CA2911408C - Benzimidazole derivatives as bromodomain inhibitors - Google Patents

Abstract

This application relates to chemical compounds which may act as inhibitors of, or which may otherwise modulate the activity of, a bromodomain-containing protein, including bromodomain-containing protein 4 (BRD4), and to compositions and formulations containing such compounds, and methods of using and making such compounds. Compounds include compounds of Formula (I) wherein R1a, R1b, R2a, R2b, R3, R4a, R4b, and R5 are described herein.

Description

DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.

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VOLUME

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BENZIMIDAZOLE DERIVATIVES AS BROMODOMAIN INHIBITORS
FIELD

[0002] This application relates to chemical compounds which may inhibit, or which may otherwise modulate the activity of, a bromodomain-containing protein, including bromodomain-containing protein 4 (BRD4), and to compositions and formulations containing such compounds, and methods of using and making such compounds.
BACKGROUND

[0003] The bromodomain and extraterminal (BET) family of proteins (BET
proteins) are readers of the epigenetic code that couple acetylation of lysine residues on histones to changes in chromatin structure and gene expression. The BET family includes BRD2, BRD3, BRD4, and BRDT, all of which are widely expressed across diverse tissues, with the exception of BRDT, whose expression is restricted to the testes. See Wu, S.Y. &
Chiang, C.M., J Biol. Chem., 282: 13141-13145 (2007). Each BET family member contains tandem bromodomains in the N-teiminal regions that specifically bind acetylated lysine residues in histones H3 and H4. Id. Once bound to histones, BET
proteins recruit protein complexes that modulate gene transcription either directly, such as transcriptional activators or repressors, or indirectly such as chromatin remodeling complexes. BRD4 is the most well studied member of the BET family and is known to preferentially recognize tetra- acetylated histone H4 epigenetic marks. See Filippakopoulos, P., et al., Cell, 149: 214-231(2012). BRD4 recruits the p-TEFb complex to nueleosomes, which in turn phosphorylates the C- terminal tail of RNA
polymerase II and increases the transcriptional elongation of neighboring genes. See Yang, Z., et al., Mol. Cell Biol., 28: 967-976 (2008); Urano, E., etal., FEBS
Lett., 582:
4053-4058 (2008).

[0004] The epigenetic code, including histone acetylation, is highly perturbed in many pathological disease states, resulting in the aberrant expression of genes that control cell fate, cell differentiation, cell survival, and inflammatory processes. See, e.g., Cohen, I., et al., Genes Cancer, 2: 631-647 (2011); Brooks, W.H., et al., J. Autoimmun., 34: J207-219 (2010); Wierda, R.J., etal., J. Cell MoL Med., 14: 1225-1240 (2010);
Shirodkar, A.V. & Marsden, P.A., Curr. Opin. Cardiol., 26: 209-215 (2011); Villeneuve, L.M., et al., Clin. Exp. Pharmacol. Physiol., 38: 401-409 (2011). BET proteins including BRD4 have been identified as important mediators of altered gene expression profiles found in numerous diseases including cancer, diabetes, obesity, atherosclerosis, cardiovascular and renal disorders, and viral infection. See Muller, S., et al., Expert Rev.
Mol. Med., 13:
e29 (2011); Zhou, M., et al., J. Virol., 83: 1036-1044 (2009); Chung, C.W., et al., J.
Med. Chem., 54: 3827-3838 (2011). For example, MYC has been implicated in the majority of human cancers and BET proteins have been identified as regulatory factors of c-Myc; inhibition of BET proteins, including BRD4, has been shown to downregulate MYC transcription. See Delmore, J.E., et al. Cell, 146, 904-17 (2011); Lover", J. et al., Cell, 153, 320-34 (2013). Inhibitors and modulators of BET proteins, including BRD4, are therefore needed.
SUMMARY

