Functionalized triazines as potent HCV entry inhibitors

Article abstract of DOI:10.1016/j.bmcl.2016.12.038

A series of potent and novel acylsulfonamide-bearing triazines were synthesized and the structure-activity relationships (SARs) as HCV entry inhibitors were evaluated. This acylsulfonamide series was derived from an early lead, 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid wherein the carboxylic acid was replaced with an acylsulfonamide moiety. This structural modification provided a class of compounds which projected an additional vector off the terminus of the acylsulfonamide functionality as a means to drive activity. This effort led to the discovery of potent analogues within this series that demonstrated sub-nanomolar EC₅₀ values in the HCV pseudotype particle (HCVpp) assay.

Full text of DOI:10.1016/j.bmcl.2016.12.038

Accepted Manuscript
Functionalized Triazines as Potent HCV Entry Inhibitors
Eric S. Mull, Li-Qiang Sun, Qian Zhao, Betsy Eggers, Kevin Pokornowski,
Guangzhi Zhai, Ramkumar Rajamani, Susan Jenkins, Melissa Kramer, Ying-
Kai Wang, Hua Fang, Daniel Tenney, Carl J. Baldick, Mark I. Cockett, Nicholas
A. Meanwell, Paul M. Scola
PII:
S0960-894X(16)31304-X
http://dx.doi.org/10.1016/j.bmcl.2016.12.038
BMCL 24527
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
2 November 2016
13 December 2016
14 December 2016
Please cite this article as: Mull, E.S., Sun, L-Q., Zhao, Q., Eggers, B., Pokornowski, K., Zhai, G., Rajamani, R.,
Jenkins, S., Kramer, M., Wang, Y-K., Fang, H., Tenney, D., Baldick, C.J., Cockett, M.I., Meanwell, N.A., Scola,
P.M., Functionalized Triazines as Potent HCV Entry Inhibitors, Bioorganic & Medicinal Chemistry Letters (2016),
doi: http://dx.doi.org/10.1016/j.bmcl.2016.12.038
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Functionalized Triazines as Potent HCV Entry Inhibitors
Eric S. Mull*a, Li-Qiang Sun*a, Qian Zhaoa, Betsy Eggersb, Kevin Pokornowskib, Guangzhi Zhaib,
Ramkumar Rajamanic, Susan Jenkinsd, Melissa Kramerd, Ying-Kai Wange, Hua Fange, Daniel Tenneyb,
Carl J. Baldickb, Mark I. Cockettb, Nicholas A. Meanwella, Paul M. Scolaa
aDepartment of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT, 06492.
bDepartment of Virology Discovery Biology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT, 06492.
cDepartment of Computer-Assisted Drug Design, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT, 06492
dDepartment of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT, 06492.
eDepartment of Lead Evaluation, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT, 06492.
KEYWORDS: Hepatitis C virus, entry inhibitor, acyl sulfonamide, triazine
ABSTRACT: A series of potent and novel acylsulfonamide-bearing triazines were synthesized and the structure-activity relation-
ships (SARs) as HCV entry inhibitors were evaluated. This acylsulfonamide series was derived from an early lead, 4-(4-(1-(4-
chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid wherein the carboxylic acid was
replaced with an acylsulfonamide moiety. This structural modification provided a class of compounds which projected an addition-
al vector off the terminus of the acylsulfonamide functionality as a means to drive activity. This effort led to the discovery of potent
analogues within this series that demonstrated sub-nanomolar EC50 values in the HCV pseudotype particle (HCVpp) assay.
Hepatitis C Virus (HCV) infection is predominantly a
chronic viral disease of the liver affecting more than 170 mil-
lion people worldwide with 4 to 5 million cases in the U.S.
alone.1-3 For just over a decade, the optimal care for patients
proved in Japan in July of 2014.12-17 The triple combination of
daclatasvir, asunaprevir, and beclabuvir has proven effective
for the treatment of individuals infected with genotype-1b and
genotype-1a viruses with the latter a more challenging patient
population to treat with direct-acting antiviral agents
(DAAs).18,19
chronically infected with HCV was
a combination of
PEGylated α-interferon (PEG-IFN) with ribavirin (RBV), nei-
ther of which are specific HCV antiviral agents.4 The first
wave of direct acting antiviral (DAA) agents that were ap-
proved, telaprevir and boceprevir, were combined with PEG-
IFN/RBV and provided a genotype-1 drug regimens with im-
proved efficacy.5,6 These regimens offered sustained viral
response (SVR) rates for genotype-1 patients naïve to therapy
of up to 75%.7 Notably, these treatments required PEG-IFN
and RBV for efficacy but added to the burden of tolerability
issues.7 This provided an impetus for the discovery of inter-
feron-free DAA cocktails with potentially improved tolerabil-
ity profiles and shorter durations of treatment. These regi-
mens consist of combinations of drugs which target the virus
at multiple points in its life cycle to overcome the emergence
of resistance. Prominent FDA-approved combinations include
Harvoni®, a combination of sofosbuvir and ledipasvir; Viekira
Pak®, which combines ombitasvir, paritaprevir and ritonavir
tablets co-packaged with dasabuvir; ZepatierTM, a combination
of elbasvir and grazoprevir; and Epclusa®, a fixed dose com-
bination of sofosbuvir and velpatasvir.8
In addition to focusing on life cycle targets of HCV, a com-
plementary approach was taken that targeted interfering with
viral entry into the host cell. This strategy has been adopted in
HIV-1 therapy20 and with respect to HCV there have been
reports of agents targeting entry through various stages and
mechanisms of action.21-27
Internal efforts led to the discovery of daclatasvir (BMS-
790052, 1)9,
a
NS5A replication complex inhibitor,
asunaprevir (BMS-650032, 2),10 a NS3 protease inhibitor, and
the non-nucleoside NS5B polymerase inhibitor beclabuvir
(BMS-791325, 3)11. The combination of asunaprevir with
daclatasvir was the first DAA regimen to demonstrate that a
chronic HCV infection could be cured without the use of PEG-
IFN/RBV and became the first all-oral, interferon- and ribavi-
rin-free regimen marketed for the treatment of individuals with
genotype-1b chronic hepatitis C infection when it was ap-
Figure 1: Internal research discoveries at Bristol-Myers
Squibb
We28 and others29 have previously reported on the discovery
of triazine-based small molecule HCV entry inhibitors. These
inhibitors were identified in high throughput (HTS) screening
campaigns using an HCV pseudotype particle assay (HCVpp).
HCVpp, consisting of lentiviral particles engineered to contain

