BENZIMIDAZOLE COMPOUNDS AND USE THEREOF FOR TREATING ALZHEIMER'S DISEASE OR HUNTINGTON'S DISEASE

COMPOSES DE BENZIMIDAZOLE ET LEUR UTILISATION POUR TRAITER LA MALADIE D'ALZHEIMER OU LA MALADIE DE HUNTINGTON

English Abstract

Benzimidazole compounds of formula (I), shown below, are disclosed. The compounds are potent human glutaminyl cyclase inhibitors. Also disclosed is a pharmaceutical composition containing one of these compounds and a pharmaceutical acceptable carrier, as well as a method of treating Alzheimer's disease or Huntington's disease by administering to a subject in need thereof an effective amount of such a compound.

French Abstract

La présente invention concerne des composés de benzimidazole de formule (I), décrite ci-dessous. Les composés sont des inhibiteurs puissants de la glutaminyl-cyclase humaine. L'invention concerne en outre une composition pharmaceutique contenant l'un de ces composés et un véhicule pharmaceutiquement acceptable, ainsi qu'un procédé de traitement de la maladie d'Alzheimer ou de la maladie de Huntington par administration à un sujet en ayant besoin d'une quantité efficace d'un tel composé.

Claims

115
What is claimed is:
1. A compound of formula (I):
<IMG>
wherein
RI is H or C1_6 alkyl;
R2 is a moiety containing a phenyl ring fused to a 5-membered heteroaryl ring,
R2 being
linked to N through the phenyl ring;
R3, R4, R5, R6, and R7, independently, are H, halo, nitro, cyano, amino, OH,
CF3,
C1-6 alkoxyl, C1-6 alkyl, C2-6 aikenyl, C2-6 alkynyl, C3-10 cycloalkyl,
heterocycloalkyl, aryl, or
heteroaryl that is optionally substituted by one or more substituents selected
from halo, nitro,
cyano, amino, OH, CF3, -COOH, -COOC1-6 alkyl, C1-6 alkoxyl, C1_6 alkyl, C2-6
alkenyl,
C2-6 alkynyl, C3-10 cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,
in which
at least one of R3, Ra, R5, R6, and R7 is heteroaryl; and
each of Ci_6 alkoxyl, C1_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3_10
cycloalkyl,
heterocycloalkyl, aryl, and heteroaryl, second or third occurrence, is
optionally substituted with
halo, nitro, cyano, amino, OH, CF3, C1-6 alkoxyl, C1-6 alkyl, C2-6 alkenyl, C2-
6 alkynyl, c3-10
cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
X is CH2 or C=0; and
Y is CH2 or C=0.
2. The compound of claim 1, wherein Y is CH2.
<IMG>
3. The compound of claim 2, wherein RI is H, X is C=0, and R2 iS

116
4. The compound of claim 3, wherein R3, R4, R5, and R6, independently, are
H, CH3,
Cl, or F.
5. The compound of claim 4, wherein R7 is heteroaryl selected from the
group
<IMG>
consisting of
3
<IMG>
, in which R8
is H, halo, nitro, cyano, amino, OH, CF3, -COOH, -COOC1-6 alkyl, C1-6 alkoxyl,
C1_6 alkyl, C2-6
alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocycloalkyl, aryl, or
heteroaryl,
each of C1-6 alkoxyl, C1_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3_10
cycloalkyl,
heterocycloalkyl, aryl, and heteroaryl being optionally substituted with halo,
nitro, cyano, amino,
OH, CF3, C1-6 alkoxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10
cycloalkyl, heterocycloalkyl,
aryl, or heteroaryl.
6. The compound of claim 5, wherein R8 is H, F, Cl, CH3, CF3, ethyl, n-
propyl,
<IMG>
<IMG>
7. The compound of claim 6, wherein R7 is
<IMG>

117
<IMG>
8. The compound of claim 1, wherein Y is C-0.
<IMG>
9. The compound of claim 8, wherein RI is H, X is C=0, and R2 1S
10. The compound of claim 9, wherein R3, R4, R5, and R6, independently, are
H, CH3,
Cl, or F.

118
<IMG>
11. The compound of claim 10, wherein R7 is
<IMG>
<IMG>
, in which R8 is H, halo, nitro, cyano, amino, OH, CF3, -COOH, -
COOC1_6 alkyl, C1_6 alkoxyl, C1_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3_10
cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl,
each of C1_6 alkoxyl, C1_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3_10
cycloalkyl,
heterocycloalkyl, aryl, and heteroaryl being optionally substituted with halo,
nitro, cyano, amino,
OH, CF3, C1-6 alkoxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10
cycloalkyl, heterocycloalkyl,
aryl, or heteroaryl.
12. The compound of claim 11, wherein R8 is H, F, Cl, CH3, CF3, ethyl, n-
propyl,
<IMG>
<IMG>
13. The compound of claim 12, wherein R7 is
<IMG>

119
<IMG>
14. The compound of claim 1, wherein RI is H and X is C=0.
<IMG>
15. The compound of claim 1, wherein R2 is
16. The compound of claim 1, wherein R3, R4, R5, and R6, independently, are
H, CH3,
Cl, or F.
<IMG>
17. The compound of claim 1, wherein R7 1S
<IMG>

120
<IMG>
, in which R8 is H, halo, nitro, cyano, amino, OH, CF3, -COOH, -
COOC1-6 alkyl, C1-6 alkoxyl, C1_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3_10
cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl,
each of C1_6 alkoxyl, C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_10
cycloalkyl,
heterocycloalkyl, aryl, and heteroaryl being optionally substituted with halo,
nitro, cyano, amino,
OH, CF3, C1_6 alkoxyl, C1-6 alkyl, C2_6 alkenyl, C2-6 alkynyl, C3_10
cycloalkyl, heterocycloalkyl,
aryl, or heteroaryl.
18. The compound of claim 17, wherein R8 is H, F, CI, CH3, CF3, ethyl, n-
propyl,
<IMG>
<IMG>
19. The compound of claim 18, wherein R7 is
<IMG>

121
<IMG>
20. The
compound of claim 1, wherein the compound is one of the following
compounds:
<IMG>

122
<IMG>

123
<IMG>

124
<IMG>

125
<IMG>
21. The compound of claim 20, wherein the compound is one of the following
compounds:
<IMG>
22. The compound of claim 1, wherein the compound is one of the following
compounds:

126
<IMG>

127
<IMG>

128
<IMG>
23. A pharmaceutical composition comprising a compound of claim 1 and a
pharmaceutically acceptable carrier.
24. Use of a compound of any one of claims 1 to 22 for treatment of
Alzheimer's
disease or Huntington's disease.
25. Use of a compound of any one of claims 1 to 22 in the manufacture of a
medicament for treatment of Alzheimer's disease or Huntington's disease.

Description

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BENZIMIDAZOLE COMPOUNDS AND USE THEREOF FOR
TREATING ALZHEIMER'S DISEASE OR HUNTINGTON'S DISEASE
BACKGROUND
Alzheimer's disease (AD) and Huntington's disease (HD) are both incurable
degenerative brain diseases.
More specifically, AD is the most common form of dementia and HD, on the other
hand, causes uncontrolled movements of the arms, legs, head, face, and upper
body. HD also
causes a decline in thinking and reasoning skills, including memory,
concentration,
judgement, and ability to plan and organize.
Both AD and HD are caused by aberrant aggregation of proteins or peptide.
Indeed,
AD is triggered by a malfunction of aggregated mutant p-amyloid peptide (A13)
and HD
arises from a toxic function of aggregated mutant huntingtin protein (HTT).
Human glutaminyl cyclase (QC) catalyzes cyclization of N-terminal residues of
glutamine or glutamate to form pyroglutamate (pG1u) on Af3 and HTT. The pG1u-
modified
Al3 and pG1u-modified HTT thus formed are aggregative, neurotoxic, and
resistant to
proteolysis. They can initiate pathological cascades, resulting in development
of AD or HD.
Inhibition of human QC has been found to diminish aggregation of both AO and
HTT
in cultured macrophage cells and in Drosophila and mouse models. See J.
Pharmacol. Exp.
'Ther. 2017, 362, 119-130; J. Med. Chem. 2017, 60, 2573-2590; Nat. Med. 2008,
14(10),
1106-1111; and Nat. Chem. Bio. 2015, 11,347-354.
As such, human QC is an emerging drug target for the treatment of AD or HD.
Currently, only a few drug candidates that inhibit QC are in clinical trials
for treating
AD or HD. There is a need to develop new QC inhibitors.
Earlier studies have shown that QC is a zinc-dependent enzyme. As such,
compounds
capable of chelating zinc at active sites of QC, e.g., benzimidazole
compounds, are potential
QC inhibitors.
SUMMARY
Certain benzimidazole compounds have been found to be QC inhibitors.
Unexpectedly, the compounds demonstrate high potency in inhibiting QC and, as
such, can
be used for treating AD or HD.

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In one aspect, this invention relates to the benzimidazole compounds of
formula (I)
below:
v
N
N¨R2
R4
R3
R5
R6 R7
(0.
X and Y, independently, are CH2 or C=0; Ri is H or C1_6 alkyl; R2 is a moiety
isss N,
containing a phenyl ring fused to a 5-membered heteroaryl ring (e.g., H ),
being
linked to N through the phenyl ring; R3, R4, R5, R6, and R7, independently,
are H, halo (e.g.,
F, Cl, Br, or I), nitro, cyano, amino, OH, CF3, Ci_6 alkoxyl, Ci_6 alkyl, C2_6
alkenyl, C2-6
alkynyl, C3-10 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl that is
optionally substituted by
one or more substituents selected from halo (e.g., F, Cl, Br, or I), nitro,
cyano, amino, OH,
CF3, -COOH, -000C1_6 alkyl, C1_6 alkoxyl, C1_6 alkyl, C2_6 alkenyl, C2_6
alkynyl, C3_10
cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein at least one of
R3, R4, R5, R6, and
R7 is heteroaryl and wherein each of C1_6 alkoxyl, C1_6 alkyl, C2-6 alkenyl,
C2_6 alkynyl, C3_10
cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, second or third
occurrence, is optionally
substituted with halo (e.g., F, Cl, Br, or I), nitro, cyano, amino, OH, CF3,
C1_6 alkoxyl, C1-6
alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocycloalkyl, aryl,
or heteroaryl.
8ss N oss..,N7R8
Examples of heteroaryl assigned to R7 include R8 , S-1 R8
N-0 css /R oss
a N, issLIN
csss-CS
/7 ----11-1" N¨R8
R8 R8
N, R8
NH
R8 and NH , in which R8 is H, halo (e.g., F, Cl, Br, or I), nitro,
cyano,
amino, OH, CF3, -COOH, -000C1_6 alkyl, C1_6 alkoxyl, C1_6 alkyl, C2-6 alkenyl,
C2-6 alkynyl,
C3-10 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of C1_6 alkoxyl,
C1-6 alkyl,
C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocycloalkyl, aryl, and
heteroaryl being

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optionally substituted with halo (e.g., F, Cl, Br, or I), nitro, cyano, amino,
OH, CF3, Ci_6
alkoxyl, C1_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3_10 cycloalkyl,
heterocycloalkyl, aryl, or
heteroaryl.
/ N N
----( j los ----1"--- ---(
/
Among specific assignments to R7 are S , S/1 ,
cl----1---3 ---f-N CF isss--------4 il-,-=CF -- (N , 3
, ___.)L
s ,
, ,
1 S
N
1-4--- - S S 1---ic7
S CF3, , s CF3
,
fi--S\ ri---S, ri--S, , õ.õ.Ø.....
/ S,, ......,__/OH
µ,..--- v--<õ,)--/ -- '%...... I ..--c,,,---7 `pi4 /
F =2e4 Z
S
..õ...a..._/
........c.)....., S 1 S
OH, 0...... F3 `tee.....--=Cs.
, 4 9
0 oss.õ....ccN 405..õ...e,/sr...4 cos.N,N___N____
N-0 , O-N , N=N1 , N=1=1 ,
csss....õN, oss...,,,e,N, cos N, iss',
,N,
is"---rNsN-- --('' N''''')...õ \ N----\7, ----"r
N--\ -"\--'. N
N94 N=714 NN
N=14 CF3 NN1 ---\\
N-N"------:---,__.____ N-N 110
1-4,NA 1-4,NA ----,NA CI
, N...,, 0
N-N el ,--- 7 '''-'1141 0" / /N oss.......f.õN
.,4 .õ,e ..___cF3
1---NA N--:'N / ---1,.*.---
/ 555.1
/ HN- HN¨ HN--//
, ,
yrs' N N
es----t*i.--CF3 csss--- ,-0,---4 "s"---f--- "s"---\Ø-CF3
, ,
/
µ--NH NH NH HN / HN 1 0 , HN
,
Oss \''',-4 cs(--C=r-CF3
\
µ--NH NH , and NH . Among specific assignments to Rs are
H,
1-----<-7 1''( 1----4 , j-------CF3 ,
F, Cl, CH3, CF3, ethyl, n-propyl, N 1 õ ,

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oil
.-N
0 * CI * 0
, and
The above-described compounds can be classified into two subsets. In one
subset, Y
is CH2 and, in the other subset, Y is C=0. Preferred compounds in each subset
feature that
N
Ri is H; X is C=0; R2 is H ; R3, R4, R5, and R6, independently, are H or F;
R7 is
"Ss zR8
Rg S Rg Rg N-0 O¨N
/NR fN 055-1R.8 FN,isss¨õ,_,CyR8
8 41.
N=rsj >==
HN=i R8 \\---NI-1 HN--I R8 NH
or , in which the
assignments to Rg are set forth in the preceding paragraph. In particularly
preferred
compounds, the assignments to R7 are also set forth in the preceding
paragraph.
The term "alkyl" herein refers to a saturated, linear, or branched hydrocarbon
moiety,
e.g., -CH3 or -CH(CH3)2. The term "alkoxy" refers to an -0(C1-6 alkyl)
radical, e.g., -OCH3
and ---OCH(CH3)2. The term "alkenyl" refers to a linear or branched
hydrocarbon moiety that
contains at least one double bond, e.g., -CfIH-CH3. The term "alkynyl" refers
to a linear
or branched hydrocarbon moiety that contains at least one triple bond, e.g., -
C--CH3. The
term "cycloalkyl" refers to a saturated mono-, di-, or tri-cyclic hydrocarbon
moiety, e.g.,
cyclohexyl. The term "heterocycloalkyl" refers to a saturated mono-, di-, or
tri-cyclic moiety
having at least one ring heteroatom (e.g., N, 0, and S), e.g., 4-
tetrahydropyranyl. The term
"aryl" refers to a hydrocarbon moiety having one or more aromatic rings.
Examples of aryl
include phenyl, phenylene, naphthyl, naphthylene, pyrenyl, anthryl, and
phenanthryl. The
term "heteroaryl" refers to a moiety having one or more aromatic rings that
contain at least
one heteroatom (e.g., N, 0, and S). Examples of heteroaryl include furyl,
furylene, tluorenyl,
pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl,
quinazolinyl, quinolyl,
isoquinolyl, and indolyl. The term "amino" refers to a radical of -N142,
4NTH(C1..6 alkyl), or -
N(Ci..6 all:3,1)2, e.g., -NHCH3 and -NHCH(CH3)2.
Alkoxy, Alkyl., alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and
heteroaryl
mentioned herein include both substituted and unsthstituted moieties, unless
specified

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otherwise. Substituents on alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl,
heterocycloalkyl, aryl,
and heteroaryl include, but are not limited to, halo, nitro, cyano, amino, OH,
CF3, -COOH, -
CO0C1-6 alkyl, C1_6 alkoxyl, C1_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3_10
cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl.
The compounds described above include the compounds themselves, as well as
their
salts, prodrugs, stereoisomers, and tautomers, if applicable. A salt, for
example, can be
formed between an anion and a positively charged group (e.g., amino) on a
compound of
formula (I). Suitable anions include chloride, bromide, iodide, sulfate,
nitrate, phosphate,
citrate, methanesulfonate, trifluoroacetate, acetate, malate, tosylate,
tartrate, fumurate,
glutamate, glucuronate, lactate, glutarate, and maleate. Likewise, a salt can
also be formed
between a cation and a negatively charged group (e.g., carboxylate) on a
compound of
formula (I). Suitable cations include sodium ion, potassium ion, magnesium
ion, calcium ion,
and an ammonium cation such as tetramethylammonium ion. The compounds also
include
those salts containing quaternary nitrogen atoms. Examples of prodrugs include
esters and
other pharmaceutically acceptable derivatives, which, upon administration to a
subject, are
capable of providing active compounds. Stereoisomers of the compounds of
formula (I) can
include cis and trans isomers, optical isomers such as (R) and (S)
enantiomers, diastereomers,
geometric isomers, rotational isomers, atropisomers, conformational isomers,
and mixtures
thereof. Tautomers of the compounds include those exhibiting more than one
type of
isomerism.
In another aspect, this invention relates to a pharmaceutical composition
containing a
compound of formula (I) and a pharmaceutical acceptable carrier.
The carrier in the pharmaceutical composition must be "acceptable" in the
sense that
it is compatible with the active ingredient of the composition (and
preferably, capable of
stabilizing the active ingredient) and not deleterious to the subject to be
treated. Examples of
carriers include colloidal silicon oxide, magnesium stearate, cellulose,
sodium lauryl sulfate,
and D&C Yellow 10.
Also within the scope of this invention is a method of treating AD or HD. The
method includes administering to a subject in need thereof an effective amount
of a
compound of formula (I).
The term "treating" refers to application or administration of the compound or
its salt,
prodrug, stereoisomer, or tautomer to a subject with the purpose to confer a
therapeutic
effect, i.e., to cure, relieve, alter, affect, ameliorate, or prevent AD or
HD, the symptom of
AD or HD, or the predisposition toward AD or HD.

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"An effective amount" is the amount of the compound or its salt, prodrug,
stereoisomer, or tautomer, which is required to confer the desired effect on
the subject.
Effective amounts vary, as recognized by those skilled in the art, depending
on route of
administration, excipient usage, and the possibility of co-usage with other
therapeutic
treatments such as use of other active agents.
A composition having a compound of formula (I) or its salt, prodrug,
stereoisomer, or
tautomer can be administered parenterally or orally. The term "parenteral" as
used herein
refers to subcutaneous, intracutaneous, intravenous, intraperitoneal,
intramuscular,
intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal,
intralesional, or intracranial
injection, as well as any suitable infusion technique.
A composition for oral administration can be any orally acceptable dosage
form, e.g.,
capsules, tablets, emulsions and aqueous suspensions, dispersions, and
solutions. In the case
of tablets, commonly used carriers include, among others, lactose and corn
starch.
Lubricating agents, such as magnesium stearate, are also typically added. For
oral
administration in a capsule form, useful diluents include lactose and dried
corn starch. When
aqueous suspensions or emulsions are administered orally, the active
ingredient can be
suspended or dissolved in an oily phase combined with an emulsifying or
suspending agent.
If desired, a sweetening, flavoring, or coloring agent can be added.
The details of one or more embodiments of the invention are set forth in the
description below. Other features, objects, and advantages of the invention
will be apparent
from the description and from the claims.
DETAILED DESCRIPTION
Disclosed in detail hereinafter are the benzimidazole compounds of formula (I)
shown
above.
Compounds of this invention that have chiral centers may exist as
stereoisomers.
Stereoisomers of the compounds of formula (I) can include cis and trans
isomers, optical
isomers such as (R) and (S) enantiomers, diastereomers, geometric isomers,
rotational
isomers, atropisomers, conformational isomers, and tautomers of the compounds,
including
compounds exhibiting more than one type of isomerism; and mixtures thereof
(such as
racemates and diastereomers). All such isomeric forms are contemplated. In
addition, the
compounds of formula (I) in the present invention may exhibit the phenomena of
tautomerism.

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Of note, the compounds of formula (I) can have an enantiorneric excess of 90%
or
higher (e.g., > 95% and ? 99%).
117 exemplary compounds of formula (I) are shown in Table 1 below:
Table 1
,o ,o ,o ,o õ0
HN¨,('
N HN¨,( N HN ¨,( N HN¨,c' N HN¨µ("
N
N 10, ..:,
N N N N
NH . Ssi
NH * ^z.'?
NH 10 S*7
NH 11# -zzi
NH
40 0 I.
s -,N S ...` N S N S N 7 N
SA).
1 2 3 4 5
õ NI
0 õ N
0 , N
0 ,0 õ0
HN¨'f HN¨T HN¨'c' HN¨'= N HN¨"." N
N N N ,
110 .,)
./
110 N 1p ==.: c....,N
NH N H NH NH
i WP NH
401 40 00
, s , s , s ..-= s ,- s
CF3 N=Iss
CF3 N=4õ
CF3
6 7 8 9 10
,0 ,0 ,0 ,0 ,0
HN ¨if N HN¨/f N HN¨T N HN¨f\,' N HN¨T N
N 10 '17
NH N * =z)
NH
OP
IP. CF3
11 12 13 14 15
N HN¨,f
N HN¨f(
N
NH N * s)
NH N al s",
NH N Ilk so'zi
NH N 110 s',
NH
010 00 40
V N"- N 0 '''= N .." N
S 1 S / ibi iv¨ i-r,1
CF3
16 17 18 19 20

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,o ,o p p p
N N
HN-4( HN--T HN--,<"
N HN¨fr
N
N
N * N)
NH N * S)
NH N
NH
NH
0 F * N F 011111r7
F F
N N'N
N¨r4
S /
--- CF3 CF3 CF3 CF3
21 22 23 24 25
p p p ,o ,o
HN¨T
N HN--1(
N HN--if
N HN--T
N HN--fr
N
(,N
*
NH &,N *N *k>
NH N * =,i
NH N * 'k
NH N =
NH
F F Filir" F
F F
.., , 7 S r S
CF3 CF3 CF3 CI CI
26 27 28 29 30
¨ .
,0 ,0 p p p
HN-1
N.,.._ HN--1(
N.,....7 HN--T
N HN--(<
N,,, HN--T
7
N
F F F. NH 4.,N . ',.7
NH 7
N * NH (NN,N * 'z'zi
: NH
0
/...... ....... ....... ¨ S
CI CI CF3 CF3 CF3
31 32 33 34 35
p p p HN¨(
p p
HN-4(
Nõ... HN-4(
N HN¨'<- N
7
N * NH 0 N * '* N.) 0 N * =Zi 0 N * Ns) 0
NH NH NH NH
V ,
/ S N'N V N V S V s
S
CF3 \--is,CF3
1111. N=St> N=1\
CF3
36
37 38 39 40
õ.0 õ N HN¨
*
Co p ,
N o ,o
HN¨µc
HN-4( 4(
N HN-4(
N
0 N '=', 0
NH N ilp
NH 0 N * ,:i
NH 0 N * si 0
NH N * S)
NH
Li Li
N''''N N N N ""N N ""N N '"N
ii.-.r.\ 1
N¨N 0 ,
N¨N-----
0 ,
N¨N\___< 0 ,
\--\
41 42 43 44 45
_

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p p p ,o p
HN-4(
Nt..,, HN--4(
61.,,.." HN-4(
N>
0 N * NN) 0 N * N.
NH NH 0 N
N * 141 CI * NiH 0 N *
NH
N N <...'N N NN N NN N 'N
4-1\/ KI-61 4-14 i,--r\i ii.-Ni .
CI
\-cF3 \-----:::_ ..... _-.---... -\_____,--..= -.\
46 47 48 49 50
. . .
õ0 õ0 õ0 õ0 ,0
HN-1 HN-1 HN---'(
N HN---'(
Nss, HN-1(
0 N * IS 0 N *
NH NH 1.,,,N AA- ',"
E lir NH N *
NH NH
F C.:: N *N "
0
F F F
N ." N N ..**N
/
j'_1\1 O-N S S-'\ S i
" It o
\ \--- ,,,,, 4,0 CF3
cF, CF3
51 52 53
54 55
fp õp õO h0 ,0
HN-'(
N NN-'(
N HN-'(
N HN-T
N HN--=(
N
N
NH N * Ssi
NH N *
NH N
NH
F lio N * F F F #
F 0
F F F
V ,
V s V ,
S N... S / S S
0F3 F CI
56
57 58 59 60
HN--T
0
N HN--if
N HN-õ 1
N HN-õ
X HN-4(
N
N * N
F ip N) N * N * N '', N
F F 110
NH NH NH NH NH
F F 4
II. 0
F F F F F
V , V
S ,
/ S / / / /
S S
S
0\
O\ \-- 0
64 65
61 62 63
. .
õ0 p p
HN-d( HN-1
N HN--'(
N:==/ N HN-
N"(
N * Ss? N * '..) N * " N * S'i N dik N>
F F F
NH NH NH NH NH
F F F F Fullirr
0
/ , 7 S 7 S 7 S
/ / N-A N-A N-A
S S
OH OH CF3 CF3 CF3
0 68 69 70
66 67

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p p p p p
HN--
N HN--"f
N HN---4(
N..i, HN¨T
N HN¨Ir
N 'P"='."7
NH N * ===*"
NH 7
N * NH N *
NH N ilkN S')
NH
F F F Fulliir"
F F
N=4õ S i S 1 5' S i
CF3 CI CI CI CI
73 74 75
71 72
0 õ0 p p 0
f
N HN-4(
N HN¨'(
N HN-4(
N HN¨,
HN¨1
4(
N * ss,
NH N = Ssi
NH N 10 s)
NH N * Ssi
NH N *N Ssi
NH
0
HN NN HN NN HN .....N
V..._¨...:k ---1,\st). HN-1( HNAI>
CH3 CF3 CH3
78 79
76 77 80
0 0 0 .õ0 0
HN--
N HN--f
N HN---f N HN--T
N HN---f
N *
NH )
NH N * Azz7
NH N *N,=)
*
NH
0
V N HN s*, HN N", HN
HN¨
CF3 _ _ N. V
/
HN
CF3 CH3 CF3 CH3
81 82 83 84 85
,0 ,0
HN
N HN¨if
N --4(
N HN¨''N * N *
N HN¨T
N
NH '', 0 N
NH * s'17 0
VL NH N * 1 0 N II
NH
F F F411111r--
0
F
.., , V S )'S V S
HN HN
CF CF3 CF3 CF3
III" 8
88 9
87 90
86
0 .õ
* 0 õ00 õ0 p
HN--,f N HN--1-
N HN-1"
N HN--K
N HN--"(
N
0 N ''.."7
NH 0 N * sz.7
NH 0 N * 0 N
NH ":i 0
NH N * =====.'7
NH
F F F OWillik F
F F V F
7 V
V
/ ,
/ ,
_
S S S S/
CF3 CF3 CF3 CF3 CF3
93
91 92 94 95

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11
p ,o N HN p
HN-1"
N -1 --1 N HN--<7 N HN-- HN e
N
O N * Ns:i. 0 )
NH N = S
NH 0 N * s':i
NH 0 N d -.1 0
NH N * ss)
NH
F F F"Illv F
F F
7 S 7 S 7 S 7 S 7 S
¨
¨ ¨
CI CI CI CI CI
98 99 100
96 97
,0 ,0 ,0 HN¨',0 HN-4
HN¨'f N HN¨',c" N HN¨'( f (
O N 'P 0
NH N * -:7 F F F411lirr N
F N N
NH 0 N * ,..)
NH 0 N ilk ==117 0
NH N * ,..)
NH
F F
7 , 7 , 7 , 7 , 7 ,
/ / / / S S S S/
CI CI CI CI
S CI
101 102 103 104 105
p o zp
O ,o HN¨,0
HN--1 H
N I\I---'(-
, HN N HN¨"(
N --1
N '
N
N * s'zi 0 N
NH 'P >*
NH 0 N s'zi *
NH 0 N *,,) 0 N *
NH s'zi
NH
HN NN HN NN HN N N 7 N 7 N
\-4CF3 HN¨ HN-%.
CH3 CH3
106 107 108 109
110
, N
o ,o
HN-.1
N 'PN Nki HN--1
p FIN-4( HN-1
NZ7 HN---1(
O N *
NH 0 N
NH
NH 0 N * =
NH 0 N * s 0 N
NH
0
7 N HN µ", HN N- HN N- 7
HN¨((¨ HN
CF3 CH3 CF3 CH3
IIII"
111 112 113 114 115
,0
HN---1
N HN----e N
O N * =ki
NH 0 N * ,t,
NH
.7 / , 7 ,
/
HN HN
CF3
116 117

