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CA3030773A1 - Symmetric or semi-symmetric compounds useful as immunomodulators - Google Patents

Symmetric or semi-symmetric compounds useful as immunomodulators Download PDF

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Publication number
CA3030773A1
CA3030773A1 CA3030773A CA3030773A CA3030773A1 CA 3030773 A1 CA3030773 A1 CA 3030773A1 CA 3030773 A CA3030773 A CA 3030773A CA 3030773 A CA3030773 A CA 3030773A CA 3030773 A1 CA3030773 A1 CA 3030773A1
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Prior art keywords
methyl
amino
hydroxyethyl
biphenyl
methoxy
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CA3030773A
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French (fr)
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Minghua Wang
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Arising International Inc
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Arising International Inc
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Abstract

A compound having Formula I:(I), or a pharmaceutical acceptable salt thereof. A is a bivalent arene or a bivalent heteroarene; Ring B and Ring B' are independently a 6-membered aromatic hydrocarbon ring, a 6-membered heterocyclic ring, a 8- to 10-membered aromatic hydrocarbon ring, or a 8- to 10-membered heterocyclic ring; Y and Y' are independently, null (direct bond), -CHR1-, -CH2-CH2-, -NR1-, -0-, -OCH2-, -CH2O-, -SCH2-, -CH2S-, -SOCH2-, -CH2SO-, or -SO2CH2-, and R1 is H, C1-6 alkyl, or C3-6 cycloalkyl.

Description

SYMMETRIC OR SEMI-SYMMETRIC COMPOUNDS USEFUL AS
IMMUNOMODULATORS
This application claims priority to US Provisional Application No. 62/370,679, filed August 3, 2016, which is incorporated by reference for all purposes as if fully set forth herein.
BACKGROUND OF THE INVENTION
Field of the Invention The present invention generally relates to compounds useful as inhibitors of the PD-1/PD-L1 protein/protein and CD80/PD-L1 protein/protein interactions.
Discussion of the Related Art Programmed cell death-1 (PD-1, CD279) protein is a member of the CD28 superfamily that can suppress activation signals upon interaction with either of its natural ligands, program cell death-ligand 1 (PD-L1, CD274, B7-H1) and PD-L2 (CD273, B7-DC).
PD-1 and its ligands are broadly expressed in immune systems and play critical roles in immune modulation including T cell activation and tolerance (Sharpe et. al., Nat. Imm.
2007). When PD-Li expressing cells contact T cells that express PD-1, it results in attenuation of T cell activities in cytokine secretion, cytolytic activity and proliferation, in response to antigenic stimulation. Conditions of tumor progression or chronic infections could lead to chronic antigen stimulation, that results in induction of PD-1 expression and eventually reduced T cell activity (so called "T cell exhaustion"). Such suggests a biological significance of PD-1/PD-L1 interaction in attenuating infectious immunity, tumor immunity and in facilitating chronic infection and tumor progression (Keir et. al., Annu Rev Immunol. 2008). PD-Li has also been shown to interact with CD80. The interaction between PD-Li and CD80 on immune cells has also been shown to inhibit immune response (Deng et.
al., J Immunol. 2015).
Monoclonal antibodies that block the PD-1-mediated immune checkpoint pathway can prevent T cell down regulation and promote immune responses against cancer and infectious diseases (Harvey et. al., Clin Pharmacol Ther 2014). Ample clinical and preclinical evidence has demonstrated that inhibition of PD-1/PD-L1 interaction with PD-1-or PD-L1-specific antibodies can restore immune response to diverse forms of cancer and infectious diseases (Dong et. al., Nat. Med. 2002; Dong et. al., J Mol. Med. 2003). To date, several PD-1/PD-Li-targeting antibodies (including pembrolizumab, nivolumab and atezolizumab) have already been approved as immuno-oncology (JO) therapeutics to treat different forms of cancer, including melanoma, non-small cell lung cancer, kidney cancer, Hodgkin lymphoma and bladder cancer, etc. Further, studies have demonstrated that interference with PD-1/PD-Li interaction can also enhance T cell activity in chronic infection systems, thus expected to function against viral infections, like HIV (Attanasio et. al., Immunity.
2016; Porichis et. al., Curr HIV/AIDS Rep. 2012). In addition, blockage of the PD-1/PD-L1 pathway can also enhance responses to vaccination, including therapeutic vaccination in the context of viral infection (Ha et. al., J. Exp. Med. 2008). More recent discoveries also suggested therapeutic value of disrupting PD1/PD-L1 interaction for patients with certain inflammation and neurodegenerative diseases like Alzheimer's disease (Bodhankar et. al., Stroke 2015;
Baruch et. al., Nat Med. 2016).
Therefore, agents that block the interaction of PD-Li with either PD-1 or CD80 are considered beneficial for diverse therapeutic areas, including but not limited to cancer, viral infection and vaccination. Despite recent approval of PD-1/PD-Li-targeting antibodies, there is still great demand for more potent, better selective and more easily administered therapeutics against PD-1/PD-L1 and/or CD80/PD-L1 protein-protein interactions. Recently, the elucidation of structural details of the human PD-1/PD-L1 complex has provided unique insights into the molecular mechanism of PD-1/PD-L1 protein-protein interaction (Zak et. al., Oncotarget 2016; Zak et. al., Structure 2015). Such has afforded an opportunity for structural-based design of small molecule inhibitors to target PD-1/PD-L1 and/or CD80/PD-interaction.
In this invention, applicant discovered potent small molecules that can have activity as inhibitors of the interaction of PD-Li with PD-1 and/or CD80, and thus may be useful for therapeutic administration to enhance immunity against cancer and/or infectious diseases.
These small molecules are expected to be useful as pharmaceuticals with desirable stability, bioavailability, therapeutic index, and toxicity values that are crucial to become efficient medicines to promote human health.
SUMMARY OF THE INVENTION
The inhibitors of the PD-1/PD-L1 protein/protein and CD80/PD-L1 protein/protein s 8 =
A
interactions are a compound having Formula I:
(I), or a pharmaceutical acceptable salt thereof. A is a bivalent arene or a bivalent heteroarene; Ring B and Ring B' are independently a 6-membered aromatic hydrocarbon
2 ring, a 6-membered heterocyclic ring, a 9- to 10-membered aromatic hydrocarbon ring, or a 9- to 10-membered heterocyclic ring; Y and Y' are independently, null (direct bond), -CHRi-, -CH2-CH2-, -NR1-, -0-, -OCH2-, -CH20-, -SCH2-, -CH2S-, -SOCH2-, -CH2S0- or -S02CH2-, and R1 is H, C16 alkyl, or C3-6 cycloalkyl; R3 and R'3 are independently H, SO2NH2, R5 R6 R,5 Re SO2NR5R6, S02NEIR7, Ni 'OH µ\-----\:µ0C113 , CH2NR5R6, or CH2NHR7, wherein R5 and R6 are independently H, Ci_6 alkyl, C3_8 cycloalkyl, or heteroaryl or R5 and R6 form a C3-8 cycloalkyl, heterocyclyl, or heteroaryl ring, and R7 is H, aryl, heteroaryl, acetyl, CH2CH2OH, CH2CH2NHCOCH3, C3-C8 alkyl carboxylic acid, C3-C8 alkyl amide, C3-C8 alkyl alcohol, -CH2-Ar, or -CH2-heterocyclyl; and R4, R'4, Z, and Z' are independently H, halogen, CHF2, CF3, CN, Ci_6 alkyl, Ci_6 alkoxy, aryl, or heteroaryl.
Further described is an isomer or tautomer thereof, a pharmaceutical acceptable solvate thereof, or a pharmaceutical acceptable prodrug thereof.
In one aspect, the Formula (I) is represented by following Formula (II):

X
I I
X3, ,õX'3\-:==1õ:õ.õ-^.õõ
R4 Y' R'4 Z' (11). Ring B and Ring B' are independently a 6-membered aromatic hydrocarbon ring or a 6-membered heterocyclic ring; X1, X'1, X2, and X'2 are independently CR2, C=0 or NR2, and R2 is H, Me, CN, halogen, OMe, CHF2, CF3, Ci_6 alkoxyl, C3_7 cycloalkyl, C3_7 heterocyclyl, or 0CH2Ar; and X3, and X'3 are independently C or N. Y and Y' are independently -CHRi-, -CH2-CH2-, -NR1-, -0-, -OCH2-, -CH20-, -SCH2-, -CH2S-, -SOCH2-, -CH2S0- or -S02CH2-, and R1 is H, C1-6 alkyl, or C3-6 cycloalkyl;
In one aspect, the Formula (I) is represented by following Formula (III):

R.3 .X' 0 X is R.4 V V' (III). Ring B and Ring B' are independently a 9- to 10-membered aromatic hydrocarbon ring or a 9- to 10-membered heterocyclic ring;Xi, and X' I are independently CR2, C=0 or NR2, and R2 is H, Me, CN, halogen, OMe, CHF2, CF3, C16 alkoxyl, C3_7 cycloalkyl, C3_7 heterocyclyl, or 0CH2Ar; X2, X'2, X3, and X'3 are independently C or N; U and U' are independently C and N;
V and V'
3 are 0, S, -(CH2)2-, -CR'-, or -N=; and Y and Y' are independently, null (direct bond), -CHRi-, -CH2-CH2-, -NR1-, -0-, -OCH2-, -CH20-, -SCH2-, -CH2S-, -SOCH2-, -CH2S0- or -, and R1 is H, C16 alkyl, or C3-6 cycloalkyl;
Ra Ra Rb ' In one aspect, in Formula (I), A is ' 1101 s ii \ sYs/ s s 'YS \ __ Ra Rb Ra Ra' Rb Ra , 1 \
,¨sc , i Nrss -- , , \
S N N-0 N¨N N¨S Ra , , , , , / N Ra / 1 Ra' N Ra' Ra' \ 0 Ra NJ Ra N
, , , , Ra' Ra' Ra' Ra' , .
. .
s N-1 Ra N Ra ---.. , , N Ra 0 , Ra S , , N , , N___ Ra' Ra' 1¨N Ra , ' :¨ :¨ --. N¨I, 0 0 s ____________________ S
, . N-1 Ra ---. I Ra LJ N Ra N Ra , , N
, , , 0 , S , ____ Ra' Ra' Ra' S Ra' \ , I,¨ I¨ I¨N
, ¨
N N N N N H , N¨I
, , = s \ \
Ra 0 Ra S Ra ---.. , Ra , , / S Ra' ` I Ra' S Ra' S Ra' , \ / , SI y , --- \ , = ..- N 1 Ra s / , Ra S , Ra Ra Ra I
, , , , \ __ \ ...k........> \ \
, 40) , , 0 N.-..,' ' N / ,'N , Ra Ra I ¨ V=V
, , , , 0 0 Rb' Rb Rb / N..........)( 0,....,\ N
õii.....:õ\ \ \ / I
)1 Ni , 40 N, , µ 14 %
1 N I \ µ
RID Ra NI,), ,or Ra ;Ra , and Ra' are independently COR', OMe, halogen, C16 alkyl, C2_6 alkynyl, C16 cycloalkyl, CN, CF3, CH2CF3; R' is C16 alkyl; Rb and Rb' are independently C16 alkyl, C2-6 alkynyl, C1-6 cycloalkyl or alkyl halogen, and V is -(CH2)2-, -CR'-, or -N=,wherein Y and Y' are independently in each occurrence -NR1-, -0-, -OCH2-, -SCH2-, -SOCH2-, or -S02CH2-, provided that the nitrogen of ring A cannot be the connecting atom with Y and Y'.
4 0 .0H
>.- 0 OH
_ µµN µµN
In one aspect, in Formula (I), CH2NR5R6 is , , 0 µ1\11 OH, or 0, 1, 2, or 3 .
H
\\N 1\11-r ,s-NOH
µ H , In one aspect, in Formula (I), CH2NHR7 is 0 , H , OH
(R) .,.Th,,µ,..r0'Nµ/M i_irc) , \ N (R- ) OH ' 1-1 s Hill?' H
N µ', N cO
s H s H
0 OH , ,\Nii.r0H ,,N.s.r0H µN .<%N=N N N
µ H H = õ \ H
, or ' N A
s H
=

Il \

\
In one aspect, in Formula (I), Ring B and Ring B' are independently z , xi . =.,.... R'3 R2 X2.s.õ.. R3 R2 .. X2, R'3 N R3 N
R'3 R2 N R3 I I I I I
/ õ, / , / r, \
µ rc 4 \ m4 \ m'4 µµ)YR4 \ R.4 µµ R4 µ µ µ \ µ \
Z Z Z Z Z' Z , NR R R2). R
'3 3 R2.. ..KR ().,....= ' rsi )N 3 R3 0 IV R'3 0 R3 2X,õ
\
IT4 \ R4 \ R4 \''''.'r R4 \\*".....r1T4 \--:N...f R4 \ \ \
Z' Z Z' Z Z Z , 0 R.3 0 R3 0 R3 N