[0005] One aspect provides for a compound of Foimula (I) /
R a V R1b R2a R2b R4a_N IV R3 R4b (I) wherein Ria and Rib are each independently C1-6 alkyl optionally substituted with from 1 to 5 r) 20 groups;
R2a and R21) are each independently H or halo;
R3 is boronic acid or halo; or -C(0)0Ra, -NHC(0)0Ra, -NHS(0)2Ra, or -S(0)2NRaRb; or selected from the group consisting of C1.10 alkyl, C1_10 alkoxy, amino, C5_10 aryl, C6_20 arylalkyl, C1_10 heteroalkyl, Cs_10 heteroaryl, and C6_20 heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R2 groups;
one of R4a and R4b is selected from the group consisting of H and C1_6 alkyl optionally substituted with from 1 to 5 R2 groups, and the other is absent;
R5 is -C(0)0Ra, -NHC(0)0Ra, -NHS(0)21e, or -S(0)2NRaRb; or selected from the group consisting of H, C1_10 alkyl, C1_10 haloalkyl, C1_10 alkoxy, amino, C5-10 aryl, C6-20 arylalkyl, C1.10 heteroalkyl, C5-10 heteroaryl, and heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R2 groups;
each Ra and Rb is independently selected from the group consisting of H, C1_10 alkyl, C5_10 aryl, C6-20 arylalkyl, C1_10 heteroalkyl, C5-10 heteroaryl, and C6-20 heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R2 groups;
and each R20 is independently selected from the group consisting of acyl, Ci_10 alkyl, C1_ alkoxy, amino, amido, amidino, C5_10 aryl, C6-20 arylalkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, Ci_10 haloalkyl, C1_10 heteroalkyl, C5-10 heteroaryl, C6-20 heteroarylalkyl, hydroxy, hydrazino, imino, oxo, nitro, sulfinyl, sulfonic acid, sulfonyl, thiocyanate, thiol, and thione;
wherein the C1..10 alkyl, C5-10 aryl, C6-20 arylalkyl, C1_10 heteroalkyl, C5-heteroaryl, and C6-20 heteroarylalkyl groups are optionally substituted with from 1 to 3 substituents independently selected from C1-6 alkyl, C5-10 aryl, halo, haloalkyl, cyano, hydroxy, and C1_6 alkoxy;
or a phaimaceutically acceptable salt thereof.

[0006] Another aspect provides for a compound selected from the group consisting of / /
V z N
HN

/ /
/ /
I. 0 HN HN
N OH < -=--- N HO
, , / /
, /

HN
.<--=--N 1 HN
===.--N

/ /
/ /
101 11111 0 .
HN HN OH
<---:::N OH.--="-N lit , , 1110 =
HN'' HN
.(p-N OH <IN OH
, , / /
/ /

HN HN OH
OH <?------:N

/ /
/ /
I
a OH I
HN HN

/ /
/ /

HN ---N
OH

IP
N
,___ iioi N OH
\
and =

[0007] Another aspect provides for a compound selected from the group consisting of N' HN HN OH
.:---'N OH 40, j=---"N
/ N
I

/ /

I
N iso \
OH
/
HN HN
N
, 4111D , / /

OH -HN I.
I

\ /
HN
HN N
N HO I N <(--;---N /
1 --- N \
, , / /

101 OH --"N 0 OH N'"---N
HN \ / HN \ /
<I-N / .<-=-N /
N \ N \
, / /

=N\OH 1.1 OH --- \
\ /
HN HN \ N
N
<(---N .<-=---N
V \ , V \ , 1110 OH N---;"---) 0 OH N----."
HN \ N HN \ N
.<-=-N
N/ <-=--N
\ , N" \
N-0 N-0 .
/z /7 F le ' HN \ N HN
N OH
N"\ rN
I

/7 Iv 101 OH Ea OH
N N
NH / I
NH / I
S --- N S---<-=--'N .-----7-' I
and \-I
100081 Another aspect provides for a compound selected from the group consisting of I, / , /
101 OH * OH

NH NH

I I I
and N
[0009] Another aspect provides for a compound selected from the group consisting of / N
N'S 10 el N* N
,---NH ,--NH
, HN HN

N /
N .I2 0 N 0 el ---NFI NH
, / X
N'S F

N F

, , R

/ /
/ / F
F
CI
N'S N'S F

/ z /
/
N
N

, , / /
/ V F
F
I. 411 F

1;..3HN0 HN . N;...

