US 2013 0085133A1

(19) United States

(12) Patent Application Publication (10) Pub. No.: US 2013/0085133 A1
Severson et al. (43) Pub. Date: Apr. 4, 2013
(54) ANTI-VIRAL TREATMENT AND ASSAY TO Publication Classification
SCREENFOR ANTI-VIRAL AGENT
(75) Inventors: Bill Severson, Birmingham, AL (US); (51) Int. Cl.
Dong Hong Chung, Prospect, KY (US); C07H 19/12 (2006.01)
C07D 47L/4 (2006.01)
Colleen B. Jonsson, Louisville, KY CI2O 1/02 (2006.01)
(US); Ellie Lucile White, Birmingham, C07D 47L/04 (2006.01)
AL (US); Lynn Rasmussen, Odenville, (52) U.S. Cl.
AL (US); Clinton Boykin Maddox, CPC .............. C07H 19/12 (2013.01); C07D 471/04
Hoover, AL (US); Subramaniam (2013.01); C07D 471/14 (2013.01); C12O
Ananthan, Birmingham, AL (US);
Ashish K. Pathak, Birmingham, AL I/025 (2013.01)
(US); Joseph A. Maddry, Birmingham, USPC ....... 514/214.02: 514/264.11: 514/43; 43.5/5:
506/10
AL (US)
(73) Assignee: Sourthern Research Institute Office of
Commercialization and Intellectual (57) ABSTRACT
Prop., Birmingham, AL (US)
(21) Appl. No.: 13/577,592 The present disclosure relates to novel compounds of formu
las (1) through (19) and to a method for treating humans
(22) PCT Filed: Feb. 8, 2011 infected with a virus including various respiratory viruses
(86). PCT No.: PCT/US11?23986 such as members of the Paramyxoviridae family (respiratory
syncytial virus (RSV), human metapneumovirus (HMPV),
S371 (c)(1), human parainfluenza virus (HPIV), measles virus, and
(2), (4) Date: Dec. 19, 2012 mumps virus) with a compound of formulas (1) through (19).
Related U.S. Application Data The present disclosure also relates to a cytopathic effect
(CPE)-based assay that will assess virus-induced CPE for
(60) Provisional application No. 61/302.383, filed on Feb. screening of compounds for treating Viral diseases or inhib
8, 2010. iting a virus.
Patent Application Publication Apr. 4, 2013 Sheet 1 of 5 US 2013/0085133 A1

/ZS(LANWHOV0\HJOE8SIDZCH?AVO)I,G
Patent Application Publication Apr. 4, 2013 Sheet 2 of 5 US 2013/0085133 A1

RSW CB2HTSDR POTENCYRATIOVS. GEOMETRIC MEAN PLOT

2.5 (FROZEN & INFECTED CELLSVS. DILUTED VIRUS ASSAYS COMPARISON)
N-92
MSR-2,019

0.5----------...--...--------................. 8.--O- - - - - - - - - - - - - - - - - - -
LOWER LIMIT OF AGREEMENT=0,493
O

7.8.9 2 3 4 5 6 7 8 9 10 20
GEOMETRIC MEAN

FIG 2
Patent Application Publication Apr. 4, 2013 Sheet 3 of 5 US 2013/0085133 A1

RSV CB2 HITSDREC50 SCATTER PLOT

(FROZEN & INFECTED CELLSVS. DILUTED VIRUS)
N-92
O
PEARSON'S CORRELATION=0.84

O 5 10 15 20 25
EC50 FROMASSAY WITH DILUTED VIRUS

FIG 3
Patent Application Publication Apr. 4, 2013 Sheet 4 of 5 US 2013/0085133 A1

RSV CB2 HITSEC90 POTENCYRATIOVS. GEOMETRIC MEAN PLOT

4.5 (FROZEN & INFECTED CELLSVS, DILUTED VIRUS COMPARISON)
N=95
MSR-2.514

UPPERLEVEL OF LIMIT OF AGREEMENT - 2.519

O S
0.5 ------------------------------................----------------------------; GREEE? - - - - - - -
LOWERLEVELOF LIMITOFAGREEMENf20.399
O

5.6 7.89 2 3 4 5 6 789 2O

A, GEOMETRIC MEAN

FIG 4
Patent Application Publication Apr. 4, 2013 Sheet 5 of 5 US 2013/0085133 A1

RSV CB2 HITSDREC90. SCATTER PLOT

(FROZEN & INFECTED CELLSVS. DILUTED VIRUS ASSAYS)

2N-95 O O
PEARSON'S CORRELATION=0.66

20

15

O 5 10 15 20 25
EC90(DILUTED VIRUS)

FIG 5
US 2013/0085133 A1 Apr. 4, 2013

ANTI-VIRAL TREATMENT AND ASSAY TO istering to said human an effective amount of at least one
SCREENFOR ANTI-VIRAL AGENT compound represented by the formulas 1-19 below:
TECHNICAL FIELD
0001. The present disclosure relates to a method for treat RI
ing humans infected with a virus including various respira
tory viruses such as members of the Paramyxoviridae family
X--
(respiratory syncytial virus (RSV), human metapneumovirus
(HMPV), human parainfluenza virus (HPIV), measles virus,
and mumps virus) with a compound of formulas (1) through
(19). The applications of this disclosure also include those
Cl)- N
2
situations in which preventing virus-induced cytopathic Air NRR2,
effect (CPE) can result in the protection against infections.
The present disclosure also relates to those compounds of this Sch O
disclosure that are novel. The present disclosure also relates 3
to a CPE-based assay that will assess virus-induced CPE for
screening of compounds for treating viral diseases or inhib
iting a virus.
BACKGROUND OF DISCLOSURE
0002 Currently, there are no commercially available vac
cines to protect humans against respiratory syncytial virus 4
(RSV). RSV is associated with substantial morbidity and
mortality and is the most common cause of bronchiolitis and
pneumonia among infants and children under one year of age.
Nevertheless, severe lower respiratory tract disease may
occuratany age, especially among the elderly or among those 5
with compromised cardiac, pulmonary, or immune systems.
The existing therapies for the acute infection are Ribavirin
and the prophylactic humanized monoclonal antibody (Syn
agis(R from MedImmune) that is limited to use in high risk
pediatric patients. The economic impact of RSV infections
due to hospitalizations and indirect medical costs is >S650
million annually. The current health burden of RSV infec
tions has increased effort towards the discovery and develop 6
ment of antivirals and vaccines for the treatment of the dis R3 R4
CaSC.
0003. The hosts or patients treated according to this dis O
closure include humans. R2 R5,
0004 Drug development efforts in this therapeutic area
have been unable to make any significant progress due to a
lack of assays suitable for High Throughput Screening. Virus NY1 R6
instability has made any work with RSV difficult and High O O
Throughput Screening problematic, therefore progress has 7
been slow in drug development. What is disclosed here is a R2 O
novel strategy that circumvents previous problems and has
allowed the development of a HTS assay for drug develop
ment. N21 OR,
SUMMARY OF DISCLOSURE
0005. The present disclosure also relates to a CPE-based
s R4 RI
assay that will assess virus-induced CPE for screening of 8
compounds for treating viral diseases or inhibiting a virus. In R7
particular, the present disclosure is concerned with a method
for Screening for compounds for use as an anti-viral agent R1
against a virus which comprises obtaining frozen cells N2 NN1
infected with said virus, thawing said infected cells and mix R R2
ing said infected cells with uninfected cells of the same type N
as the infected cells, contacting the mixture of said infected
cells and uninfected cells with a compound to be screened and 2
R5 N R3,
determining the viability of said cells.
0006 Another aspect of the present disclosure relates to a R4
method for treating a human infected with a virus by admin
US 2013/0085133 A1 Apr. 4, 2013
2

-continued -continued
9 O 14
NR3R
N R,
N n nNNR5R6, J. N
R2RN l N 2 afni X3- O o, Y
R8

X2 XI
15
10 O

NHR,
Y
1 \,
Y. Y
X3 NY
O

X2 XI
16
2
R X

3 11 R1 S
X-R,
R R*, 17
4
R2 R
21 -(
us.” RS 1's N
-s-s-sM X-R,
12 R2 N
COR R6
RI
R2 R5 18

R3 R*,
Air 19
13
R6
R7
R3
R8

0007 a pharmaceutically acceptable salt thereof, a solvate

thereof, or a prodrug thereof; wherein in formula 1,
10008 each R' and R is independently chosen from the
group consisting of hydrogen, Substituted or unsubstituted
alkyl, substituted or unsubstituted alkyl, substituted or unsub
stituted aryl, substituted or unsubstituted heteroaryl, substi
tuted or unsubstituted arylalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocyclic,
hydroxy, alkoxy, carbonyloxy, halogen, azido, cyano, nitro,
alkylthio, carboxyl, carboxylate ester, carboxamido, amino,
and mono- or di-substituted amino;
US 2013/0085133 A1
0009 wherein in formula 2,
0010 n=1, 2, or 3:
0011 X is chosen from sulfur, oxygen, and substituted or
unsubstituted nitrogen;
0012 Ar is chosen from the group consisting of substi
tuted or unsubstituted aryl, substituted or unsubstituted ary
lalkyl, substituted or unsubstituted heteroaryl, substituted or
unsubstituted cycloalkyl, or substituted or unsubstituted het
erocyclic;
I0013 R' and Rare independently chosen from the group
consisting of hydrogen, Substituted or unsubstituted alkyl,
substituted or unsubstituted unsaturated alkyl; substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted arylalkyl, substituted or unsub
stituted cycloalkyl, substituted or unsubstituted heterocyclic,
and acyl:
0014 wherein in formula 3,
00.15 X is chosen from oxygen or substituted nitrogen,
0016 R', R, and Rare independently chosen from the
group consisting of hydrogen, Substituted or unsubstituted
alkyl, substituted or unsubstituted unsaturated alkyl, substi
tuted or unsubstituted aryl, substituted or unsubstituted het
eroaryl, substituted or unsubstituted arylalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted hetero
cyclic, hydroxy, alkoxy, carbonyloxy, halogen, azido, cyano,
nitro, alkylthio, carboxyl, carboxylate esters, carboxamido,
amino, and mono- or di-substituted amino;
0017 R is chosen from the group consisting of hydrogen,
substituted or unsubstituted alkyl, substituted or unsubsti
tuted unsaturated alkyl, substituted or unsubstituted aryl, sub
stituted or unsubstituted heteroaryl, substituted or unsubsti
tuted arylalkyl, substituted or unsubstituted cycloalkyl,
Substituted or unsubstituted heterocyclic, acyl, carboxyl, car
boxylate esters, and carboxamido;
0.018 wherein in formula 4.
0019 n=0, 1, or 2:
I0020. Ar' may be attached directly to the nitrogen atom
without the linking carbonyl group and if both carbonyl
groups are present, then one of the nitrogen atoms may be
replaced by carbon;
I0021 Ar' and Arare eachindependently chosen from the
group consisting of Substituted or unsubstituted aryl, Substi
tuted or unsubstituted arylalkyl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted cycloalkyl, and sub
stituted or unsubstituted heterocyclic;
0022 wherein in formula 5,
0023 the ring designated C is optional but if present may
be saturated or partially or fully unsaturated;
0024 ifring C is absent, then the pyrrole ring may option
ally have one or two additional substituents instead;
0.025 X is substituted or unsubstituted carbon or substi
tuted or unsubstituted nitrogen;
0026 R'-R, R, and R when X—C, are each indepen
dently chosen from the group consisting of hydrogen, Substi
tuted or unsubstituted alkyl, substituted or unsubstituted
unsaturated alkyl, substituted or unsubstituted aryl, substi
tuted or unsubstituted heteroaryl, substituted or unsubstituted
arylalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocyclic, hydroxy, alkoxy, carbonyloxy,
halogen, azido, cyano, nitro, alkylthio, carboxyl, carboxylate
esters, carboxamido, amino, and mono- or di-substituted
amino;
0027 when ring C is absent, then the one or two additional
Substituents on the pyrrole ring, if present, are independently
Apr. 4, 2013
chosen from the group consisting of hydrogen, Substituted or
unsubstituted alkyl, substituted or unsubstituted unsaturated
alkyl, substituted or unsubstituted aryl, substituted or unsub
stituted heteroaryl, substituted or unsubstituted arylalkyl,
substituted or unsubstituted cycloalkyl, substituted or unsub
stituted heterocyclic, hydroxy, alkoxy, carbonyloxy, halogen,
azido, cyano, nitro, alkylthio, carboxyl, carboxylate esters,
carboxamido, amino, and mono- or di-substituted amino;
(0028 R when X—N, and R7 are each independently cho
Sen from the group consisting of hydrogen, Substituted or
unsubstituted alkyl, substituted or unsubstituted unsaturated
alkyl, substituted or unsubstituted aryl, substituted or unsub
stituted heteroaryl, substituted or unsubstituted arylalkyl,
substituted or unsubstituted cycloalkyl, substituted or unsub
stituted heterocyclic, acyl, carboxyl, carboxylate esters, and
carboxamido;
0029 wherein in formula 6,
0030 n=1, 2, or 3:
10031) R' is chosen from the group consisting of substi
tuted or unsubstituted alkyl, substituted or unsubstituted
unsaturated alkyl, substituted or unsubstituted aryl, substi
tuted or unsubstituted heteroaryl, substituted or unsubstituted
arylalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocyclic, hydroxy, alkoxy, alkylthio.
amino, and mono- or di-substituted amino;
10032 R is chosen from the group consisting of hydrogen,
substituted or unsubstituted alkyl, substituted or unsubsti
tuted unsaturated alkyl, substituted or unsubstituted aryl; sub
stituted or unsubstituted heteroaryl, substituted or unsubsti
tuted arylalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocyclic, acyl, carboxylate
esters, and carboxamido;
0033 R-R are each independently chosen from the
group consisting of hydrogen, Substituted or unsubstituted
alkyl, substituted or unsubstituted unsaturated alkyl, substi
tuted or unsubstituted aryl, substituted or unsubstituted het
eroaryl, substituted or unsubstituted arylalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted hetero
cyclic, hydroxy, alkoxy, carbonyloxy, halogen, azido, cyano,
nitro, alkylthio, carboxyl, carboxylate esters, carboxamido,
amino, and mono- or di-substituted amino;
0034 wherein in formula 7.
0035 X is chosen from oxygen and sulfur,
I0036) R' is chosen from the group consisting of hydrogen,
substituted or unsubstituted alkyl, substituted or unsubsti
tuted unsaturated alkyl, substituted or unsubstituted aryl, sub
stituted or unsubstituted heteroaryl, substituted or unsubsti
tuted arylalkyl, substituted or unsubstituted cycloalkyl,
Substituted or unsubstituted heterocyclic including glycosyl
rings, acyl, carboxylate esters, and carboxamido;
0037 R and Rare each independently chosen from the
group consisting of hydrogen, Substituted or unsubstituted
alkyl, substituted or unsubstituted unsaturated alkyl, substi
tuted or unsubstituted aryl, substituted or unsubstituted het
eroaryl, substituted or unsubstituted arylalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted hetero
cyclic, hydroxy, alkoxy, carbonyloxy, halogen, azido, cyano,
nitro, alkylthio, carboxyl, carboxylate esters, carboxamido,
amino, and mono- or di-substituted amino;
I0038 R is chosen from the group consisting of hydrogen,
substituted or unsubstituted alkyl, substituted or unsubsti
tuted unsaturated alkyl, substituted or unsubstituted aryl, sub
stituted or unsubstituted heteroaryl, substituted or unsubsti
US 2013/0085133 A1
tuted arylalkyl, substituted or unsubstituted cycloalkyl, and
substituted or unsubstituted heterocyclic;
0039 wherein in formula 8,
I0040) R' is chosen from the group consisting of hydrogen,
substituted or unsubstituted alkyl, substituted or unsubsti
tuted unsaturated alkyl, substituted or unsubstituted aryl, sub
stituted or unsubstituted heteroaryl, substituted or unsubsti
tuted arylalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocyclic, acyl, carboxylate
esters, and carboxamido;
0041) R' through R7 are each independently chosen from
the group consisting of hydrogen, Substituted or unsubsti
tuted alkyl, substituted or unsubstituted unsaturated alkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted arylalkyl, substituted
or unsubstituted cycloalkyl, substituted or unsubstituted het
erocyclic, hydroxy, alkoxy, carbonyloxy, halogen, azido,
cyano, nitro, alkylthio, carboxyl, carboxylate esters, carboxa
mido, amino, and mono- or di-Substituted amino;
0.042 wherein in formula 9.
0043 n=0, 1, or 2:
0044) R' through Rare independently chosen from the
group consisting of hydrogen, Substituted or unsubstituted
alkyl, substituted or unsubstituted unsaturated alkyl, substi
tuted or unsubstituted aryl, substituted or unsubstituted het
eroaryl, substituted or unsubstituted arylalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted hetero
cyclic, acyl, carboxylate esters, and carboxamido;
I0045 R7 and Rare independently chosen from the group
consisting of hydrogen, Substituted or unsubstituted alkyl,
substituted or unsubstituted unsaturated alkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted arylalkyl, substituted or unsub
stituted cycloalkyl, substituted or unsubstituted heterocyclic,
hydroxy, alkoxy, carbonyloxy, halogen, azido, cyano, nitro,
alkylthio, carboxyl, carboxylate esters, carboxamido, amino,
and mono- or di-substituted amino;
0046 wherein in formula 10,
0047 n=0, 1, or 2:
0048 X is chosen from the group consisting of N, O, and
S;
I0049) R' through R" are independently chosen from the
group consisting of hydrogen, Substituted or unsubstituted
alkyl, substituted or unsubstituted unsaturated alkyl, substi
tuted or unsubstituted aryl, substituted or unsubstituted het
eroaryl, substituted or unsubstituted arylalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted hetero
cyclic, hydroxy, alkoxy, carbonyloxy, halogen, azido, cyano,
nitro, alkylthio, carboxyl, carboxylate esters, carboxamido,
amino, and mono- or di-substituted amino;
0050 R is chosen from the group consisting of hydrogen,
substituted or unsubstituted alkyl, substituted or unsubsti
tuted unsaturated alkyl, substituted or unsubstituted aryl, sub
stituted or unsubstituted heteroaryl, substituted or unsubsti
tuted arylalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocyclic, acyl, carboxylate
esters, and carboxamido;
0051 Aris chosen from the group consisting of hydrogen,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted arylalkyl, substituted
or unsubstituted cycloalkyl, and substituted or unsubstituted
heterocyclic;
Apr. 4, 2013
0052 wherein in formula 1 1,
0053 X and Y are independently chosen from C and N:
10054) R' through R" are independently chosen from the
group consisting of hydrogen; Substituted or unsubstituted
alkyl, substituted or unsubstituted unsaturated alkyl, substi
tuted or unsubstituted aryl, substituted or unsubstituted het
eroaryl, substituted or unsubstituted arylalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted hetero
cyclic, hydroxy, alkoxy, carbonyloxy, halogen, azido, cyano,
nitro, alkylthio, carboxyl, carboxylate esters, carboxamido,
amino, and mono- or di-substituted amino;
0055 if X—CorY—C, then either may independently be
substituted by additional R moieties chosen from the group
consisting of hydrogen; Substituted or unsubstituted alkyl,
substituted or unsubstituted unsaturated alkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted arylalkyl, substituted or unsub
stituted cycloalkyl, substituted or unsubstituted heterocyclic,
hydroxy, alkoxy, carbonyloxy, halogen, azido, cyano, nitro,
alkylthio, carboxyl, carboxylate esters, carboxamido, amino,
and mono- or di-substituted amino;
0056 wherein in formula 12,
I0057 R' is chosen from the group consisting of hydrogen,
substituted or unsubstituted alkyl, substituted or unsubsti
tuted unsaturated alkyl, substituted or unsubstituted aryl, sub
stituted or unsubstituted heteroaryl, substituted or unsubsti
tuted arylalkyl, substituted or unsubstituted cycloalkyl, and
substituted or unsubstituted heterocyclic;
(0058 R° through R" are independently chosen from the
group consisting of hydrogen, Substituted or unsubstituted
alkyl, substituted or unsubstituted unsaturated alkyl, substi
tuted or unsubstituted aryl, substituted or unsubstituted het
eroaryl, substituted or unsubstituted arylalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted hetero
cyclic, hydroxy, alkoxy, carbonyloxy, halogen, azido, cyano,
nitro, alkylthio, carboxyl, carboxylate esters, carboxamido,
amino, and mono- or di-substituted amino;
0059 Aris chosen from the group consisting of hydrogen,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted arylalkyl, substituted
or unsubstituted cycloalkyl, and substituted or unsubstituted
heterocyclic;
0060 wherein in formula 13,
0061) R' through R', R'' and Rare independently cho
Sen from the group consisting of hydrogen, Substituted or
unsubstituted alkyl, substituted or unsubstituted unsaturated
alkyl, substituted or unsubstituted aryl, substituted or unsub
stituted heteroaryl, substituted or unsubstituted arylalkyl,
substituted or unsubstituted cycloalkyl, substituted or unsub
stituted heterocyclic, hydroxy, alkoxy, carbonyloxy, halogen,
azido, cyano, nitro, alkylthio, carboxyl, carboxylate esters,
carboxamido, amino, and mono- or di-substituted amino;
I0062) R' is chosen from the group consisting of hydro
gen, Substituted or unsubstituted alkyl, Substituted or unsub
stituted unsaturated alkyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or unsub
stituted arylalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocyclic, acyl, carboxylate
esters, and carboxamido;
0063 wherein in formula 14,
I0064 X', X, and X are independently chosen from the
group consisting of O, S, N, C, and halogen;
I0065 whenever any of X, X, and X is not halogen, they
may be independently further substituted from the group
US 2013/0085133 A1
consisting of hydrogen, Substituted or unsubstituted alkyl,
substituted or unsubstituted unsaturated alkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted arylalkyl, substituted or unsub
stituted cycloalkyl, substituted or unsubstituted heterocyclic,
acyl, carboxylate esters, and carboxamido;
0066 whenever any of X, X, and X is C, they may
additionally be substituted from the group consisting of
hydroxy, alkoxy, carbonyloxy, halogen, azido, cyano, nitro,
alkylthio, carboxyl, amino, and mono- or di-substituted
amino;
0067 the R group is chosen from the group consisting of
hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted unsaturated alkyl, substituted or unsubstituted
aryl, substituted or unsubstituted heteroaryl, substituted or
unsubstituted arylalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocyclic,
hydroxy, alkoxy, carbonyloxy, halogen, azido, cyano, nitro,
alkylthio, carboxyl, carboxylate esters, carboxamido, amino,
and mono- or di-substituted amino;
0068 wherein in formula 15,
0069 X', X, and X’ are independently chosen from the
group consisting of O, S, N, C, and halogen;
0070 whenever any of these groups is not halogen, they
may be independently further substituted from the group
consisting of hydrogen, Substituted or unsubstituted alkyl,
substituted or unsubstituted unsaturated alkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted arylalkyl, substituted or unsub
stituted cycloalkyl, substituted or unsubstituted heterocyclic,
acyl, carboxylate esters, and carboxamido;
(0071 whenever any of X, X, and X is C, they may
additionally be substituted from the group consisting of
hydroxy, alkoxy, carbonyloxy, halogen, azido, cyano, nitro,
alkylthio, carboxyl, amino, and mono- or di-substituted
amino;
0072 Y', Y', and Y are independently chosen from the
group consisting of N and C:
0073 R is chosen from the group consisting of hydrogen,
substituted or unsubstituted alkyl, substituted or unsubsti
tuted unsaturated alkyl, substituted or unsubstituted aryl, sub
stituted or unsubstituted heteroaryl, substituted or unsubsti
tuted arylalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocyclic, acyl, carboxylate
esters, and carboxamido;
0074 wherein in formula 16,
0075 X is chosen from the group consisting of N and C:
0076 R', R, and R are independently chosen from the
group consisting of hydrogen, Substituted or unsubstituted
alkyl, substituted or unsubstituted unsaturated alkyl, substi
tuted or unsubstituted aryl, substituted or unsubstituted het
eroaryl, substituted or unsubstituted arylalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted hetero
cyclic, hydroxy, alkoxy, carbonyloxy, halogen, azido, cyano,
nitro, alkylthio, carboxyl, carboxylate esters, carboxamido,
amino, and mono- or di-substituted amino;
0077 if X—C, it may be further independently substituted
by a group from the group consisting of hydrogen; Substituted
or unsubstituted alkyl, substituted or unsubstituted unsatur
ated alkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted aryla
lkyl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocyclic, hydroxy, alkoxy, carbonyloxy,
Apr. 4, 2013
halogen, azido, cyano, nitro, alkylthio, carboxyl, carboxylate
esters, carboxamido, amino, and mono- or di-substituted
amino;
0078 wherein in formula 17,
0079) R' through R are independently chosen from the
group consisting of hydrogen, Substituted or unsubstituted
alkyl, substituted or unsubstituted unsaturated alkyl, substi
tuted or unsubstituted aryl, substituted or unsubstituted het
eroaryl, substituted or unsubstituted arylalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted hetero
cyclic, hydroxy, alkoxy, carbonyloxy, halogen, azido, cyano,
nitro, alkylthio, carboxyl, carboxylate esters, carboxamido,
amino, and mono- or di-substituted amino;
0080 R is chosen from the group consisting of hydrogen,
substituted or unsubstituted alkyl, substituted or unsubsti
tuted unsaturated alkyl; substituted or unsubstituted aryl, sub
stituted or unsubstituted heteroaryl, substituted or unsubsti
tuted arylalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocyclic, acyl, carboxylate
esters, and carboxamido;
0081 wherein in formula 18,
I0082 X is chosen from the group consisting of O, S, and
N:
I0083) R' and Rare independently chosen from the group
consisting of hydrogen, Substituted or unsubstituted alkyl,
substituted or unsubstituted unsaturated alkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted arylalkyl, substituted or unsub
stituted cycloalkyl, substituted or unsubstituted heterocyclic,
hydroxy, alkoxy, carbonyloxy, halogen, azido, cyano, nitro,
alkylthio, carboxyl, carboxylate esters, carboxamido, amino,
and mono- or di-substituted amino;
I0084 if X—N, then it is substituted by a moiety chosen
from the group consisting of hydrogen, Substituted or unsub
stituted alkyl, substituted or unsubstituted unsaturated alkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted arylalkyl, substituted
or unsubstituted cycloalkyl, substituted or unsubstituted het
erocyclic, acyl, carboxylate esters, and carboxamido;
0085 wherein in formula 19,
0086 n=0 or 1:
I0087 if n=0, the substituent R' does not occur;
I0088 X is chosen from the group consisting of C, O, S,
and N:
19089 if X—C or X—N, then it may substituted by a group
R!';
0090 if X=O or X=S, then substituent R' does not
occur,
0091 if n=1 and X—C or N, then the bond to X internal to
the seven-membered ring may optionally be unsaturated;
0092) R' and R' in the case X=N, are independently
chosen from the group consisting of hydrogen, Substituted or
unsubstituted alkyl, substituted or unsubstituted unsaturated
alkyl, substituted or unsubstituted aryl, substituted or unsub
stituted heteroaryl, substituted or unsubstituted arylalkyl,
substituted or unsubstituted cycloalkyl, substituted or unsub
stituted heterocyclic, acyl, carboxylate esters, and carboxa
mido;
0093 R through R. R' in the caseX—C, and substituent
R' in the case n=1, are independently chosen from the group
consisting of hydrogen, Substituted or unsubstituted alkyl,
substituted or unsubstituted unsaturated alkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted arylalkyl, substituted or unsub
US 2013/0085133 A1 Apr. 4, 2013