12
Among the 117 compounds listed above, Compounds 9 and 10 are the two
enantiomers of Compound 8; Compounds 33 and 34 are the two enantiomers of
Compound
13; Compounds 35 and 36 are the two enantiomers of Compound 16; Compounds 53
and 54
are the two enantiomers of Compound 25; and Compounds 55 and 56 are the two
enantiomers of Compound 28.
Compounds 9, 34, 36, 54, and 56 are preferred.
Methods for synthesizing the compounds of formula (I) are well known in the
field.
Note that the procedures for preparing as many as 67 compounds, i.e.,
Compounds 1-67, are
set forth in EXAMPLE 1 below.
The compounds thus prepared can be initially screened using in vitro assays
for their
potency in inhibiting the activity of glutaminyl cyclase (QC). The in vitro
assays are set forth
in EXAMPLE 2 below. Further, the prepared compounds can be subsequently
evaluated
using in vivo assays. The in vivo assays are set forth in EXAMPLE 3 below. The
selected
compounds can be further tested to verify their efficacy in treating AD or HD.
Based on the
results, appropriate dosage ranges and administration routes can be
investigated and
determined.
All reagents and solvents were purchased from commercial suppliers and used
without further purification unless otherwise noted. All anhydrous reactions
were performed
under a nitrogen atmosphere using dry solvents. All reactions were monitored
by thin layer
chromatography using Merck silica gel 60 F254 glass-backed plate. Column
chromatography
was performed by Merck silica gel 60 (0.040-0.063 mm, 230 _____________ 100
mesh). Purity of the final
compounds was determined on a Hitachi 2000 series HPLC system with a reverse
phase
C18 column (Agilent ZORBAX Eclipse XDB-C18 5 m, 4.6 mm x 150 mm), operating
at
25 C. Mobile phase A was acetonitrile. Mobile phase B was 10 mM NI-140Ac
aqueous
solution containing 0.1% formic acid. The gradient system started from A/B
(10%/90%) at 0
mm to A/B (90%/10%) at 45 min. The flow rate of the mobile phase was 0.5
mL/min, and
the injection volume of the sample was 5 L. Peaks were detected at 254 nm.
The purity of
all tested compounds is >95%. LC/MS data were measured on an Agilent MSD-1100
ESI-
MS/MS System. All tested compounds were detected at UV 254 nm unless otherwise
stated.
1H NMR spectra were measured by Varian Mercury-300 and Varian Mercury-400
spectrometers, and the chemical shifts (6) were reported in parts per million
(ppm) relative to
the resonance of the solvent peak. Multiplicities are reported with the
following
abbreviations: s (singlet), d (doublet), t (triplet), q (quartet), quin
(quintet), m (multiplet), or
br (broad).
Date Regue/Date Received 2022-08-25

13
Without further elaboration, it is believed that one skilled in the art can,
based on the
above description, utilize the present invention to its fullest extent. The
specific
embodiments described in EXAMPLES 1-3 below are, therefore, to be construed as
merely
illustrative, and not limitative of the remainder of the disclosure in any way
whatsoever.
EXAMPLE 1: Preparation and Characterization of Compounds
Compounds 1-67 were prepared by Synthetic Methods 1-18 respectively shown in
Schemes 1-18 below.
Synthetic Method 1
Compounds 1-4, each having a 1,3-thiazol-2-y1 ring, were prepared according to
the
synthetic procedures shown in Scheme 1 below. (4-Formylphenyl)boronic acid 118
was
coupled with 2-bromothiazole derivatives 119a-d under a Suzuki-coupling
condition to
afford 4-(1,3-thiazol-2-yObenzaldehyde derivatives 120a-d. The core structure
of
imidazolidinone ring was built in the following three steps. TMSCN was added
to a solution
of benzaldehydes 120a-d and 1H-benzimidazol-5-amine 121 in acetic acid. The
reaction
mixture was stirred at room temperature for 2 hours and then worked up to
yield amino
acetonitriles 122a-d, which were hydrogenated using Raney Nickel catalyst in
acetic acid at
5-10 C to afford diamines 123a-d. In the final step, 1,1'-carbonyldiimidazole
(CDI) was
added to a solution of diamines 123a-d in THY and then stirred at 75 C for 18
hours.
Compounds 1-4 were obtained after purification by column chromatography.
Scheme 1
a R = H H2N N
j. b R = CH3 HN
N R c R = cyclopropyl N N
OH 119a-d d R = CF3 0 R¨e:S 121
0 =
bH Rcl(PPh3)4, K2CO3, H20, EtOH, H NIR TMSCN,
AcOH, r t , 2 h N
toluene, 115 C, 24 h NH
118 120a-d
CN
122a-d
0
HN--f
N lir NH
Raney Nickel, H2 (1atm) N
CDI, TEA
AcOH, 5 -10 C, 8 h THF, 75 C, 18 h
NH compound 1 R = H
compound 2 R = CH3
S 'N compound 3 R = cyclopropyl
123a-d NH2 \=( compound 4 R = CF3
Date Regue/Date Received 2022-08-25

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14
Synthetic Method 2
4-(2-Cyclopropy1-1,3thiazol-4-yl)benzaldehyde 127, a precursor, was
synthesized
under two different Suzuki-coupling conditions shown in Scheme 2 below. 2,4-
Dibromo-1,3-
thiazole 124, a starting material, was selectively coupled at 2-position with
cyclopropylboronic acid 125 using Pd(OAc)2 as a catalyst. The resultant
product 126 was
coupled at 4-position with (4-formylphenyl)boronic acid 118 using Pd(dppf)C12
as a catalyst
to afford precursor 127 having a 1,3-thiazol-4-y1 ring. This precursor was
then applied to the
procedures shown in Synthetic Method 1 for forming imidazolidinone to obtain
the final
compound (Compound 5).
Scheme 2
0 pH
>¨Ek [3,
OH OH
125 118
t$
,¨Br
K3PO4, Pd(OAc)2, Xantphos s K2CO3, Pd(cippf)C12,
THF, 70 C, 15 h 1,2-dimelhoxyethane, 80 C, 16 h
124 126
H2N 40 is,
HN¨\\
0 121 S Raney Nickel, H2 (1atm)
_____________________________________________________________ 3.-
S TMSCN, AcOH, it, 2 h AcOH, 5 -10 C, 8 h
H NH
127
128 CN
0
1 HN¨f
N *
>=-N
IS _______________________________________ NH
COI, TEA
THF, 75 C, 18h
NH
N compound 5
NH2
129 $
c>,
Synthetic Method 3
Compounds 6-8, each having a 3-thiazol-5-y1 ring, were prepared in eight steps
as
shown in Scheme 3 below. Commercially available starting material 4-
(bromoacety1)-
benzonitrile 130 was transformed into 4-(aminoacetyl)benzonitrile
hydrochloride 131 after a
substitution reaction using HMTA followed by refluxing in a solution of
hydrochloride acid
in ethanol. Compound 131 was then acetylated with variable anhydrides 132a-c
to obtain
amides 133a-c, which were subsequently treated with the Lawesson's reagent in
THF or
toluene under reflux to afford (1,3-thiazol-5-yl)benzonitrile analogs 134a-c.
The benzonitrile
analogs 134a-c were reduced by DIBAL-H to form benzaldehyde precursors 135a-c.
These

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precursors were then applied to the procedures shown in Synthetic Method 1 for
forming
imidazolidinone to obtain Compounds 6-8.
Scheme 3
o o
A A a. RR : CcyHcI03 IP
NC 0 propyl
1. HMTA, CHCI3, r.t., overnight NC R 132a-c R I/
c R = CF3
_______________________________ 1 IN
Br NH2
2. HCI, Et0H, 75 C, overnight Et3N, DCM, 0
C, 1 h
0 0 HCI
130 131
0
NC so NC 401 s
0 Lawesson's reagent DIBAL-H H
____________________________ Y ___________________ V.-
NAR THF or toluene, 1 ..--R toluene, 2 h S
i ---R
0 H reflux, overnight N
N
133a-c 134a-c 135a-c
H2N 0 N
N> R HN---s\
R HN--
H
101 __________________________________________________________ IP
N -----8 -----8
121 N N N Raney Nickel, H2 (latm) N _
--- 11
TMSCN, AcOH, r.t., 2 h 40 AcOH, 5 -10 C, 4 h NH NH
CN
136a-c 137a-c NH2
,0
HN-4(
N 0 Ns>
NH
CDI, TEA compound 6 R = CH3
_____________ ).- compound 7 R = cyclopropyl
THF, 75 C, 18 h compound 8 R = CF3
7 s
N=
R
Synthetic Method 4
Compounds 11 and 29-32, each having a thiophen-2-y1 ring, were prepared by the
synthetic procedures shown in Scheme 4 below. 4-Bromobenzaldehydes 138a-d were
each
coupled with 2-substituted thiophene 139a or 139b under a Suzuki-coupling
condition to
afford benzaldehyde precursors 140a-e. These precursors were then applied to
the
procedures shown in Synthetic Method 1 for forming imidazolidinone to obtain
Compounds
11 and 29-32.

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16
Scheme 4
.2N so N
\> R4 HN-
H N
R3 150 C, 4 h 1
RI R2 139a. R4=CH3 Ri R2 N
0 iii=
Br __________ 139b. R4=C1
p 0 R
S 4
\ I 121
_____________________________________________________________ p / S
..., R3 0
Pd(OAc)2, KOAc, DMA, TMSCN, AcOH, r t , 2 h
H H NH
R3 R2
138a-d 140a-e R1 CN
a. R1=1-1, R2=H, R3=H a. R1=1-
1, R2=H, R3=H, R4=CH3 141a-e
b. R1=h1, R2=F, R3=H b. R1=h1, R2=H, R3=H, ReCI
C. Ri=F, R2=H, R3=H C. Ri=H, R2=F, R3=H, ReCI
d. Ri=F, R2=1-1, R3=F d. Ri=F, R2=H, R3=1-1, ReCI
e. Ri=F, R2=1-1, R3=F, R4=C1
p
R4 N
HN-- N
NH
Raney Nickel, H2 (iatm) I S R3 IP CDI, TEA N
_________________________________________ R1 141111r"
AcOH, 5 -10 CC, 4 h THF, 75 C, 18 h
NH compound 11 Ri=H, R2=1-I,
R3= 1, R4=C H3
R2 R2
compound 29 R1=11, R2=1-1, R3=1-1, ReCI
R1 v s
compound 30 Ri=h1, R2=F, R3--tH, ReCI
142 _
NH
compound 31 R1 F, R2= H, R3= H, R4 CI
a-e
R4 compound 32 Ri=F, R2=1-1, R3=F, R4=C1
Synthetic Method 5
Compound 12, having a thiophen-2-y1 ring, was prepared by the synthetic
procedures
shown in Scheme 5. 4-Acetyl benzonitrile 143 was a-methylenated using
FeC13.6H20 and
K2S208 in dimethylacetamide (DMA). The resultant a-methylene product 144
reacted with
cyclopropanecarbaldehyde under a Stetter condition to form 1,4-dicarbonyl
compound 146.
This dicarbonyl compound was then treated with the Lawesson's reagent under
refluxing in
toluene to afford 4-(5-cyclopropylthiophen-2-y1) benzonitrile 147, which was
reduced by
DABAL-H to form benzaldehyde precursor 148. This precursor was then applied to
the
procedures shown in Synthetic Method 1 for forming imidazolidinone to obtain
Compound
12.

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17
Scheme 5
Ph \
NC NC Ls
FeC136H20, K2S208 I 145
DMA, 110 C, 4 h cyclopropanecarbaldehyde,
Et3N,
00 Et0H, 70 C, 12 h
143 144
0
NC NC
0 Lawesson's reagent DABAL-H H
_______________________________________________________ YR
toluene, 110 tone, 2h
h
0 / /
146 147 148
H2N N
S S
121 Raney Nickel, H2 (1atm)
TMSCN, AcOH, r.t., 2 h AcOH, 5 -10 C, 4 h
NH NH
CN
149 150 NH2
HN¨((
N
NH
CDI, TEA
THE, 75 C 18h
compound 12
s
Synthetic Method 6
Compounds 13 and 22-24, each having a thiophen-2-y1 ring, were prepared by the
synthetic procedures shown in Scheme 6. 4-Bromobenzaldehydes 138a-d were each
coupled
with thiophene under two different Suzuki-coupling conditions to form 4-
(thiophen-2-y1)-
benzaldehydes 152a-d. The benzaldehydes were iodinated by N-iodosuccinimide
(NIS) to
produce iodinated products 153a-d, which were trifluoromethylated using methyl
difluoro-
(fluoro-sulfonyl) acetate 154 and copper iodide to afford precursors 155a-d.
These
precursors were then applied to the procedures shown in Synthetic Method 1 for
forming
imidazolidinone to obtain Compounds 13 and 22-24.

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18
Scheme 6
o s
H 0
Br Pd(OAc)2, KOAc
DMA, 130 C, 20 h 0 R1 0 Ri
138a
R2 S
R2 R2
S
0 R1 s?...-Sn(nE3 -11)3 H H
NIS, AcOH, CHCI3, R3 / r.t., 8 h
0
H 151 152a-d 153a-d
R3 Br Pd(PPh3)4, toluene
reflux, 16 h
138b-d
b. Ri=H, R2=F, R3=H
c. Ri=F, R2=H, R3=H
d. Ri=F, R2=H, R3=F
0
N CF3 HN--
0 0
F ,S'!..x)1.0---
0 Ri H2N is / S
FE R3 101 N
R2 H ...--
154 H 121
Cul, NMP, DMF, 70 C, 13 h S TMSCN, AcOH, r.t., 2 h
NH
R3 1 / CF3 R2
R1 CN
155a-d 156a-d
J
HN¨OT
CF3 HN---
N N N
CU, TEA AA
NH
/ S R1 401 F21111111r7
Raney Nickel, H2 (latm) ...-- R3 0
_____________ a ________________________ ).-
AcOH, 5 -10 C, 4 h NH THF, 75 C 18 h R2 compound 13
Ri=H, R2=H, R3=H
R2 compound 22 Ri=H, R2=F, R3=H
Ri /* s compound 23 Ri=F,
R2=H, R3=H
NH2 _
157a-d compound 24 Ri=F, R2=H,
R3=F
CF3
Synthetic Method 7
Compounds 14-16 and 25-28, each having a thiophen-3-y1 ring, were prepared by
the
synthetic procedures shown in Scheme 7. Various (4-formylphenyl) boronic acids
were
coupled with 3-bromothiophene derivatives 158a-c under a Suzuki-Miyaura
coupling
condition. The resultant products 159a-g were then applied to the procedures
shown in
Synthetic Method 1 for forming imidazolidinone to obtain Compounds 14-16 and
25-28.

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19
Scheme 7
a
Br-J,,, b RRii7cHH3
.-
R1 c R1=CF3
0 . BON 158a-c . 01/4_,
H OH Fd(PPh3)4, NaHCO3, H20, H"-=/ \----i''R1
H2N 0 N\Ns HN---\\
N
(CH20Me)2, reflux, 5 h i R1
N
118 159a-c
R 4 0
121 H S ...--
,
Br_cj, TMSCN, AcOH NH
r t , 2 h R3
R2 R3 0F3 R2 R3
L 2
__________________________ 0 R2 CN
0 OH 158c /ms, B, / S
H -W- OH pd(pRh3)4, NaHCO3, H20, H --- 160a-g
CF3
(CH20Me)2, reflux, 5 h
R4 R4.159d.g
118d-g
d. R2=H, R3=F, R4=H
e. R2=F, R3=H, R4=H
f. R2=F, R3=H, R4=F
g. R2=F, R3=F, R4=H
./.,0
R1
HN ________________________ \\ HN-T
N
N N 10 =Zzi
Raney Nickel, H2 (latm) S R4 0 CD, TEA NH
I. ---- a R2 R4
AcOH, 5-10 C, 4 h THF, 75 C, 18 h
N
R3 H R3 compound 14 RI=H, R2=H,
R3=H, R4=H
compounde 15 R1=CH3, R2=H, R3=H, R4=1-I
R2
NH2 ..," compound 16 RI=CF3,
R2=H, R3=H, R4=H
161a-g s / compound 25 RI=CF3, R2=H,
R3=F, R4=H
R1 compound 26 RI=CF3, R2=F, R3=H, R4=H
compound 27 R1=CF3, R2=F, R3=H, R4=F
compound 28 R1=CF3, R2=F, R3=F, R4=H
Synthetic Method 8
Compound 17, having a thiophen-3-y1 ring, was prepared by the synthetic
procedures
shown in Scheme 8 below. Starting material 159a was selectively brominated by
bromine or
NBS in acetic acid to afford 2-brominated thiophene product 162, which was
coupled with
cyclopropyl-boronic acid under a Suzuki-coupling condition to form 4-(2-
cyclopropyl-
thiophen-3-yl)benzaldehyde 163. This benzaldehyde was then applied to the
procedures
shown in Synthetic Method 1 for forming imidazolidinone to obtain Compound 17.

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Scheme 8
OH 0
0
0
OH
Br2 or 125 NBS
AcOH, r.t., 2 days s K3PO4, Pd(OAc)2, Xantphos
THF, 70 C, 15 h
159a 162 Br 163
H2N is N
121 40 40 Raney
Nickel, H2 (1atm)
- -
TMSCN, AcOH, rt., 2 h AcOH, 5 -10 C, 4 h NH
NH
CN 164 165 NH2
HN¨'f
N *NH
CD!, TEA
THF, 75 C, 18 h
compound 17
V,
Synthetic Method 9
Compound 18, having a 1,2,4-oxadiazol-3-y1 ring, was prepared by the synthetic
procedures shown in Scheme 9. 4-Formylbenzonitrile 166, a starting material,
was protected
by monoethyleneglycol (MEG) to form acetal 167, which reacted with
hydroxylamine
hydrochloride to afford amidoxime 168. The amidoxime was acetylated by
cyclopropanecarbonyl chloride and then refluxed in toluene to form 1,2,4-
oxadiazole 170,
which was deprotected under acidic condition. The resultant product 171
reacted with
TMSCN and 1H-benzimidazol-5-amine 121 in acetic acid at room temperature for 2
hours
and was then worked up to yield amino acetonitrile 172. The amino acetonitrile
was
hydrogenated with a Pd/C catalyst in acetic acid at room temperature overnight
to afford
diamine 173. In the final step, 1,1'-carbonyldiimidazole was added to a
solution of diamine
173 in THF and then stirred at 75 C for 18 hours. Compound 18 was finally
obtained after
purification by column chromatography.

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21
Scheme 9
o MEG, PTSA 0 NH2OH.HCI, Na2CO3 .
H CNI. ,--
toluene, reflux, 3 h ______________ ^-0 * CN
Et0H/H20 (2/1), 100 C, 2 h I' ...-0 *
\NH2
----0 N-
OH
166 167 168
0
[: ¨C1 NH2 = ro * N...--,...rA conc. HCI
' C = \ \ _____________ l.
pyridine, DCM, DMF 0 N- 0 toluene, reflux, 15 h
L...0 N-C) THF/H20 (4/1)
r.t., 4 h 65 C, 6 h
169 170
0
H2N 0 N
N> HN--- HN---
0
N N
NH --= <=----N
121 Os _...N 01 Pd/C, H2 (latm) 0,
0 = NN___.17A . N _________________ r- N
TMSCN, AcOH, it, 2 h AcOH, r.t., 18 h
H N-C) 41 NH NH
171
CN
172 NH2
173
,0
HN-1
N
N .NH
CDI, TEA
__________ .
THF, 75 C, 18h
N' N compound 18
Synthetic Method 10
Compound 19, having a 1,2-oxazol-3-y1 ring, was prepared by the synthetic
procedures shown in Scheme 10. Cyclopropanecarbaldehyde 174, the starting
material,
reacted with hydroxylamine hydrochloride to afford oxime 175, which was
treated first with
N-chlorosuccinimide (NCS) and then with 4-ethynylbenzaldehyde 176 in DMF at
room
temperature to form 1,2-oxazole precursor 177. This precursor was then applied
to the
procedures shown in Synthetic Method 9 for forming imidazolidinone to obtain
Compound
19.

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Scheme 10
H2N N
11
\ ,/,)
FI , __________________________ .11 \ N,OH C3
( --- N>
0 H
NH2OH.HCI, K2CO3 176 0 O¨N 121
H H20, 85 C, 3 h H 1. NCS, pyridine, DMF H TMSCN, AcOH,
r.t., 2 h
174 175 2. 125, TEA, it., 3 h 177
,0
HN¨'f
HN--\\ HN¨\\
N N N le N'
¨.,
Os .....
110 CD!, TEA NH
N _______________________ x N = 40/
AcOH, r.t., 18 h THF, 75 18h
NH NH
compound 19
CN N"
178 NH2 % /
179 0
Synthetic Method 11
Compounds 20 and 21, each having a 2H-tetrazol-5-y1 ring, were prepared by the
synthetic procedures shown in Scheme 11. 4-Forrnylbenzonitrile 166, the
starting material,
reacted with sodium azide and ammonium chloride in DMF under refluxing to form
tetrazole
compound 180, which was substituted by variable alkyl halides to afford
precursors 181a-b.
These precursors were then applied to the procedures shown in Synthetic Method
9 for
forming imidazolidinone to obtain Compounds 20 and 21.

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Scheme 11
0
CN ___________________________
1. NaN3, NH4CI, DMF 0
P-NH 1-1CI N... I
-N R-X
K2CO3, MeCN, 50 C w
reflux, overnight
166 180
2. 1N HCI(aq), 0 C
H2N N
N-N
0110 Pd/C, H2 (1atm)
0 =
N-N-R
/
N
Nir-N TMSCN, AcOH, r.t., 2 h AcOH, r.t., 18 h
NH
181a R = n-propyl
181b R = isopropyl CN
182a-b
0
N 110
N-N NH
Nis, I CDI, TEA
NH THF, 75 C, 18h compound 20 R = n-propyl
L. N'N
compound 21 R = isopropyl
183a-b NH2 N-Nis
Synthetic Method 12
Compound 37, having a 1,3-thiazol-2-y1 ring, was prepared by the synthetic
procedures shown in Scheme 12. (4-Acetylphenyl)boronic acid 184 was coupled
with 2-
bromo-4-(trifluoromethyl)-1,3-thiazole 119d under a Suzuki-coupling condition.
The
resultant product 185 was oxidized by selenium dioxide to afford glyoxal 186.
The glyoxal
was mixed with benzimidazolylurea 187 in HCl/AcOH (1/40 v/v) and then refluxed
overnight. After removing the solvents under reduced pressure, the residue was
treated with
excess ammonia solution in methanol for several hours. The crude product was
purified by
column chromatography to yield Compound 37.

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Scheme 12
Br¨ON
0 B4OH 119dCF3 0 = S Se02, H20,
dioxane
\
OH Pd(PPh3)4, K2CO3, H20,
N C F3 100 C, overnight
Et0H,
184 185
toluene, 115 C, 24 h
<,rsl
N NH2 N slti
NH
0 187
\
0 N 1. HCI HOAc, 120 C, overnight
186
2. excess NH3 in MeCH compound 37
S
CF3
Synthetic Method 13
Compound 38, having a 1,3-thiazol-4-y1 ring, was prepared by the synthetic
procedures shown in Scheme 13. 4-Bromo-2-cyclopropy1-1,3-thiazole 126, an
intermediate
prepared following Synthetic Method 2, was coupled with (4-
acetylphenyl)boronic acid 184
under a Suzuki-coupling condition. The resultant coupling product 188 was
oxidized by
selenium dioxide to glyoxal 189. Compound 38 was formed from glyoxal 189 and
benzimidazolylurea 187 via a cycloaddition reaction. The procedures were the
same those
shown in Synthetic Method 12.
Scheme 13
o apH
OH
0
184 L __________________________ ,kµ Se02, H20, dioxane s)-1 s
K2CO3, Pd(dPPOCl2, \7 s¨ 100 C, ovemight 0
1,2-dimethoxyethane, 80 C, 16 h
126 188
189
0
(õN1 so 0
0 HN1 N,)
N NH2
NH
187
1. HCI, HOAc, 120 C, overnight
2. excess NH3 in Me0H compound 38
N

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Synthetic Method 14
Compounds 39 and 40, each having a 1,3-thiazol-5-y1 ring, were prepared by the
synthetic procedures shown in Scheme 14. 1,3-'Thiazol-5-ylbenzonitriles 134b-
c,
intermediates prepared following Synthetic Method 3, were acetylated by
methylmagnesium
bromide. The resultant acetyl products 190b-c were oxidized by selenium
dioxide to
glyoxals 191b-c. Compounds 39 and 40 were formed from glyoxals 191b-c and
benzimidazolylurea 187 via a cycloaddition reaction. The procedures were the
same as those
shown in Synthetic Method 12.
Scheme 14
o 0
NC 0
CH3MgBr Se02, H20, dioxane
THF, 0 C to r.t., 100 C, overnight H
overnight
134b R = cyclopropyl 190b R = cyclopropyl 191b R = cyclopropyl
134c R = CF3 190c R = CF3 191c R = CF3
0
,
N NH2 *
NH
187 N
1. HCI, HOAc, 120 C, overnight compound 39 R = cyclopropyl
2. excess NH3 in Me0H compound 40 R = CF3
Synthetic Method 15
Compounds 41-52, each having a 2H-tetrazol-5-y1 ring, were prepared by the
synthetic procedures shown in Scheme 15. Starting material 143 reacted with
sodium azide
and ammonium chloride under refluxing in DMF to form tetrazole 192, which was
substituted with variable alkyl halides to give precursors 193a-1. These
precursors were then
applied to the procedures shown in Synthetic Method 12 for forming hydantoin
to yield
Compounds 41-52.

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Scheme 15
CN _________ NaN3, NH4Cl
DMF, reflux, 18 hj. 0 N-
/
N,N HCI R-X N-N-R
K2CO3, MeCN, 50 C
143 192 193a-I
0
0 HN¨f
NANH2 0 N
NH
SeO2, H20, dioxane 0 N-N-R 187
100 C, overnight 0 1. HCI, HOAc, 120 C, overnight
2. excess NH3 in Me0H compounds 41-52
194a-I N
siR
compound 41 R = CH3
compound 42 R = n-propyl compound 48 R =
compound 43 R = isopropyl =/
compound 44 R = isobutyl compound 49 R
compound 45 R CI
compound 50 R = =
compound 46 RqCF3 compound 51 R= .. = OCH3
0=K,
compound 47 = compound 52 R
Synthetic Method 16
Compound 57 having a 1,3-thiazol-5-y1 ring was prepared by the synthetic
procedures
shown in the Scheme 16. Starting material 131 was acetylated with adamantane-l-
carbonyl
chloride 195 to obtain amide 196. Subsequently, the amide 196 was mixed with
the
Lawesson's reagent under reflux in THF to afford (1,3-thiazol-5-ye-
benzonitrile 197, which
was reduced by DIBAL-H to form benzaldehyde 198. The benzaldehyde 198 was then
applied to the procedures shown in Synthetic Method 1 for forming
imidazolidinone to obtain
Compound 57.

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Scheme 16
Cl
NC 0 0 NC 0 0 NC so
195 õAig Lawesson's reagent
________________________ ai ___________________________ 1
N
THF, reflux, overnight
NH Et3N, DCM, 0 C, 1 h H
0 HCI 0 N
131 196 197
H2N soi N
0 \> HN¨,,,
N
H H (1...s N
DIBAL-H 121 N 110 Raney Nickel, H2
(1atm)
______ r r ____________________________ ar
toluene, 1 S¨P TMSCN, AcOH, r t , 2 h
NH AcOH, 5 -10 C, 4 h
-70 C,1 h N
198 CN
199
,p
HN-i"
N
"s)
N NH
q.._s CD!, TEA
N
1001 yo.
THF, 75 C, 18 h
NH
NH2 N.121
7 S
200
compound 57
Synthetic Method 17
Compounds 58-65 each having a thiophen-3-y1 ring were prepared by the
synthetic
procedures shown in Scheme 17. 2,3-Difluoro-4-fonnylphenylboronic acid 118g
was
coupled with 3-bromothiophene derivatives 158a-b and 158d-i under a Suzuki-
Miyaura
coupling condition. The resulting products 201a-h were then applied to the
procedures
shown in Synthetic Method 1 for forming imidazolidinone to obtain Compound 58-
65.