/ N . µ
\\
R.4 \ 2.....õ.......7-. \ 0 . µ µ
Z' CI I \ , µ , , , , 0 R2 \o 0 0 3 N R'3 R \ / ri R3 R3 0 R3 is R3 0õy=-=zz....,,,,.... õ. -.. =-=iõ...--. \
N µµ) µµ) µ 0 .
, , CI I .
R2 R R2 2' I R3 R3' NC is R3 FV3 / N R'3 \\N µ,....õ N R4' µµ......----\
Z Z' - R3 - R3 R3 R3' \\A 110 R4 ,,A 10 R4' µ 0 R4 µA 10 R4' Z Z' Z Z' , , , , R3 .._).... ....R3' : - 7.3 3 ' ) --..... .., N-N N N.__ N-/ R4 / R4' \A ,N / R4 µA ,N / IV
µ N \ N \ N µ N
Z Z' Z Z' , , , , R3 ) -_,...7.3' ....R3 R3' .......\ ---. .._. ____..._. ....
\eõ,=cõ. / R4 ,e....4-,..- / R4' \eõ.1,N / R4 µµc N
/ R4' Z Z' Z Z' , , , - R3 - R3' R3 R3' S S N N
\\A 1110 R4 ,,A 10 R4' µ 0 R4 µ,, 10 R4' S , S
Z Z' Z Z' , , , , - R3 R3' R3 R3' - - µv N.__ N___ N R4 N R4' µ Ni R4 µ Ni R4' \ - V
. V
Z Z' Z Z' , , , R3 R3' ,r \4.õ. R4 --...
/ N4.....N
R3' Rq v .... ,N-..,õ....( -N
`N , N , .--R
r.1 N -Z z, ' = - - = - NI/ R4' R2 R3 R2' )....z...._...< R3' 1\ ( 1 / N \e...N
x., /
N
, N , N
Z , or Z' . Y
and Y' are independently in each occurrence null (direct bond), -NR1-, -0-, -CH20-, or -CH2S, provided that U in ring B and U' in ring B' cannot be nitrogen.
In one aspect, in Formula (I), R3 and R'3 are the same, R4 and R'4 are the same, Y and Y' are the same, Z and Z' are the same, or Ring B and Ring B' are the same.
In one aspect, in Formula (I), R3 and R'3 are the same, R4 and R'4 are the same, Y and Y' are the same, Z and Z' are the same, and Ring B and Ring B' are the same.
In one aspect, the inhibitors of the PD-1/PD-L1 protein/protein and CD80/PD-L1 protein/protein interactions are 2-({ [4-( { 3 '-[(4- { [(2-hydroxyethyl)amino]methyl } -2-methylphenoxy)methy1]-2,2'-dimethyl-[ 1,1 '-biphenyl]-3 -yl}methoxy)-3 -methylphenyl]methyl } amino)ethan- 1 -ol, 2-{ [(4-{ [3 -({ 4-[(azetidin- 1 -yl)methy1]-2-methylphenoxy}methyl)-2-chlorophenyl]methoxy}-3-methylphenyl)methyl]amino}ethan-1-ol, 14(44 [3 -({4-[(azetidin-l-yl)methyl]-2-methylphenoxy Imethyl)-2-chlorophenyl]methoxy } -3 -methylphenyl)methyl]azetidine, (2S)- 1- {
[44{3'4(44 [(2 S)-2-carboxypiperidin- 1 -yl]methyl } -3 ,5-dimethoxyphenoxy)methy1]-2,2'-dimethy141, 1 '-biphenyl] -3 -yl}methoxy)-2,6-dimethoxyphenyl]methyl } piperidine-2-carboxylic acid, (2 S)-1 -{ [44{3'4(44 [(2-hydroxyethyl)amino]methyl } -3,5 -dimethoxyphenoxy)methy1]-2,2'-dimethyl-[ 1, 1 '-biphenyl]-3 -yl}methoxy)-2,6-dimethoxyphenyl]methyl }
piperidine-2-carboxylic acid, 2-({ [44{3'4(44 [(2-hydroxyethyl)amino]methyl } -3 , 5-dimethoxyphenoxy)methy1]-2,2'-dimethyl-[ 1, 1 '-biphenyl]-3 -yl}methoxy)-2,6-dimethoxyphenyl]methyl } amino)ethan- 1 -ol, 1 -{ [44{3'4(44 [(2-hydroxyethyl)amino]methyl} -2-methylphenoxy)methy1]-2,2'-dimethy141, 1 '-biphenyl] -3 -y1 } methoxy)-2-methoxyphenyl]methyl } azetidin-3 -ol, 2-{ [(6-{ [3 -(5- { [(5-{ [(2-hydroxyethyl)amino]methyl} -6-methoxypyridin-2-yl)oxy]methyl } -4-methylthiophen-3 -y1)-2-methylphenyl]methoxy } -2-methoxypyridin-3 -yl)methyl] amino ethan- 1 -ol, 2-({ [4-({4-[(4-{ [(2-hydroxyethyl)amino]methyl} -3 -methoxyphenoxy) methy1]-3-methylthiophen-y1 } methoxy)-2-methoxyphenyl]methyl } amino)ethan- 1 -ol, 2-({ 4-[(azetidin-1 -yl)methy1]-2-methylphenoxy } methyl)-6- { [4-({ [(4-oxoazetidin-2-yl)methyl] amino } methyl)phenoxy]methyl }benzonitrile, N-(2- { [(4-{ [3 -({ 4-[(azetidin- 1 -yl)methy1]-2-methylphenoxy}methyl)-2-cyanophenyl]methoxy}
phenyl)methyl]amino} ethyl)acetamide, 2-({ 4-[(azetidin- 1 -yl)methy1]-2-methylphenoxy } methyl)-6-[(4- { [(2-hydroxyethyl)amino]methyl } phenoxy)methyl]benzonitrile, 2-({ 4- [(azetidin- 1 -yl)methy1]-2-methylphenoxy} methyl)-6-({4-[(azetidin-1-y1)methyl]phenoxy}
methyl)benzonitrile, 2-({ [4-({ 4-[(4-{ [(2-hydroxyethyl)amino]methyl } -3,5 -dimethoxyphenoxy)methy1]- 1H-indol- 1 -yl Imethyl)phenyl]methyl Iamino)ethan- 1 -ol, 2-({ [4-({ 1-[(4- { [(2-hydroxyethyl)amino]methyl Iphenyl)methy1]- 1H-indazol-4-ylImethoxy)-2, 6-dimethoxyphenyl]methyl 1 amino)ethan- 1 -ol, 2,6-bis[(4-{ [(2-hydroxyethyl)amino]methyl 1 -3 -methoxyphenoxy)methylThenzonitrile, N-[(4-{ [3'-({ 4-[(cyclopropylamino)methy1]-3, 5 -dimethoxyphenoxy }methyl)-2,2'-dimethy141, 1'-bipheny1]-3-yl]methoxy 1 -2,6-dimethoxyphenyl)methyl] cyclopropanamine, 4- { [({4-[(3'-{ [3 ,5-dimethoxy-4-({ [(4-oxoazetidin-2-yl)methyl] amino 1 methyl)phenoxy]methyl 1 -2,2'-dimethyl-[ 1, 1'-bipheny1]-3 -yl)methoxy]-2,6-dimethoxyphenylImethyl)amino]methylIazetidin-2-one, 2-[({6-[(3'-{ [(5-{ [(2-hydroxyethyl)amino]methyl}pyridin-2-yl)oxy]methyl 1 -2,2'-dimethy141, 1'-bipheny1]-3 -yl)methoxy]pyridin-3 -ylImethyl)amino] ethan- 1-01, 24({6-[(3'-{ [(5- { [(2-hydroxyethyl)amino]methyl 1 -6-methoxypyridin-2-yl)oxy]methyl 1 -2,2'-dimethyl-[ 1, 1'-bipheny1]-3 -yl)methoxy]-2-methoxypyridin-3 -y1Imethyl)amino] ethan- 1-01, N-{24({6-[(3'-{ [(5- { [(2-acetamidoethyl)amino]methyl} -6-methoxypyridin-2-yl)oxy]methyl 1 -2,2'-dimethyl-[ 1, 1'-bipheny1]-3 -yl)methoxy]-2-methoxypyridin-3 -y1Imethyl)amino] ethyl Iacetamide, (2R,4R)-1-({ 6-[(3 '- { [(5- { [(2R,4R)-2-carb oxy-4-hydroxypyrroli din- 1 -yl]methyl 1-6-methoxypyridin-2-yl)oxy]methyl 1 -2,2'-dimethyl-[ 1, 1'-bipheny1]-3 -yl)methoxy]-2-methoxypyridin-3 -ylImethyl)-4-hydroxypyrrolidine-2-carboxylic acid, (2R,4R)-4-hydroxy-1 -({ 6-[(3 '-{ [(5-{ [(2-hydroxyethyl)amino]methyl 1 -6-methoxypyridin-2-yl)oxy]methyl 1 -2,2'-dimethyl-[ 1, 1'-bipheny1]-3 -yl)methoxy]-2-methoxypyridin-3 -y1Imethyl)pyrrolidine-2-carboxylic acid, (3R)- 1- { [4-({ 3 '-[(4-{ [(3R)-3-hydroxypyrrolidin-1-yl]methyl 1 -2-methylphenoxy)methy1]-2,2'-dimethyl-[ 1, 1'-bipheny1]-3-ylImethoxy)-3-methylphenyl]methylIpyrrolidin-3-ol, (2R,4R)- 1 - { [4-({ 3 '-[(4- { [(2R,4R)-2-carboxy-4-hydroxypyrrolidin-1-yl]methyl 1 -2-methylphenoxy)methy1]-2,2'-dimethyl4 1, 1'-bipheny1]-3 -yl Imethoxy)-3 -methylphenyl]methyl 1 -4-hydroxypyrrolidine-2-carboxylic acid, 2-({ [4-({3'-[(4-{ [(2-hydroxyethyl)amino]methyl 1 -3,5 -dimethoxyphenoxy)methy1]-2'-methy141, 1'-bipheny1]-3-ylImethoxy)-2,6-dimethoxyphenyl]methylIamino)ethan- 1 -ol, 2-[({4-[(2-{ 3 -[(4-{ [(2-hydroxyethyl)amino]methyl 1 -3,5 -dimethoxyphenoxy)methy1]-2-methylphenyl Ipyridin-4-yl)methoxy]-2,6-dimethoxyphenyl Imethyl)amino] ethan- 1 -ol, 2-[({4-[(6- { 3 -[(4-{ [(2-hydroxyethyl)amino]methyl 1 -3,5 -dimethoxyphenoxy)methy1]-2-methylphenyl Ipyridin-2-yl)methoxy]-2,6-dimethoxyphenyl Imethyl)amino] ethan- 1 -ol, 2-({ [4-({2'-chloro-3'-[(4-{ [(2-hydroxyethyl)amino]methyl 1 -2-methylphenoxy)methy1]-[ 1, 1'-bipheny1]-3 -ylImethoxy)-3 -methylphenyl]methyl 1 amino)ethan- 1 -ol, 3,3 '-bi s[(4- { [(2-hydroxyethyl)amino]methyl 1 -3, 5-dimethoxyphenoxy)methylM 1, 1'-bipheny1]-2-carbonitrile, 3,3 '-bi s({ [(5-{
[(2-hydroxyethyl)amino]methyl 1 -6-methoxypyridin-2-yl)oxy]methyl })-[ 1, 1'-bipheny1]-2-carbonitrile, 3,3 '-bi s({ [(5-{ [(2-hydroxyethyl)amino]methyl}pyridin-2-yl)oxy]methyl 1)41, 1'-biphenyl]-2-carbonitrile, 3,3 '-bis(14-[(azetidin-1-yl)methyl]-3 ,5-dimethoxyphenoxy Imethyl)-[ 1, 1'-biphenyl]-2-carbonitrile, 3,3 '-bi s(14-[(3 -hydroxyazetidin- 1 -yl)methy1]-3 ,5-dimethoxyphenoxy }methyl)-[ 1, 1'-biphenyl]-2-carbonitrile, 3,3 '-bi s({ [3, 5-dimethoxy-4-(1 [(4-oxoazetidin-2-yl)methyl] amino 1 methyl)phenoxy]methyl })-[ 1, 1'-biphenyl]-2-carbonitrile, 3,3 '-bi s [(4-{ [(2-hydroxyethyl)amino]methyl 1 -2-methylphenoxy)methy1]-[ 1, 1'-biphenyl]-2-carbonitrile, N-12-[(16-[(2'-cyano-3'-{ [(5-{ [(2-acetamidoethyl)amino]methyl methoxypyridin-2-yl)oxy]methyl 141, 1'-biphenyl]-3 -yl)methoxy]-2-methoxypyridin-3 -yl Imethyl)amino] ethyl Iacetamide, 2-[(4-{ [(2-hydroxyethyl)amino]methyl 1 -3,5 -dimethoxyphenoxy)methy1]-6-14-[(4- { [(2-hydroxyethyl)amino]methyl 1 -3,5 -dimethoxyphenoxy)methyl]pyridin-2-y1 Ibenzonitrile, 2-[(4-{ [(2-hydroxyethyl)amino]methyl 1 -2-methylphenoxy)methy1]-6-14-[(4-{ [(2-hydroxyethyl)amino]methyl 1 -2-methylphenoxy)methyl]pyridin-2-y1 Ibenzonitrile, 2-1 [(5 -{ [(2-hydroxyethyl)amino]methyl 1 -6-methoxypyridin-2-yl)oxy]methyl 1 -644-1 [(5-{ [(2-hydroxyethyl)amino]methyl 1 -6-methoxypyridin-2-yl)oxy]methylIpyridin-2-y1)benzonitrile, 2-M44(243-R44 [(2-hydroxyethyl)amino]methyl 1 -2-methylphenoxy)methy1]-2-methylphenyl }pyridin-4-yl)methoxy]-3 -methylphenylImethyl)amino]ethan-1-ol, 3,3'-bis({ [(5-{ [(2-hydroxyethyl)amino]methylIpyridin-2-yl)oxy]methyl})-[1, 1'-biphenyl]-2,2'-dicarbonitrile, 3,3 '-bis [(4- { [(2-hydroxyethyl)amino]methyl 1 -2-methylphenoxy)methy1]-[1, 1'-biphenyl]-2,2'-dicarbonitrile, 3,3 '-bi s[(4-{ [(2-hydroxyethyl)amino]methyl Iphenoxy)methy11-[ 1, 1'-biphenyl]-2,2'-dicarbonitrile, 5,5'-bis[(4-{ [(2-hydroxyethyl)amino]methyl 1 -2-methylphenoxy)methy1143 ,3 '-bipyridine]-4,4'-dicarbonitrile, 2-M44(443-R44 [(2-hydroxyethyl)amino]methyl 1 -3,5 -dimethoxyphenoxy)methy1]-2-methylphenyl 1 -3 -methylthiophen-2-yl)methoxy]-2,6-dimethoxyphenyl Imethyl)amino] ethan- 1 -ol, 2-[(14-[(4-{3 -[(4-{ [(2-hydroxyethyl)amino]methyl 1 -2-methylphenoxy)methy1]-2-methylphenyl 1 -3 -methylthiophen-2-yl)methoxy]-3 -methylphenyl Imethyl)amino] ethan- 1 -ol, 241 [441 5'4(4-{ [(2-hydroxyethyl)amino]methyl 1 -2-methylphenoxy)methy1]-4,4'-dimethyl-[3,3'-bithiophene]-5-ylImethoxy)-3 -methylphenyl]methyl Iamino)ethan- 1 -ol, 2-G[4415'4(44 [(2-hydroxyethyl)amino]methyl 1 -2-methylphenoxy)methy11- 1, 1'-dimethyl- 1H, 1'H-[2,2'-bipyrrole]-5-ylImethoxy)-3 -methylphenyl]methyl 1 amino)ethan- 1 -ol, 5-[(5-{
[3 '-(1 5 -[(5-cyanopyridin-3 -yl)methoxy]-4- { [(2-hydroxyethyl)amino]methyl 1 -2-methylphenoxy Imethyl)-2,2'-dimethy141, 1'-biphenyl]-3-yl]methoxy 1 -2-1 [(2-hydroxyethyl)amino]methyl 1 -4-methylphenoxy)methyl]pyridine-3 -carbonitrile, 2-(1[4-(13'-[(4-{[(2-hydroxyethyl)amino]methyl 1 -2-methyl-5 -[(pyridin-3 -yl)methoxy]phenoxy)methy1]-2,2'-dimethyl-[ 1, 1'-bipheny1]-3-ylImethoxy)-5-methyl-2-[(pyridin-3-yl)methoxy]phenyl]methylIamino)ethan- 1 -ol, 5-[(4-chloro-5-{ [3 '-(12-chloro-
5-[(5-cyanopyridin-3 -yl)methoxy]-4- { [(2-hydroxyethyl)amino]methyl Iphenoxy Imethyl)-2,2'-dimethyl-[ 1, 1'-bipheny1]-3-yl]methoxy 1 -2- { [(2-hydroxyethyl)amino]methyl}phenoxy)methyl]pyridine-3-carbonitrile, 5 -[(5- { [3 '-(1 5 -[(5-cyanopyridin-3 -yl)methoxy]-2-methyl-4-[(methylamino)methyl]phenoxy Imethyl)-2,2'-dimethyl-[ 1, 1'-bipheny1]-3-yl]methoxy 1 -4-methy1-2-[(methylamino)methyl]phenoxy)methyl]pyridine-3 -carbonitrile, 54(54 [3 '-(1 5-[(5-cyanopyri din-3 -yl)methoxy]-4-(hydroxymethyl)-2-methylphenoxy Imethyl)-2,2'-dimethyl-[ 1, 1'-bipheny1]-3 -yl]methoxy 1 -2-(hydroxymethyl)-4-methylphenoxy)methyl]pyridine-3 -carbonitrile, 5-[(3 -1 [3 '-(1 5-[(5-cyanopyridin-3 -yl)methoxy]-2-methylphenoxy Imethyl)-2,2'-dimethyl-[ 1, 1'-bipheny1]-3-yl]methoxy 1 -4-methylphenoxy)methyl]pyridine-3 -carbonitrile, 5-[(5- { [3 '-(1 5-[(5-cyanopyridin-3 -yl)methoxy]-4-(hydroxymethyl)-2-methylphenoxy }methyl)-2-methyl-[ 1, 1'-bipheny1]-3 -yl]methoxy 1 -2-(hydroxymethyl)-4-methylphenoxy)methyl]pyridine-3 -carbonitrile, 3,3 '-bi s({ 5 -[(5 -cyanopyridin-3 -yl)methoxy]-4-1 [(2-hydroxyethyl)amino]methyl 1 -2-methylphenoxy Imethyl)-[ 1, 1'-bipheny1]-2,2'-dicarbonitrile, 5-(14-chloro-5-[(2-cyano-3'-{ [(5-{ [(2-hydroxyethyl)amino]methyl}pyridin-2-yl)oxy]methyl 141, 1'-bipheny1]-3-yl)methoxy]-2-{ [(2-hydroxyethyl)amino]methyl}phenoxy}methyl)pyridine-3-carbonitrile, 5-1 [5 -(12-cyano-Y-[(4- { [(2-hydroxyethyl)amino]methyl 1 -2-methylphenoxy)methy1]-[1, 1'-bipheny1]-3-ylImethoxy)-2-{ [(2-hydroxyethyl)amino]methyl 1 phenoxy]methyl }pyridine-3 -carbonitrile, 5-{ [4-chloro-5 -(12-cyano-3 '4(4-1 [(2-hydroxyethyl)amino]methyl 1 -2-methylphenoxy)methy1]-[ 1, 1'-bipheny1]-3 -ylImethoxy)-2- { [(2-hydroxyethyl)amino]methyl Iphenoxy]methyl }pyridine-3 -carbonitrile, 3'4(4-1 [(2-hydroxyethyl)amino]methyl 1 -2-methylphenoxy)methy1]-3 4(44 [(2-hydroxyethyl)amino]methyl 1 -3 -[(pyridin-3 -yl)methoxy]phenoxy)methy1]-[ 1, 1'-bipheny1]-2-carbonitrile, 5-1 [5-(12'-cyano-3 '4(4-1 [(2-hydroxyethyl)amino]methyl 1 -2-methylphenoxy)methy1]-[ 1, 1'-bipheny1]-3 -ylImethoxy)-2-{ [(2-hydroxyethyl)amino]methyl 1-4-methylphenoxy]methyl }pyridine-3 -carbonitrile, 5-1 [5-(12-cyano-3 '4(4-1 [(2-hydroxyethyl)amino]methyl 1 -2-methylphenoxy)methy1]-[ 1, 1'-bipheny1]-3 -ylImethoxy)-2-{ [(2-hydroxyethyl)amino]methyl 1 -4-methylphenoxy]methyl }pyridine-3 -carbonitrile, 5 -[(4-chloro-2- { [(2-hydroxyethyl)amino]methyl 1 -5-[(3'- { [(5-{ [(2-hydroxyethyl)amino]methyl}pyridin-2-yl)oxy]methyl 1 -2,2'-dimethy141,1 '-biphenyl]-3 -yl)methoxy]phenoxy)methyl]pyridine-3 -carbonitrile, 5-(14-chloro-5-[(2-cyano-3'-{ [(5-{ [(2-hydroxyethyl)amino]methyl}pyridin-2-yl)oxy]methyl 1 -[ 1, 1'-bipheny1]-3 -yl)methoxy]-2-[(cyclopropylamino)methyl]phenoxy Imethyl)pyridine-3-carbonitrile, 5-1 [5-(12-cyano-3 '-[(4-{ [(2-hydroxyethyl)amino]methyl 1 -3,5 -dimethoxyphenoxy)methy1]-2'-methy141, 1'-bipheny1]-3 -ylImethoxy)-2-{ [(2-hydroxyethyl)amino]methyl 1 -4-methylphenoxy]methyl }pyridine-3 -carbonitrile, 5-[(5-{ [2-cyano-3'-(15-[(5-cyanopyridin-3-yl)methoxy]-4-{ [(2-hydroxyethyl)amino]methyl 1 -2-methylphenoxy Imethyl)-[ 1, 1'-bipheny1]-3 -yl]methoxy 1 -2-{ [(2-hydroxyethyl)amino]methyl 1 -4-methylphenoxy)methyl]pyridine-3 -carbonitrile, 2-(1 [4-(13 '4(4-1 [(2-hydroxyethyl)amino]methyl 1 -3 -[(pyridin-3 -yl)methoxy]phenoxy)methy1]-2,2'-dimethyl-[ 1, 1'-bipheny1]-3 -ylImethoxy)-3 -methylphenyl]methyl 1 amino)ethan-1 -ol, 5-[(4-chloro-2-{ [(2-hydroxyethyl)amino]methyl 1 -5413 '4(4-1 [(2-hydroxyethyl)amino]methyl 1 -3,5-dimethoxyphenoxy)methy1]-2-methyl4 1, 1'-bipheny1]-3 -yl }methoxy)phenoxy)methyl]pyridine-3 -carbonitrile, 5-[(2-{ [(2-hydroxyethyl)amino]methyl 1 -5413 '4(4-1 [(2-hydroxyethyl)amino]methyl 1 -2-methylphenoxy)methy1]-2,2'-dimethyl-[ 1, 1'-bipheny1]-3-ylImethoxy)-4-methylphenoxy)methyl]pyridine-3-carbonitrile, 5 -[(2-{ [(2-hydroxyethyl)amino]methyl 1 -5-(13'4(4-1 [(2-hydroxyethyl)amino]methyl 1 -3 ,5-dimethoxyphenoxy)methy1]-2,2'-dimethyl-[ 1, 1'-bipheny1]-3 -ylImethoxy)-4-methylphenoxy)methyl]pyridine-3 -carbonitrile, 241 [4-(13'-[(4- { [(2-hydroxyethyl)amino]methyl 1 -2-methyl-5-[(pyridin-3 -yl)methoxy]phenoxy)methy1]-2,2'-dimethyl-[1, 1'-bipheny1]-3 -ylImethoxy)-2,6-dimethoxyphenyl]methyl Iamino)ethan- 1 -ol, 5-1 [(3- { [(2-hydroxyethyl)amino]methyl 1 -64(3 '- { [(5-{ [(2-hydroxyethyl)amino]methyl 1 -6-methoxypyridin-2-yl)oxy]methyl 1 -2,2'-dimethyl-[ 1, 1'-bipheny1]-3 -yl)methoxy]pyridin-2-yl)oxy]methyl }pyridine-3 -carbonitrile, 241 [4413 '-[(2-chloro-4-{ [(2-hydroxyethyl)amino]methyl 1 -5-[(pyridin-3 -yl)methoxy]phenoxy)methy1]-2,2'-dimethyl-[ 1, 1'-bipheny1]-3 -ylImethoxy)-3 -methylphenyl]methyl Iamino)ethan- 1 -ol, 5-[(5-{
[2-cyano-3 '-(1 5-[(5 -cyanopyri din-3 -yl)methoxy]-4-(hydroxymethyl)-2-methylphenoxy Imethyl)-2'-methyl-[ 1, 1'-bipheny1]-3 -yl]methoxy 1 -2-(hydroxymethyl)-4-methylphenoxy)methyl]pyridine-3 -carbonitrile, 5-(12-[(azetidin- 1 -yl)methy1]-5- { [3 '-(14-[(azetidin-1 -yl)methy1]-5-[(5-cyanopyridin-3 -yl)methoxy]-2-methylphenoxy}methyl)-2-cyano-[1, 1'-bipheny1]-3 -yl]methoxy 1 -4-methylphenoxy Imethyl)pyridine-3 -carbonitrile, 5 -(12-[(azetidin- 1 -yl)methy1]-5-{ [3 '-(14-[(azetidin-1 -yl)methy1]-5-[(5-cyanopyridin-3 -yl)methoxy]-2-methylphenoxy}methyl)-2,2'-dimethy141, 1'-bipheny1]-3-yl]methoxy 1 -4-methylphenoxy Imethyl)pyridine-3-carbonitrile, 2-[(1243 '46-1 [(2-hydroxyethyl)amino]methyl 1 -[ 1,2,4]triazolo[ 1, 5-a]pyridin-2-y1)-2,2'-dimethy141, 1'-bipheny1]-3-y1]-[1,2,4]triazolo[1,5-a]pyridin-6-ylImethyl)amino]ethan-1-ol, 2-[({2-[3 '-(6-{ [(2-hydroxyethyl)amino]methyl Iimidazo[1,2-a]pyridin-2-y1)-2,2'-dimethyl4 1, 1'-bipheny1]-3 -yl]imidazo[ 1,2-a]pyridin-6-ylImethyl)amino] ethan- 1 -ol, 24( {243 '-(6-{
[(2-hydroxyethyl)amino]methyl 1 -1,3 -benzoxazol-2-y1)-2,2'-dimethyl-[ 1, 1'-bipheny1]-3 -y1]-1,3 -benzoxazol-6-y1 I methyl)amino] ethan- 1 -ol, 24{243'454 [(2-hydroxyethyl)amino]methyl 1 -1,3 -benzoxazol-2-y1)-2,2'-dimethyl-[ 1, 1'-bipheny1]-3 -y1]- 1,3 -benzoxazol-5-ylIamino)ethan-1 -ol, 2-R{243'454 [(2-hydroxyethyl)amino]methyl} -1,3 -benzothiazol-2-y1)-2,2'-dimethyl-[ 1, 1'-bipheny1]-3 -y1]- 1,3 -benzothiazol-5-ylImethyl)amino] ethan- 1 -ol, 2-R{243'464 [(2-hydroxyethyl)amino]methyl 1 -1,3 -benzothiazol-2-y1)-2,2'-dimethyl4 1, 1'-bipheny1]-3 -y1]- 1,3 -benzothiazol-6-ylImethyl)amino] ethan- 1-01, 3,3 '-bi s(6- { [(2-hydroxyethyl)amino]methyl 1 -[1,2,4]triazolo[1,5-a]pyridin-2-y1)41, 1'-bipheny1]-2,2'-dicarbonitrile, 3,3 '-bi s(6- { [(2-hydroxyethyl)amino]methyl 1 -1,3 -benzoxazol-2-y1)41, 1'-bipheny1]-2,2'-dicarbonitrile, 2-[({2-[3 '-(7-{ [(2-hydroxyethyl)amino]methyl 1 -[ 1,2,4]triazolo[ 1,5-a]pyridin-2-y1)-2,2'-dimethyl-[ 1, 1'-bipheny1]-3 -y1]-[ 1,2,4]triazolo[ 1,5-a]pyridin-7-ylImethyl)amino]ethan-1 -ol, 2-{ [(8-chl oro-2- { 3'- [(4- { [(2-hydroxyethyl)amino]methyl I -2-methylphenoxy)methyl] -2,2'-dimethyl-[ 1, 1'-bipheny1]-3 -yl 1 -[ 1,2,4]triazolo[ 1,5-a]pyridin-6-yl)methyl] amino}
ethan- 1-01, 3 -(8-chloro-6- { [(2-hydroxyethyl)amino]methyl 1 -[ 1,2,4]triazolo[ 1, 5-a]pyridin-2-y1)-3 '-[(4- { [(2-hydroxyethyl)amino]methyl 1 -2-methylphenoxy)methy1]-[ 1, 1'-bipheny1]-2-carbonitrile, 3'-[(4-{ [(2-hydroxyethyl)amino]methyl 1 -3,5 -dimethoxyphenoxy)methy1]-3 -(6-{
[(2-hydroxyethyl)amino]methyl 1 -[ 1,2,4]triazolo[ 1, 5-a]pyridin-2-y1)-[ 1, 1'-bipheny1]-2-carbonitrile, 3'4(44 [(2-hydroxyethyl)amino]methyl 1 -2-methylphenoxy)methy1]-3 -(6- { [(2-hydroxyethyl)amino]methyl 1 -[ 1,2,4]triazolo[ 1, 5-a]pyridin-2-y1)-[ 1, 1'-bipheny1]-2-carbonitrile, 2- { [(2- { 3'4(44 [(2-hydroxyethyl)amino]methyl 1 -2-methylphenoxy)methy1]-2,2'-dimethyl-[ 1, 1'-bipheny1]-3 -yl 1 -1,3 -benzoxazol-6-yl)methyl] amino} ethan-1-01, 3 -(5-{ [(2-hydroxyethyl)amino]methyl 1 -1,3 -benzoxazol-2-y1)-3 '-[(4-{ [(2-hydroxyethyl)amino]methyl 1 -2-methylphenoxy)methy1]-[1, 1'-bipheny1]-2-carbonitrile, 2-{ [(2-{ 3 '-[(4-{
[(2-hydroxyethyl)amino]methyl 1 -2-methylphenoxy)methy1]-2,2'-dimethy141, 1'-bipheny1]-3 -yl 1 -1,3 -benzoxazol-5-yl)methyl] amino} ethan- 1-01, 2-{ [(2-{ 3 '-[(4-{ [(2-hydroxyethyl)amino]methyl 1 -2-methylphenoxy)methy1]-2,2'-dimethy141, 1'-bipheny1]-3 -yl 1 -1,3 -benzothiazol-5-yl)methyl] amino} ethan- 1-01, 2- { [(2- { 3 '-[(4- { [(2-hydroxyethyl)amino]methyl 1 -2-methylphenoxy)methy1]-2,2'-dimethy141, 1'-bipheny1]-3 -yl 1 -1,3 -benzothiazol-6-yl)methyl] amino} ethan- 1-01, 2- { [(2- { 3 '-[(4- { [(2-hydroxyethyl)amino]methyl 1 -2-methylphenoxy)methy1]-2,2'-dimethy141, 1'-bipheny1]-3 -yl 1 -[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]amino} ethan- 1-01, 3'4(44 [(2-hydroxyethyl)amino]methyl 1 -2-methylphenoxy)methy1]-3 -(6- { [(2-hydroxyethyl)amino]methyl 1 -[ 1,2,4]triazolo[ 1, 5-a]pyridin-2-y1)-2'-methyl-[ 1, 1'-bipheny1]-2-carbonitrile, 2-1 [(4-chloro-2- { 3 '4(4-1 [(2-hydroxyethyl)amino]methyl 1 -2-methylphenoxy)methy1]-2,2'-dimethyl-[ 1, 1'-bipheny1]-3 -yl 1- 1,3 -benzoxazol-
6-yl)methyl] amino 1 ethan- 1-01, 3 -(4-chloro-6-{ [(2-hydroxyethyl)amino]methyl 1- 1,3 -benzoxazol-2-y1)-3 '4(4-1 [(2-hydroxyethyl)amino]methyl} -2-methylphenoxy)methy1]-[1, 1'-bipheny1]-2-carbonitrile, 3 -(5-1 [(2-hydroxyethyl)amino]methyl 1- 1,3 -benzoxazol-2-y1)-3'-[(4-{ [(2-hydroxyethyl)amino]methyl 1 -3,5 -dimethoxyphenoxy)methy1]-[ 1, 1'-bipheny1]-2-carbonitrile, 3 -(4-chloro-6-{ [(2-hydroxyethyl)amino]methyl 1- 1,3 -benzoxazol-2-y1)-3'-[(4-{ [(2-hydroxyethyl)amino]methyl 1 -2-methylphenoxy)methy1]-2'-methyl4 1, 1'-bipheny1]-2-carbonitrile, 2-R1243'454 [(2-hydroxyethyl)amino]methyl 1 -2H-indazol-2-y1)-2,2'-dimethyl-[ 1, 1'-bipheny1]-3 -y1]-2H-indazol-5-ylImethyl)amino]ethan- 1-01, 2-R1243'464 [(2-hydroxyethyl)amino]methyl 1 -2H-indazol-2-y1)-2,2'-dimethyl-[ 1, 1'-bipheny1]-3 -y1]-2H-indazol-6-ylImethyl)amino]ethan-1 -01, 2-[(1243 '46-1 [(2-hydroxyethyl)amino]methyl Iimidazo[1,2-b]pyridazin-2-y1)-2,2'-dimethyl-[ 1, 1'-bipheny1]-3 -yl]imidazo[1,2-b]pyridazin-6-ylImethyl)amino]ethan- 1-01, 2-R1643'424 [(2-hydroxyethyl)amino]methyl Iimidazo[1,2-b] [ 1,2,4]triazin-6-y1)-2,2'-dimethyl-[ 1, 1'-bipheny1]-3 -yl]imidazo[ 1,2-b] [1,2,4]triazin-2-ylImethyl)amino] ethan- 1-01, 2-R1243'464 [(2-hydroxyethyl)amino]methyl Iimidazo[1,2-a]pyrazin-2-y1)-2,2'-dimethyl-[ 1, 1'-bipheny1]-3 -yl]imidazo[1,2-a]pyrazin-6-ylImethyl)amino]ethan-1 -01, 241 [4413 42-(4-{ [(2-hydroxyethyl)amino]methylIpheny1)-7-methyl-1,3 -benzoxazol-6-y1]-2-methylphenyl Imethoxy)-3 -methylphenyl]methyl Iamino)ethan- 1-01, 241 [4413 4243 -1 [(2-hydroxyethyl)amino]methylIpheny1)-7-methyl-1,3 -benzoxazol-6-y1]-2-methylphenyl Imethoxy)-3 -methylphenyl]methyl Iamino)ethan- 1-01, 2-1[04642444 [(2-hydroxyethyl)amino]methylIpheny1)-7-methyl-1,3 -benzoxazol-6-y1]-7-methyl- 1,3 -benzoxazol-2-ylIphenyl)methyl] amino 1 ethan- 1 -ol, 2-1[0464243 -1 [(2-hydroxyethyl)amino]methylIpheny1)-7-methyl-1,3 -benzoxazol-6-y1]-7-methyl- 1,3 -benzoxazol-2-ylIphenyl)methyl] amino 1 ethan- 1 -ol, 2-R1243'454 [(2-hydroxyethyl)amino]methyl 1 -2,3 -dihydro-1H-isoindo1-2-y1)-2,2'-dimethy141, 1'-bipheny1]-3 -y1]-2,3 -dihydro- 1H-i soindo1-5-ylImethyl)amino] ethan- 1 -ol, or 2-[(1 643'43 -1 [(2-hydroxyethyl)amino]methyl 1 -2-methoxy-5H,6H,7H-pyrrolo[3 ,4-b]pyridin-6-y1)-2,2'-dimethyl-[ 1, 1'-bipheny1]-3 -y1]-2-methoxy-51-1,6H,7H-pyrrolo[3,4-b]pyridin-3 -yl Imethyl)amino] ethan- 1 -ol.

In another aspect, described herein is a pharmaceutical composition comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In another aspect, described herein is a method of treating a disease associated with the modulation of PD-1/PD-L1 or CD80/PD-L1 interaction comprising administering to a patient the compound of Formula (I) or a pharmaceutically acceptable salt thereof.
In another aspect, in the method, the disease is an infection, inflammation cancer, or neurodegenerative disorders like Alzheimer's disease.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the invention as claimed.
BRIEF DESCRIPTION OF THE DRAWINGS
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the principles of the invention.
In the drawings:
Figure 1 shows the docking pose of compound I-1 in PD-Li dimer.
Figure 2 shows the docking pose of compound I-10 in PD-Li dimer.
DETAILED DESCRIPTION OF THE ILLUSTRATED EMBODIMENTS
Reference will now be made in detail to embodiments of the present invention, example of which is illustrated in the accompanying drawings.
Prodrugs mean any compound which releases an active parent drug according to Formula (I) in vivo when such prodrug is administered to a mammalian subject.
Prodrugs of a compound of Formula (I) are prepared by modifying functional groups present in the compound of Formula (I) in such a way that the modifications may be cleaved in vivo to release the parent compound. Prodrugs may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds.
Tautomers mean compounds produced by the phenomenon wherein a proton of one atom of a molecule shifts to another atom. Tautomers also refer to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. One of ordinary skill in the art would recognize that other tautomeric ring atom arrangements are possible. All such isomeric forms of these compounds are expressly included in the present disclosure.
Isomers mean compounds having identical molecular formulae but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed stereoisomers. Stereoisomers that are not mirror images of one another are termed diastereomers, and those that are non-superimposable mirror images of each other are termed enantiomers. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. A chiral compound can exist as either individual enantiomer or as a mixture thereof. Unless otherwise indicated, the description is intended to include individual stereoisomers as well as mixtures.
Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. Solvates refer to a complex formed by combination of solvent molecules with the compound of Formula (I). The solvent can be an organic compound, an inorganic compound, or a mixture thereof.
Pharmaceutically acceptable salts represent those salts which are, within the scope of medical judgement, suitable for use in contact for the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. They may be obtained during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable mineral acid such as hydrochloric acid, phosphoric acid, or sulfuric acid, or with an organic acid such as for example ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, methanesulfonic acid, and the like. The acid function can be reacted with an organic or a mineral base, like sodium hydroxide, potassium hydroxide or lithium hydroxide.
Therapeutically effective amount means an amount of compound or a composition of the present invention effective in inhibiting the PD-1/PD-L1 protein/protein and CD80/PD-Ll protein/protein interactions, and thus producing the desired therapeutic effect.
As used herein, the term alkyl refers to a monovalent straight or branched chain, saturated aliphatic hydrocarbon radical having a number of carbon atoms in the specified range. For example, C16 alkyl refers to any of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and iso-propyl, ethyl and methyl. Alkyl also includes saturated aliphatic hydrocarbon radicals wherein one or more hydrogen atoms are replaced with deuterium, for example, CD3.

The term branched alkyl refers to an alkyl group as defined above except that straight chain alkyl groups in the specified range are excluded. As defined herein, branched alkyl includes alkyl groups in which the alkyl is attached to the rest of the compound via a secondary or tertiary carbon. For example, isopropyl is a branched alkyl group.
The term cycloalkyl refers to any monocyclic ring of an alkane having a number of carbon atoms in the specified range. For example, C3_6cycloalkyl refers to cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl.
The term halogen refers to fluorine, chlorine, bromine and iodine (alternatively referred to as fluor , chloro, bromo, and iodo).
The term haloalkyl refers to an alkyl group as defined above in which one or more of the hydrogen atoms have been replaced with a halogen (i.e., F, Cl, Br and/or I). For example, Ch6haloalkyl refers to a Ci to C6 linear or branched alkyl group as defined above with one or more halogen substituents. The term fluoroalkyl has an analogous meaning except that the halogen substituents are restricted to fluoro. Suitable fluoroalkyls include the series (CH2)0-4CF3.
The term C(0) or CO refers to carbonyl. The terms S(0)2 or SO2 refers to sulfonyl.
The term 5(0) or SO refers to sulfinyl.
The term aromatic hydrocarbons (sometimes arene or aryl hydrocarbon) refers to hydrocarbons with sigma bonds and delocalized pi electrons between carbon atoms forming rings.
The term aryl (Ar) refers to phenyl, naphthyl, tetrahydronaphthyl, idenyl, dihydroindenyl and the like. An aryl of particular interest is phenyl.
The term heterocyclic refers to heteroaryl, saturated heterocyclic, and unsaturated heterocyclic with a double bond.
The term heteroaryl refers to (i) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, 0 and S, or (ii) is a heterobicyclic ring selected from quinolinyl, isoquinolinyl, and quinoxalinyl. Suitable 5-and 6-membered heteroaromatic rings include, for example, pyridyl (also referred to as pyridinyl), pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thienyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, oxatriazolyl, thiazolyl, isothiazolyl, and thiadiazolyl. A class of heteroaryls of interest consists of (i) 5- and 6-membered heteroaromatic rings containing from 1 to 3 heteroatoms independently selected from N, 0 and S, and (ii) heterobicyclic rings selected from quinolinyl, isoquinolinyl, and quinoxalinyl.