stituted cycloalkyl, substituted or unsubstituted heterocyclic, -continued

hydroxy, alkoxy, carbonyloxy, halogen, azido, cyano, nitro, 5
alkylthio, carboxyl, carboxylate esters, carboxamido, amino,
and mono- or di-substituted amino.
0094. A still further aspect of the present disclosure relates
to preventing virus-induced cytopathic effect (CPE) in a
human patient for protection against infections which com
prises administering to said human an effective amount of at
least one compound represented by the formulas 1-19 as
disclosed herein above.
0095. The present disclosure is also concerned with those 6
compounds defined above that are novel.
0096. Still other objects and advantages of the present
disclosure will become readily apparent by those skilled in R5,
the art from the following detailed description, wherein it is
shown and described preferred embodiments, simply by way
of illustration of the best mode contemplated. As will be R6
realized the disclosure is capable of other and different
embodiments, and its several details are capable of modifica
tions in various obvious respects, without departing from the 7
disclosure. Accordingly, the description is to be regarded as
illustrative in nature and not as restrictive.

SUMMARY OF FIGURES
0097 FIG. 1 is a Venn diagram of activities of tested
compounds from the assay according to the present disclo
Sure and from the diluted virus assay. 8
0098 FIG. 2 is a MSR plot of potency ratio vs. geometric
means for the ECs analysis
0099 FIG. 3 is a scatter plot and analysis for the ECso
analysis.
0100 FIG. 4 is a MSR plot of potency ratio vs. geometric
means for the ECoo analysis.
0101 FIG. 5 is a scatter plot and analysis for the EC
analysis.
BEST AND VARIOUS MODES
0102 The compounds employed according to the present 9
disclosure are represented by the formulas 1-19 below:

N R2, 10
N le
N S
2
Arn X pi
NRR2,
O
3
X R3
R2 /
N

RI
) \ -
S
N
11

4
O / \ O

Arl
)-(\-4.) Ar,
US 2013/0085133 A1 Apr. 4, 2013

-continued -continued
12 17
COR R4

R2 R5 R N

R3 R4, R2 N
X-R,
V
RI R6
Air
18
13
6
R R7

R 19
R8

optionally in their stereoisomerically pure form, a pharma

ceutically acceptable salt thereof, a Solvate thereof, a prodrug
thereof, and mixtures thereof.
(0103) Informula 1, each R" and R is independently cho
Sen from the group consisting of hydrogen, Substituted or
unsubstituted alkyl, Substituted or unsubstituted alkyl, Sub
stituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted arylalkyl, substituted
or unsubstituted cycloalkyl, substituted or unsubstituted het
14
erocyclic, hydroxy, alkoxy, carbonyloxy, halogen, azido,
O cyano, nitro, alkylthio, carboxyl, carboxylate ester, carboxa
mido, amino, and mono- or di-substituted amino.
HN
R, 0104 Examples of this class of compounds include
ABOO369924 and AB00370.063.
ls N1 N 0105. In formula 2, n=1, 2, or 3:
X3- O
O
0106 X is chosen from sulfur, oxygen, and substituted or
unsubstituted nitrogen;
0107 Ar is chosen from the group consisting of substi
tuted or unsubstituted aryl, substituted or unsubstituted ary
lalkyl, substituted or unsubstituted heteroaryl, substituted or
X2 XI unsubstituted cycloalkyl, or substituted or unsubstituted het
erocyclic;
I0108) R' and Rare independently chosen from the group
15 consisting of hydrogen, Substituted or unsubstituted alkyl,
O substituted or unsubstituted unsaturated alkyl; substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
NHR, substituted or unsubstituted arylalkyl, substituted or unsub
Y
stituted cycloalkyl, substituted or unsubstituted heterocyclic,
1 \,
Y. Y and acyl.
X3 NY 0109 Examples of this class include AB00345103,
O
AB0034.1850, AB00756405, AB00358122, AB00289457,
AB003061 12, AB00368252, and AB00293237.
0110 Informula 3, X is chosen from oxygen or substituted
X2 XI
nitrogen;
I0111) R', R, and R are independently chosen from the
R2
16 group consisting of hydrogen, Substituted or unsubstituted
X alkyl, substituted or unsubstituted unsaturated alkyl, substi