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Scheme 17
H2N 0 N
Br¨a Ri
HN¨\\
1
F F R1
0 . pH
158a-b, _______________ d-h 0
/ S 121
a
H 1DH Pd(PPh3)4, NaHCO3, H20, H
N
TMSCN, AcOH (CH20Me)2, reflux, 5 h R1 NH
r t , 2 h F
118g 201a-h
F CN
a Ri=H a Ri=F
b R1=CH3 b R1=01 202a-h
d Ri=-F c R1-=CH3
e Ri=CI d R1=CH2CH3
f Ri=CH2CH3 e R1=CH2OCH3
g R1=CH200H3 f Ri=CH20CH2CH3
h R1=-CH2OCH2CH3 g R1-=0020H2
i R1=CO2CH3 h Ri=H
0
R1
HN--\\ HN--=
N N
CDI TEA F N
* ..)
Raney Nickel, H2 (latrn) S
IP ________________________________ , NH
_____________ a- --- r
AcOH, 5 -10 C, 4 h THF, 75 C, 18 h
NH compound 58 Ri=F
F F F
compound 59 R1-=CI
NH2 , , compound 60 R1=CH3
/ compound 61 R1=CH2CH3
203a-.h S compound 62 R1=CH2OCH3
R1 compound 63 R1=-CH200H2CH3
compound 64 R1=CO2CH3
compound 65 Ri=H
Synthetic Method 18
Compound 66 was prepared through hydrolysis reaction of compound 64 in a
solution
of potassium hydroxide in methanol shown in Scheme 18. Compound 67 was
prepared
through reduction of compound 64 by LAH in dry THF also shown in this scheme.
Scheme 18
,0 HN¨ , HN¨
o ,p
HN¨ T
N T
N /f
N
N * s)
NH * ''
N N 1p
F so
, _________________________
, THF, reflux, 3 h FF N H SI F
NH
LAN
F KOH, Me0H, 60 C, 1.5 h F SO
7 , 7 , 7 ,
S/ S/ S/ OH 0 OH
\
0 0
compound 67 compound 64
compound 66
Below are the detailed procedures of preparing Compounds 1-67 following
Synthetic
Methods 1-18 set forth above and the analytical data of the intermediates and
the final
products generated in these procedures.

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4-(1,3-thiazol-2-yl)benzaldehyde (Compound 120a)
o *
The (4-foratylphenyl)boronic acid 118 (0.30 g, 2.0 mmol), 2-bromo-1,3-thiazole
119a
(0.33 g, 2.0 mmol), Pd(PPh3)4 (0.12 g, 0.1 mmol), aqueous solution of
potassium carbonate
(0.4 M, 5 mL), ethanol (5 mL) and toluene (2mL) were added to a 50 mL flask
under
nitrogen. The reaction mixture was stirred at 115 C for 24 hours and then
cooled to room
temperature. After removing the solvent, the crude residue was purified by
column
chromatography on silica gel using EA/hexane (1/5) as eluent. The product 120a
was
obtained as a white solid at a yield of 95%.
4-(4-methyl-1,3-thiazol-2-yl)benzaldehyde (Compound 120b)
s,
\ I
The 4-(4-methyl-1,3-thiazol-2-yflbenzaldehyde 120b was prepared from the
Suzuki-
coupling of (4-formylphenyl)boronic acid 118 and 2-bromo-4-methyl-1,3-thiazole
119b. The
procedures were the same as the synthesis of Compound 120a. The product 120b
was
obtained as a white solid at a yield of 90%.
4-(4-cyclopropy1-1,3-thiazol-2-yl)benzaldehyde (Compound 120c)
\Nisv
The 4-(4-cyclopropy1-1,3-thiazol-2-yl)benzaldehyde 120c was prepared from the
Suzuki-coupling of (4-formylphenyl)boronic acid 118 and 2-bromo-4-cyclopropy1-
1,3-
thiazole 119c. The procedures were the same as the synthesis of Compound 120a.
The
product 120c was obtained as a white solid at a yield of 92%.
4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]benzaldehyde (Compound 120d)
0 *
N r
3
The 4[4-(trifluoromethyl)-1,3-thiazol-2-ylThenzaldehyde 120d was prepared from
the
Suzuki-coupling of (4-formylphenyl)boronic acid 118 and 2-bromo-4-
(trifluoromethyl)-1,3-
thiazole 119d. The procedures were the same as the synthesis of Compound 120a.
The
product 120d was obtained as a white solid at a yield of 90%.

30
(1H-benzimidazol-5-ylamino)[4-(1,3-thiazol-2-yl)phenyl]acetonitrile (Compound
122a)
HN--\\
CS
1110
NH
CN
To the solution of 1H-benzimidazol-5-amine 121 (0.68 g, 5.11 mmol) in acetic
acid
(20 mL), the Compound 120a (1.06 g, 5.62 mmol) was added and stirred at room
temperature
for 20 minutes. TMSCN (1 mL) was added dropwise to the reaction mixture and
continuously stirred for 2 hours. After reaction completing, the reaction
mixture was
concentrated under reduced pressure to yield a viscous liquid. The viscous
liquid was diluted
with ethyl acetate (10 mL) and water. The diluted solution was adjusted to the
pH 6-7 with
ammonia at an ice-bath. The neutralized solution was extracted with ethyl
acetate (20 mL x
4), dried over sodium sulfate, filtered and concentrated under reduced
pressure to yield a
viscous dark-yellow solid. The solid was dissolved in ethyl acetate (15 mL)
and brine (15
mL). The mixture was stirred at room temperature for 2 minutes to form the
pale-yellow
precipitates. The pale-yellow precipitates were filtered and washed with
water. The filtrate
was dried over sodium sulfate and concentrated under reduced pressure to
obtain the pale-
yellow solid. Those pale-yellow solids were combined as the desired product
122a at a yield
of 96%.
(1H-benzimidazol-5-ylamino)14-(4-methy1-1,3-thiazol-2-y1)phenyliacetonitrile
(Compound 122b)
HN-
NH
CN
The (1H-benzimidazol-5-ylamino)[4-(4-methyl-1,3-thiazol-2-
yl)phenyllacetonitrile
122b was prepared from the addition of 1H-benzimidazol-5-amine 121, TMSCN and
Compound 120b. The procedures were the same as the synthesis of Compound 122a.
The
product 122b was obtained as a pale-yellow solid at a yield of 97%.
Date Regue/Date Received 2022-08-25

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(1H-benzimidazol-5-ylamino)[444-cyclopropy1-1,3-thiazol-2-
yl)phenyl]acetonitrile
(Compound 122c)
HN-
N
NH
CN
The (1H-benzimidazol-5-ylamino)[4-(4-cyclopropy1-1,3-thiazol-2-
y1)phenyliacetonitrile 122c was prepared from the addition of 1H-benzimidazol-
5-amine 121,
TMSCN and Compound 120c. The procedures were the same as the synthesis of
Compound
122a. The product 122c was obtained as a pale-yellow solid at a yield of 95%.
(1H-benzimidazol-5-ylamino)(4-[4-(trifluoromethyl)-1,3-thiazol-2-
yl]phenyl}acetonitrile
(Compound 122d)
F3C-e 1101
N
NH
CN
The (1H-benzimidazol-5-ylamino) {4- [4-(trifluoromethyl)-1 ,3 -thiazol-2-
yl]phenyll-
acetonitrile 122d was prepared from the addition of 1H-benzimidazol-5-amine
121, TMSCN
and Compound 120d. The procedures were the same as the synthesis of Compound
122a.
The product 122d was obtained as a pale-yellow solid at a yield of 96%.
M-(1H-benzimidazol-5-y1)-1-[4-(1,3-thiazol-2-y1)phenyl]ethane-1,2-diamine
(Compound 123a)
HN--\\
NH
NH2
The Compound 122a (5.0 g, 15.08 mmol) was dissolved in acetic acid (200 mL)
and
then stirred at 10 C for 5 minutes. The Raney Nickel reagent was added to the
stirring
solution and refilled hydrogen three times. The reaction mixture was stirred
under hydrogen
at 10 C for 8 hours. The catalyst was removed by filtration through celite.
The filtrate was
concentrated under reduced pressure to obtain the crude product. The crude
product was
purified by column chromatography on silica gel using methanol
/dichloromethane (1/19) as
eluent. The product 123a was obtained as a yellow viscous liquid at a yield of
60%.

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N'-(1H-benzimidazol-5-y1)-144-(4-methyl-1,3-thiazol-2-yl)phenyl]ethane-1,2-
diamine
(Compound 123b)
HN-\\
_CS
1110
NH
NH2
The NI-(1H-benzimidazol-5-y1)-1-[4-(4-methy1-1,3-thiazol-2-yephenyllethane-1,2-
diamine 123b was prepared from the hydrogenation of Compound 122b with the
Raney
Nickel reagent as catalyst. The procedures were the same as the synthesis of
Compound
123a. The product 123b was obtained as a yellow viscous liquid at a yield of
50%.
N41H-benzimidazol-5-y1)-1-[4-(4-cyclopropyl-1,3-thiazol-2-y1)phenynethane-1,2-
diamine (Compound 123c)
H N-
1110
NH
NH2
The NI-(1H-benzimidazol-5-y1)-1-[4-(4-cyclopropy1-1,3-thiazol-2-
yephenyllethane-
1,2-diamine 123c was prepared from the hydrogenation of Compound 122c with the
Raney
Nickel reagent as catalyst. The procedures were the same as the synthesis of
Compound
123a. The product 123c was obtained as a yellow viscous liquid at a yield of
54%.
N1-(1H-benzimidazol-5-y1)-1-{4-[4-(trifluoromethyl)-1,3-thiazol-2-
yl]phenyllethane-1,2-
diamine (Compound 123d)
F3C-e0
S 1011
NH
NH2
The NI -(1H-benzimidazol-5-y1)-1- {444-(trifluoromethyl)-1,3-thiazol-2-
yl]phenyl -
ethane-1,2-diamine 123d was prepared from the hydrogenation of Compound 122d
with the
Raney Nickel reagent as catalyst. The procedures were the same as the
synthesis of
Compound 123a. The product 123d was obtained as a yellow viscous liquid at a
yield of
40%.

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1-(1H-benzimidazol-5-y1)-5-[4-(1,3-thiazol-2-y1)phenyl]imidazolidin-2-one
(Compound
1)
õ0
HN--4(
N*
NH
11101
S
\./
To the solution of 1,1'-carbonyl diimidazole (2.21 g, 20.5 mmol) and
trimethylamine
(7.5 mL) in anhydrous THF (100 mL), the solution of Compound 123a (4.56 g,
13.6 mmol)
in anhydrous THF (100 mL) was added dropwise by additional funnel at room
temperature.
The resulting mixture was heated to 75 C and stirred for 18 hours. After
cooling to room
temperature, the reaction mixture was concentrated under reduced pressure. The
crude
residue was purified by column chromatography on silica gel using
methanol/dichloromethane (1/19) as eluent. The product (Compound 1) was
obtained as a
white solid at a yield of 70%. 41 NMR (400MHz, CD30D) 6 3.39 (dd, 1H, J = 7.0,
9.2 Hz),
4.02 (dd, 1H, J = 9.2, 9.2 Hz), 5.55 (dd, 1H, J = 7.0, 9.2 Hz), 7.31 (d, 1H, J
= 8.8 Hz), 7.48 (d,
1H, J = 8.8 Hz), 7.52 (d, 2H, J = 8.2 Hz), 7.56 (s, 1H), 7.57 (s, 1H), 7.82
(d, 1H, J = 3.6 Hz),
7.88 (d, 2H, J = 8.2 Hz), 8.06 (s, 1H); LC/MS (ESI) m/z: 362.1 [M + Hr.
1-(1H-benzimidazol-5-y1)-5-[4-(4-methyl-1,3-thiazol-2-yl)phenyl]imidazolidin-2-
one
(Compound 2)
,0
HN-1
N
N' S
The 1-(1H-benzimidazol-5-y1)-5-[4-(4-methyl-1,3-thiazol-2-
yl)phenyl[imidazolidin-
2-one (Compound 2) was prepared from the cycloaddition of 1,1'-carbonyl
diimidazole and
Compound 123b. The procedures were the same as the synthesis of Compound 1.
The
product (Compound 2) was obtained as a white solid at a yield of 66%. 41 NWIR
(400MHz,
DMSO-d6) 6 2.37 (s, 3H), 3.13 (dd, 1H, J = 6.6, 8.8 Hz), 3.87 (dd, 1H, J =
8.8, 9.2 Hz), 5.58
(dd, 1H, J = 6.6, 9.2 Hz), 7.01 (s, 1H)õ 7.27 (s, 2H), 7.40 (s, 1H), 7.46 (d,
2H, J = 8.2 Hz),
7.57 (s, 1H), 7.83 (d, 2H, J = 8.2 Hz), 8.07 (s, 1H); LC/MS (ES!) m/z: 376.2
[M -- H].

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1-(1H-benzimidazol-5-y1)-5-[4-(4-cyclopropyl-1,3-thiazol-2-
y1)phenyllimidazolidin-2-one
(Compound 3)
,0
HN-l<
N
NH
N S
The 1-(1H-benzimidazol-5-y1)-5-[4-(4-cyclopropy1-1,3-thiazol-2-
yflphenyflimidazolidin-2-one (Compound 3) was prepared from the cycloaddition
of 1,1'-
carbonyl diimidazole and Compound 123c. The procedures were the same as the
synthesis of
Compound 1. The product (Compound 3) was obtained as a white solid at a yield
of 71%.
NMR (400MHz, DMSO-d6) 5 0.80-0.84 (m, 2H), 0.85-0.90 (m, 2H), 2.05-2.09 (m,
1H),
3.12 (dd, 1H, J = 6.4, 8.8 Hz), 3.87 (dd, 1H, J = 8.8, 9.2 Hz), 5.57 (dd, 1H,
J = 6.4, 9.2 Hz),
7.02 (s, 1H), 7.26 (s, 2H), 7.39 (d, 1H, J = 8.4 Hz), 7.45 (d, 2H, J = 7.8
Hz), 7.55 (s, 1H), 7.79
(d, 2H, J = 7.8 Hz), 8.07 (s, 1H), 12.27 (s, 1H); LC/MS (ESI) m/z: 402.2 [M +
Hr.
1-(1H-benzimidazol-5-y1)-5-{444-(trifluoromethyl)-1,3-thiazol-2-
yllphenyllimidazolidin-
2-one (Compound 4)
HN-,0
N
NH
N=/ S
F3C)-/
The 1-(1H-benzimidazol-5-y1)-5- {4- [4-(trifluoromethyl)-1,3-thiazol-2-
yllphenyl)-
imidazolidin-2-one (Compound 4) was prepared from the cycloaddition of
carbonyl
diimidazole and Compound 123d. The procedures were the same as the synthesis
of
Compound 1. The product (Compound 4) was obtained as a white solid at a yield
of 67%.
NMR (300MHz, DMSO-d6) 5 3.14 (dd, 1H, J = 6.3, 8.7 Hz), 3.89 (dd, 1H, J = 8.7,
9.0
Hz), 5.62 (dd, 1H, J = 6.3, 9.0 Hz), 7.02 (d, 1H, J = 8.7 Hz), 7.28 (s, 1H),
7.40 (d, 1H, J = 8.7
Hz), 7.52 (d, 2H, .1 = 8.1 Hz), 7.57 (s, 1H), 7.92 (d, 2H, J = 8.1 Hz), 8.08
(s, 1H), 8.50 (s, 1H),
12.21 (s, 1H); LC/MS (ESI) m/z: 430.2 [M -4- Hr.

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4-bromo-2-cyclopropy1-1,3-thiazole (Compound 126)
BrN
L
The palladium acetate (0.025 g, 0.11mmol) and Xantphos (0.066 g, 0.11 mmol)
were
added in THF (22 mL) that degassed under argon. Then, the reaction mixture was
stirred at
room temperature for 5 minutes. The 2,4-dibromo-1,3-thiazole 124 (1.09 g, 4.50
mmol),
cyclopropylboronic acid 125 (0.58 g, 6.70 mmol) and potassium phosphate (2.86
g) were
added to the reaction mixture and flushed with argon. The reaction mixture was
stirred at 70
C for 15 hours. After cooling to room temperature, the reaction mixture was
filtered and
washed with dichloromethane. The filtrate was concentrated under reduced
pressure and
purified by column chromatography on silica gel using hexane as eluent. The
product 126
was obtained as a colorless oil at a yield of 81%.
4-(2-cyclopropy1-1,3-thiazol-4-yl)benzaldehyde (Compound 127)
\x_<===
S
The (4-formylphenyl)boronic acid 118 (0.33 g, 2.2 mmol), 4-bromo-2-cyclopropyl-
1,3-thiazole 126 (0.41 g, 2.0 mmol), Pd(dppf)C12 (0.08 g, 0.1 mmol), potassium
carbonate
(0.41 g) and 1,2-dimethoxyethane (20 mL) were added to a 50 mL round-bottom
flask under
nitrogen. The reaction mixture was stirred at 80 C for 16 hours and then
cooled to room
temperature. The reaction mixture was partitioned between ethyl acetate and
water. The
organic layers were collected, dried over sodium sulfate, filtered and
concentrated under
reduced pressure. The residue was purified by column chromatography on silica
gel using
hexane/ether (10/1) as eluent. The product 127 was obtained as a white solid
at a yield of
55%. 1H NMR (300MHz, CDC13) .5 1.10-1.16 (m, 4H), 2.32-2.39 (m, 1H), 7.40 (s,
1H), 7.89
(d, 2H, J = 8.4 Hz), 8.03 (d, 2H, J = 8.4 Hz), 10.01 (s, 1H); LC/MS (ESI) m/z:
230.1 IM +
1-1]+.

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(1H-benzimidazol-5-ylamino)[442-cyclopropy1-1,3-thiazol-4-
yl)phenyl]acetonitrile
(Compound 128)
H N
N
N H
C N
The (1H-benzimidazol-5-ylamino)[4-(2-cyclopropy1-1,3-thiazol-4-
yl)phenyl[acetonitrile 128 was prepared from the addition of 1H-benzimidazol-5-
amine 121,
TMSCN and Compound 127. The procedures were the same as the synthesis of
Compound
122a. The product 128 was obtained as a pale-yellow solid at a yield of 93%.
M-(11-1-benzimidazol-5-y1)-144-(2-cyclopropy1-1,3-thiazol-4-yl)phenyl]ethane-
1,2-
diamine (Compound 129)
H
N
N H
N 2
The N1-(1H-benzimidazol-5-y1)-1-[4-(2-cyclopropy1-1,3-thiazol-4-
yephenyllethane-
1,2-diamine 129 was prepared from the hydrogenation of Compound 128 with the
Raney
Nickel reagent as catalyst. The procedures were the same as the synthesis of
Compound
123a. The product 129 was obtained as a yellow viscous liquid at a yield of
52%.
1-(1H-benzimidazol-5-y1)-5-[4-(2-cyclopropyl-1,3-thiazol-4-
yl)phenyl]imidazolidin-2-one
(Compound 5)
0
H N ¨g
N
NH
N
S

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The 1-(1H-benzimidazol-5-y1)-5-[4-(2-cyclopropy1-1,3-thiazol-4-
y1)phenyllimidazolidin-2-one (Compound 5) was prepared from the cycloaddition
of 1,1'-
carbonyl diimidazole and product (129). The procedures were the same as the
synthesis of
Compound 1. The product (Compound 5) was obtained as a white solid at a yield
of 73%.
NMR (300MHz, DMSO-d6) 6 0.93-0.98 (m, 2H), 1.08-1.16 (m, 2H), 2.34-2.42 (m,
1H),
3.13 (dd, 1H, J = 6.6, 9.0 Hz), 3.85 (dd, 1H, J = 8.7, 9.0 Hz), 5.52 (dd, 1H,
J = 6.6, 8.7 Hz),
6.98 (s, 1H), 7.25 (d, 1H, J = 8.1 Hz), 7.37-7.40 (m, 3H), 7.54 (s, 1H), 7.72
(s, 1H), 7.80 (d,
2H, J = 8.1 Hz), 8.07 (s, 1H), 12.24 (s, 1H); LC/MS (ESI) miz: 402.2 [M + Hr.
4-Glycylbenzonitrile hydrochloride (Compound 131)
NC
NH2
0 HCI
The 4-(bromoacetyl)benzonitrile 130 (22.4 g, 100 mmol) and
hexamethylenetetramine
(HMTA, 15.4 g, 110 mmol) were dissolved in chloroform (900 mL). The reaction
mixture
was stirred at room temperature overnight. The precipitates were filtered and
washed with
ethanol and ether. The resulting solids were suspended in the mixture of
HCl/ethanol (48
mL/240 mL) and then stirred at 75 C overnight. The precipitates were filtered
when the
solution was still warm. The filtrate was concentrated to remove solvents.
Some acetone
(100 mL) was added and stirred for an hour. The precipitates were filtered and
washed with
acetone and ether. The product 131 was obtained as an off-white solid in a
quantum yield
and without further purification. 1HNMR (300MHz, DMSO-d6) 6 4.62 (s, 2H), 8.06
(d, 2H,
J = 8.4 Hz), 8.16 (d, 2H, J = 8.4 Hz), 8.59 (s, 2H); LC/MS (ESI) m/z: 161.1 [M
+ H1+.
N-[2-(4-cyanophenyI)-2-oxoethyl]acetamide (Compound 133a)
NC
0
1\1)
0
The triethylamine (21 mL) was added to the suspending solution of Compound 131
(10 g, 50.85 mmol) in dichloromethane (330 mL) and stirred at room temperature
for 10
minutes. The acetic anhydride (7.79 g, 76.28 mmol) was diluted in
dichloromethane (20 mL)
and then added to the reaction solution during 30 minutes by additional funnel
at an ice-bath.
The resulting mixture was continuously stirred at room temperature for an
hour. The reaction
was quenched by water and extracted with dichloromethane. The organic layers
were
collected, dried over sodium sulfate, filtered and concentrated under reduced
pressure. The

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crude residue was purified by column chromatography on silica gel using ethyl
acetate/hexane (1/2) as eluent. The product 133a was obtained as a yellow
solid at a yield of
70%.
Art2-(4-cyanopheny1)-2-oxoethylkyclopropanecarboxamide (Compound 133b)
NC
0
HN-j-LV
0
The N12-(4-cyanopheny1)-2-oxoethyl]cyclopropanecarboxamide 133b was prepared
from the acetylation of Compound 131 with cyclopropanecarboxylic anhydride
132b. The
procedures were the same as the synthesis of Compound 133a. The product 133b
was
obtained as a yellow solid at a yield of 73%. 1H NMR (400MHz, DMSO-do) 60.65-
0.68 (m,
4H), 1.70 (m, 1H), 4.64 (d, 2H, J = 5.4 Hz), 8.01 (d, 2H, J = 8.4 Hz), 8.10
(d, 2H, J = 8.4 Hz),
8.51 (t, 1H, d, J = 5.4 Hz); LC/MS (ES!) m/z: 229.1 [IA + Hr.
AT-[2-(4-cyanopheny1)-2-oxoethy1]-2,2,2-trifluoroacetamide (Compound 133c)
NC
0
N F3
0
The N42-(4-cyanopheny1)-2-oxoethy1]-2,2,2-trifluoroacetamide 133c was prepared
from the acetylation of Compound 131 with trifluoroacetic anhydride 132c. The
procedures
were the same as the synthesis of Compound 133a. The product 133c was obtained
as a
yellow solid at a yield of 73%.
4-(2-methy1-1,3-thiazol-5-y1)benzonitrile (Compound 134a)
NC
S,
The Compound 133a (0.3 g, 1.48 mmol) and Lawesson's reagent (0.9 g, 2.22 mmol)
were dissolved in THF (20 mL). The reaction mixture was refluxed and stirred
for 17 hours.
After removing the solvent, the crude residue was purified by column
chromatography on
silica gel using ethyl acetate/hexane (1/10) as eluent. The product 134a was
obtained as a
yellow solid at a yield of 70%.

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4-(2-cyclopropy1-1,3-thiazol-5-yl)benzonitrile (Compound 134b)
NC
The 4-(2-cyclopropy1-1,3-thiazol-5-yl)benzonitrile 134b was prepared from the
cyclization of Compound 133b with the Lawesson's reagent in THF. The
procedures were
the same as the synthesis of Compound 134a. The product 134b was obtained as a
yellow
solid at a yield of 67%. 41 NMR (300MHz, CDC13) 6 1.10-1.21 (m, 4H), 2.31-2.35
(m, 1H),
7.59 (d, 2H, J = 8.4 Hz), 7.66 (d, 2H, J = 8.4 Hz), 7.84 (s, 1H); LC/MS (ESI)
m/z: 227.1 [M +
H[ .
4[2-(trifluoromethyl)-1,3-thiazol-5-yllbenzonitrile (Compound 134c)
NC
The 4[2-(trifluoromethyl)-1,3-thiazol-5-yllbenzonitrile 134c was prepared from
the
cyclization of Compound 133c with the Lawesson's reagent in toluene. The
procedures were
the same as the synthesis of Compound 134a. The product 134e was obtained as a
yellow
solid at a yield of 65%. NMR (400MHz, CDC13) 6 7.68 (d, 2H, J = 8.8 Hz),
7.74 (d, 2H, J
= 8.8 Hz), 8.15 (s, 1H); LC/MS (ESI) miz: 255.1 [M + Hr.
4-(2-methy1-1,3-thiazol-5-yl)benzaldehyde (Compound 135a)
0
Ss
To a solution of Compound 134a (1.57 g, 7.86 mmol) in anhydrous toluene (100
mL)
that cooled at -70 C, the solution of DIBAL-H in toluene (1.2M, 13.1 mL) was
added
dropwise by using additional funnel. The reaction mixture was stirred at -70
C under argon
for an hour and then quenched with 1N HC1(aq) (20 mL). The reaction mixture
was stirred
continuously at room temperature overnight. The reaction mixture was partition
between
ethyl acetate and water. The organic layers were collected, washed with brine,
dried over
sodium sulfate, filtered and concentrated under reduced pressure. The crude
residue was
purified by column chromatography on silica gel using ethyl acetate/hexane
(1/5) as eluent.
The product 135a was obtained as a yellow solid at a yield of 63%.

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4-(2-cyclopropy1-1,3-thiazol-5-yl)benzaldehyde (Compound 135b)
0
The 4-(2-cyclopropy1-1,3-thiazol-5-ypbenzaldehyde 135b was prepared from the
reduction of Compound 134b with the DIBAL-H reagent. The procedures were the
same as
the synthesis of Compound 135a. The product 135b was obtained as a yellow
solid at a yield
of 66%. 1HNMR (300MHz, CDC13) .5 1.13-1.20 (m, 4H), 2.31-2.35 (m, 1H), 7.65
(d, 2H, J
= 6.9 Hz), 7.87-7.89 (m, 3H), 9.99 (s, 1H); LC/MS (ESI) m/z: 230.1 [M + Hr.
4[2-(trifluoromethyl)-1,3-thiazol-5-yllbenzaldehyde (Compound 135c)
0
The 4-[2-(trifluoromethyl)-1,3-thiazol-5-yflbenzaldehyde 135c was prepared
from the
reduction of Compound 134c with the DIBAL-H reagent. The procedures were the
same as
the synthesis of Compound 135a. The product 135c was obtained as a yellow
solid at a yield
of 65%.
(1H-benzimidazol-5-ylamino)[4-(2-methyl-1,3-thiazol-5-y1)phenyl]acetonitrile
(Compound 136a)
HN¨\\
NH
CN
The (1H-benzimidazol-5-ylamino)[4-(2-methyl-1,3-thiazol-5-
yl)phenyl]acetonitrile
136a was prepared from the addition of 1H-benzimidazol-5-amine 121, TMSCN and
Compound 135a. The procedures were the same as the synthesis of Compound 122a.
The
product 136a was obtained as a pale-yellow solid at a yield of 90%.