Heteroaryls of particular interest are pyrrolyl, imidazolyl, pyridyl, pyrazinyl, quinolinyl (or quinolyl), isoquinolinyl (or isoquinolyl), and quinoxalinyl.
Examples of 4- to 7-membered, saturated heterocyclic rings within the scope of this invention include, for example, azetidinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, pyrrolidinyl, imidazolidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, hexahydropyrimidinyl, thiazinanyl, thiazepanyl, azepanyl, diazepanyl, tetrahydropyranyl, tetrahydrothiopyranyl, and dioxanyl. Examples of 4- to 7-membered, unsaturated heterocyclic rings within the scope of this invention include mono-unsaturated heterocyclic rings corresponding to the saturated heterocyclic rings listed in the preceding sentence in which a single bond is replaced with a double bond (e.g., a carbon-carbon single bond is replaced with a carbon-carbon double bond).
It is understood that the specific rings listed above are not a limitation on the rings which can be used in the present invention. These rings are merely representative.
Synthetic methods for preparing the compounds of the present invention are illustrated in the following Schemes, Methods, and Examples. Starting materials are commercially available or may be prepared according to procedures known in the art or as described herein. The compounds of the invention are illustrated by means of the specific examples shown below. However, these specific examples are not to be construed as forming the only genus that is considered as the invention. These examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily appreciate that known variations in the conditions and processes can be used to prepare such compounds.
Compounds of the present invention can be synthesized by following the steps outlined in General Schemes 1-7, which comprise different sequences of assembling intermediates II ¨ XII. Starting materials are either commercially available or made by known procedures in the reported literature or as illustrated.
When A is a bivalent bi-aryl or bi-heteroaryl core, a symmetric or semi-symmetric compound of Formula (I) can be synthesized via Suzuki palladium catalyzed cross-coupling of aryl/heteroaryl halide (II) and aryl/heteroaryl boronic acid/ester (III) as shown in Scheme 1-3.
Scheme 1 Z
R4 ;OH
Z Ra I3:43 Ra Ra Rc.--C. X2 01 Hal RO, 0 1. Suzuki coupling , ., B
R'd Ra' Y
2. NaBH4 (Y=CO2R) Ra' Y 1. Mitsunobu .
Y
CYC' or Os2CO3/K2O03 R3 X2 Ra' Z
or NBS (Y=CH2OH) 2. Reductive amination ii III IV l-a Hal = Cl, Br or I Y = CH2OH, CH2Br Y = CH20 V = CO2R, CH2OH
Ra , , , Ra' In Scheme 1, A is , R3¨R4, R3 ' ¨R4 ' , X1_3, X' 1_3, Y, Y', Z and Z' are defined as in Formula (I).
Scheme 2 X2',...õ. R3' Hal RO
Z Ra X2,R3' Suzuki coupling Z Ra X1.
R
I
.4 Y
j , 40 X ' i Inv ______________________________________________________ .- R4 ,........),..
CD1)3 + µ 0 B ,X3 '=J' r 'r "..RA' Pd cat. base, heat W ())3 Y' R4' ........,, , X1 ........,, , X1 Ra' Z' R3 X2 ' O ' Ra Z' R3 X2 Base = TEA
II III Cs2CO3 I-a Hal = Cl, Br or I R, R = H, or form a cylic ester Ra , , , Ra' In Scheme 2, A is , R3¨R4, R3 ' ¨R4 ' , X1_3, X' 1_3, Y, Y', Z and Z' are defined as in Formula (I).
Scheme 3 Z Ra , X2' R3' Suzuki coupling Z Ra /Y Xi',,r;
___________________________________________________ , R4 ....õ.õ....1., .2( to ito xl.sx2. R3.
V3 igt Hal RO, io ,,, + B y ' )/'a4. pd cat. base, heat V3 y -- X3' n. 3 " ./..',. õ ... X2 rt 2 R r '0 Ra. Z' R3 X2 Ra' R4' Base = TEA z IV III Cs2CO3 K2CO3 I-b Hal = Cl, or Br R, R' = H, or form a cylic ester Ra , , , ,--, O
I HeV
.
.
In Scheme 3, A is Ra' ' , R3-1t4, R3 ' ¨R4', X1_3, X'13, Y, Y', Z and Z' are defined as in Formula (I).
When A is a bi-heteroaryl core, a semi-symmetric compound of Formula (I) can be synthesized via Chan-Lam copper catalyzed C-N coupling reaction of aryl/heteroaryl boronic acid (III) with N-H containing aryl/heteroaryl (V) as shown in Scheme 3.
Scheme 4 - Xi , R3' ., X2' R3' Chan-Lam coupling o 40 x,.,...õ_ x,(;;\ R4 _______________________________________________ )'( =,)(3') R4 )-.' -.X..."-ANH
+ HO, 0 ,x3,, B C))3 I N
r I-...--... R4' Cu (OAC)2, Py, air õ...... õxl ....,.....7.-I Ra Y' )R,I.
Z' .õ--õ, ...,.1 , R3 X2 HO Ra Z' V III I-O
Ra , In Scheme 4, A is S, R3¨R4, R3'¨R4', X1-3, V1-3, Y, Y', Z and Z' are defined as in Formula (I).
When A is a bivalent aryl or heteroaryl core, a symmetric or semi-symmetric compound of Formula (I) can be synthesized via Mitsunobu reaction of aryl/heteroaryl alcohol (VI) and aryl/heteroaryl phenol (VII). A compound of formula (I) can also be prepared by 0-alkylation or N-alkylation of aryl/heteroaryl (VII or IX) with aryl/heteroaryl halides (VIII) under basic condition (Scheme 4 to 5cheme6).
Scheme 5 Ra XjX2 R3 Mitsunobu reaction R3, X2Xi Ra Xj X2 R3 or 0-alkylation R 10 R + I

R4 0 10 C) R4 Z Z Z
R=OH, Mitsunobu reaction VI VII R= Br, 0-alkylation of phenol I-d 2 eqv. Symmetric compound R = Br, OH
Ra , , ., ' .
In Scheme 5, A is Si , R3¨R4, R3'¨', Xi_3, X' 1_3, Y, Y', Z and Z' are defined as in Formula (I).
Scheme 6 X2' R3' Mitsunobu reaction 0 Ra X2' R3 0 Ra ' Xi' xi' - or 0-alkylation 1 NaBH4 or LAH
0 0 R + _______________ ,- 0 0 HO R4' Z
Z
VIII VII R=OH, Mitsunobu reaction IX
R= Br, 0-alkylation of phenol R = Br, OH
Xj X2, R3 X2' R3' HOR -4 R3,,, X2Xi Ra Xi' X2,...õ, R3' Ra Xi' - Z -HO 40 0 VII R4' ______ 0 0)i 4 ,N D ' Z Mitsunobu reaction Z Z
X
l-e Semi-symmetric compound Ra ss In Scheme 6, A is 101 , R3-R4, R3'-R4', X1_3, X'1_3, Y, Y', Z and Z' are defined as in Formula (I).
Scheme 7 X2' R3.
X1' Mitsunobu reaction 101 HN OH + I Or HORtt. ________________________________ HN
V-V 7 V=\/' ^2 n3 XI VII XII
R3 X2 xi Alkylation, I Br Base, heat R4 RLIN
I v =' I-f hN
/
In Scheme 7, A is Nr-V , - R3-R4, X1-3, X' 1-3, Y, Y', Z and Z' are defined as in Formula (I).
The general ways of preparing target molecules (I) by using intermediates II ¨
XII are outlined in Scheme 1-7. A mixture of enantiomers, diastereomers, cis/trans isomers resulted from the process can be separated into their single components by chiral salt technique, chromatography using normal phase, reverse phase or chiral column, depending on the nature of the separation.
It should be understood that in the description and formulae shown above, the various groups A, B and B', - R3-R4, R3'-R4', X1_3, X'1_3, Y, Y', Z and Z' and other variables are as defined above, except where otherwise indicated. Furthermore, for synthetic purposes, the compounds of Schemes 1-7 are mere representative with elected radicals to illustrate the general synthetic methodology of the compound of Formula (I) as defined herein.
Abbreviations used in the following examples and elsewhere herein are:
Ac20 acetic anhydride ACN Acetonitrile BOP ammonium 4-(3-(pyridin-3-ylmethyl)ureido)benzenesulfinate CDC13 deuterated chloroform Cs2CO3 cesium carbonate CuSO4 copper sulfate 6 chemical shift DCM dichloromethane or methylene chloride DCE 1,2-dichloroethane DEAD diethyl azodicarboxylate DIAD diisopropyl azodicarboxylate DIEA N,N-diisopropylethylamine DMA N,N-dimethylacetamide DME dimethoxyethane DMF N,N-dimethylformamide DMP Dess-Martin Periodinane DMSO dimethylsulfoxide DMSO-d6 deuterated dimethylsulfoxide dppf 1,1'-Bis(diphenylphosphino)ferrocene EDCI N-(3-dimethylaminopropy1)-N'-ethylcarbodiimide hydrochloride EDTA ethylenediaminetetraacetic acid ee enantiomeric excess Et0Ac ethyl acetate Et0H ethanol 1H NMR proton nuclear magnetic resonance HOAc acetic acid HATU 2-(3H41,2,3]triazolo[4,5-b]pyridin-3-y1)-1,1,3,3-tetramethylisouronium hexafluorophosphate HC1 hydrochloric acid HOBT 1H-benzo[d][1,2,3]triazol-1-ol hydrate HPLC high pressure liquid chromatography Hz hertz IPA isopropyl alcohol KOAc potassium acetate K2CO3 potassium carbonate LAH lithium aluminum hydride LCMS liquid chromatography/mass spectrometry (M+1) mass + 1 m-CPBA m-chloroperbenzoic acid Me0H methanol MeMgBr methyl magnesium bromide MS mass spectrometry NaB H4 sodium borohydride NaBH(OAc)3 sodium triacetoxyborohydride NaB H3 CN sodium cyanoborohydride Na2SO4 sodium sulfate NB S N-bromosuccinimide Pd(dppf)C12 [1,11-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) Palladium tetrakis Tetrakis(triphenylphosphine)palladium(0) Rt retention time TBAF tetrabutyl ammonium fluoride TBDMS-C1 Tert-butyl dimethylsilyl chloride TEA triethylamine THF tetrahydrofuran TLC thin layer chromatography Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene 2G Pd Xphos Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropy1-1,1'-bipheny1)[2-(2'-amino-1,1'-biphenyl)]palladium(II) t-butyl Xphos 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl Representative Examples Example 1: 2-({ [4-({ 3'4(44 [(2-hydroxyethyl)amino]methyl -2-methylphenoxy) methy1]-2,2'-dimethy141, 1 '-biphenyl]-3 -y1} methoxy)-3 -methylphenyl]methyl amino)ethan-1-ol (I-1).
NOH
0 0 wi HON

The compound of Example 1 was synthesized via the route shown in the scheme below.

0 0 tps.,0 >c o' 0 0 Op '0 Br HO 40 Br H2SO4, Me0H Br Pd(dppf)C12, KOAc 0 Step-1 dioxane, 110 C 111-1 Pd(dppf)C12, CsF
11-1 11-2 dioxane, 110 C 1V-1 Step-2 Step-3 H
HO "glir' 0 H
LAH, THF HO PBr3 Br 0 OH Br ______ DCM K2CO3, CH3CN
Step-4 1V-2 Step-5 1V-3 Step-6 0 1V-4 NaBH4, Et0H
Step-7 1-1 Step-1: methyl 3-bromo-2-methylbenzoate (II-2) To a solution of 3-bromo-2-methylbenzoic acid II-1 (10 g, 47 mmol) in 150 mL
of Me0H was added concentrated H2SO4 (10 mL) dropwise. The mixture was stirred at overnight. The solvent was evaporated and the remaining mixture was adjusted to pH 9 by adding saturated NaHCO3 solution. The mixture was extracted with ethyl acetate. The organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (petroleum ether : ethyl acetate = 150 : 1) to give the product as a yellow oil (10.1 g, 94%). 11-INMR (400 MHz, CDC13) 6 7.72 (d, J= 8.0 Hz, 1H),
7.69 (d, J=
8.0 Hz, 1H), 7.09 (t, J= 8.0 Hz, 7.6Hz, 1H), 3.90 (s, 3H), 2.63 (s, 3H).
Step-2: 2-methyl-3 -(4,4,5,5 -tetramethyl-1,3 ,2-di oxab orol an-2-y1) benzoate (III-1) A mixture of methyl 3-bromo-2-methylbenzoate 11-2 (3g, 13.1 mmol), 4,4,4',4',5,5,5',5'-octamethy1-2,2'-bi(1,3,2-dioxaborolane (4 g, 15.7 mmol), Pd(dppf)C12 (670 mg, 0.9 mmol), KOAc (2.6 g, 26.2 mmol) in 150 mL of dioxane was stirred at 110 C under N2 overnight. The reaction mixture was filtered and concentrated, then extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated.
The crude was purified by column chromatography (petroleum ether : ethyl acetate = 80 : 1) to give a product as a green oil (2.9 g, 81%). 11-1 NMR (400 MHz, CDC13) 6 7.86-7.82 (m, 2H), 7.22-7.21 (m, 1H), 3.88 (s, 3H), 2.74 (s, 3H), 1.36 (s, 12H).
Step-3: dimethyl 2,2'-dimethyl-[1,1'-biphenyl]-3,3'-dicarboxylate (IV-1) To a solution of 2-methyl-3-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1) benzoate III-1 (1.5 g, 5.4 mmol), methyl-3-bromo-2-methylbenzoate 11-2 (1.1 g, 4.9 mmol), CsF (2.2 g, 14.7 mmol), and Pd(dppf)C12 (250 mg, 0.07 mmol) in 40 mL of dioxane was added 10 mL
of H20. The mixture was stirred at 110 C under N2 overnight. The reaction mixture was filtered and concentrated, then extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated. The product was purified by column chromatography (petroleum ether : ethyl acetate = 80 : 1) to give a product as a green oil (1.5g, 92%). 1E1 NMR (400 MHz, CDC13) 6 7.86 (d, J= 1.6 Hz, 1H), 7.84 (d, J= 1.6 Hz, 1H), 7.29 (t, J = 7.6 Hz, 7.6 Hz, 2H), 7.24 (d, J= 1.2 Hz, 1H), 7.22 (d, J= 1.2 Hz, 1H), 3.92 (s, 6H), 2.22 (s, 6H).
Step-4: (2,2'-dimethyl-[1, 1'-biphenyl] -3 ,3 '-diy1)dimethanol (IV-2) To a solution of ester IV-1 (1.26 g, 4.2 mmol) in 50 ml of THF was added LiA1H4 (638 mg, 16.8 mmol) was added. The mixture was stirred at 0 C for five hours, then quenched with 0.6 mL H20, 0.6 mL 10% NaOH and 1.8 mL H20. The resulting mixture was filtered and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated. The product was purified by column chromatography (petroleum ether :
ethyl acetate = 10 : 1) to give the product as a white solid (831 mg, 82%).
1E1 NMR (400 MHz, CDC13) 6 7.39 (d, J= 7.6 Hz, 2H), 7.23 (d, J = 7.6 Hz, 2H), 7.07 (d, J =
7.2 Hz, 2H), 4.77 (s, 4H), 2.03 (s, 6H).
Step-5: 3,3 '-bi s(bromomethyl)-2,2'-dimethy1-1,1'-biphenyl, IV-3 To a solution of (2,2'-dimethy141,1'-biphenyl]-3,3'-diy1)dimethanol IV-2 (300 mg, 1.2 mmol) in 50 mL of dichloromethane was added PBr3 (650 mg, 2.4 mmol) dropwise at 0 C.
The mixture was stirred at 0 C overnight. It was quenched with water. The mixture was extracted with dichloromethane. The organic layer was dried over Na2SO4, filtered and concentrated. The product was purified by column chromatography (petroleum ether : ethyl acetate = 150: 1) to give the desired product IV-3 as a yellow solid (337 mg, 76%). 1E1 NMR
(400 MHz, CDC13) 6 7.35 (d, J = 7.6 Hz, 2H), 7.22 (t, J = 7.6 Hz, 7.2 HZ, 2H), 7.09 (d, J =
7.2 Hz, 2H), 4.59 (s, 4H), 2.09 (s, 6H).
Step-6: 4,4'-(((2,2'-dimethyl-[1, 1'-biphenyl] -3 ,3 '-diy1)bi s(methyl ene))bi s(oxy))bi s(3 -methyl benzaldehyde), IV-4 A mixture of 3,3'-bis(bromomethyl)-2,2'-dimethy1-1,1'-biphenyl, IV-3 (337 mg, 0.92 mmol), 4-hydroxy-3-methylbenzaldehyde (272 mg, 2.0 mmol) and K2CO3 (386 mg, 2.8 mmol) in 20 mL of acetonitrile was stirred at room temperature overnight. The mixture was concentrated and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated. The product IV-4 was obtained a yellow solid (415 mg, 95%). 1E1 NMR (400 MHz, CDC13) 6 9.88 (s, 2H), 7.74-7.73 (m, 4H), 7.48 (d, J= 7.2 Hz, 2H), 7.30 (t, J= 7.6 Hz, 7.6 Hz, 2H), 7.18 (d, J= 7.6 Hz, 2H), 7.07 (d, J= 8.0 Hz, 2H), 5.21 (s, 4H), 2.33 (s, 6H), 2.07 (s, 6H).
Step-7: 2-({ [44{3'4(44 [(2-hydroxyethyl)amino]methyl} -2-methylphenoxy)methy1]-2,2'-dimethy141,1'-biphenyl]-3-ylImethoxy)-3-methylphenyl]methylIamino)ethan-1 -ol, I-1.
A mixture of aldehyde IV-4 (100 mg, 0.21 mmol) and 2-aminoethanol (77 mg, 1.26 mmol) in 15 mL of Et0H was stirred at 85 C for 3 hours. When it cooled down to room temperature, NaBH4(32 mg, 0.84 mmol) was added at 0 C and stirred for two hours. It was quenched with 2 ml of saturated NaCl. The resulting mixture was concentrated, then diluted with dichloromethane, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (dichloromethane : methanol = 10 : 1) to give the title compound I-1 as a white solid (30 mg, 27%). 1E1 NMR (400 MHz, DMSO-d6) 6 7.49 (d, J =
7.2 Hz, 2H), 7.29 (t, J = 7.6 Hz, 7.6 Hz, 2H), 7.10 (d, J= 9.6 Hz, 6H), 7.02 (d, J= 8.0 Hz, 2H), 5.13 (s, 4H), 4.45 (t, J= 5.2 Hz, 4.8 Hz, 2H), 3.60 (s, 4H), 3.45 (dd, J=
5.6 Hz, 5.2 Hz, 4H), 2.54 (d, J= 6.0 Hz, 4H), 2.17 (s, 6H), 2.01 (s, 6H). LCMS: m/z +569.52 [M+H]t Example 2: 2- { [(4- { [3 -( { 4- [(azetidin-1-yl)methyl]-2-methylphenoxy}methyl)-2-chlorophenyl]methoxy -3 -methylphenyl)methyl] amino ethan-l-ol (I-2).
HON
WI CI = N3 The compound of Example 2 was synthesized via the route shown in the scheme below.

CI CI HO 110 (3, CI =EINH H CI
1.0 eqv.
1.1 NBS, DCM
Br Br ___________ 0 0 K2CO3, MeCN, rt NaBH3CN, Me0H
Step-1 Step-2 AcOH
IV-5 Step-3 0 ao 0 0 ao 0 Step-4 NaBH3CN, Me0H
AcOH
CI = ND

Step-1: synthesis of 1,3 -b i s(bromomethyl)-2-chlorobenzene To the solution of 2-chloro-1,3-dimethylbenzene (10 g, 71 mmol) in CC14 (200 mL) was added NB S (28 g, 157 mmol) and BOP (172 mg, 0.71 mmol). The mixture was heated to reflux for 16 hours. LC-MS indicated that the reaction was completed. The reaction mixture was cooled down, filtered, and concentrated. The residue was crystallized with hexane to give white solid (5 g, 24%).
Step-2: synthesis of 4,4'-(2-chloro-1,3-phenylene)bis(methylene)bi s(oxy)bi s(3 -methyl benzaldehyde) (IV-5) To the solution of 1,3-bis(bromomethyl)-2-chlorobenzene (200 mg, 0.67 mmol) and 4-hydroxy-3-methylbenzaldehyde (192 mg, 1.4 mmol) in acetonitrile (10 mL) was added K2CO3 (195 mg, 138 mmol). The suspended solution was stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate (50 mL), and the organic layer was washed with brine. Then the organic layer was concentrated and purified by silica gel column (Petroleum ether : ethyl acetate = 2 : 1) to give the title compound as white solid (200 mg, 73%).
Step-3: synthesis of 4-(3-((4-(azetidin-1-ylmethyl)-2-methylphenoxy)methyl)-2-chlorobenzyloxy)-3-methylbenzaldehyde (IV-6) and 1- [(4- { [3 -( { 4-[(azetidin-1 -yl)methy1]-2-methylphenoxy}methyl)-2-chlorophenyl]methoxy -3 -methylphenyl)methyl]
azetidine (I-3) To the solution of 4,4'-(2-chloro-1,3-phenylene)bis(methylene)bis(oxy)bis(3-methylbenzaldehyde) IV-5 (200 mg, 0.49 mmol) in Me0H (5 mL) was added azetidine hydrochloride (46 mg, 0.49 mmol). After stirring for 30 minutes, NaBH3CN (30 mg, 0.49 mmol) was added and the mixture was stirred for 16 hours at room temperature.
The reaction was quenched with the water, then extracted with ethyl acetate. The combined organic layer was dried, concentrated and purified by silica gel column (dichloromethane :
Me0H = 25 : 1 to 15 : 1) to give IV-6 (60 mg) and 1-3 (50 mg).
14(44 [3 -( { 4-[(azetidin-1-yl)methyl]-2-methylphenoxy}methyl)-2-chlorophenyl]methoxy }-3-methylphenyl)methyl]azetidine (I-3): 1H NMR (400MHz, ): 6 7.57 (d, J = 7.6 Hz, 2H), 7.34 (t, J = 7.6 Hz, 1H), 7.12 (s, 2H), 7.07 (d, J= 8.0 Hz, 2H), 6.84 (d, J= 7.2 Hz, 2H), 5.19 (s, 4H), 3.53 (s, 4H), 3.26 (t, J = 7.2 Hz, 8H), 2.31 (s, 6H), 2.11 (m, 4H). LCMS: m/z + 491.3 [M+H].
Step-4: synthesis of 2-{ [(4- { [3 -({4-[(azetidin-1-yl)methy1]-2-methylphenoxy}methyl)-2-chlorophenyl] methoxy -3 -methylphenyl)methyl] amino ethan-l-ol (I-2) To the solution of aldehyde IV-6 (60 mg, 0.13 mmol) in Me0H (2 mL) was added 2-aminoethanol (16 mg, 0.27 mmol). After stirring for 30 minutes, NaCNBH3 (17 mg, 0.27 mmol) was added and the mixture was stirred for 16 hours at room temperature.
Quenched the reaction with the water, and extracted with ethyl acetate. The combined organic layer was concentrated and purified by silica gel column (dichloromethane : Me0H = 10 :
1)to give 1-2 (30 mg). 1H NMR (400 MHz, CDC13): 6 7.57 (d, J = 7.6 Hz, 2H), 7.34 (t, J = 7.6 Hz, 1H), 7.14-7.05 (m, 4H), 6.84 (t, J = 7.6 Hz, 2H), 5.19 (s, 4H), 3.73 (s, 2H), 3.66 (t, J= 4.2 Hz, 2H), 3.51 (s, 2H), 3.24 (t, J= 4.2 Hz, 4H), 2.78 (m, 2H), 2.32 (s, 3H), 2.31 (s, 3H), 2.12-2.08 (m, 2H). LCMS: m/z + 495.2 [M+H].
Example 3: (2 S)-1- { [44{3'4(44 [(2S)-2-carboxypiperidin-1-yl]methyl -3,5-dimethoxyphenoxy)methy1]-2,2'-dimethyl-[1, 1'-bipheny1]-3 -ylImethoxy)-2,6-dimethoxyphenyl]methylIpiperidine-2-carboxylic acid (I-4).
COON

The compound of Example 3 was synthesized via the route shown in the scheme below.

o o o 0 COOH
H HNC.

Br HO 0 0 0 Br __________________________ 1.1 NaBH3CN, Me0H
K2CO3, DMF

COOH COOH
NigNNiN
0 411) 0 0õ, 1V-8 COOH O 1-4 Step-1: 4,4'-(2,2'-dimethylbipheny1-3 ,3 '-diy1)bi s(methylene)bi s(oxy)bi s(2,6-dim ethoxyb enzal dehy de) (IV-7) To a solution of 3,3'-bis(bromomethyl)-2,2'-dimethy1-1,1'-biphenyl, IV-3 (500 mg, 1.4 mmol), 4-hydroxy-2,6-dimethoxybenzaldehyde (497 mg, 2.7 mmol), K2CO3 (447 mg, 3.2 mmol) in 10 mL of DMF was stirred at room temperature overnight. The mixture was diluted with water, filtered to give a pale solid (600 mg, 77%). The crude was used for next step without further purification. 1E1 NMR (400 MHz, CDC13) 6 10.37 (s, 2H), 7.34-7.17 (m, 6H), 6.20 (s, 4H), 5.18 (s, 4H), 3.89 (s, 12H), 2.10 (s, 6H).
Step-2: (S)-1-(4-((3'44-formy1-3,5-dimethoxyphenoxy)methyl)-2,2'-dimethylbipheny1-3-yl)methoxy)-2,6-dimethoxybenzyl)piperidine-2-carboxylic acid (IV-8) &
(2S)- 1-{ [44{3'4(44 [(2S)-2-carboxypiperidin-1-yl]methyl -3,5-dimethoxyphenoxy)methy1]-2,2' -dimethy141, 1'-bipheny1]-3 -ylImethoxy)-2,6-dimethoxyphenyl]methylIpiperidine-2-carboxylic acid (I-4) To a solution of aldehyde IV-7 (300 mg, 0.52 mmol) in Me0H (5 mL) was added (S)-piperidine-2-carboxylic acid (68 mg, 0.52 mmol) and Cat. AcOH. After stirring for 30 minutes, NaBH3CN (32 mg, 0.52 mmol) was added and the mixture was stirred for 16 hours at room temperature. Quenched the reaction with the water, and extracted with ethyl acetate.
The combined organic layer was concentrated and purified by silica gel column (dichloromethane : Me0H = 25 : 1 to 10: 1) to give IV-8 (110 mg) and 1-4 (30 mg). 1-4: 1E1 NMR (400MHz, DMSO-d6): 6 7.50 (d, J= 7.5 Hz, 2H), 7.30 (t, J = 7.5 Hz, 2H), 7.11 (d, J =
7.5 Hz, 2H), 6.42 (s, 4H), 5.20 (s, 4H), 4.10 (s, 4H), 3.79 (s, 13H), 3.12 (s, 2H), 3.04 (s, 2H), 2.63 (s, 2H), 2.02 (s, 6H), 1.81 (s, 4H), 1.55 (s, 4H), 1.39 (s, 4H). LCMS:
m/z + 819.43 [M+Na]+.
Example 4: (2 S)- 1 - { [44{3'4(44 [(2-hydroxyethyl)amino]methyl -3,5-dimethoxyphenoxy)methy1]-2,2'-dimethyl-[1, 1'-bipheny1]-3 -ylImethoxy)-2,6-dimethoxyphenyl]methylIpiperidine-2-carboxylic acid (I-5).