RI
X-R,
S
tuted or unsubstituted aryl, substituted or unsubstituted het
eroaryl, substituted or unsubstituted arylalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted hetero
cyclic, hydroxy, alkoxy, carbonyloxy, halogen, azido, cyano,
US 2013/0085133 A1
nitro, alkylthio, carboxyl, carboxylate esters, carboxamido,
amino, and mono- or di-substituted amino;
I0112 R is chosen from the group consisting of hydrogen,
substituted or unsubstituted alkyl, substituted or unsubsti
tuted unsaturated alkyl, substituted or unsubstituted aryl, sub
stituted or unsubstituted heteroaryl, substituted or unsubsti
tuted arylalkyl, substituted or unsubstituted cycloalkyl,
Substituted or unsubstituted heterocyclic, acyl, carboxyl, car
boxylate esters, and carboxamido.
0113. Examples of this class include AB00298501,
AB00297372, AB00372085, AB00728757, AB00276706,
and ABOO796970.
0114. In formula 4, n=0, 1, or 2.;
I0115) Ar' may be attached directly to the nitrogen atom
without the linking carbonyl group and if both carbonyl
groups are present, then one of the nitrogen atoms may be
replaced by carbon;
0116 Ar" and Arfare each independently chosen from the
group consisting of Substituted or unsubstituted aryl, Substi
tuted or unsubstituted arylalkyl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted cycloalkyl, and sub
stituted or unsubstituted heterocyclic.
0117 Examples of this class include AB00312102,
AB00311948, AB003 15446, AB00319534, AB00298665,
AB00299386, AB00317214, AB00284323, AB00299547,
and AB00309842.
0118 Informula 5, the ring designated C is optional but if
present may be saturated or partially or fully unsaturated;
0119) ifring C is absent, then the pyrrole ring may option
ally have one or two additional substituents instead;
0120 X is substituted or unsubstituted carbon or substi
tuted or unsubstituted nitrogen;
0121) R'-R. R. and R when X—C, are each indepen
dently chosen from the group consisting of hydrogen, Substi
tuted or unsubstituted alkyl, substituted or unsubstituted
unsaturated alkyl, substituted or unsubstituted aryl, substi
tuted or unsubstituted heteroaryl, substituted or unsubstituted
arylalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocyclic, hydroxy, alkoxy, carbonyloxy,
halogen, azido, cyano, nitro, alkylthio, carboxyl, carboxylate
esters, carboxamido, amino, and mono- or di-substituted
amino;
0122 when ring C is absent, then the one or two additional
Substituents on the pyrrole ring, if present, are independently
chosen from the group consisting of hydrogen, Substituted or
unsubstituted alkyl, substituted or unsubstituted unsaturated
alkyl, substituted or unsubstituted aryl, substituted or unsub
stituted heteroaryl, substituted or unsubstituted arylalkyl,
substituted or unsubstituted cycloalkyl, substituted or unsub
stituted heterocyclic, hydroxy, alkoxy, carbonyloxy, halogen,
azido, cyano, nitro, alkylthio, carboxyl, carboxylate esters,
carboxamido, amino, and mono- or di-substituted amino;
(0123 R when X=N, and Rare eachindependently cho
Sen from the group consisting of hydrogen, Substituted or
unsubstituted alkyl, substituted or unsubstituted unsaturated
alkyl, substituted or unsubstituted aryl, substituted or unsub
stituted heteroaryl, substituted or unsubstituted arylalkyl,
substituted or unsubstituted cycloalkyl, substituted or unsub
stituted heterocyclic, acyl, carboxyl, carboxylate esters, and
carboxamido.
(0.124 Examples of this class include AB00722846,
AB00275559, AB00705281, AB00279132, and
ABOO291O74.
Apr. 4, 2013
0.125 Informula 6, n=1, 2, or 3:
I0126) R' is chosen from the group consisting of substi
tuted or unsubstituted alkyl, substituted or unsubstituted
unsaturated alkyl, substituted or unsubstituted aryl, substi
tuted or unsubstituted heteroaryl, substituted or unsubstituted
arylalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocyclic, hydroxy, alkoxy, alkylthio.
amino, and mono- or di-substituted amino;
I0127 R’ is chosen from the group consisting of hydrogen,
substituted or unsubstituted alkyl, substituted or unsubsti
tuted unsaturated alkyl, substituted or unsubstituted aryl; sub
stituted or unsubstituted heteroaryl, substituted or unsubsti
tuted arylalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocyclic, acyl, carboxylate
esters, and carboxamido;
I0128 R-R are each independently chosen from the
group consisting of hydrogen, Substituted or unsubstituted
alkyl, substituted or unsubstituted unsaturated alkyl, substi
tuted or unsubstituted aryl, substituted or unsubstituted het
eroaryl, substituted or unsubstituted arylalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted hetero
cyclic, hydroxy, alkoxy, carbonyloxy, halogen, azido, cyano,
nitro, alkylthio, carboxyl, carboxylate esters, carboxamido,
amino, and mono- or di-substituted amino;
I0129. Examples of this class include AB00302018,
AB00300194, AB00302020, AB00301782, and
ABOO3O1184.
0.130 Informula 7, X is chosen from oxygen and sulfur,
I0131) R' is chosen from the group consisting of hydrogen,
substituted or unsubstituted alkyl, substituted or unsubsti
tuted unsaturated alkyl, substituted or unsubstituted aryl, sub
stituted or unsubstituted heteroaryl, substituted or unsubsti
tuted arylalkyl, substituted or unsubstituted cycloalkyl,
Substituted or unsubstituted heterocyclic including glycosyl
rings, acyl, carboxylate esters, and carboxamido;
(0132 R and Rare each independently chosen from the
group consisting of hydrogen, Substituted or unsubstituted
alkyl, substituted or unsubstituted unsaturated alkyl, substi
tuted or unsubstituted aryl, substituted or unsubstituted het
eroaryl, substituted or unsubstituted arylalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted hetero
cyclic, hydroxy, alkoxy, carbonyloxy, halogen, azido, cyano,
nitro, alkylthio, carboxyl, carboxylate esters, carboxamido,
amino, and mono- or di-substituted amino;
0.133 R is chosen from the group consisting of hydrogen,
substituted or unsubstituted alkyl, substituted or unsubsti
tuted unsaturated alkyl, substituted or unsubstituted aryl, sub
stituted or unsubstituted heteroaryl, substituted or unsubsti
tuted arylalkyl, substituted or unsubstituted cycloalkyl, and
substituted or unsubstituted heterocyclic;
I0134) Examples of this class include AB00355044,
AB00318401, AB00319298, AB00318114, and
ABOO316243.
0.135 Informula 8,
10136) R' is chosen from the group consisting of hydrogen,
substituted or unsubstituted alkyl, substituted or unsubsti
tuted unsaturated alkyl, substituted or unsubstituted aryl, sub
stituted or unsubstituted heteroaryl, substituted or unsubsti
tuted arylalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocyclic, acyl, carboxylate
esters, and carboxamido;
10137 R through Rare each independently chosen from
the group consisting of hydrogen, Substituted or unsubsti
tuted alkyl, substituted or unsubstituted unsaturated alkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
US 2013/0085133 A1
heteroaryl, substituted or unsubstituted arylalkyl, substituted
or unsubstituted cycloalkyl, substituted or unsubstituted het
erocyclic, hydroxy, alkoxy, carbonyloxy, halogen, azido,
cyano, nitro, alkylthio, carboxyl, carboxylate esters, carboxa
mido, amino, and mono- or di-Substituted amino.
0138 Examples of this class include AB00280244.
0139 Informula 9, n=0, 1, or 2:
I0140) R' through Rare independently chosen from the
group consisting of hydrogen, Substituted or unsubstituted
alkyl, substituted or unsubstituted unsaturated alkyl, substi
tuted or unsubstituted aryl, substituted or unsubstituted het
eroaryl, substituted or unsubstituted arylalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted hetero
cyclic, acyl, carboxylate esters, and carboxamido;
I014.1) R' and Rare independently chosen from the group
consisting of hydrogen, Substituted or unsubstituted alkyl,
substituted or unsubstituted unsaturated alkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted arylalkyl, substituted or unsub
stituted cycloalkyl, substituted or unsubstituted heterocyclic,
hydroxy, alkoxy, carbonyloxy, halogen, azido, cyano, nitro,
alkylthio, carboxyl, carboxylate esters, carboxamido, amino,
and mono- or di-substituted amino;
0142. Examples of this class include SRI-10531.
0143 Informula 10, n=0, 1, or 2:
0144 X is chosen from the group consisting of N, O, and
S.
(0145) R' through R" are independently chosen from the
group consisting of hydrogen, substituted or unsubstituted
alkyl, substituted or unsubstituted unsaturated alkyl, substi
tuted or unsubstituted aryl, substituted or unsubstituted het
eroaryl, substituted or unsubstituted arylalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted hetero
cyclic, hydroxy, alkoxy, carbonyloxy, halogen, azido, cyano,
nitro, alkylthio, carboxyl, carboxylate esters, carboxamido,
amino, and mono- or di-substituted amino;
I0146) R is chosen from the group consisting of hydrogen,
substituted or unsubstituted alkyl, substituted or unsubsti
tuted unsaturated alkyl, substituted or unsubstituted aryl, sub
stituted or unsubstituted heteroaryl, substituted or unsubsti
tuted arylalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocyclic, acyl, carboxylate
esters, and carboxamido;
0147 Aris chosen from the group consisting of hydrogen,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted arylalkyl, substituted
or unsubstituted cycloalkyl, and substituted or unsubstituted
heterocyclic.
0148 Examples of this class include AB00285095.
0149. In formula 1 1, X and Y are independently chosen
from C and N:
I0150) R' through R" are independently chosen from the
group consisting of hydrogen; Substituted or unsubstituted
alkyl, substituted or unsubstituted unsaturated alkyl, substi
tuted or unsubstituted aryl, substituted or unsubstituted het
eroaryl, substituted or unsubstituted arylalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted hetero
cyclic, hydroxy, alkoxy, carbonyloxy, halogen, azido, cyano,
nitro, alkylthio.; carboxyl, carboxylate esters, carboxamido,
amino, and mono- or di-substituted amino;
0151 if X—CorY—C, then either may independently be
substituted by additional R moieties chosen from the group
consisting of hydrogen; Substituted or unsubstituted alkyl,
substituted or unsubstituted unsaturated alkyl, substituted or
Apr. 4, 2013
unsubstituted aryl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted arylalkyl, substituted or unsub
stituted cycloalkyl, substituted or unsubstituted heterocyclic,
hydroxy, alkoxy, carbonyloxy, halogen, azido, cyano, nitro,
alkylthio, carboxyl, carboxylate esters, carboxamido, amino,
and mono- or di-substituted amino.
0152 Examples of this class include AB00292655,
AB00877180, and AB00356285.
I0153. In formula 12, R' is chosen from the group consist
ing of hydrogen, Substituted or unsubstituted alkyl, Substi
tuted or unsubstituted unsaturated alkyl, substituted or unsub
stituted aryl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted arylalkyl, substituted or unsub
stituted cycloalkyl, and substituted or unsubstituted hetero
cyclic;
I0154 R through R" are independently chosen from the
group consisting of hydrogen, Substituted or unsubstituted
alkyl, substituted or unsubstituted unsaturated alkyl, substi
tuted or unsubstituted aryl, substituted or unsubstituted het
eroaryl, substituted or unsubstituted arylalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted hetero
cyclic, hydroxy, alkoxy, carbonyloxy, halogen, azido, cyano,
nitro, alkylthio, carboxyl, carboxylate esters, carboxamido,
amino, and mono- or di-substituted amino;
0155 Aris chosen from the group consisting of hydrogen,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted arylalkyl, substituted
or unsubstituted cycloalkyl, and substituted or unsubstituted
heterocyclic;
0156 Examples of this class include AB00275199.
O157. In formula 13, R through R', R'' and R' are
independently chosen from the group consisting of hydrogen,
substituted or unsubstituted alkyl, substituted or unsubsti
tuted unsaturated alkyl, substituted or unsubstituted aryl, sub
stituted or unsubstituted heteroaryl, substituted or unsubsti
tuted arylalkyl, substituted or unsubstituted cycloalkyl,
Substituted or unsubstituted heterocyclic, hydroxy, alkoxy,
carbonyloxy, halogen, azido, cyano, nitro, alkylthio, car
boxyl, carboxylate esters, carboxamido, amino, and mono- or
di-Substituted amino;
I0158 R' is chosen from the group consisting of hydro
gen, Substituted or unsubstituted alkyl, Substituted or unsub
stituted unsaturated alkyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or unsub
stituted arylalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocyclic, acyl, carboxylate
esters, and carboxamido.
0159. Examples of this class include AB00700560.
(0160. In formula 14, X, X, and X’ are independently
chosen from the group consisting of O, S, N, C, and halogen;
(0161 whenever any of X, X, and X is not halogen, they
may be independently further substituted from the group
consisting of hydrogen, Substituted or unsubstituted alkyl,
substituted or unsubstituted unsaturated alkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted arylalkyl, substituted or unsub
stituted cycloalkyl, substituted or unsubstituted heterocyclic,
acyl, carboxylate esters, and carboxamido;
(0162 whenever any of X, X, and X is C, they may
additionally be substituted from the group consisting of
hydroxy, alkoxy, carbonyloxy, halogen, azido, cyano, nitro,
alkylthio, carboxyl, amino, and mono- or di-substituted
amino;
US 2013/0085133 A1
0163 the R group is chosen from the group consisting of
hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted unsaturated alkyl, substituted or unsubstituted
aryl, substituted or unsubstituted heteroaryl, substituted or
unsubstituted arylalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocyclic,
hydroxy, alkoxy, carbonyloxy, halogen, azido, cyano, nitro,
alkylthio, carboxyl, carboxylate esters, carboxamido, amino,
and mono- or di-substituted amino.
0164. Examples of this class include SRI-7958 and
ABOO174524.
(0165. In formula 15, X, X, and X are independently
chosen from the group consisting of O, S, N, C, and halogen;
0166 whenever any of these groups is not halogen, they
may be independently further substituted from the group
consisting of hydrogen, Substituted or unsubstituted alkyl,
substituted or unsubstituted unsaturated alkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted arylalkyl, substituted or unsub
stituted cycloalkyl, substituted or unsubstituted heterocyclic,
acyl, carboxylate esters, and carboxamido;
(0167 whenever any of X, X, and X is C, they may
additionally be substituted from the group consisting of
hydroxy, alkoxy, carbonyloxy, halogen, azido, cyano, nitro,
alkylthio, carboxyl, amino, and mono- or di-substituted
amino;
(0168 Y', Y', and Y are independently chosen from the
group consisting of N and C:
01.69 R is chosen from the group consisting of hydrogen,
substituted or unsubstituted alkyl, substituted or unsubsti
tuted unsaturated alkyl, substituted or unsubstituted aryl, sub
stituted or unsubstituted heteroaryl, substituted or unsubsti
tuted arylalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocyclic, acyl, carboxylate
esters, and carboxamido
(0170 Examples of this class include AB00430481.
0171 Informula 16, X is chosen from the group consisting
of N and C:
(0172 R', R, and Rare independently chosen from the
group consisting of hydrogen, Substituted or unsubstituted
alkyl, substituted or unsubstituted unsaturated alkyl, substi
tuted or unsubstituted aryl, substituted or unsubstituted het
eroaryl, substituted or unsubstituted arylalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted hetero
cyclic, hydroxy, alkoxy, carbonyloxy, halogen, azido, cyano,
nitro, alkylthio, carboxyl, carboxylate esters, carboxamido,
amino, and mono- or di-substituted amino;
(0173 if X—C, it may be further independently substituted
by a group from the group consisting of hydrogen; Substituted
or unsubstituted alkyl, substituted or unsubstituted unsatur
ated alkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted aryla
lkyl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocyclic, hydroxy, alkoxy, carbonyloxy,
halogen, azido, cyano, nitro, alkylthio, carboxyl, carboxylate
esters, carboxamido, amino, and mono- or di-substituted
amino.
(0174 Examples of this class include AB00310808,
AB00361531, AB00310910, AB00313042, AB00313952,
AB00355020, AB00367930, AB00310739, AB00309154,
AB00309859, AB00299380, AB00747970, and
ABOO372O85.
(0175 Informula 17, R through Rare independently cho
Sen from the group consisting of hydrogen, Substituted or
Apr. 4, 2013
unsubstituted alkyl, substituted or unsubstituted unsaturated
alkyl, substituted or unsubstituted aryl, substituted or unsub
stituted heteroaryl, substituted or unsubstituted arylalkyl,
substituted or unsubstituted cycloalkyl, substituted or unsub
stituted heterocyclic, hydroxy, alkoxy, carbonyloxy, halogen,
azido, cyano, nitro, alkylthio, carboxyl, carboxylate esters,
carboxamido, amino, and mono- or di-substituted amino;
(0176) R' is chosen from the group consisting of hydrogen,
substituted or unsubstituted alkyl, substituted or unsubsti
tuted unsaturated alkyl; substituted or unsubstituted aryl, sub
stituted or unsubstituted heteroaryl, substituted or unsubsti
tuted arylalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocyclic, acyl, carboxylate
esters, and carboxamido.
(0177. Examples of this class include AB00369924,
AB00627942, AB002.96415, AB00308659, AB00321587,
AB00709376, AB00358081, AB003.68222, AB00342188,
AB00369934, AB00348716, and AB003.64575.
0.178 Informula 18, X is chosen from the group consisting
of O, S, and N:
(0179 R' and Rare independently chosen from the group
consisting of hydrogen, Substituted or unsubstituted alkyl,
substituted or unsubstituted unsaturated alkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted arylalkyl, substituted or unsub
stituted cycloalkyl, substituted or unsubstituted heterocyclic,
hydroxy, alkoxy, carbonyloxy, halogen, azido, cyano, nitro,
alkylthio, carboxyl, carboxylate esters, carboxamido, amino,
and mono- or di-substituted amino;
0180 if X—N, then it is substituted by a moiety chosen
from the group consisting of hydrogen, Substituted or unsub
stituted alkyl, substituted or unsubstituted unsaturated alkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted arylalkyl, substituted
or unsubstituted cycloalkyl, substituted or unsubstituted het
erocyclic, acyl, carboxylate esters, and carboxamido.
0181 Examples of this class include AB00724801,
AB00725275, AB00430481, AB00767910, AB002.92171
AB00356597, AB00372085, AB00358926, and
ABOO37O949.
0182 Informula 19,
0183 n=0 or 1;
0184 if n=0, the substituent R' does not occur;
0185. X is chosen from the group consisting of C, O, S,
and N:
10186. if X—C or X—N, then it may substituted by a group
R!';
0187 if X=O or X—S, then substituent R' does not
occur,
0188 if n=1 and X—C or N, then the bond to X internal to
the seven-membered ring may optionally be unsaturated;
(0189 R' and R' in the case X=N, are independently
chosen from the group consisting of hydrogen, Substituted or
unsubstituted alkyl, substituted or unsubstituted unsaturated
alkyl, substituted or unsubstituted aryl, substituted or unsub
stituted heteroaryl, substituted or unsubstituted arylalkyl,
substituted or unsubstituted cycloalkyl, substituted or unsub
stituted heterocyclic, acyl, carboxylate esters, and carboxa
mido;
(0190. R through R. R' in the caseX—C, and substituent
R' in the case n=1, are independently chosen from the group
consisting of hydrogen, Substituted or unsubstituted alkyl,
substituted or unsubstituted unsaturated alkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
US 2013/0085133 A1
substituted or unsubstituted arylalkyl, substituted or unsub
stituted cycloalkyl, substituted or unsubstituted heterocyclic,
hydroxy, alkoxy, carbonyloxy, halogen, azido, cyano, nitro,
alkylthio, carboxyl, carboxylate esters, carboxamido, amino,
and mono- or di-substituted amino.
(0191 Examples of this class include AB00139215,
AB00276381, and AB00370949.
0192 Listed below are definitions of various terms used to
describe this invention. These definitions apply to the terms as
they are used throughout this specification, unless otherwise
limited in specific instances, either individually or as part of a
larger group.
0193 Typical aliphatic acyl groups contain 1 to 6 carbon
atoms and include formyl, acetyl and propionyl.
0194 Typical aromatic acyl groups include unsubstituted
and alkyl Substituted aromatic groups containing 7 to 10
carbonatoms in the aromatic ring. When substituted the alkyl
group typically contains 1-6 carbon atoms. Typical aromatic
acyl groups include benzoyland para-toluoyl.
(0195 The term “alkyl refers to straight or branched chain
unsubstituted hydrocarbon groups of typically 1 to 22 carbon
atoms, more typically 1 to 8 carbon atoms, and even more
typically 1 to 4 carbon atoms.
0196. Examples of suitable alkyl groups include methyl,
ethyl and propyl. Examples of branched alkyl groups include
isopropyl and t-butyl.
(0197) The term “cycloalkyl refers to optionally substi
tuted, saturated cyclic hydrocarbon ring systems, preferably
containing 1 to 3 rings and 3 to 7 carbons per ring which may
be further fused with an unsaturated C-C, carbocyclic ring.
Exemplary groups include cyclopropyl, cyclobutyl, cyclo
pentyl, cyclohexyl, cyclopropylmethyl cycloheptyl, cyclooc
tyl, cyclodecyl cyclododecyl and adamantyl. Exemplary
Substituents include one or more alkyl groups as described
above, or one or more groups described above as alkyl Sub
stituents.
0198 Examples of unsaturated alkyl groups include ethy
nyl, cyclopentenyl, and allyl. Examples of Substituted alkyl
groups include 2-methoxyethyl, 2.2.2-trifluoroethyl, and
2-diethylaminocyclopentenyl.
0199 The alkoxy group typically contains 1 to 6 carbon
atoms. Suitable alkoxy groups typically contain 1-6 carbon
atoms and include methoxy, ethoxy, propoxy and butoxy.
0200 Suitable haloalkyl groups typically contain 1-6 car
bonatoms and can be straight or branched chain and include
Cl, Br, F or I, substituted alkyl groups including the above
specifically disclosed alkyl groups.
0201 Suitable alkenyl groups typically contain 2-6 carbon
atoms and include ethenyl and propenyl.
0202 Suitable haloalkenyl groups typically contain 1-6
carbon atoms and include Cl, Br For I, substituted alkenyl
groups including the above specifically disclosed alkenyl
groups.
0203 Suitable alkynyl groups typically contain 1-6 car
bon atoms and include ethynyl and propynyl.
0204 Suitable monoalkylamino groups contain 1-6 car
bonatoms and include monomethylamino, monoethylamino,
mono-isopropylamino, mono-n-propylamino, mono-isobu
tyl-amino, mono-n-butylamino and mono-n-hexylamino.
The alkyl moiety can be straight or branched chain.
0205 Suitable dialkylamino groups contain 1-6 carbon
atoms in each alkyl group. The alkyl groups can be the same
or different and can be straight or branched chain. Examples
of Some Suitable groups are dimethylamino, diethylamino,
Apr. 4, 2013
ethylmethylamino, dipropylamino, dibutylamino, dipenty
lamino, dihexylamino, methylpentylamino, ethylpropy
lamino and ethylhexylamino.
0206 Examples of halo groups are Cl, F. Brand I.
0207. The term “aryl” refers to monocyclic or polycyclic
aromatic hydrocarbon groups having 6 to 14 carbon atoms in
the ring portion, such as phenyl, naphthyl, biphenyl, and
diphenyl groups, each of which may be substituted Such as
with a halo or alkyl group.
(0208. The term “aralkyl or “alkylaryl” refers to an aryl
group bonded directly through an alkyl group, such as benzyl
or phenethyl.
0209. The term "heteroaryl', refers to an optionally sub
stituted, unsaturated aromatic cyclic group, for example,
which is a 5 to 7 membered monocyclic, 7 to 11 membered
bicyclic, or 10 to 15 membered tricyclic ring system, which
has at least one heteroatom and at least one carbonatom in the
ring. Each ring of the heterocyclic group containing a het
eroatom may have 1, 2 or 3 heteroatoms selected from nitro
gen atoms, oxygen atoms and Sulfur atoms, where the nitro
gen and Sulfur heteroatoms may also optionally be oxidized
and the nitrogen heteroatoms may also optionally be quater
nized. Examples of heteroaryl groups are pyridyl, imidazolyl,
oxazolyl, thiazolyl, isothiazolyl, furyl, thienyl and indolyl.
0210. The terms "heterocycle”, “heterocyclic” and “het
erocyclo” refer to an optionally substituted, fully saturated or
unsaturated, aromatic or nonaromatic cyclic group, for
example, which is a 4 to 7 membered monocyclic, 7 to 11
membered bicyclic, or 10 to 15 membered tricyclic ring sys
tem, which has at least one heteroatom and at least one carbon
atom in the ring. Each ring of the heterocyclic group contain
ing a heteroatom may have 1, 2 or 3 heteroatoms selected
from nitrogen atoms, oxygen atoms and Sulfur atoms, where
the nitrogen and Sulfur heteroatoms may also optionally be
oxidized and the nitrogen heteroatoms may also optionally be
quaternized. The heterocyclic group may be attached at any
heteroatom or carbon atom. Examples of heterocycles and
heteroaryls include, but are not limited to, aZetidine, pyrrole,
imidazole, pyrazole, pyridine, pyrazine, pyrimidine,
pyridazine, indolizine, isoindole, indole, dihydroindole,
indazole, purine, quinolizine, isoquinoline, quinoline,
phthalazine, naphthylpyridine, quinoxaline, quinazoline, cin
noline, pteridine, carbazole, carboline, phenanthridine, acri
dine, phenanthroline, isothiazole, phenazine, isoxazole, phe
noxazine, phenothiazine, imidazolidine, imidazoline,
piperidine, piperazine, indoline, phthalimide, 1.2.3,4-tet
rahydroisoquinoline, 4,5,6,7-tetrahydrobenzobthiophene,
thiazole, thiazolidine, thiophene, benzobthiophene, mor
pholinyl, thiomorpholinyl (also referred to as thiamorpholi
nyl), piperidinyl, pyrrolidine, tetrahydrofuranyl, furyl, fura
nyl, pyridyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl,
tetrazolyl pyrazinyl, benzofuranyl, benzothiophenyl,
quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyra
Zolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carba
Zolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl,
isooxazolyl pyrrolyl, quinazolinyl, cinnolinyl, phthalazinyl,
Xanthinyl, hypoxanthinyl, thiophene, furan, isopyrrole, 1.2,
3-triazole, 1,2,4-triazole, oxazole, thiazole, pyrimidine, aziri
dines, thiazole, 1.2.3-oxadiazole, thiazine, pyrrolidine,
oxaziranes, morpholinyl, pyrazolyl pyridazinyl, pyrazinyl,
quinoxalinyl, Xanthinyl, hypoxanthinyl, pteridinyl, 5-azacy
tidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl,
pyrrolopyrimidinyl, pyrazolopyrimidinyl, adenine, N6-alky
lpurines, N6-benzylpurine, N6-halopurine, N6-vinypurine,
US 2013/0085133 A1
N6-acetylenic purine, N6-acyl purine, N6-hydroxyalkyl
purine, N6-thioalkyl purine, thymine, cytosine, 6-azapyrimi
dine, 2-mercaptopyrmidine, uracil, N5-alkyl-pyrimidines,
N5-benzylpyrimidines, N5-halopyrimidines, N5-vinyl-pyri
midine, N5-acetylenic pyrimidine, N5-acyl pyrimidine,
N5-hydroxyalkyl purine, and N6-thioalkyl purine, and isox
azolyl.
0211. The heteroaromatic and heterocyclic moieties can
be optionally substituted as described above for aryl, includ
ing substituted with one or more substituents selected from
hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy,
alkyl, heterocycle, halo, carboxy, acyl, acyloxy, amido, nitro,
cyano, Sulfonic acid, Sulfate, phosphonic acid, phosphate, or
phosphonate, either unprotected, or protected as necessary, as
known to those skilled in the art, for example, as taught in
Greene, et al., Protective Groups in Organic Synthesis, John
Wiley and Sons, Second Edition, 1991.
0212. The term “carboxylate ester” (e.g., carboxylic acid
ester) refers to a carboxy group —C(=O)CR', wherein R is
substituted or unsubstituted alkyl, substituted or unsubsti
tuted alkenyl, substituted or unsubstituted alkynyl, substi
tuted or unsubstituted carbocyclic, substituted or unsubsti
tuted heterocyclic, substituted or unsubstituted aryl, or
substituted or unsubstituted aralkyl.
0213 When any of the above groups are substituted,
unless stated otherwise, they are typically substituted with at
least one member selected from the group consisting of alkyl,
hydroxyl, alkoxy, amino, halo and halogenated alkyl. A typi
cal halogenated alkyl is a fluoroalkyl such as trifluoromethyl.
0214. The terms “effective amount’ or “therapeutically
effective amount” refer to an amount of the compound of the
invention sufficient to provide a benefit in the treatment or
prevention of viral disease, to delay or minimize symptoms
associated with viral infection or viral-induced disease, or to
cure orameliorate the disease or infection or cause thereof. In
particular, a therapeutically effective amount means an
amount sufficient to provide a therapeutic benefit in vivo.
Used in connection with an amount of a compound of the
invention, the term preferably encompasses a non-toxic
amount that improves overall therapy, reduces or avoids
symptoms or causes of disease, or enhances the therapeutic
efficacy of or synergies with another therapeutic agent
0215. The term “treating refers to relieving the disease,
disorder, or condition, i.e., causing regression of the disease,
disorder, and/or condition; preventing a disease, disorder, or
condition from occurring in an animal that may be predis
posed to the disease, disorder and/or condition, but has not yet
been diagnosed as having it; and/or inhibiting the disease,
disorder, or condition, i.e., arresting its development.
0216. It is of course understood that the compounds of the
present disclosure relate to all optical isomers and stereo
isomers at the various possible atoms of the molecule, unless
specified otherwise.
0217. The compounds according to this disclosure may
form prodrugs at hydroxyl or amino functionalities using
alkoxy, amino acids, etc. groups as the prodrug forming moi
eties. For instance, the hydroxymethyl position may form
mono-, di- or triphosphates and again these phosphates can
form prodrugs.
0218. Preparations of such prodrug derivatives are dis
cussed in various literature sources (examples are: Alexander
et al., J. Med. Chem. 1988, 31,318: Aligas-Martin et al., PCT
WO pp/41531, p. 30). The nitrogen function converted in
Apr. 4, 2013
preparing these derivatives is one (or more) of the nitrogen
atoms of a compound of the disclosure.
0219. “Pharmaceutically acceptable salts' refer to deriva
tives of the disclosed compounds wherein the parent com
pound is modified by making acid or base salts thereof. The
compounds of this disclosure form acid and base addition
salts with a wide variety of organic and inorganic acids and
bases and includes the physiologically acceptable salts which
are often used in pharmaceutical chemistry. Such salts are
also part of this disclosure. Typical inorganic acids used to
form such salts include hydrochloric, hydrobromic,
hydroiodic, nitric, Sulfuric, phosphoric, hypophosphoric and
the like. Salts derived from organic acids, such as aliphatic
mono and dicarboxylic acids, phenyl Substituted alkonic
acids, hydroxyalkanoic and hydroxyalkandioic acids, aro
matic acids, aliphatic and aromatic sulfonic acids, may also
be used. Such pharmaceutically acceptable salts thus include
acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate,
benzoate, chlorobenzoate, dinitrobenzoate, hydroxyben
Zoate, methoxybenzoate, methylbenzoate, o-acetoxyben
Zoate, naphthalene-2-benzoate, bromide, isobutyrate, phe
nylbutyrate, B-hydroxybutyrate, butyne-1,4-dioate, hexyne
1,4-dioate, cabrate, caprylate, chloride, cinnamate, citrate,
formate, fumarate, glycollate, heptanoate, hippurate, lactate,
malate, maleate, hydroxymaleate, malonate, mandelate,
mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate,
teraphthalate, phosphate, monohydrogenphosphate, dihydro
genphosphate, metaphosphate, pyrophosphate, propiolate,
propionate, phenylpropionate, Salicylate, Sebacate. Succinate,
suberate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sul
fonate, benzene-Sulfonate, p-bromobenzenesulfonate, chlo
robenzenesulfonate, ethanesulfonate, 2-hydroxyethane
Sulfonate, methanesulfonate, naphthalene-1-sulfonate,
naphthalene-2-sulfonate, p-toleunesulfonate, Xylene
Sulfonate, tartarate, and the like.
0220 Bases commonly used for formation of salts include
ammonium hydroxide and alkali and alkaline earth metal
hydroxides, carbonates, as well as aliphatic and primary, sec
ondary and tertiary amines, aliphatic diamines. Bases espe
cially useful in the preparation of addition salts include
Sodium hydroxide, potassium hydroxide, ammonium
hydroxide, potassium carbonate, methylamine, diethy
lamine, and ethylene diamine.
0221 "Solvates’ refers to the compound formed by the
interaction of a solvent and a solute and includes hydrates.
Solvates are usually crystalline Solid adducts containing Sol
vent molecules within the crystal structure, in either stoichio
metric or non-stoichiometric proportions.
0222. The term “comprising (and its grammatical varia
tions) as used herein is used in the inclusive sense of “having
or “including and not in the exclusive sense of "consisting
only of. The terms “a” and “the as used herein are under
stood to encompass the plural as well as the singular.
0223 Following is a discussion of the protocols employed
concerning the assay of according to the present disclosure.
0224. In particular, a cytopathogenic based assay (CPE) to
screen large compound libraries (>100,000 compounds)
against respiratory syncytial virus (RSV) strain Long has
been developed according to this disclosure. The assay mea
sures RSV virus-induced CPE in HEp-2 cells using cell
viability as the end point. An important aspect of the present
disclosure that allowed the development of an HTS compat
US 2013/0085133 A1
ible assay was the use of virally infected frozen cells in place
of the conventional infectious virus as the source of infectious
material in the assay.
0225 Cell Culture:
0226 HEp-2 cells (ATCCCCL-23, American Tissue Cul
ture Type) were maintained as adherent cell lines in Optimem
1 with 2 mM L-glutamine and 5% fetal bovine serum (FBS)
at 37° C. in a humidified 5% CO atmosphere. Cells were
passaged as needed and harvested from flasks using 0.25%
trypsin-EDTA.
0227 Assay Media Preparation of Complete DMEM/
F12:
0228 50 mL Pen/Strep/Glutamine (Gibco, Cat #10378)
was added to four liters of room temperature DMEM/F12
(Sigma, Cat if D6434) and the pH adjusted to 7.5 using 1N
NaOH. The medium was sterile filtered through a 0.2um filter
and 10 mL of HI-FBS was added per 500 mL of media.
0229. Infectious Material Frozen Infected Virus Cell
Preparation:
0230. Two vials of RSV (strain Long) containing 1x107
pfu/mL was thawed using an Eppendorf thermomixer for 13
min at 15°C., with shaking at 350 rpm. Two mL of the virus
stock was added to a T-225 flask containing 3.0x10 HEp-2
cells in 30 mL Complete DMEM/F12. The cells were incu
bated for 18-20 hat 37° C., 5% CO, 90% relative humidity.
The medium was aspirated and the cells washed with 10 mL
PBS without Mg" or Ca". Cells were harvested from flasks
using 0.25% trypsin-EDTA. The cells were resuspended in a
freezing medium of 95% fetal calf serum and 5% DMSO to a
final cell density of 2x10 cells/mL. One mL aliquots of this
virus infected cell Suspension were dispensed to cryovials
and cells were rate frozen to -80° C. Frozen infected cells
were then transferred to -150° C. for long term storage.
Assay Protocols:
0231 Single Dose Compound Preparation:
0232 For single dose screening, compounds or carrier
control (DMSO) were diluted to 6x in Complete DMEM/F12
and 5ul was dispensed to assay plates (3% DMSO or 60 uM
compound in 3% DMSO).
0233 Dose Response Compound Preparation:
0234 Test compounds were evaluated by measuring their
antiviral activity, cell toxicity, and selectivity. Test com
pounds were serially diluted in a plate to plate matrix or
“stacked plate' matrix. All 320 compounds in a source plate
were diluted together resulting in a 10 point dose response
dilution series. It was visualized as a serial dilution series
proceeding vertically through a stack of plates with the high
dose plate on top and the low dose plate on the bottom. The
final plate well concentration ranged from 50 uM to 0.097 uM
for the Enamine compound library; 25ug/mL to 0.048 ug/mL
for the Chembridge compound library:50 uM to 0.097 uM for
the SRI Proprietary library; 25 uM to 0.048 uM for the Ole
Miss library; 50 ug/mL to 0.097 ug/mL and 30 ug/mL to
0.058 ug/mL for the SRI Collaborator library and a final
DMSO concentration of 0.5%.
Apr. 4, 2013
0235 Control Drug:
0236. The positive control drug for this assay, ribavirin.
Hruska, J. F., et al., Effects of ribavirin on respiratory syncy
tial virus in vitro. Antimicrob Agents Chemother, 1980.
17(5): p. 770-5. (#196066, MP Biomedicals, Solon, Ohio)
was solubilized in DMSO. It was diluted and added to the
assay plates as described for test compounds. Final concen
tration for ribavirin was 35 uM. All wells contained 0.5%
DMSO.
0237) Preparation of HEp-2 Cells:
0238 Cells were harvested and resuspended to 80,000
cells per ml in Complete DMEM/F12.
0239 Frozen infected HEp-2 Cells:
0240 Cells were thawed in a room temperature water bath
with gentle agitation. The tube was inverted 5-10. Cells were
diluted to 80,000 cells per ml by adding the contents of the
vial to 24 ml of cold (4°C.) media.
0241 Assay Set Up:
0242 Twenty five ul of uninfected HEp-2 cells were
plated in the cell control wells. Frozen infected cells were
combined with uninfected HEp-2 cells at a 1:100 ratio.
Twenty five ul of the cell mixture was added to the virus
control and compound wells. All cell plating was conducted
using a Matrix WellMate and cells were maintained at room
temperature with stirring during the plating process. The
assay plates were incubated for six days at 37°C., 5% CO,
and 90% relative humidity.
0243 Endpoint Read:
0244. Following the six day incubation period, the assay
plates were equilibrated to room temperature for 30 min and
an equal volume (30 uL) of Cell Titer-Glo reagent (Promega
Inc.) was added to each well using a WellMate (Matrix, Hud
son, N.H.) and plates were incubated for an additional 10 min
at room temperature. At the end of the incubation, lumines
cence was measured using a PerkinElmer EnvisionTM multi
label reader (PerkinElmer, Wellesley, Mass.) with an integra
tion time of 0.1 s.
0245 Data Analysis:
0246 Data was analyzed using ActivityBase software
(IDBS, Inc, Guilford, UK). thirty two control wells contain
ing cells only and twenty four wells containing cells and virus
were included on each assay plate and used to calculate Z.
value for each plate and to normalize the data on a per plate
basis. The overall Z score for the campaign were 0.7. Results
are reported as percent (%) CPE inhibition and were calcu
lated using the following formula: % CPE inhibition=100*
(Test Cmpd-Med Virus)/(Med Cells-Med Virus). Eight rib
avirin positive control wells were included on each plate for
quality control purposes, but were not used in Z calculations.
Dose Response: Confirmation of active compounds were
done in two formats, the CPE assay described above to evalu
ate antiviral activity and a cytotoxicity assay used to evaluate
the toxicity of the compounds, Antiviral activity is described
as percent CPE inhibition=100*((luminescence compound
well-median luminescence virus control)/(median lumines
cence cell control-median luminescence virus control. In the
toxicity assay, results are described as percent viability and
the calculation is the same. 100% viability in a compound
well would indicate 100% inhibition of viral CPE in the
antiviral assay or no toxicity in the cytotoxicity assay. The Z
US 2013/0085133 A1
factor values were calculated from 1 minus (3*standard
deviation of cell control (Oc) plus 3*standard deviation of the
virus control (OV)/mean cell control signal (vc) minus mean
virus control signal (VV). Zhang, J. H., T. D. Chung, and K. R.
Oldenburg, A Simple Statistical Parameter for Use in Evalu
ation and Validation of High Throughput Screening Assays. J
Biomol Screen, 1999. 4(2): p. 67-73.
0247 The signal/background (S/B) was calculated from
mean cell control signal (v) divided by the mean virus con
trol signal (v). The signal/noise (S/N) was calculated from
mean cell control signal (vc) minus mean virus control signal
(v) divided by the (standard deviation of the cell control
signal (v.) minus the standard deviation of the virus control
signal (v)'2). Zhang, J. H., T. D. Chung, and K. R. Olden
burg, A Simple Statistical Parameter for Use in Evaluation
and Validation of High Throughput Screening Assays. J Bio
mol Screen, 1999. 4(2): p. 67-73.
0248. An ECs (for CPE inhibition) and ICs (for cell
viability) were calculated for each substance using the 4
parameter Levenburg-Marquardt algorithm with parameter A
locked at 0 and parameter Blocked at 100. Standard devia
tion, normalized chi2 and hill slope were used to evaluate the
curves. Values were not extrapolated beyond the tested range
of concentrations.
0249. The criteria for determining compound activity are
based on percent inhibition of CPE. Of the substances dem
onstrating activity, they have been scored based on their
selectivity index, which is defined as ICs/ECs.
0250 In order to demonstrate the reliability of the assay of
the present disclosure, the present assay was compared to the
diluted virus RSV assays as discussed herein below.
0251 1280 hits selected and cherry-picked from CB2
library were tested in dose response in two RSV assays. One
assay used frozen and infected cells according to the present
disclosure, the other used diluted virus. ECso and E.Coo results
for each compound were calculated. To compare these two
assays, ECso and E.Coo results from two parallel assays are
examined. The Venn diagram of activities of these com
pounds from two assays is shown in FIG. 1.
0252. As to the analysis of ECso, only compounds that are
active in both assays, and with numerical ECso values are
examined, which makes 92 compounds included in the analy
sis. For analysis of EC, 95 compounds that are active in both
assays are included in the analysis. However, due to limited
number (8) of compounds with both numerical results of
ECoo, which is not a large enough sample size to make any
convincing statistical conclusion, non-numerical ECoo results
of these 95 compounds are approximated as below in Table 1:
TABLE 1.
Number of compounds with E.Coo value approximation (out of 95
Frozen & Infected Diluted Virus
Cells E.Coo ECoo
>1.563 to 1.563 1 1
>3.125 to 3.125 2 2
>6.25 to 6.25 4 9
>12.5 to 12.5 9 12
>25 to 25 59 63
Apr. 4, 2013
0253 FIG.2 shows the ECs analysis, which is a MSR plot
of potency ratio vs. geometric means. The Potency Ratio is
the ECso from assay with frozen and infected cells divided by
ECs from diluted cells assay. The horizontal axis is the geo
metric mean of the two ECso results of each and every com
pound. The Minimum Significant Ratio (MSR), Limits of
Agreement, and 95% confidence interval of average potency
ratio (fold shift) are used to test the quality.
0254 The MSR is the smallest potency ratio between two
compounds that is statistically significant. The acceptable
values of MSR for a good reproducibility is MSR<3. From
this experiment, MSR=2.019, which is within acceptable
range, or these two assays are leading to equivalent ECso
results, with 95% confidence, within the interested potency
range from 0.049 to 25 pg/ml.
0255. The acceptance range for Limits of Agreement is
between 0.33 and 3. From the analysis above, the Limits of
Agreement of the two assays is (0.493, 2.01), where both
upper and lower limit meet the criteria.
0256 The point estimate of the average fold shift in ECso
is 0.996, which shows, in average, the ECso result from assay
with frozen and infected cells is 99.6% of those from the assay
with diluted virus, which is very close to a perfect result of 1
from two exactly equivalent assays. According to the 95%
confidence interval of the average potency ratio (fold shift in
ECs), which is (0.943, 1.052), 1 is included in this interval.
This confirms the conclusion drawn based on the point esti
mate of potency ratio.
(0257. From the scatter plot and analysis in FIG. 3, the
correlation of ECs results from frozen & infected cells vs.
diluted virus assays is 0.84, which shows strong correlation
and significant linearity.
0258 FIG. 4 shows the EC analysis, which is a MSR plot
of potency ratio vs. geometric means. Potency Ratio is the
EC from assay with frozen and infected cells divided by
ECoo from diluted cells assay. Horizontal axis is the geomet
ric mean of the two EC results of every compound. Mini
mum Significant Ratio (MSR), Limits of Agreement, and
95% confidence interval of average potency ratio (fold shift)
are used to test the quality.
(0259 From this experiment, MSR=2.514, which is within
acceptable range (<3), or these two assays are leading to
equivalent EC results, with 95% confidence, within the
interested potency range from 0.049 to 25 ug/ml.
0260 The acceptance range for Limits of Agreement is
between 0.33 and 3. From the analysis above, the Limits of
Agreement of the two assays is (0.399, 2.519), where both
upper and lower limit meet the criteria.
0261 The point estimate of the average fold shift in ECso
is 1.002, which shows, in average, the ECoo result from assay
with the frozen and infected cells is 1.002 times of those from
the assay with diluted virus, which is close to an exact result
of 1 from two equivalent assays. According to the 95% con
fidence interval of the average potency ratio (fold shift in
EC), which is (0.933, 1.073), 1 is included in this interval.
This confirms the conclusion drawn based on the point esti
mate of potency ratio.
0262 The correlation and scatter plot is shown in FIG. 5.
The correlation of EC results from frozen & infected cells
vs. diluted virus assays is 0.66, which shows moderate cor
relation and linearity.
0263. The compounds presented below in Table 2 have
been identified by the assay of the present disclosure.
US 2013/0085133 A1 Apr. 4, 2013
15