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(1H-benzimidazol-5-ylamino)[442-cyclopropy1-1,3-thiazol-5-
yl)phenyl]acetonitrile
(Compound 136b)
HN-
LJiNH
CN
The (1H-benzimidazol-5-ylamino)l4-(2-cyclopropyl-1,3-thiazol-5-
yl)phenyllacetonitrile 136b was prepared from the addition of 1H-benzimidazol-
5-amine 121,
TMSCN and Compound 135b. The procedures were the same as the synthesis of
Compound
122a. The product 136b was obtained as a pale-yellow solid at a yield of 92%.
(1H-benzimidazol-5-ylamino){4-[2-(trifluoromethyl)-1,3-thiazol-5-
yl]phenyllacetonitrile
(Compound 136c)
F3C H
11101
NH
CN
The (1H-benzimidazol-5-ylamino) 4-12-(trifluoromethyl)- 1,3 -thiazol-5-
yllphenyl 1 -
acetonitrile 136c was prepared from the addition of 1H-benzimidazol-5-amine
121, TMSCN
and Compound 135c. The procedures were the same as the synthesis of Compound
122a.
The product 136c was obtained as a pale-yellow solid at a yield of 90%.
N1-(1H-benzimidazol-5-y1)-1-[4-(2-methyl-1,3-thiazol-5-yl)phenyl]ethane-1,2-
diamine
(Compound 137a)
NH
NH2
The Nk1H-benzimidazol-5-y1)-1-14-(2-methyl-1,3-thiazol-5-yephenyllethane-1,2-
diamine 137a was prepared from the hydrogenation of Compound 136a with the
Raney
Nickel reagent as catalyst. The procedures were the same as the synthesis of
Compound
123a. The product 137a was obtained as a yellow viscous liquid at a yield of
50%.

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N'-(1H-benzimidazol-5-y1)-144-(2-cyclopropy1-1,3-thiazol-5-y1)phenyl]ethane-
1,2-
diamine (Compound 137b)
HN--\\
LLCNH
NH2
The N'-(1H-benzimidazol-5-y1)-1-14-(2-cyclopropy1-1,3-thiazol-5-
yephenyflethane-
1,2-diamine 137b was prepared from the hydrogenation of Compound 136b with the
Raney
Nickel reagent as catalyst. The procedures were the same as the synthesis of
Compound
123a. The product 13M was obtained as a yellow viscous liquid at a yield of
54%.
N1-(1H-benzimidazol-5-y1)-144-[2-(trifluoromethyl)-1,3-thiazol-5-
yl]phenyllethane-1,2-
diamine (Compound 137c)
F3C HNNQS
--\\
)1--S
NH
NH 2
The NI -(1H-benzimidazol-5-y1)-1- { 4- [2-(tri fluoromethyl)-1,3-thiazol-5-
yl]pheny11-
ethane-1,2-diamine 137c was prepared from the hydrogenation of Compound 136c
with the
Raney Nickel reagent as catalyst. The procedures were the same as the
synthesis of
Compound 123a. The product 137c was obtained as a yellow viscous liquid at a
yield of
50%.
1-(1H-benzimidazol-5-y1)-5-[4-(2-methyl-1,3-thiazol-5-yl)phenyl]imidazolidin-2-
one
(Compound 6)
H N-1(
N$
NH
¨S
N

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The 1-(1H-benzimidazol-5-y1)-5-[4-(2-methy1-1,3-thiazol-5-
yl)phenyl]imidazolidin-
2-one (Compound 6) was prepared from the cycloaddition of 1,1'-carbonyl
diimidazole and
Compound 137a. The procedures were the same as the synthesis of Compound 1.
The
product (Compound 6) was obtained as a white solid at a yield of 71%. 1H NMR
(400MHz,
CD30D) 8 2.64 (s, 3H), 3.30-3.36 (m, 1H), 3.97 (dd, 1H, J = 8.6, 9.2 Hz), 5.48
(dd, 1H, J =
7.6, 8.6 Hz), 7.29 (d, 1H, J = 8.8 Hz), 7.39 (d, 2H, J = 8.0 Hz), 7.45-7.46
(m, 3H), 7.55 (s,
1H), 7.76 (s, 1H), 8.06 (s, 1H); LC/MS (ESI) miz: 376.3 [M + Hr.
1-(1H-benzimidazol-5-y1)-5-[4-(2-cyclopropyl-1,3-thiazol-5-
y1)phenyl]imidazolidin-2-one
(Compound 7)
0
HN¨f
N
NH
1110
S
The 1-(1H-benzimidazol-5-y1)-5-[4-(2-cyclopropy1-1,3-thiazol-5-
yl)phenyl]imidazolidin-2-one (Compound 7) was prepared from the cycloaddition
of 1,1'-
carbonyl diimidazole and Compound 137b. The procedures were the same as the
synthesis
of Compound 1. The product (Compound 7) was obtained as a white solid at a
yield of 74%.
1H NMR (400MHz, DMSO-d6) 8 0.92-0.95 (m, 2H), 1.06-1.11 (m, 2H), 2.32-2.39(m,
1H),
3.10 (dd, 1H, J = 6.4, 9.2 Hz), 3.84 (dd, 1H, J = 8.4, 9.2 Hz), 5.53 (dd, 1H,
J = 6.4, 8.4 Hz),
6.99 (s, 1H), 7.26 (s, 1H), 7.37-7.39 (m, 3H), 7.50 (d, 2H, J = 8.0 Hz), 7.54
(s, 1H), 7.88 (s,
1H), 8.07 (s, 1H), 12.23 (s, 1H); LC/MS (ESI) mk: 402.2 [M + Hr.

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1-(1H-benzimidazol-5-y1)-54442-(trifluoromethyl)-1,3-thiazol-5-
yl]phenyllimidazolidin-
2-one (Compound 8)
0
HN
N
NH
1111111
V S
N
C F3
The 1-(1H-benzimidazol-5-y1)-5- { 4- [2-(trifluoromethyl)-1,3-thiazol-5-
yllphenyl I -
imidazolidin-2-one (Compound 8) was prepared from the cycloaddition of 1,1'-
carbonyl
diimidazole and Compound 137c. The procedures were the same as the synthesis
of
Compound 1. The product (Compound 8) was obtained as a white solid at a yield
of 70%.
1H NMR (400MHz, CD30D) 6 3.37 (dd, 1H, J = 7.2, 8.8 Hz), 4.01 (dd, 1H, J =
8.8, 9.2 Hz),
5.56 (dd, 1H, J = 7.2, 9.2 Hz), 7.31 (d, 1H, J = 8.0 Hz), 7.47 (d, 1H, J = 8.0
Hz), 7.50 (d, 2H,
J = 8.4 Hz), 7.58 (s, 1H), 7.63 (d, 2H, J = 8.4 Hz), 8.07 (s, 1H), 8.18 (s,
1H); LC/MS (ESI)
m/z: 430.2 [NI+ Hr.
(5S)-1-(1H-benzimidazol-5-y1)-54442-(trifluoromethyl)-1,3-thiazol-5-yl]phenyll-
imidazolidin-2-one (Compound 9)
0
HN¨f
N \\.
NH
S
N-1\
CF3

45
(5R)-1-(1H-benzimidazol-5-y1)-5- {442-(trifluoromethyl)-1,3-thiazol-5-yl]
phenyll-
imidazolidin-2-one (Compound 10)
HN
czN
NH
s
N=(
CF3
The enantiomers (Compounds 9 and 10) were separated from Compound 8 by HPLC
using CHIRALPAK IC. The isomer fractions were respectively collected and the
optical
pure isomers (Compounds 9 and 10) were thus obtained by removing the solvent
under
reduced pressure. 1-11NMR (400MHz, CD30D) 3.37 (dd, 1H, J = 7.2, 8.8 Hz), 4.01
(dd,
1H, J = 8.8, 9.2 Hz), 5.56 (dd, 1H, J = 7.2, 9.2 Hz), 7.31 (d, 1H, J = 8.0
Hz), 7.47 (d, 1H, J =
8.0 Hz), 7.50 (d, 2H, J = 8.4 Hz), 7.58 (s, 1H), 7.63 (d, 2H, J = 8.4 Hz),
8.07 (s, 1H), 8.18 (s,
1H); LC/MS (ESI) m/z: 430.2 nvi + Hit
4-(5-methylthiophen-2-yl)benzaldehyde (Compound 140a)
0
/
The 4-bromobenzaldehyde 138a (1.85 g, 10.0 mmol), 2-methylthiophene 139a (1.96
g, 20.0 mmol), potassium acetate (1.96 g, 20.0 mmol) and palladium acetate
(0.002 g, 0.01
mmol) were dissolved in dimethylacetamide (DMA). The reaction mixture was
purged with
argon and stirred at 150 C for 4 hours. The reaction mixture was cooled to
room
temperature and extracted with dichloromethane. The organic layers were
collected, washed
with brine, dried over sodium sulfate, filtered and concentrated under reduced
pressure. The
crude residue was purified by column chromatography on silica gel using
pentane/ether (1/4)
as eluent. The product 140a was obtained as a white solid at a yield of 92%.
Date Regue/Date Received 2022-08-25

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(1H-benzimidazol-5-ylamino)[445-methylthiophen-2-yl)phenyl]acetonitrile
(Compound
141a)
H N
S
011
N H
C N
The (1H-benzimidazol-5-ylamino)[4-(5-methylthiophen-2-yOphenyl]acetonitrile
141a
was prepared from the addition of 1H-benzimidazol-5-amine 121, TMSCN and
Compound
140a. The procedures were the same as the synthesis of Compound 122a. The
product 141a
was obtained as a pale-yellow solid at a yield of 90%.
/111-(1H-benzimidazol-5-y1)-1-[4-(5-methylthiophen-2-y1)phenyl]ethane-1,2-
diamine
(Compound 142a)
H N-
N-\\
S
NH
N H2
The M-(1H-benzimidazol-5-y1)-1-H--(5-methylthiophen-2-yl)phenyl]ethane-1,2-
diamine 142a was prepared from the hydrogenation of Compound 141a with the
Raney
Nickel reagent as catalyst. The procedures were the same as the synthesis of
Compound
123a. The product 142a was obtained as a yellow viscous liquid at a yield of
55%.
1-(1H-benzimidazol-5-y1)-5-[4-(5-methylthiophen-2-yl)phenyl]imidazolidin-2-one
(Compound 11)
H N
N *N H
S

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The 1-(1H-benzimidazol-5-y1)-5-[4-(5-methylthiophen-2-yl)phenyl]imidazolidin-2-
one (Compound 11) was prepared from the cycloaddition of 1,1'-carbonyl
diimidazole and
Compound 142a. The procedures were the same as the synthesis of Compound 1.
The
product (Compound 11) was obtained as a white solid at a yield of 63%. 41 NMR
(400MHz,
CD30D) 8 2.44 (s, 3H), 3.39 (dd, 1H, J = 7.6, 8.8 Hz), 3.97 (dd, 1H, J = 8.8,
9.2 Hz), 5.40
(dd, 1H, J = 7.6, 9.2 Hz), 6.67 (d, 1H, J = 3.0 Hz), 7.05 (d, 1H, J = 3.0 Hz),
7.26 (d, 1H, J =
8.8 Hz), 7.33 (d, 2H, J = 8.0 Hz), 7.45-7.47 (m, 3H), 7.52 (s, 1H), 7.99 (s,
1H); LC/MS (ESI)
m/z: 375.3 IM + Hr.
4-acryloylbenzonitrile (Compound 144)
NC
0
The 4-acetylbenzonitrile 143 (0.73 g, 5.0 mmol), FeC13.6H20 (0.14 g, 0.5
mmol),
K2S208 (2.7 g, 10.0 mmol) and DMA (20 mL) were sequentially added to the round-
bottle
flask. The reaction mixture was stirred at 110 C for 4 hours. Upon completion
of the
reaction (monitored by TLC), the resulting mixture was diluted with ether and
washed with
brine. The organic layers were dried over sodium sulfate, filtered and
concentrated under
reduced pressure. The crude residue was purified by colurnn chromatography on
silica gel
using ethyl acetate/ether (1/4) as eluent. The product 144 was obtained as an
off-white solid
at a yield of 40%.
4-(4-oxopentanoyl)benzonitrile (Compound 146)
NC
0
0
The product 144 (2.0 g, 12.7 mmol), cyclopropanecarbaldehyde (1.2 mL, 15.3
mmol),
triethylamine (1.2 mL, 8.6 mmol) and 2-(2-hydroxyethyl)-3-methyl-4-
benzylthiazolium
chloride 145 (0.65 g, 15.2 mmol) were sequentially added to the round-bottle
flask. The
reaction mixture was stirred at 70 C overnight. Upon completion of the
reaction (monitored
by TLC), the resulting mixture was partitioned between ether and water. The
organic layers
were washed with water, 2 M HC1 and brine. After drying over sodium sulfate,
filtering and
concentrating in vacuo, the crude residue was purified by column
chromatography on silica
gel using ethyl acetate/hexane (1/3) as eluent. The product 146 was obtained
as a yellow
liquid at a yield of 50%.

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4-(5-cyclopropylthiophen-2-yl)benzonitrile (Compound 147)
NC
/
The 4-(5-cyclopropylthiophen-2-yl)benzonitrile 147 was prepared from the
cyclization of product 146 with the Lawesson's reagent in THF. The procedures
were the
same as the synthesis of Compound 134a. The product 147 was obtained as a
yellow solid at
a yield of 75%.
4-(5-cyclopropylthiophen-2-yl)benzaldehyde (Compound 148)
0
/
The 4-(5-cyclopropylthiophen-2-yl)benzaldehyde 148 was prepared from the
reduction of Compound 147 with the DIBAL-H reagent. The procedures were the
same as
the synthesis of Compound 135a. The product 148 was obtained as a yellow solid
at a yield
of 64%.
(1H-benzimidazol-5-ylamino)[4-(5-cyclopropylthiophen-2-y1)phenyl]acetonitrile
(Compound 149)
S
---- 41$
NH
CN
The (1H-benzimidazol-5-ylamino)[4-(5-cyclopropylthiophen-2-
yl)phenyllacetonitrile
149 was prepared from the addition of 1H-benzimidazol-5-amine 121, TMSCN and
Compound 148. The procedures were the same as the synthesis of Compound 122a.
The
product 149 was obtained as a pale-yellow solid at a yield of 91%.

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N'-(1H-benzimidazol-5-y1)-144-(5-cyclopropylthiophen-2-yl)phenyl]ethane-1,2-
diamine
(Compound 150)
S
--- lb
NH
NH2
The NI-(1H-benzimidazol-5-y1)-1-[4-(5-cyclopropylthiophen-2-yl)phenyllethane-
1,2-
diamine 150 was prepared from the hydrogenation of Compound 149 with the Raney
Nickel
reagent as catalyst. The procedures were the same as the synthesis of Compound
123a. The
product 150 was obtained as a yellow viscous liquid at a yield of 53%.
1-(1H-benzimidazol-5-y1)-5-[4-(5-cyclopropylthiophen-2-yl)phenyl]imidazolidin-
2-one
(Compound 12)
N
NH
s
The 1-(1H-benzimidazol-5-y1)-544-(5-cyclopropylthiophen-2-
yl)phenylilmidazolidin-2-one (Compound 12) was prepared from the cycloaddition
of 1,1'-
carbonyl diimidazole and product 150. The procedures were the same as the
synthesis of
Compound 1. The product (Compound 12) was obtained as a white solid at a yield
of 69%.
11-1 NMR (400MHz, CD30D) 5 0.67-0.71 (m, 2H), 0.96-1.01 (m, 2H), 2.03-2.09 (m,
1H),
3.36 (dd, 1H, J = 6.8, 8.8 Hz), 3.97 (dd, 1H, J = 8.8, 9.2 Hz), 5.45 (dd, 1H,
J = 6.8, 9.2 Hz),
6.69 (d, 1H, J = 3.6 Hz), 7.08 (d, 1H, J = 3.6 Hz), 7.29 (d, 1H, J = 8.8 Hz),
7.36 (d, 2H, J =
8.4 Hz), 7.46-7.49 (m, 3H), 7.54 (s, 1H), 8.06 (s, 1H); LC/MS (ESI) in/z:
401.3 [M + Hr.

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4-(thiophen-2-yl)benzaldehyde (Compound 152a)
0
H)L
/
The 4-bromobenzaldehyde 138a (1.85 g, 10.0 mmol), thiophene (6.72 g, 80.0
mmol),
potassium acetate (1.96 g, 20.0 mmol) and palladium acetate (0.002 g, 0.01
mmol) were
dissolved in DMA (50 mL). The reaction mixture was purged with argon and
stirred at 130
C for 20 hours. The reaction mixture was cooled to room temperature and
removed the
solvent in vacuo. The crude residue was purified by column chromatography on
silica gel
using pentane/ether (1/4) as eluent. The product 152a was obtained as a light-
yellow solid at
a yield of 60%.
4-(5-iodothiophen-2-yl)benzaldehyde (Compound 153a)
0
/ I
The Compound 152a (0.94 g, 5.0 mmol) and N-iodosuccinimide (2.81 g, 12.5 mmol)
were added to the 500 mL flask. The flask was flushed with nitrogen and then
added
chloroform (200 mL) and acetic acid (16 mL). The reaction mixture was stirred
at room
temperature for 8 hours. The reaction mixture was washed with saturated sodium
thiosulfate
solution (75 mL), saturated sodium bicarbonate solution (75 mL), and water (75
mL). The
organic layers were collected, dried over sodium sulfate, filtered and
concentrated in vacuo.
The crude residue was purified by column chromatography on silica gel using
dichloromethane/hexane (1/1) as eluent. The product 153a was obtained as a
yellow solid at
a yield of 75%.
4-[5-(trifluoromethypthiophen-2-yl]benzaldehyde (Compound 155a)
0
C F3
A mixture of Compound 153a (0.31 g, 1.0 mmol), methyl
difluoro(fluorosulfonyl)acetate 154 (0.96 g, 5.0 mmol), copper iodide (0.23 g,
1.2 mmol), N-
methylpyrrolidine (NMP, 1.2 mL) and DMF (10 mL) was stirred at 70 C for 13
hours. The

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reaction mixture was quenched with saturated aqueous ammonium chloride (15
mL), diluted
with water (10 mL), filtered through celite, and extracted with ethyl acetate.
The organic
layers were collected, dried over sodium sulfate, filtered and concentrated in
vacuo. The
crude residue was purified by column chromatography on silica gel using ethyl
acetate/hexane (1/6) as eluent. The product 155a was obtained as a yellow
solid at a yield of
70%.
(1H-benzimidazol-5-ylamino){4-[5-(trifluoromethyl)thiophen-2-
yl]phenyllacetonitrile
(Compound 156a)
F3C
/ S
NH
CN
HN¨
The (1H-benzimidazol-5-ylamino){ 4- )5-(trifluoromethypthiophen-2-yl]phenyl ) -

acetonitrile 156a was prepared from the addition of 1H-benzimidazol-5-amine
121, TMSCN
and Compound 155a. The procedures were the same as the synthesis of Compound
122a.
The product 156a was obtained as a pale-yellow solid at a yield of 88%.
AP-(1H-benzimidazol-5-y1)-1-{445-(trifluoromethypthiophen-2-yllphenyllethane-
1,2-
diamine (Compound 157a)
H\\
F3C N¨
/ S
11110
NH
NH2
The IV' -(1H-benzimidazol-5 -y1)-1- { 4- [5 -(trifluoromethyl)thiophen-2-
yl]phenyflethane-1,2-diamine 157a was prepared from the hydrogenation of
Compound 156a
with the Raney Nickel reagent as catalyst. The procedures were the same as the
synthesis of
Compound 123a. The product 157a was obtained as a yellow viscous liquid at a
yield of
49%.

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1-(1H-benzimidazol-5-y1)-5-{445-(trifluoromethyl)thiophen-2-
yl]phenyllimidazolidin-2-
one (Compound 13)
HN-4(
N ===:y
NH
S
CF3
The 1-(1H-benzimidazol-5-y1)-5-(4-[5-(trifluoromethypthiophen-2-yl]pheny1}-
imidazolidin-2-one (Compound 13) was prepared from the cycloaddition of 1,1'-
carbonyl
diimidazole and Compound 157a. The procedures were the same as the synthesis
of
Compound 1. The product (Compound 13) was obtained as a white solid at a yield
of 67%.
1I-1 NMR (300MHz, CD30D) 6 3.36 (dd, 1H, J = 6.9, 9.3 Hz), 3.99 (dd, 1H, J =
9.3, 9.3 Hz),
5.51 (dd, 1H, J = 6.9, 9.3 Hz), 7.29-7.32 (m, 2H), 7.43-7.48 (m, 4H), 7.55-
7.60 (m, 3H), 8.06
(s, 1H); LC/MS (ESI) m/z: 429.2 FM + Hr.
4-(thiophen-3-yl)benzaldehyde (Compound 159a)
The 3-bromothiophene 158a (1.96 g, 12.0 mmol), (4-formylphenyl)boronic acid
118
(2.70 g, 18.0 mmol), ethylene glycol dimethyl ether (17 mL), water (10 mL) and
sodium
bicarbonate (3.02 g, 36.0 mmol) were placed in a 50 mL round-bottom flask.
After adding
Pd(PPh3)4 (0.69 g, 0.6 mmol) at room temperature, the reaction mixture was
refluxed for 5
hours. The resulting mixture was extracted with ethyl acetate and water. The
organic layers
were collected, washed with brine, dried over sodium sulfate, filtered and
concentrated under
reduced pressure. The crude residue was purified by column chromatography on
silica gel
using toluene/hexane (2/1) as eluent. The product 159a was obtained as a pale
yellow oil at a
yield of 95%.
4-(5-methylthiophen-3-yl)benzaldehyde (Compound 159b)
OH/
The 4-(5-methylthiophen-3-yl)benzaldehyde 159b was prepared from the Suzuki-
Miyaura coupling of (4-formylphenyl)boronic acid 118 and 3-bromo-5-
methylthiophene

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158b. The procedures were the same as the synthesis of Compound 159a. The
product 159b
was obtained as a pale-yellow oil at a yield of 92%.
4-[5-(trifluoromethyl)thiophen-3-yl]benzaldehyde (Compound 159c)
CF3
The 4[5-(trifluoromethyl)thiophen-3-ylThenzaldehyde 159c was prepared from the
Suzuki-Miyaura coupling of (4-formylphenyl)boronic acid 118 and 3-bromo-(5-
trifluoromethyl)-thiophene 158c. The procedures were the same as the synthesis
of
Compound 159a. The product 159c was obtained as a pale-yellow oil at a yield
of 85%.
(1H-benzimidazol-5-ylamino)[4-(thiophen-3-yl)phenyl]acetonitrile (Compound
160a)
1110
NH
CN
The (1H-benzimidazol-5-ylamino)[4-(thiophen-3-yl)phenyllacetonitrile 160a was
prepared from the addition of 1H-benzimidazol-5-amine 121, TMSCN and Compound
159a.
The procedures were the same as the synthesis of Compound 122a. The product
160a was
obtained as a pale-yellow solid at a yield of 92%.
(1H-benzimidazol-5-ylamino)[4-(5-methylthiophen-3-y1)phenyl]acetonitrile
(Compound
160b)
011
NH
CN
The (1H-benzimidazol-5-ylamino)[4-(5-methylthiophen-3-yl)phenyllacetonitrile
160b
was prepared from the addition of 1H-benzimidazol-5-amine 121, TMSCN and
Compound
159b. The procedures were the same as the synthesis of Compound 122a. The
product 160b
was obtained as a pale-yellow solid at a yield of 90%.

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(1H-benzimidazol-5-ylamino){4-[5-(trifluoromethyl)thiophen-3-
yl]phenyllacetonitrile
(Compound 160c)
F3C
S
111011
NH
CN
HN¨
The (1H-benzimidazol-5-ylamino) { 4- [5 -(trifluoromethyl)thiophen-3 -
yl]phenyl } -
acetonitrile 160c was prepared from the addition of 1H-benzimidazol-5-amine
121, TMSCN
and Compound 159c. The procedures were the same as the synthesis of Compound
122a.
The product 160c was obtained as a pale-yellow solid at a yield of 85%.
N41H-benzimidazol-5-y1)-1-[4-(thiophen-3-yl)phenyl]ethane-1,2-diamine
(Compound
161a)
H
1110
NH
N H2
The N'-(1H-benzimidazol-5-y1)-1-[4-(thiophen-3-yOphenyllethane-1,2-diamine
161a
was prepared from the hydrogenation of Compound 160a with the Raney Nickel
reagent as
catalyst. The procedures were the same as the synthesis of Compound 123a. The
product
was obtained as a yellow viscous liquid at a yield of 53%.
N1-(1H-benzimidazol-5-y1)-1-[4-(5-methylthiophen-3-y1)phenyl]ethane-1,2-
diamine
(Compound 161b)
HN--\\
S
11111 N H
NH2
The NI-(1H-benzimidazol-5-y1)-1-[4-(5-methylthiophen-3-yl)phenyllethane-1,2-
diamine 161b was prepared from the hydrogenation of Compound 160b with the
Raney

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Nickel reagent as catalyst. The procedures were the same as the synthesis of
Compound
123a. The product 16th was obtained as a yellow viscous liquid at a yield of
50%.
N1-(1H-benzimidazol-5-y1)-1-{4-[5-(trifluoromethypthiophen-3-yl]phenyllethane-
1,2-
diamine (Compound 161c)
F3C
S
HN-
NH
NH2
The NI -(1H-benzimidazol-5-y1)-1- 4- [5-(trifluoromethyl)thiophen-3-
yliphenyll ethane-1,2-diamine 161c was prepared from the hydrogenation of
Compound 160c
with the Raney Nickel reagent as catalyst. The procedures were the same as the
synthesis of
Compound 123a. The product 161c was obtained as a yellow viscous liquid at a
yield of
51%.
1-(1H-benzimidazo1-5-y1)-5-[4-(thiophen-3-yl)phenyl]imidazolidin-2-one
(Compound
14)
0
N *NH
,
S
The 1-(1H-benzimidazol-5-y1)-5-[4-(thiophen-3-y1)phenyl]imidazolidin-2-one
(Compound 14) was prepared from the cycloaddition of 1,1'-carbonyl diimidazole
and
Compound 161a. The procedures were the same as the synthesis of Compound 1.
The
product (Compound 14) was obtained as a white solid at a yield of 73%. 41 NMR
(300MHz,
CD30D) 6 3.38 (dd, 1H, J = 6.9, 9.0 Hz), 3.99 (dd, 1H, J = 9.0, 9.3 Hz), 5.48
(dd, 1H, J = 6.9,
9.3 Hz), 7.05 (s, 1H), 7.30 (d, 1H, J = 8.4 Hz), 7.37-7.48 (m, 4H), 7.54-7.60
(m, 3H), 7.68 (s,
1H), 8.06 (s, 1H); LC/MS (ESI) m/z: 361.3 [M + Hr.

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1-(1H-benzimidazol-5-y1)-5-[4-(5-methylthiophen-3-y1)phenyl]imidazolidin-2-one
(Compound 15)
0
N
NH
,
The 1-(1H-benzimidazol-5-y1)-5-[4-(5-methylthiophen-3-yl)phenyl]imidazolidin-2-
one (Compound 15) was prepared from the cycloaddition of 1,1'-carbonyl
diimidazole and
Compound 161b. The procedures were the same as the synthesis of Compound 1.
The
product (Compound 15) was obtained as a white solid at a yield of 75%. 11-1
NMR (300MHz,
CD30D) 6 2.40 (s, 3H), 3.30 (dd, 1H, J = 7.5, 9.0 Hz), 3.90 (dd, 1H, J = 9.0,
9.0 Hz), 5.38
(dd, 1H, J = 7.5, 9.0 Hz), 6.95 (s, 1H), 7.17 (s, 1H), 7.26-7.31 (m, 3H), 7.42-
7.45 (m, 3H),
7.55 (s, 1H), 8.03 (s, 1H); LC/MS (ESI) m/z: 375.1 [M + Hr.
1-(1H-benzimidazol-5-y1)-5-14-[5-(trifluoromethyl)thiophen-3-
yl]phenyllimidazolidin-2-
one (Compound 16)
/,0
HN¨((
N$
NH
,
CF3
The 1-(1H-benzimidazol-5-y1)-5- { 4- [5-(trifluoromethyl)thiophen-3-yl]phenyll-
imidazolidin-2-one (Compound 16) was prepared from the cycloaddition of 1,1'-
carbonyl
diimidazole and Compound 161c. The procedures were the same as the synthesis
of
Compound 1. The product (Compound 16) was obtained as a white solid at a yield
of 67%.
NMR (300MHz, CD30D) 6 3.36 (dd, 1H, J = 6.9, 9.0 Hz), 3.99 (dd, 1H, J = 9.0,
9.3 Hz),
5.50 (dd, 1H, J = 6.9, 9.3 Hz), 7.30 (d, 1H, J = 8.1 Hz), 7.41-7.47 (m, 3H),
7.56-7.58 (m, 3H),
7.81 (s, 2H), 8.05 (s, 1H); LC/MS (ESI) m/z: 429.1 [M + H[ .