, and I,, HN .

[0010] Another aspect provides for a compound selected from the group consisting of / / I,, HN N
N
<r 01 NH2 .<(=- 411 , 0 , I /
V V

HN 41, NH2 N

/ /

2_.--NH lel 2--NH 5 OH N
, 0 HN
.<I_\ _..1 _N 0 .--=-N 01 / /
/ /

: 1\1.,_____N 1.1 NH SOH I
OH

/ /
/ /
0 ik N N0 <
?--NH *

\ / z N
O
N 4111 .---- N N
N-' <I-NH 0 N

/ Iv/
lo , N H
N N
)---\ 1101 1111 I ,..- N N H 0 I I
N , V , O

N I HN Si .....-' N
<rNH or N I

// I,, O
HN = ..NH HN Si N ----N
<2=-"N 'Thl <1-----N
, 0 , / /

lir l , el CD.\
N
HN N / NH
FIN
.----=. j-"--,=N I ,., N 0 , , / \ .

1.1 ------ 0 IP

N
HN HN
<--------.N X NH ------N
a l , F3C , O-N
\
X

/
Z

HN 1 '''' N
'>,---N 1 / HN ....-- , ;') HN 0 )---='N --N
N"
S
// .S7' O-N O-N
\ \
N N
S/\ S

N / \ HN 0 /\
HN

_NI 0 110 , / \
/ N

HN NH

..--->----N
-0 0 N_Z
/ IN
, \
O-N O-N
1 \
N N.

N SI 1 \ N HN
7...:N 110 ,-NH NH , , O-N O-N
\
N N\
1101 -,. 1110 7----"N
, HO
OH
, / /
/ /

HN ----NH N ----NH
-14 , "_--NH
-NH H2N , N 1 \ N HN ----NH
)\--NH NH )------N ---14 HN <(-NH
t , A

/ N

HN .---NH HN 1. 1 N

O-N O-N
\
N \ N
HN la ,HN
N ' O-N O-N
\
N X \
0 1\11 114111 N N
iN
.(--NH <I-NH 0 , /V /
. , HN 1. 1 '''.
I HN' 1 <1=N
<-.-----N , 0 N 0 N , I
(..

/ /
V V

HN 410 õHN \ s:__ N
<rN N , HO

/ /
/ V
HN . N--N HN N4 <----=N )-......- <rN Nzz_.-K

/ /
/. V
HN a N."( HN . 1\1.4 , , / /
Z V

.<-=---N = , .,,(-=--N 1:-....1 , I, \
N.
HN Si N".....N N 01111 --NH /
, , N' /
N Z
110 111Pr I I P
HN NH HN NH
, --14 , / /
Z /
1110 lir FIN' HN NH
HN
<((-"N 0 IF , N 0' H

/ /
V ,r HN 1.1 .<-----N 1. HN' \N410 I NH
, , / /
/ /
SI -. lel HN 1 I HN -.. 1 1 .----r-N
N OH .<-..-:-.N N OH

/ I
/ /
1410 o HN HN

.(:'-------N <?------N 1411 N
0 ' / /
/ /
40 Oil Nil N 1 "N N
IN
NH, .<-,---N\
, / / z /

I

N HN NH
<r N
\ ,--N' / /

, / /

0 0 !
HN 1 ' N HN

/

/ /
v 7 Si lal ---HN N NH
\:N 111 ....tNH -N`
F\
F , / \

0 / , I
N ---- NH HN
'b-NH ---N' )--:--N N
F
114, , F3C , F

O-N O-N
\ \
N
HN .
--=-=- 0 HN -"N ---)=---'N N_Z
/ "

, , NH

O-N O-N
\ \
N N

HN
):------N 110 HN
I
HN /------ I
1 ,- N
0=S=0 N,N/
..

lel H.<1\I_N 0 NH
and 0 .
[0011] Another aspect provides for a compound selected from the group consisting of /, Iv IP Z HN .0 0 0 0 11. S' HN S
1 )L--N HN
I
4=:---N HN HO
F I) -, ID