TABLE 2
Compound
ID Supplier Supplier ID Structure ECso CCso
ABOOOS3361 SRI SRI-16259 HO 47.90 -SO.OO
Repository

HO

AB00076694 Chembridge 2 5249.955 16.36 -2S.OO

HN
O
N
CH

Br

ABOO132114 Chembridge 2 794-1435 20.72 >25.00

OO HN

AB00139215 Chembridge 2 S983631 S 10.9S >2S.OO

OC N F F
F

ABOO1731.90 SRI SRI-11111 20.97 -SO.OO

Repository

ABOO174524 SRI SRI-10013 3.25 -SO.OO

Repository

HO
US 2013/0085133 A1 Apr 4, 2013
16

TABLE 2-continued
Compound
ID Supplier Supplier ID Structure ECso CCso
AB00275199 Chembridge 2 5128772 H3C 13.02

O
HO CH3

AB00275543 Chembridge 2 5157225 C C 16.21

O

HO S OH

O
C C

AB00275559 Chembridge 2 S161544

HC -CH 6.29

AB00275625 Chembridge 2 5175085 15.23

N N y
OH S
AB00275773 Chembridge 2 S210996 10.17

Br

NH

AB00275918 Chembridge 2 5222210 HO OH 20.46

OH

OH

AB00276073 Chembridge 2 5231477 S.12

US 2013/0085133 A1 Apr. 4, 2013
17

TABLE 2-continued
Compound
ID Supplier Supplier ID Structure ECso CCso
AB00276221 Chembridge 2 5245877 17.59 >25.00

CH3

AB00276381 Chembridge 2 12.2O >2S.OO

AB00276394 Chembridge 2 5255764 15.2O >2S.OO

AB00276634 Chembridge 2 52861.87 15.78 -2S.OO

- C

AB00276706 Chembridge 2 53.12109 19.61 >2S.OO

AB00278348 Chembridge 2 5567669 12.60 -2S.OO

AB00279132 Chembridge 2 5665705

US 2013/0085133 A1 Apr. 4, 2013
18

TABLE 2-continued
Compound
ID Supplier Supplier ID Structure ECso CCso
AB00279343 Chembridge 2 5687656 SH CH3 20.69 -2S.OO

Br

O O
N CH3

AB00279389 Chembridge 2 568958O CH3 O 14.18 -2S.OO

O CH3
N OH

18.89 -2S.OO
AB00280085 Chembridge 2 5764853 "Ne CH3
S

N O
O)'s
S
NH

AB00280244 Chembridge 2 57907OO HC 8.62 >25.00

3

N
N \
CH3
N

HC

CH

AB00280499 Chembridge 2 5802791 NH 6.6O >25.00

C O O

AB00282102 Chembridge 2 S9294.00

O's NH 11.98 -2S.OO

F O O

AB00282821 Chembridge 2 6010355

O's Br 14.49 -25.OO

NH CH3

SO O
-> r
O
HC1 n
O
US 2013/0085133 A1 Apr. 4, 2013
19

TABLE 2-continued

Compound
ID Supplier Supplier ID Structure ECso CCso

AB00283422 Chembridge 2 6O4S122 O 15.83 >2S.OO

Br

OC21 ny ls
HN N1 N N

AB00283699 Chembridge 2 6048378 CH3 12.88 -2S.OO

CH3

H3C t! O
HO

AB00284323 Chembridge 2 6O76447 17.54 -2S.OO

AB00284847 Chembridge 2 6125986 22.48 -2S.OO

AB00285095 Chembridge 2 6133629 9.72 >2S.OO

CH3
US 2013/0085133 A1 Apr. 4, 2013
20

TABLE 2-continued

Compound
ID Supplier Supplier ID Structure ECso CCso

AB00287.440 Chembridge 2 6314397 R 17.84 -2S.OO

NH2
o2S

H3C
SN NH

O O)-
N
N O

AB00287600 Chembridge 2 6334319 C 12.6S >2S.OO

C

O) /
O
OH

AB00287736 Chembridge 2 6349777 16.16 -2S.OO

C N
S S-N-1
'Oln N 21

AB00288908 Chembridge 2 6431,174 21.57 >25.00

AB00289145 Chembridge 2 6438978

OC N1\o1Nuo O 24.24 -25.OO

O N

s O
AB00289457 Chembridge 2 6464487 2.97 -2S.OO

ors
US 2013/0085133 A1 Apr. 4, 2013
21

TABLE 2-continued

Compound
ID Supplier Supplier ID Structure ECso CCso

AB00290004 Chembridge 2 652O943 O 23.21 >25.00

OH
Br

NH AHs
O
O
O

AB00290142 Chembridge 2 6535527 19.44 >25.OO

HN NH HN

ne O
CH

AB00291074 Chembridge 2 6606287 20.59 -2S.OO

AB00291408 Chembridge 2 6624234 24.18 -2S.OO

HC 1N1N S ul OH
H

AB002.91789 Chembridge 2 6631212 H3C N N 10.96 -2S.OO

HC
SH
N
HC
H3C N
O

HC
No O
CH
US 2013/0085133 A1 Apr. 4, 2013
22

TABLE 2-continued

Compound
ID Supplier Supplier ID Structure ECso CCso

AB00292155 Chembridge 2 6651233 15.74 -2S.OO

AB00292.171 Chembridge 2 6652641 CH3 7.64 -2S.OO

O
/

O
/ C
HC
HC-O

AB00292352 Chembridge 2 6663053 C CH 8.56 -25.00

AB00292655 Chembridge 2 66948O3 CH3 10.88 -2S.OO

AB00293237 Chembridge 2 6743233

F

OO
O 10.32 >2S.OO

CH

O
--X K -O- O
V
CH

AB00293238 Chembridge 2 6743321 CH 11.40 -2S.OO

OH
US 2013/0085133 A1 Apr. 4, 2013
23

TABLE 2-continued
Compound
ID Supplier Supplier ID Structure ECso CCso
AB00293678 Chembridge 2 6786686 HC 18.64 -2S.OO

O
Ol a
O

NH
HC NH

AB00293683 Chembridge 2 6787055 18.82 >2S.OO

OH N

HC

O N

AB00293926 Chembridge 2 68.26767 S 10.80 -2S.OO

rN
su O

c F
AB00294368 Chembridge 2 6880473 N 14.97 -2S.OO

()
AB00294484 Chembridge 2 68841.33 HN O 16.44 >25.OO

AB00294809 Chembridge 2 6894.993 Br

HN Ol
NN
NH2

20.29 >2S.OO

O)-
N O
- 3
CH

O
-Nso
CH2
US 2013/0085133 A1 Apr. 4, 2013
24

TABLE 2-continued
Compound
ID Supplier Supplier ID Structure ECso CCso
AB00294826 Chembridge 2 6895791 F 16.73 >2S.OO

AB00294.890 Chembridge 2 6898236 Br 22.51 >25.00

N O

O O
s(U)-Nir YO
AB00296051 Chembridge 2 6941649 7. S 16.7O >2S.OO

OC
HN

"... O

AB002.96320 Chembridge 2 6944380 -O 8.34 -2S.OO

HC
NH O

AB002.96345 Chembridge 2 694.4510 N 18.87 -2S.OO

OC--O
) H3C CH3

AB00296415 Chembridge 2 6944917 N 4.88 -2S.OO

O
N
CH3
CH3
US 2013/0085133 A1 Apr. 4, 2013
25

TABLE 2-continued
Compound
ID Supplier Supplier ID Structure ECso CCso
AB00296680 Chembridge 2 694.7330 12.88 -2S.OO

N
O No.
C
HN

O O
NCH,
OH

AB00297372 Chembridge 2 6958221 HC 10.88 -2S.OO

HC
O

O. e "
S N

AB00297463 Chembridge 2 6959378 O 16.33 >2S.OO

N CH3

2
N

AB002974.82 Chembridge 2 69595.57 O 14.09 -2S.OO

HC
NH

H3C
O

H3C 1.
AB00297971 Chembridge 2 6968195 CH3 19.21 >2S.OO

HN
V O
O

Yv
O
S

O O O
US 2013/0085133 A1 Apr. 4, 2013
26

TABLE 2-continued
Compound
ID Supplier Supplier ID Structure ECso CCso
AB00297982 Chembridge 2 6968340 11.04 -2S.OO

CH

AB00298,501 Chembridge 2 3.14 -2S.OO

AB00298660 Chembridge 2 6982394 13.48 -2S.OO

AB00298665 Chembridge 2 6982423 12.14 >25.OO

AB00298862 Chembridge 2 6985389 20.44 -25.OO

AB00299031 Chembridge 2 6988OOO 21.69 -2S.OO

H
US 2013/0085133 A1 Apr. 4, 2013
27

TABLE 2-continued
Compound
ID Supplier Supplier ID Structure ECso CCso
AB00299290 Chembridge 2 6991621 15.84 -2S.OO

CH
O 3
O
N N
CH
O
O NH CH3

AB00299380 Chembridge 2 69929OO 10.41 >2S.OO

O

HC
NH

19 HN

AB00299386 Chembridge 2 6992994 12.34 -2S.OO

O

C
NH C

AB00299547 Chembridge 2 6996310 18.06 -2S.OO

O

Br

AB00299924 Chembridge 2 70O2398 Br 22.42 >25.00

CH O

AB00300194 Chembridge 2 7004218

O
3

N 1n-1N1N

CH
US 2013/0085133 A1 Apr. 4, 2013
28

TABLE 2-continued
Compound
ID Supplier Supplier ID Structure ECso CCso
AB003.01183 Chembridge 2 701.2535 S O 22.6S >25.00

susO Br

OH

AB003.01184 Chembridge 2 701.2545 O 2.53 >2S.OO

N
O2
O

N 11a-N
O

CH3

AB00301352 Chembridge 2 701,3771 21.07 -2S.OO

N 1N1-N-N
O

AB003.01378 Chembridge 2 7013938 17.77 >25.00

O
N

O
N 1-1-N-N
O
US 2013/0085133 A1 Apr. 4, 2013
29

TABLE 2-continued

Compound
ID Supplier Supplier ID Structure ECso CCso

AB00301782 Chembridge 2 7017760 O 2.01 >2S.OO

V
2N
o21
O

N 1N-1-N-N

AB00302018 Chembridge 2 702O237 3.40 -2S.OO

{O O

O N 1N1\-N
O

AB00302020 Chembridge 2 7020263 HC 15.13 >2S.OO

O 1n-1N-N
O

CH

AB00302396 Chembridge 2 7028652 23.83 >25.00

TC)
US 2013/0085133 A1 Apr. 4, 2013
30

TABLE 2-continued
Compound
ID Supplier Supplier ID Structure ECso CCso
AB003.02454 Chembridge 2 7032008 CH 15.34 -2S.OO

Ol
COO
O
AB00302921 Chembridge 2 7052098 O HC 20.27 -2S.OO
V
HC O

Br O

AB00303357 Chembridge 2 7089660 21.92 >25.00

N
S

Br

Q
AB00304418 Chembridge 2 7113935 10.72 >2S.OO

NN
-O
M
7\
O O

AB00304690 Chembridge 2 7115690 13.21 >2S.OO

HO
O
H3C

HC
3 S NH O

AB00305611 Chembridge 2 7125924 HC 17.08 -2S.OO

HC O CH

H3C
AB00306112 Chembridge 2 7135263 5.86 -2S.OO
C

O NH
NN N-1Ns
US 2013/0085133 A1 Apr. 4, 2013
31

TABLE 2-continued

Compound
ID Supplier Supplier ID Structure ECso CCso

AB00306917 Chembridge 2 7151203 17.31 >2S.OO

O)
ON:
S

AB00307079 Chembridge 2 71.54359 O 14.33 >2S.OO

N N

s^-
N
O Cl
O
C

AB00307412 Chembridge 2 7169548 O 21.14 -25.OO

Ort: O

p
H3C

AB003O8659 Chembridge 2 7192352 O 8.66 -2S.OO

NH
US 2013/0085133 A1 Apr. 4, 2013
32

TABLE 2-continued

Compound
ID Supplier Supplier ID Structure ECso CCso

AB003O8859 Chembridge 2 7196715 O 20.48 -2S.OO

OH

HN

OOC S N

AB00309154 Chembridge 2 7204366 6.41 >25.OO

O F
N

HC
O)-NH
S
F

AB00309238 Chembridge 2 72O6567 O 20.28 -2S.OO

OS i?
SN+

N
N

H3C
O
N S

AB00309550 Chembridge 2 7215163 OH 16.31 >2S.OO

O
YCH,
Br

AB00309817 Chembridge 2 7223091 14.3S >2S.OO

US 2013/0085133 A1 Apr. 4, 2013
33

TABLE 2-continued

Compound
ID Supplier Supplier ID Structure ECso CCso

AB00309842 Chembridge 2 7223323 C 12.31 >2S.OO

N O
C N N C

( \su
C

AB00309859 Chembridge 2 7223481 6.84 -2S.OO

O
?h
O
CH3
HO NH

O
^- O S
O CH3
AB00310156 Chembridge 2 7227882 10.38 -2S.OO
C

O
HN O-CH

O
/
H3C

AB00310224 Chembridge 2 722874O

S O Br
24.46 -25.OO

H3C O
HN

O
O
HC

AB00310729 Chembridge 2 7236843 1411 >25.OO

O N
O

OO
US 2013/0085133 A1 Apr. 4, 2013
34

TABLE 2-continued
Compound
ID Supplier Supplier ID Structure ECso CCso
AB00310739 Chembridge 2 7236979 HN 6.31 >25.00
O

HN CH

O CH3

AB00310767 Chembridge 2 7237493 -CH3 15.04 -2S.OO

CH3 O O

issus N

issus CH3
Cl

23.6S >25.00
AB00310808 Chembridge 2 72381.38 -C
HN O

S -4 NH2
19.62 >2S.OO
AB00310846 Chembridge 2 7238770 Q
Br HN

AB00310910 Chembridge 2 7239916 1.15 -2S.OO

AB00311298 Chembridge 2 7247789 S O C 7.72 >25.00

HN

O
US 2013/0085133 A1 Apr. 4, 2013
35

TABLE 2-continued

Compound
ID Supplier Supplier ID Structure ECso CCso

AB00311411 Chembridge 2 72SOO49 F 22.7O >25.00

O

O F
HN N
C

AB00311948 Chembridge 2 7257552 C 2.32 >2S.OO

M O
C N N C

( \su
C

AB00312102 Chembridge 2 7259967 3.71 >2S.OO

H3C N N CH3

AB00313012 Chembridge 2 7275.865 CH, CH3 17.97 >25.00

O. O
HN
HN

O C
CH

AB00313042 Chembridge 2 7276383 1.89 -2S.OO

Osul S
AB00313091 Chembridge 2 7277298 HC 19.46 -2S.OO

CH
O HN

N CH
NH O

CH
US 2013/0085133 A1 Apr. 4, 2013
36

TABLE 2-continued

Compound
ID Supplier Supplier ID Structure ECso CCso

AB00313218 Chembridge 2 7279713 22.18 -2S.OO

AB00313952 Chembridge 2 7305797 2.72 >2S.OO

HN
O O C
HN
O HN

AB00314111 Chembridge 2 731O127 6.97 -2S.OO

H3C i-N
O

O
HN F

F F

F F

AB00314248 Chembridge 2 73.14590 F 23.83 >25.00

C
F
O
HN
O C

HC

AB00314279 Chembridge 2 73.15214 23.47 -2S.OO

O
HN

O-CH
US 2013/0085133 A1 Apr. 4, 2013
37

TABLE 2-continued
Compound
ID Supplier Supplier ID Structure ECso CCso
AB00315446 Chembridge 2 73.546O7 C 12.OO >2S.OO

CH

rN O
HN Nu
O
n N+

AB00315731 Chembridge 2 735678O CH 21.07 -2S.OO

AB00315918 Chembridge 2 735818O 15.37 >25.00

O N

/ .
O

AB00316243 Chembridge 2 7362106 H3CN 18.51 >2S.OO

O

He1\o h
HC 1s

AB00317095 Chembridge 2 73731.93 OH 24.33 >25.00

C
O N O N

CH
US 2013/0085133 A1 Apr. 4, 2013
38

TABLE 2-continued

Compound
ID Supplier Supplier ID Structure ECso CCso

AB00317165 Chembridge 2 7374281 HC 19.46 -2S.OO

N.