COOH COOH
H2N--,0H zn NaBH3CN, Me0H HON 111111 O 0, 1V-8 To a solution of IV-8 (110 mg, 0.16 mmol) in Me0H (5 mL) was added 2-aminoethanol (20 mg, 0.32 mmol) and catalytical amount of acetic acid. After stirring for 30 minutes, NaBH3CN (20 mg, 0.32 mmol) was added and the mixture was stirred for 16 hours at room temperature. The reaction was quenched with the water, and extracted with AcOEt.
The combined organic layers were dried over anhydrous Na2SO4 and concentrated.
The residue was purified by silica gel column (dichloromethane : Me0H = 25 : 1 to 10 : 1) to give 1-5 (40 mg). 11-1 NMR (400MHz, DMSO-d6): 7.49 (d, J= 7.2 Hz, 2H), 7.29 (t, J = 7.2 Hz, 2H), 7.10 (s, 2H), 6.41 (s, 2H), 6.35 (s, 2H), 5.19 (s, 2H), 5.16 (s, 2H), 4.10 (s, 2H), 3.78 (s, 6H), 3.75 (s, 6H), 3.61 (s, 2H), 3.22-3.03 (m, 6H), 2.61 (s, 1H), 2.02 (s, 6H), 1.82 (s, 2H), 1.55 (s, 2H), 1.39 (s, 2H). LCMS: m/z + 729.45 [M+H].
Example 5: 2-G[4413'4(44 [(2-hydroxyethyl)amino]methyl} -3,5-dimethoxy phenoxy)methy1]-2,2'-dimethy141,1'-biphenyl]-3-ylImethoxy)-2,6-dimethoxyphenyl]
methylIamino)ethan-l-ol (I-6).
o o joH
=40H
OH

NaBH3CN, Me0H HON
O 0.õ w.7 10 To a solution of aldehyde IV-7 (80 mg, 0.14 mmol) in Me0H (5 mL) was added 2-aminoethanol (34 mg, 0.56 mmol) and catalyst AcOH. After stirring for 30 minutes, NaBH3CN (34 mg, 0.56 mmol) was added and the mixture was stirred for 16 hours at room temperature. The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column (dichloromethane:Me0H = 25 : 1 to 10 : 1) to give 1-6 (40 mg): lEINMR (400 MHz, CDC13) 6 7.45 (d, J= 7.4 Hz, 2H), 7.29 (t, J = 7.6 Hz, 2H), 7.15 (d, J = 7.5 Hz, 2H), 6.24 (s, 4H), 5.09 (s, 4H), 4.43 ( brs, 20H), 3.81 (s, 12H), 3.64-3.63 (m, 4H), 3.49-3.22 (m, 8H), 2.08 (s, 6H). LCMS: m/z + 683.35 [M+Na]t Example 6: 1-1[4-(13'-[(4-{[(2-hydroxyethyl)amino]methyl} -2-methyl phenoxy)methy1]-2,2'-dimethy141,1'-biphenyl]-3-ylImethoxy)-2-methoxyphenyl]methyl azetidin-3 -ol (I-7).

oJc 0 el N3OH
HON

The preparation of Intermediate (II-5): 1-(4-((3-bromo-2-methylbenzyl)oxy)-2-m ethoxyb enzyl)azeti din-3 -ol o o o 0 N
DIAD, PPh3 H a Br io OH + H ,,.. Br __________________ . Br OH
HO THF, 0 C to RT AcOH, NaBH3CN

Step-I Step-2 Step-1: 4-((3 -b rom o-2-methylb enzyl)oxy)-2-m ethoxyb enz al dehy de (II-4) H
Br I.0 Diisopropyl azodicarboxylate (1.1 mmol) in tetrahydrofuran (1.5 mL) is added dropwise to a cooled (0 C) solution of 4-hydroxy-2-methoxybenzaldehyde (1.1 mmol), triphenyl phosphine (1.1 mmol) and (3-bromo-2-methylphenyl)methanol 11-3 (1.0 mmol) in dry tetrahydrofuran (3 mL). The resulting reaction mixture is allowed to slowly warm to room temperature with stirring overnight. The product is filtered from the reaction mixture using a Buchner filter funnel and rinsed with tetrahydrofuran (approx.
3 mL) then dried in vacuo at room temperature to yield the title compound 11-4. The crude is used for next step without further purification.
Step-2: 1-(4-((3 -b rom o-2-m ethylb enzyl)oxy)-2-m ethoxyb enzyl)azeti din-3 -ol (II-5) Br 40) 1=1\..3 OH

A mixture of 4-((3-bromo-2-methylbenzyl)oxy)-2-methoxy benzaldehyde (1 mmol), azetidin-3-ol (3 mmol) and AcOH (5 mmol) in DMF is stirred at RT for 4-16 h.
Then sodium cyanoborohydride (3 mmol) is added and the mixture is stirred at RT
until reductive amination is complete (-16 h). Further purification of the crude via reverse phase preparative HPLC or normal phase column chromatography yield the desired product 11-5.
The preparation of Intermediate (III-3): 3-methy1-442-methyl-3-(4,4,5,5-tetram ethyl- 1,3 ,2-di oxab orol an-2-yl)b enzyl)oxy)b enz al dehy de B

A solution of 4-hydroxy-3-methylbenzaldehyde (1.1 mmol), triphenyl phosphine (1 . 1 mmol) and (2-methyl-3 -(4,4,5, 5 -tetramethyl- 1,3 ,2-di oxab orolan-2-yl)phenyl)methanol (1.0 mmol) in dry THF (6 mL) is cooled in an ice bath. Diisopropyl azodicarboxylate (1.1 mmol) in THF (6 mL) is added dropwise. The resulting yellow solution is allowed to slowly warm to room temperature while stirring overnight. The solvent is removed and the residue is purified on a silica column with a mixture of hexanes:ethyl acetate.
Collected fractions to afford the desired product (III-3).
The preparation of 1- [4-({ 3'-[(4- [(2-hydroxyethyl)amino]methyl phenoxy)methy1]-2,2'-dimethy141, 1 '-biphenyl] -3 -yl methoxy)-2-methoxyphenylmethyl azeti din-3 -ol (I-7) H
Na, 2nd G Pd XPhos + Br OH ______ 0 0 io 0 K3PO4, Et0H, RT

111-3 Step-1 Na =

H
OH
0= Na AcOH, NaBH(OAc)3 40 (N
0, Step-2 OH

Step-1: 4-((3'-((4-((3 -hy droxy az etidin- 1 -yl)m ethyl)-3 -methoxy phenoxy)m ethyl)-2,2'-dimethyl-[ 1,1 '-biphenyl]-3 -yl)methoxy)benzaldehyde OH

C) Tetrahydrofuran solvent and aqueous 0.5M potassium tribasic phosphate solutions were sparged with nitrogen for 15 minutes prior to dispensing for use. In a round-bottom flask charge 4-((3 '-((4-((3 -hy droxy azetidin- 1 -y pmethy 1)-3 -methoxy phenoxy)methyl)-2,2'-dimethy141,1'-biphenyl] -3 -y 1)methoxy)-3 -methy lb enzaldehy de 111-3 (1 .2 mmol), 1-(4-((3-bromo-2-methylbenzyl)oxy)-2-methoxybenzyl)azetidin-3-ol (II-5) (1.0 mmol) and 2G Pd Xphos precatalyst (0.03 mmol)(CAS number 1310584-5), add previously deoxygenated tetrahydrofuran (5 mL) and 0.5 M aq potassium phosphate, tribasic solution (5 mL, 2.5 mmol), place under nitrogen and sparged with additional nitrogen for 10 minutes. The reaction is stirred under nitrogen at room temperature for 2 days. Ethyl acetate (12 mL) is added to the reaction followed by 8 mL of brine then the reaction is partitioned in a separatory funnel. The organic extract is washed ( lx) with brine and dried over magnesium sulfate, filtered and solvent removed in vacuo using a rotary evaporator. The crude reaction product is purified by silica gel chromatography eluting with an appropriate gradient of ethyl acetate/hexanes to yield a pure title compound.
Step-2: 1-{ [44{3'4(44 [(2-hydroxyethyl)amino]methyl }
phenoxy)methy1]-2,2'-dimethyl-[1, l'-biphenyl] -3 -y1} methoxy)-2-methoxyphenyl]methyl } azeti din-3 -ol (I-7) A mixture of 4-((3 '4(44(3 -hydroxyazeti din-l-yl)methyl)-3 -methoxyphenoxy) methyl)-2,2'-dimethy141,1'-biphenyl]-3-y1)methoxy)benzaldehyde (1 mmol), 2-aminoethan-1 -ol (3 mmol) and AcOH (5 mmol) in DMF is stirred at RT for 4-16 h. Then Sodium triacetoxyborohydride (3 mmol) is added and the mixture is stirred at RT until reductive amination is complete (typically overnight). Further purification of the crude via reverse phase preparative HPLC yields the desired product 1-7.
Example 7: 2- { [(6-{ [3 -(54 [(5- { [(2-hydroxyethyl)amino]methyl} -6-methoxypyridin-2-yl)oxy]methyl } -4-methylthiophen-3-y1)-2-methylphenyl]methoxy } -2-methoxypyridin-3 -yl)methyl] amino ethan-l-ol (I-8).
o' H I I \ 0 N H
HO N

The Preparation of Intermediate (II-6): (4-bromo-3-methylthiophen-2-yl)methanol rOH ____________________________________ THF, -5 C: 3h Br OH
-5 C to rt To a solution of 4-bromo-3-methylthiophenecarboxylic acid (2 g; 0.95 mmol) in THF (20 mL) was added borane-THF complex (1M, 18.19 mL; 18.19 mmol) dropwise, at 0 C. Subsequently, the reaction mixture was stirred for 1 hour at 60 C. To this reaction mixture was added 1M HC1 (30 mL), at 0 C, and the resulting mixture was stirred at RT for 10 minutes. The resulting mixture was concentrated in vacuo and the residue was partitioned between Et0Ac and 5% aqueous NaHCO3-solution. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The product 11-6 (2.2 g;
100%) was used without further purification. (Ref: WO 2012004378).

2nd G Pd XPhos B, Br ,OH _____________________ CI 2 eqv.
HO 40 0 _.. OH
\
K3PO4, Et0H, RT HO OHCs2CO3, Pd(OAc)2 tBu-XPhos, Toluene, 80 C
111-2 114 Step - 1 Step -2 OH
rcrCI 2 eqv. 0 N
S AcOH, NaBH3CN HON N
0 0,, 0 Step-3 1-8 Step-1: (4-(3 -(hy droxym ethyl)-2-m ethyl pheny1)-3 -m ethylthi ophen-2-yl)m ethanol HO
\ OH
Tetrahydrofuran solvent and aqueous 0.5M potassium tribasic phosphate solutions were sparged with nitrogen for 15 minutes prior to dispensing for use. In a round-bottom flask charge (2-methyl-3 -(4,4,5 ,5-tetramethy 1-1,3 ,2-dioxaborolan-2-y 1)pheny 1)methanol 111-2 (1.2 mmol), (4-bromo-3-methylthiophen-2-yl)methanol (II-6) (1.0 mmol) and 2G palladium Xphos precatalyst (0.03 mmol)(CAS number 1310584-14-5), add previously deoxygenated tetrahydrofuran (5 mL) and 0.5 M aq potassium phosphate, tribasic solution (5 mL, 2.5 mmol), place under nitrogen and sparged with additional nitrogen for 10 minutes. The reaction is stirred under nitrogen at room temperature for 2 days. Ethyl acetate (12 mL) is added to the reaction followed by 8 mL of brine then the reaction is partitioned in a separatory funnel. The organic extract is washed (1x) with brine and dried over magnesium sulfate, filtered and solvent removed in vacuo using a rotary evaporator. The crude reaction product is purified by silica gel chromatography eluting with an appropriate gradient of ethyl acetate/hexanes to yield a pure title compound.
Step-2: 6-{ [3454 [(5-formy1-6-methoxypyridin-2-yl)oxy]methyl -4-methylthiophen-3 -y1)-2-methylphenyl]methoxy}-2-methoxypyridine-3 -carb aldehyde <0 0 () Cesium carbonate (4.0 mmol, 2 eqv.), palladium(II) acetate (0.2 mmol, 0.1 eqv.), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (t-butyl Xphos) (0.4 mmol, 0.2 eqv.), 6-chloro-2-methoxynicotinaldehyde (2.6 mmol, 1.3 eqv.), and (4-(3-(hydroxymethyl)-2-methylpheny1)-3-methylthiophen-2-yl)methanol (1.0 mmol, 2N) are combined in a mL round bottom flask equipped with a stir bar. Toluene (12 mL) is added and the mixture is purged with a stream of argon for 5 minutes. The reaction is sealed and heated at 80 C overnight. The soluble portion of the crude reaction is charged to a 25g silica gel column with dichloromethane and chromatographed with an appropriate gradient of ethyl acetate in hexanes. A fraction containing a compound tested positive for an aldehyde using 2,4 dinitrophenyl hydrazine stain. This aldehyde-positive fraction is isolated and used for next step reaction.
Step-3: 2- { [(6-{ [3-(5-{ [(5-{ [(2-hydroxyethyl)amino]methy1}-6-methoxypyridin-2-yl)oxy] methyl } -4-methylthiophen-3-y1)-2-methylphenyl]methoxy }

methoxypyridin-3-yl)methyl]aminoIethan-1-ol (1-8) A mixture of 64[3-(5-{[(5-formy1-6-methoxypyridin-2-yl)oxy]methyl}-4-methyl thiophen-3-y1)-2-methylphenyl]methoxy}-2-methoxypyridine-3-carbaldehyde (1 mmol, 2N), 2-aminoethan-1-ol (6 mmol, 3 eqv.) and AcOH (10 mmol, 5 eqv.) in DMF (5 mL) is stirred at RT for 4-16 h. Then sodium cyanoborohydride (6 mmol, 3 eqv.) is added and the mixture is stirred at RT until reductive amination is complete (typically overnight).
Further purification of the crude via reverse phase preparative HPLC yields the desired product 1-8.
Example 8: 2-(f [4-({4-[(4- f [(2-hydroxy ethyl)amino]methyl } -3 -methoxy phenoxy) methyl]-3-methylthiophen-2-ylfmethoxy)-2-methoxyphenyl]methylf amino)ethan-l-ol (1-9) o o o o o o HO = H
LiBH4, THF 2 eqv.
______________________ HOOH __________________ H =
H
S -40 C to 0 C S ::h3, N2(CO2CHM92) 00 11-7 Step-1 S
Step-2 o' 1;) 2 eqv.
AcOH, NaBH3CN

Step-3 S

Step-1: (3 -methylthi ophene-2,4-diy1)dimethanol HOOH
To a round-bottom flask is charged dimethyl 3-methylthiophene-2,4-dicarboxylate (1.0 mmol, 2N) and tetrahydrofuran (10 mL). The mixture is stirred until a clear solution is obtained. The solution is cooled to - 40 C and lithium borohydride (4 mmol, 2 eqv.) is added portion wise over 15 minutes. After all the lithium borohydride is added, the reaction is slowly brought to room temperature and stirred overnight. When TLC or LCMS analysis showed that the starting material is consumed, saturated aqueous ammonium chloride is charged to a multineck round-bottom flask and cooled to -(inner temperature). Added crude reaction slowly over 15 minutes. After addition is complete the temperature is maintained at - 5 C for 20 minutes. The reaction is diluted with dichloromethane (15 ml) and the layers are separated. The aqueous layer is extracted with dichloromethane (1 x 15 ml) and the combined organic portions are washed with 1.5 N aqueous hydrochloric acid (1 x 1.3 ml), saturated aqueous sodium chloride (1 x 1.3 ml) and dried over sodium sulfate. The solvent was removed under reduced pressure to give a crude product. The crude material was dissolved in minimum amount of dichloromethane and cooled in ice bath. Petroleum ether was added until white solid formed. The solid was collected by filtration, washed with petroleum ether and dried under vacuum to give the title compound. (Ref: WO 2010125102 Al) Step-2: 4-( { 4-[(4-formy1-3 -m ethoxyphenoxy)m ethyl] -3 -m ethylthi ophen-2-yl}methoxy)-2-methoxyb enzal dehyde Diisopropyl azodicarboxylate (2.2 mmol, 1.1 eqv.) in tetrahydrofuran (2.5 mL) is added dropwise to a cooled (0 C) solution of 4-hydroxy-2-methoxybenzaldehyde (2.2 mmol, 1.1 eqv.), triphenyl phosphine (2.2 mmol, 1.1 eqv.) and (3-methylthiophene-2,4-diy1)dimethanol (1.0 mmol, 2N) in dry tetrahydrofuran (6 mL). The resulting reaction mixture is allowed to slowly warm to room temperature with stirring overnight.
The product is filtered from the reaction using a Buchner filter funnel and rinsed with tetrahydrofuran (approx. 5 mL) then dried in vacua at room temperature to yield the title compound. The crude is used for next step without further purification.
Step-3: 2-({ [44{44(44 [(2-hydroxyethyl)amino]methyl} -3-methoxyphenoxy) methy1]-3-methylthiophen-2-y1 } methoxy)-2-methoxyphenyl]methyl } amino)ethan-l-ol (1-9) H N N OH

A mixture 4-({4-[(4-formy1-3-methoxyphenoxy)methy1]-3-methylthiophen-2-y1 } methoxy)-2-methoxybenzaldehyde (1 mmol, 2N), 2-aminoethan-1-ol (6 mmol, 3 eqv.) and AcOH (10 mmol, 5 eqv.) in DMF (5 mL) is stirred at RT for 4-16 h. Then sodium cyanoborohydride (6 mmol, 3 eqv.) is added and the mixture is stirred at RT
until reductive amination is complete (typically overnight). The crude is purified via reverse phase preparative HPLC to give the title compound 1-9.
Example 9: 2-({4-[(azetidin-1-yl)methyl]-2-methylphenoxy }methyl)-6-{ [4-({
[(4-oxoazetidin-2-yl)methyl] amino }methyl)phenoxy]methyl }benzonitrile (1-10) 0 I I 0 H HCI=HN 0 I I
HO NO
0 OH __ D1AD, PPh3 0 1.1 AcOH, NH4BH(0A03 0 0 11 8 THE, 0 C to RT Step-2 - Step-1 I I

_______ HO 0 NO HO I.
H
LiBH4, THF I I
' NO
-40 C to 0 C 0 0 D1AD, PPh3 Step-3 THE, 0 C to RT
Step-4 111-5 2 eqv.o o5 No AcOH, NaBH3CN
Step-3 1-10 Step-1: methyl 2-cyano-3-((4-formy1-2-methylphenoxy)methyl)benzoate A solution of 4-hydroxy-3-methylbenzaldehyde (1.1 mmol), triphenyl phosphine (1.1 mmol) and methyl 2-cyano-3-(hydroxymethyl)benzoate (1.0 mmol) in dry THF
(5 mL) is cooled in an ice bath. Diisopropyl azodicarboxylate (1.1 mmol) in THF
(5 mL) is added dropwise. The resulting yellow solution is allowed to slowly warm to room temperature while stirring overnight. The solvent is removed and the residue is purified on a silica column with a mixture of hexanes:ethyl acetate. Collected fractions to afford the desired product.
Step-2: methyl 3-((4-(azetidin-1-ylmethyl)-2-methylphenoxy)methyl)-2-cyanobenzoate 0 H = No A solution of tetramethyl ammonium triacetoxyborohydride (2.0 mmol, 2 eqv.) and azetidine hydrochloride salt (2.0 mmol, 2 eqv.) in dichloromethane (12 mL) is added to a solution of methyl 2-cyano-3-((4-formy1-2-methylphenoxy)methyl)benzoate (1.0 mmol, 1 eqv.) in dichloromethane (12 mL). The reaction mixture is stirred at room temperature overnight. The reaction is quenched by the addition of saturated sodium bicarbonate. The organic layer, is washed with saturated, aqueous sodium chloride and dried (Na2SO4). The crude residue is then purified by reverse phase preparative HPLC
using a methanol-water-TFA buffer system to yield the title compound.
Step-3: 2-((4-(azetidin-1-ylmethyl)-2-methylphenoxy)methyl)-6-(hy droxym ethyl) benzonitrile =I I NO

To a round-bottom flask is charged methyl 3-((4-(azetidin-l-ylmethyl)-2-methylphenoxy)methyl)-2-cyanobenzoate (1.0 mmol) and tetrahydrofuran (5 mL).
The mixture is stirred until a clear solution is obtained. The solution is cooled to - 40 C and lithium borohydride (2 mmol, 2 eqv.) is added portion wise over 15 minutes.
After all the lithium borohydride is added, the reaction is slowly brought to room temperature and stirred overnight. When TLC or LCMS analysis showed that all starting material is consumed, saturated aqueous ammonium chloride is charged to a multineck round-bottom flask and cooled to - 5 C (inner temperature) to which is added the crude reaction mixture slowly over 15 minutes. After addition is complete the temperature is maintained at - 5 C for 20 minutes. The reaction is diluted with dichloromethane (15 ml) and the layers are separated. The aqueous layer is extracted with dichloromethane (1 x 15 ml) and the combined organic portions are washed with 1.5 N aqueous hydrochloric acid (1 x 1.3 ml), saturated aqueous sodium chloride ( 1 x 1.3 ml) and dried over sodium sulfate. The solvent was removed under reduced pressure to give a crude product. The crude material was dissolved in minimum amount of dichloromethane and cooled in ice bath. Petroleum ether was added until white solid formed. The solid was collected by filtration, washed with petroleum ether and dried under vacuum to give the title compound. (WO 2010125102 Al) Step-4: 2-((4-(azetidin-1-ylmethyl)-2-methylphenoxy)methyl)-6-((4-formylphenoxy) methyl)benzonitrile (III-5) H I I = No 0 is 0 A solution of 4-hydroxybenzaldehyde (1.1 mmol), triphenyl phosphine (1.1 mmol) and 2-((4-(azeti din-l-ylm ethyl)-2-m ethylphenoxy)m ethyl)-6-(hy droxym ethyl)b enzonitrile (1.0 mmol) in dry THF (5 mL) is cooled in an ice bath. Diisopropyl azodicarboxylate (1.1 mmol) in THF (5 mL) is added dropwise. The resulting yellow solution is allowed to slowly warm to room temperature while stirring overnight. The solvent is removed and the residue is purified on a silica column with a mixture of hexanes:ethyl acetate.
Collected fractions to afford the desired product (III-5).
Step-5: 2-({4-[(azetidin-1-yl)methyl]-2-methylphenoxy methyl)-6- {
[4-({ [(4-oxoazetidin-2-yl)methyl ] amino I methyl)phenoxy]methyl Ibenzonitrile (I-10) A mixture 2-((4-(azetidin-1-ylmethyl)-2-methylphenoxy)methyl)-6-((4-formylphenoxy) methyl) benzonitrile (1 mmol), 4-(aminomethyl)azetidin-2-one (3 mmol, 3 eqv.) and AcOH (5 mmol, 5 eqv.) in DMF (5 mL) is stirred at RT for 4-16 h.
Then sodium cyanoborohydride (3 mmol, 3 eqv.) is added and the mixture is stirred at RT until reductive amination is complete (typically overnight). The crude is purified via reverse phase preparative HPLC to give the title compound I-10.
Examples 10 ¨ 12 ,R5 HN
H N3 Rg 0 0 AcO R5= 40 NoH, NaBH3CN Rg 111-5 1-11, 1-12 8.1-13 General procedure of reductive amination:
A mixture aldehyde (1 equiv), appropriate amine or amino acid (3 equiv) and AcOH (5 equiv) in DMF was stirred at RT for 4-16 h. Then sodium cyanoborohydride (3 equiv) was added and the mixture was stirred at RT until reductive amination is complete (typically overnight). Product was purified via preparative HPLC with the following conditions: Column: XBridge C18, 19 x 200 mm, 5-1.1m particles;
Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B:
95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 20-60% B over 30 minutes, then a 5- minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation.
Example 10: N-(2- { [(4- { [3 -( {4- [(azetidin-1-yl)methy 1]-2-methyl phenoxy}methyl)-2-cyanophenyl]methoxy}phenyl)methyl]amino}ethyl)acetamide (I-11) H N
...r. N ......,..--,. N at, H

Compound I-11 is prepared in the same manner as the general procedure described above using aldehyde (III-5) and N-(2-aminoethyl)acetamide.
Example 11: 2-({4-[(azetidin-1-yl)methyl]-2-methylphenoxy{ methyl) -64(4-{ [(2-hydroxyethyl)amino]methyl {phenoxy)methylThenzonitrile (I-12) N
HON Al H

Compound 1-12 is prepared in the same manner as the general procedure described above using aldehyde (III-5) and 2-aminoethan-1-ol.
Example 12: 2-({4-[(azetidin-1-yl)methy11-2-methylphenoxyl methyl)-6-({4-[(azetidin-1-y1)methyllphenoxyl methyl)benzonitrile (1- 13 ) N
C/N a 1 1 4N3 Compound 1-13 is prepared in the same manner as the general procedure described above using aldehyde (III-5) and azetidine hydrochloride salt.
Example 13: 2-({ [44{44(44 [(2-hydroxyethyl)amino]methyl { -3,5-dimethoxyphenoxy) methyl]-1H-indo1-1-y1{methyl)phenyl]methyl{ amino)ethan-l-ol (I-14) H so S

HN 0 OH + a H PPh3, DIAD
,.. HN Br I. ,0 HO "Ile' 0 Cs2CO3, DMF
III-5 I Step-1 Step-2 2 eqv. HON
dimh EN1,---,.,,,OH
0, 110 N I. ,0 H
N ¨
AcOH, NaBH3CN 0 0 w 0 Step-3 1-14 Step-1: 441H-indo1-4-yl)methoxy)-2,6-dimethoxybenzaldehyde o O 1 is HN

A solution of 4-hydroxy-2,6-dimethoxybenzaldehyde (1.1 mmol), triphenyl phosphine (1.1 mmol) and (1H-indo1-4-yl)methanol (1.0 mmol) in dry THF (5 mL) is cooled in an ice bath. Diisopropyl azodicarboxylate (1.1 mmol) in THF (5 mL) is added dropwise. The resulting yellow solution is allowed to slowly warm to room temperature while stirring overnight. The solvent is removed and the residue is purified on a silica column with a mixture of hexanes:ethyl acetate. Collected fractions to afford the desired product.
Step-2: 441-(4-formylbenzy1)-1H-indol-4-yl)methoxy)-2,6-dimethoxy benzaldehyde lel 0 I. 0 NaH (1 mol equiv) is dissolved in anhydrous DMF (5 mL/mmol) under argon and cooled to 0 C. To this mixture is added 4((1H-indo1-4-yl)methoxy)-2,6-dimethoxy benzaldehyde (1 mol equiv) dissolved in anhydrous DMF (3 mL/mmol). The reaction is stirred for 15 min at 0 C followed by the addition of 4-(bromomethyl) benzaldehyde (1 mol equiv) in anhydrous DMF (2 mL/mmol). The reaction is stirred for 2 h at 70 C
and then quenched by the addition of H20 (30 mL). The organic products are extracted with Et0Ac (3 x 30 mL), washed with H20 (2 x 30 mL), brine (15 mL), dried over Na2SO4, filtered and concentrated in vacuo to yield the title compound.
Step-3 :2-({ [44{4- [(4- { [(2-hydroxyethyl)amino]methyl } -3,5-dimethoxyphenoxy)methyl] -1H-indo1-1 -y 1 } methy 1)phenyl] methy 1 }
amino)ethan-l-ol (I-14).

HN

A mixture 441-(4-formylbenzy1)-1H-indol-4-yl)methoxy)-2,6-dimethoxy benzaldehyde (1 mmol), 2-aminoethan- 1 -ol (3 mmol, 3 eqv.) and AcOH (5 mmol, 5 eqv.) in DMF (5 mL) is stirred at RT for 4-16 h. Then sodium cyanoborohydride (3 mmol) is added and the mixture is stirred at RT until reductive amination is complete (typically overnight). The crude is purified via reverse phase preparative HPLC to give the title compound 1-14.