the HCV envelope proteins E1 and E2, are a validated system
for studying the early steps of HCV entry.28 Our initial triazine
HTS hit 4 (Fig. 2) exhibited modest potency toward genotypes
1a and 1b but poor rat microsomal stability and PAMPA per-
meability. SARs borne out of exploration of the substituents
on the triazine core led to the identification of the early lead
compound 5, which showed an improvement in genotype 1a
potency along with a more favorable microsomal stability
profile. In an effort to further advance this triazine series with
respect to potency and drug-like properties, SARs were ex-
plored at the terminus of each aryl group. Described herein
are our efforts to replace the carboxyl moiety with groups that
expand the binding silhouette in this series. It should be noted
that acylsulfonamides were selected as the functional group
with which to explore this seam of SARs, viewed as promising
since the acidity
found in the parent acid series would be preserved while fur-
ther interactions with the target could be explored by modifi-
cations to the terminus of this functionality. In the event, a
number of compounds from this novel chemotype displayed
enhanced inhibitory activity toward genotype 1a and 1b virus
infectivity when compared to 5 and the details of these find-
ings are described herein.
The synthesis of lead 5 was previously disclosed.30 The
general synthetic routes to the series of analogs discussed in
Table 1 and Table 2 are shown in Scheme 1. Compound 5
was elaborated by coupling of the acid moiety with a subset of
alkyl sulfonamides mediated by EDC to form
acylsulfonamides 6-13. Similarly, compound 5 was coupled
with tert-butyl (2-sulfamoylethyl)carbamate using PyBOP as a
coupling agent to form 30 followed by Boc deprotection with
HCl in dioxane to afford 14 in excellent yield.
Compound 14 was further modified by reductive amination
to form substituted amines 15-16 and 19-21. Cyclic amines
17-18 were prepared from 14 by di-alkylation. In addition to
amine analogs 15-21, compound 14 was also converted to a
series of amides by reaction with either an acid chloride to
give 22 or by peptide coupling with carboxylic acids to afford
23-24, to ureas 25-27 by reaction with isocyanates and, finally,
to carbamates 28-29 by reaction with chloroformates.
As noted, exploration of SARs of the triazine lead 5 focused
on replacement of carboxylic acid functionality with a variety
of acylsulfonamides (Table 1).
Interestingly, simple
acylsulfonamides proved to be more active than the parent
acid 5.
a
Figure 2. Structure of HTS hit and early lead. Parallel artifi-
cial membrane assay (PAMPA).
Scheme 1. Reagents and conditions: (a) sulfonamide or sulfamide, EDC, DMAP, DIEA, DMF, RT, 16 h; (b) tert-butyl 2-
sulfamoylethylcarbamate, PyBOP, DIEA, DCM, RT, 72 h; (c) 4N HCl in dioxane, 1 h; (d) diiodo or dibromo alkane, K2CO3, ACN,
65 °C, 16 h or RCHO, NaBH(O2CCH3)3, AcOH, DCM, RT, 4 h; (e) RCOCl, ROCOCl, or RNCO, DIEA, DCM, RT, 0.25 h or
RCOOH, PyBOP, DIEA, DCM, RT, 16 h.