NH

H3C CH3
O HN 1

AB00317214 Chembridge 2 7375133 O O Ol 12.36 >25.OO

N
o2 NH Br
N

AB00317272 Chembridge 2 7376125 O 22.28 -2S.OO

CH3 O
CH3
H3C NH O
N

AB00317410 Chembridge 2 7378526 1.CH O 22.84 -2S.OO

O O

NH NH 1--"
AB00317604 Chembridge 2 7382761 23.69 -2S.OO
CH3 O
CH
H3C NH
N C

O
US 2013/0085133 A1 Apr. 4, 2013
39

TABLE 2-continued
Compound
ID Supplier Supplier ID Structure ECso CCso
AB00317685 Chembridge 2 73841.33 O 20.88 -2S.OO

HN

O CH
C N1
OH

AB00318114 Chembridge 2 7396766 1. CH3 3.37 -2S.OO

CH3 O
O

CH3
HN o1

AB00318264 Chembridge 2 7402594 O 22.89 -2S.OO

C
NH

N
He1\o ( }
AB00318335 Chembridge 2 7403644 O-O. 24.18 -2S.OO
S A
S-2 S
US 2013/0085133 A1 Apr. 4, 2013
40

TABLE 2-continued

Compound
ID Supplier Supplier ID Structure ECso CCso

AB00318401 Chembridge 2 74O44-85 O O 2.39 -2S.OO

HC1

AB00318606 Chembridge 2 74O7414 23.46 -2S.OO

o2 NO O NH
Ol NH1--"
O

AB00318952 Chembridge 2 74.13330 OH 22.23 >25.00

CH

AB00319298 Chembridge 2
Br -O N

2.76 -2S.OO

AB00319373 Chembridge 2 742228O H3C 24.42 >25.OO

F IO NHrS O O
US 2013/0085133 A1 Apr. 4, 2013
41

TABLE 2-continued
Compound
ID Supplier Supplier ID Structure ECso CCso
AB00319534 Chembridge 2 7424977 CH 13.77 >25.00

ON
O

AB00321587 Chembridge 2 7495455 H3C 9.15 -2S.OO

O

N
2

O
NO
HC1 ()
AB00322577 Chembridge 2 75101.93 CH 18.67 -2S.OO

HN N

AB00326733 Chembridge 2 7581498 18.7S >2S.OO

AB00335740 Chembridge 2 768O889 21.07 -2S.OO

AB00339206 Chembridge 2 7721729 OH 21.87 -2S.OO

US 2013/0085133 A1 Apr 4, 2013
42

TABLE 2-continued
Compound
ID Supplier Supplier ID Structure ECso CCso
AB00339302 Chembridge 2 7722O14 C 12.28

AB0034.0723 Chembridge 2 7727457

's-1n
N

CH
OO 19.75

AB0034.1850 Chembridge 2 7735547

o, HC
O

2.19

N
a

O S

NY HN
O

AB00342188 Chembridge 2 7738549 13.11

AB00344427 Chembridge 2 7756992 17.87

HN
C
US 2013/0085133 A1 Apr. 4, 2013
43

TABLE 2-continued

Compound
ID Supplier Supplier ID Structure ECso CCso

AB00345103 Chembridge 2 7767847 H3C 2.18 -2S.OO

O

2
H3C N S
O

HN

rN
su
AB0034.8154 Chembridge 2 7790928 10.62 >2S.OO
C NH

NH S F

Il-4 HN

AB00348268 Chembridge 2 7791503 (" 21.4S >25.00

O

HC-O p-O) {
N-( O
O
AB00348716 Chembridge 2 7793889 s 17.26 -2S.OO
O

HN
NH O

ON CH
AB00349666 Chembridge 2 77994.03 F 21.17 -2S.OO

F NH HC
NH S O
US 2013/0085133 A1 Apr. 4, 2013
44

TABLE 2-continued
Compound
ID Supplier Supplier ID Structure ECso CCso
AB00349705 Chembridge 2 7799604 CH3 1924 -2S.OO

CH3
HN

O N-( O

AB00351451 Chembridge 2 78.10486 O 17.51 >2S.OO

C HN

AB00353001 Chembridge 2 7823760 18.43 >2S.OO

HC
No
AB00353228 Chembridge 2 78.26467 9.78 -2S.OO

CH HN NH

O CH3
AB00355020 Chembridge 2 7844977 NH N 2.77 >25.00

HO

AB00355044 Chembridge 2 7845082 6.39 -2S.OO

US 2013/0085133 A1 Apr. 4, 2013
45

TABLE 2-continued

Compound
ID Supplier Supplier ID Structure ECso CCso

AB00356285 Chembridge 2 7853019 HC 4.04 >25.OO

O N
(O NH
Ns
MV
O O

AB00356597 Chembridge 2 7855992 N2N 11.59 -2S.OO

O O us O O\-
S NH
O CH3
HC-O

AB00358081 Chembridge 2 7873254 (S (O) 12.07 -2S.OO

N (O)
Br

AB00358122 Chembridge 2 7873874 CH 20.13 >25.00

O

Null NH

Br

AB00358926 Chembridge 2 7885310 "S2 s" 12.6S >2S.OO

O)-(O.
NN
HC

AB0035.9127 Chembridge 2 7887.469 O 18.92 >2S.OO

HN O
H3C Y
O CH3

AB00359299 Chembridge 2 78.89870 S-CH 6.76 -2S.OO

US 2013/0085133 A1 Apr. 4, 2013
46

TABLE 2-continued

Compound
ID Supplier Supplier ID Structure ECso CCso

AB00359685 Chembridge 2 7900141 9.42 >2S.OO

HN NH O

AB00359707 Chembridge 2 7900656 11.38 -2S.OO

CH3 O
N
NH
O C

AB00361531 Chembridge 2 7908294 O.83 >2S.OO

C

O
S NH
O
F

AB00362388 Chembridge 2 7913440 / \ O 16.96 -2S.OO

( V /
N
pH
O

O2 V s
O C

AB00362750 Chembridge 2 791S246 CH 21.04 -2S.OO

/
He—V N CH3

AB00362810 Chembridge 2 7.915470 r 21.06 -2S.OO

(5- DOcy F
US 2013/0085133 A1 Apr. 4, 2013
47

TABLE 2-continued

Compound
ID Supplier Supplier ID Structure ECso CCso

AB00362846 Chembridge 2 7915886 4.47 -2S.OO

O
CH
/
NH C O

F O
M
HC

AB00362891 Chembridge 2 7916224 S 23.40 -2S.OO

AB00363547 Chembridge 2 792.1332 13.33 >2S.OO

Br CH3

HN O O
CH.
S
O

AB00363859 Chembridge 2 79251.87 12.60 -2S.OO

H3C

AB00364099 Chembridge 2 79.26973 HO 19.2S >2S.OO

AB00364575 Chembridge 2 7929964 17.76 -2S.OO

O
/
HC
US 2013/0085133 A1 Apr. 4, 2013
48

TABLE 2-continued
Compound
ID Supplier Supplier ID Structure ECso CCso
AB00364640 Chembridge 2 793O397 HC 11.54 -2S.OO

O
W NH
a'i\
H.C. O1
NH O CH
o1
O
HC1
AB00364858 Chembridge 2 7932123 21.21 >25.00

H2C=

AB00365318 Chembridge 2 7935438 O 11.56 -2S.OO

rol l NH NH

O
NCH,
AB003.65647 Chembridge 2 793.7929 19.3O >2S.OO

CH
NH

AB00366410 Chembridge 2 7943717

O

O
O-O 20.23 >25.00

O- Br
AB00367559 Chembridge 2 7947858
-O-F

O 19.58 -2S.OO

O
AB00367930 Chembridge 2 7949301
N-(D 5.77 >25.00

in IO S

Or O
US 2013/0085133 A1 Apr. 4, 2013
49

TABLE 2-continued
Compound
ID Supplier Supplier ID Structure ECso CCso

AB00368222 Chembridge 2 79.50829 12.26 -2S.OO

AB00368252 Chembridge 2 7951033 C

* O. O.
NH
1N1 CH3
O O
YCH,
AB00369287 Chembridge 2 79.57878 9.56 -2S.OO

O
Br
NH O

HO

AB00369510 Chembridge 2 795.9554 10.42 >2S.OO

C HC N
O NNY
HN y
Br H3C

AB00369798 Chembridge 2 796.1748 S-CH 11.60 -2S.OO

NH
C

AB00369924 Chembridge 2 7962703 NN 1.71 >2S.OO

29 /
N
N

O (O

AB00369934 Chembridge 2 7962752 13.63 >2S.OO

AB00370002 Chembridge 2 7963355 CH3 22.02 >25.00

US 2013/0085133 A1 Apr. 4, 2013
50

TABLE 2-continued
Compound
ID Supplier Supplier ID Structure ECso CCso

AB00370063 Chembridge 2 796.3817 1.97 -2S.OO

29
O

O
AB00370331 Chembridge 2 4.2O >25.00

AB00370446 Chembridge 2 79675.99 4.37 -2S.OO

Cl
C

AB00370838 Chembridge 2 22.46 -2S.OO

AB00370949 Chembridge 2 7974136 18.84 -2S.OO

AB00371387 Chembridge 2 79.79329 12.6S >2S.OO

US 2013/0085133 A1 Apr. 4, 2013
51

TABLE 2-continued

Compound
ID Supplier Supplier ID Structure ECso CCso

AB00371866 Chembridge 2 798.5842 S N 13.72 >2S.OO

2e1)-1

CH3

AB00372085 Chembridge 2 798.94.45 an 1164 -25.OO

N
iO
N
N

H3C - / N O
S

AB00372475 Chembridge 2 7994.058 HN 21.04 -2S.OO

H3C N

NH S N CH

AB00372624 Chembridge 2 7995866 O 23.60 -2S.OO

HO

Y-5.
ls N S

AB00373143 Chembridge 2 9003855 O. O 1427 -2S.OO

\/N N
(O) 2N
ABOO373945 SRI SRI-4094 F 13.26 -SO.OO
Repository N1 N
O O
1. N O

2O
N2

ABOO374695 SRI SRI-15298 46.84 -SO.OO

Repository N
NH2
US 2013/0085133 A1 Apr. 4, 2013
52

TABLE 2-continued

Compound
ID Supplier Supplier ID Structure ECso CCso

ABOO375242 SRI SRI-13404 H3C 41.9S >SO.OO

Repository )
O O
NH2 CH O
S S
HN
N HN-(O
HN
us N N
N
O

HC
y
ABOO37S379 SRI SRI-15666 OH 39.16 -SO.OO
Repository

Br

ABOO43O151 SRI SRI-1594 F 38.41 >SO.OO

Repository F F
N
HN a

HN N C

ABOO430481 SRI SRI-15875 HN 38.8O >SO.OO

Reposito
p ry O

R O R N N
N2
R
S

HO OH

ABOO430484 SRI SRI-16O22 -CH3 33.7O >SO.OO

Repository HN

O O)N N OH
S
US 2013/0085133 A1 Apr. 4, 2013
53

TABLE 2-continued

Compound
ID Supplier Supplier ID Structure ECso CCso

ABOO443629 SRI SRI-16681 NH2 NH2 35.64 -SO.OO

Reposito

p ry N=N-O-O-N-N

asno
OY asno
OY
O O

ABOO443953 SRI SRI-18287 21.34 -SO.OO

Repository

ABOO444131 SRI SRI-18727 18.78 -SO.OO

Repository

ABOO444372 SRI SRI-21483 10.87 -SO.OO

Repository HO
O
US 2013/0085133 A1 Apr. 4, 2013
54

TABLE 2-continued

Compound
ID Supplier Supplier ID Structure ECso CCso

ABOOS14356 SRI SRI-17934 f 23.40 -SO.OO

Repository Os

O
f SSSo
O N

Ors
N Ns
\ 'S / N

4. f
S
O po
s SO O
O

ABOOS14453 SRI SRI-19094 O 7.23 >SO.OO

Repository
OH

CH3
N
O CH3

ABOOS36652 Enamine T5242183 H3C H3C 38.72 >SO.OO

N.
s 2
o21 N

O)-N O

CH

ABOO695369 Profectus SRI-22810 35.78 x-50.00

US 2013/0085133 A1 Apr. 4, 2013
55

TABLE 2-continued
Compound
ID Supplier Supplier ID Structure ECso CCso
ABOO700S60 SRI SRI-23046 11.29 -SO.OO
Repository

ABOO7.09376 Enamine TOSO1-6404 10.80 -SO.OO

O \ CH
(A \ KO N

HC
CH

ABOO712667 Enamine TOSO8-7698 C 23.98 -SO.OO

NH

N CH3
M
N

HC
ABOO712684 Enamine TOSO8-9789 CH 21.91 >SO.OO

s CH
C
O O 21 NN

- O
21 CH
C O
O O
US 2013/0085133 A1 Apr. 4, 2013
56

TABLE 2-continued

Compound
ID Supplier Supplier ID Structure ECso CCso
ABOO717474 Enamine TS499.063 12.17 -SO.OO

NH C

?o S
NCH,
ABOO718339 Enamine
TO516-5070 r 1.14 -SO.OO

ON \ N-N
\ S
e

HC

ABOO718457 Enamine TOS16-74O2 23.84 -SO.OO

ABOO719359 Enamine TOS16-8387 29.77 >50.00

US 2013/0085133 A1 Apr. 4, 2013
57

TABLE 2-continued
Compound
ID Supplier Supplier ID Structure ECso CCso
ABOO720414 Enamine TOS 18-6946 C 49.1S >SO.OO

OS
O

HN
S.
2s.
NO
HC

HC

ABOO721928 Enamine TOS2O-4430 N 41.90 -SO.OO

O CH
CH
H3C
O O

NH

2
2

ABOO722846 Enamine TS221 190 NH 1.74 -SO.OO

"S- N
O
O
EN

HC
US 2013/0085133 A1 Apr. 4, 2013
58

TABLE 2-continued

Compound
ID Supplier Supplier ID Structure ECso CCso

ABOO723775 Enamine TS234633 23.43 >SO.OO

CH3

ABOO724801 Enamine TS248808 16.2S >SO.OO

HC

ABOO72S240 Enamine T5255725 43.31 >SO.OO

US 2013/0085133 A1 Apr. 4, 2013
59

TABLE 2-continued

Compound
ID Supplier Supplier ID Structure ECso CCso

ABOO725275 Enamine TS256425 Br 28.48 -SO.OO

N
HNO
y S

O 2N

H3C
NH2

ABOO72S538 Enamine T5259183 C 6.30 -SO.OO

Y O
HN r
H3C O
O

N S

s N CH3

O
O

CH3

ABOO726710 Enamine TS269946 30.87 -SO.OO

US 2013/0085133 A1 Apr. 4, 2013
60

TABLE 2-continued
Compound
ID Supplier Supplier ID Structure ECso CCso
ABOO7283O3 Enamine TS286991 O 28.29 -SO.OO
OS/
N
O-N CH

H3C
NH

s S

2s N
SO N

HN

CH3

ABOO728757 Enamine T5293387 NH2 18.11 >SO.OO

N
Šs
CH3

O
F
S N S

Orr N

ABOO72876O Enamine TS2934.03 37.89 -SO.OO

HN O

S
US 2013/0085133 A1 Apr. 4, 2013
61

TABLE 2-continued
Compound
ID Supplier Supplier ID Structure ECso CCso
ABOO739576 Enamine T5497119 24.71 >SO.OO

NH

ABOO739796 Enamine T5531438 22.23 >SO.OO

Q
HN

O
W
N

ABOO741842 Enamine TS493974 F. F 26.67 -SO.OO

ABOO747970 Enamine T55.35819 10.7S >SO.OO

US 2013/0085133 A1 Apr. 4, 2013
62

TABLE 2-continued

Compound
ID Supplier Supplier ID Structure ECso CCso

ABOO756405 Enamine TS647248 F 11.45 -SO.OO

HN

O O

HN

H3C
CH3

ABOO764110 Enamine T5729768 F 41.53 >SO.OO

2
O

ABOO766545 Enamine T5770620 O 26.1S >SO.OO

H3C
)-N OH

O)-y Y. N
V
US 2013/0085133 A1 Apr. 4, 2013
63

TABLE 2-continued
Compound
ID Supplier Supplier ID Structure ECso CCso
ABOO767910 Enamine T5788.513 NH2 6.07 -SO.OO
HC

O SN

2s N
SO
HN
Y-2
O
N
CH
ABOO776619 Enamine T5872935 O 27.27 >50.00

CH

NH

O HN
O

NH
O

O
ABOO784993 Enamine T5948830 Cl C 12.04 -SO.OO

X- NH
O HN -(
O

ABOO78SO32 Enamine T5949075 46.45 c-SO.OO

HC
O
O
/ N N-S
N
W V / ||
O
N
US 2013/0085133 A1 Apr. 4, 2013
64

TABLE 2-continued
Compound
ID Supplier Supplier ID Structure ECso CCso
ABOO7851.38 Enamine TS9493.68 7.52 >50.00
C

O HC
HN

O
O N

H3C
ABOO785889 Enamine TS941086 O 23.40 -SO.OO

?h ric) N

O
Br

CH

ABOO796257 Enamine TS829062 HN 24.84 -SOOO

CH

O
O O

H3C
CH
HC

ABOO796961 Enamine 16OO6611 CH3 31.8S >SO.OO

Br
S N

8. O
US 2013/0085133 A1 Apr. 4, 2013
65

TABLE 2-continued
Compound
ID Supplier Supplier ID Structure ECso CCso
ABOO796970 Enamine 16OO6652 CH3 10.64 -SO.OO

ABOO797753 Enamine T5990173

HCV
F

S
S N

H3C
Y
s
HN-(
O
O

) )-K
'N-(
O
29.90 -SO.OO

ABOO798716 Enamine 49.8O >SO.OO

T5978325 Ol
O

HN O

ABOO80O399 Enamine T6034146 40.86 -SO.OO

O
( N/
C

CH
US 2013/0085133 A1 Apr. 4, 2013
66

TABLE 2-continued
Compound
ID Supplier Supplier ID Structure ECso CCso
ABOO8O2246 Enamine 9.58 -SO.OO

OCS
ABOO804772 Enamine 43.37 -SO.OO

CH3

ABOO87718O SRI 15.11 >SO.OO

Repository
SRI-23668 Ol
N N

s HN

ABOO87736S SRI SRI-23648 38.79 -SO.OO

Repository
US 2013/0085133 A1 Apr. 4, 2013
67

TABLE 2-continued
Compound
ID Supplier Supplier ID Structure ECso CCso
ABOO877398 SRI SRI-238.78 O 40.09 -SO.OO
Repository
H3C
OH

HC S HN

ABOO8774OS SRI SRI-23887 O 27.77 >50.00

Repository
OH

O)-st
S
O

SRI-101 SRI SRI-101 H H H 35.73 >50.00

Repository
N N N 2O

o1
ors CH3 NH O

SRI-10531 SRI SRI-10531 O 9.09 -SO.OO

Repository ls
HN CH O O
N OH
N HN S

us HN
HN N
O
HO

SRI-4711 SRI SRI-4711 H -CH3 24.53 >SO.OO

Repository N

(CN O2
R N

HO OH

SRI-7958 SRI SRI-7958 O 2.40 -SO.OO

Repository
H

N N 1.O
n
s
O
HO R R
US 2013/0085133 A1 Apr. 4, 2013
68

0264 Virus Titer Reduction culated TCIDso value was used to further prioritize the scaf
0265. To evaluate the effect of test compounds on the folds identified in the primary screen and confirmed in the
production of infectious progeny virus, a virus titer Reduction dose response confirmatory assay.
(VTR) assay was performed on test compounds confirmed in
the HTS dose response assays. Four concentrations of each TABLE 3
compound were evaluated (Table 3). Briefly, the four concen Test compound concentrations for VTR assay
trations of test compounds, HEp-2 cells (8x10 per well) and
RSV. Long strain (MOI=0.9) were plated in 96 well microtiter Library Test Compound Concentrations
plates. The plates were incubated for 48 hours. Fifteen (15) ul Enamine SO M 25 M 12.5 LM 6.25 M
of 10-fold serial dilution of progeny virus containing medium CB2 25 ug/ml 12.5 lug/ml 6.25 ug/ml 3.12 ugml
from respective samples (test compound treated or untreated) SRI Repository SO M 25 M 12.5 LM 6.25 M
was transferred to infect fresh HEp-2 cells (2x10 cells per Ole Miss
SRI Collaborator
2S M
30 ug/ml
12.5 M
15 ugml
6.25 uM
7.5 ug/ml
3.12 uM
3.75 ugml
well) in a 384 well format. Plates were incubated for an SRI Collaborator 50 ug/ml 25 ugml 12. lug/ml 6.25 ugml
additional 6 days and luminescence was measured using Cell
Titer-Glo reagent (Promega Inc.) to determine cell viability. A
well exhibiting equal to or greater than 50% cell viability was 0266 Three hundred and twelve active test compounds
considered negative for virus infection. A well showing lesser identified in the dose response assays (Table 2) were selected
than 50% cell viability was regarded as positive for virus for titer reduction analysis. Forty-nine test compounds were
infection. Four replicates for each virus dilution were ana identified based on the criteria of activity: more than 10 fold
lyzed and the number of virus positive wells (out of 4) was reduction in the progeny titer (> 1 of log reduction) at 12 ug/ml
plotted versus the dilution. TCIDs was calculated to be the and an efficacy ECso value equal to or less than 10 g/ml
dilution that produced two positive wells out of four using (Table 4). There were at least 19 distinct chemotypes apparent
ActivityBase software (IDBS, Inc, Guilford, UK). The cal in the 49 compounds screened by TCIDs.
TABLE 4

