hydro-
gen bond directly to the backbone of Leu41 and the carbamate car-
bonyl makes a hydrogen bond via a conserved water molecule to
Ile151. The piperidine substituent extends towards the S10 and
S2 pocket instead of directing at the S10 pocket that the benzyl sub-
stituents occupy. It appears the most significant interaction is van
der Waals contact between the methylene of piperidine ring and
residues His57, Cys58 and Cys42. Surprisingly, the carbonyl does
not make any hydrogen bonds with the protein.
A representative synthesis of pyridazine C6-Cl and pyridazin-6-
one analogs is shown in Scheme 1. The ketophosphonate (22) was
obtained in high yield by treating dimethyl methylphosphonate
with n-BuLi before reacting with phenylalanine derivative 21. Con-
densation of 22 with ethyl 2-(4-nitrophenyl)-2-oxoacetate under
basic conditions, followed by ring closing with hydrazine formed
the pyridazinone 23. The methyl carbamate was installed by nitro
reduction of 23, and then by treating the aniline 24 with methyl
chloroformate to provide 25 in excellent yield. The Boc was removed
from 25, and then amide coupling with 279 gave compound 5. When
intermediate 25 was treated with POCl3, C6-chloropyridazine amine
Compd
Core
FXIa Kia (nM)
10
aPTTb EC1.5x
11
(lM)
5
6c
22
19
7
6.1
10
14
11
9.3
2.2
50
32
8
9
9.6
1.9
36
10
11
12
11
13
31
45
a
Ki values were obtained from purified human enzyme at 25 °C and were
averaged from multiple determinations (n ꢀ 2), as described in reference 8.
bActivated partial thromboplastin time (aPTT) in vitro clotting assay was performed
in human plasma as described in reference 8. cCompound 6 is racemic.
Table 3
P10 SAR of chloropyridazine
Compd
Core
R
FXIa Kia (nM)
aPTTb
EC1.5x
(lM)
14
4-F-Ph
9.3
22
15
16
17
18
3-F-Ph
10
12
89
26
17
4-pyridyl
6.2
8.8
7.5
19
20
6.6
4.0
1.6
0.9
a
Ki values were obtained from purified human enzyme at 25 °C and were averaged from multiple determinations (n ꢀ 2), as described in reference 8. bActivated partial
thromboplastin time (aPTT) in vitro clotting assay was performed in human plasma as described in reference 8.
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Z. Hu et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
provide 8 and 11 respectively. In addition, C6 carboxylation was
realized through the corresponding C6 triflate intermediate 31 pre-
pared from 25, to afford ester 32. Further functional group trans-
formation and the installation of the P1 group gave compounds
12 and 13.
The synthesis of compound 17 is outlined in Scheme 3. The pro-
tected amino ester 36 was prepared by Horner-Wittig condensa-
tion of aldehyde 33 and phosphonate 34 followed by asymmetric
hydrogenation. Then by following a similar procedure as described
in Scheme 1, aniline 37 was obtained, from which the P1 group was
installed to give 38. Methyl carbamate formation and removal of
Boc provided 39. Final acetylation and diastereomer separation
by reverse phase preparative HPLC yielded 17.
The synthesis of 18 is described in Scheme 4. By following a
similar procedure as described in Scheme 1, the tert-butyl ester
pyridazinone intermediate 41 was prepared from appropriately
protected aspartic acid derivative 40. Following steps of functional
group transformations, tert-butyl ester 41 was converted to methyl
ester 43 via acid 42. Pyridazinone 43 was then converted to
chloropyridazine followed by hydrolysis of the methyl ester to give
acid 44. Amide coupling followed by P1 installation provided 18.
Scheme 1. Reagents and conditions: (a) dimethyl methyl phosphonate, n-BuLi,
THF, -78 to 0 °C, 95% (b) i, ethyl 2-(4-nitrophenyl)-2-oxoacetate, K2CO3, EtOH, 0 °C,
30 min; ii, hydrazine, 0 °C, 20 min, 83% (c) Zn, NH4Cl, MeOH, 100% (d) methyl
chloroformate, pyridine, DCM, 0 °C, 1 h, 95% (e) POCl3, acetonitrile/chloroform, 65
°C, 3 h, 78% (f) DIEA, DMF, 85% (g) i, TFA in DCM (1/1), 100%; ii, DIEA, DMF, 80%
26 was obtained, which coupled with 27 to give 9. Other analogs
with chloropyridazine core with different P10 (14–16, Table 3) were
prepared by following a similar procedure starting with the appro-
priate amino ester analogs of 21.