/ /

9. 1101 9 HN S'`) -N FIN 0 )------"N 41 . NO .0 -0,--NH

/ /

la 9. 9.
HN S' , \ HNa S ' HIV 0 )--:--Al FIN
</--NH
, .. NH
NC> , = N-0 N-0 / /
/ /
I. 9 la 9, HN S-;
HN S ' =----N HIVI it :S> ' NH
NO
, / /
/ .7 HN S'-' HN S'`) )=---N HIV
HN ):=N FIN
NO 7---\ ..../--NH
NO
. , 0 N
\ ______________________________________________ / , / /

0 9. 0 9 HN S
HN S'-' )--:---N 41>----N HIV
Ej---NH
NO c6--NH
NO
, / /
Z /
, 0 9. a 9 HN S-.
HN S
)::---N HIV)=---N 41 /---NH
NOF _7(-NH
NI:1) / F F

/ /

HN SHN
0\ rNH
ID
> , /

/ /
Z /
SO HN 1110 9.
S HN S
)=---.N 41 >=-"N HIVNr....\
S
HS
NO
\ LI
, , 9?

N-0 I,,/
Z
1.1 9 101 9 HN S-' HN SC) >N 41 NO
\ NC> and 0 .
[0012] Another aspect provides for a compound selected from the group consisting of / /
/ Z