TCID- TCID- TCID- TCID

SO Re- SO Re- SO Re- SO Re
duction duction duction duction
Compound Sup- Supplier (a) 3 6 (a) 12(a) 25 (a)
ID plier ID Structure ug/ml ugml ug/ml ugml

AB00289457 Chem- 6464487 O OH 1.OO 4.90 6.73 6.57

bridge
2

O 1n O

ABOO3O8659 Chem- 7192352 O 2.82 3.64 6.43 6.40

bridge
2 NH N

NH

AB00313042 Chem- 7276383 3.56 5.24 5.43 6.40

bridge
2 S O O
(O)Nul NH S
ABOO369.287 Chem- 79.57878 1.OO 3.31 4.73 6.57
bridge
2 O
Br
NH O

HO
US 2013/0085133 A1 Apr 4, 2013
69

TABLE 4-continued

AB00359685 Chem 7900141 1.00 2.13 4.40 4.94

bridge
2

AB00279132 Chem 5665705 1.00 3.63 4.22 3.83

bridge
2

NH

C
O
AB00280499 Chem 5802791 NH 2.55 2.38 3.69 2.96
bridge
2

AB00353228 Chem
bridge
78.26467
co's CH
1.5 5 2.87 3.42 3.43

2
O

CH HN NH
CH
O

ABOO369924 Chem 7962703 1.00 2.62 3.22 2.61

bridge
2
29
O
* ()N
AB00370446 Chem 79675.99 O O 1.00 1.32 3.21 6.57
bridge HC \/
2
* ns O iN
Cl
HN C
US 2013/0085133 A1 Apr. 4, 2013
70

TABLE 4-continued
ABOO345103 Chem- 776.7847 HC 1.00 1.31 3.20 2.86
bridge
2 O

ABOO361531 Chem- 7908294 1.55 1.74 3.09 3.78

bridge C
2 N O

NH

AB002985O1 Chem- 698.0267 CH 1.82 2.38 2.90 3.78

bridge
2
O /-/

O)-)S

AB002.96320 Chem- 6944380 1.55 1.38 2.90 4.66

bridge
2

ABOO362846 Chem- 7915886 1.00 1.92 2.82 S.48

bridge
2

CH3
US 2013/0085133 A1 Apr 4, 2013
71

TABLE 4-continued
ABOO302018 Chem 702O237 1.66 2.64 2.68 3.07
bridge
2 O

1N-1-

ABOO312102 Chem 7259967 1.53 1.86 2.68 2.39

bridge
2

N N CH
( \su
AB00367930 Chem 7949301 1.82 1.04 2.68 6.40
bridge
2

AB00356285 Chem 7853019 1.14 1.38 2.42 3.78

bridge
2

ABOO341850 Chem 7735547 1.00 2.30 2.41 2.23

bridge
2

HC
US 2013/0085133 A1 Apr. 4, 2013
72

TABLE 4-continued
ABOO27SSS9 Chen S161544 H3C CH3 1.00 1.93 2.21 1.93
bridge
2

AB00355020 Chem 7844977 NH N 1.00 1.01 2.20 2.55

bridge
IC)
S OH
HO

AB00285095 Chem 6133629 1.00 1.32 1.99 2.56

bridge

CH3

AB00359299 Chem 78.89870 S-CH 1.00 122 1.99 2.83

bridge

AB003.01184 Chem 701.2545 O (2) 1.53 1.67 1.90 1.88

bridge

CH3

AB00310739 Chem 7236979 HN 1.03 1.86 1.90 2.39

bridge
HN CH

CH3

AB00311298 Chem 7247789 1.53 1.86 1.90 1.88

bridge
US 2013/0085133 A1 Apr 4, 2013
73

TABLE 4-continued
ABOO368252 Chem 7951033 C 1.00 1.30 1.72 4.94
bridge
2
1n-N.

AB00370331 Chem 7966004 -0.15 1.39 1.70 2.89

bridge
2

AB00306112 Chem 7135263 1.85 1.38 1.68 2.88

bridge C
2

AB00280244 Chem 57907OO 1.55 1.36 1.55 2.89

bridge
2

CH3
ABOO301782 Chem 7017760 1.55 1.64 1.42 O.87
bridge
2

AB00309154 Chem 72O4366 1.54 1.38 1.42 1.88

bridge
2
US 2013/0085133 A1 Apr. 4, 2013
74

TABLE 4-continued

AB00314111 Chem- 731 O127 1.00 1.01 1.41 3.05

bridge
2 S-NH

ABOO276O73 Chem- S231477 1.00 1.39 3.57

bridge
2

TCID TCID TCID TCID- TCID

SO Re SO Re SO Re SO Re- SO Re
duction duction duction duction duction
Compound Sup- Supplier (a) 3 (a) 5 (a) 12 (a) 25 (a) 50
ID plier ID Structure ug/ml ugml ug/ml ugml ug/ml

ABOO174524 SRI SRI 4.58 S.98 5.56 5.87

Repos- 10013
itory

SRI-7958 SRI SRI 3.58 S.98 5.56 5.87

Repos- 7958
itory

HO
US 2013/0085133 A1 Apr. 4, 2013
75

TABLE 4-continued
AB00311948 Chem 7257552 C 3.13 4.64 5.56 S.90
bridge
2

C N N C

ABOO318114 Chem 7396766 CH 2.42 4.69 5.56 S.90

bridge CH, O
2

ABOO72S538 Ena T5259183 2.95 4.98 5.56 5.87

mine

AB00319298 Chem O.84 3.09 4.56 S.90

bridge
2
US 2013/0085133 A1 Apr. 4, 2013
76

TABLE 4-continued

ABOO7851.38 Ena- TS9493.68 1.96 4.24 4.56 3.87

mine C

O HC
HN
N
N
O
HC

ABOO7OS281 SRI JSO 63 4.75 4.20 5.56 S.90

Colla
borator O N HN
N.
O O

ABOO8O2246 En- T6O13876 F 2.26 3.98 4.42 5.87

amine F
F

HC HN

C. S.N

O
/
H3C

ABOO292352 Chem- 6663053 O Cl CH3 122 2.31 3.82 S.90

bridge
2
N
C
O

ABOOS14453 SRI SRI- O O.O6 3.33 4.47 4.87

Repos- 19094
itory OH

CH
N
O CH

ABOO296415 Chem- 694.4917 N 1.74 2.48 2.59 S.90

bridge
2
O
N

O
N
CH
CH3
US 2013/0085133 A1 Apr. 4, 2013
77

TABLE 4-continued
AB00300194 Chem 7004218 1.41 1.83 2.04 2.56
bridge O
2 CH

O 1. 1N1-S-N
N
O

CH3
SRI-10531 SRI SRI O16 0.97 -0.02 O.28
Repos- 10531
itory

(3) indicates text missing or illegible when filed

Many of the compounds described in the Tables above are -continued

commercially available. Compounds that are not commer CONHR
cially available can be readily synthesized by those skilled in
the art. Furthermore, the compounds of the instant disclosure
can be prepared according to the exemplary procedures
described below.
0267 Compounds of formula 5 can be prepared using the
methodology described in International Patent Application
NHAC
N
N1N1 S
CHBr O NHR i
1. NaN3
2. HH

Publication No. WO 2009/016119 to Wagner et al., entitled C N2 21

“Substituted N-Heterocyclic Arylsulfonylaminomethylphos
2
phonic Acid Derivatives as Medicaments for Treatment of O
Type I and II Diabetes Mellitus and Process for their Prepa
ration.” which is incorporated herein by reference in its NHAC N
entirety. H
N
0268 Compounds of formula 9 can be prepared according N1 N1 N N
to the general procedure set forth below in Example 1 for
synthesis of SRI 10531. NH
l N2 2
R CO2H

SRI 10531
Example 1
3
Synthesis of SRI 10531
0270 A. Compound 1 (4.0 g) was treated with acetic anhy
0269 dride (80 mL) at 150° C. for 30 min. The solvent was evapo
rated and the residue purified by a silica gel column to give a
colorless solid intermediate (3.27 g).
0271 B. To a solution of the intermediate from step (A)
(1.0 g) in 200 mL of anhydrous CC1, 0.2 mL of bromine was
NH2 added and the solution was refluxed for 4 hours. The solvent
was removed and the residue was purified on a column to give
N N N CH3 Ac2O Br2 1.17 g of compound 2 as a colorless Solid.
0272 C. To a solution of 1.869 g of 4-aminobenzoyl-L-
C N2 2 glutamic acid in 10 mL of N,N-dimethylacetamide was added
1.60 g of 2.
0273. The mixture was stirred at room temperature for 48
h. The solvent was evaporated and the residue was purified via
US 2013/0085133 A1
column chromatography over silica gel to give a colorless
solid (0.82 g). This material (100 mg) in 5 mL of N.N-
dimethylacetamide was treated with NaN (100 mg). The
mixture was stirred at 95-100° C. for 5 h. The solution was
then concentrated and the residue purified on a column, fol
lowed by catalytic hydrogenation (Pd C in ethanol, H. 20
psi) to afford SRI 10531 as a colorless solid (65 mg).
0274 Compounds of formula 1 1 can be prepared using the
methodology described in U.S. Patent Application Publica
tion No. 20030187040 to Pevarello et al., entitled “2-Ureidot
hiazole Derivatives, Process for Their Preparation, and Their
Use as Antitumor Agents. Patent US 20030187040, which is
incorporated herein by reference in its entirety See, e.g.,
example 16, Preparation of Imidazol-2-alpyridin-2-yl
methanamine.
0275 Compounds of formula 13 can be prepared accord
ing to the general procedure set forth below in Example 2 for
synthesis of AB00700560.
Example 2
Synthesis of AB00700560
0276
H O
N NH2
microwave
-- -es
Xylene
COH 200°C.
O colorless Solid (3.2 g).
O log to 1-O-benzyl-2,3,4-triacetylribose. Compounds of for
0277. A mixture of 3,4-dihydro-1H-1-benzazepine-2,5-
dione (0.175 g, 1.0 mmol) and anthranilic acid (0.15g, 2.2
mmol) in a 12 mL quartz reaction vessel was irradiated in a
focused monomode microwave reactor at 200° C. for 10 min.
The reaction mixture was cooled, treated with water and the
mixture was basified with conc. aqueous NH-OH. The mix
ture was then extracted with CHCl, dried with anhydrous
NaSO, filtered, and the filtrate was concentrated to dryness
under reduced pressure. The residue obtained was purified by
chromatography over a column of silica using 4% MeOH in
CHCl as the eluent to obtain 0.07 g (18% yield) of the
product.
0278 Compounds of formula 14, can be prepared using
standard nucleoside coupling reactions, for example, by cou
pling 6-azauracil (commercially available) or its analog to
1-O-benzyl-2,3,4-triacetylribose. Compounds of formula 14
Apr. 4, 2013
can be prepared according to the general procedure set forth
below in Example 3 for synthesis of AB00174524.
Example 3
Synthesis of AB00174524
0279
O
O
HO /
O N-N
O O
HC CH
0280 6-AZauridine (5.0 g) and copper sulphate (anhy
drous, 10 g) were Suspended in 125 mL of anhydrous acetone
in an atmosphere of dry argon. To the mixture 0.13 mL of
concentrated sulfuric acid was added and stirred for 64 hours
at room temperature. The mixture was filtered. To the filtrate
was added ammonia/methanol (2 ml), and the solution was
evaporated. The residue was recrystallized from ethyl acetate
and dried in vacuo over POs to give the desired product as a
0281 Compounds of formula 15, can be prepared using
standard nucleoside coupling reactions, for example, by cou
pling triazolylformamide (commercially available) or its ana
mula 15 can be prepared according to the general procedure
set forth above in Example 3.
0282 Compounds of formula 17 can be prepared using the
methodology described in Ouyang et al., Synthesis and Fluo
rescent Properties of 2-(1H-Benzimidazol-2-yl)-phenol
Derivatives, JoURNAL OF HETEROCYCLIC CHEMISTRY 41(3): 359
65 (2004), which is incorporated herein by reference in its
entirety.
Formulations
0283. The compounds of the present disclosure can be
administered by any conventional means available for use in
conjunction with pharmaceuticals, either as individual thera
peutic agents or in a combination of therapeutic agents. They
can be administered alone, but generally administered with a
pharmaceutical carrier selected on the basis of the chosen
route of administration and standard pharmaceutical practice.
The compounds can also be administered in conjunction with
other therapeutic agents.
0284. The pharmaceutically acceptable carriers described
herein, for example, vehicles, adjuvants, excipients, or dilu
ents, are well-known to those who are skilled in the art.
Typically, the pharmaceutically acceptable carrier is chemi
cally inert to the active compounds and has no detrimental
side effects or toxicity under the conditions of use. The phar
maceutically acceptable carriers can include polymers and
polymer matrices.
US 2013/0085133 A1
79
0285. The compounds of this disclosure can be adminis
tered by any conventional method available for use in con
junction with pharmaceuticals, either as individual therapeu
tic agents or in a combination of therapeutic agents.
0286 The dosage administered will, of course, vary
depending upon known factors, such as the pharmacody
namic characteristics of the particular agent and its mode and
route of administration; the age, health and weight of the
recipient; the nature and extent of the symptoms; the kind of
concurrent treatment; the frequency of treatment; and the
effect desired. A daily dosage of active ingredient can be
expected to be about 0.001 to 1000 milligrams (mg) per
kilogram (kg) of body weight, with the preferred dose being
0.1 to about 30 mg/kg.
0287 Dosage forms (compositions suitable for adminis
tration) typically contain from about 1 mg to about 500 mg of
active ingredient per unit. In these pharmaceutical composi
tions, the active ingredient will ordinarily be present in an
amount of about 0.5-95% weight based on the total weight of
the composition.
0288 The active ingredient can be administered orally in
Solid dosage forms, such as capsules, tablets, and powders, or
in liquid dosage forms, such as elixirs, syrups and Suspen
sions. It can also be administered parenterally, insterile liquid
dosage forms. The active ingredient can also be administered
intranasally (nose drops) or by inhalation of a drug powder
mist. Other dosage forms are potentially possible Such as
administration transdermally, via patch mechanism or oint
ment.
0289 Formulations suitable for oral administration can
consist of (a) liquid solutions, such as an effective amount of
the compound dissolved in diluents, such as water, Saline, or
orange juice; (b) capsules, Sachets, tablets, lozenges, and
troches, each containing a predetermined amount of the
active ingredient, as Solids or granules; (c) powders; (d) Sus
pensions in an appropriate liquid; and (e) Suitable emulsions.
Liquid formulations may include diluents, such as water and
alcohols, for example, ethanol, benzyl alcohol, propylene
glycol, glycerin, and the polyethylene alcohols, either with or
without the addition of a pharmaceutically acceptable Surfac
tant, Suspending agent, or emulsifying agent. Capsule forms
can be of the ordinary hard- or soft-shelled gelatin type con
taining, for example, Surfactants, lubricants, and inert fillers,
Such as lactose. Sucrose, calcium phosphate, and corn starch.
Tablet forms can include one or more of the following: lac
tose, Sucrose, mannitol, corn starch, potato starch, alginic
acid, microcrystalline cellulose, acacia, gelatin, guar gum,
colloidal silicon dioxide, croscarmellose sodium, talc, mag
nesium Stearate, calcium Stearate, Zinc Stearate, Stearic acid,
and other excipients, colorants, diluents, buffering agents,
disintegrating agents, moistening agents, preservatives, fla
Voring agents, and pharmacologically compatible carriers.
Lozenge forms can comprise the active ingredient in a flavor,
usually Sucrose and acacia or tragacanth, as well as pastilles
comprising the active ingredient in an inert base. Such as
gelatin and glycerin, or Sucrose and acadia, emulsions, and
gels containing, in addition to the active ingredient, Such
carriers as are known in the art.
0290 The compounds of the present disclosure, alone or
in combination with other Suitable components, can be made
into aerosol formulations to be administered via inhalation.
These aerosol formulations can be placed into pressurized
acceptable propellants, such as dichlorodifluoromethane,
Apr. 4, 2013
propane, and nitrogen. They also may be formulated as phar
maceuticals for non-pressured preparations, such as in a
nebulizer or an atomizer.
0291 Formulations suitable for parenteral administration
include aqueous and non-aqueous, isotonic sterile injection
Solutions, which can contain anti-oxidants, buffers, bacteri
ostats, and solutes that render the formulation isotonic with
the blood of the intended recipient, and aqueous and non
aqueous sterile Suspensions that can include Suspending
agents, solubilizers, thickening agents, stabilizers, and pre
servatives. The compound can be administered in a physi
ologically acceptable diluent in a pharmaceutical carrier,
Such as a sterile liquid or mixture of liquids, including water,
saline, aqueous dextrose and related Sugar Solutions, an alco
hol. Such as ethanol, isopropanol, or hexadecyl alcohol, gly
cols, such as propylene glycol or polyethylene glycol Such as
poly(ethyleneglycol) 400, glycerol ketals, such as 2.2-dim
ethyl-1,3-dioxolane-4-methanol, ethers, an oil, a fatty acid, a
fatty acid ester or glyceride, or an acetylated fatty acid glyc
eride with or without the addition of a pharmaceutically
acceptable Surfactant. Such as a Soap or a detergent, Suspend
ing agent, such as pectin, carbomers, methylcellulose,
hydroxypropylmethylcellulose, or carboxymethylcellulose,
or emulsifying agents and other pharmaceutical adjuvants.
0292 Oils, which can be used in parenteral formulations
include petroleum, animal, vegetable, or synthetic oils. Spe
cific examples of oils include peanut, soybean, Sesame, cot
tonseed, corn, olive, petrolatum, and mineral. Suitable fatty
acids for use in parenteral formulations include oleic acid,
Stearic acid, and isostearic acid. Ethyl oleate and isopropyl
myristate are examples of suitable fatty acid esters. Suitable
Soaps for use in parenteral formulations include fatty alkali
metal, ammonium, and triethanolamine salts, and Suitable
detergents include (a) cationic detergents such as, for
example, dimethyldialkylammonium halides, and alkylpyri
dinium halides, (b) anionic detergents such as, for example,
alkyl, aryl, and olefin Sulfonates, alkyl, olefin, ether, and
monoglyceride Sulfates, and Sulfo Succinates, (c) nonionic
detergents such as, for example, fatty amine oxides, fatty acid
alkanolamides, and polyoxyethylene polypropylene copoly
mers, (d) amphoteric detergents such as, for example, alkyl
B-aminopropionates, and 2-alkylimidazoline quaternary
ammonium salts, and (e) mixtures thereof.
0293. The parenteral formulations typically contain from
about 0.5% to about 25% by weight of the active ingredient in
solution. Suitable preservatives and buffers can be used in
Such formulations. In order to minimize or eliminate irritation
at the site of injection, such compositions may contain one or
more nonionic Surfactants having a hydrophile-lipophile bal
ance (HLB) of from about 12 to about 17. The quantity of
Surfactant in Such formulations ranges from about 5% to
about 15% by weight. Suitable surfactants include polyeth
ylene Sorbitan fatty acid esters, such as Sorbitan monooleate
and the high molecular weight adducts of ethylene oxide with
a hydrophobic base, formed by the condensation of propylene
oxide with propylene glycol.
0294 Pharmaceutically acceptable excipients are also
well-known to those who are skilled in the art. The choice of
excipient will be determined in part by the particular com
pound, as well as by the particular method used to administer
the composition. Accordingly, there is a wide variety of Suit
able formulations of the pharmaceutical composition of the
present disclosure. The following methods and excipients are
merely exemplary and are in no way limiting. The pharma
US 2013/0085133 A1
ceutically acceptable excipients preferably do not interfere
with the action of the active ingredients and do not cause
adverse side-effects. Suitable carriers and excipients include
Solvents such as water, alcohol, and propylene glycol, Solid
absorbants and diluents, Surface active agents, Suspending
agent, tableting binders, lubricants, flavors, and coloring
agents.
0295 The formulations can be presented in unit-dose or
multi-dose sealed containers, such as ampules and vials, and
can be stored in a freeze-dried (lyophilized) condition requir
ing only the addition of the sterile liquid excipient, for
example, water, for injections, immediately prior to use.
Extemporaneous injection Solutions and Suspensions can be
prepared from Sterile powders, granules, and tablets. The
requirements for effective pharmaceutical carriers for inject
able compositions are well known to those of ordinary skill in
the art. See Pharmaceutics and Pharmacy Practice, J.B. Lip
pincott Co., Philadelphia, Pa., Banker and Chalmers, Eds.
238-250 (1982) and ASHP Handbook on Injectable Drugs,
Toissel, 4th ed., 622-630 (1986).
0296 Formulations suitable for topical administration
include lozenges comprising the active ingredient in a flavor,
usually Sucrose and acacia or tragacanth; pastilles comprising
the active ingredient in an inert base, such as gelatin and
glycerin, or Sucrose and acacia; and mouthwashes compris
ing the active ingredient in a suitable liquid carrier, as well as
creams, emulsions, and gels containing, in addition to the
active ingredient, Such carriers as are known in the art.
0297. Additionally, formulations suitable for rectal
administration may be presented as Suppositories by mixing
with a variety of bases Such as emulsifying bases or water
soluble bases. Formulations suitable for vaginal administra
tion may be presented as pessaries, tampons, creams, gels,
pastes, foams, or spray formulas containing, in addition to the
active ingredient, such carriers as are known in the art to be
appropriate.
0298 Suitable pharmaceutical carriers are described in
Remington’s Pharmaceutical Sciences, Mack Publishing
Company, a standard reference text in this field.
0299 The dose administered to an animal, particularly a
human, in the context of the present disclosure should be
Sufficient to affect a therapeutic response in the animal over a
reasonable time frame. One skilled in the art will recognize
that dosage will depend upon a variety of factors including a
condition of the animal, the body weight of the animal, as well
as the severity and stage of the condition being treated.
0300. A suitable dose is that which will result in a concen
tration of the active agentina patient which is known to affect
the desired response. The preferred dosage is the amount
which results in maximum inhibition of the condition being
treated, without unmanageable side effects.
0301 The size of the dose also will be determined by the
route, timing and frequency of administration as well as the
existence, nature, and extend of any adverse side effects that
might accompany the administration of the compound and
the desired physiological effect.
0302) Useful pharmaceutical dosage forms for adminis
tration of the compounds according to the present disclosure
can be illustrated as follows:
Hard Shell Capsules
0303 A large number of unit capsules are prepared by
filling standard two-piece hard gelatine capsules each with
Apr. 4, 2013
100 mg of powdered active ingredient, 150 mg of lactose, 50
mg of cellulose and 6 mg of magnesium Stearate.
Soft Gelatin Capsules
0304. A mixture of active ingredient in a digestible oil
Such as soybean oil, cottonseed oil or olive oil is prepared and
injected by means of a positive displacement pump into mol
ten gelatin to form Soft gelatin capsules containing 100 mg of
the active ingredient. The capsules are washed and dried. The
active ingredient can be dissolved in a mixture of polyethyl
ene glycol, glycerin and Sorbitol to prepare a water miscible
medicine mix.
Tablets
0305. A large number of tablets are prepared by conven
tional procedures so that the dosage unit was 100 mg of active
ingredient, 0.2 mg. of colloidal silicon dioxide, 5 mg of mag
nesium Stearate, 275 mg of microcrystalline cellulose, 11 mg.
of starch, and 98.8 mg of lactose. Appropriate aqueous and
non-aqueous coatings may be applied to increase palatability,
improve elegance and stability or delay absorption.
Immediate Release Tablets/Capsules
0306 These are solid oral dosage forms made by conven
tional and novel processes. These units are taken orally with
out water for immediate dissolution and delivery of the medi
cation. The active ingredient is mixed in a liquid containing
ingredient Such as Sugar, gelatin, pectin and Sweeteners.
These liquids are solidified into solid tablets or caplets by
freeze drying and solid state extraction techniques. The drug
compounds may be compressed with viscoelastic and ther
moelastic Sugars and polymers or effervescent components to
produce porous matrices intended for immediate release,
without the need of water.
0307 Moreover, the compounds of the present disclosure
can be administered in the form of nose drops, or metered
dose and a nasal or buccal inhaler. The drug is delivered from
a nasal Solution as a fine mist or from a powder as an aerosol.
0308 All publications, patents and patent applications
cited in this specification are herein incorporated by refer
ence, and for any and all purpose, as if each individual pub
lication, patent or patent application were specifically and
individually indicated to be incorporated by reference. In the
case of inconsistencies, the present disclosure will prevail.
0309 The foregoing description of the disclosure illus
trates and describes the present disclosure. Additionally, the
disclosure shows and describes only the preferred embodi
ments but, as mentioned above, it is to be understood that the
disclosure is capable of use in various other combinations,
modifications, and environments and is capable of changes or
modifications within the scope of the concept as expressed
herein, commensurate with the above teachings and/or the
skill or knowledge of the relevant art.
0310. The embodiments described hereinabove are further
intended to explain best modes known of practicing it and to
enable others skilled in the art to utilize the disclosure in such,
or other, embodiments and with the various modifications
required by the particular applications or uses. Accordingly,
the description is not intended to limit it to the form disclosed
herein. Also, it is intended that the appended claims be con
strued to include alternative embodiments.
US 2013/0085133 A1 Apr. 4, 2013
81