Example-14: 2-({[4-({ 1-[(4-{[(2-hydroxyethyl)amino]methyl} phenyl)methy1]-1H- indazol-4-y1} methoxy)-2,6-dimethoxyphenyl] methy 1 } amino)ethan- 1 -ol (I-15) HON OH
N
rsi Compound 1-15 is prepared in the same manner as the procedure described for I-14 except using (11-14ndazo1-4-y1)methanoi (III-6) and azetidine hydrochloride salt.
Example-15: 2,6-bis[(4-{[(2-hydroxyethypamino]methy1}-3-methoxyphenoxy)methyl] benzonitrile, 1-16 o 0 I I H
0 II 0 LIBH4, THF HO so -o ,o HO ______________________ OH
e -40 C to 0 C 0 DIAD, PPh3 0 0 Step-1 THF, 0 C to RI
Step-2 2 eqv.
AcOH, NaBH3CN 0 io 0 0 Step-3 The detailed procedures for step1-3 are described in Example 9.
Example-16: preparation of compound 1-17, 1-18, 1-19, 1-20 and 1-21.
HO-ArCHO NHRR', 2 eqv.
2 eqv.
Br K2CO3AcCN
Br _______________________ OHCAr'o ArCHO ____ NaBH3CN, Me0H
, , RT or heat R'RNH2CAr oArCH2NRR
1-17, 1-18, 1-19, 1-20 & 1-21 Standard protocol for alkylation:
A mixture of 3,3'-bis(bromomethyl)-2,2'-dimethy1-1,1'-biphenyl, IV-3 (1.0 mmol), an appropriate hydroxy-aryl aldehyde(phenols) (2.17 mmol) and K2CO3 (2.5 mmol) in 20 mL of acetonitrile (or DMF) is stirred at room temperature or elevated temperature for 16 h. The mixture was concentrated and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product is subjected purification by normal column chromatography or reversed phase HPLC.

Standard protocol for reductive amination:
A mixture of aldehyde (1.0 mmol, 2N) and an appropriate amine (6.0 mmol, 3 eqv) in 60 mL of Et0H was stirred at 85 C for 3 hours. When it cooled down to room temperature, NaBH3CN (6 mmol, 3 eqv) was added at 0 C and stirred for two hours. It is quenched with 2 ml of saturated NaCl. The resulting mixture is concentrated, then diluted with dichloromethane, dried over Na2SO4, filtered and concentrated. The crude product is purified by column chromatography (dichloromethane : methanol ) to give the title compound 1-17-21.
Example-17: preparation of compound 1-22, 1-23, 1-24 and 1-25.
o o o 0 N I NH
HO OH 2eqv. CI 0 NHRR', 2 eqv.
I I
_________________________________________ HyrN1 Cs2CO3, Pd(0A02, NaBH3CN, Me0H
IV-2 tBu-XPhos,Toluene, 80 C 0 IV-9 N

1-22, 1-23, 1-24 & 1-25 Standard protocol for C-0 coupling reaction:
Cesium carbonate (4.0 mmol, 2 eqv.), palladium(II) acetate (0.2 mmol, 0.1 eqv.), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (t-butyl Xphos) (0.4 mmol, 0.2 eqv.), 6-chloro-2-methoxynicotinaldehyde (2.6 mmol, 1.3 eqv.), and (2,2`-dimethyl-[1,1`-biphenyl]-3,3'-diyi)dimethano1 IV-2 (1.0 mmol, 2N) are combined in a 25 mL
round bottom flask equipped with a stir bar. Toluene (12 mL) is added and the mixture is purged with a stream of argon for 5 minutes. The reaction is sealed and heated at 80 C
overnight. The soluble portion of the crude reaction is charged to a silica gel column with dichloromethane and chromatographed with an appropriate gradient of ethyl acetate in hexanes. A fraction containing a compound tested positive for an aldehyde using 2,4 dinitrophenyl hydrazine stain. This aldehyde-positive fraction is isolated and used for next step reaction.
Next step is followed by a standard protocol for reductive amination described for I-17 to 1-21.
Example-18: 2-({ [44{3'4(4- { [(2-hydroxyethyl)amino]methyl } -3,5-dimethoxyphenoxy) methyl]-2'-methyl41,1'-biphenyl]-3 -yl} methoxy)-2,6-dimethoxyphenyl] methy 1 } amino) ethan- 1 -o 1, 1-26.

0 0(ii I LAH, THF Ho C1 i B(OH)2 Br 0 Pd(dppf)C12, KOAc dioxane, 1 1 0 C 0 Step-2 OH
111-4 11-2 Step-1 IV-1O 1V-11 110 0 40 __________ PBr3 Br Ho s: 0 NaCN2BeHciv3;Et0H
Br __________________________ DCM K2CO3, CH3CN
0 0 Step-3 1V-12 Step-4 IV-13 Step-5 HON

Step-1. di m ethyl 2-m ethyl-[ 1, 1 Lbipheny1]-3,3 `-dicarb oxylate (IV-10) To a solution of (3 -(methoxycarbanyl) phenyl)boronic acid 111-4 (1.10 mmol), methyl-3-bromo-2-methylbenzoate 11-2 (1.0 mmol), CsF (3.0 mmol), and Pd(dppf)C12 (0.02 mmol) in 8 mL of dioxane is added 2 mL of H20. The mixture is stirred at 110 C
under N2 overnight. The reaction mixture is filtered and concentrated, then extracted with ethyl acetate.
The organic layer is dried over Na2SO4, filtered and concentrated. The product is purified by column chromatography (petroleum ether: ethyl acetate) to yield title product IV-10.
Step-2: (2-methyl -[1 , 1 '-biphenyl]-3,3'-diy1)di m ethanol (IV-!!) To a solution of dimethyl 2-methy141, l'-bipheny1]-3,3'-dicarboxylate, IV-10 (1.0 mmol) in 12 ml of THF was added LiA1H4 (4.0 mmol) is added. The mixture is stirred at 0 C
for five hours, then quenched with 0.15 mL H20, 0.15 mL 10% NaOH and 0.45 mL
H20.
The resulting mixture is filtered and extracted with ethyl acetate. The organic layer is dried over Na2SO4, filtered and concentrated. The product was purified by column chromatography (petroleum ether/ethyl acetate) to yield the title molecule IV-11.
Step-3: 3,3-bis(bromomethyl)-2-methyl-1 , 1 -biphenyl, IV-12 To a solution of (2-methyl-[1,1`-bipheny1]-3,3'-diyi)dimethano1 IV-!! (1.0 mmol) in 40 mL of dichloromethane is added PBr3 (2.0 mmol) dropwise at 0 'C. The mixture is stirred at 0 C overnight. It is quenched with water. The mixture was extracted with dichloromethane.
The organic layer is dried over Na2SO4, filtered and concentrated. The product is purified by column chromatography (petroleum ether: ethyl acetate) to give the desired product IV-12.

Step-4&5: follow the standard alkylation and reductive amination procedures described for Example-16 to yield the title compound 1-26.
Example-19: 3,3'-bis({ [(5- { [(2-hydroxy ethyl)amino]methyl } -6-methoxy pyridin-2-y 1)oxy ]methyl })-[1,1'-bipheny1]-2-carbonitrile, 1-30.

0 CN 0 CN LIBH4, MeON

__________________________________ 0 0 B(OH)2 + Br so Pd(dppf)Cl2, KOAc HO OH 0 1-2h, rt dioxane, 110 C
111-4 11-9 Step-1 1V-14 Step-2 IV-15 I H2N..---....õOH CN
r)o) 0 1 H
CI CN N 2 eqv.
,¨
Cs2CO3, Pd(OAc)2, N NaBH3CNEt0H HON

Step-4 1-30 tBu-XPhos,Toluene, r Step-3 Step-1: dimethyl 2-cyano41,1'-bipheny11-3,3'-dicarboxylate (IV-14) To a solution of (3-(methoxycarbony1) phenyl)boronic acid 111-4 (1.10 mmol), methyl 3-bromo-2-cyanobenzoate 11-9 (1.0 mmol), CsF (3.0 mmol), and Pd(dppf)C12 (0.02 mmol) in 8 mL of dioxane is added 2 mL of H20. The mixture is stirred at 110 C under N2 overnight.
The reaction mixture is filtered and concentrated, then extracted with ethyl acetate. The organic layer is dried over Na2SO4, filtered and concentrated. The product is purified by column chromatography (petroleum ether: ethyl acetate) to yield title product IV-14.
Step-2: 3,31-bis(hydroxymethy1)41,11-bipheny1]-2-carbonitri1e (IV-15) To a solution of LiB114 (5-10 mmol) in Me0H (6 trit) is added dimethyl 2-cyano-[1,]'-bipheny1]-3,3'-dicarboxylate EV44 (1.0 nmtol), The resulting mixture is stirred at rt. A
TLC or LCMS analysis is conducted after 1 hour. When TLC/LCMS analyses indicate that the starting material is consumed, the solvent is removed in vacuo. The residue is dissolved in DCM (20 mL) and washed with H20 (10 mL), The organic layer is dried over Na2Sa4, filtered and concentrated to afford the desired alcohol IV45, Step-3: 3,3'-bis(45-formy1-6-methoxypyridin-2-yl)oxy)methyl)-[ 1, 1 I-biphenyl:I-2-carboni tiil e, IV-16 Cesium carbonate (4.0 mmol, 2 eqv.), palladium(II) acetate (0.2 mmol, 0.1 eqv.), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (t-butyl Xphos) (0.4 mmol, 0.2 eqv.), 6-chloro-2-methoxynicotinaldehyde (2.6 mmol, 1.3 eqv.), and 3,3'-bis(hydroxymethyl)-[1,17-bipheny1]-2-carbonitrile IV-15 (1.0 mmol, 2N) are combined in a 25 mL
round bottom flask equipped with a stir bar. Toluene (12 mL) is added and the mixture is purged with a stream of argon for 5 minutes. The reaction is sealed and heated at 80 C
overnight. The soluble portion of the crude reaction is charged to a silica gel column with dichloromethane and chromatographed with an appropriate gradient of ethyl acetate in hexanes. A fraction containing a compound tested positive for an aldehyde using 2,4 dinitrophenyl hydrazine stain. This aldehyde-positive fraction is isolated and used for next step reaction.
Step-4: follow the standard reductive amination procedures described for Example-16 to yield the title compound 1-30.
Example-20: 3,3'-bis[(4-{ [(2-hydroxyethyl)amino]methyl } -3,5-dimethoxyphenoxy)methyl] -[1,1 '-biphenyl] -2- carbonitrile, 1-31.

PBr3 Br Br 0 411 0 DCM K2CO3, DMF = 0 1V-15 Step-1 P/-17 Step-2 0 0 1V-18 2 eqv. 0 0 NaBH3CN, Et0H HON
Step-3 0 Step-1: 3,3'-bis(bromomethy1)41,1`-biphenyl]-2-carbonitrile, IV-17 To a solution of 3,31-bis(hydroxyrnethy1)[1,1'-bipheny1]-2-carbonitrile IV-15 (1.0 mmol) in 40 mL of dichloromethane is added PBr3 (2.0 mmol) dropwise at 0 C.
The mixture is stirred at 0 C overnight. It is quenched with water. The mixture is extracred with dichloromethane. The organic layer is dried over Na2SO4, filtered and concentrated. The product is purified by column chromatography (petroleum ether/ethyl acetate) to give the desired product IV-17.
Step-2: 3,3'-bis((4-formy1-3,5-dimethox3,Thenoxy)methyl)-[1,1'-bipheny1]-2-carbonitrile, IV-18 A mixture of 3,3`-bis(bromomethy1)41,11-bipheny11-2-carbonitri1e, IV-17 (1.0 mmol), 4-hydroxy-2,6-dimethoxybenzaldehyde (2.17 mmol) and K2CO3 (2.5 mmol) in 7 mL
of DMF
is stirred at room temperature (or at 60-80 'C) for 16 h. The mixture is concentrated and extracted with ethyl acetate. The organic layer is dried over Na2SO4, filtered and concentrated. The crude product is subjected purification by normal column chromatography or reversed phase HPLC to yield the desired product IV-18.

Step-3: 3,3'-bis[(4-{[(2-hydroxyethyl)amino]methy1}-3,5-dimethoxyphenoxy)methyl] 41,1'-bipheny1]-2-carbonitrile, 1-31.
III
OH
o HON
C) To a solution of aldehyde IV-18 (1.0 mmol) in Me0H (30 mL) is added 2-aminoethanol (4.0 mmol) and acetic acid (0.5 mmol). After stirring for 30 minutes, NaBH3CN (4.0 mmol) is added and the mixture is stirred for 16 hours at room temperature.
The reaction is quenched with the water, and extracted with AcOEt. The combined organic layers is dried over anhydrious Na2SO4 and concentrated. The residue is purified by silica gel column (dichloromethane/ Me0H) to give the title compound 1-31.
The following compounds, I-32--I-49 (in Table 1) are prepared in the same mannar as Example 18-20 from appropriate aldehyde intermediates and amines to provide the title compounds.
The compounds listed in Table 1 are prepared using methods similar to those described for the preparation of I-1 to 1-31.
Table 1 2-(1[4-(134(4-1[(2-tiNOH
hy droxy ethy Damino] methy11-2 -I-1 methylphenoxy)methy1]-2,2'-dimethy141,1'- 0 biphenyl] -3 -y1 1methoxy)-3 - 0 N
methy 'phenyl] methyllamino)ethan- 1-01 HO
2-{ 1(4-1 13 -(144(azetidin- 1 -yemethyl] -2 -CI NO

methylphenoxylmethyl)-2-chlorophenyl] methoxy 1 -3 - o o methy 1pheny Dmethyl] amino lethan- 1-01 14(4-1 13 -(144(azetidin- 1 -yemethyl] -2-methylphenoxylmethyl)-2- C/N N
1-3 io op o chlorophenyl] methoxy 1 -3 - 0 0 methy 1pheny Dmethyl] azetidine (2 S)-1-114-(13'4(4-11(2 S)-2- COOH
carboxypiperidin-1-yl]methy11-3,5-dimethoxyphenoxy)methy1]-2,2'-climethyl- oI o Nc ., oI
11,F-biphenyl] -3 -y1 1methoxy)-2,6-dimethoxyphenyl]methyllpiperidine-2-carboxylic acid COOH 0 (2S)-1-{ [44134(4-1 [(2- o COOH
hy droxy ethy Damino] methy11-3 ,5-dimethoxyphenoxy)methyl] -2,2'-climethyl- \ 41 0 L''''' nil Iii-[1,F-biphenyl] -3-ylImethoxy)-2,6- H

I
dimethoxyphenylimethyllpiperidine-2- HON
carboxylic acid o o 2-(1 [44134(4-1 [(2-hy droxy ethy Damino] methy11-3,5-1-6 dimethoxyphenoxy)methy1]-2,2'-climethyl- o 0 H
H

I
[1,F-biphenyl] -3-ylImethoxy)-2,6- HON
dimethoxyphenyl]methyllamino)ethan-l-ol lo, 1-1 [44134(4-1 [(2- 0 hy droxy ethy Damino] methy11-2-I-7 methylphenoxy)methy1]-2,2'-dimethyl-[1,1'- 0 0 Na biphenyl] -3-ylImethoxy)-2- H

OH
methoxyphenyl] methyl 1 azeticlin-3-ol HON
2-11(6-11345-11(5-11(2- 0' hy droxy ethy Damino] methy11-6-&N -- NOH
methoxypyridin-2-yDoxy]methy11-4- 0 methy lthiophen-3 -y1)-2- N 0 ,.r S
methy 'phenyl] metho xy 1-2 -metho xypy ridin-3 - HO N
yOmethyl] aminolethan-1 -ol 0 2-(1[4-(144(4-1[(2- HON 0 0 NOH
hydroxy ethypam inolm ethyl} -3 -H H
1-9 methoxyphenoxy) methy11-3-methylthiophen-2-ylImethoxy)-2- 00 m ethoxyphenyllm ethyl} am ino)ethan-1 -ol S
2 -(14- Razetidin- 1 -yl)m ethyl] -2 - N
methylphenoxy 1 m ethyl)-6-1 [4-({ [(4- 0 NO
I. N
ii I-10 oxoazetidin-2-0 1.-ral H
yl)m ethyl] am inolm ethyl)phenoxylm ethyl} 0 10 0 benzonitrile H N
N-(2-{ (4-{[ [3 -(144(azetidin- 1 -yl)m ethyl] -.IN'=NI 40 2 -m ethy 1phenoxy 1m ethyl)-2 - H I I 0 N3 cy anophenyl] m ethoxy 1 0 0 0 pheny Dm ethyl] am inolethypacetam ide N
2 -(14- Razetidin- 1 -yl)m ethyl] -2 - HON 0 I I
m ethy 1phenoxy }methyl)-6-{(4- 1 [(2 - H
1-12 00) N3 hydroxyethypam inolm ethyl 1 phenoxy)m eth 0 0 0 yllbenzonitrile N
2 -(14- Razetidin- 1 -yl)m ethyl] -2 - r' 1-13 m ethylphenoxy 1 methyl)-6-(14-[(azetidin- '----/N 0 H 0 NO
1 -yl)m ethyllphenoxy 1 methyl)benzonitrile 0 110 0 o 241[44144R4-W2-OH
hydroxyethypam ino]m ethyl} -3,5- ¨

N
dim ethoxyphenoxy)m ethy1]-1H-indo1-1 -yl 1methyl)phenyl]methyl 1 amino)ethan- 1 -ol 0 0 0 I

2-(1[4-(114(4-1[(2- HON s N_ 401 N H
hydroxyethypam ino]m ethyl} phenyl)m ethyl NI H
] -1 H-indazol-4-y1 1methoxy)-2,6-. 0 0 dim ethoxyphenylim ethyl} am ino)ethan-1 -ol I

N
2,6-bis [(4-1[(2- H 0 N am 1 1 0 N..--,õ,..OH
1-16 hydroxyethypamino]methy11-3- H H
methoxyphenoxy)methyl]benzonitrile 0 10 0 0 I
N-R4-1[3'414- o [(cyclopropylam ino)m ethy1]-3,5 - NA
o1 0 H
dim ethoxyphenoxylm ethyl)-2,2'-dim ethyl- o 1-17 o oI
[1,1'-biphenyl] -3 -ylim ethoxy1-2,6- Oil dim ethoxyphenyl)m ethyl] cycloprop anam in v,' o e o N4(4-{ [3'4{4-Rcyclopropylam ino)m ethy1]-3,5 -40 ril 1-0 dim ethoxyphenoxylm ethyl)-2,2'-dim ethyl- o 0 [1,1'-biphenyl] -3 -ylim ethoxy1-2,6-N
dim ethoxyphenyl)m ethyl] cyclopropanam in e 0 2-R16+3'-11(5-11(2-hydroxyethypamino]methyllpyridin-2-I-19 yl)oxy]methy11-2,2'-dimethyl-[1,1'- 0 1 1 H
CY
H I -I
biphenyl] -3 -yl)m ethoxy]pyridin-3 - N N
HO
yllmethypamino]ethan-1-ol (3R)-1-1 [4-(13'-[(4-1[(3R)-3-hydroxypyrrolidin-l-yl]methy11-2- HO
1-20 m ethylphenoxy)m ethyl] -2,2 '-dim ethyl- 0 0 NQ
[1,1'-bipheny1]-3-yllmethoxy)-3- o =0 OH
methylphenyl]methyllpyrrolidin-3-ol o (2R,4R)-1 -{ [4-(13'-[(4-1[(2R,4R)-2-Nt...0 H
carboxy-4-hydroxypyrrolidin-1 -ylim ethyll-2 -m ethylphenoxy)m ethyl] -2,2 '-dim ethyl- HO
1-21 o i [1,1'-bipheny1]-3-yllmethoxy)-3-r o ISI
OH
methylphenyl]methy11-4-hydroxypyrrolidine-2-carboxylic acid HO-40 o 2-R16+3'-11(5-11(2-hydroxyethypam ino]m ethy11-6- N ...-K.,,..-^,N.---,...õ-OH
methoxypyridin-2-yl)oxy]methy11-2,2'- 0 ,U H

dim ethyl- [1,1'-biphenyl] -3 -yl)m ethoxy] -2 - H I 1 m ethoxypyridin-3 -y1 Imethypam ino]ethan- HON.......õ..ThN
1 -ol (:) N-124(16-[(3'-{[(5-1[(2- o H
acetamidoethypaminomethy11-6- ] ...õN
methoxypyridin-2-yl)oxy]methy11-2,2'-1-23 o dim ethyl- [1,1'-bipheny1] -3 -yl)m ethoxy] -2 -methoxypyridin-3-H
yllm ethypam ino] ethyl} acetam ide o (2R,4R)- 1-({6-{(3'-{ [(5 -1 R2R,4R)-2- o 0 OH
N":"
carboxy-4-hydroxypyrrolidin- 1 -yllm ethyl 1-Ni...
6-m ethoxypyridin-2-ylioxylm ethyl} -2,2'- HO I t 1-24 o dim ethyl- 111,1 '-bipheny11-3 -ylim ethoxy] -2-.\N OH
methoxypyridin-3-y1lmethy1)-4-hydroxypyrrolidine-2-carboxylic acid o HO AO
(2R,4R)-4-hydroxy- 1-({64(3'-{ [(5-1 R2- o 0 OH
hydroxyethypam inolm ethyl} -6-m ethoxypyridin-2-ylioxylm ethyl }-2,2'-1-25 o dim ethyl- [1, 1 '-bipheny11-3 -ylim ethoxy] -2- H I 1 0 OH
methoxypyridin-3-yllmethyppyrrolidine-2- HON............--yN
carboxylic acid o o 241[4413'4(4-{ (2-hydroxyethypam inolm ethyl} -3 ,5-O o An N....-..,,OH
H
1-26 dim ethoxyphenoxy)m ethy11-2'-m ethy141, l'-1W o o H I
biphenyl] -3 -yl 1m ethoxy)-2,6- HON
dim ethoxyphenyllm ethyl} am inoiethan- 1 -ol o, o 2-[(14-[(2-13-[(4-1[(2-hydroxyethypam inolm ethyl} -3,5- I 1 INI 0 N
OH
H
1-27 dim ethoxyphenoxy)m ethy11-2- 0 0 0 .--m ethylphenyl Ipyridin-4-ylim ethoxy] -2,6-HON
dim ethoxyphenyl} m ethyliam ino] ethan- 1 -ol O
oci 2-[(14-[(2-13-[(4-1[(2-hydroxyethypam inolm ethyl} -3 ,5-ol I An N ---..,,OH
H
1-28 dim ethoxyphenoxy)m ethy11-2- 0 N---m ethylphenyl Ipyridin-4-ylim ethoxy] -2,6- HON =
dim ethoxyphenyl} m ethyliam ino] ethan- 1 -ol o, o 2-({ [4-(12'-ch1oro-3 '- [(4-{ [(2-hydroxyethypam inolm ethyl} -2- I a am N.--......õ.=OH
H
1-29 m ethylphenoxy)m ethyl] 41, l'-biphenyl] -3 - 0 0 H
1r 0 0 yllmethoxy)-3-HON
m ethylphenyllm ethyl I am ino)ethan- 1-01 O
o 3,3'-bis(1[(5-{[(2-hydroxyethypam inolm ethyl} -6- o I H
1-30 1 o m ethoxypyridin-2-ylioxylm ethyl 1)- [1, 1'-F1;11 I 'N
biphenyl] -2-carbonitrile Ho o, o N
3 ,3'-bis [(4-{ [(2- I I
.....,...oH
o1 hydroxyethypam inolm ethyl} -3 ,5-o 1-31 o 14 ?
dim ethoxyphenoxy)m ethyl+ [1, 1'- H
IW
biphenyl] -2-carbonitrile HON
I:) 3,3'-bis(1[(5-{[(2- N
hydroxyethypam inolm ethyl} pyridin-2- I H

ylioxylmethyll)41,1'-bipheny11-2- H() 0 carbonitrile HO"..---N ,..-N

o N
I I
3,3 '-bis({4- Razetidin-1 -yl)m ethyl] -3,5 -O o 0 No 1-33 dim ethoxyphenoxy I m ethy1)41,1'-biphenyl] -2-carbonitrile C\N 1W 0 01 1:) o N
3,3 '-bis (14- [(3 -hydroxyazetidin-1 - I I
oI Na yl)m ethyl] -3,5 - HO

dim ethoxyphenoxy I m ethy1)41,1'- a C\N II
biphenyl] -2-carbonitrile o, o N
3,3'-bis(1[3,5-dimethoxy-4-(1[(4- I I
O o am N
oxo azetidin-2-H F--- in.**'Cio H
yl)m ethyl] am ino I m ethyl)phenoxylm ethyl} ) o..__INI-1 N 50 ?
-[1,1'-biphenyl] -2-carbonitrile o, 3,3'-bis[(4-1[(2- N
I I
.....,,OH
hydroxyethypam inolm ethyl} -2-1-36 o m ethylphenoxy)m ethyl] -[1,1'-biphenyl] -2-H
IW 0 el carbonitrile HON
N-124(16-[(2'-cyano-3'-{ [(5-1[(2- 'o acetamidoethypaminolmethy11-6- II H
m ethoxypyridin-2 -ypoxylm ethyl I 41,1 1-37o o ' biphenyl] -3 -yl)m ethoxy] -2 -)1 H 1 NN ' m ethoxypyridin-3 - H 0 ylImethypaminolethyllacetamide 2-[(4-1 [(2-hydroxyethy1)am inolm ethyl I - N o 1 I I Ai N.,.......õ,OH
3,5 -dim ethoxyphenoxy)m ethyl] -6- {4- [(4- N
I H
1-38 1 [(2 -hydroxyethypam inolm ethyl I -3,5- o o ...--H 110 0 ?
dim ethoxyphenoxy)m ethyllpyridin-2-HO.....-...õ.N
yl I benzonitrile o, 2 - [(4-1 [(2 -hydroxyethypam inolm ethyl I -2-N
m ethylphenoxy)m ethyl] -6-14-[(4-1 [(2-N
1-39 hydroxyethypam inolm ethyl} -2- 40 0 I .... 0 40 ' methylphenoxy)methyllpyridin-2- H
HON
yl I benzonitrile o 2-1 [(5-1 [(2-hydroxyethypam inolm ethyl I -6- N
m ethoxypyridin-2 -ypoxylm ethyl I -6-(4- N I H
1-40 1 [(5 -1 [(2 -hydroxyethypam inolm ethyl} -6- ,,,, o H I
m ethoxypyridin-2 -ypoxylm ethyl I pyridin- HON
2-yl)benzonitrile o, 24(144(2-134(4-{[(2-hydroxyethypam inolm ethyl} -2-, I N
An N.....-..,,OH
H
1-41 m ethylphenoxy)m ethyl] -2 - 0 H
methylphenyl I pyridin-4-yl)m ethoxy] -3 - HON
methylphenyl I m ethypam inolethan-1 -ol N
3,3'-bis(111(5-{11(2-hydroxyethypam inolm ethyl} pyridin-2 - I H
1-42 o o y1)oxylmethy11)41,1'-bipheny1l-2,2'- H I -I
N.,........-..,....,N
dicarbonitrile HO' I I
N

N
3 ,3 '-bis [(4-{ 11(2- I i N...--.,....õ-OH
hydroxyethypam inolm ethyl} -2-S1-43 o m ethylphenoxy)m ethyl] 4 1, 1-biphenyl]- H
0 lei H
2,2'-dicarbonitrile HON
INI
N
3 ,3 '-bis [(4-{ 11(2-H
1-44 hydroxyethypam inolm ethyl}
phenoxy)m eth 0 o o WI
H
y1] 4 1, 1'-bipheny11-2,2'-dic arbonitrile HON
INI
N
5,5'-bis[(4-{[(2-hydroxyethypam inolm ethyl} -2-1-45 0 ..., .....
0 wi m ethylphenoxy)m ethyl] 43 ,3'-bipyridine] - H I , 4,4'-dicarbonitrile HON
Ni I N
24(144(3-154(4-{11(2- 0--hydroxyethypam inolm ethyl} -3,5- I
.."........,OH
dim ethoxyphenoxy)m ethy11-4- 0 1 0 m ethylthiophen-3 -yll -2- IW \ = o il HON S
m ethylphenyl)m ethoxy] -2,6- 1 dim ethoxyphenyl} m ethypam ino] ethan- 1 -ol 24(144(4-134(4-{11(2-hydroxyethypam inolm ethyl} -2-3 -m ethylthiophen-2-yl)m ethoxy1-3 - HON
m ..."..,...0F1 1-47 m ethylphenoxy)m ethyl] -2 -m ethylphenyl} - is 0 H 1 \ 0 = il s m ethylphenyl 1m ethypam inolethan- 1-01 2-(1[4-(15'4(4-{[(2-/......./OH
hydroxyethypam inolm ethyl} -2- N

1-48 m ethylphenoxy)m ethyl] -4,4'-dim ethyl- s \
[3,3 '-bithiophene] -5 -y1 1 m ethoxy)-3 - H 110 \
m ethylphenyllm ethyl I am ino)ethan- 1-01 HON
2-(1[4-(15'4(4-{[(2-/......./OH
N
hydroxyethypam inolm ethyl} -2-, I * H
1-49 m ethylphenoxy)m ethyl] - 1,1 '-dim ethyl-1H, 1 'H112,2'-bipyrrole] -5 -y1 1 m ethoxy)-3 - H \OI "N".."--"-cN----// o i m ethylphenyllm ethyl I am ino)ethan- 1-01 HON
Exam ple-21:
5-[(5-{ [3 '-({ 5-[(5-cyanopyridin-3-yl)methoxy]-4-{ [(2-hydroxyethyl) amino]methy1}-2-methylphenoxy}methyl)-2,2'-dimethy141,1'-biphenyl]-3-yl]methoxy 1 -2-{ [(2-hydroxyethyl)amino]methy1}-4-methylphenoxy)methyl]pyridine-3-carbonitrile, 1-50.