Analogs of C6 substituted pyridazine were prepared according
to Scheme 2 from intermediate 29. Hydrogenation of 29 to remove
C6-Cl gave C6-H intermediate 30, which was converted to C6-H
pyridazine analog 3. The C6-Cl intermediate was converted to
C6-Me via Suzuki-Miyaura cross coupling reaction, and the C6-Cl
was also converted to C6-OMe via SNAr reaction with NaOMe to
Scheme 3. (a) DBU, DCM, rt, 74% (b) (+)-1,2-bis((2S,5S)-2,5-diethyl phospholano)
benzene(cyclooctadiene) rhodium (I) trifluoromethane sulfonate (1 mmol%), H2 (50
psi), MeOH, 100% (c) Scheme 1 a–c, 25% for 3 steps (d) Scheme 1 f, 64% (e) Scheme
1d-e, 24% (f) i, AcCl, DCM/pyridine, 72%; ii, reverse HPLC separation of
diastereomers.
Scheme 2. Reagents and conditions: (a) Boc2O, TEA, MeCN, 84% (b) H2, Pd/C, MeOH,
100% (c) i, TFA, DCM; ii, 27, DIEA, DMF, 48% for 2 steps (d) methylboronic acid, (t-
Bu3P)2Pd, K3PO4, dioxane/H2O, 90 °C, 54% (e) NaOMe, 91% (f) Tf2O, pyridine, 0 °C –
rt, 48% (g) CO, Pd(OAc)2, DPPF, MeOH, DIEA, 55 °C, 85% (h) i, c, 85%; ii, NaOH, MeOH-
H2O, 100% (i) BOP, DIEA, DMF, 0 °C – rt, methylamine HCl salt, 95%
Scheme 4. Reagents and conditions: (a) Scheme 1a-d, 33% for 4 steps (b) i, TFA/
DCM (1/1 v/v), rt, 1 h; ii, Boc2O, TEA, THF/H2O, 97% for two steps (c) TMSCH2N2,
DCM, MeOH, 100% (d) i, POCl3, CHCl3; ii, Boc2O, TEA/DCM; iii, LiOH, THF/H2O, 55%
for three steps (e) i, (R)-pyrrolidin-3-ol HCl salt, PyBOP, DIEA, DMF, 88%; ii, TFA/
DCM, rt; iii, 28, DIEA, DMF, rt, 80%
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Z. Hu et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
5
The analogs with C3-Cl and other substitutions were prepared
according to Scheme 5. By utilizing a modified Minisci procedure,14
alkylation of 3,6-dichloropyridazine with either Cbz or phthalim-
ide (Phth) protected amino acids afforded 4-substituted-3,6-
dichloropyridazine 45–47. While preparing 47, the hydrolyzed
product 48 was obtained as well in low yield. Suzuki coupling to
introduce 4-methyl carbamoylphenyl P20 group gave intermediates
49–51. The protecting groups were removed to afford amines 52
and 53. The racemic amines 52 and 53 were resolved by chiral
SFC chromatography, and the enantiomerically pure amines were
coupled with 27 to afford 10 and 54. By following a similar proce-
dure, 48 was converted to C3-pyridazinone analog 6. From 54, the
P10 amide analogs (19–20) were obtained by following a similar
synthesis as described in Scheme 1. Intermediate 51 was converted
to product 4 and 7 as described in the Scheme 5.
Pharmacokinetic profiles of selected compounds were evalu-
ated in dogs using cassette dosing, and the results are listed in
Table 4.
The more potent C3-(un)substituted pyridazine regioisomers
with phenyl and amide P10 groups (4, 10 and 19) demonstrated
moderate clearance and volume of distribution. No oral bioavail-
ability was observed even though improved HLM stability were
observed for 10 and 19. The C6-(un)substituted pyridazine deriva-
tives (3, 8, 9 and 14), demonstrated moderate oral exposure with
bioavailability ranging from 12 to 18%. Low clearance, low to mod-
erate volume of distribution and slightly longer half-lives were
observed. Even though permeability (Caco-2 or PAMPA, data not
shown) of these compounds was not affirmative to draw a conclu-
sion due to poor solubility for some of them, the intramolecular H-
bonding of the N3-nitrogen with the amide NH of P1 linker could
enhance permeability, and therefore improve oral bioavailability.