What is claimed is: -continued

1. A method for treating a human infected with a virus by Air NRR2,
administering to said human an effective amount of at least
one compound represented by the formulas 16, 46, 1, 7, 17.
5, 3, 2, 18, 19, 11, 9, 8, 10, 12, 13, 14 and 15 below:
sts O
18

16
R2 X

RI S
X- R3, 19

O / \ O
Arl )-( )
11

NR3R
N
N1 N1 N nNR5R6,
R2RN - N- 21 a.
R2 O R8

Na OR, R7

1. R4 N 1. N Y R1
R1 R R2
N
17
R4
2
R5 N R3,
R N
R4

R
2 N
X-R,
V
O
10

R6
R
R4 1. XR5,
R3
n

R2 2N
RI XAir
12
COR
US 2013/0085133 A1 Apr. 4, 2013
82

-continued cycloalkyl, substituted or unsubstituted heterocyclic,

6
13 hydroxy, alkoxy, carbonyloxy, halogen, azido, cyano,
R R7 nitro, alkylthio, carboxyl, carboxylate esters, carboxa
mido, amino, and mono- or di-substituted amino;
R3 wherein in formula 4,
R8 n=0, 1, or 2.
Ar" may be attached directly to the nitrogenatom without
the linking carbonyl group and if both carbonyl groups
are present, then one of the nitrogen atoms may be
replaced by carbon;
Ar' and Arare each independently chosen from the group
consisting of Substituted or unsubstituted aryl, Substi
tuted or unsubstituted arylalkyl, substituted or unsubsti
tuted heteroaryl, substituted or unsubstituted cycloalkyl,
and substituted or unsubstituted heterocyclic;
wherein in formula 6,
n=1, 2, or 3:
R" is chosen from the group consisting of Substituted or
unsubstituted alkyl, substituted or unsubstituted unsat
14 urated alkyl, substituted or unsubstituted aryl, substi
tuted or unsubstituted heteroaryl, substituted or unsub
stituted arylalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocyclic,
hydroxy, alkoxy, alkylthio, amino, and mono- or di
Substituted amino;
R is chosen from the group consisting of hydrogen, Sub
stituted or unsubstituted alkyl, substituted or unsubsti
tuted unsaturated alkyl, substituted or unsubstituted
aryl; substituted or unsubstituted heteroaryl, substituted
or unsubstituted arylalkyl, substituted or unsubstituted
15 cycloalkyl, substituted or unsubstituted heterocyclic,
O acyl, carboxylate esters, and carboxamido;
R-R are each independently chosen from the group con
Y
NHR or sisting of hydrogen, Substituted or unsubstituted alkyl,
substituted or unsubstituted unsaturated alkyl, substi
1 \,
Y. Y tuted or unsubstituted aryl, substituted or unsubstituted
X3 NY heteroaryl, substituted or unsubstituted arylalkyl, sub
stituted or unsubstituted cycloalkyl, substituted or

X2
- XI
wherein in formula 1,
a pharmaceutically acceptable salt thereof, a solvate
thereof, or a prodrug thereof;
wherein in formula 16,
X is chosen from the group consisting of N and C.
R", R, and Rare independently chosen from the group
consisting of hydrogen, Substituted or unsubstituted
alkyl, substituted or unsubstituted unsaturated alkyl,
substituted or unsubstituted aryl, substituted or unsub
stituted heteroaryl, substituted or unsubstituted aryla
lkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocyclic, hydroxy, alkoxy, carbony
loxy, halogen, azido, cyano, nitro, alkylthio, carboxyl,
carboxylate esters, carboxamido, amino, and mono- or
di-substituted amino;
if X—C, it may be further independently substituted by a
group from the group consisting of hydrogen; Substi
tuted or unsubstituted alkyl, substituted or unsubstituted
unsaturated alkyl, substituted or unsubstituted aryl, sub
stituted or unsubstituted heteroaryl, substituted or
unsubstituted arylalkyl, substituted or unsubstituted
unsubstituted heterocyclic, hydroxy, alkoxy, carbony
loxy, halogen, azido, cyano, nitro, alkylthio, carboxyl,
carboxylate esters, carboxamido, amino, and mono- or
di-substituted amino;
each R" and R is independently chosen from the group
consisting of hydrogen, Substituted or unsubstituted
alkyl, substituted or unsubstituted alkyl, substituted or
unsubstituted aryl, substituted or unsubstituted het
eroaryl, substituted or unsubstituted arylalkyl, substi
tuted or unsubstituted cycloalkyl, substituted or unsub
stituted heterocyclic, hydroxy, alkoxy, carbonyloxy,
halogen, azido, cyano, nitro, alkylthio, carboxyl, car
boxylate ester, carboxamido, amino, and mono- or di
Substituted amino;
wherein in formula 7.
X is chosen from oxygen and Sulfur,
R" is chosen from the group consisting of hydrogen, Sub
stituted or unsubstituted alkyl, substituted or unsubsti
tuted unsaturated alkyl, substituted or unsubstituted
aryl, substituted or unsubstituted heteroaryl, substituted
or unsubstituted arylalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocyclic
including glycosyl rings, acyl, carboxylate esters, and
carboxamido;
US 2013/0085133 A1
83
RandR are each independently chosen from the group
consisting of hydrogen, Substituted or unsubstituted
alkyl, substituted or unsubstituted unsaturated alkyl,
substituted or unsubstituted aryl, substituted or unsub
stituted heteroaryl, substituted or unsubstituted aryla
lkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocyclic, hydroxy, alkoxy, carbony
loxy, halogen, azido, cyano, nitro, alkylthio, carboxyl,
carboxylate esters, carboxamido, amino, and mono- or
di-substituted amino;
R is chosen from the group consisting of hydrogen, Sub
stituted or unsubstituted alkyl, substituted or unsubsti
tuted unsaturated alkyl, substituted or unsubstituted
aryl, substituted or unsubstituted heteroaryl, substituted
or unsubstituted arylalkyl, substituted or unsubstituted
cycloalkyl, and substituted or unsubstituted heterocy
clic;
wherein in formula 17,
R" through R are independently chosen from the group
consisting of hydrogen, Substituted or unsubstituted
alkyl, substituted or unsubstituted unsaturated alkyl,
substituted or unsubstituted aryl, substituted or unsub
stituted heteroaryl, substituted or unsubstituted aryla
lkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocyclic, hydroxy, alkoxy, carbony
loxy, halogen, azido, cyano, nitro, alkylthio, carboxyl,
carboxylate esters, carboxamido, amino, and mono- or
di-substituted amino;
R is chosen from the group consisting of hydrogen, sub
stituted or unsubstituted alkyl, substituted or unsubsti
tuted unsaturated alkyl; substituted or unsubstituted
aryl, substituted or unsubstituted heteroaryl, substituted
or unsubstituted arylalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocyclic,
acyl, carboxylate esters, and carboxamido;
wherein in formula 5,
the ring designated C is optional but if present may be
Saturated or partially or fully unsaturated;
if ring C is absent, then the pyrrole ring may optionally
have one or two additional Substituents instead;
X is substituted or unsubstituted carbon or substituted or
unsubstituted nitrogen;
R'-R, R, and R when X=C, are each independently
chosen from the group consisting of hydrogen, Substi
tuted or unsubstituted alkyl, substituted or unsubstituted
unsaturated alkyl, substituted or unsubstituted aryl, sub
stituted or unsubstituted heteroaryl, substituted or
unsubstituted arylalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocyclic,
hydroxy, alkoxy, carbonyloxy, halogen, azido, cyano,
nitro, alkylthio, carboxyl, carboxylate esters, carboxa
mido, amino, and mono- or di-substituted amino;
when ring C is absent, then the one or two additional
Substituents on the pyrrole ring, if present, are indepen
dently chosen from the group consisting of hydrogen,
substituted or unsubstituted alkyl, substituted or unsub
stituted unsaturated alkyl, substituted or unsubstituted
aryl, substituted or unsubstituted heteroaryl, substituted
or unsubstituted arylalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocyclic,
hydroxy, alkoxy, carbonyloxy, halogen, azido, cyano,
nitro, alkylthio, carboxyl, carboxylate esters, carboxa
mido, amino, and mono- or di-substituted amino;
Apr. 4, 2013
R when X=N, and R are each independently chosen
from the group consisting of hydrogen, Substituted or
unsubstituted alkyl, substituted or unsubstituted unsat
urated alkyl, substituted or unsubstituted aryl, substi
tuted or unsubstituted heteroaryl, substituted or unsub
stituted arylalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocyclic,
acyl; carboxyl, carboxylate esters, and carboxamido;
wherein in formula 3,
X is chosen from oxygen or Substituted nitrogen,
R", R, and R are independently chosen from the group
consisting of hydrogen, Substituted or unsubstituted
alkyl, substituted or unsubstituted unsaturated alkyl,
substituted or unsubstituted aryl, substituted or unsub
stituted heteroaryl, substituted or unsubstituted aryla
lkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocyclic, hydroxy, alkoxy, carbony
loxy, halogen, azido, cyano, nitro, alkylthio, carboxyl,
carboxylate esters, carboxamido, amino, and mono- or
di-substituted amino;
R is chosen from the group consisting of hydrogen, Sub
stituted or unsubstituted alkyl, substituted or unsubsti
tuted unsaturated alkyl, substituted or unsubstituted
aryl, substituted or unsubstituted heteroaryl, substituted
or unsubstituted arylalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocyclic,
acyl, carboxyl, carboxylate esters, and carboxamido;
wherein in formula 2,
n=1, 2, or 3:
X is chosen from Sulfur, oxygen, and Substituted or unsub
stituted nitrogen;
Ar is chosen from the group consisting of Substituted or
unsubstituted aryl, substituted or unsubstituted aryla
lkyl, substituted or unsubstituted heteroaryl, substituted
or unsubstituted cycloalkyl, or substituted or unsubsti
tuted heterocyclic;
R" and Rare independently chosen from the group con
sisting of hydrogen, Substituted or unsubstituted alkyl,
substituted or unsubstituted unsaturated alkyl; substi
tuted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted arylalkyl, sub
stituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocyclic, and acyl:
wherein in formula 18,
X is chosen from the group consisting of O, S, and N:
R" and Rare independently chosen from the group con
sisting of hydrogen, Substituted or unsubstituted alkyl,
substituted or unsubstituted unsaturated alkyl, substi
tuted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted arylalkyl, sub
stituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocyclic, hydroxy, alkoxy, carbony
loxy, halogen, azido, cyano, nitro, alkylthio, carboxyl,
carboxylate esters, carboxamido, amino, and mono- or
di-substituted amino;
if X—N, then it is substituted by a moiety chosen from the
group consisting of hydrogen, Substituted or unsubsti
tuted alkyl, substituted or unsubstituted unsaturated
alkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
arylalkyl, substituted or unsubstituted cycloalkyl, sub
stituted or unsubstituted heterocyclic, acyl, carboxylate
esters, and carboxamido;
US 2013/0085133 A1
84
wherein in formula 19,
if n=0, the substituent R' does not occur;
X is chosen from the group consisting of C, O, S, and N:
if X=C or X=N, then it may substituted by a group R':
if X=O or X=S, then substituent R" does not occur;
if n=1 and X=C or N, then the bond to X internal to the
seven-membered ring may optionally be unsaturated;
R" and R' in the case X=N, are independently chosen
from the group consisting of hydrogen, Substituted or
unsubstituted alkyl, substituted or unsubstituted unsat
urated alkyl, substituted or unsubstituted aryl, substi
tuted or unsubstituted heteroaryl, substituted or unsub
stituted arylalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocyclic,
acyl, carboxylate esters, and carboxamido;
R through R. R' in the caseX—C, and substituent R'' in
the case n=1, are independently chosen from the group
consisting of hydrogen, Substituted or unsubstituted
alkyl, substituted or unsubstituted unsaturated alkyl,
substituted or unsubstituted aryl, substituted or unsub
stituted heteroaryl, substituted or unsubstituted aryla
lkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocyclic, hydroxy, alkoxy, carbony
loxy, halogen, azido, cyano, nitro, alkylthio, carboxyl,
carboxylate esters, carboxamido, amino, and mono- or
di-substituted amino.
wherein in formula 1 1,
X and Y are independently chosen from C and N:
R" through R" are independently chosen from the group
consisting of hydrogen; Substituted or unsubstituted
alkyl, substituted or unsubstituted unsaturated alkyl,
substituted or unsubstituted aryl, substituted or unsub
stituted heteroaryl, substituted or unsubstituted aryla
lkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocyclic, hydroxy, alkoxy, carbony
loxy, halogen, azido, cyano, nitro, alkylthio, carboxyl,
carboxylate esters, carboxamido, amino, and mono- or
di-substituted amino;
if X—C or Y—C, then either may independently be sub
stituted by additional R moieties chosen from the group
consisting of hydrogen; Substituted or unsubstituted
alkyl, substituted or unsubstituted unsaturated alkyl,
substituted or unsubstituted aryl, substituted or unsub
stituted heteroaryl, substituted or unsubstituted aryla
lkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocyclic, hydroxy, alkoxy, carbony
loxy, halogen, azido, cyano, nitro, alkylthio, carboxyl,
carboxylate esters, carboxamido, amino, and mono- or
di-substituted amino;
wherein in formula 9,
n=0, 1, or 2:
R" through R are independently chosen from the group
consisting of hydrogen, Substituted or unsubstituted
alkyl, substituted or unsubstituted unsaturated alkyl,
substituted or unsubstituted aryl, substituted or unsub
stituted heteroaryl, substituted or unsubstituted aryla
lkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocyclic, acyl, carboxylate esters,
and carboxamido;
R" and Rare independently chosen from the group con
sisting of hydrogen, Substituted or unsubstituted alkyl,
substituted or unsubstituted unsaturated alkyl, substi
tuted or unsubstituted aryl, substituted or unsubstituted
Apr. 4, 2013
heteroaryl, substituted or unsubstituted arylalkyl, sub
stituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocyclic, hydroxy, alkoxy, carbony
loxy, halogen, azido, cyano, nitro, alkylthio, carboxyl,
carboxylate esters, carboxamido, amino, and mono- or
di-substituted amino;
wherein in formula 8,
R" is chosen from the group consisting of hydrogen, Sub
stituted or unsubstituted alkyl, substituted or unsubsti
tuted unsaturated alkyl, substituted or unsubstituted
aryl, substituted or unsubstituted heteroaryl, substituted
or unsubstituted arylalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocyclic,
acyl, carboxylate esters, and carboxamido;
R’ through R" are each independently chosen from the
group consisting of hydrogen, Substituted or unsubsti
tuted alkyl, substituted or unsubstituted unsaturated
alkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
arylalkyl, substituted or unsubstituted cycloalkyl, sub
stituted or unsubstituted heterocyclic, hydroxy, alkoxy,
carbonyloxy, halogen, azido, cyano, nitro, alkylthio, car
boxyl, carboxylate esters, carboxamido, amino, and
mono- or di-substituted amino;
wherein in formula 10,
n=0, 1, or 2:
X is chosen from the group consisting of N, O, and S;
R" through R are independently chosen from the group
consisting of hydrogen, substituted or unsubstituted
alkyl, substituted or unsubstituted unsaturated alkyl,
substituted or unsubstituted aryl, substituted or unsub
stituted heteroaryl, substituted or unsubstituted aryla
lkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocyclic, hydroxy, alkoxy, carbony
loxy, halogen, azido, cyano, nitro, alkylthio, carboxyl,
carboxylate esters, carboxamido, amino, and mono- or
di-substituted amino;
R is chosen from the group consisting of hydrogen, Sub
stituted or unsubstituted alkyl, substituted or unsubsti
tuted unsaturated alkyl, substituted or unsubstituted
aryl, substituted or unsubstituted heteroaryl, substituted
or unsubstituted arylalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocyclic,
acyl, carboxylate esters, and carboxamido;
Ar is chosen from the group consisting of hydrogen, Sub
stituted or unsubstituted aryl, substituted or unsubsti
tuted heteroaryl, substituted or unsubstituted arylalkyl,
substituted or unsubstituted cycloalkyl, and substituted
or unsubstituted heterocyclic;
wherein in formula 12,
R" is chosen from the group consisting of hydrogen, Sub
stituted or unsubstituted alkyl, substituted or unsubsti
tuted unsaturated alkyl, substituted or unsubstituted
aryl, substituted or unsubstituted heteroaryl, substituted
or unsubstituted arylalkyl, substituted or unsubstituted
cycloalkyl, and substituted or unsubstituted heterocy
clic;
R° through R" are independently chosen from the group
consisting of hydrogen, Substituted or unsubstituted
alkyl, substituted or unsubstituted unsaturated alkyl,
substituted or unsubstituted aryl, substituted or unsub
stituted heteroaryl, substituted or unsubstituted aryla
lkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocyclic, hydroxy, alkoxy, carbony
US 2013/0085133 A1 Apr. 4, 2013
85

loxy, halogen, azido, cyano, nitro, alkylthio, carboxyl, stituted or unsubstituted cycloalkyl, substituted or
carboxylate esters, carboxamido, amino, and mono- or unsubstituted heterocyclic, acyl, carboxylate esters, and
di-substituted amino; carboxamido;
Ar is chosen from the group consisting of hydrogen, Sub whenever any of X, X, and X is C, they may additionally
stituted or unsubstituted aryl, substituted or unsubsti be substituted from the group consisting of hydroxy,
tuted heteroaryl, substituted or unsubstituted arylalkyl, alkoxy, carbonyloxy, halogen, azido, cyano, nitro, alky
substituted or unsubstituted cycloalkyl, and substituted lthio, carboxyl, amino, and mono- or di-substituted
or unsubstituted heterocyclic;
wherein in formula 13, amino;
R" through R', R'' and R' are independently chosen Y', Y, and Y are independently chosen from the group
from the group consisting of hydrogen, Substituted or consisting of N and C.
unsubstituted alkyl, substituted or unsubstituted unsat R is chosen from the group consisting of hydrogen, Substi
urated alkyl, substituted or unsubstituted aryl, substi tuted or unsubstituted alkyl, substituted or unsubstituted
tuted or unsubstituted heteroaryl, substituted or unsub unsaturated alkyl, substituted or unsubstituted aryl, sub
stituted arylalkyl, substituted or unsubstituted stituted or unsubstituted heteroaryl, substituted or
cycloalkyl, substituted or unsubstituted heterocyclic,
hydroxy, alkoxy, carbonyloxy, halogen, azido, cyano, unsubstituted arylalkyl, substituted or unsubstituted
nitro, alkylthio, carboxyl, carboxylate esters, carboxa cycloalkyl, substituted or unsubstituted heterocyclic,
mido, amino, and mono- or di-substituted amino; acyl, carboxylate esters, and carboxamido.
R" is chosen from the group consisting of hydrogen, Sub 2. The method of claim 1 wherein the virus is a respiratory
stituted or unsubstituted alkyl, substituted or unsubsti virus.
tuted unsaturated alkyl, substituted or unsubstituted 3. The method of claim 1 wherein the virus is selected from
aryl, substituted or unsubstituted heteroaryl, substituted
or unsubstituted arylalkyl, substituted or unsubstituted the group consisting of the families Paramyxoviridae, human
cycloalkyl, substituted or unsubstituted heterocyclic, metapneumovirus, human parainfluenza virus, measles virus,
acyl, carboxylate esters, and carboxamido; and mumps virus.
wherein in formula 14, 4. The method of claim 1 wherein the virus is respiratory
X', X, and X are independently chosen from the group syncytial virus.
consisting of O, S, N, C, and halogen; 5. A method for preventing virus-induced cytopathic effect
whenever any of X, X, and X is not halogen, they may be (CPE) in a human patient for protection against infections
independently further substituted from the group con which comprises administering to said human an effective
sisting of hydrogen, Substituted or unsubstituted alkyl, amount of at least one compound represented by formulas 16,
substituted or unsubstituted unsaturated alkyl, substi 4, 6, 1, 7, 17, 5, 3, 2, 18, 19, 11, 9, 8, 10, 12, 13, 14 and 15,
tuted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted arylalkyl, sub
stituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocyclic, acyl, carboxylate esters, and 2
16
carboxamido;
whenever any of X, X, and X is C, they may additionally
be substituted from the group consisting of hydroxy,
alkoxy, carbonyloxy, halogen, azido, cyano, nitro, alky
lthio, carboxyl, amino, and mono- or di-substituted
R1 O)- S
4
amino; O / \ O
the R group is chosen from the group consisting of hydro
gen, substituted or unsubstituted alkyl, substituted or Arl
)-(\–4.) Ar,
unsubstituted unsaturated alkyl, substituted or unsubsti
tuted aryl, substituted or unsubstituted heteroaryl, sub R3 R4
6
stituted or unsubstituted arylalkyl, substituted or unsub
stituted cycloalkyl, substituted or unsubstituted O
heterocyclic, hydroxy, alkoxy, carbonyloxy, halogen,
azido, cyano, nitro, alkylthio, carboxyl, carboxylate R2 R5,
esters, carboxamido, amino, and mono- or di-substituted
amino; pi R6
wherein in formula 15, O O
X', X, and X’ are independently chosen from the group 1
consisting of O, S, N, C, and halogen; RI
whenever any of these groups is not halogen, they may be
independently further substituted from the group con
sisting of hydrogen, Substituted or unsubstituted alkyl, N
X-y- N R2,
substituted or unsubstituted unsaturated alkyl, substi
tuted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted arylalkyl, sub
US 2013/0085133 A1 Apr. 4, 2013
86