HN N
)z---."-N 0 <rN 0 *

/ /
Z /
N HN
= <(--N 0 .<=-"-N 0 , , / /

-----N N
.<\___N 0 \
, , O-N

HN
HN HN
0=S=0 .<(-7=-N
and Iv a X) HN
<r-N
[0013] Another aspect provides for a phaimaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
[0014] Another aspect provides for a use of a compound of Foimula (I), or a pharmaceutically acceptable salt thereof, in therapy. Another aspect provides for a method of treating a subject having a disease or condition responsive to the inhibition of a bromodomain-containing protein, comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some aspects, the bromodomain-containing protein is BRD4.
[0015] In some aspects, the disease or condition is chosen from an autoimmune disease, an inflammatory disease, a neurodegenerative disease, a cardiovascular disorder, a renal disorder, a viral infection, and obesity. In some aspects, the disease or condition is chosen from rheumatoid arthritis, osteoarthritis, atherosclerosis, psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, asthma, chronic obstructive airways disease, pneurnonitis, dennatitis, alopecia, nephritis, vasculitis, atherosclerosis, Alzheimer's disease, hepatitis, primary biliary cirrhosis, sclerosing cholangitis, diabetes (including type I diabetes), and acute rejection of transplanted organs. In some aspects the disease or condition is cancer, including hematological cancers, lymphoma, multiple myelomas, leukemias, a neoplasm or a tumor (for example a solid tumor). In some aspects the disease or condition is a neoplasm or cancer of the colon, rectum, prostate (for example castrate resistant prostate cancer), lung (for example non-small cell lung cancer, and small-cell lung cancer), pancreas, liver, kidney, cervix, uterus, stomach, ovary, breast (for example basal or basal-like breast cancer, and triple-negative breast cancer), skin (for example melanoma), the nervous system (including the brain, meninges, and central nervous system, including a neuroblastoma, a glioblastoma, a meningioma, and a medulloblastoma). In some aspects the disease or condition is a carcinoma. In some aspects, the disease or condition is hepatocellular carcinoma. In some aspects, the disease or condition is a lymphoma. In some aspects, the disease or condition is a B-cell lymphoma. In some aspects, the disease or condition is Burkitt's lymphoma. In some aspects, the disease or condition is diffuse large B-cell lymphoma.
In some aspects, the disease or condition is multiple myeloma. In some aspects, the disease or condition is chronic lymphocytic leukemia. In some aspects the disease or condition is NUT midline cardinoma. In some aspects the subject is a human.
[0016] In some aspects, the compound is administered intravenously, intramuscularly, parenterally, nasally, or orally. In one aspect, the compound is administered orally.
[0017] Also provided is a method of inhibiting a bromodomain, comprising contacting the bromodomain with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
[0018] Also provided is the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or condition responsive to bromodomain inhibition.
[0019] Also provided is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy. Further provided is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in treating a subject having a disease or condition responsive to the inhibition of a bromodomain-containing protein.
Also provided is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treatment described above. Also provided is the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a subject having a disease or condition responsive to the inhibition of a bromodomain-containing protein. Also provided is the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in a method of treatment described above.
[0020] Also provided are kits that include a compound of Fomiula (I), or a pharmaceutically acceptable salt thereof. In one aspect, the kit further includes instructions for use. In one aspect, a kit includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and instructions for use of the compounds in the treatment of the diseases or conditions described above.
[00211 Also provided are articles of manufacture that include a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In one embodiment, the container may be a vial, jar, ampoule, preloaded syringe, or an intravenous bag.
BRIEF DESCRIPTION OF FIGURES
[0022] FIG. 1 shows compound 1020-18 inhibited the viability of 240 cancer cell lines.
= Relative IC50 values are reported.
[0023] FIG. 2 shows inhibition of tumor growth in an MM. I S xenograft model by compound 1020-18.
[00241 FIG. 3 shows inhibition of tumor growth in a DHL-10 xenograft model by compound 1020-18.
[0025] FIG. 4 shows inhibition by compound 1020-18 of BRD4 binding at the IgH
superenhancer.
DETAILED DESCRIPTION
[0026] Described herein are compounds of Formula (I), which include compounds of Formulae (Ia), (lb), (Ic), (Id) and (le), compositions and foimulations containing such compounds, and methods of using and making such compounds.
[0027] One aspect of the current disclosure relates to compounds of Formula (I) R,a Rib R2a R2b R4b R5 (I) wherein Ria and Rib are each independently C1_6 alkyl optionally substituted with from 1 to 5 A groups;
R2a and R2b are each independently H or halo;