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4-(5-bromothiophen-3-yl)benzaldehyde (Compound 162)
0
HAC
Br
Bromine (5.0 g, 32.0 mmol) in 50 mL of glacial acetic acid was added dropwise
to a
solution of Compound 159a (6.0 g, 32.0 mmol) in 65 mL of glacial acetic acid.
The resulting
yellow solution was stirred at room temperature for 2 days. The reaction
mixture was diluted
with 300 mL of water and extracted with ethyl acetate (100 mL x 2). The
combined organic
layers were washed with saturated aqueous sodium bicarbonate, dried over
sodium sulfate,
filtered and concentrated under reduced pressure. The crude residue was
purified by column
chromatography on silica gel using ethyl acetate /hexane (1/9) as eluent. The
product 162
was obtained as a yellow solid at a yield of 73%.
4-(5-cyclopropylthiophen-3-yl)benzaldehyde (Compound 163)
0 S
The palladium acetate (0.025 g, 0.11mmol) and Xantphos (0.066 g, 0.11 mmol)
were
added in THF (22 mL) that degassed under argon. Then, the reaction mixture was
stirred at
room temperature for 5 minutes. The 4-(5-bromothiophen-3-yl)benzaldehyde 162
(0.73 g,
3.0 mmol), cyclopropylboronic acid 125 (0.58 g, 6.70 mmol) and potassium
phosphate (2.86
g) were added to the reaction mixture and flushed with argon. The reaction
mixture was
stirred at 70 C for 15 hours. After cooling to room temperature, the reaction
mixture was
filtered and washed with dichloromethane. The filtrate was concentrated under
reduced
pressure and purified by column chromatography on silica gel using hexane as
eluent. The
product 163 was obtained as a yellow solid at a yield of 84%.

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(1H-benzimidazol-5-ylamino)[4-(5-cyclopropylthiophen-3-yl)phenyl]acetonitrile
(Compound 164)
S
110
NH
CN
The (1H-benzimidazol-5-ylamino)[4-(5-cyclopropylthiophen-3-
yl)phenyllacetonitrile
164 was prepared from the addition of 1H-benzimidazol-5-amine 121, TMSCN and
Compound 163. The procedures were the same as the synthesis of Compound 122a.
The
product 164 was obtained as a pale-yellow solid at a yield of 81%.
N1-(1H-benzimidazol-5-y1)-1-[4-(5-cyclopropylthiophen-3-y1)phenyl]ethane-1,2-
diamine
(Compound 165)
S
40/
NH
NH2
The N1-(1H-benzimidazol-5-y1)-1-[4-(5-cyclopropylthiophen-3-yephenyllethane-
1,2-
diamine 165 was prepared from the hydrogenation of Compound 164 with the Raney
Nickel
reagent as catalyst. The procedures were the same as the synthesis of Compound
123a. The
product 165 was obtained as a yellow viscous liquid at a yield of 49%.

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1-(1H-benzimidazol-5-y1)-544-(5-eyclopropylthiophen-3-yl)phenyl]imidazolidin-2-
one
(Compound 17)
0
HN¨g
N 100, ,
NH
/
The 1-(1H-benzimidazol-5-y1)-5-[4-(5-cyclopropylthiophen-3-
yl)phenyllimidazolidin-2-one (Compound 17) was prepared from the cycloaddition
of 1,1'-
carbonyl diimidazole and Compound 165. The procedures were the same as the
synthesis of
Compound 1. The product (Compound 17) was obtained as a white solid at a yield
of 65%.
1H NMR (300MHz, CD30D) 5 0.59-0.63 (m, 2H), 0.91-0.96 (m, 2H), 2.00-2.09 (m,
1H),
3.39 (dd, 1H, J = 6.9, 9.0 Hz), 4.00 (dd, 1H, J = 9.0, 9.3 Hz), 5.50 (dd, 1H,
J = 6.9, 9.3 Hz),
6.69 (d, 1H, J = 5.4 Hz), 7.05 (d, 1H, J = 5.4 Hz), 7.32 (dd, 1H, J = 1.8, 8.7
Hz), 7.41-7.45
(m, 3H), 7.46 (d, 2H, J = 8.1 Hz), 7.58 (d, 1H, J = 1.8 Hz), 8.06 (s, 1H);
LC/MS (ESI) m/z:
401.2 [M + Hr.
4-(1,3-dioxolan-2-yl)benzonitrile (Compound 167)
CC) * CN
0
To a round-bottom flask equipped with a Dean-Stark trap was successively added
4-
formylbenzonitrile 166 (7.68 g, 58.6 mmol), a catalytic amount of p-Ts0H
(PTSA) and
toluene (150 mL). After stirring 5 minutes at room temperature, the
monoethyleneglycol
(MEG) (13 mL, 234.3 mmol) was added dropwise. The reaction mixture was
refluxed for 3
hours and cooled to room temperature. After removing toluene under reduced
pressure, sat.
Na2CO3(aq) was added to quench the reaction and partitioned between DCM and
water. The
organic phases were collected, washed with brine, dried over sodium sulfate,
filtered and
concentrated under reduced pressure. The viscous residue was treated with
hexane at ice-
bath to form the product 167 as a yellow solid in a quantum yield.

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4-(1,3-dioxolan-2-y1)-N'-hydroxybenzenecarboximidamide (Compound 168)
0 N-A OH
To the solution of the Compound 167 (7.6 g, 43.4 mmol) in ethanol/water (2/1,
75
nth), hydroxylamine hydrochloride (10.6 g, 151.8 mmol) and sodium carbonate
(9.2 g, 86.8
mmol) were added at room temperature. The reaction mixture was stirred at 100
C for 2
hours. After concentrating under reduced pressure, the residue was poured into
water (50
mL) and stirred for 30 minutes. The precipitates were filtered and washed with
cold water to
give the product 168 as a white solid at a yield of 83%.
N'-[(cyclopropylcarbonyl)oxy]-4-(1,3-dioxolan-2-yl)benzenecarboximidamide
(Compound 169)
C N H2
0
To the suspension of the Compound 168 (1.8 g, 8.65 mmol) in DCM (100 mL),
pyridine (1.4 mL, 17.30 mmol) and cyclopropanecarbonyl chloride (0.02 mL,
11.20 mmol)
were added dropwise under nitrogen at room temperature. The reaction mixture
was stirred
at room temperature for 4 hours and then partitioned between DCM and water.
The organic
phases were collected, washed with brine, dried over sodium sulfate, filtered
and
concentrated under reduced pressure. The crude residue was purified by column
chromatography on silica gel using DCM/methanol (9/1) as eluent to give the
product 169 as
a white solid at a yield of 60%.
5-cyclopropy1-344-(1,3-dioxolan-2-yl)phenyl]-1,2,4-oxadiazole (Compound 170)
N-0
0
The starting material 169 (1.1 g, 3.98 mmol) was dissolved in toluene (40 mL).
The
reaction mixture was refluxed for 15 hours and then cooled to room
temperature. After
removing the solvent under reduced pressure, the crude residue was purified by
column
chromatography on silica gel using EA/hexane (1/4) as eluent to give the
product 170 as a
white solid at a yield of 70%.

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4-(5-cyclopropy1-1,2,4-oxadiazol-3-yl)benzaldehyde (Compound 171)
0
N-C)
To the solution of the Compound 170 (1.2 g, 4.64 mmol) in THF/H20 (4/1, 30
mL),
the con. HC1 was added dropwise. The reaction mixture was stirred at 65 C for
6 hours and
then cooled to room temperature. The reaction mixture was partitioned between
DCM and
water. The organic phases were collected, washed with brine, dried over sodium
sulfate,
filtered and concentrated under reduced pressure. The crude residue was
purified by column
chromatography on silica gel using EA/hexane (1/9) as eluent to give the
product 171 as a
white solid at a yield of 97%.
(1H-benzimidazol-5-ylamino)[4-(5-cyclopropyl-1,2,4-oxadiazol-3-
y1)phenyl]acetonitrile
(Compound 172)
111011
0,
NH
CN
The (1H-benzimidazol-5-ylamino)[4-(5-cyclopropy1-1,2,4-oxadiazol-3-yl)phenyl]-
acetonitrile 172 was prepared from the addition of 1H-benzimidazol-5-amine
121, TMSCN
and Compound 171. The procedures were the same as the synthesis of Compound
122a. The
product 172 was obtained as a pale-yellow solid at a yield of 86%.
ATI--(1H-benzimidazol-5-y1)-144-(5-cyclopropyl-1,2,4-oxadiazol-3-
y1)phenyflethane-1,2-
diamine (Compound 173)
HN-
NH
NH2
The N1-(1H-benzimidazol-5 -y1)-1- [445 -cyclopropy1-1,2,4-oxadiazol-3 -
yl)phenyllethane-1,2-diamine 173 was prepared from the hydrogenation of
Compound 172

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with Pd/C as catalyst. The procedures were the same as the synthesis of
Compound 123a.
The product 173 was obtained as a yellow viscous liquid at a yield of 55%.
1-(1H-benzimidazol-5-y1)-5-[4-(5-cyclopropy1-1,2,4-oxadiazol-3-
yl)phenyl]imidazolidin-
2-one (Compound 18)
0
N *NH
1011
N N
OJ>.
The 1-(1H-benzimidazol-5-yl)-5-[4-(5-cyclopropy1-1,2,4-oxadiazol-3-yl)phenyl]-
imidazolidin-2-one (Compound 18) was prepared from the cycloaddition of 1,1'-
carbonyl
diimidazole and Compound 173. The procedures were the same as the synthesis of
Compound 1. The product (Compound 18) was obtained as a white solid at a yield
of 68%.
NMR (300MHz, DMS0- d6) .5 1.12-1.19 (m, 2H), 1.21-1.28 (m, 2H), 2.31-2.38 (m,
1H),
3.13 (dd, 1H, J = 6.3, 8.7 Hz), 3.89 (dd, 1H, J = 8.7, 9.0 Hz), 5.60 (dd, 1H,
J = 6.3, 9.0 Hz),
6.98-7.03 (m, 1H), 7.19 (br. s, 1H), 7.35-7.59 (m, 4H), 7.88 (d, 2H, J = 7.8
Hz), 8.07 (s, 1H),
12.23 (s, 1H); LC/MS (ESI) m/z: 387.1 [M + Hr.
4-(3-cyclopropy1-1,2-oxazol-5-yl)benzaldehyde (Compound 177)
0 0¨N
The cyclopropanecarboxaldehyde 174 (1.0 g, 14.26 mmol), hydroxylamine
hydrochloride (0.99 g, 14.26 mmol) and potassium carbonate (2.17 g, 15.68
mmol) were
dissolved in H20 (25 mL). The reaction mixture was stirred at 85 C for 3
hours and then
cooled to room temperature. The reaction mixture was partitioned between ether
and water.
The organic phases were collected, washed with brine, dried over sodium
sulfate, filtered and
concentrated under reduced pressure. The crude product 175 was used in next
step without
any further purification. To the solution of Compound 175 and NCS (1.9 g,
14.26 mmol) in
DMF (30 mL), the catalytic amount of pyridine was added under argon. The
reaction
mixture was stirred at room temperature for 2 hours. After cooling to 0 C, 4-

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ethynylbenzaldehyde 176 (1.9 g, 14.26 mmol) and triethylamine (3 mL) were
added. The
reaction mixture was continuously stirred at room temperature for 3 hours. The
reaction
mixture was partitioned between EA and water. The organic phases were
collected, washed
with brine, dried over sodium sulfate, filtered and concentrated under reduced
pressure. The
crude residue was purified by column chromatography on silica gel using
EA/hexane (1/8) as
eluent to give the product 177 as a yellow solid at overall yield of 54%.
(1H-benzimidazol-5-ylamino)[4-(5-cyclopropyl-1,2-oxazol-3-
y1)phenyl]acetonitrile
(Compound 178)
11110
NH
CN
The (1H-benzimidazol-5-ylamino)[4-(5-cyclopropy1-1,2-oxazol-3-
yl)phenyllacetonitrile 178 was prepared from the addition of 1H-benzimidazol-5-
amine 121,
TMSCN and Compound 177. The procedures were the same as the synthesis of
Compound
122a. The product 178 was obtained as a pale-yellow solid at a yield of 83%.
N1-(1H-benzimidazol-5-y1)-1-[4-(5-cyclopropyl-1,2-oxazol-3-y1)phenyl]ethane-
1,2-
diamine (Compound 179)
0,
NH
NH2
The Nk1H-benzimidazol-5-y1)-114-(5-cyclopropy1-1,2-oxazol-3-y1)phenyllethane-
1,2-diarnine 179 was prepared from the hydrogenation of Compound 178 with Pd/C
as
catalyst. The procedures were the same as the synthesis of Compound 123a. The
product
179 was obtained as a yellow viscous liquid at a yield of 49%.

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1-(1H-benzimidazol-5-y1)-544-(5-cyclopropyl-1,2-oxazol-3-
yl)phenyl]imidazolidin-2-one
(Compound 19)
0
HN
N *NH
N
/
0
OP'
The 1-(1H-benzimidazol-5-y1)-5-[4-(5-cyclopropy1-1,2-oxazol-3-
y1)phenyl]imidazolidin-2-one (Compound 19) was prepared from the cycloaddition
of 1,1'-
carbonyl diimidazole and Compound 179. The procedures were the same as the
synthesis of
Compound 1. The product (Compound 19) was obtained as a white solid at a yield
of 58%.
1H NMR (400MHz, DMS0- do) 6 0.75-0.79 (m, 2H), 0.99-1.04 (m, 2H), 1.98-2.02
(m, 1H),
3.13 (dd, 1H, J = 6.3, 9.0 Hz), 3.88 (dd, 1H, J = 8.7, 9.0 Hz), 5.59 (dd, 1H,
J = 6.3, 8.7 Hz),
6.68 (s, 1H), 7.01 (s, 1H), 7.26 (d, 1H, J = 8.4 Hz), 7.40 (d, 1H, J = 8.4
Hz), 7.49 (d, 2H, J =
7.8 Hz), 7.56 (s, 1H), 7.72 (d, 2H, J = 7.8 Hz), 7.79 (s, 1H), 8.08 (s, 1H);
LC/MS (ESI) nilz:
386.2 [M + H].
4-(2H-tetrazol-5-yl)benzaldehyde hydrochloride (Compound 180)
H CI
H NN
To the solution of 4-formylbenzonitrile 166 (1.31 g, 10.0 mmol) in DMF (10
mL),
sodium azide (0.72 g, 11 mmol) and ammonium chloride (0.14 g, 2.5 mmol) were
added
under nitrogen. The reaction mixture was refluxed overnight and then cooled to
room
temperature. The reaction mixture was diluted with water and extracted with
DCM. The
aqueous phase was chilled in ice and acidified by adding 1N HC1(aq). After
filtering, the
precipitates were washed with water and ether to obtain the product 180 as a
yellow solid at a
yield of 94%.
4-(2-propy1-2H-tetrazol-5-yl)benzaldehyde (Compound 181a)
0
/

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To the suspension of the Compound 180 (2.1 g, 10.0 mmol) in acetonitrile (20
mL),
potassium carbonate (2.76 g, 20 mmol) and 1-bromopropane (2.46 g, 20 mmol)
were added
under nitrogen. The reaction mixture was stirred at 50 C overnight and then
cooled to room
temperature. The reaction mixture was partitioned between EA and water. The
organic
phases were collected, washed with brine, dried over sodium sulfate, filtered
and
concentrated under reduced pressure. The crude residue was purified by column
chromatography on silica gel using EA/hexane (1/4) as eluent to give the
product 181a as a
yellow solid at a yield of 76%.
4-[2-(propan-2-y1)-2H-tetrazol-5-yl]benzaldehyde (Compound 181b)
0
/
N
Isopropanol (1.2 g, 20.0 mmol) was added to the solution of the Compound 180
(2.1
g, 10.0 mmol) in trifluoromethanesulfonic acid (20 mL) under nitrogen. The
reaction mixture
was stirred at room temperature for an hour. The reaction mixture was poured
into water and
treated with sat. NaHCO3(aq) until pH = 8-9. The mixture was partitioned
between DCM and
water. The organic phases were collected, washed with brine, dried over sodium
sulfate,
filtered and concentrated under reduced pressure. The crude residue was
purified by column
chromatography on silica gel using EA/hexane (1/4) as eluent to give the
product 181b as a
yellow solid at a yield of 54%.
(1H-benzimidazol-5-ylamino)[4-(2-propyl-2H-tetrazol-5-y1)phenyl]acetonitrile
(Compound 182a)
H N-
N - N
Nis, I
NH
CN
The (1H-benzimidazol-5-ylamino)[4-(2-propy1-2H-tetrazol-5-
yl)phenyl]acetonitrile
182a was prepared from the addition of 1H-benzimidazol-5-amine 121, TMSCN and
Compound 181a. The procedures were the same as the synthesis of Compound 122a.
The
product 182a was obtained as a pale-yellow solid at a yield of 86%.

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(1H-benzimidazol-5-ylamino){4-[2-(propan-2-y1)-2H-tetrazol-5-
yl]phenyllacetonitrile
(Compound 182b)
HN¨
N¨N
N.
11101
NH
CN
The (1H-benzimidazol-5-ylamino) { 4- [2-(propan-2-y1)-2H-tetrazol-5-yllphenyl}
-
acetonitrile 182b was prepared from the addition of 1H-benzimidazol-5-amine
121, TMSCN
and Compound 181b. The procedures were the same as the synthesis of Compound
122a.
The product 182b was obtained as a pale-yellow solid at a yield of 81%.
N1-(1H-benzimidazol-5-y1)-1-[4-(2-propyl-2H-tetrazol-5-yl)phenyl]ethane-1,2-
diamine
(Compound 183a)
H N-
N¨N
I
NH
NH2
The N'-(1H-benzimidazol-5-y1)-1-}4-(2-propyl-2H-tetrazol-5-ypphenyllethane-1,2-
diamine 183a was prepared from the hydrogenation of Compound 182a with Pd/C as
catalyst. The procedures were the same as the synthesis of Compound 123a. The
product
183a was obtained as a yellow viscous liquid at a yield of 50%.
N1-(1H-benzimidazol-5-y1)-1-{4-[2-(propan-2-y1)-2H-tetrazol-5-yl]phenyllethane-
1,2-
diamine (Compound 183b)
N¨N
NH
NH2
The NI -(1H-benzimidazol-5-y1)-1- {4-[2-(propan-2-y1)-2H-tetrazol-5-
yl]phenyl }ethane-1,2-diamine 183b was prepared from the hydrogenation of
Compound

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182b with Pd/C as catalyst. The procedures were the same as the synthesis of
Compound
123a. The product 183b was obtained as a yellow viscous liquid at a yield of
45%.
1-(1H-benzimidazol-5-y1)-5-[4-(2-propyl-2H-tetrazol-5-y1)phenyl]imidazolidin-2-
one
(Compound 20)
0
H N
N
NH
N N
N-N1
The 1-(1H-benzimidazol-5-y1)-5-[4-(2-propy1-2H-tetrazol-5-
yl)phenyflimidazolidin-
2-one (Compound 20) was prepared from the cycloaddition of 1,1'-carbonyl
diimidazole and
Compound 183a. The procedures were the same as the synthesis of Compound 1.
The
product (Compound 20) was obtained as a white solid at a yield of 60%. 41 NMR
(300MHz,
DMS0- d6) 0.83 (t, 3H, J = 7.2 Hz), 1.87-1.99 (m, 2H), 3.14 (dd, 1H, J = 6.3,
8.7 Hz), 3.89
(dd, 1H, J = 8.7, 9.0 Hz), 4.64 (t, 2H, J = 7.2 Hz), 5.60 (dd, 1H, J = 6.3,
9.0 Hz), 7.01 (s, 1H),
7.26 (d, 1H, J = 8.9 Hz), 7.39 (d, 1H, J = 8.9 Hz), 7.52-7.57 (m, 3H), 7.98
(d, 2H, J = 8.4 Hz),
8.07 (s, 1H), 12.21 (s, 1H); LC/MS (ESI) m/z: 389.2 [M + Hr.
1-(1H-benzimidazol-5-y1)-5-14-[2-(propan-2-y1)-2H-tetrazol-5-
yl]phenyllimidazolidin-2-
one (Compound 21)
0
H N
N *NH
11011
N N
N ¨ N
The 1-(1H-benzimidazol-5-y1)-5- {4- [2-(propan-2-y1)-2H-tetrazol-5-yl[phenyl }
-
imidazolidin-2-one (Compound 21) was prepared from the cycloaddition of 1,1'-
carbonyl
diimidazole and Compound 183b. The procedures were the same as the synthesis
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Compound 1. The product (Compound 21) was obtained as a white solid at a yield
of 62%.
1H NMR (400MHz, DMS0- d6) 6 1.56 (d, 6H, J = 6.4 Hz), 3.14 (dd, 1H, J = 6.4,
8.8 Hz),
3.89 (dd, 1H, J = 8.8, 9.2 Hz), 5.09-5.15 (m, 1H), 5.60 (dd, 1H, J = 6.4, 9.2
Hz), 7.04 (s, 1H),
7.26 (d, 1H, J = 7.6 Hz), 7.39 (d, 1H, J = 8.8 Hz), 7.52-7.57 (m, 3H), 7.97
(d, 2H, J = 8.4 Hz),
8.07 (s, 1H), 12.25 (s, 1H); LC/MS (ESI) m/z: 389.2 IM + Hr.
3-fluoro-4-(thiophen-2-yl)benzaldehyde (Compound 152b)
0
\ I
A mixture of tributyl(thiophen-2-yl)stannane 151 (6.62 g, 17.7 mmol), 4-bromo-
3-
fluorobenzaldehyde 138b (3.0 g, 14.8 mmol) and Pd(PPh3)4 (0.51 g, 0.43 mmol)
in toluene
(160 mL) was refluxed for 16 hours. After cooling to room temperature, the
solvent was
removed under reduced pressure. The residue was diluted with dichloromethane
and filtered
through celite. The organic phase was washed with water, dried over sodium
sulfate, filtered
and concentrated. The crude product was purified by column chromatography on
silica gel
using dichloromethane/hexane (1/9) as eluent. The product 152b was obtained as
a pale-
yellow solid at a yield of 70%.
2-fluoro-4-(thiophen-2-yl)benzaldehyde (Compound 152c)
0
\ I
The 2-fluoro-4-(thiophen-2-yl)benzaldehyde 152c was prepared from the Suzuki-
coupling of 4-bromo-2-fluorobenzaldehyde 138c and tributyl(thiophen-2-
yl)stannane 151
using Pd(PPh3)4 as a catalyst. The procedures were the same as the synthesis
of the
Compound 152b.
The product 152c was obtained as a pale-yellow solid at a yield of 68%.
2,6-difluoro-4-(thiophen-2-yl)benzaldehyde (Compound 152d)
0
\ I
The 2,6-difluoro-4-(thiophen-2-yl)benzaldehyde 152d was prepared from the
Suzuki-
coupling of 4-bromo-2,6-difluorobenzaldehyde 138d and tributyl(thiophen-2-
yl)stannane 151

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using Pd(PPh3)4 as a catalyst. The procedures were the same as the synthesis
of the
Compound 152b. The product 152d was obtained as a pale-yellow solid at a yield
of 56%.
3-fluoro-4-(5-iodothiophen-2-yl)benzaldehyde (Compound 153b)
0
\ I
The 3-fluoro-4-(5-iodothiophen-2-yl)benzaldehyde 153b was prepared from the
selective iodination of the Compound 152b using N-iodosuccinimide. The
procedures were
the same as the synthesis of the Compound 153a. The product 153b was obtained
as a
yellow-green solid at a yield of 77%.
2-fluoro-4-(5-iodothiophen-2-yl)benzaldehyde (Compound 153c)
0
\ I
The 2-fluoro-4-(5-iodothiophen-2-yl)benzaldehyde 153c was prepared from the
selective iodination of the Compound 152c using N-iodosuccinimide. The
procedures were
the same as the synthesis of the Compound 153a. The product 153c was obtained
as a
yellow-green solid at a yield of 75%.
2,6-difluoro-4(5-iodothiophen-2-yl)benzaldehyde (Compound 153d)
0
\ I
The 2,6-difluoro-4-(5-iodothiophen-2-yl)benzaldehyde 153d was prepared from
the
selective iodination of the Compound 152d using N-iodosuccinimide. The
procedures were
the same as the synthesis of the Compound 153a. The product 153d was obtained
as a
yellow-green solid at a yield of 71%.
3-fluoro-4-[5-(trifluoromethypthiophen-2-yl]benzaldehyde (Compound 155b)
Fs C 3
\
The 3-fluoro-445-(trifluoromethyl)thiophen-2-ylThenzaldehyde 155b was prepared
from the trifluoromethylation of the Compound 153b that treated with methyl

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difluoro(fluorosulfonyl)acetate 154 and copper iodide. The procedures were the
same as the
synthesis of the Compound 155a. The product 155b was obtained as a yellow
solid at a yield
of 70%.
2-fluoro-4-[5-(trifluoromethypthiophen-2-yl]lbenzaldehyde (Compound 155c)
0 CF3
\ I
The 2-fluoro-4[5-(trifluoromethyl)thiophen-2-yllbenzaldehyde 155c was prepared
from the trifluoromethylation of the Compound 153c that treated with methyl
difluoro(fluorosulfonyl)acetate 154 and copper iodide. The procedures were the
same as the
synthesis of the Compound 155a. The product 155c was obtained as a yellow
solid at a yield
of 72%.
2,6-difluoro-4-[5-(trifluoromethyl)thiophen-2-yl]benzaldehyde (Compound 155d)
0 CF3
\ I
The 2,6-difluoro-4-[5-(trifluoromethyl)thiophen-2-yl]benzaldehyde 155d was
prepared from the trifluoromethylation of the Compound 153d that treated with
methyl
difluoro(fluorosulfonyl)acetate 154 and copper iodide. The procedures were the
same as the
synthesis of the Compound 155a. The product 155d was obtained as a yellow
solid at a yield
of 67%.
1-(1H-benzimidazol-5-y1)-5-{3-fluoro-445-(trifluoromethyl)thiophen-2-
yl]phenyll-
imidazolidin-2-one (Compound 22)
0
N 110
NH
4110/
S
CF3
The 1-(1H-benzimidazol-5-y1)-5- {3-fluoro-4-[5-(trifluoromethyl)thiophen-2-
yl]phenyl j-imidazolidin-2-one (Compound 22) was prepared from the Compound
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three-steps synthesis of imidazolidinone formation. The procedures were the
same as the
synthesis of Compound 1. The product (Compound 22) was obtained as a white
solid at an
overall yield of 27%. 41 NMR (300MHz, CD30D) 6 3.36 (dd, 1H, J = 6.9, 9.0 Hz),
4.01 (dd,
1H, J = 9.0, 9.6 Hz), 5.54 (dd, 1H, J = 6.9, 9.6 Hz), 7.27-7.34 (m, 3H), 7.41
(d, 1H, J = 3.9
Hz), 7.48-7.51 (m, 2H), 7.59-7.67 (m, 2H), 8.07 (s, 1H); LC/MS (ESI) m/z:
447.0 [M + Hr.
1-(1H-benzimidazol-5-y1)-5-12-fluoro-445-(trifluoromethyl)thiophen-2-Aphenyll-
imidazolidin-2-one (Compound 23)
0
H
N
F NH
S
C F3
The 1-(1H-benzimidazol-5-y1)-5- { 2-fluoro-4- [5-(trifluoromethyl)thiophen-2-
yl[phenyl }-imidazolidin-2-one (Compound 23) was prepared from the Compound
155c in
three-steps synthesis of imidazolidinone formation. The procedures were the
same as the
synthesis of Compound 1. The product (Compound 23) was obtained as a white
solid at an
overall yield of 25%. NMR
(300MHz, CD30D) 6 3.44 (dd, 1H, J = 6.0, 9.0 Hz), 4.05 (dd,
1H, J = 9.0, 9.3 Hz), 5.83 (dd, 1H, J = 6.0, 9.3 Hz), 7.31-7.51 (m, 7H), 7.60
(d, 1H, J = 2.1
Hz), 8.08 (s, 1H); LC/MS (ESI) m/z: 447.1 [M + Hr.
1-(1H-benzimidazol-5-y1)-5-12,6-difluoro-4-[5-(trifluoromethyl)thiophen-2-
yl]phenyll-
imidazolidin-2-one (Compound 24)
/,0
H N¨((
N
N H
F FIIIV
V S
CF3
The 1-(1H-benzimidazol-5-y1)-5- {2,6-difluoro-4-[5-(trifluoromethyl)thiophen-2-
yl[phenyl}imidazolidin-2-one (Compound 24) was prepared from the Compound 155d
in

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three-steps synthesis of imidazolidinone formation. The procedures were the
same as the
synthesis of Compound 1. The product (Compound 24) was obtained as a white
solid at an
overall yield of 21%. 41 NMR (300MHz, CD30D) 6 3.65 (dd, 1H, J = 7.2, 9.3 Hz),
4.05 (dd,
1H, J = 9.3, 10.5 Hz), 6.01 (dd, 1H, J = 7.2, 10.5 Hz), 7.23-7.28 (m, 3H),
7.39-7.41 (m, 1H),
7.46-7.50 (m, 2H), 7.57 (d, 1H, J = 1.8 Hz), 8.08 (s, 1H); LC/MS (ESI) in/z:
465.1 [M + H].
3-fluoro-4-[5-(trifluoromethypthiophen-3-yl]benzaldehyde (Compound 159d)
\ ____ S
\ ____ /
C F3
The 3-fluoro-445-(trifluoromethyl)thiophen-3-yllbenzaldehyde 159d was prepared
from the Suzuki-Miyaura coupling of (2-fluoro-4-formylphenyl)boronic acid 118d
and 3-
bromo-(5-trifluoromethyl)thiophene 158c. The procedures were the same as the
synthesis of
Compound 159a. The product 159d was obtained as a pale-yellow solid at a yield
of 60%.
2-fluoro-4-[5-(trifluoromethypthiophen-3-yl]benzaldehyde (Compound 159e)
CF3
The 2-fluoro-4-[5-(trifluoromethyl)thiophen-3-yl]benzaldehyde 159e was
prepared
from the Suzuki-Miyaura coupling of (3-fluoro-4-formylphenyl)boronic acid 118e
and 3-
bromo-(5-trifluoromethyl)thiophene 158c. The procedures were the same as the
synthesis of
Compound 159a. The product 159e was obtained as a pale-yellow solid at a yield
of 53%.
2,6-difluoro-4-[5-(trifluoromethyl)thiophen-3-yl]benzaldehyde (Compound 1591)
0 S
CF3
The 2,6-difluoro-4-[5-(trifluoromethypthiophen-3-yllbenzaldehyde 1591 was
prepared from the Suzuki-Miyaura coupling of (3,5-difluoro-4-
formylphenyl)boronic acid
118f and 3-bromo-(5-trifluoromethyl)thiophene 158c. The procedures were the
same as the
synthesis of Compound 159a. The product 1591 was obtained as a pale-yellow
solid at a
yield of 33%.