-continued -continued

R2 O

Na OR3,
1. R4
R1
17
R4
3
R N

2 N
X- R5,
R V
R6
R

10

X 3
R2 N
R

RI
) \, y-,
S N
12

Air NRR2,
Nx pi

13
US 2013/0085133 A1
87
-continued
O
14
R, or
HN
X3- O 1. N1 N
O stituted or unsubstituted alkyl, substituted or unsubsti
X2 XI
O
15
NHR or
Y substituted or unsubstituted unsaturated alkyl, substi
Y. | \, Y
X3 NY
O
X2 XI
wherein in formula 1,
a pharmaceutically acceptable salt thereof, a solvate
thereof, or a prodrug thereof;
wherein in formula 16,
X is chosen from the group consisting of N and C:
R", R, and Rare independently chosen from the group
consisting of hydrogen, Substituted or unsubstituted
alkyl, substituted or unsubstituted unsaturated alkyl,
substituted or unsubstituted aryl, substituted or unsub
stituted heteroaryl, substituted or unsubstituted aryla
lkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocyclic, hydroxy, alkoxy, carbony
loxy, halogen, azido, cyano, nitro, alkylthio, carboxyl,
carboxylate esters, carboxamido, amino, and mono- or
di-substituted amino;
if X—C, it may be further independently substituted by a
group from the group consisting of hydrogen; Substi
tuted or unsubstituted alkyl, substituted or unsubstituted
unsaturated alkyl, substituted or unsubstituted aryl, sub
stituted or unsubstituted heteroaryl, substituted or
unsubstituted arylalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocyclic,
hydroxy, alkoxy, carbonyloxy, halogen, azido, cyano,
nitro, alkylthio, carboxyl, carboxylate esters, carboxa
mido, amino, and mono- or di-substituted amino;
wherein in formula 4,
n=0, 1, or 2:
Ar' may be attached directly to the nitrogenatom without
the linking carbonyl group and if both carbonyl groups
are present, then one of the nitrogen atoms may be
replaced by carbon;
Ar' and Arare each independently chosen from the group
consisting of Substituted or unsubstituted aryl, Substi
tuted or unsubstituted arylalkyl, substituted or unsubsti
tuted heteroaryl, substituted or unsubstituted cycloalkyl,
and substituted or unsubstituted heterocyclic;
wherein in formula 6,
n=1, 2, or 3:
R" is chosen from the group consisting of Substituted or
unsubstituted alkyl, substituted or unsubstituted unsat
Apr. 4, 2013
urated alkyl, substituted or unsubstituted aryl, substi
tuted or unsubstituted heteroaryl, substituted or unsub
stituted arylalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocyclic,
hydroxy, alkoxy, alkylthio, amino, and mono- or di
Substituted amino;
R is chosen from the group consisting of hydrogen, Sub
tuted unsaturated alkyl, substituted or unsubstituted
aryl; substituted or unsubstituted heteroaryl, substituted
or unsubstituted arylalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocyclic,
acyl, carboxylate esters, and carboxamido;
R-R are each independently chosen from the group con
sisting of hydrogen, Substituted or unsubstituted alkyl,
tuted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted arylalkyl, sub
stituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocyclic, hydroxy, alkoxy, carbony
loxy, halogen, azido, cyano, nitro, alkylthio, carboxyl,
carboxylate esters, carboxamido, amino, and mono- or
di-substituted amino;
each R" and R is independently chosen from the group
consisting of hydrogen, Substituted or unsubstituted
alkyl, substituted or unsubstituted alkyl, substituted or
unsubstituted aryl, substituted or unsubstituted het
eroaryl, substituted or unsubstituted arylalkyl, substi
tuted or unsubstituted cycloalkyl, substituted or unsub
stituted heterocyclic, hydroxy, alkoxy, carbonyloxy,
halogen, azido, cyano, nitro, alkylthio, carboxyl, car
boxylate ester, carboxamido, amino, and mono- or di
Substituted amino;
wherein in formula 7.
X is chosen from oxygen and Sulfur,
R" is chosen from the group consisting of hydrogen, Sub
stituted or unsubstituted alkyl, substituted or unsubsti
tuted unsaturated alkyl, substituted or unsubstituted
aryl, substituted or unsubstituted heteroaryl, substituted
or unsubstituted arylalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocyclic
including glycosyl rings, acyl, carboxylate esters, and
carboxamido;
R° and Rare each independently chosen from the group
consisting of hydrogen, Substituted or unsubstituted
alkyl, substituted or unsubstituted unsaturated alkyl,
substituted or unsubstituted aryl, substituted or unsub
stituted heteroaryl, substituted or unsubstituted aryla
lkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocyclic, hydroxy, alkoxy, carbony
loxy, halogen, azido, cyano, nitro, alkylthio, carboxyl,
carboxylate esters, carboxamido, amino, and mono- or
di-substituted amino;
R is chosen from the group consisting of hydrogen, Sub
stituted or unsubstituted alkyl, substituted or unsubsti
tuted unsaturated alkyl, substituted or unsubstituted
aryl, substituted or unsubstituted heteroaryl, substituted
or unsubstituted arylalkyl, substituted or unsubstituted
cycloalkyl, and substituted or unsubstituted heterocy
clic;
wherein in formula 17,
R" through R are independently chosen from the group
consisting of hydrogen, Substituted or unsubstituted
US 2013/0085133 A1
88
alkyl, substituted or unsubstituted unsaturated alkyl,
substituted or unsubstituted aryl, substituted or unsub
stituted heteroaryl, substituted or unsubstituted aryla
lkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocyclic, hydroxy, alkoxy, carbony
loxy, halogen, azido, cyano, nitro, alkylthio, carboxyl,
carboxylate esters, carboxamido, amino, and mono- or
di-substituted amino;
R is chosen from the group consisting of hydrogen, Sub
stituted or unsubstituted alkyl, substituted or unsubsti
tuted unsaturated alkyl; substituted or unsubstituted
aryl, substituted or unsubstituted heteroaryl, substituted
or unsubstituted arylalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocyclic,
acyl, carboxylate esters, and carboxamido;
wherein in formula 5,
the ring designated C is optional but if present may be
Saturated or partially or fully unsaturated;
if ring C is absent, then the pyrrole ring may optionally
have one or two additional Substituents instead;
X is substituted or unsubstituted carbon or substituted or
unsubstituted nitrogen;
R'-R, R, and R when X=C, are each independently
chosen from the group consisting of hydrogen, Substi
tuted or unsubstituted alkyl, substituted or unsubstituted
unsaturated alkyl, substituted or unsubstituted aryl, sub
stituted or unsubstituted heteroaryl, substituted or
unsubstituted arylalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocyclic,
hydroxy, alkoxy, carbonyloxy, halogen, azido, cyano,
nitro, alkylthio, carboxyl, carboxylate esters, carboxa
mido, amino, and mono- or di-substituted amino;
when ring C is absent, then the one or two additional
Substituents on the pyrrole ring, if present, are indepen
dently chosen from the group consisting of hydrogen,
substituted or unsubstituted alkyl, substituted or unsub
stituted unsaturated alkyl, substituted or unsubstituted
aryl, substituted or unsubstituted heteroaryl, substituted
or unsubstituted arylalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocyclic,
hydroxy, alkoxy, carbonyloxy, halogen, azido, cyano,
nitro, alkylthio, carboxyl, carboxylate esters, carboxa
mido, amino, and mono- or di-substituted amino;
R when X=N, and R7 are each independently chosen
from the group consisting of hydrogen, Substituted or
unsubstituted alkyl, substituted or unsubstituted unsat
urated alkyl, substituted or unsubstituted aryl, substi
tuted or unsubstituted heteroaryl, substituted or unsub
stituted arylalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocyclic,
acyl; carboxyl, carboxylate esters, and carboxamido;
wherein in formula 3,
X is chosen from oxygen or Substituted nitrogen,
R", R, and Rare independently chosen from the group
consisting of hydrogen, Substituted or unsubstituted
alkyl, substituted or unsubstituted unsaturated alkyl,
substituted or unsubstituted aryl, substituted or unsub
stituted heteroaryl, substituted or unsubstituted aryla
lkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocyclic, hydroxy, alkoxy, carbony
loxy, halogen, azido, cyano, nitro, alkylthio, carboxyl,
carboxylate esters, carboxamido, amino, and mono- or
di-substituted amino;
Apr. 4, 2013
R is chosen from the group consisting of hydrogen, Sub
stituted or unsubstituted alkyl, substituted or unsubsti
tuted unsaturated alkyl, substituted or unsubstituted
aryl, substituted or unsubstituted heteroaryl, substituted
or unsubstituted arylalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocyclic,
acyl, carboxyl, carboxylate esters, and carboxamido;
wherein in formula 2,
n=1, 2, or 3:
X is chosen from Sulfur, oxygen, and Substituted or unsub
stituted nitrogen;
Ar is chosen from the group consisting of Substituted or
unsubstituted aryl, substituted or unsubstituted aryla
lkyl, substituted or unsubstituted heteroaryl, substituted
or unsubstituted cycloalkyl, or substituted or unsubsti
tuted heterocyclic;
R" and Rare independently chosen from the group con
sisting of hydrogen, Substituted or unsubstituted alkyl,
substituted or unsubstituted unsaturated alkyl; substi
tuted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted arylalkyl, sub
stituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocyclic, and acyl:
wherein in formula 18,
X is chosen from the group consisting of O, S, and N:
R" and Rare independently chosen from the group con
sisting of hydrogen, Substituted or unsubstituted alkyl,
substituted or unsubstituted unsaturated alkyl, substi
tuted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted arylalkyl, sub
stituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocyclic, hydroxy, alkoxy, carbony
loxy, halogen, azido, cyano, nitro, alkylthio, carboxyl,
carboxylate esters, carboxamido, amino, and mono- or
di-substituted amino;
if X—N, then it is substituted by a moiety chosen from the
group consisting of hydrogen, Substituted or unsubsti
tuted alkyl, substituted or unsubstituted unsaturated
alkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
arylalkyl, substituted or unsubstituted cycloalkyl, sub
stituted or unsubstituted heterocyclic, acyl, carboxylate
esters, and carboxamido;
wherein in formula 19,
n=0 or 1;
if n=0, the substituent R' does not occur;
X is chosen from the group consisting of C, O, S, and N:
if X=C or X=N, then it may substituted by a group R':
if X=O or X=S, then substituent R' does not occur;
if n=1 and X=C or N, then the bond to X internal to the
seven-membered ring may optionally be unsaturated;
R" and R' in the case X=N, are independently chosen
from the group consisting of hydrogen, Substituted or
unsubstituted alkyl, substituted or unsubstituted unsat
urated alkyl, substituted or unsubstituted aryl, substi
tuted or unsubstituted heteroaryl, substituted or unsub
stituted arylalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocyclic,
acyl, carboxylate esters, and carboxamido;
R° through R. R' in the caseX—C, and substituent R' in
the case n=1, are independently chosen from the group
consisting of hydrogen, Substituted or unsubstituted
alkyl, substituted or unsubstituted unsaturated alkyl,
substituted or unsubstituted aryl, substituted or unsub
US 2013/0085133 A1
89
stituted heteroaryl, substituted or unsubstituted aryla-
lkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocyclic, hydroxy, alkoxy, carbony-
loxy, halogen, azido, cyano, nitro, alkylthio, carboxyl,
carboxylate esters, carboxamido, amino, and mono- or
di-substituted amino.
wherein in formula 1 1,
X and Y are independently chosen from C and N:
R" through R are independently chosen from the group
consisting of hydrogen; Substituted or unsubstituted
alkyl, substituted or unsubstituted unsaturated alkyl,
substituted or unsubstituted aryl, substituted or unsub-
stituted heteroaryl, substituted or unsubstituted aryla-
lkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocyclic, hydroxy, alkoxy, carbony-
loxy, halogen, azido, cyano, nitro, alkylthio, carboxyl,
carboxylate esters, carboxamido, amino, and mono- or
di-substituted amino;
if X—C or Y—C, then either may independently be sub-
stituted by additional R moieties chosen from the group
consisting of hydrogen; Substituted or unsubstituted
alkyl, substituted or unsubstituted unsaturated alkyl,
substituted or unsubstituted aryl, substituted or unsub-
stituted heteroaryl, substituted or unsubstituted aryla-
lkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocyclic, hydroxy, alkoxy, carbony-
loxy, halogen, azido, cyano, nitro, alkylthio, carboxyl,
carboxylate esters, carboxamido, amino, and mono- or
di-substituted amino;
wherein in formula 9,
n=0, 1, or 2:
R" through R are independently chosen from the group
consisting of hydrogen, Substituted or unsubstituted
alkyl, substituted or unsubstituted unsaturated alkyl,
substituted or unsubstituted aryl, substituted or unsub
stituted heteroaryl, substituted or unsubstituted aryla
lkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocyclic, acyl, carboxylate esters,
and carboxamido;
R" and Rare independently chosen from the group con
sisting of hydrogen, Substituted or unsubstituted alkyl,
substituted or unsubstituted unsaturated alkyl, substi
tuted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted arylalkyl, sub
stituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocyclic, hydroxy, alkoxy, carbony
loxy, halogen, azido, cyano, nitro, alkylthio, carboxyl,
carboxylate esters, carboxamido, amino, and mono- or
di-substituted amino;
wherein in formula 8,
R" is chosen from the group consisting of hydrogen, Sub
stituted or unsubstituted alkyl, substituted or unsubsti
tuted unsaturated alkyl, substituted or unsubstituted
aryl, substituted or unsubstituted heteroaryl, substituted
or unsubstituted arylalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocyclic,
acyl, carboxylate esters, and carboxamido;
R through R" are each independently chosen from the
group consisting of hydrogen, Substituted or unsubsti
tuted alkyl, substituted or unsubstituted unsaturated
alkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
arylalkyl, substituted or unsubstituted cycloalkyl, sub
stituted or unsubstituted heterocyclic, hydroxy, alkoxy,
Apr. 4, 2013
carbonyloxy, halogen, azido, cyano, nitro, alkylthio, car
boxyl, carboxylate esters, carboxamido, amino, and
mono- or di-substituted amino;
wherein in formula 10,
n=0, 1, or 2:
X is chosen from the group consisting of N, O, and S;
R" through R" are independently chosen from the group
consisting of hydrogen, Substituted or unsubstituted
alkyl, substituted or unsubstituted unsaturated alkyl,
substituted or unsubstituted aryl, substituted or unsub
stituted heteroaryl, substituted or unsubstituted aryla
lkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocyclic, hydroxy, alkoxy, carbony
loxy, halogen, azido, cyano, nitro, alkylthio, carboxyl,
carboxylate esters, carboxamido, amino, and mono- or
di-substituted amino;
R is chosen from the group consisting of hydrogen, Sub
stituted or unsubstituted alkyl, substituted or unsubsti
tuted unsaturated alkyl, substituted or unsubstituted
aryl, substituted or unsubstituted heteroaryl, substituted
or unsubstituted arylalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocyclic,
acyl, carboxylate esters, and carboxamido;
Ar is chosen from the group consisting of hydrogen, Sub
stituted or unsubstituted aryl, substituted or unsubsti
tuted heteroaryl, substituted or unsubstituted arylalkyl,
substituted or unsubstituted cycloalkyl, and substituted
or unsubstituted heterocyclic;
wherein in formula 12,
R" is chosen from the group consisting of hydrogen, Sub
stituted or unsubstituted alkyl, substituted or unsubsti
tuted unsaturated alkyl, substituted or unsubstituted
aryl, substituted or unsubstituted heteroaryl, substituted
or unsubstituted arylalkyl, substituted or unsubstituted
cycloalkyl, and substituted or unsubstituted heterocy
clic;
R’ through R are independently chosen from the group
consisting of hydrogen, Substituted or unsubstituted
alkyl, substituted or unsubstituted unsaturated alkyl,
substituted or unsubstituted aryl, substituted or unsub
stituted heteroaryl, substituted or unsubstituted aryla
lkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocyclic, hydroxy, alkoxy, carbony
loxy, halogen, azido, cyano, nitro, alkylthio, carboxyl,
carboxylate esters, carboxamido, amino, and mono- or
di-substituted amino;
Ar is chosen from the group consisting of hydrogen, Sub
stituted or unsubstituted aryl, substituted or unsubsti
tuted heteroaryl, substituted or unsubstituted arylalkyl,
substituted or unsubstituted cycloalkyl, and substituted
or unsubstituted heterocyclic;
wherein in formula 13,
R" through R', R'' and R' are independently chosen
from the group consisting of hydrogen, Substituted or
unsubstituted alkyl, substituted or unsubstituted unsat
urated alkyl, substituted or unsubstituted aryl, substi
tuted or unsubstituted heteroaryl, substituted or unsub
stituted arylalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocyclic,
hydroxy, alkoxy, carbonyloxy, halogen, azido, cyano,
nitro, alkylthio, carboxyl, carboxylate esters, carboxa
mido, amino, and mono- or di-substituted amino;
R" is chosen from the group consisting of hydrogen, Sub
stituted or unsubstituted alkyl, substituted or unsubsti
US 2013/0085133 A1
90
tuted unsaturated alkyl, substituted or unsubstituted
aryl, substituted or unsubstituted heteroaryl, substituted
or unsubstituted arylalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocyclic,
acyl, carboxylate esters, and carboxamido;
wherein in formula 14,
X', X, and X’ are independently chosen from the group
consisting of O, S, N, C, and halogen;
whenever any of X, X, and X is not halogen, they may be
independently further substituted from the group con
sisting of hydrogen, Substituted or unsubstituted alkyl,
substituted or unsubstituted unsaturated alkyl, substi
tuted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted arylalkyl, sub
stituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocyclic, acyl, carboxylate esters, and
carboxamido;
whenever any of X, X, and X is C, they may additionally
be substituted from the group consisting of hydroxy,
alkoxy, carbonyloxy, halogen, azido, cyano, nitro, alky
lthio, carboxyl, amino, and mono- or di-substituted
amino;
the R group is chosen from the group consisting of hydro
gen, substituted or unsubstituted alkyl, substituted or
unsubstituted unsaturated alkyl, substituted or unsubsti
tuted aryl, substituted or unsubstituted heteroaryl, sub
stituted or unsubstituted arylalkyl, substituted or unsub
stituted cycloalkyl, substituted or unsubstituted
heterocyclic, hydroxy, alkoxy, carbonyloxy, halogen,
azido, cyano, nitro, alkylthio, carboxyl, carboxylate
esters, carboxamido, amino, and mono- or di-substituted
amino;
wherein in formula 15,
X', X, and X’ are independently chosen from the group
consisting of O, S, N, C, and halogen;
whenever any of these groups is not halogen, they may be
independently further substituted from the group con
sisting of hydrogen, Substituted or unsubstituted alkyl,
substituted or unsubstituted unsaturated alkyl, substi
tuted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted arylalkyl, sub
stituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocyclic, acyl, carboxylate esters, and
carboxamido;
whenever any of X, X, and X is C, they may additionally
be substituted from the group consisting of hydroxy,
Apr. 4, 2013
alkoxy, carbonyloxy, halogen, azido, cyano, nitro, alky
lthio, carboxyl, amino, and mono- or di-substituted
amino;
Y', and Y are independently chosen from the group con
sisting of N and C:
R is chosen from the group consisting of hydrogen, Substi
tuted or unsubstituted alkyl, substituted or unsubstituted
unsaturated alkyl, substituted or unsubstituted aryl, sub
stituted or unsubstituted heteroaryl, substituted or
unsubstituted arylalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocyclic,
acyl, carboxylate esters, and carboxamido.
6. The method of claim 5 wherein the virus is a respiratory
virus.
7. The method of claim 5 wherein the virus is selected from
the group consisting of the families Paramyxoviridae, human
metapneumovirus, human parainfluenza virus, measles virus,
and mumps virus.
8. The method of claim 5 wherein the virus is respiratory
syncytial virus.
9. A method for screening for compounds for use as an
anti-viral agent against a virus which comprises obtaining
frozen cells infected with said virus, thawing said infected
cells and mixing said infected cells with uninfected cells of
the same type as the infected cells, contacting the mixture of
said infected cells and uninfected cells with a compound to be
screened and determining the viability of said cells.
10. The method of claim 9 wherein the virus is a respiratory
virus.
11. The method of claim 9 wherein the virus is selected
from the group consisting of the families Paramyxoviridae,
human metapneumovirus, human parainfluenza virus,
measles virus, and mumps virus.
12. The method of claim 9 wherein the virus is respiratory
syncytial virus.
13. The method of claim 9 wherein said cells are HEp-2
cells.
14. The method of claim 9 wherein the infected cells are
admixed with uninfected cells in a weight ratio of 1:100.
15. The method of claim 1, which comprises administering
to said human an effective amount of at least one compound
represented by the formula 16.
16. The method of claim 1, which comprises administering
to said human an effective amount of at least one compound
represented by the formula 16.
k k k k k