For example acylmethylsulfonamide 6, acylethysulfonamide 7 and acylcyclopropylsulfonamide 8 afforded a 2- to 6-fold increase in
potency in the HCVpp GT-1a assay with a 2-fold enhancement in activity against HCVpp-GT1b. However, this potency advantage
was lost with isopropylsulfonamide 9 and N,N-dimethylsulfamide 10 as these analogues had activity similar to 5. Since a crystal
structure of compounds from this chemical series bound to the target was not available, these SARs were not directly interpretable.
This initial data set was built upon by the construction of the phenylsulfonamide derivative 11 which exhibited 3-fold enhanced
potency against HCVpp-GT1a and HCVpp-GT1b. Interestingly, further modification of the phenyl moiety in 11, providing 12 and
13, resulted in a decrease in GT-1a inhibitory potency while having a negligible impact on GT-1b inhibitory activity in comparison
with corresponding parent compound 11.
We next turned to furthering the activity gains observed for acylsulfonamide analogues bearing linear aliphatic side chains (com-
pounds 6 and 7) by building in additional functionality at the terminus of the alkyl group. To that end, the set of beta-substituted
ethyl acylsulfonamides 14-30 was prepared as shown in Table 2. Substantial activity gains were realized in this series while the in
vitro metabolic stability profile of these compounds was similarly favorable. For example, the introduction of an amine to the ter-
minus of the acylsulfonamide group in 7 provided compound 14. This analogue demonstrated a 3-fold increase in potency in the
HCVpp GT-1a assay, while maintaining GT-1b activity comparable to the parent 7. Interestingly, PAMPA permeability values for
14 were improved over the parent analogue 7, a somewhat surprising result given that 14 is zwitterionic in nature. The microsomal
stability for 14 was excellent and consistent with the introduction of additional polarity to the molecule when compared to 7.
The favorable profile observed with compound 14 catalyzed a more in-depth evaluation of amine derivatives. To that end, the
acylsulfonamide analogues 15-18 bearing secondary amine moieties were prepared. The inhibitory activity profile of this class was
excellent and a substantial improvement over simple amine 14. Optimal activity was found with the more lipophilic amines 15-17,
wherein half-maximal HCVpp inhibitory values of less than 10 nM were observed for both the 1a and 1b genotypes. The more
active of these analogues, compound 16, was only slightly more active versus GT-1a when compared to 14; however, 16 was some
50-fold more active than 14 against GT-1b. A slight erosion in activity was observed by introduction of the more polar morpholino
group in 18, suggestive of the importance of van der Waals interactions as a means to drive activity in this region of the target pro-
tein. Compounds 15-18 exhibited poor to moderate PAMPA permeability, but it is of particular interest to note that these com-
pounds showed a trend toward increased PAMPA permeability values when the lipophilicity of these substituents was increased.
Primary amine derivatives were also explored and further activity gains realized. For example, isopropylamine 19 and
neopentylamine 20 were both active in GT-1a and GT-1b HCVpp assays with EC50 values of less than 1 nM. Interestingly, the ac-
tivity of amine 20 was essentially equal against GT-1a and GT-1b in this assay with values of 0.78 nM and 0.72 nM, respectively.
In addition, compound 20 exhibited a promising PAMPA value of 651 nm/s, a notable improvement compared to the progenitor 14.
Encouraged by the potency and in vitro ADME profile of 20 (90% remaining in RLM after 10 minutes) this compound was selected
for in vivo dosing to rats to benchmark the pharmacokinetic properties of this series. Somewhat surprisingly, 20 was apparently not
absorbed after oral dosing as the compound was not detectable in plasma (Table 3). The IV kinetics for 20 were more favorable,
with moderate clearance and a modest half-life observed. While additional studies were required to provide a clear understanding
of the poor absorption properties of 20, we reasoned that transporters were possibly playing a role and turned to resolving this issue
with additional analogue synthesis around progenitor 14.
To that end, amide, carbamate and urea derivatives of amine 14 were explored. The SARs within each of these functional classes
with respect to HCVpp inhibitory activity was consistent with that observed in the amine series wherein activity increased with in-
creasing lipophilicity of the terminal alkyl group. This SAR point was most compelling in the urea series with the tert-butyl ana-
logue 27 some 10-fold more active than the simple methyl derivative 25. Nonetheless, these three amide-derived series proved less
potent than the most potent amines. Moreover, while the microsomal stabilities of compounds 22-30 were favorable, the PAMPA
values for this set of analogues was poor. It was hypothesized that the polarity associated with the addition of a H-bond donor in
the case of compounds 22-24 as well as 28-30, and two H-bond donors with respect to 25-27 limit the permeability in these classes
of compounds.
Table 1. Antiviral Activities of compounds 5-13
HLM/RLM
GT-1a
EC50
(nM)
GT-1b
EC50
(nM)
Stability
(% remaining
after 10
PAMPA
(nm/s)b
Compd
R
minutes)a
5
6
36
224
114
89/99
59
11
Me
6.1
100/85