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2,3-difluoro-4-[5-(trifluoromethyl)thiophen-3-yl]benzaldehyde (Compound 159g)
0
S
CF3
The 2,3-difluoro-4-[5-(trifluoromethypthiophen-3-yllbenzaldehyde 159g was
prepared from the Suzuki-Miyaura coupling of (2,3-difluoro-4-
formylphenyl)boronic acid
118g and 3-bromo-(5-trifluoromethyl)thiophene 158e. The procedures were the
same as the
synthesis of Compound 159a. The product 159g was obtained as a pale-yellow
solid at a
yield of 29%.
1-(1H-benzimidazol-5-y1)-543-fluoro-445-(trifluoromethyl)thiophen-3-yl]phenyll-
imidazolidin-2-one (Compound 25)
0
N =.?
NH
(161
,
CF3
The 1-(1H-benzimidazol-5-y1)-5- { 3-fluoro-445-(trifluoromethyl)thiophen-3-
yl]pheny1)-imidazolidin-2-one (Compound 25) was prepared from the Compound
159d in
three-steps synthesis of imidazolidinone formation. The procedures were the
same as the
synthesis of Compound 1. The product (Compound 25) was obtained as a white
solid at an
overall yield of 25%. 1H NMR (300MHz, CD30D) 8 3.37 (dd, 1H, J = 6.9, 9.0 Hz),
4.01 (dd,
1H, J = 9.0, 9.3 Hz), 5.54 (dd, 1H, J = 6.9, 9.3 Hz), 7.24-7.34 (m, 3H), 7.49
(d, 1H, J = 8.7
Hz), 7.56-7.61 (m, 2H), 7.80 (d, 1H, J = 0.9 Hz), 7.90 (s, 1H), 8.08 (s, 1H);
LC/MS (ESI)
nilz: 447.0 [M + H].

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1-(1H-benzimidazol-5-y1)-5-{2-fluoro-445-(trifluoromethyl)thiophen-3-
yl]phenyll-
imidazolidin-2-one (Compound 26)
0
N$ F NH
,
C F3
The 1-(1H-benzimidazol-5-y1)-5- [2-fluoro-4-[5-(trifluoromethyl)thiophen-3-
ylthenyllimidazolidin-2-one (Compound 26) was prepared from the Compound 159e
in
three-steps synthesis of imidazolidinone formation. The procedures were the
same as the
synthesis of Compound 1. The product (Compound 26) was obtained as a white
solid at an
overall yield of 27%. 1H NMR (300MHz, CD30D)15 3.44 (dd, 1H, J = 6.3, 9.0 Hz),
4.05 (dd,
1H, J = 9.0, 9.6 Hz), 5.82 (dd, 1H, J = 6.3, 9.6 Hz), 7.33 (dd, 1H, J = 1.2,
8.7 Hz), 7.42-7.50
(m, 4H), 7.60 (d, 1H, J = 2.0 Hz), 7.86 (d, 1H, J = 1.2 Hz), 7.93 (d, 1H, J =
2.0 Hz), 8.07 (s,
1H); LC/MS (ESI) m/z: 447.0 [M + Hr.
1-(1H-benzimidazol-5-y1)-5-{2,6-difluoro-445-(tritluoromethyl)thiophen-3-
yl]pheny1}-
imidazolidin-2-one (Compound 27)
0
N
F Flair/H
CF3
The 1-(1H-benzimidazol-5-y1)-5- {2,6-difluoro-4-[5-(trifluoromethypthiophen-3-
yl]phenyflimidazolidin-2-one (Compound 27) was prepared from the Compound 159f
in
three-steps synthesis of imidazolidinone formation. The procedures were the
same as the
synthesis of Compound 1. The product (Compound 27) was obtained as a white
solid at an
overall yield of 21%. 41 NMR (300MHz, CD30D) ö 3.65 (dd, 1H, J = 7.2, 9.3 Hz),
4.04 (dd,
1H, J = 9.3, 10.2 Hz), 6.00 (dd, 1H, J = 7.2, 10.2 Hz), 7.24-7.28 (m, 3H),
7.48 (d, 1H, J = 8.7

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Hz), 7.56 (d, 1H, J = 1.8 Hz), 7.84 (s, 1H), 7.95 (d, 1H, J = 1.8 Hz), 8.07
(s, 1H); LC/MS
(ESI) ink: 465.1 [M + H]t
1-(1H-benzimidazol-5-y1)-5-12,3-difluoro-4-[5-(trifluoromethyl)thiophen-3-
yl]phenyll-
imidazolidin-2-one (Compound 28)
0
N 40,
NH
,
C F3
The 1-(1H-benzimidazol-5-y1)-5- { 2,3 -difluoro-445 -(trifluoromethyl)thiophen-
3 -
yflphenyl}imidazolidin-2-one (Compound 28) was prepared from the Compound 159g
in
three-steps synthesis of imidazolidinone formation. The procedures were the
same as the
synthesis of Compound 1. The product (Compound 28) was obtained as a white
solid at an
overall yield of 20%. 1H NMR (300MHz, CD30D) 6 3.46 (dd, 1H, J = 6.3, 9.0 Hz),
4.07 (dd,
1H, J = 9.0, 9.6 Hz), 5.87 (dd, 1H, J = 6.3, 9.6 Hz), 7.23-7.40 (m, 3H), 7.50
(d, 1H, J = 8.4
Hz), 7.61 (d, 1H, J = 1.8 Hz), 7.82 (s, 1H), 7.97 (s, 1H), 8.09 (s, 1H); LC/MS
(ESI)
465.1 [1\4 + Hr.
4-(5-chlorothiophen-2-yl)benzaldehyde (Compound 140b)
CI
The 4-(5-chlorothiophen-2-yl)benzaldehyde 140b was prepared from the Suzuki-
coupling of 4-bromobenzaldehyde 138a and 2-chlorothiophene 139b. The
procedures were
the same as the synthesis of Compound 140a. The product 140b was obtained as a
yellow
solid at a yield of 74%.
4(5-chlorothiophen-2-y1)-3-fluorobenzaldehyde (Compound 140c)
<XCI
H ¨
The 4-(5-chlorothiophen-2-y1)-3-fluorobenzaldehyde 140c was prepared from the
Suzuki-coupling of 4-bromo-3-fluorobenzaldehyde 138b and 2-chlorothiophene
139b. The

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procedures were the same as the synthesis of Compound 140a. The product 140c
was
obtained as a yellow solid at a yield of 69%.
4-(5-chlorothiophen-2-yI)-2-fluorobenzaldehyde (Compound 140d)
s CI
\ I
The 4-(5-chlorothiophen-2-y1)-2-fluorobenzaldehyde 140d was prepared from the
Suzuki-coupling of 4-bromo-2-fluorobenzaldehyde 138c and 2-chlorothiophene
139b. The
procedures were the same as the synthesis of Compound 140a. The product 140d
was
obtained as a yellow solid at a yield of 67%.
4-(5-chlorothiophen-2-yI)-2,6-difluorobenzaldehyde (Compound 140e)
0 s CI
\ I
The 4-(5-chlorothiophen-2-y1)-2,6-difluorobenzaldehyde 140e was prepared from
the
Suzuki-coupling of 4-bromo-2,6-fluorobenzaldehyde 138d and 2-chlorothiophene
139b. The
procedures were the same as the synthesis of Compound 140a. The product 140e
was
obtained as a yellow solid at a yield of 60%.
1-(1H-benzimidazol-5-y1)-5-[4-(5-chlorothiophen-2-y1)phenyl]imidazolidin-2-one
(Compound 29)
0
HN
N *NH
1110
s
CI
The 1-(1H-benzimidazol-5-y1)-5-[4-(5-chlorothiophen-2-yl)phenyl]imidazolidin-2-
one (Compound 29) was prepared from the Compound 140b in three-steps synthesis
of
imidazolidinone formation. The procedures were the same as the synthesis of
Compound 1.
The product (Compound 29) was obtained as a white solid at an overall yield of
28%. 11-1
NMR (300MHz, CD30D) 3.36 (dd, 1H, J = 6.9, 9.0 Hz), 3.99 (dd, 1H, J = 9.0, 9.3
Hz),

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5.48 (dd, 1H, J = 6.9, 9.3 Hz), 6.90 (d, 1H, J = 3.9 Hz), 7.12 (d, 1H, J = 3.9
Hz), 7.30 (d, 1H,
J = 9.0 Hz), 7.40 (d, 2H, J = 8.4 Hz), 7.45-7.49 (m, 3H), 7.54 (d, 1H, J = 2.1
Hz), 8.06 (s,
1H); LC/MS (ESI) m/z: 395.0 [M + H]t
1-(1H-benzimidazol-5-y1)-5-[4-(5-chlorothiophen-2-y1)-3-
fluorophenyl]imidazolidin-2-
one (Compound 30)
0
H N
NH
4101
V S
CI
The 1-(1H-benzimidazol-5-y1)-5-[4-(5-chlorothiophen-2-y1)-3-fluorophenyll-
imidazolidin-2-one (Compound 30) was prepared from the Compound 140c in three-
steps
synthesis of imidazolidinone formation. The procedures were the same as the
synthesis of
Compound 1. The product (Compound 30) was obtained as a white solid at an
overall yield
of 24%. 1H NMR (400MHz, CD30D) 8 3.36 (dd, 1H, J = 6.8, 9.2 Hz), 4.00 (dd, 1H,
J = 9.2,
9.2 Hz), 5.52 (dd, 1H, J = 6.8, 9.2 Hz), 6.95 (d, 1H, J = 4.0 Hz), 7.23-7.26
(m, 3H), 7.31 (d,
1H, J = 8.0 Hz), 7.49 (d, 1H, J = 8.4 Hz), 7.56-7.59 (m, 2H), 8.08 (s, 1H);
LC/MS (ESI) m/z:
413.0 [M + Hr.
1-(1H-benzimidazol-5-y1)-5-[4-(5-chlorothiophen-2-y1)-
241uorophenyl]imidazolidin-2-
one (Compound 31)
0
H N
N F * s=*
N H
401
s
CI
The 1-(1H-benzimidazol-5-y1)-5-[4-(5-chlorothiophen-2-y1)-2-fluorophenyll-
imidazolidin-2-one (Compound 31) was prepared from the Compound 140d in three-
steps
synthesis of imidazolidinone formation. The procedures were the same as the
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Compound 1. The product (Compound 31) was obtained as a white solid at an
overall yield
of 25%. 1H NMR (300MHz, CD30D) 6 3.42 (dd, 1H, J = 6.6, 9.0 Hz), 4.03 (dd, 1H,
J = 9.0,
9.6 Hz), 5.78 (dd, 1H, J = 6.6, 9.6 Hz), 6.91 (d, 1H, J = 4.2 Hz), 7.17 (d,
1H, J = 4.2 Hz),
7.24-7.42 (m, 4H), 7.48 (d, 1H, J = 8.4 Hz), 7.58 (d, 1H, J = 1.8 Hz), 8.07
(s, 1H); LC/MS
(ESI) m/z: 413.0 [M + Hr.
1-(1H-benzimidazol-5-y1)-544-(5-ehlorothiophen-2-y1)-2,6-
difluorophenyl]imidazolidin-
2-one (Compound 32)
0
F NH
VS
CI
The 1-(1H-benzimidazol-5-y1)-5-[4-(5-chlorothiophen-2-y1)-2,6-difluorophenyll-
imidazolidin-2-one (Compound 32) was prepared from the Compound 140e in three-
steps
synthesis of imidazolidinone formation. The procedures were the same as the
synthesis of
Compound 1. The product (Compound 32) was obtained as a white solid at an
overall yield
of 20%.
(5R)-1-(1H-benzimidazol-5-y1)-5-1445-(trifluoromethyl)thiophen-2-
yl]phenyllimidazolidin-2-one (Compound 33)
0
HN
*NH
V S
CF3

79
(5S)-1-(1H-benzimidazol-5-y1)-5-1445-(trifluoromethyl)thiophen-2-
yllphenyllimidazolidin-2-one (Compound 34)
0
HN
7
NH
S
CF3
The enantiomers (Compounds 33 and 34) were separated from Compound 13 by
HPLC using CHIRALPAK AD-H. The isomer fractions were respectively collected
and the
optical pure isomers (Compounds 33 and 34) were thus obtained by removing the
solvent
under reduced pressure. 1H NMR (300MHz, CD30D) ö 3.36 (dd, 1H, J = 6.9, 9.3
Hz), 3.99
(dd, 1H, J = 9.3, 9.3 Hz), 5.51 (dd, 1H, J = 6.9, 9.3 Hz), 7.29-7.32 (m, 2H),
7.43-7.48 (m,
4H), 7.55-7.60 (m, 3H), 8.06 (s, 1H); LC/MS (ESI) m/z: 429.2 [M + Hr.
(510-1-(1H-benzimidazol-5-y1)-5-{445-(trifluoromethyl)thiophen-3-
yllphenyllimidazolidin-2-one (Compound 35)
0
HN
N N,N
7
N H
CF3
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80
(5S)-1-(1H-benzimidazol-5-y1)-5-1445-(trifluoromethyl)thiophen-3-
yllphenyllimidazolidin-2-one (Compound 36)
0
HN¨
NH
,
C F3
The enantiomers (Compounds 35 and 36) were separated from Compound 16 by
HPLC using CHIRALPAIC AD-H. The isomer fractions were respectively collected
and the
optical pure isomers (Compounds 35 and 36) were thus obtained by removing the
solvent
under reduced pressure. 11-INMR (300MHz, CD30D) 8 3.36 (dd, 1H, J = 6.9, 9.0
Hz), 3.99
(dd, 1H, J = 9.0, 9.3 Hz), 5.50 (dd, 1H, J = 6.9, 9.3 Hz), 7.30 (d, 1H, J =
8.1 Hz), 7.41-7.47
(m, 3H), 7.56-7.58 (m, 3H), 7.81 (s, 2H), 8.05 (s, 1H); LC/MS (ESI) m/z: 429.1
[M + H]t
1-1444-(trifluoromethyl)-1,3-thiazol-2-yl]phenyliethanone (Compound 185)
0
\
N
3
The 1-14-[4-(trifluoromethyl)-1,3-thiazol-2-yl]phenyl}ethanone 185 was
prepared
from the Suzuki-coupling of (4-acetylphenyl)boronic acid 184 and Compound
119d. The
procedures were the same as the synthesis of Compound 120a. The product 185
was
obtained as a white solid at a yield of 83%. 4INMR (400MHz, CDC13) 8 2.65 (s,
3H), 7.82
(s, 1H), 8.05 (cl, 2H, J = 8.6 Hz), 8.09 (d, 2H, J = 8.6 Hz); LC/MS (ESI) m/z:
271.7 WI + Hr.
oxo{4I4-(trifluoromethyl)-1,3-thiazol-2-yliphenyllacetaldehyde (Compound 186)
0
\ I
0 N r
3
The Compound 185 (10.0 g, 36.86 mmol) and selenium dioxide (6.95 g, 62.67
mmol)
were dissolved in H20/1,4-dioxane (8 mL/160 mL). The reaction mixture was
stirred at 100
C overnight. The black solid was filtered through celite and washed with ethyl
acetate. The
filtrate was concentrated under the reduced pressure. The residue was purified
by column
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chromatography on silica gel using ethyl acetate/hexane (1/1) as eluent. The
product 186 was
obtained as a yellow solid at a yield of 100%.
1-(1H-benzimidazol-5-y1)-5-{4-[4-(trifluoromethyl)-1,3-thiazol-2-
yl]phenyllimidazolidine-2,4-dione (Compound 37)
0
0 N
NH
N S
F3C)=/
The Compound 186 (9.0 g, 31.55 mmol) and 1-(1H-benzimidazol-6-yl)urea 187
(5.56
g, 31.55 mmol) were dissolved in HCl/AcOH (3 mL/120 mL). The reaction mixture
was
stirred at 120 C overnight. After removing the solvents, the residue was
treated with the
excess ammonia in methanol at an ice-bath and stirred at room temperature for
an hour. The
precipitates were filtered and washed with ethyl acetate and water to get the
pure product.
The filtrate was concentrated and recrystallized in ethyl acetate. The white
solids were
collected as the product (Compound 37) at a yield of 45%. 11-1 NMR (300MHz,
DMSO-d6) 6
6.13 (s, 1H), 7.27 (s, 1H), 7.43 (s, 1H), 7.55 (d, 2H, J = 8.4 Hz), 7.71 (s,
1H), 7.94 (d, 2H, J =
8.4 Hz), 8.16 (s, 1H), 8.52 (s, 1H), 11.43 (s, 1H), 12.41 (s, 1H); LC/MS (ESI)
rn/z: 444.2 [NI
+ Hr.
1-[4-(2-cyclopropy1-1,3-thiazol-4-yl)phenyl]ethanone (Compound 188)
The 144-(2-cyclopropy1-1,3-thiazol-4-yl)phenyflethanone 188 was prepared from
the
Suzuki-coupling of (4-acetylphenyl)boronic acid 184 and Compound 126 with
Pd(dppf)C12 as
catalyst. The procedures were the same as the synthesis of Compound 127. The
product 188
was obtained as a white solid at a yield of 57%. 1H NMR (400MHz, CDC13) 6 1.09-
1.16 (m,
4H), 2.32-2.37 (m, 1H), 2.60 (s, 3H), 7.35 (s, 1H), 7.94 (d, 2H, J = 8.8 Hz),
7.97 (d, 2H, J =
8.8 Hz); LC/MS (ES!) m/z: 244.1 [M + H].

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[4-(2-cyclopropy1-1,3-thiazol-4-yl)phenyl](oxo)acetaldehyde (Compound 189)
0
The [4-(2-cyclopropy1-1,3-thiazol-4-y1)phenyl](oxo)acetaldehyde 189 was
prepared
from the oxidation of Compound 188 by selenium dioxide. The procedures were
the same as
the synthesis of Compound 186. The product 189 was obtained as a yellow solid
at a yield of
100%.
1-(1H-benzimidazol-5-y1)-5-[4-(2-cyclopropy1-1,3-thiazol-4-
yl)phenyl]imidazolidine-2,4-
dione (Compound 38)
0
HN¨g
0 N 110
NH
V N
The 1-(1H-benzimidazol-5-y1)-5-[4-(2-cyclopropy1-1,3-thiazol-4-y1)phenyll-
imidazolidine-2,4-dione (Compound 38) was prepared from the cycloaddition of 1-
(1H-
benzimidazol-6-yl)urea 187 and Compound 189. The procedures were the same as
the
synthesis of Compound 37. The product (Compound 38) was obtained as a white
solid at a
yield of 49%. 'H NMR (400MHz, DMSO-d6) .5 1.00-1.03 (m, 2H), 1.08-1.11 (m,
2H), 2.36-
2.42 (m, 1H), 6.03 (s, 1H), 7.28 (s, 1H), 7.41 (d, 2H, J = 8.0 Hz), 7.48 (s,
1H), 7.69 (s, 1H),
7.77 (s, 1H), 7.83 (d, 2H, J = 8.0 Hz), 8.15 (s, 1H), 11.38 (s, 1H), 12.41 (s,
1H); LC/MS (ESI)
m/z: 416.2 [M + Hr.
1-[4-(2-cyclopropy1-1,3-thiazol-5-yl)phenyl]ethanone (Compound 190b)
0

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To the solution of Compound 134b (0.23 g, 1.0 mmol) in anhydrous THF (4 mL),
the
methylmagnesium bromide in THF (1M, 2 mL) was added dropwise at 0 C. Then,
the
reaction mixture was stirred at room temperature overnight. The saturated
aqueous solution
of ammonium chloride was added to quench the reaction. The aqueous layer was
extracted
with ethyl acetate. The organic layers were collected, washed with brine,
dried over sodium
sulfate, filtered and concentrated under reduced pressure. The residue was
purified by
column chromatography on silica gel using ethyl acetate/hexane (1/4) as
eluent. The product
190b was obtained as a yellow solid at a yield of 48%. 41NMR (300MHz, CDC13) 6
1.13-
1.19 (m, 4H), 2.30-2.35 (m, 1H), 2.61 (s, 3H), 7.58 (d, 2H, J = 8.0 Hz), 7.85
(s, 1H), 7.96 (d,
2H, J = 8.0 Hz); LC/MS (ESI) m/z: 244.1 [M + Hr.
1-14-[2-(trifluoromethyl)-1,3-thiazol-5-yl]phenyllethanone (Compound 190c)
0
---CF3
The 1-{4-[2-(trifluoromethyl)-1,3-thiazol-5-yl[phenyliethanone 190c was
prepared
from the methylation of Compound 134c. The procedures were the same as the
synthesis of
Compound 190b. The product 190c was obtained as a yellow solid at a yield of
49%. '1-1
NMR (400MHz, CDC13) 6 2.64 (s, 3H), 7.69 (d, 2H, J = 8.0 Hz), 8.04 (d, 2H, J =
8.0 Hz),
8.17 (s, 1H); LC/MS (ESI) m/z: 271.7 [M + H].
[4-(2-cyclopropy1-1,3-thiazol-5-yl)phenyl](oxo)acetaldehyde (Compound 191b)
0
0
The [4-(2-cyclopropy1-1,3-thiazol-5-yl)phenyll(oxo)acetaldehyde 191b was
prepared
from the oxidation of Compound 190b by selenium dioxide. The procedures were
the same
as the synthesis of Compound 186. The product 191b was obtained as a yellow
solid at a
yield of 100%.

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oxot4[2-(trifluoromethyl)-1,3-thiazol-5-yllphenyllacetaldehyde (Compound 191c)
0
0
>-CF3
The oxo 4- [2-(trifluoromethyl)-1,3-thiazol-5-yflphenyl } acetaldehyde 191c
was
prepared from the oxidation of Compound 190c by selenium dioxide. The
procedures were
the same as the synthesis of Compound 186. The product 191c was obtained as a
yellow
solid at a yield of 100%.
1-(1H-benzimidazol-5-y1)-5-[4-(2-cyclopropy1-1,3-thiazol-5-
yl)phenyl]imidazolidine-2,4-
dione (Compound 39)
0
0 N S)
NH
1101
S
The 1-(1H-benzimidazol-5-y1)-5-[4-(2-cyclopropy1-1,3-thiazol-5-yl)phenyll-
imidazolidine-2,4-dione (Compound 39) was prepared from the cycloaddition of 1-
(1H-
benzimidazol-6-yl)urea 187 and Compound 191b. The procedures were the same as
the
synthesis of Compound 37. The product (Compound 39) was obtained as a white
solid at a
yield of 57%. 1H NMR (400MHz, DMSO-d6) 6 0.93-0.99 (m, 2H), 1.01-1.11 (m, 2H),
2.33-
2.39 (m, 1H), 6.05 (s, 1H), 7.33 (d, 1H, J = 8.6 Hz), 7.41 (d, 2H, J = 8.0
Hz), 7.48 (d, 1H, J =
8.6 Hz), 7.53 (d, 2H, J = 8.0 Hz), 7.70 (d, 1H, J = 1.2 Hz), 7.91 (s, 1H),
8.18 (s, 1H), 11.39 (s,
1H), 12.47 (s, 1H); LC/MS (ESI) m/z: 416.2 [M + Hr.

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1-(1H-benzimidazol-5-y1)-5-{442-(trifluoromethyl)-1,3-thiazol-5-
yl]phenyl}imidazolidine-2,4-dione (Compound 40)
0
0 N*NH
S
N=(
CF3
The 1-(1H-benzimidazol-5-y1)-5- {4- [2-(trifluoromethyl)-1,3-thiazol-5-
yflphenyl )-
imidazolidine-2,4-dione (Compound 40) was prepared from the cycloaddition of 1-
(1H-
benzimidazol-6-yl)urea 187 and Compound 191c. The procedures were the same as
the
synthesis of Compound 37. The product (Compound 40) was obtained as a white
solid at a
yield of 30%. 41 NMR (400MHz, DMSO-d6) .5 6.12 (s, 1H), 7.35 (s, 1H), 7.47-
7.52 (m, 3H),
7.71-7.75 (m, 3H), 8.16 (s, 1H), 8.48 (s, 1H), 11.44 (s, 1H), 12.43 (s, 1H);
LC/MS (ESI) m/z:
444.2 [M + H].
1-[4(2H-tetrazol-5-yl)phenyl]ethanone (Compound 192)
O HN-NH
HCI
To the solution of 4-acetylbenzonitrile 143 (4.35 g, 30.0 mmol) in DMF (30
mL),
sodium azide (2.15 g, 33 mmol) and ammonium chloride (0.40 g, 7.5 mmol) were
added
under nitrogen. The reaction mixture was refluxed overnight and then cooled to
room
temperature. The reaction mixture was diluted with water and extracted with
DCM. The
aqueous phase was chilled in ice and acidified by adding IN HC1(aq). After
filtering, the
precipitates were washed with water and ether to obtain the product 192 as a
yellow solid at a
yield of 94%.