NC
1:11 OHO

HO Cs 0 HO 0 110 OH __ 2CO3, DMF, PPh3, DIAD 0 75 C, 2h 0 THF, 0 C to rt 0 OH

Step-2 Step-1 NCr7 NC
XO
gilr&
H2N**. H 0 2 eqv. 0 WI
NaBH3CN, Et0H HO
Step-3 N
Step-1: 4,4`-(02,21-dimethy14 I , l'-biphenyl]-3 s(methylene))bi s(oxy))bi s(2-hydroxy-5-methyl benzaidehyde), A mixture of 2,4-dihydroxy-5-methylbenzaldehyde (2.2 mmol), triphenylphosphine (2.2 mmol) and (2,2'-dimethy141,1'-biphenyl]-3,3'-diy1)dimethanol (1.0 mmol) is dissolved in dry tetrahydrofuran (14 mL) and cooled to 0 C.
Diisopropyl azodicarboxylate (2.2 mmol) in tetrahydrofuran (14 mL) is added dropwise. The resulting yellow solution is allowed to slowly warm to room temperature overnight. Solvent is removed by rotary evaporator. The crude is purified with an eluent (hexanes:ethyl acetate) on a silica gel column to afford the desired product, IV-19.
Step-2: 5,5'-(4(42,2'-di m ethyl- [ I , -bipli eny1]-3 `-diy1)bi s(rne thy]
ene))bi s(oxy))-bis(6-formy14-methyl-3, I -phenylene))bis(oxy))bis(methylene))dinicotinonitrile, 1V-20 Cesium carbonate (3.0 mmol), 4,4(((2,T-dimethyl4 I '-bipheny1i-3 ,3'-diyi )bis(methylene))bis(oxy))bis(2-hydroxy-5-methylbenzaldehyde) (1.0 mmol) and 5-(chloromethyl)nicotinonitrile (4.0 mmol) are stirred at 75 C for 3 hours in dimethyl formamide(5 mL). The reaction is filtered and concentrated. The residue is purified with a mixture of hexane:ethyl acetate on a silica gel column to afford the desired product IV-20.
Step-3: 54(54 [3 '-({ 5-[(5-cyanopyridin-3-yl)methoxy]-4- [(2-hydroxyethyl)amino]-methyl -2-methylphenoxy}methyl)-2,2'-dimethy141,1'-biphenyl]-3-yl]methoxy -2-{ [(2-hydroxyethyl) amino]methy1}-4-methylphenoxy)methyl]pyridine-3-carbonitrile, 1-50.
To a solution of aldehyde IV-20 (1.0 mmol) in Me0H (30 mL) is added 2-aminoethanol (4.0 mmol) and acetic acid (0.5 mmol). After stirring for 30 minutes, NaBH3CN (4.0 mmol) is added and the mixture is stirred for 16 hours at room temperature.
The reaction is quenched with the water, and extracted with ethyl acetate. The combined organic layers are dried over anhydrious Na2SO4 and concentrated. The residue is purified by silica gel column (eluent: DCM/ Me0H) to give the title compound 1-50.
Example-22: 5-[(5-{ [3'-({ 5- [(5-cyanopyridin-3 -yl)methoxy]-4-(hydroxymethyl)-2-methylphenoxy methyl)-2,2'-dimethy141, 1'-bipheny1]-3 -yl]methoxy -2-(hydroxymethyl)-4-methylphenoxy)methyl]pyridine-3-carbonitrile, 1-54.
NCN NC
I rsj Nal3H4 OH
0 0 40 ________ \ N
NC NC
5,5'-((((((2,21-dimethy141, 11-bipheny11-3,3'-diyObis(methylene)) bis(oxy))bi s(6-formy1-4-m ethy1-3 , 1 -phenyl eno)bi s(oxy))bi s(methy I en e))dini cotin oni tril e, 1V-20 (1.0 mmo) is dissolved in ethanol (15 mL), and NaBH4 (2.4 mmol) is added in small portions over 30 min to the stirred solution with ice cooling. The resulting solution is then stirred for 4-6 h at room temperature and a NaOH (1 M, 15 mL) solution was added to quench the reaction. The ethanol is removed by evaporation, the aqueous phase is extracted with ethyl acetate three times and the combined organic phase was washed with NaOH (1.0 M, 15 mL), water (15 mL) and brine (15 mL) and dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by a silica gel column chromatography (eluent:
ethyl acetate/petroleum ether) to yield the title molecule 1-54.
Example-23: 5- { [4-chloro-5-({2-cyano-3'-[(4-{ [(2-hydroxyethyl)amino] methyl I -2-methylphenoxy)methy1]- [1, 1'-bipheny1]-3 -y1} methoxy)-2- { [(2-hydroxyethyl) amino]methyl phenoxy] methyl I pyridine-3 -carb onitril e, 1-59.

OH
ON a OH
Br 0 CN

\o 01 8õ.0 ., \ ,0 CI Si"(:) 0 >\õsi\
6 Pd(dppf)Cl2, KOAc ______ OH
PPh3, DIAD ' \ CI
dioxane, 110 C
111-8 THF, 0 C tort Step-1 Step-2 NC
NC
I isi CN

CI..õ. N TBAF 0, IV
CN a 0 CN e N3 _______ ,..
_______ ' ..,Si-0 Cs2CO3, DMF, 0 THF, rt HO

75 C, 2h \ CI
CI PPh3, DIAD
THF, 0 C to rt Step-4 Step-3 Step-5 NC
NCri I rsi .--, H2N -OH

2 eqv. CN An N.---,,OH
CN a N21 NaBH3CN, Et0H 0 H
H
r 0 W

CI

Step-6 HON
0,=

Intermediate 111-8 is prepared by the literature procedure described in Tetrahedron, 69(16), 3465-3474, 2013.
osB-B):) TBDMSCI d O \ -0 el B-0 \ Si 0 Si ,.. Br __________ \
HO 0 ______ - \
Br 4-DMAP, THF Pd(dppf)C12, KOAc 0 C, 24h, rt dioxane, 110 C 111-8 Step-1 Step-2 Step-1: 3 '-(((tert-butyldimethyl silyl)oxy)methyl)-3-(hydroxymethyl)-[1,1`-biphenyl]-2-carbonitrile, 1140.
To a solution of tert-butyldimethyl((3-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-yl)benzyl)oxy)silane 111-8 (1.10 mmol), 2-bromo-6-(hydroxymethyl) benzonitrile (1.1 g, 1.0 mmol), KOAc (2.0 mmol), and Pd(dppf)C12 (0.07 mmol) in 8 mL of dioxane is added 2 mL of H20. The mixture is stirred at 110 C under N2 overnight. The reaction mixture is filtered and concentrated, then extracted with ethyl acetate. The organic layer is dried over Na2SO4, filtered and concentrated. The product is purified by column chromatography (petroleum ether: ethyl acetate) to give a desired product II-10.
Step-2: 3 '-(((tert-butyldi m ethylsilyl)oxy)m ethy1)-3 -((2-chi oro-4-form y1-hydroxyphenoxy) methy1)41,1'-biphenyl]-2-carbonitrile, IV-22.
A mixture of 5-chloro-2,4-dihydroxybenzaldehyde (1.1 mmol), triphenylphosphine (1.1 mmol) and 3'-(((tert-butyldimethyl silypoxy)methy1)-3-(hydroxymethyl)41,1'-bipheny11-2-carbonitrile, II-10 (1.0 mmol) is dissolved in dry tetrahydrofuran (7 mL) and cooled to 0 C. Diisopropyl azodicarboxylate (1.1 mmol) in tetrahydrofuran (7 mL) is added dropwise. The resulting yellow solution is allowed to slowly warm to room temperature overnight. Solvent is removed by rotary evaporator. The crude is purified with an eluent (hexanes:ethyl acetate) on a silica gel column to afford the desired product, IV-22.
Step-3: 545-((3'-(((tert-butyldimethylsilyl)oxy)methyl)-2-cyano-[1, ] '-bipheny1]-3-y1) methoxy)-4-chloro-2-foinlylphenoxy)methypnicotinonitrile, IV-23.
Cesium carbonate (1.5 mmol), 31-(((tert-butylditnethylsilyl)oxy) Inethyl)-3-((2-ch1oro-4-formy1-5-hydrox7õ,phenoxy)methyl)4 1, I '-bipheny1]-2-carbonitrile, IV-23 (1.0 mmol) and 5-(chloromethyl)nicotinonitrile (2.0 mmol) are stirred at 75 C for 3 hours in dimethyl formamide(5 mL). The reaction is filtered and concentrated. The residue is purified with a mixture of hexane:ethyl acetate on a silica gel column to afford the desired product IV-23.
Step-4: 5-44-ch1oro-5 -((2-cyano-3 '-(hydroxymethyl)-[ 1,1 '-biphenyI]-3 yl )methoxy)-2-formyl phenoxy)methyl)nieotinonitrile, IV-24.
To a solution of 54543'-(((tert-buty1dimethy1si1y1)oxy)methyl)-2-cyano41,1'-biphenyl-J-3-y!) methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitri1e, IV-23 (1,0 mmol) in THF (5 mL) is added tetrabutylamrnoniurn fluoride in THE' (1M
solution in THF, 2 niL., 2.0 nimol) drop wise at 0 C. The reaction mixture is stirred at rt for 1 h and is diluted with 1120 (10 mt.) and extracted with Et0Ac (3 20 mi.). The combined organic layer is dried over Na2SO4 and was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent hexane/Et0Ac 30:70) to afford desired product IV-24.
Step-5: 544-chloro-5-42-cyano-3'-((4-forinyl.-2-inethylphenoxy)inethyl)41,1'-biphenyli-3-y1)methoxy)-24ormy1phenoxy)methypnicotinonitri1e, IV-25.
A mixture of 4-hydroxy-3-methylbenzaldehyde (1.1 mmol), triphenylphosphine (1 . 1 mmol) and 544-chloro-542-cyano-3'-(hydroxymethy )11 , 1'-bi phenyl ]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile, IV-24 (1.0 mmol) is dissolved in dry tetrahydrofuran (7 mL) and cooled to 0 C. Diisopropyl azodicarboxylate (1.1 mmol) in tetrahydrofuran (7 mL) is added dropwise. The resulting yellow solution is allowed to slowly warm to room temperature overnight. Solvent is removed by rotary evaporator. The crude is purified with an eluent (hexanes:ethyl acetate) on a silica gel column to afford the desired product, IV-25.

Step-6: 5-1[4-chi oro-5-({2-cyano-3'- [(4- { [(2-hydroxyethyl)amino]methylI-2-methyl phenoxy) methyl]-[1,1'-bipheny1]-3-ylImethoxy)-2-{ [(2-hydroxyethyl)amino]methyl Iphenoxy] methyl}pyridine-3-carbonitrile, 1-59.
A mixture of aldehyde IV-25 (1.0 mmol, 2N), 2-aminoethan- 1 -ol (6 mmol, 3 eqv.) and AcOH (10 mmol, 5 eqv.) in DMF (10 mL) is stirred at RT for 4-16 h.
Then sodium cyanoborohydride (6 mmol, 3 eqv.) is added and the mixture is stirred at RT
until reductive amination is complete (typically overnight). The crude is purified via reverse phase preparative HPLC to give the title compound 1-59.
Example 24: 5-[(4-chloro-2-{ [(2-hydroxyethyl)amino]methyl 1 -5 -(13'-[(4-{[(2-hydroxyethyl) amino]methyl 1 -3,5-dimethoxyphenoxy)methy1]-2-methyl-[1,1'-biphenyl]-3-ylImethoxy) phenoxy)methyl]pyridine-3-carbonitrile, 1-69.
The compound 1-69 can be synthesized by Method A shown below::
OH
0 >\,..\ OH
v0 . \ ., .. 0..
.. 0 6 Pd(dppf)Cl2, KOAc _IcSi.0\ OH a PPh3, DIAD ' \ CI
dioxane, 110 C
1114 THF, 0 C tort Step-1 Step-2 C

I

a 0 _______________________________ .- 0 ,.,..cSI-0 CS2003, Lopnr, 0 THF, rt HO
75 C, 2h \ CI 0 CI PPh3, DIAD
THF, 0 C to rt Step-4 Step-3 Step-5 CN
CN NI
Nil H21%1OH 0 2 eqv. ., I
re,..õ_,..OH

0 a NaBH3CN, Et0H HO 0 0 0 Step-6 "---.."*---N H
0,=0, (:) r 0, 0, 1V-29 149 Step-1-6 in Method A: follow the stardard procedures described for Example-23 to yield the tiltle compound 1-69.
The compound 1-69 can be synthesized by Method B shown below:

N,CN
OH I 0 Aihõ, 0 40 0 ON /
0, I. BO---r HO .111 CI ... -N O. 111-9 Br CI a -0 ________ ._ -0 OH Br 0 0 MP' Cs2CO3, DMF, Br a, 0=-o ______________ O Pd(dppf)C12, KOAc PPh3, DIAD CI 75 C, 2h dioxane, 1 1 0 C
THF, 0 C to rt CI
Step-1 11-12 Step-2 III-30 Step-3 CN

1 40 -0 H2N-----0H o 0 , .
0 , I. 0 CI 2 eqv.
NaBH3CN, Et0H _____________________ . I
0 0 0 "
0 Fi , Step-4 N
eH 0 0 CI
1V-31 (Ds Preparation of intermediate 111-9:

0, gl Br B-13, 1 I.
0.,... 0 0 I 40 0, 0 0 , 01111 _______________________ .
PPh3, DIAD 0 -0 B
0 - , lo ' 0, Br Pd(dppf)C12, KOAc dioxane, 1 1 0 C 0 THF, 0 C to rt \
0, 111-9 All steps in Method B: follow the stardard procedures described for Example-23 to yield the tiltle compound 1-69.
The compounds listed in Table 2 are prepared using methods similar to those described for the preparation of 1-50, 1-54, 1-59 and 1-69.
Table 2 N-, -CN
I
54(5-{ [3 '-(15-[(5-cyanopyridin-3 -y Dmethoxy] -4-1 [(2 - o hy droxy ethy Damino] methy11-2 - 0 NoH

methylphenoxylmethyl)-2,2'-dimethyl- I H
o [1,1'-bipheny1] -3 -yl] methoxy 1-2-1 [(2 - H

NI
hy droxy ethy Damino] methy11-4-HO
,6 CN o methylphenoxy)methyl]pyridine-3-carbonitrile \ N
?

2-(1[4-(13'-[(4-1[(2-hy droxy ethy Damino] methy11-2 -methyl- o 5-[(py ridin-3 - 0 N
...--...õ.OH
y Dmethoxy]phenoxy)methyl] -2,2'- H
1-51 o dimethyl4 1, 1'-biphenyl] -3 -yllmethoxy)- H
ir o 5-methy1-24(pyridin-3- HON
yl)methoxy]phenyl]methyllamino)ethan o \ N

C

54(4-chloro-5-1[3'-(12-ch1oro-54(5-cyanopyriclin-3 -yemetho xy] -4-1 (2-[ Lo hy dro xy ethyDamino] methyllphenoxy 1m ci 1-52 ethyl)-2,2'-climethy141, l'-biphenyl] -3 - 0 0 0 0 '11' OH
H
yl] methoxy } -2 -{ [(2- HO"-'---N a hydroxyethyDamino]methyl}phenoxy)m o rb ,6 ethyl]pyridine-3-caonitrile \ N
CN
C
ri N
-[(5 -{ [3 '-(15 -[(5-cyanopyridin-3 -y Dmethoxy] -2 -methy1-4- Lo [(methylamino)methyl]phenoxy }methyl) 1-53 -2,2 '-dimethyl- [ 1, l'-biphenyl] -3 - H 0 0 0 0 '1( yl] methoxy }-4-methy1-2- ,N
[(methylamino)methyl]phenoxy)methyl] (:),6 py ridine-3 -carbonitrile \ N
CN
C
Nj Ni 5 -[(5 -{ [3 '-(15 -[(5-cyanopyridin-3 -yOmethoxy] -4-(hy dro xy methyl)-2 - Lo methylphenoxy } methyl)-2,2'-dimethyl- 0 OH
1-54 [ 1, l'-biphenyl] -3 -yl] methoxy } -2- 0 0 o (hydroxymethyl)-4- HO
methy 1phenoxy)methyl]py ridine-3 - 6o carbonitrile \ N
CN, C
1. N1 54(3-1[3'-({54(5-cyanopyridin-3-yOmethoxy] -2 -methy 1pheno xy } methyl)-2,2 '-dimethyl-[ 1, l'-biphenyl] -3- S1-55 o yl] methoxy }-4- Ir o methy 1phenoxy)methyl]py ridine-3 - o carbonitrile CNN
C
l' Ni 54(5-1[3'-(154(5-cyanopyridin-3-yOmethoxy]-4-(hydroxymethyl)-2- Lo methylphenoxy } methyl)-2 -methyl-[ 1,1- 410 OH
1-56 bipheny 1] -3 -yl] metho xy } -2 - 0 o o (hydroxymethyl)-4- HO
methy 1phenoxy)methyl]py ridine-3 - 01 carbonitrile CN Q Ni:?*-, "CN
I /
3,3 '-bis(15 4(5 -cyanopy ridin-3 - o yOmethoxy] -4-1 [(2 - CN
1-57 hydroxyethyDamino]methy11-2- o o methylphenoxy } methyl)-[ 1, l'-biphenyl] - He- NEI 10 CN
2,2'-dicarbonitrile o CN N

NC?"CN
I /
-[(5 -{ [2 -cy ano-3 '-(15 -[(5 -cy anopy ridin-3-yl)methoxy] -4-1 [(2- o hydroxyethyDamino]methy11-2-methylphenoxy } methy1)41, l'-b (phenyl] -IW
H
1-58 o 3-y1]methoxy 1 -2-1 [(2- H
o hydroxyethyDamino]methy11-4- HON
methylphenoxy)methyl]pyridine-3- o carbonitrile CNN
Nq.CN
5-1[4-c h1oro-5-(12-cyano-3'4(4-1 [(2- 1 hy droxy ethy Damino] methy11-2-methy 1pheno xy)methyl] -[1, l'-b (phenyl] - o 3-yllmethoxy)-2-1[(2-hy dro xy ethyDamino] methyllphenoxy] m o H
ethyllpyridine-3-carbonitrile H
= 0 CI
HO-'N
Nj?"'",. .CN
5-(14-chloro-54(2-cyano-3'-{ [(5-{ [(2- 1 hy dro xy ethyDamino] methyl}py ridin-2-yl)o xy] methyll- [1,1'-biphenyl] -3 - o yOmethoxy] -2 -{ (2- ...-..,,OH
hy dro xy ethyDamino] methyl}phenoxy 1m jrs,o CN 0 [1 o ethyl)pyridine-3-carbonitrile H I
HO-'N CI
Nq.CN
5-1 [5-(12-cyano-34(4-1 [(2- 1 hy droxy ethy Damino] methy11-2-methy 1pheno xy)methyl] -[1, l'-b (phenyl] - o 3-yllmethoxy)-2-{ [(2-hy dro xy ethyDamino] methyl}phenoxy] m o H
ethyllpyridine-3-carbonitrile H
= 0 HO-'N
3'4(4-{(2- I
hydroxyethyDamino]methy1}-2-methylphenoxy)methy1]-34(4-1 [(2-o 1-62 hydroxyethyDamino]methy11-3-CN alb N...^..,,,OH
[(pyridin-3- H
0 o yOmethoxy]phenoxy)methy1]-[1,1'- H 0 biphenyl] -2-carbonitrile HONI
5-1 [5-(12'-cyano-3'4(4-1 [(2- Ni?,.., .cN

hydroxyethyDamino]methy11-2-methy 1pheno xy)methyl] -[1, l'-b (phenyl] -o 1-63 3-y1lmethoxy)-2-{ [(2-hydroxyethyDamino]methy1}-4- An N...-....._,,OH
carbonitrile HO-'N
H
o methy 1phenoxy] methyl Ipy ridine-3- o H

5-1 [5-(12-cyano-34(4-1 [(2- Ni?,.., .cN

hydroxyethyDamino]methy11-2-methy 1pheno xy)methyl] -[1, l'-b (phenyl] -o 1-64 3-y1lmethoxy)-2-{ [(2-hydroxyethyDamino]methy1}-4- H
0 o methy 1phenoxy] methyl Ipy ridine-3- o H =0 OH
carbonitrile HO-'N

5-1 [5-(12'-cyano-3'4(4-1 [(2- Nq.CN

hy droxy ethy Damino] methy11-2-methylphenoxy)methy1]-[1,1'-bipheny1]-o 1-65 3-y1lmethoxy)-2-1[(2-A OH
n N....,, hy droxy ethy Damino] methy11-4-H

methy 1phenoxy] methyl 1py ridine-3- o W
carbonitrile HON-' CI
NCN
5-(14-ch1oro-54(2-cyano-3'-{ [(5-1[(2-y hy dro xy ethyDamino] methyllpy ridin-2-yl)o xy] methyll- [1,1'-biphenyl] -3 - Lo N
yOmethoxy] -2 -CN
[(cy clopropy lamino)methy l]phenoxy 1m N 0 0 H

ethyl)pyridine-3-carbonitrile HON CI
2-(1[4-(134(4-1[(2- I isj hydroxyethyDamino]methy11-3-[(pyridin-3-o 1-67 y Dmethoxy] phenoxy)methyl] -2,2'-OH
dimethyl41,1'-biphenyl] -3 -yllmethoxy)- H
0 o 3 -methy 'phenyl] methyllamino)ethan-1- H 0 5-1 [5-(12'-cyano-3'4(4-1 [(2- Nq.cN

hy droxy ethy Damino] methy11-2-methylphenoxy)methy1]-[1,1'-bipheny1]-o 1-68 3-y1lmethoxy)-2-1 [(2-hy droxy ethy Damino] methy11-4- An N....,,OH
H
o methy 1phenoxy] methyl 1py ridine-3- o W
H

carbonitrile HO-'N CN
N CN
54(4-chloro-2-1[(2- 1 hy droxy ethy Damino] methy11-5-(13' -[(4-1 [(2 -hy droxy ethy eamino]methy11-3,5 - o 1-69 dimethoxyphenoxy)methyl] -2-methyl- Ai oI o H
[ 1, 1'-biphenyl] -3 -yllmethoxy)phenoxy)methyl] py ridine- H
=0 CI
3 -carbonitrile HO N
o, -[(2 -{ [(2-hydroxyethyeamino]methyl}- Nq.cN

5413'4(4-1 [(2-hy droxy ethy Damino] methy11-2-o 1-70 methy 1pheno xy)methyl] -2,2'-dimethyl-[1,1 '-biphenyl] -3 -y1 1methoxy)-4- An N....,,OH
H
0 o methylphenoxy)methyl]pyridine-3- o W
H
carbonitrile HO-'N
N CN
5 -[(2 -{ [(2-hydroxyethyeamino]methyl}- 1 54134(4-1 [(2-hy droxy ethy Damino] methy11-3,5- o 1-71 dimethoxyphenoxy)methy1]-2,2'-oI o H
dimethyl-[1,1'-biphenyl] -3 -yllmethoxy)-4-methy 1phenoxy)methyl] py ridine-3 - H
=0 carbonitrile HO N
o, 2-(1[4-(134(4-1[(2- Q
hydroxyethyDamino]methy11-2-methyl-54(pyriclin-3- Lo yOmethoxy]phenoxy)methy1]-2,2'-1-72 N...--,õ.-OH
dimethy141,1'-bipheny1]-3-yllmethoxy)- I
ir0 o 0 'I

2,6- H
dimethoxyphenyl]methyllamino)ethan- HONI
1-ol o Example 25: 24({243'-(6-{[(2-hydroxyethyl)amino]methyl}41,2,4]triazolo[1,5-a]pyridin-2-y1)-2,2'-dimethyl-[1,1'-biphenyl]-3-y1]-[1,2,4]triazolo[1,5-a]pyridin-6-yl Imethyl)amino] ethan- 1 -ol, 1-73.
The compound 1-73 can be synthesized via the route shown in the scheme below.
B(OH)2 0 0 (H0)2B 0 t-BuONO, CuBrx N /
N-1:0,1, ' Br¨

H2N¨ ...... _ N ----- MeCN, rt to 60 C N-- ---- Pd(PPh3)4, k3PO4.
1A-dioxane, 110 C 0 A11-1(13u-02, _IV
N ____ OH Dess-Martin DCM, -78 C, rt N
/CII-- / periodinane _______ HO
N

...._ N.---.õõOH
HON
AcOH, NaBH3CN HO's'---N N

Example 26: 24( {243 '-(6-{ [(2-hydroxyethyl)amino]methyl Iimidazo[1,2-a]pyridin-2-y1)-2,2'-dimethyl-[ 1,1 '-biphenyl]-3 -yl]imidazo[1,2-a]pyridin-6-ylImethyl) amino] ethan- 1 -ol, 1-74.
The compound 1-74 can be synthesized via the route shown in the scheme below.
o o o JohnPhos 0 CuBr2, AcOEt 0 B(OH)2 + Br 0 Br _______________________________________________________ >- Br KF, Pd(0A02 ,.,I 80 C, 2h 0 THF, rt, >24h `-' CN
I I¨
AIH(iBu)2, .., / N ¨ CuCN, DMF hl H2N zhl /Nz / _______________________ Nlz ' 0 I re -78 C; 10 min iPrOH, 90 C, 4h ¨
c( NC
I
OH
/-----/
N

r N /
_FN I N
r AcOH, NaBH3CN HON
0-p- 1-74 Example 27: 24( {243 '-(6-{ [(2-hydroxyethyl)amino]methyl 1 -1,3 -benzoxazol-2-y1)-2,2'-dimethy141, 1 '-biphenyl]-3 -y1]-1,3 -benzoxazol-6-ylImethyl)amino] ethan-1 -ol, 1-75.
The compound 1-75 can be synthesized via the route shown in the scheme below.