7
8
Et
c-Pr
12.2
14.5
32
165
108
253
283
73.6
91.1
52.7
100/85
100/85
100/96
86/76
28
31
9
i-Pr
10
11
12
13
Me2N
Ph
39.6
13.4
54.6
25.8
100/100
100/100
100/99
182
265
193
2-Me-Ph
4-F-Ph
aMetabolic stability in human liver microsomes (HLM) and
rat liver microsomes (RLM) values are percentage remaining
after 10 minutes of incubation. bPAMPA values were deter-
mined at pH 7.4.
Table 2. Antiviral Activities of compounds 7, 14-30
HLM/RLM
Stability
(% remain-
ing after 10
minutes)a
GT-1a
EC50
(nM)
GT-1b
EC50
(nM)
PAMPA
(nm/s)b
Compd
R
7
H
12.2
4.2
165
147
8.9
28
153
45
14
15
16
17
18
19
20
21
H2N
Me2N
Et2N
100/100
89/100
99/98
3.2
1.8
3.4
73
1.3
6.1
96/98
124
35
17
26
78/97
i-PrNH
t-BuCH2NH
BnNH
0.40
0.78
3.6
0.87
0.72
6.0
89/100
89/90
45
651
49
99/100
22
23
8.5
26.7
26.3
95/100
86/84
7
18.5
13
24
25
12.9
13.3
20.1
23.6
90/aa
1
97/100
40
26
27
4.3
3.2
4.3
2.0
100/97
96/93
45
49

28
29
5.3
1.8
13.9
2.6
90/100
100/73
39
71
30
2.2
2.2
92/93
111
aMetabolic stability in human liver microsomes (HLM) and rat
liver microsomes (RLM) values are percentage remaining after
b
10 minutes of incubation. PAMPA values were determined at
pH 7.4.
In conclusion, replacement of the carboxylic acid group in compound 5 with an acylsulfonamide moiety led to the discovery of a
series of compounds which showed exquisite potency with EC50 values of less than 1 nM in the HCVpp assay against genotypes 1a
and 1b. This level of activity represented an increase in potency compared to the parent carboxylic acid of up to 15-fold for geno-
type 1a and up to 200-fold versus genotype 1b. Activity was derived, in part, by lipophilic groups at the β-position of the
acylsulfonamide group, suggesting that van der Waals forces were playing a critical role in securing potency. While the in vitro
microsomal stability of compounds in this chemical class was excellent, the PK profile of representative compound 20 was poor
since no oral absorption was observed. This series demonstrated the utility of the triazine chemotype in securing excellent potency
and encouraged additional efforts within this series to expand genotype coverage and improve pharmacokinetic parameters, which
will be described in due course.
Table 3. Rat PK profile of compound 20
Cl
Vss (L/kg)c
0.6
t1/2 (h)d PO AUC (nM*h)e
(mL/min/kg)b
22.5
2.6
<LLQf
aRespective IV/PO dosing levels: rat (2/5 mg/kg, n = 2) Vehi-
cle: PEG-400/ethanol/solutol (92.5/5/2.5, v/v) for rat-IV/PO.
bPharmacokinetic clearance. Volume of distribution. Plasma
half-life. ePharmacokinetic area under curve. fLower limit of
quantification.
c
d
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Functionalized trazines as potent HCV entry
inhibitors
Eric S. Mull*, Li-Qiang Sun*, Qian Zhao, Betsy Eggers, Kevin Pokornowski, Guangzhi Zhai,
Ramkumar Rajamani, Susan Jenkins, Melissa Kramer, Ying-Kai Wang, Hua Fang, Daniel Tenney,
Carl J. Baldick, Mark I. Cockett, Nicholas A. Meanwell, Paul M. Scola