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1-(1H-benzimidazol-5-y1)-5-[4-(2-methyl-2H-tetrazol-5-y1)phenyl]imidazolidine-
2,4-
dione (Compound 41)
0
0 N
NH
N N
N-NI
The 1-(1H-benzimidazol-5-y1)-544-(2-methy1-2H-tetrazol-5-
yl)phenyl[imidazolidine-
2,4-dione (Compound 41) was prepared from the cycloaddition of 1-(1H-
benzimidazol-6-
yl)urea 187 and Compound 194a. The procedures were the same as the synthesis
of
Compound 37. The product (Compound 41) was obtained as a white solid at a
yield of 17%.
NMR (400MHz, DMSO-d6) 6 4.38 (s, 3H), 6.12 (s, 1H), 7.28 (br s, 1H), 7.47 (br
s, 1H),
7.57 (d, 2H, J = 8.4 Hz), 7.72 (s, 1H), 8.00 (d, 2H, J = 8.4 Hz), 8.16 (s,
1H), 11.46 (br s, 1H),
12.44 (br s, 1H); LC/MS (ES!) ink: 375.1 [M + H].
1-(1H-benzimidazol-5-y1)-5-[4-(2-propy1-2H-tetrazol-5-yl)phenyl]imidazolidine-
2,4-
dione (Compound 42)
0
HN-f
0 N
NH
110
N
N-1V
The 1-(1H-benzimidazol-5-y1)-5-[4-(2-propy1-2H-tetrazol-5-
yl)phenyl[imidazolidine-
2,4-dione (Compound 42) was prepared from the cycloaddition of 1-(1H-
benzimidazol-6-
yl)urea 187 and Compound 194b. The procedures were the same as the synthesis
of
Compound 37. The product (Compound 42) was obtained as a white solid at a
yield of 33%.
NMR (300MHz, DMSO-do) 6 0.84 (t, 3H, J = 7.5 Hz), 1.87-1.99 (m, 2H), 4.65 (t,
2H, J =
6.8 Hz), 6.12 (s, 1H), 7.34 (br s, 1H), 7.47 (br s, 1H), 7.57 (d, 2H, J = 8.4
Hz), 7.71 (s, 1H),
8.00 (d, 2H, J = 8.4 Hz), 8.15 (s, 1H), 11.43 (s, 1H), 12.41 (s, 1H); LC/MS
(ES!) m/z: 403.2
[M + Hr.

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1-(1H-benzimidazol-5-y1)-54442-(propan-2-y1)-2H-tetrazol-5-
yl]phenyllimidazolidine-
2,4-dione (Compound 43)
0
H N
0 N *N H
N N
N¨Nt
The 1-(1H-benzimidazol-5-y1)-5- { 4- [2-(propan-2-y1)-2H-tetrazol-5-yl[phenyl
} -
imidazolidine-2,4-dione (Compound 43) was prepared from the cycloaddition of 1-
(1H-
benzimidazol-6-yl)urea 187 and Compound 194c. The procedures were the same as
the
synthesis of Compound 37. The product (Compound 43) was obtained as a white
solid at a
yield of 28%. 1H NMR (400MHz, DMSO-d6) 6 1.57 (d, 6H, J = 6.4 Hz), 5.09-5.16
(m, 1H),
6.11 (s, 1H), 7.27 (hr s, 1H), 7.42 (hr s, 1H), 7.57 (d, 2H, J = 8.4 Hz), 7.71
(s, 1H), 8.00 (d,
2H, J = 8.4 Hz), 8.15 (s, 1H), 11.43 (s, 1H), 12.41 (s, 1H); LC/MS (ESI) nilz:
403.2 [M + Hr.
1-(1H-benzimidazol-5-y1)-5-14-[2-(2-methylpropyl)-2H-tetrazol-5-
yl]phenyllimidazolidine-2,4-dione (Compound 44)
0
H N
0 N
NH
N.% '1'1
N-N
The 1-(1H-benzimidazol-5-y1)-5- { 4- [2-(2-methylpropy1)-2H-tetrazol-5-
yliphenyl } -
imidazolidine-2,4-dione (Compound 44) was prepared from the cycloaddition of 1-
(1H-
benzimidazol-6-yl)urea 187 and Compound 194d. The procedures were the same as
the
synthesis of Compound 37. The product (Compound 44) was obtained as a white
solid at a
yield of 34%. 1H NMR (400MHz, DMSO-d6) 6 0.86 (d, 6H, J = 6.4 Hz), 2.22-2.29
(m, 1H),
4.53 (d, 2H, J = 6.8 Hz), 6.12 (s, 1H), 7.28 (hr s, 1H), 7.47 (hr s, 1H), 7.57
(d, 2H, J = 8.0

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Hz), 7.72 (s, 1H), 8.01 (d, 2H, J = 8.0 Hz), 8.16 (s, 1H), 11.45 (s, 1H),
12.42 (s, 1H); LC/MS
(ESI) m/z: 417.2 [M + H].
1-(1H-benzimidazol-5-y1)-5-14-[2-(cyclopropylmethyl)-2H-tetrazol-5-yl]phenyll-
imidazolidine-2,4-dione (Compound 45)
0
H N
0 N
NH
N N
o I
N ¨N
The 1-(1H-benzimidazol-5-y1)-5-{4-[2-(cyclopropylmethyl)-2H-tetrazol-5-
ylthenyll-imidazolidine-2,4-dione (Compound 45) was prepared from the
cycloaddition of
1-(1H-benzimidazol-6-ypurea 187 and Compound 194e. The procedures were the
same as
the synthesis of Compound 37. The product (Compound 45) was obtained as a
white solid at
a yield of 31%. 1H NMR (300MHz, DMSO-d6) 60.42-0.45 (m, 2H), 0.54-0.58 (m,
2H),
1.33-1.41 (m, 1H), 4.57 (d, 2H, J = 7.2 Hz), 6.12 (s, 1H), 7.29 (br s, 1H),
7.46 (br s, 1H), 7.58
(d, 2H, J = 8.4 Hz), 7.72 (s, 1H), 8.01 (d, 2H, J = 8.4 Hz), 8.15 (s, 1H),
11.43 (s, 1H), 12.41
(s, 1H); LC/MS (ESI) m/z: 415.1 [M + H].
1-(1H-benzimidazol-5-y1)-5-14-[2-(2,2,2-trifluoroethyl)-21-1-tetrazol-5-
yl]phenyll-
imidazolidine-2,4-dione (Compound 46)
0
H N
0 N$\)
NH
N N
o I
N ¨N
F3C
The 1-(1H-benzimidazol-5-y1)-5- { 4- [2-(2,2,2-trifluoroethyl)-2H-tetrazol-5-
yl]phenyll-imidazolidine-2,4-dione (Compound 46) was prepared from the
cycloaddition of

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1-(1H-benzimidazol-6-ypurea 187 and Compound 194f. The procedures were the
same as
the synthesis of Compound 37. The product (Compound 46) was obtained as a
white solid at
a yield of 36%. 41 NMR (300MHz, DMSO-d6) 6 6.01 (q, 2H, J = 8.7 Hz), 6.15 (s,
1H), 7.36
(br s, 1H), 7.48 (br s, 1H), 7.61 (d, 2H, J = 8.4 Hz), 7.73 (s, 1H), 8.04 (d,
2H, J = 8.4 Hz),
8.17 (s, 1H), 11.49 (br s, 1H), 12.41 (br s, 1H); LC/MS (ESI) m/z: 443.2 [M +
Hit
1-(1H-benzimidazol-5-y1)-5-14-[2-(prop-2-yn-1-y1)-2H-tetrazol-5-
yl]phenyllimidazolidine-2,4-dione (Compound 47)
0
H N
0 N
NH
(11011
N N
N ¨
The 1-(1H-benzimidazol-5-yl)-5- {4- [2-(prop-2-yn-l-y1)-2H-tetrazol-5-yl]
phenyl )-
imidazolidine-2,4-dione (Compound 47) was prepared from the cycloaddition of 1-
(1H-
benzimidazol-6-yl)urea 187 and Compound 194g. The procedures were the same as
the
synthesis of Compound 37. The product (Compound 47) was obtained as a white
solid at a
yield of 36%. III NMR (300MHz, DMSO-d6) 6 5.75 (d, 1H, J = 1.5 Hz), 6.07 (d,
1H, J = 6.6
Hz), 6.14 (s, 1H), 7.29 (br s, 1H), 7.47 (br s, 1H), 7.59 (d, 2H, J = 8.0 Hz),
7.72 (s, 1H), 8.02
(d, 2H, J = 8.0 Hz), 8.16 (s, 1H), 8.24 (dd, 1H, J = 1.5, 6.6 Hz), 11.47 (br
s, 1H), 12.44 (s,
1H); LC/MS (ESI) m/z: 399.1 [M + Hr.

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1-(1H-benzimidazol-5-y1)-5-{442-(but-2-yn-1-y1)-2H-tetrazol-5-
yl]phenyllimidazolidine-
2,4-dione (Compound 48)
0
H N
0 N 110
NH
N N
The 1-(1H-benzimidazol-5-y1)-5- {4-[2-(but-2-yn-1-y1)-2H-tetrazol-5-yllpheny11-
imidazolidine-2,4-dione (Compound 48) was prepared from the cycloaddition of 1-
(1H-
benzimidazol-6-yl)urea 187 and Compound 194h. The procedures were the same as
the
synthesis of Compound 37. The product (Compound 48) was obtained as a white
solid at a
yield of 34%. 41 NMR (300MHz, DMSO-do) 6 1.83 (s, 3H), 5.65 (d, 2H, J = 1.8
Hz), 6.13
(s, 1H), 7.34 (d, 1H, J = 6.6 Hz), 7.48 (d, 1H, J = 8.7 Hz), 7.58 (d, 2H, J =
7.8 Hz), 7.72 (s,
1H), 8.02 (d, 2H, J = 7.8 Hz), 8.16 (s, 1H), 11.44 (s, 1H), 12.41 (s, 1H);
LC/MS (ES!) m/z:
413.1 11µ4 + Hr.
1-(1H-benzimidazol-5-y1)-5-(442-(pent-2-yn-1-y1)-2H-tetrazol-5-
yl]phenyl}imidazolidine-2,4-dione (Compound 49)
0 7
N * NH
N
N-14
The 1-(1H-benzimidazol-5-y1)-5- { 4- {2-(pent-2-yn-1-y1)-2H-tetrazol-5-
yllpheny11-
imidazolidine-2,4-dione (Compound 49) was prepared from the cycloaddition of 1-
(1H-
benzimidazol-6-yl)urea 187 and Compound 194i. The procedures were the same as
the
synthesis of Compound 37. The product (Compound 49) was obtained as a white
solid at a

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yield of 32%. III NMR (300MHz, DMSO-d6) 1.03 (t, 3H, J = 7.5 Hz), 2.17-2.26
(m, 2H),
5.65 (t, 2H, J = 2.1 Hz), 6.11 (s, 1H), 7.29 (br s, 1H), 7.46 (br s, 1H), 7.58
(d, 2H, J = 8.4 Hz),
7.71 (s, 1H), 8.01 (d, 2H, J = 8.4 Hz), 8.15 (s, 1H), 11.43 (br s, 1H), 12.42
(br s, 1H); LC/MS
(ESI) m/z: 427.1 [M + H].
1-(1H-benzimidazol-5-y1)-5-14-[2-(4-chlorobenzy1)-2H-tetrazol-5-
yl]phenyllimidazolidine-2,4-dione (Compound 50)
HN-=
0 N 110
NH
N-N
CI
The 1-(1H-benzimidazol-5-y1)-5- 4- [2-(4-chlorobenzy1)-2H-tetrazol-5-
yl[pheny11-
imidazolidine-2,4-dione (Compound 50) was prepared from the cycloaddition of 1-
(1H-
benzimidazol-6-yl)urea 187 and Compound 194j. The procedures were the same as
the
synthesis of Compound 37. The product (Compound 50) was obtained as a white
solid at a
yield of 43%. 41 NMR (300MHz, DMSO-d6) ö 5.98 (s, 2H), 6.11 (s, 1H), 7.25 (d,
1H, J =
8.1 Hz), 7.36-7.50 (m, 5H), 7.56 (d, 2H, J = 8.4 Hz), 7.70 (s, 1H), 7.99 (d,
2H, J = 8.4 Hz),
8.15 (s, 1H), 11.44 (s, 1H), 12.41 (s, 1H); LC/MS (ESI) m/z: 485.1 [M + Hr.

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1-(1H-benzimidazol-5-y1)-5-{442-(4-methoxybenzy1)-2H-tetrazol-5-yllphenyll-
imidazolidine-2,4-dione (Compound 51)
HN-4(
0 N
NH
N N
1-1
The 1-(1H-benzimidazol-5-y1)-5- {4- [2-(4-methoxybenzy1)-2H-tetrazol-5-
yllpheny11-
imidazolidine-2,4-dione (Compound 51) was prepared from the cycloaddition of 1-
(1H-
benzimidazol-6-yl)urea 187 and Compound 194k. The procedures were the same as
the
synthesis of Compound 37. The product (Compound 51) was obtained as a white
solid at a
yield of 22%. 1H NMR (300MHz, DMSO-d6) 6 3.71 (s, 3H), 5.86 (s, 2H), 6.15 (s,
1H), 6.91
(d, 2H, J = 8.4 Hz), 7.33 (d, 2H, J = 8.4 Hz), 7.42 (br s, 2H), 7.55 (d, 2H, J
= 8.1 Hz), 7.70 (s,
1H), 7.98 (d, 2H, J = 8.1 Hz), 8.15 (s, 1H), 11.43 (s, 1H), 12.41 (s, 1H);
LC/MS (ESI) m/z:
481.2 [M + Hr.
1-(1H-benzimidazol-5-y1)-5-(4-{2-[(3-methy1-1,2-oxazol-5-yl)methy1]-2H-
tetrazol-5-
yllphenyl)imidazolidine-2,4-dione (Compound 52)
HN-4(
0 7
N 10 NH
N N
N-N
The 1-(1H-benzimidazol-5-y1)-5-(4-{2-[(3-methyl-1,2-oxazol-5-yemethyll-2H-
tetrazol-5-y1 1 phenyl)imidazolidine-2,4-dione (Compound 52) was prepared from
the
cycloaddition of 1-(1H-benzimidazol-6-yl)urea 187 and Compound 1941. The
procedures

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were the same as the synthesis of Compound 37. The product (Compound 52) was
obtained
as a white solid at a yield of 52%. 1H NMR (400MHz, DMSO-d6) 5 2.20 (s, 3H),
6.12 (s,
1H), 6.24 (s, 2H), 6.51 (s, 1H), 7.27 (br s, 1H), 7.46 (br s, 1H), 7.58 (d,
2H, J = 8.0 Hz), 7.71
(s, 1H), 8.00 (d, 2H, J = 8.0 Hz), 8.16 (s, 1H), 11.30 (br s, 1H), 12.42 (br
s, 1H); LC/MS
(ESI) m/z: 456.1 [M + H].
Nt2-(4-cyanopheny1)-2-oxoethyl]tricyclo[3.3.1.13'7]decane-1-carboxamide
(Compound
196)
NC 0
0
The N-[2-(4-cyanopheny1)-2-oxoethyl]tricyclo 113.3.1. 13,7]decane-1-
carboxamide 196
was prepared through the acetylation of compound 131 with adamantane- 1-
carbonyl chloride
195. The experimental procedures were the same as the synthesis of compound
133a. The
product 196 was obtained as a yellow solid at a yield of 53%. 11-1 NMR
(400MHz, CDC13) 5
1.71-1.78 (m, 6H), 1.92 (s, 6H), 2.07 (s, 3H), 4.74 (d, 2H, J = 4.0 Hz), 6.65
(s, 1H), 7.81 (d,
2H, J = 8.6 Hz), 8.07 (d, 2H, J = 8.6 Hz); LC/MS (ESI) m/z: 323.3 [M + H].
4-[2-(tricyclo[3.3.1.13,7]dec-1-y1)-1,3-thiazol-5-yllbenzonitrile (Compound
197)
NC
The 442-(tricyclo[3.3.1.13,7]dec-1-y1)-1,3-thiazol-5-yl]benzonitrile 197 was
prepared
from the cyclization of compound 196 with the Lawesson's reagent in THF. The
experimental procedures were the same as the synthesis of compound 134a. The
product 197
was obtained as a white solid at a yield of 49%. 41 NMR (400MHz, CDC13) 5 1.80
(s, 6H),
2.08 (s, 6H), 2.13 (s, 3H), 7.61-7.67 (m, 4H), 7.94 (s, 1H); LC/MS (ESI) m/z:
321.3 [M +
H].
4-[2-(tricyclo[3.3.1.13,7]dec-1-y1)-1,3-thiazol-5-yl]benzaldehyde (Compound
198)
0
The 4[2-(tricyclo[3.3.1.13.7[dec-1-y1)-1,3-thiazol-5-yl[benzaldehyde 198 was
prepared from the reduction of compound 197 with the DIBAL-H reagent. The
experimental
procedures were the same as the synthesis of compound 135a. The product 198
was obtained

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as a yellow solid at a yield of 83%. 'FINMR (300MHz, CDC13) 1.81 (s, 6H), 2.10
(s, 6H),
2.14 (s, 3H), 7.70 (d, 2H, J = 8.4 Hz), 7.89 (d, 2H, J = 8.4 Hz), 7.98 (s,
1H), 10.00 (s, 1H);
LC/MS (ESI) m/z: 324.3 [M + Hr.
(1H-benzimidazol-5-ylamino){4-[2-(tricyclo[3.3.1.13,7]dec-1-y1)-1,3-thiazol-5-
yl]phenyllacetonitrile (Compound 199)
HN
q_s
NH
CN
The (1H-benzimidazol-5-ylamino) { 442-(tricyclo [3 .3.1.13,7[dec-1-y1)-1,3-
thiazol-5-
yl[phenyl acetonitrile 199 was prepared from the addition of 1H-benzimidazol-5-
amine 121,
TMSCN and compound 198. The experimental procedures were the same as the
synthesis of
compound 122a. The product 199 was obtained as a pale-yellow solid at a yield
of 91%.
N1-(1H-benzimidazol-5-y1)-1-{442-(tricyclo[3.3.1.13,7]dec-1-y1)-1,3-thiazol-5-
yl]phenyllethane-1,2-diamine (Compound 200)
HN
NH
NH2
The NI -(1H-benzimidazol-5 -y1)-1- { 4- [2-(tricyclo [3.3.1.13,7]dec-1-y1)-1,3-
thiazol-5-
yllphenyljethane-1,2-diamine 200 was prepared from the hydrogenation of
compound 199
with the Raney Nickel reagent as catalyst. The experimental procedures were
the same as the
synthesis of compound 123a. The product 200 was obtained as a yellow viscous
liquid at a
yield of 60%.

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1-(1H-benzimidazol-5-y1)-5-{442-(tricyclo[3.3.1.13,7]dec-1-y1)-1,3-thiazol-5-
yl]phenyl}imidazolidin-2-one (Compound 57)
0
N$
NH
1110
s
N121
The 1-(1H-benzimidazo1-5-y1)-5- 442-(tricyclo[3.3.1.13,7]dec-1-y1)-1,3-thiazol-
5-
yl]phenyl Iimidazolidin-2-one (Compound 57) was prepared from the
cycloaddition of 1,1'-
carbonyl diimidazole and compound 200. The experimental procedures were the
same as the
synthesis of Compound 1. The product (Compound 57) was obtained as a yellow
solid at a
yield of 78%. 'FINMR (400MHz, CD30D) El 1.75 (s, 6H), 2.03 (s, 6H), 2.05 (s,
3H), 3.32-
3.36 (m, 1H), 3.97 (dd, 1H, J = 9.2, 9.2 Hz), 5.49 (dd, 1H, J = 6.8, 9.2 Hz),
7.30 (d, 1H, J =
8.8 Hz), 7.40 (d, 2H, J = 8.4 Hz), 7.45-7.49 (m, 3H), 7.56 (s, 1H), 7.79 (s,
1H), 8.06 (s, 1H);
LC/MS (ESI) m/z: 496.4 FM + Hr.
2,3-difluoro-4-(5-fluorothiophen-3-y1)benzaldehyde (Compound 201a)
F F
0 S
The 2,3-difluoro-4-(5-fluorothiophen-3-yl)benzaldehyde 201a was prepared from
the
Suzuki-Miyaura coupling of 2,3-difluoro-4-formylphenylboronic acid 118g and 4-
bromo-2-
fluorothiophene 158d. The experimental procedures were the same as the
synthesis of
compound 159a. The product 201a was obtained as a pale-yellow oil at a yield
of 42%.
4-(5-chlorothiophen-3-y1)-2,3-difluorobenzaldehyde (Compound 201b)
F F
0 S
CI
The 4-(5-chlorothiophen-3-y1)-2,3-difluorobenzaldehyde 201b was prepared from
the
Suzuki-Miyaura coupling of 2,3-difluoro-4-formylphenylboronic acid 118g and 4-
bromo-2-

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chlorothiophene 158e. The experimental procedures were the same as the
synthesis of
compound 159a. The product 20th was obtained as a pale-yellow oil at a yield
of 45%.
2,3-difluoro-4-(5-methylthiophen-3-yl)benzaldehyde (Compound 201c)
0 S
The 2,3-difluoro-4-(5-methylthiophen-3-yl)benzaldehyde 201c was prepared from
the
Suzuki-Miyaura coupling of 2,3-difluoro-4-formylphenylboronic acid 118g and 4-
bromo-2-
methylthiophene 158b. The experimental procedures were the same as the
synthesis of
compound 159a. The product 201c was obtained as a pale-yellow oil at a yield
of 53%.
4-(5-ethylthiophen-3-y1)-2,3-difluorobenzaldehyde (Compound 201d)
S
The 4-(5-ethylthiophen-3-y1)-2,3-difluorobenzaldehyde 201d was prepared from
the
Suzuki-Miyaura coupling of 2,3-difluoro-4-formylphenylboronic acid 118g and 4-
bromo-2-
ethylthiophene 158f. The experimental procedures were the same as the
synthesis of
compound 159a. The product 201d was obtained as a pale-yellow oil at a yield
of 56%.
2,3-difluoro-4-[5-(methoxymethyl)thiophen-3-yl]benzaldehyde (Compound 201e)
0 S
ON.
The 2,3-difluoro-4-15-(methoxymethyl)thiophen-3-ylIbenzaldehyde 201e was
prepared from the Suzuki-Miyaura coupling of 2,3-difluoro-4-
formylphenylboronic acid
118g and 4-bromo-2-(methoxymethyl)thiophene 158g. The experimental procedures
were
the same as the synthesis of compound 159a. The product 201e was obtained as a
pale-
yellow oil at a yield of 49%.
4[5-(ethoxymethyl)thiophen-3-y1]-2,3-difluorobenzaldehyde (Compound 2011)
0
S
The 445-(ethoxymethyl)thiophen-3-y11-2,3-difluorobenzaldehyde 201f was
prepared
from the Suzuki-Miyaura coupling of 2,3-difluoro-4-formylphenylboronic acid
118g and 4-
bromo-2-(ethoxymethypthiophene 158h. The experimental procedures were the same
as the

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synthesis of compound 159a. The product 201f was obtained as a pale-yellow oil
at a yield
of 48%.
methyl 4-(2,3-difluoro-4-formylphenyl)thiophene-2-earboxylate (Compound 201g)
0 S
ON.
0
The methyl 4-(2,3-difluoro-4-formylphenyl)thiophene-2-carboxylate 201g was
prepared from the Suzuki-Miyaura coupling of 2,3-difluoro-4-
formylphenylboronic acid
118g and methyl 4-bromothiophene-2-carboxylate 158i. The experimental
procedures were
the same as the synthesis of compound 159a. The product 201g was obtained as a
pale-
yellow oil at a yield of 42%.
2,3-difluoro-4-(thiophen-3-yl)benzaldehyde (Compound 201h)
0 S
The 2,3-difluoro-4-(thiophen-3-yObenzaldehyde 201h was prepared from the
Suzuki-
Miyaura coupling of 2,3-difluoro-4-formylphenylboronic acid 118g and 3-
bromothiophene
158a. The experimental procedures were the same as the synthesis of compound
159a. The
product 201h was obtained as a pale-yellow oil at a yield of 54%.
(1H-benzimidazol-5-ylamino)[2,3-difluoro-4-(5-fluorothiophen-3-
yl)phenyl]acetonitrile
(Compound 202a)
HN--\\
110
NH
F CN
The (1H-benzimidazol-5-ylamino)[2,3-difluoro-4-(5-fluorothiophen-3-yl)phenyli-
acetonitrile 202a was prepared from the addition of 1H-benzimidazol-5-amine
121, TMSCN
and compound 201a. The experimental procedures were the same as the synthesis
of
compound 122a. The product 202a was obtained as a pale-yellow solid at a yield
of 85%.

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(1H-benzimidazol-5-ylamino)[445-chlorothiophen-3-y1)-2,3-
difluorophenyl]acetonitrile
(Compound 202b)
CI
11110
NH
F CN
The (1H-benzimidazol-5-ylamino)[4-(5-chlorothiophen-3-y1)-2,3-
difluorophenyllacetonitrile 202b was prepared from the addition of 1H-
benzimidazol-5-
amine 121, TMSCN and compound 201b. The experimental procedures were the same
as the
synthesis of compound 122a. The product 202b was obtained as a pale-yellow
solid at a
yield of 79%.
(1H-benzimidazol-5-ylamino)[2,3-difluoro-4-(5-methylthiophen-3-
y1)phenyl]acetonitrile
(Compound 202c)
HN-\\
110
NH
F CN
The (1H-benzimidazol-5-ylamino)[2,3-difluoro-4-(5-methylthiophen-3-
yl)phenyl]acetonitrile 202c was prepared from the addition of 1H-benzimidazol-
5-amine 121,
TMSCN and compound 201c. The experimental procedures were the same as the
synthesis
of compound 122a. The product 202c was obtained as a pale-yellow solid at a
yield of 88%.
(1H-benzimidazol-5-ylamino)[4-(5-ethylthiophen-3-y1)-2,3-
difluorophenyl]acetonitrile
(Compound 202d)
HN-\\
NH
F CN
The (1H-benzimidazol-5-ylamino)l4-(5-ethylthiophen-3-y1)-2,3-difluorophenyl]-
acetonitrile 202d was prepared from the addition of 1H-benzimidazol-5-amine
121, TMSCN
and compound 201d. The experimental procedures were the same as the synthesis
of
compound 122a. The product 202d was obtained as a pale-yellow solid at a yield
of 81%.