The selectivity profiles of representative pyridazine FXIa inhibi-
tors are listed in Table 5. These compounds are highly selective
against a panel of relevant serine proteases. Compounds 3, 9 and
10 demonstrated some weak activity against FXa and/or plasma
kallikrein
Scheme 5. Reagents and conditions: (a) (NH4)2S2O8, AgNO3, TFA, H2O, 75 °C, 13%
(45); 23% (46); 18% (47) and 5% (48) (b) (4-((methoxycarbonyl) amino)phenyl)
boronic acid, Pd2(dba)3, t-Bu3P, Cs2CO3, dioxane, 90 °C, 31% (49); 41% (50); 45% (51)
(c) H2, Pd/C, MeOH, 84% for 49 and 90% for 51; or hydrazine, EtOH, 73% for 50 (d) i,
Chiralcel OD, eluted with 80% EtOH-MeOH (1:1) - 20% heptane ii, 27, DIEA, DMF, rt,
16 h, for 54, 68%; for 10, 70% (e) i, TFA, DCM, 100%; ii, isobutylchloroformate, DIEA,
DMF, amine, 0 °C – rt, 95% (f) i, methylboronic acid, (t-Bu3P)2Pd, K3PO4, dioxane, 90
°C, 55% ii, c and d-ii (g) i, H2, MeOH, 100% ii, d, 80%
In summary, derivatives of pyridazine and pyridazinone were
identified as potent and selective FXIa inhibitors. Among these FXIa
inhibitors, C3-(un)substituted derivatives were more potent than
Table 4
PK profiles of selected compoundsa
Compd
Cl (mL/min/kg)
Vdss (L/kg)
t1/2 (h)
F (%)
HLM Tb1/2 (min)
4
18.2
15.5
24.7
8.9
9.2
6.3
1.4
2.1
1.2
1.3
1.2
2.3
1.5
1.1
1.8
0.9
1.8
2.0
7.1
6.7
<3
<3
<3
18
14
16
12
9.6
31
36
9.1
5.1
8.6
20
10
19
3
8
9
14
5.1
a
Compounds were dosed at 0.2–0.5 mg/kg po, and 0.2–0.4 mg/kg iv dosing in a cassette format; dosing vehicles: 10% DMAC - 10% EtOH -10% PG -70% water for iv, and 10%
EtOH - 70% PEG400 - 20% TPGS for po. bHuman liver microsome half-life (HLM T1/2) of compounds were determined by following the method described in Ref. 15
Table 5
Human Serine Protease Selectivity Profile for 3, 8, 9 and 10.
Human Enzyme Ki (nM)a
3
8
9
10
Factor XIa
Factor VIIa
Factor IXa
Factor Xa
Thrombin
Trypsin
Plasma Kallikrein
Activated Protein C
Plasmin
TPA
Urokinase
Chymotrypsin
7.0
10
9.6
1.9
>13300
>13300
39,300
>3000
>13300
>6220
1370
>64400
>53400
>14700
>29730
>27200
>13300
>73700
200
3280
22,000
1940
10,600
3730
192
16,300
4490
994
NTb
840
>13300
>6220
268
68,000
38,100
>14700
>29730
11,900
>13300
>6220
>6000
>64400
76,600
10,100
>29730
>27200
13,330
29,600
a
All Ki values in nM were obtained using human purified enzymes. bNot tested
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Z. Hu et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
2013;33:1670–1678;
C6-(un)substituted isomers. The C6-(un)substituted pyridazine
derivatives demonstrated moderate oral bioavailability in pharma-
cokinetic studies in dogs.
(e) Zhang H, Lowenberg EC, Crosby JR, et al. Blood. 2010;116:4684–4692.
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Acknowledgments
(d) Doggen CJM, Rosendaal FR, Meijers JCM. Blood. 2006;108:4045–4051;
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The authors would like to thank Dr. James R. Corte and Dr. Wil-
liam R. Ewing for helpful discussions and review of the manuscript.
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PC, Quan ML, Watson CA, et al. Thromb Thrombolysis. 2015;40(4):416–423.
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8. EC1.5x is defined as the plasma concentration of FXIa inhibitor required to
increase aPTT to 1.5-times baseline. See: Hangeland JJ, Friends TJ, Rossi KA,
et al. J Med Chem. 2014;57:9915–9932.
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.bmcl.2018.02.049.
9. Pinto DJP, Smallheer JM, Corte JR, et al. Bioorg Med Chem Lett.
2015;25:1635–1642.
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