HO &
e HO
LiOH SOCl2, DCM, e ____________________________________ OH CI
dioxane, 15 min, 0 THF/Me0H/H20 0 0 210 C

N * ,./ N Dess-Martin " 0 0 * ___ . * 0 0 *
OH periodinane _________________________________________________________________________ ..-0 µ HO
N N

N N

\ NOH
0, * \
H . 0 0 * H
N HO
AcOH, NaBH3CN HON N

Example 28: 3 -(5-{ [(2-hydroxyethyl)amino]methyl 1- 1,3 -benzoxazol-2-y1)-3'-[(4-{ [(2-hydroxyethyl)amino]methyl 1 -2-methylphenoxy)methy1]-[ 1, 1 '-biphenyl]-2-carbonitrile, 1-87.
The compound 1-87 can be synthesized via the route shown in the scheme below:
N

N
HO 0 R 0 Br 0 0 ,... HO N
11 0 .,.., HO
e -6-IR< o ________ o, 10 PPh3, DIAD
Pd(dppf)C12, KOAc THF, 0 C to rt dioxane, 110 C
Step-1 Step-2 \
N 1) SOCl2,DMF N
11 0 11 0 *
LiOH 0 2) 0 0 I
THF/H20/Me0H 0, 0 OH HO I
1.1 0, 1101 N
Step-3 H2N
Step-4 OH
/----/
NH

N
2 eqv. 11 0 *
________ ...- I

NaBH3CN, Et0H H

HO...---........õN
Step-5 The compounds listed in Table 3 are prepared using methods similar to those described for the preparation of 1-73, 1-74 and 1-87.

Table 3 ...........................................=.............::::::::::::::::::::::
::.............................................................................
.........:::::::::::,:::::::::::::::::::.õ,..........................,.........
................................................................:::::::::.=
...............................................................................
...............................................................................
...............................................................................
.............
----------------------------------------------------------------------------------------------------------------------------...............................................................................
...............................................................................
...............................................................................
...............................................................................
................................
õ....õ....õ....õ....õ....õ....,,,,,,,,,,,,,,,,,,,,,,,,,,,,õ.,....õ....õ....õ...
.õ....õ...,....õ.....,....õ....,....õ....õ....õ....õ....õ....õ....õ....õ....õ
2-[(12-[3'-(6-I[(2-hydroxyethyDamino]methy11-/........./OH
[1,2,4] triazolo [1,5-a]py ridin-2-y1)-2,2'- N'Nµ N
N-N) 5 -'..-- H
1-73 dimethy141,1'-biphenyl] -3-yl] - Ho-...../"N/--C)=---N
/ /
H --[1,2,4] triazolo [1,5-a]py ridin-6- N
ylImethyDamino]ethan-1-01 24(1243'-(6-1[(2-OH
hydroxyethyDamino]methyllimidazo [1,2- 1/----./
) ------ -1 1-74 a]py ridin-2-y1)-2,2'-dimethy141,1'-biphenyl] -3-yl]imidazo[1,2-a]pyridin-6- N
ylImethyDamino]ethan-1-01 21(1213'-(6-1[(2-OH
hydroxyethyD H i l amino]methy11-1,3-benzoxazol-2- N
o-..../-N AI o tip H
y 1)-2,2'-dimethy141,1'-biphenyl] -3-yl] -1,3- H N
benzoxazol-6-ylImethyDamino]ethan-1-ol N
2-G243'45-1 [(2-hy droxyethy eamino] methyll-1'- /
Aim 1,3-benzoxazol-2-y1)-2,2'-dimethy141, N
1-76 H Ili N N 111/ H
biphenyl] -3-yl] -1,3-benzoxazol-5- N 0 yllamino)ethan-1-ol Ho/---/
24(1243'-(5-1[(2-Aim hydroxyethyDamino]methy11-1, N
1-77 H IIIP N3-benzothiazol- /

2-y 1)-2,2'-dimethy141,1'-biphenyl] -3-yl] -1,3- N s benzothiazol-5-ylImethyeamino]ethan-1-ol Ho/--/
24(1243'-(6-1[(2- N
/........../OH
1-78 \ N
t hydroxyethyDamino]methy11-1,3-benzothiazol- H
Aam ip s s 40 2-y 1)-2,2'-dimethy141,1'-biphenyl] -3-yl] -1,3- H
N
benzothiazol-6-ylImethye Namino]ethan-1-ol Ho/--/
3,3'-bis(6-1 [(2-hy droxy ethy Damino] methyl_ 1 - N\ /N., NI

\''''N%
1-79 [1,2,4]triazo10 1' [1,5-a]pyridin-2-y1)41,-HO N
......õ."... N ----....... N - N \\
biphenyl] -2,2'-dicarbonitrile H \ N

,,,,OH
3,3'-bis(6-1 [(2-hy droxy ethy Damino] methyl_ 1 - N(\ \ H 1-80 1,3-benzoxazol-2-y1)41, P-biphenyl]-2,2'-N
HON... el 0 \\
dicarbonitrile H / N
N
24({243'(7{ (2 hy droxy ethy Daminol mealy I 1 - /----/
,N N
[ 1-81 1,2,41triazolo [ 1,5-al py ridin-2 ,T- N--r CT El dimethy141,1'-biphenyl] -3 -y 11- N......./C/ L. 1:1 =NN /
N
111,2,41triazoio[ I, 5-al py ridia-7- HO""
yipnethyDaminolethan- I. -01 2-{ [(8-ch1oro-2-13 '4(4-1 (2-[ ,N N¨' hy droxy ethy Damino] methy11-2 - HO-- \ N-- -----H
1-82 methy 1phenoxy)methyl] -2,2'-dimethyl-[ 1,1- \--NH
biphenyl] -3 -y1141,2,4]triazolo [1,5 -a]pyridin-6- 41 0 a yl)methyl] amino lethan- 1-01 3 -(8-chloro-6-1 (2-[ /N-N
...õ N.---........OH
hydroxyethyDamino]methyll- H
N....- ."--[1,2,4]triazolo [1,5-a]pyriclin-2 -y1)-3'4(4-1 [(2 -1-83 HO- \ \\ CI
hy droxy ethy Damino] methy11-2 -methy 1pheno xy)methyl] -[1, l'-b iphenyl] -2 - 40 o carbonitrile 3 '-[(4-1 [(2-hy droxy ethy Damino] methy11-3 ,5 - /N-N--------N.---,OH
dimethoxy pheno xy)methyl] -3 -(6-1 [(2 - HO- \ -0 N% H
1-84 hydroxyethyDamino]methyll- \¨NH * 0 \\
[1,2,4]triazo10 [1,5-a]pyriclin-2 -y1)41, l'- N
biphenyl] -2-carbonitrile ¨o 3 '-[(4-1 [(2-hy droxy ethy Damino] methy11-2 -H
methy 1phenoxy)methyl] -3 -(6-1 [(2- N---j NH
1-85 hydroxyethyDamino]methyll- HO- \
\- \\
N
[1,2,4]triazolo [1,5-a]pyriclin-2 -y1)41, l'- 40 o biphenyl] -2-carbonitrile 2-1[(2-13'4(4-1[(2- r OH
hy droxy ethy Damino] methy11-2 - HO-....v... 0 HN--1 NH
1-86 methy 1phenoxy)methyl] -2,2'-dimethyl-[ 1,1- \ O
b ipheny 1] -3 -y11- 1,3 -benzo xazol-6-yl)methyl] amino lethan- 1-01 3 -(5 -1 [(2 -hy dro xy ethyeamino] methyll- 1,3 -b enzoxazol-2-y1)-3 ' -[(4-{ [(2 - HO-- \
N HN
/ .1-87 hy droxy ethy Damino] methy1}-2 -L-NH
methy 1pheno xy)methyl] -[1, l'-b iphenyl] -2 -0 o \ \ o carbonitrile N
J.-OH
2-1[(2-13'-[(4-1[(2-HN
hy droxy ethy Damino] methy11-2 - HO--\ N
1-88 methy 1phenoxy)methyl] -2,2'-dimethyl4 1, l'-b ipheny 1] -3 -y11- 1,3 -benzo xazol-5 -411 o o W-yOmethyl] amino lethan- 1-01 2-1[(2-13'-[(4-1[(2- \s r&
hy droxy ethy Damino] methy11-2 - N illir 1-89 methy 1phenoxy)methyl] -2,2'-dimethyl-[ 1, l'- HO-\_ HN
NH
biphenyl] -3 -y11- 1,3 -benzothiazol-5 - . 0 LOH
yl)methyl] amino lethan- 1-01 2-1[(2-13'-[(4-1[(2- s 0 N.---........OH
\
hy droxy ethy Damino] methy11-2 - N
1-90 methy 1phenoxy)methyl] -2,2'-dimethyl-[ 1, l'- HO- \ H
\-NH
biphenyl] -3 -y11- 1,3 -benzothiazol-6- 40 o yl)methyl] amino lethan- 1-01 2-1[(2-13'-[(4-1[(2-H
hy droxy ethy Damino] methy11-2 - N---j 1-91 methy 1phenoxy)methyl] -2,2'-dimethyl4 1,1- HO- \
\-NH
biphenyl] -3 -y1141,2,4]triazolo [1,5 -a]pyridin-6- 40 o yl)methyl] amino lethan- 1-01 3 '-[(4-1 [(2-hy droxy ethy Damino] methy11-2 -H
methy 1phenoxy)methyl] -3 -(6-1 [(2- NI...-1-92 hy droxy ethy Damino] methyll- HO- \
N
[ 1,2,4] triazolo [ 1,5-a] py riclin-2 -y1)-2'-methyl- 40 o [ 1, l'-biphenyl] -2 -carbonitrile 2-1 [(4-chloro-2-13'4(4-1 [(2- o \ 110 ",.."..,,OH
hy droxy ethy Damino] methy11-2 - N
1-93 methy 1phenoxy)methyl] -2,2'-dimethyl4 1,1- HO- \
\-NH CI
b ipheny 1] -3 -y11- 1,3 -benzo xazol-6- 40 o yl)methyl] amino Iethan- 1 -ol N,..
3 -(4-chloro-6-1 [(2 - o \
110 "..,,OH
hy dro xy ethyDamino] methyll- 1,3 -benzo xazol-2 - N
1-94 y1)-3 '-[(4-1 [(2-hy droxy ethyDamino] methy11-2 - HO- \
N
methy 1pheno xy)methyl] - [1, l'-b iphenyl] -2 - 40 o carbonitrile 3 -(5-{ [(2 -hy dro xy ethyeamino] methyll- 1,3 - o benzoxazol-2-y1)-3' - [ (4-1 (2-[ HO- \ -0 -NH
N,........--,..OH
1-95 hy droxy ethy Damino] methy11-3 ,5 - . o \\
dimethoxy pheno xy)methyl] 41, l'-b iphenyl] -2- N

carbonitrile N
3 -(4-chloro-6-1 [(2 - o \
110 ,.."..,,OH
hy droxy ethy Damino] methyll- 1,3 -benzoxazol-2 - N
1-96 y1)-3 '-[(4-1 [(2-hy droxy ethyDamino] methy11-2 - HO- \
\-NH \\ CI
N
methy 1phenoxy)methyl] -2'-methyl-[ 1, l'- 40 o biphenyl] -2-carbonitrile 24(1243'-(5-1[(2-/......._/OH
hy dro xy ethyDamino] methy11-2H-indazol-2 -y1)- N
1-97 jik7 N H
2,2 '-dimethyl-[ 1, 1'-biphenyl] -3 -yl] -2H-indazol- HO---/--[`il.-110 -yl}methyeamino] ethan- 1-01 N
24(1243'-(6-1[(2-/....._/oH
hy dro xy ethyDamino] methy11-2H-indazol-2 -y1)- N, N
1-98 2,2 '-dimethyl-[ 1, 1'-biphenyl] -3 -yl] -2H-indazol- HO-Y-1 Ni H
AO
6-ylImethyeamino] ethan- 1-01 24(1243'-(6-1[(2-OH
hy droxy ethy Damino] methyllimidazo [1,2- /----../
1-99 b] py ridazin-2 -y1)-2,2 '-dimethyl- [ 1, l'-biphenyl] - isi-N ss, 3 -yl] imidazo [ 1,2 -b] py ridazin-6- N
ylImethyDamino] ethan- 1-01 24(1643'-(2-1[(2-OH
hy dro xy ethyDamino] methyllimidazo [1,2- z----../
I-100 b] [ 1,2,4] triazin-6-y1)-2,2 '-dimethyl-{ 1, l'- ju-N ss, , ril b ipheny 1] -3 -yl] imidazo [ 1,2 -b] [ 1,2,4] triazin-2 -yl}methyDamino] ethan- 1-01 24(1243'-(6-1[(2-OH
hy droxy ethy Damino] methyllimidazo [1,2-I-101 a] py razin-2 -y1)-2,2 '-climethyl- [1, l'-b iphenyl] -3 -yl] imidazo [ 1,2-a] py razin-6-ylImethyDamino] ethan- 1-01 2-({ [4-G34244-I [(2-_/
hy droxy ethy Damino] methy 1 Ipheny1)-7-methyl- o 0 -OH
HN
1-102 1,3 -benzoxazol-6-yl] -2-HON
methy 'phenyl} methoxy)-3 -methy 'phenyl] methyl} amino)ethan-1-01 2-({ [4-G34243-I [(2-oH
hy droxy ethy Damino] methy 1 Ipheny1)-7-methyl-NH
1-103 1,3 -benzoxazol-6-yl] -2- o methy 'phenyl} methoxy)-3 -*
HON
methy 'phenyl] methyl} amino)ethan-1-ol 2-1 R4-164244-I [(2-/N
hy droxy ethy Damino] methy 1 Ipheny1)-7-methyl-1,3 -benzoxazol-6-yl] -7-methy1-1,3 -benzoxazol-2-y llpheny Dmethyl] aminolethan-1-ol OH
2-1 R3-164243-I [(2- = /11 hy droxy ethy Damino] methy 1 Ipheny1)-7-methyl-NH

1,3 -benzoxazol-6-yl] -7-methy1-1,3 -benzoxazol HN
-2-y llpheny Dmethyl] aminolethan-1-ol HO
24(1243'45-I [(2-OH
hydroxyethyDamino]methy11-2,3-clihydro-1H-1-106 isoindo1-2-y1)-2,2'-climethy141, P-biphenyl] -3 - N H
yl] -2,3 -dihy dro-1H -isoindo1-5- HO 4 yllmethyDamino]ethan-1-ol 24(1643'43-I [(2-OH
hydroxyethyDamino]methy11-2-methoxy-5H,6H,7H-py rrolo [3 ,4-b]py ridin-6-y1)-2,2'- \c) N
1-107 o dimethy141,1'-biphenyl] -3 -yl] -2-methoxy- H N
5H,6H,7H-py rrolo [3 ,4-b]py ridin-3 -HO
yllmethyDamino]ethan-1-ol The compounds disclosed herein, but not listed in Table 1-3 above, can be prepared in a similar manner as Compounds I-1 to 1-105.
DOCKING EXPERIMENTS
Compounds I-1 and 1-10 are selected as ligands to bind PD-Li dimer. Figure 1 shows docking pose of compound I-1 in PD-Li dimer (Panel A). Figure 2 shows docking pose of compound I-10 in PD-Li dimer (Panel B) Method of Docking: the protein model was built based on PDB structure of PD-Li dimer (pdb code: 5j8o) in which Y56 conformation in B chain was rebuilt to allow access to both sides of the ligand core structure. Ligands were docked using rdock and docking poses were selected based on docking score and visual inspection.
Figure legend: the ligand binding site at the dimer interface was displayed in an orientation in which chain A and chain B were located above and below the ligand respectively. Ligands were displayed in ball and stick representation.
Surfaces were created surrounding the ligand binding site and were clipped to allow ligand to be better displayed.

As shown in Figures 1 and 2, compounds I-1 and 1-5 dock well with PD-L1 dimer.
In both cases, hydrophobic channel accommodates the designed novel core scaffold in the center; two pseudo symmetrical side chains attached to the core are extended to either side of the dimer interface. It is believed that such designed inhibitors can effectively induce/stabilize PD-L1 dimer formation, therefore potently disrupting PD-1/PD-L1 protein-protein and CD80/PD-L1 protein-protein interaction. Other compounds disclosed herein are believed to exhibit the same properties in docking experiments. Thus, these compounds can also be potent and selective inhibitors of the PD-1/PD-L1 protein/protein and protein/protein interactions.
BIOLOGICAL ASSAY
The activity of the compounds of Formula (I) to inhibit PD-1/PD-L1 protein-protein interaction can be readily investigated using biochemical and cellular assays well accepted in the field.
Homogenous time-resolved fluorescence (HTRF) binding assay:
The ability of the designed compounds to physically disrupt PD-1/PD-L1 interaction was measured by HTRF binding assay. The interaction of PD-1 and PD-Ll was assessed using soluble, purified preparations of the extracellular domains of the two proteins. For PD-1, the tag is the Fc portion of immunoglobulin (PD-1-Ig). For PD-L1, it is the 6 histidine motif (PD-Li-His). All required fusion proteins with desired tags were obtained from commercial sources. HTRF assay buffer consists of lxPBS supplemented with 0.1% (w/v) bovine serum albumin and 0.05% (v/v) Tween-20. For the binding assay, PD-Li-His (30 nM
final) and PD-1-Ig (10 nM final) in HTRF assay buffer were pre-incubated at RT for 30 min, followed by addition of inhibitors and incubated for another 30 min. HTRF detection was achieved using Tb cryptate-labeled anti-Ig antibody (1 nM final) and d2-labeled anti-His antibody (20 nM
final). Antibodies were diluted in HTRF assay buffer and dispensed on top of the binding reaction. The reaction mixture was allowed to equilibrate for 60 min at RT
before the resulting signal (665nm/620nm ratio) was obtained using an EnVision fluorometer. Final DMSO concentration in the solution is 0.2%. Additional binding assays can be established between PD- 1-Ig and PD-L2-His or CD8O-His/PD-L1 -Ig, in a similar format. The IC50 of the designed compounds in disrupting PD-1/PD-L1 interaction will be expected to fall in the range of 0.01 nM to 100 uM, depending on the corresponding structure-activity relationship.
IC50 determination was performed by fitting the curve of percent control activity versus the log of the inhibitor concentration using the GraphPad Prism 5.0 software.

Compounds of the present disclosure, as exemplified in Examples 1-6, showed ICso values in the following ranges: A: IC50 < 0.1 uM; B: 0.1 uM < IC50<1.0 uM; C:
0.1 uM <
IC50 < 25 uM
Data obtained for the representative compounds using the PD-1/PD-L1 homogenous time- resolved fluorescence (HTRF) binding assay described in Example 29 is shown in Table 4.
Table 4 mcianymmwmpomp.tpuguiRyiegima T-cell activation assay:
The ability of the designed compounds to functionally inhibit PD-1/PD-L1 interaction on a cellular level can be measured by T-cell activation assay. Human peripheral blood mononuclear cells (PBMC) can be isolated from blood buffy coats by commercial kits available. CD4+ T cells can be isolated with CD4 enrichment kit as per the manufacturer's instructions. Mouse Ig capture beads can be coated with anti-CD3, anti-CD28 and PD-Li Fc fusion by incubation under rotation at 4 C. CD4+ T cells can be cultured in 96-well plates together with coated beads, with or without designed compounds at varying concentrations for 3 days at 37 C in RPMI1640 Glutamax I supplemented with 4% human AB serum.

Culture supernatant can be removed to measure cytokine expression (e.g. IFNs, IL-2) by ELISA, DELFIA or Luminex technology. The amount of cytokine can be determined by comparing with a standard curve of known amounts of human cytokines. The remaining T
cells can be quantified by standard cell proliferation/survival assays (e.g.
Thymidine incorporation, CellTiter-Glo) according to manufacturer's instructions. Potent inhibitor compounds will disrupt PD-Li protein binding to PD-1 on the T cell surface, thus resulting in enhanced cytokine expression and promotion of T cell proliferation/activity.
Mixed lymphocyte reaction:
The ability of the designed compounds to functionally inhibit endogenous PD-Li interaction and promote T cell activity can be measured by mixed lymphocyte reaction assay. Human PBMCs can be isolated from leukapheresis packs using Ficoll-Paque Plus as per the manufacturer's instructions. Cells can be cultured in serum-free RPMI
1640 for short period at 37 C. After removal of nonadherent cells, remaining monocytes can be cultured in RPMI 1640 supplemented with 5% human AB serum, 2 ng/mL GM-CSF, and 10 ng/mL
IL4.
Fresh media with cytokine supplements can be added every 2 to 3 days. Mature dendritic cells can be induced by addition of TNFa on day 6 and culture for 24 hours.
CD4+ T cells can be isolated from PBMCs using magnetic beads as per the manufacturer's instructions. CD4+
T cells can be cultured in 96 well-flat bottom plates together with allogeneic dendritic cells at an optimal ratio (e.g. 1:2.5), using RPMI 1640 supplemented with 10% human AB
serum.
Dendritic cells can be treated with 100 mg/mL of mitomycin C before addition.
Designed compounds or DMSO can be added as desired. Cytokine expression and T cell proliferation/activity can be measured as indicated above according to manufacturer's instructions. Potent inhibitor compound is expected to promote cytokine expression and T
cell proliferation/activity.
The compounds of Formula (I) possess activity as inhibitors of the PD-1/PD-L1 interaction, and therefore, may be used in the treatment of diseases dependent on or associated with the PD-1/PD-L1 interaction. Through inhibition of the PD-1/PD-L1 interaction, the compounds of the present disclosure may be utilized to treat infectious diseases such as Hepatitis C, as well as multiple forms of cancer.
It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the spirit or scope of the invention. Thus, it is intended that the present invention cover the modifications and variations of this invention provided they come within the scope of the appended claims and their equivalents.

Claims (15)

WHAT IS CLAIMED IS:
1. A compound having Formula I:
(I), or a pharmaceutical acceptable salt thereof, wherein:
A is a bivalent arene or a bivalent heteroarene;
Ring B and Ring B' are independently a 6-membered aromatic hydrocarbon ring, a membered heterocyclic ring, a 9- to 10-membered aromatic hydrocarbon ring, or a 9- to 10-membered heterocyclic ring;
Y and Y' are independently null (direct bond), -CHR 1-, -CH 2-CH 2-, -NR 1-, -O-, -OCH 2-, -CH 2O-, -SCH 2-, -CH 2S-, -SOCH 2-, -CH 2SO-, or -SO 2CH 2-, and R1 is H, C1-6 alkyl, or C3-6 cycloalkyl;
R3 and R'3 are independently H, SO 2NH 2, SO 2NR 5R6, SO 2NHR 7, , CH 2NR 5R6, or CH 2NHR 7, wherein R5 and R6 are independently H, C1-6 alkyl, 8 cycloalkyl, or heteroaryl or R5 and R6 form a C3-8 cycloalkyl, heterocyclyl, or heteroaryl ring, and R7 is H, aryl, heteroaryl, acetyl, CH 2CH 2OH, CH 2CH 2NHCOCH 3, C3-C8 alkyl carboxylic acid, C3-C8 alkyl amide, C3-C8 alkyl alcohol, -CH 2-Ar, or -CH 2-heterocyclyl; and R4, R'4, Z, and Z' are independently H, halogen, CHF 2, CF 3, CN, C1-6 alkyl, alkoxy, aryl, or heteroaryl.
2. The compound of claim 1, wherein the Formula (I) is represented by following Formula (II):
Ring B and Ring B' are independently a 6-membered aromatic hydrocarbon ring or a 6-membered heterocyclic ring;