99
(1H-benzimidazol-5-ylamino){2,3-difluoro-4-[5-(metboxymethypthiophen-3-
Aphenyllacetonitrile (Compound 202e)
0
NH
F CN
The (1H-benzimidazol-5-ylamino){2,3-difluoro-445-(methoxymethypthiophen-3-
yllphenyl}acetonitrile 202e was prepared from the addition of 1H-benzimidazol-
5-amine
121, TMSCN and compound 201e. The experimental procedures were the same as the
synthesis of compound 122a. The product 202e was obtained as a pale-yellow
solid at a
yield of 84%.
(1H-benzimidazol-5-ylamino){445-(ethoxymethyl)thiophen-3-y1]-2,3-
difluorophenyl}acetonitrile (Compound 2021)
0
S
NH
F CN
The (1H-benzimidazol-5-ylamino){4-[5-(ethoxymethypthiophen-3-y11-2,3-
difluorophenyllacetonitrile 202f was prepared from the addition of 1H-
benzimidazol-5-
amine 121, TMSCN and compound 201f. The experimental procedures were the same
as the
synthesis of compound 122a. The product 202f was obtained as a pale-yellow
solid at a yield
of 90%.
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Methyl 4-{4-[(1H-benzimidazol-5-ylamino)(eyano)methyl]-2,3-
difluorophenyllthiophene-2-earboxylate (Compound 202g)
\ 0
0
S
401
HN-
NH
F CN
The methyl 4-{ 4-[(1H-benzimidazol-5-ylamino)(cyano)methyl]-2,3-
difluorophenyll thiophene-2-carboxylate 202g was prepared from the addition of
1H-
benzimidazol-5-amine 121, TMSCN and compound 201g. The experimental procedures
were the same as the synthesis of compound 122a. The product 202g was obtained
as a pale-
yellow solid at a yield of 81%.
(1H-benzimidazol-5-ylamino)[2,3-difluoro-4-(thiophen-3-yl)phenyl]acetonitrile
(Compound 202h)
HN-\\
NH
F CN
The (1H-benzimidazol-5-ylamino)[2,3-difluoro-4-(thiophen-3-
yl)phenyljacetonitrile
202h was prepared from the addition of 1H-benzimidazol-5-amine 121, TMSCN and
compound 201h. The experimental procedures were the same as the synthesis of
compound
122a. The product 202h was obtained as a pale-yellow solid at a yield of 92%.
A0-(1H-benzimidazol-5-y1)-1-[2,3-difluoro-4-(5-fluorothiophen-3-
y1)phenyflethane-1,2-
diamine (Compound 203a)
HN-\\
NH
NH2
The NI -(1H-benzimidazol-5-y1)-1-[2,3-difluoro-4-(5-fluorothiophen-3-
yl)phenyl[ethane-1,2-diamine 203a was prepared from the hydrogenation of
compound 202a
with the Raney Nickel reagent as catalyst. The experimental procedures were
the same as the

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synthesis of compound 123a. The product 203a was obtained as a yellow viscous
liquid at a
yield of 43%.
N1-(1H-benzimidazol-5-y1)-1-[4-(5-chlorothiophen-3-y1)-2,3-
difluorophenyl]ethane-1,2-
diamine (Compound 203b)
CI
NH
NH2
The N' -(1H-benzimidazol-5 -y1)- 1- [445 -chloro thiophen-3 -y1)-2,3-
difluorophenyllethane-1,2-diamine 203b was prepared from the hydrogenation of
compound
202b with the Raney Nickel reagent as catalyst. The experimental procedures
were the same
as the synthesis of compound 123a. The product 203b was obtained as a yellow
viscous
liquid at a yield of 40%.
ATI-(1H-benzimidazol-5 -y1)-1-[2,3-difluoro-4 -(5-methyl thiophen-3-
yl)phenyl]ethane-1,2-
diamine (Compound 203c)
HN--\\
NH
NH2
The I \ 11-(1H-benzimidazol-5 -y1)-1- [2,3-difluoro-4-(5 -methylthiophen-3 -
yl)phenyl[ethane-1,2-diamine 203c was prepared from the hydrogenation of
compound 20k
with the Raney Nickel reagent as catalyst. The experimental procedures were
the same as the
synthesis of compound 123a. The product 203c was obtained as a yellow viscous
liquid at a
yield of 53%.

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N'-(1H-benzimidazol-5-y1)-144-(5-ethylthiophen-3-y1)-2,3-difluorophenyllethane-
1,2-
diamine (Compound 203d)
S
NH
NH2
The AR -(1H-benzimidazol-5-y1)-1-[4-(5-ethylthiophen-3-y1)-2,3-
difluorophenyllethane-1,2-diamine 203d was prepared from the hydrogenation of
compound
202d with the Raney Nickel reagent as catalyst. The experimental procedures
were the same
as the synthesis of compound 123a. The product 203d was obtained as a yellow
viscous
liquid at a yield of 51%.
N1-(1H-benzimidazol-5-y1)-1-{2,3-difluoro-4-[5-(methoxymethypthiophen-3-
yl]phenyliethane-1,2-diamine (Compound 203e)
0
NH
NH2
The N1-(1H-benzimidazol-5-y1)-1- {2,3-difluoro-4-[5-(methoxymethyl)thiophen-3-
yllphenyliethane-1,2-diamine 203e was prepared from the hydrogenation of
compound 202e
with the Raney Nickel reagent as catalyst. The experimental procedures were
the same as the
synthesis of compound 123a. The product 203e was obtained as a yellow viscous
liquid at a
yield of 46%.
NI--(1H-benzimidazol-5-y1)-1-14-[5-(ethoxymethypthiophen-3-y1]-2,3-
difluorophenyllethane-1,2-diamine (Compound 203f)
0
S
NH
NH2
The N1-(1H-benzimidazol-5-y1)-1- { 4- [5-(ethoxymethyl)thiophen-3-yl] -2,3-
difluorophenyll ethane-1,2-diamine 203f was prepared from the hydrogenation of
compound

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202f with the Raney Nickel reagent as catalyst. The experimental procedures
were the same
as the synthesis of compound 123a. The product 203f was obtained as a yellow
viscous
liquid at a yield of 49%.
methyl 4-{442-amino-1-(1H-benzimidazol-5-ylamino)ethy11-2,3-
difluorophenyllthiophene-2-earboxylate (Compound 203g)
HN¨
\ 0
0
1011
NH
NH2
The methyl 4-14-12-amino-1-(1H-benzimidazol-5-ylamino)ethyl]-2,3-
difluorophenyl}thiophene-2-carboxylate 203g was prepared from the
hydrogenation of
compound 202g with the Raney Nickel reagent as catalyst. The experimental
procedures
were the same as the synthesis of compound 123a. The product 203g was obtained
as a
yellow viscous liquid at a yield of 47%.
NI--(1H-benzimidazol-5-y0-1-[2,3-difluoro-4-(thiophen-3-y1)phenyl]ethane-1,2-
diamine
(Compound 203h)
HN-
NH
NH2
The IV' -(1H-benzimidazol-5-y1)-1-[2,3-difluoro-4-(thiophen-3-yl)phenyl]ethane-
1,2-
diamine 203h was prepared from the hydrogenation of compound 202h with the
Raney
Nickel reagent as catalyst. The experimental procedures were the same as the
synthesis of
compound 123a. The product 203h was obtained as a yellow viscous liquid at a
yield of
58%.

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1-(1H-benzimidazol-5-y1)-542,3-difluoro-4-(5-fluorothiophen-3-
y1)phenyllimidazolidin-
2-one (Compound 58)
/i0
HN-=
N$
NH
F
The 1-(1H-benzimidazol-5-y1)-5-12,3-difluoro-4-(5-fluorothiophen-3-
yl)phenyllimidazolidin-2-one (Compound 58) was prepared from the cycloaddition
of 1,1'-
carbonyl diimidazole and compound 203a. The experimental procedures were the
same as
the synthesis of Compound 1. The product (Compound 58) was obtained as a white
solid at a
yield of 71%.
1-(1H-benzimidazol-5-y1)-5-[4-(5-ehlorothiophen-3-y1)-2,3-
difluorophenyl]imidazolidin-
2-one (Compound 59)
0
N$)
NH
F
,
CI
The 1-(1H-benzimidazol-5-y1)-5-14-(5-chlorothiophen-3-y1)-2,3-
difluorophenyllimidazolidin-2-one (Compound 59) was prepared from the
cycloaddition of
1,1'-carbonyl diimidazole and compound 203b. The experimental procedures were
the same
as the synthesis of Compound 1. The product (Compound 59) was obtained as a
white solid
at a yield of 74%. 1HNMR (300MHz, CD30D) ö 3.44 (dd, 1H, J = 6.3, 9.3 Hz),
4.05 (dd,
1H, J = 9.3, 9.6 Hz), 5.83 (dd, 1H, J = 6.3, 9.6 Hz), 7.17-7.34 (m, 4H), 7.48-
7.51 (m, 2H),
7.60 (d, 1H, J = 1.8 Hz), 8.07 (d, 1H, J = 3.9 Hz); LC/MS (ES!) in/z: 431.0 IM
+ Hr.

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1-(1H-benzimidazol-5-y1)-5-[2,3-difluoro-4-(5-methylthiophen-3-
y1)phenyl]imidazolidin-
2-one (Compound 60)
N
NH
,
The 1-(1H-benzimidazol-5-y1)-5-[2,3-difluoro-4-(5-methylthiophen-3-
yl)phenyl]imidazolidin-2-one (Compound 60) was prepared from the cycloaddition
of 1,1'-
carbonyl diimidazole and compound 203c. The experimental procedures were the
same as
the synthesis of Compound 1. The product (Compound 60) was obtained as a white
solid at a
yield of 70%. 1H NMR (300MHz, CD30D) ö 2.45 (s, 3H), 3.43 (dd, 1H, J = 6.3,
9.0 Hz),
4.04 (dd, 1H, J = 9.0, 9.3 Hz), 5.81 (dd, 1H, J = 6.3, 9.3 Hz), 7.02 (s, 1H),
7.18-7.38 (m, 4H),
7.49 (d, 1H, J = 8.4 Hz), 7.59 (s, 1H), 8.07 (s, 1H); LC/MS (ES!) m/z: 411.3
[M + Hr.
1-(1H-benzimidazol-5-y1)-5-[4-(5-ethylthiophen-3-y1)-2,3-
difluorophenyl]imidazolidin-2-
one (Compound 61)
/,0
N *NH
The 1-(1H-benzimidazol-5-y1)-5-[4-(5-ethylthiophen-3-y1)-2,3-difluorophenyl[-
imidazolidin-2-one (Compound 61) was prepared from the cycloaddition of 1,1'-
carbonyl
diimidazole and compound 203d. The experimental procedures were the same as
the
synthesis of Compound 1. The product (Compound 61) was obtained as a white
solid at a
yield of 70%. 41 NMR (400MHz, CD30D) ö 1.28 (t, 3H, J = 7.6 Hz), 2.83 (q, 2H,
J = 7.6
Hz), 3.44 (dd, 1H, J = 6.4, 9.2 Hz), 4.05 (dd, 1H, J = 9.2, 9.6 Hz), 5.82 (dd,
1H, J = 6.4, 9.6
Hz), 7.05 (s, 1H), 7.15-7.19 (m, 1H), 7.26-7.34 (m, 2H), 7.41 (s, 1H), 7.50
(d, 1H, J = 8.8
Hz), 7.60 (s, 1H), 8.08 (s, 1H); LC/MS (ES!) m/z: 425.1 [M + Hr.

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1-(1H-benzimidazol-5-y1)-5-{2,3-difluoro-4-[5-(methoxymethyl)thiophen-3-
yflphenyl}imidazolidin-2-one (Compound 62)
/,0
HN-4(
N *NH
,
0
The 1-(1H-benzimidazol-5-y1)-5-12,3-difluoro-4-[5-(methoxymethyl)thiophen-3-
yllphenyl}imidazolidin-2-one (Compound 62) was prepared from the cycloaddition
of 1,1'-
carbonyl diimidazole and compound 203e. The experimental procedures were the
same as
the synthesis of Compound 1. The product (Compound 62) was obtained as a white
solid at a
yield of 76%. 1H NMR (400MHz, CD30D) 6 3.34 (s, 3H), 3.45 (dd, 1H, J = 6.8,
9.2 Hz),
4.05 (dd, 1H, J = 9.2, 9.2 Hz), 4.59 (s, 2H), 5.82 (dd, 1H, J = 6.4, 9.2 Hz),
7.17-7.21 (m, 1H),
7.28-7.34 (m, 3H), 7.50 (d, 1H, J = 8.4 Hz), 7.60 (s, 1H), 7.62 (s, 1H), 8.08
(s, 1H); LC/MS
(ESI) m/z: 441.3 [M + Hr.
1-(1H-benzimidazol-5-y1)-5-(445-(ethoxymethyl)thiophen-3-y11-2,3-
difluorophenyllimidazolidin-2-one (Compound 63)
0
N *NH
0
The 1-(1H-benzimidazol-5-y1)-5- [ 4- [5-(ethoxymethyl)thiophen-3-yll -2,3-
difluorophenyl imidazolidin-2-one (Compound 63) was prepared from the
cycloaddition of
1,1'-carbonyl diimidazole and compound 203f. The experimental procedures were
the same
as the synthesis of Compound 1. The product (Compound 63) was obtained as a
white solid
at a yield of 72%. 1H NMR (400MHz, CD30D) 6 1.19 (t, 3H, J = 7.2 Hz), 3.45
(dd, 1H, J =
6.4, 9.2 Hz), 3.54 (q, 2H, J = 7.2 Hz), 4.05 (dd, 1H, J = 9.2, 9.6 Hz), 4.63
(s, 2H), 5.83 (dd,

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1H, J = 6.4, 9.6 Hz), 7.17-7.20 (m, 1H), 7.26-7.34 (m, 3H), 7.50 (d, 1H, J =
8.4 Hz), 7.61 (m,
2H), 8.08 (s, 1H); LC/MS (ESI) m/z: 455.3 [M + Hr.
methyl 4-1443-(1H-benzimidazol-5-y1)-2-oxoimidazolidin-4-y11-2,3-
difluorophenyl}thiophene-2-carboxylate (Compound 64)
HN-4(
N *NH
0
The methyl 4-14-[3-(1H-benzimidazol-5-yl)-2-oxoimidazolidin-4-yl1-2,3-
difluorophenyl thiophene-2-carboxylate (Compound 64) was prepared from the
cycloaddition of 1,1'-carbonyl diimidazole and compound 203g. The experimental
procedures were the same as the synthesis of Compound 1. The product (Compound
64) was
obtained as a white solid at a yield of 75%. NMR (300MHz, DMSO-d6) 6 3.16-
3.29 (m,
1H), 3.81 (s, 3H), 3.94 (dd, 1H, J = 9.0, 9.3 Hz), 5.84 (dd, 1H, J = 5.4, 9.3
Hz), 7.11 (s, 1H),
7.17 (dd, 1H, J = 6.9, 7.5 Hz), 7.30 (br s, 1H), 7.43-7.54 (m, 2H), 7.61 (s,
1H), 8.06-8.10 (m,
1H), 8.22 (s, 1H), 8.23 (s, 1H), 12.29 (br s, 1H); LC/MS (ESI) m/z: 455.1 [M +
Hr.
1-(1H-benzimidazol-5-y1)-5-[2,3-difluoro-4-(thiophen-3-yl)phenyl]imidazolidin-
2-one
(Compound 65)
HN-'\4
N
NH
F
,
The 1-(1H-benzimidazol-5-yl)-5-[2,3-difluoro-4-(thiophen-3-
yl)phenyllimidazolidin-
2-one (Compound 65) was prepared from the cycloaddition of 1,1'-carbonyl
diimidazole and
compound 203h. The experimental procedures were the same as the synthesis of
Compound
1. The product (Compound 65) was obtained as a white solid at a yield of 79%.
41 NMR
(400MHz, CD30D) 6 3.45 (dd, 1H, J = 6.8, 9.2 Hz), 4.06 (dd, 1H, J = 9.2, 9.6
Hz), 5.83 (dd,

108
1H, J = 6.8, 9.6 Hz), 7.20 (m, 1H), 7.31-7.36 (m, 3H), 7.44-7.52 (m, 2H), 7.61
(s, 1H), 7.66
(s, 1H), 8.08 (s, 1H); LC/MS (ESI) m/z: 397.1 [M + Hr.
4-(443-(1H-benzimidazol-5-yl)-2-oxoimidazolidin-4-yl]-2,3-
difluorophenyl}thiophene-2-
carboxylic acid (Compound 66)
0
HN¨
NH
z ,
OH
0
To the solution of the compound 64 (0.45 g, 1.0 mmol) in methanol (10 mL),
potassium hydroxide (0.07 g, L2 mmol) was added. The reaction mixture was
stirred at 60
C for 1.5 hours and then cooled to room temperature. The reaction mixture was
neutralized
by 1N HCl() to pH 7. After removing the solvent, the crude residue was
purified by reverse
phase column chromatography on C-18 silica gel using methanol/H20 (1/1) as
eluent to give
the product 66 as a white solid at a yield of 81%. 1HNMR (400MHz, DMSO-d6) 5
3.26 (dd,
1H, J = 5.6, 9.2 Hz), 3.92 (dd, 1H, J = 9.2, 9.2 Hz), 4.18 (br s, 1H), 5.80
(dd, 1H, J = 5.6, 9.2
Hz), 7.12-7.15 (m, 2H), 7.29 (br s, 1H), 7.40-7.46 (m, 2H), 7.52 (s, 1H), 7.61
(s, 1H), 7.67 (s,
1H), 8.09 (s, 1H); LC/MS (ES!) m/z: 441.0 [M + Hr.
1-(1H-benzimidazol-5-yl)-5-12,3-difluoro-4-[5-(hydroxymethyl)thiophen-3-
yl]phenyllimidazolidin-2-one (Compound 67)
0
HN _____ f
NH
,
OH
A solution of compound 64 (0.45 g, 1.0 mmol) in dry THF (5 mL) was added
dropwise to a refluxing, magnetically stirring slurry of LAH (1.5 mmol) in dry
THF (7.5
mL). The reaction mixture was held at reflux for 3 hours, terminated by
dropwise addition of
1 mL saturated MgSO4 solution and filtered by Celite. The filtrate was
partitioned between
Date Regue/Date Received 2022-08-25

109
ethyl acetate and water. The organic phases were dried over MgSO4 and
evaporated on a
rotary evaporator. The residue was purified by column chromatography on silica
gel using
methanol/DCM (1/10) as eluent to give the product 67 as a white solid at a
yield of 92%.
Separation of Enantiomers of Compound 8
The chiral separation of Compound 8 was completed by HPLC using CHIRALPAK
IC. The isomer fractions were respectively collected and the optical pure
isomers
(Compounds 9 and 10) were thus obtained by removing the solvent under reduced
pressure.
Results of this separation are shown below:
Column: CHIRALPAK4 IC (IC00CE-0L002),
Column size: 0.46 cm I.D. x 25 cm L,
Injection: 0.5 ul,
Mobile phase: 100% methanol,
Flow rate: 1.0 ml/min,
Detection: UV 214 nm,
Temperature: 35 C,
HPLC equipment: Shimadzu LC-20AD (CP-HPLC-06),
Retention El (Compound 9): 5.494 min,
Retention E2 (Compound 10): 6.379 min.
Separation of Enantiomers of Compound 13
The chiral separation of Compound 13 was completed by HPLC using
CHIRALPAK AD-H. The isomer fractions were respectively collected and the
optical pure
isomers (Compounds 33 and 34) were thus obtained by removing the solvent under
reduced
pressure. Results of this separation are shown below:
Column: CHIRALPAK AD-H (ADHOCD-UE022),
Column size: 0.46 cm I.D. x 15 cm L,
Injection: 1.0 ul,
Mobile phase: Hexane/Et0H=60/40 (v/v),
Flow rate: 1.0 ml/min,
Detection: UV 214 nm,
Temperature: 35 C,
HPLC equipment: Shimadzu LC-20AT (CP-HPLC-09),
Retention El (Compound 33): 4.270 min,
Retention E2 (Compound 34): 5.679 mm.
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110
Separation of Enantiomers of Compound 16
The chiral separation of Compound 16 was completed by HPLC using
CHIRALPAK AD-H. The isomer fractions were respectively collected and the
optical pure
isomers (Compounds 35 and 36) were thus obtained by removing the solvent under
reduced
pressure. Results of this separation are shown below:
Column: CHIRALPAK' AD-H (ADHOCD-UE022),
Column size: 0.46 cm ID. x 15 cm L,
Injection: 2.0 ul,
Mobile phase: Hexane/Et0H=70/30 (v/v),
Flow rate: 1.0 ml/min,
Detection: UV 214 nm,
Temperature: 35 C,
HPLC equipment: Shimadzu LC-20AD (CP-HPLC-08),
Retention El (Compound 35): 7.273 min,
Retention E2 (Compound 36): 9.232 min.
Separation of Enantiomers of Compound 25
The chiral separation of Compound 25 was completed by HPLC using
CHIRALPAK AD-H. The isomer fractions were respectively collected and the
optical pure
isomers (Compounds 53 and 54) were thus obtained by removing the solvent under
reduced
pressure. Results of this separation are shown below:
Column: CHIRALPAK AD-H (ADHOCD-UE022),
Column size: 0.46 cm I.D. x 15 cm L,
Injection: 2.0 ul,
Mobile phase: Hexane/Et0H=70/30 (v/v),
Flow rate: 1.0 ml/min,
Detection: UV 214 nm,
Temperature: 35 C,
HPLC equipment: Shimadzu LC-20AD (CP-HPLC-08),
Retention El (Compound 53): 2.166 min,
Retention E2 (Compound 54): 2.767 min.
Separation of Enantiomers of Compound 28
The chiral separation of Compound 28 was completed by HPLC using
CHIRALPAK AD-H. The isomer fractions were respectively collected and the
optical pure
Date Regue/Date Received 2022-08-25

111
isomers (Compounds 55 and 56) were thus obtained by removing the solvent under
reduced
pressure. Results of this separation are shown below:
Column: CHIRALPAK AD-H (ADHOCD-UE022),
Column size: 0.46 cm I.D. x 15 cm L,
Injection: 2.0 ul,
Mobile phase: Hexane/Et0H=70/30 (v/v),
Flow rate: 1.0 ml/min,
Detection: UV 214 nm,
Temperature: 35 C,
HPLC equipment: Shimadzu LC-20AD (CP-HPLC-08),
Retention El (Compound 55): 3.827 min,
Retention E2 (Compound 56): 7.914 min.
EXAMPLE 2: In vitro Activity Screening of Compounds
QC Activity Assay
An enzymatic activity assay of QC was conducted at 25 C using a fluorescent
substrate, i.e., L-glutaminyl 2-naphthylamide (Gln-I3NA). See Huang et al.,
Biochem.
2008, 411,181-190. A 100 1 reaction mixture was prepared. It contained 300 M
of
fluorogenic substrate, ¨0.2 units of auxiliary enzyme human pyroglutamyl
aminopeptidase I
(PAP I) (in which one unit is defined as the amount of human PAP I needed to
hydrolyze 1
mol of pG1u-3NA per minute under the same assay condition), and an
appropriately diluted
aliquot of recombinant QC in 50 mM of Tris¨HCl at pH 8Ø Excitation and
emission
wavelengths were set at 320 and 410 nm, respectively. The reaction was
initiated by the
addition of QC. The enzymatic activity of QC was determined from the amount of
released
13NA and was calculated using a standard curve for I3NA under the same assay
conditions.
Measurements were made using a SynergyTM H4 microplate reader (BioTek,
Winooski,
Vermont, USA).
Enzyme Kinetic Assay
Kinetic constants were determined at pH 8.0 and 25 C using Gln-i3NA as the
substrate. Also see Huang et al., Biochem. 1 2008, 411, 181-190. The reaction
was initiated
by adding QC to the 100 I reaction mixture described above. The initial rate
was measured
with less than 10% substrate depletion for the first 2-12 minutes. Since a
weak substrate
inhibition was observed, kinetic parameters Km, V, and K, were evaluated by
fitting an
equation, i.e., vo = Vmax[S]l (Km + [S] + [S]2/K), to initial velocity data by
nonlinear
regression using a KaleidaGraph software (Synergy Software, Reading,
Pennsylvania,
Date Regue/Date Received 2022-08-25

112
USA), where vo is an initial velocity, Vmax is an limiting rate, Si[ is a
substrate concentration,
K. is a Michaelis constant, and K, is an inhibition constant.
QC Inhibition Assay
An inhibition activity assay of QC inhibitors was conducted. See Huang et al.,
I
Biol. Chem. 2011, 286, 12439-12449. A reaction mixture containing 300 tiM of
Gln-13NA
and -0.2 units of human PAP I was prepared. QC was first incubated with an
inhibitor at
25 C for 30 minutes and the enzyme-inhibitor mixture was then added to the
reaction
mixture to initiate the cyclization reaction. An IC50 value was obtained by
fitting an initial
reaction rate versus an inhibitor concentration using KaleidaGraphg. A K,
value of the
inhibitor was calculated according to an equation IC50 = KO + [S]/K.). See
Segel, Enzyme
Kinetics: Behavior and Analysis of Rapid Equilibrium and Steady-State Enzyme
Systems,
pp. 100-118. New York: John Wiley & Sons, 1993. In this equation, [S] is a
substrate (i.e.,
Gln-13NA) concentration and K. is a Michaelis-Menten constant. The lower the
K, value, the
higher the inhibitor's QC inhibition rate.
The K, values of Compounds 1-29, 33-57, and 59-65, obtained from the
inhibition
assay set forth above, are shown in Table 2 below.
Table 2
Compound K, (jiM) Compound K, (iM) Compound K, (jiM)
1 0.053 25 0.071 49 0.010
2 0.100 26 0.114 50 0.013
3 0.348 27 0.066 51 0.024
7 0.021 28 0.039 52 0.397
8 0.049 29 0.072 53 3.417
9 0.016 33 0.736 54 0.023
0.964 34 0.069 55 1.592
11 0.100 35 2.053 56 0.007
12 0.132 36 0.032 57 0.087
13 0.124 37 0.018 , 59 0.019
14 0.106 38 0.004 60 0.007
0.076 39 0.004 61 0.016
16 0.112 40 0.009 62 0.006
17 0.151 41 0.012 , 63 0.011
18 0.134 42 0.005 64 0.013
19 0.058 43 0.008 65 0.020
0.057 44 0.010
21 0.036 45 0.004
22 0.156 46 0.008
23 0.124 47 0.006
24 0.101 48 0.010
Date Regue/Date Received 2022-08-25

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As shown in this table, Compounds 1-29, 33-57, and 59-65 all have Ki values
within
the nano molar range. Note that a low Ki value indicates a high QC inhibition
rate. Clearly,
these compounds possess superior inhibition potency against QC.
Inhibition of QC has been reported to diminish aggregation of Af3 and HTT in
cultured macrophage cells and in Drosophila and mouse models. Thus, Compounds
1-29, 33-
57, and 59-65, as potent QC inhibitors, are drug candidates for treating AD or
HD.
EXAMPLE 3: In vivo Activity of Compounds
Compound 37 showed strong potency (Ki = 0.018 uM) in inhibiting QC and a
desired
pharmacokinetic property (F% = 11) in mice (F% being the fraction of an oral
administered
drug that reaches systemic circulation). The compound was therefore selected
for further
animal studies in a transgenic mouse model using APP/PSI mice (Jackson Lab,
ME). See
Schilling et al., Nat. Med. 2008, 14, 1106-1111 and Li etal., J. Med. Chem.
2017, 60, 6664-
6677. APP/PS1 mice are double transgenic mice expressing a chimeric
mouse/human
amyloid precursor protein (Mo/HuAPP695swe) and a mutant human presenilin 1
(PS1-dE9),
both directed to CNS neurons. These two mutations are associated with early-
onset
Alzheimer's disease. In the animal studies, 4-month-old APP/PS1 mice were
housed at a 12
hour day/12 hour night cycle with free access to water and food. Compound 37
was orally
administered to the APP/PS1 mice for 3.5 months to determine its in vivo
activity. The
cognitive function and brain pathology of each mouse were analyzed after the
administration.
The resultant analytical data exhibited depletion of AP deposits in brain
tissues of the
APP/PS1 mice.
The same in vivo assay was performed on Compound 28, which showed that this
compound had high inhibitory activity (Ki = 0.039 uM) and a superior
pharmacokinetic
property with desired oral bioavailability (F% = 25) in APP/PS1 mice.
The above two assays demonstrate both the potency and the efficacy of
Compounds
28 and 37 as QC inhibitors for treating AD.
OTHER EMBODIMENTS
All of the features disclosed in this specification may be combined in any
combination. Each feature disclosed in this specification may be replaced by
an alternative
feature serving the same, equivalent, or similar purpose. Thus, unless
expressly stated
otherwise, each feature disclosed herein is only an example of a series of
equivalent or
similar features.

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From the above description, one skilled in the art can easily ascertain the
essential
characteristics of the present invention and, without departing from the
spirit and scope
thereof, can make various changes and modifications of the invention to adapt
it to various
usages and conditions. Thus, other embodiments are also within the scope of
the following
claims.