X1, X'1, X2, and X'2 are independently C R2, C=O or NR 2, and R2 is H, Me, CN, halogen, OM e, CHF 2, CF 3, C1-6 alkoxyl, C3-7 cycloalkyl, C3-7 heterocyclyl, or OCH 2Ar;
X3, and X'3 are independently C or N; and Y and Y' are independently -CHR 1-, -CH 2-CH 2-, -NR 1-, -O-, -OCH 2-, -CH2 O-, -SCH 2-, -CH 2S-, -SOCH 2-, -CH 2SO-, or -SO 2CH 2-, and R1 is H, C1-6 alkyl, or C3-6 cycloalkyl.
3. The compound of claim 1, wherein the Formula (I) is represented by following Formula (III):
Ring B and Ring B' are independently a 9- to 10-membered aromatic hydrocarbon ring or a 9- to10 -membered heterocyclic ring;
X1, and X'1 are independently CR 2, C=O or NR 2, and R2 is H, Me, CN, halogen, OM e, CHF 2, CF 3, C1-6 alkoxyl, C3-7 cycloalkyl, C3-7 heterocyclyl, or OCH
2Ar;
X2, and X'2, X3, and X' 3 are independently C or N;
U and U' are independently C and N;
V and V' are O, S, -(CH 2)2-, -CR'-, or -N=; and Y and Y' are independently null (direct bond), -CHR 1-, -CH 2-CH 2-, -NR 1-, -O-, -OCH 2-, -CH2 O-, -SCH 2, -CH 2S-, -SOCH 2-, -CH 2SO-, or -SO 2CH 2-, and R1 is H, C1-6 alkyl, or C3-6 cycloalkyl.
4. The compound of claim 1, 2, or 3, wherein A is and Ra are independently COR, OM e, halogen, C1-6 alkyl, C2-6 alkynyl, C1-6 cycloalkyl, CN, CF 3, CH 2CF 3; R' is C1-6 alkyl; Rb and Rb' are independently C1-6 alkyl, C2-6 alkynyl, C1-6 cycloalkyl or alkyl halogen; and V is -(CH 2)2-, -CR' -, or -N=.
5. The compound of claim 1, 2, 3, or 4, wherein CH 2NR 5R6 is
6. The compound of claim 1, 2, 3, or 4, wherein CH 2NHR 7 is
7. The compound of claim 1, 2, or 3, wherein Ring B and Ring B' are independently
8. The compound of claim 2, wherein Ring B and Ring B' are independently
9. The compound of claim 3, wherein Ring B and Ring B' are independently
10. The compound of claim 1, 2, or 3 wherein R3 and R'3 are the same, R4 and R'4 are the same, Y and Y' are the same, Z and Z' are the same, or Ring B and Ring B' are the same; or R3 and R'3 are the same, R4 and R'4 are the same, Y and Y' are the same, Z and Z' are the same, and Ring B and Ring B' are the same.
12. The compound of claim 1, 2, or 3, wherein the compound is 2-({[4-({3'-[(4-{[(2-hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]-2,2'-dimethyl-[1,1'-biphenyl]-3-yl}methoxy)-3-methylphenyl]methyl}amino)ethan-1-ol; 2-{[(4-{[3-({4-[(azetidin-1-yl)methyl]-2-methylphenoxy}methyl)-2-chlorophenyl]methoxy}-3-methylphenyl)methyl]amino}ethan-1-ol; 1-[(4-{[3-({4-[(azetidin-1-yl)methyl]-2-methylphenoxy}methyl)-2-chlorophenyl]methoxy}-3-methylphenyl)methyl]azetidine;
(2S)-1-{[4-({3'-{(4-{[(2S)-2-carboxypiperidin-1-yl]methyl}-3,5-dimethoxyphenoxy)methyl]-2,2'-dimethyl-[1,1'-biphenyl]-3-yl}methoxy)-2,6-dimethoxyphenyl]methyl}piperidine-2-carboxylic acid; (2S)-1-{[4-({3'-[(4-{[(2-hydroxyethyl)amino]methyl}-3,5-dimethoxyphenoxy)methyl]-2,2'-dimethyl-[1,1'-biphenyl]-3-yl}methoxy)-2,6-dimethoxyphenyl]methyl}piperidine-2-carboxylic acid; 2-({[4-({3'-[(4-{[(2-hydroxyethyl)amino]methyl}-3,5-dimethoxyphenoxy)methyl]-2,2'-dimethyl-[1,1'-biphenyl]-3-yl}methoxy)-2,6-dimethoxyphenyl]methyl}amino)ethan-1-ol; 1-{[4-({3'-[(4-{[(2-hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]-2,2'-dimethyl-[1,1'-biphenyl]-3-yl}methoxy)-2-methoxyphenyl]methyl}azetidin-3-ol ; 2-{[(6-{[3-(5-{[(5-{[(2-hydroxyethyl)amino]methyl}-6-methoxypyridin-2-yl)oxy]methyl}-4-methylthiophen-3-yl)-2-methylphenyl]methoxy}-2-methoxypyridin-3-yl)methyl]amino}ethan-1-ol; 2-({[4-({4-[(4-[(2-hydroxyethyl)amino]methyl}-3-methoxyphenoxy) methyl]-3-methylthiophen-2-yl} methoxy)-2-methoxyphenyl]methyl}amino)ethan-1-ol; 2-({4-[(azetidin-1-yl)methyl]-2-methylphenoxy}methyl)-6-{[4-({[(4-oxoazetidin-2-yl)methyl]amino}methyl)phenoxy]methyl}benzonitrile; N-(2-{[(4-{[3-({4-[4-[(azetidin-1-yl)methyl]-2-methylphenoxy}methyl)-2-cyanophenyl]methoxy}
phenyl)methyl]amino}ethyl)acetamide; 2-({4-[(azetidin-1-yl)methyl]-2-methylphenoxy}methyl)-6-[(4-{[(2-hydroxyethyl)amino]methyl}phenoxy)methyl]benzonitrile; 2-({4-[(azetidin-1-yl)methyl]-2-methylphenoxy} methyl)-6-({4-[(azetidin-1-yl)methyl]phenoxy}
methyl)benzonitrile; 2-({[4-({4-[(4-{[(2-hydroxyethyl)amino]methyl} -3,5-dimethoxyphenoxy)methyl]-1H-indol-yl}methyl)phenyl]methyl}amino)ethan-1-ol; 2-({[4-({1-[(4-{[(2-hydroxyethyl)amino]methyl}phenyl)methyl]-1H-indazol-4-yl}methoxy)-2,6-dimethoxyphenyl]methyl}amino)ethan-1-ol; 2,6-bis[(4-{[(2-hydroxyethyl)amino]methyl}-3-methoxyphenoxy)methyl]benzonitrile; N-[(4-{[3'-({4-[(cyclopropylamino)methyl]-3,5-dimethoxyphenoxy}methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl]methoxy}-2,6-dimethoxyphenyl)methyl]cyclopropanamine; 4-{[({4-[(3'-{[3,5-dimethoxy-4-({[(4-oxoazetidin-2-yl)methyl]amino}methyl)phenoxy]methyl}-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy]-2,6-dimethoxyphenyl}methyl)amino]methyl}azetidin-2-one; 2-[({6-[(3'-{[(5-{[(2-hydroxyethyl)amino]methyl}pyridin-2-yl)oxy]methyl}-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy]pyridin-3-yl}methyl)amino]ethan-1-ol; 2-[({6-[(3'-{[(5-{[(2-hydroxyethyl)amino]methyl} -6-methoxypyridin-2-yl)oxy]methyl} -2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy]-2-methoxypyridin-3-yl}methyl)amino] ethan-1-ol; N-{2-[({6-[(3'-{[(5-{[(2-acetamidoethyl)amino]methyl}-6-methoxypyridin-2-yl)oxy]methyl}-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy]-2-methoxypyridin-3-yl}methyl)amino]ethyl}acetamide;
(2R,4R)-1-({6-[(3-{[(5-{[(2R,4R)-2-carboxy-4-hydroxypyrrolidin-1-yl]methyl}-6-methoxypyridin-2-yl)oxy]methyl} -2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy]-2-methoxypyridin-3-yl}methyl)-4-hydroxypyrrolidine-2-carboxylic acid; (2R,4R)-4-hydroxy-1-({6-[(3'-{[(5-{[(2-hydroxyethyl)amino]methyl}-6-methoxypyridin-2-yl)oxy]methyl}-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy]-2-methoxypyridin-3-yl}methyl)pyrrolidine-2-carboxylic acid; (3R)-1-{[4-({3'-[(4-{[(3R)-3-hydroxypyrrolidin-1-yl]methyl}-2-methylphenoxy)methyl]-2,2'-dimethyl-[1,1'-biphenyl]-3-yl}methoxy)-3-methylphenyl]methyl}pyrrolidin-3-ol; (2R,4R)-1-{[4-({3'-[(4-{[(2R,4R)-2-carboxy-4-hydroxypyrrolidin-1-yl]methyl}-2-methylphenoxy)methyl]-2,2'-dimethyl-[1,1'-biphenyl]-3-yl}methoxy)-3-methylphenyl]methyl}-4-hydroxypyrrolidine-2-carboxylic acid; 2-({[4-({3'-[(4-{[(2-hydroxyethyl)amino]methyl}-3,5-dimethoxyphenoxy)methyl]-2'-methyl-[1,1'-biphenyl]-3-yl}methoxy)-2,6-dimethoxyphenyl]methyl}amino)ethan-1-ol; 2-[({4-[(2-{3-[(4-{[(2-hydroxyethyl)amino]methyl}-3,5-dimethoxyphenoxy)methyl]-2-methylphenyl}pyridin-4-yl)methoxy]-2,6-dimethoxyphenyl}methyl)amino]ethan-1-ol; 2-[({4-[(6-[{3-[(4-{[(2-hydroxyethyl)amino]methyl-3,5-dimethoxyphenoxy)methyl]-2-methylphenyl}pyridin-yl)methoxy]-2,6-dimethoxyphenyl}methyl)amino]ethan-1-ol; 2-({[4-({2'-chloro-3'-[(4-{[(2-hydroxyethyl)amino]methyl-2-methylphenoxy)methyl]-[1,1'-biphenyl]-3 -yl}methoxy)-3-methylphenyl]methyl}amino)ethan-1-ol;3,3'-bis[(4-{[(2-hydroxyethyl)amino]methyl-3,5-dimethoxyphenoxy)methyl]-[1,1'-biphenyl]-2-carbonitrile; 3,3'-bis({[(5-{[(2-hydroxyethyl)amino]methyl-6-methoxypyridin-2-yl)oxy]methyl})-[1,1'-biphenyl]-2-carbonitrile; 3,3'-bis({[(5-{[(2-hydroxyethyl)amino]methyl}pyridin-2-yl)oxy]methyl})-[1,1'-biphenyl]-2-carbonitrile; 3,3'-bis({4-[(azetidin-1-yl)methyl]-3,5-dimethoxyphenoxy}methyl)-[1,1'-biphenyl]-2-carbonitrile; 3,3'-bis({4-[(3-hydroxyazetidin-1-yl)methyl]-3,5-dimethoxyphenoxy}methyl)-[1,1'-biphenyl]-2-carbonitrile; 3,3'-bis({[3,5-dimethoxy-4-({[(4-oxoazetidin-2-yl)methyl] amino}methyl)phenoxy]methyl})-[1,1'-biphenyl]-2-carbonitrile;
3,3'-bis[(4-{[(2-hydroxyethyl)amino]methyl-2-methylphenoxy)methyl]-[1,1'-biphenyl]-2-carbonitrile; N-{2-[({6-[(2'-cyano-3'-{[(5-{[(2-acetamidoethyl)amino]methyl}-6-methoxypyridin-2-yl)oxy]methyl}-[1,1'-biphenyl]-3-yl)methoxy]-2-methoxypyridin-yl}methyl)amino]ethyl}acetamide; 2-[(4-{[(2-hydroxyethyl)amino]methyl-3,5-dimethoxyphenoxy)methyl]-6-4-[(4-[(2-hydroxyethyl)amino]methyl-3,5-dimethoxyphenoxy)methyl]pyridin-2-yl}benzonitrile; 2-[(4-{[(2-hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]-6-{4-[(4-{[(2-hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]pyridin-2-yl}benzonitrile; 2-{[(5-[(2-hydroxyethyl)amino]methyl}-6-methoxypyridin-2-yl)oxy]methyl-6-(4-{[(5-{[(2-hydroxyethyl)amino]methyl}-6-methoxypyridin-2-yl)oxy]methyl}pyridin-2-yl)benzonitrile;
2-[({4-[(2-{3-[(4-{[(2-hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]-2-methylphenyl}pyridin-4-yl)methoxy]-3-methylphenyl}methyl)amino]ethan-1-ol;
3,3'-bis({[(5-{[(2-hydroxyethyl)amino]methyl}pyridin-2-yl)oxy]methyl})-[1,1'-biphenyl]-2,2'-dicarbonitrile; 3,3'-bis[(4-{[(2-hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]-[1,1'-biphenyl]-2,2'-dicarbonitrile; 3,3'-bis[(4-{[(2-hydroxyethyl)amino]methyl}phenoxy)methyl]-[1,1'-biphenyl]-2,2'-dicarbonitrile; 5,5'-bis[(4-{[(2-hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]-[3,3'-bipyridine]-4,4'-dicarbonitrile; 2-[({4-[(4-{3-[(44-{[(2-hydroxyethyl)amino]methyl-3,5-dimethoxyphenoxy)methyl]-2-methylphenyl}-3-methylthiophen-2-yl)methoxy]-2,6-dimethoxyphenyl}methyl)amino]ethan-1-ol; 2-[({4-[(4-{3-[(4-{[(2-hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]-2-methylphenyl}-methylthiophen-2-yl)methoxy]-3 -methylphenyl}methyl)amino]ethan-1-ol; 2-({[4-({5'-[(4-[(2-hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]-4,4'-dimethyl-[3,3'-bithiophene]-5-yl}methoxy)-3-methylphenyl]methyl}amino)ethan-1-ol; 2-({[4-({5'-[(4-{[(2-hydroxyethyl)amino]methyl-2-methylphenoxy)methyl]-1,1'-dimethyl-1H,1'H-[2,2'-bipyrrole]-5-yl}methoxy)-3-methylphenyl]methyl}amino)ethan-1-ol; 5-[(5-{[3'-({5-[(5-cyanopyridin-3-yl)methoxy]-4-{[(2-hydroxyethyl)amino]methyl}-2-methylphenoxy}methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl]methoxy}-2-{[(2-hydroxyethyl)amino]methyl}-methylphenoxy)methyl]pyridine-3-carbonitrile; 2-({[4-({3'-[(4-{[(2-hydroxyethyl)amino]methyl-2-methyl-5-[(pyridin-3-yl)methoxy]phenoxy)methyl]-2,2'-dimethyl-[1,1'-biphenyl]-3-yl}methoxy)-5-methyl-2-[(pyridin-3-yl)methoxy]phenyl]methyl}amino)ethan-1-ol; 5-[(4-chloro-5-{[3'-({2-chloro-5-[(5-cyanopyridin-3-yl)methoxy]-4-[(2-hydroxyethyl)amino]methyl}phenoxy}methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl]methoxy-2-{[(2-hydroxyethyl)amino]methyl}phenoxy)methyl]pyridine-3-carbonitrile; 5-[(5-{[3'-({5-[(5-cyanopyridin-3-yl)methoxy]-2-methyl-4-[(methylamino)methyl]phenoxy}methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl]methoxy-4-methyl-2-[(methylamino)methyl]phenoxy)methyl]pyridine-3-carbonitrile; 5-[(5-{[3'-({5-[(5-cyanopyridin-3-yl)methoxy]-4-(hydroxymethyl)-2-methylphenoxy}methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl]methoxy-2-(hydroxymethyl)-4-methylphenoxy)methyl]pyridine-carbonitrile; 5-[(3-{[3'-({5-[(5-cyanopyridin-3-yl)methoxy]-2-methylphenoxy}methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl]methoxy-4-methylphenoxy)methyl]pyridine-3-carbonitrile; 5-[(5-{[3'-({5-[(5-cyanopyridin-3-yl)methoxy]-4-(hydroxymethyl)-2-methylphenoxy}methyl)-2-methyl-[1,1'-biphenyl]-3-yl]methoxy}-2-(hydroxymethyl)-4-methylphenoxy)methyl]pyridine-3-carbonitrile; 3,3'-bis({5-[(5-cyanopyridin-3-yl)methoxy]-4-{[(2-hydroxyethyl)amino]methyl-2-methylphenoxy}methyl)-[1,1'-biphenyl]-2,2'-dicarbonitrile; 5-({4-chloro-5-[(2-cyano-3'-{[(5-{[(2-hydroxyethyl)amino]methyl}pyridin-2-yl)oxy]methyl}-[1,1'-biphenyl]-3-yl)methoxy]-2-{[(2-hydroxyethyl)amino]methyl}phenoxy}methyl)pyridine-3-carbonitrile; 5-{[5-({2-cyano-3'-[(4-{[(2-hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]-[1,1'-biphenyl]-3-yl}methoxy)-2-{[(2-hydroxyethyl)amino]methyl}phenoxy]methyl}pyridine-3-carbonitrile; 5-[4-chloro-5-({2-cyano-3'-[(4-1{[(2-hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]-[1,1'-biphenyl]-3-yl}methoxy)-2-{[(2-hydroxyethyl)amino]methyl}phenoxy]methyl}pyridine-3-carbonitrile; 3'4(4-{[(2-hydroxyethyl)amino]methyl-2-methylphenoxy)methyl]-3-[(4-{[(2-hydroxyethyl)amino]methyl-3-[(pyridin-3-yl)methoxy]phenoxy)methyl]-[1,1'-biphenyl]-2-carbonitrile; 5-{[5-({2'-cyano-3'-[(4-{[(2-hydroxyethyl)amino]methyl-2-methylphenoxy)methyl]-[1,1'-biphenyl]-3-yl}methoxy)-2-{[(2-hydroxyethyl)amino]methyl}-4-methylphenoxy]methyl}pyridine-3-carbonitrile; 5-{[5-({2-cyano-3'-[(4-{[(2-hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]-[1,1'-biphenyl]-3-yl}methoxy)-2-{[(2-hydroxyethyl)amino]methyl-4-methylphenoxy]methyl}pyridine-3-carbonitrile;
5-[(4-chloro-2-{[(2-hydroxyethyl)amino]methyl}-5-[(3'-{[(5-{[(2-hydroxyethyl)amino]methyl}pyridin-2-yl)oxy]methyl}-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy]phenoxy)methyl]pyridine-3-carbonitrile; 5-({4-chloro-5-[(2-cyano-3'-{[(5-{[(2-hydroxyethyl)amino]methyl}pyridin-2-yl)oxy]methyl}-[1,1'-biphenyl]-3-yl)methoxy]-2-[(cyclopropylamino)methyl]phenoxy}methyl)pyridine-3-carbonitrile; 5-{[5-({2-cyano-3'-[(4-{[(2-hydroxyethyl)amino]methyl-3,5-dimethoxyphenoxy)methyl]-2'-methyl-[1,1'-biphenyl]-3-yl}methoxy)-2-{ [(2-hydroxyethyl)amino]methyl}-4-methylphenoxy]methyl}pyridine-3-carbonitrile; 5-[(5-{[2-cyano-3'-({ 5-[(5-cyanopyridin-3-yl)methoxy]-4-{[(2-hydroxyethyl)amino]methyl-2-methylphenoxy}methyl)-[1,1'-biphenyl]-3-yl]methoxy}-2-{[(2-hydroxyethyl)amino]methyl}-4-methylphenoxy)methyl]pyridine-3-carbonitrile; 2-({[4-({3'-[(4-{[(2-hydroxyethyl)amino]methyl}-3-[(pyridin-3-yl)methoxy]phenoxy)methyl]-2,2'-dimethyl-[1,1'-biphenyl]-3-yl}methoxy)-3-methylphenyl]methyl}amino)ethan-1-ol;
5-[(4-chloro-2-{[(2-hydroxyethyl)amino]methyl}-5-({3'-[(4-{[(2-hydroxyethyl)amino]methyl}-3,5-dimethoxyphenoxy)methyl]-2-methyl-[1,1'-biphenyl]-3-yl}methoxy)phenoxy)methyl]pyridine-3-carbonitrile; 5-[(2-{[(2-hydroxyethyl)amino]methyl}5-({3'-[(4-{[(2-hydroxyethyl)amino]methyl-2-methylphenoxy)methyl]-2,2'-dimethyl-[1,1'-biphenyl]-3-yl}methoxy)-4-methylphenoxy)methyl]pyridine-3-carbonitrile; 5-[(2-{[(2-hydroxyethyl)amino]methyl}-5-({3'-[(4-{[(2-hydroxyethyl)amino]methyl}-3,5-dimethoxyphenoxy)methyl]-2,2'-dimethyl-[1,1'-biphenyl]-3-yl}methoxy)-4-methylphenoxy)methyl]pyridine-3-carbonitrile;
2-({[4-({3'-[(4-{[(2-hydroxyethyl)amino]methyl}-2-methyl-5-[(pyridin-3-yl)methoxy]phenoxy)methyl]-2,2'-dimethyl-[1,1'-biphenyl]-3-yl}methoxy)-2,6-dimethoxyphenyl]methyl}amino)ethan-1-ol;
5-{[(3-{[(2-hydroxyethyl)amino]methyl}-6-[(3'-{[(5-{[(2-hydroxyethyl)amino]methyl}-6-methoxypyridin-2-yl)oxy]methyl}-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy]pyridin-2-yl)oxy]methyl}pyridine-3-carbonitrile; 2-({[4-({3'-[(2-chloro-4-{[(2-hydroxyethyl)amino]methyl}-5-[(pyridin-3-yl)methoxy]phenoxy)methyl]-2,2'-dimethyl-[1,1'-biphenyl]-3-yl}methoxy)-3-methylphenyl]methyl}amino)ethan-1-ol; 5-[(5-{[2-cyano-3'-({5-[(5-cyanopyridin-3-yl)methoxy]-4-(hydroxymethyl)-2-methylphenoxy}methyl)-2'-methyl-[1,1'-biphenyl]-3-yl]methoxy}-2-(hydroxymethyl)-4-methylphenoxy)methyl]pyridine-3-carbonitrile; 5-({2-[(azetidin-1-yl)methyl]-5-{[3'-({4-[(azetidin-1-yl)methyl]-5-[(5-cyanopyridin-3-yl)methoxy]-2-methylphenoxy}methyl)-2-cyano-[1,1'-biphenyl]-3-yl]methoxy-4-methylphenoxy}methyl)pyridine-3-carbonitrile; 5-({2-[(azetidin-1-yl)methyl]-5-{[3'-({4-[(azetidin-1-yl)methyl]-5-[(5-cyanopyridin-3-yl)methoxy]-methylphenoxy}methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl]methoxy-4-methylphenoxy}methyl)pyridine-3-carbonitrile; 2-[({2-[3'-(6-{[(2-hydroxyethyl)amino]methyl}-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl]-[1,2,4]triazolo[1,5-a]pyridin-6-yl}methyl)amino]ethan-1-ol; 2-[({2-[3'-(6-{[(2-hydroxyethyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl]imidazo[1,2-a]pyridin-6-yl}methyl)amino]ethan-1-ol; 2-[({2-[3'-(6-{[(2-hydroxyethyl)amino]methyl-1,3-benzoxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl]-1,3-benzoxazol-6-yl}methyl)amino]ethan-1-ol; 2-({2-[3'-(5-{[(2-hydroxyethyl)amino]methyl-1,3-benzoxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl]-1,3-benzoxazol-5-yl}amino)ethan-1-ol; 2-[({2-[3'-(5-{[(2-hydroxyethyl)amino]methyl}-1,3-benzothiazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl]-1,3-benzothiazol-5-yl}methyl)amino]ethan-1-ol; 2-[({2-[3'-(6-{[(2-hydroxyethyl)amino]methyl}-1,3-benzothiazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl]-1,3-benzothiazol-6-yl}methyl)amino]ethan-1-ol;3,3'-bis(6-{[(2-hydroxyethyl)amino]methyl}-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-[1,1'-biphenyl]-2,2'-dicarbonitrile; 3,3'-bis(6-{[(2-hydroxyethyl)amino]methyl}-1,3 -benzoxazol-2-yl)-[1,1'-biphenyl]-2,2'-dicarbonitrile; 2-[({2-[3'-(7-{[(2-hydroxyethyl)amino]methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl]-[1,2,4]triazolo[1,5-a]pyridin-7-yl}methyl)amino]ethan-1-ol; 2-{[(8-chloro-2-{3'-[(4-{[(2-hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl] -2,2'-dimethyl-[1,1'-biphenyl]-3-yl}-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]amino}ethan-1-ol; 3-(8-chloro-6-{[(2-hydroxyethyl)amino]methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-3'-[(4-{[(2-hydroxyethyl)amino]methyl-2-methylphenoxy)methyl]-[1,1'-biphenyl]-2-carbonitrile; 3'-[(4-{[(2-hydroxyethyl)amino]methyl-3,5-dimethoxyphenoxy)methyl]-3-(6-{[(2-hydroxyethyl)amino]methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-[1,1'-biphenyl]-carbonitrile; 3'-[(4-{[(2-hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]-3-(6-{[(2-hydroxyethyl)amino]methyl}-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-[1,1'-biphenyl]-carbonitrile; 2-{[(2-{3'-[(4-{[(2-hydroxyethyl)amino]methyl-2-methylphenoxy)methyl]-2,2'-dimethyl-[1,1'-biphenyl]-3-yl}-1,3-benzoxazol-6-yl)methyl]amino}ethan-1-ol; 3-(5-{[(2-hydroxyethyl)amino]methyl}-1,3 -benzoxazol-2-yl)-3'-[(4-{[(2-hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]-[1,1'-biphenyl]-2-carbonitrile; 2-{[(2-{3'-[(4-{[(2-hydroxyethyl)amino]methyl-2-methylphenoxy)methyl]-2,2'-dimethyl-[1,1'-biphenyl]-3-yl}-1,3-benzoxazol-5-yl)methyl]amino}ethan-1-ol; 2-{[(2-{3'-[(4-{[(2-hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]-2,2'-dimethyl-[1,1'-biphenyl]-3-yl}1-1,3-benzothiazol-5-yl)methyl]amino}ethan-1-ol; 2-1[(2-{3'4(4-{[(2-hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]-2,2'-dimethyl-[1,1'-biphenyl]-3-yl}-1,3-benzothiazol-6-yl)methyl]amino}ethan-1-ol; 2-1[(2-{3'4(4-{[(2-hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]-2,2'-dimethyl}-[1,1'-biphenyl]-3-yl}-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]amino}ethan-1-ol;3'-[(4-{[(2-hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]-3-(6-{[(2-hydroxyethyl)amino]methyl}-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2'-methyl-[1,1'-biphenyl]-2-carbonitrile; 2-{[(4-chloro-2-{ 3'-[(4-{[(2-hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]-2,2'-dimethyl-[1,1'-biphenyl]-3-yl}-1,3-benzoxazol-6-yl)methyl]amino}ethan-1-ol; 3-(4-chloro-6-{[(2-hydroxyethyl)amino]methyl}-1,3-benzoxazol-2-yl)-3'-[(4-{[(2-hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]-[1,1'-biphenyl]-2-carbonitrile; 3-(5-1{[(2-hydroxyethyl)amino]methyl}-1,3-benzoxazol-2-yl)-3'-[(4-{[(2-hydroxyethyl)amino]methyl} -3,5-dimethoxyphenoxy)methyl]-[1,1'-biphenyl]-carbonitrile; 3-(4-chloro-6-[(2-hydroxyethyl)amino]methyl} -1,3-benzoxazol-2-yl)-3'-[(4-{[(2-hydroxyethyl)amino]methyl} -2-methylphenoxy)methyl]-2'-methyl-[1,1'-biphenyl]-2-carbonitrile; 2-[({2-[3'-(5-{[(2-hydroxyethyl)amino]methyl}-2H-indazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl]-2H-indazol-5-yl}methyl)amino]ethan-1-ol; 2-[({2-[3'-(6-{[(2-hydroxyethyl)amino]methyl} -2H-indazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl]-2H-indazol-6-yl}methyl)amino]ethan-1-ol; 2-[({2-[3'-(6-{[(2-hydroxyethyl)amino]methyl} imidazo[1,2-b]pyridazin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3 -yl]imidazo[1,2-b]pyridazin-6-yl}methyl)amino]ethan-1-ol; 2-[({6-[3'-(2-{[(2-hydroxyethyl)amino]methyl}imidazo[1,2-b][1,2,4]triazin-6-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl]imidazo[1,2-b][1,2,4]triazin-2-yl}methyl)amino]ethan-1-ol;2-[({2-[3'-(6-{[(2-hydroxyethyl)amino]methyl} imidazo[1,2-a]pyrazin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl]imidazo[1,2-a]pyrazin-6-yl}methyl)amino]ethan-1-ol; 2-({[4-({3-[2-(4-{[(2-hydroxyethyl)amino]methyl}phenyl)-7-methyl-1,3 -benzoxazol-6-yl]-2-methylphenyl}methoxy)-3-methylphenyl]methyl}amino)ethan-1-ol; 2-(1[4-({3-[2-(3-{[(2-hydroxyethyl)amino]methyl}phenyl)-7-methyl-1,3 -benzoxazol-6-yl]-2-methylphenyl}methoxy)-3-methylphenyl]methyl}amino)ethan-1-ol; 2-{[(4-{6-[2-(4{[(2-hydroxyethyl)amino]methyl}phenyl)-7-methyl-1,3 -benzoxazol-6-yl]-7-methyl-1,3-benzoxazol-2-yl}phenyl)methyl]amino}ethan-1-ol; or 2-{[(3-{6-[2-(3-{[(2-hydroxyethyl)amino]methyl}phenyl)-7-methyl-1,3-benzoxazol-6-yl]-7-methyl-1,3-benzoxazol-2-yl}phenyl)methyl]amino}ethan-1-ol, 2-[({2-[3'-(5-{[(2-hydroxyethyl)amino]methyl}-2,3-dihydro-1H-isoindol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl]-2,3 -dihydro-1H-isoindol-5-yl}methyl)amino]ethan-1-ol, or 2-[({6-[3'-(3-{[(2-hydroxyethyl)amino]methyl}-2-methoxy-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl]-2-methoxy-5H,6H,7H-pyrrolo[3,4-b]pyridin-3-yl}methyl)amino] ethan-1-ol
12. A pharmaceutical composition comprising the compound of claim 1, 2, or 3, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
13. A method of treating a disease associated with the modulation of PD-or CD80/PD-L1 interaction comprising administering to a patient the compound of claim 1, 2, or 3 or a pharmaceutically acceptable salt thereof.
14. The method of claim 13, wherein the disease is an infection, inflammation, cancer, or neurodegenerative disorder.
15. The method of claim 14, wherein the disease is Alzheimer's disease.
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