R3 is boronic acid or halo; or -C(0)0R5, -NHC(0)0R3, -NHS(0)2Ra, or -S(0)2NR5Rb; or selected from the group consisting of Ci_10 alkyl, C1_10 alkoxy, amino, C5_10 aryl, C6_20 arylalkyl, C1_10 heteroalkyl, C5_10 heteroaryl, and C6_20 heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R2 groups;
one of R4a and R4b is selected from the group consisting of H and Ci_6 alkyl optionally substituted with from 1 to 5 R2 groups, and the other is absent;
R5 is -C(0)0Ra, -NHC(0)0R5, -NHS(0)2Ra, or -S(0)2NRaRb; or selected from the group consisting of H, C1_10 alkyl, C1_10 haloalkyl, C1_10 alkoxy, amino, C5-10 aryl, C6-20 arylalkyl, Ci_10 heteroalkyl, C5-10 heteroaryl, and heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R2 groups;
each Ra and Rb is independently selected from the group consisting of H, C1_10 alkyl, C5_10 aryl, C6-20 arylalkyl, C1_10 heteroalkyl, C5-10 heteroaryl, and C6-20 heteroarylalkyl, each of which is optionally substituted with from I to 5 R2 groups;
and each R2 is independently selected from the group consisting of acyl, Ci_10 alkyl, Cl-io alkoxy, amino, amido, amidino, C5_10 aryl, C6-20 arylalkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, C1_10 haloalkyl, Ci_io heteroalkyl, C5_10 heteroaryl, C6-20 heteroarylalkyl, hydroxy, hydrazino, imino, oxo, nitro, sulfinyl, sulfonic acid, sulfonyl, thiocyanate, thiol, and thione;
wherein the Ci_io alkyl, C5_10 aryl, C6-20 arylalkyl, C1_10 heteroalkyl, C5-10 heteroaryl, and C6_20 heteroarylalkyl groups are optionally substituted with from 1 to 3 substituents independently selected from C1_6 alkyl, C5-10 aryl, halo, haloalkyl, cyano, hydroxy, and Ci-6 alkoxY;
or a pharmaceutically acceptable salt thereof.
[0028] Compounds of Formula (I) (which include compounds of any of Formulae (Ia), (lb), (Ic), (Id) and (le), described below) can include, independently, one or more of the following features. It will be recognized that features specified in each embodiment may be combined with other specified features to provide further embodiments.
[0029] In some compounds, Ria and Rib are each independently C1-6 alkyl which, as defined herein, includes alkenyl, alkynyl and cycloalkyl. In some compounds, Ria and Rib are different, and in other compounds Ria and Rib are the same. In some compounds, Ria and Rib are each independently a C1-6 alkyl optionally substituted with 1-5 R2 groups. In some compounds, Ria and Rib are both methyl. In some compounds, one of Ria or Rib is a methyl and the other is a methyl substituted with a hydroxy. In some compounds, Ria and Rib are both methyl substituted with a hydroxy. In some compounds, one of Ria or Rib is a methyl and the other is a methyl substituted with an amine. In some compounds, Ria and Rib are both methyl substituted with an amine.
[0030] In some compounds, R2a and R2b are both H. In some compounds, R2a and R2b are both halo. In some compounds, one of R2a and R2b is H and the other is halo. In some compounds the halo is -F or -Cl.
[0031] In some compounds, R3 is boronic acid, a boronic acid ester, or halo.
In some compounds, R3 is -C(0)01e, -NHC(0)0Ra, -NHS(0)2Ra, or -S(0)2NRaRb wherein Ra and Rb are described above. In some compounds, R3 is -C(0)0Ra, -NHC(0)0Ra, -NHS(0)2Ra, or -S(0)2NRaRb, wherein each Ra and Rb is independently C1_10 alkyl, C5-10 aryl, C1_10 heteroalkyl or C5_10 heteroaryl, each of which may be optionally substituted as described above. For example, in some compounds R3 is -C(0)0Ra, -NHC(0)0Ra, -NHS(0)2Ra, or -S(0)2NRaRb, wherein each Ra and Rb is independently C5_10 aryl or C5-10 heteroaryl. In some compounds, R3 is selected from the group consisting of C1_10 alkyl, C1.10 alkoxy, amino, C5_10 aryl, C6-20 arylalkyl, C1_10 heteroalkyl, C5_10 heteroaryl, and C6..
20 heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R2 groups, wherein R2 is described above. In some compounds, R3 is C1_10 alkyl, C1_10 alkoxy, or C1.10 heteroalkyl, each of which may be optionally substituted as described above. In some compounds, the heteroalkyl is a heterocycloalkyl. In other compounds, R3 is C6-20 arylalkyl or C6-20 heteroarylalkyl, each of which may be optionally substituted as described above. In other compounds, R3 is C5,10 aryl, C6-20 arylalkyl, C5_10 heteroaryl, or C6_20 heteroarylalkyl, each of which may be optionally substituted as described above.
In some compounds, R3 is amino optionally substituted as described above. For example, in some compounds R3 is -NH2, and in other compounds R3 is -NRYR!, wherein RY and Rz together with the nitrogen to which they are bonded form a Ci_io heteroalkyl or C5_10 heteroaryl, each of which may be optionally substituted as described above.
[0032] Other non-limiting examples of R3 include the following:
:55*5 *\/ , c OH
-rs.sS ,:ssss OH , HO __ OH
/ OH
csss 01-11 \ntinf, :ssSiD
HN
HO))-3 *
OH

s, \pfS 0 .5 j,5,5. I\V 1 N
N , r\l"N N N N
OH I N
OH I oFf 1 N- OH 1 s" y OH 1.-N
N , N
N
OH ¨S S
N
\ OH 1 ''''= OH 1 N, N ,-- , S--, N , N.. N--p , _ _ `) H
OH OH
c,55.50o 1 HN

, , , I

kl 5.55 N ,..õ,,,,,,k 0 0 õz.:....., Z---N'H , /
'c's5S N, ./. N N .,,..4 c?SxA,.. µ/;
Np.3 rss5.. N
N I
.L . , _ ..._ /, , - --= - , 0 , IA, ..,N ' 0 , I
I N ' 1 I
N
0 ,S, I 0 N ss,S3 HN

sS-55 sES:5 i , /
N .-sss5, HN AL .,..N 0 * 0 W ,s3 ' H ' 0 0 , H , I
14111 sS.S, "... ( a 0 A = se, "5., , HO N HO N.,,,,, .,..
y 1 ...r. , r-----T
HN,Tsss5..., N..,,.. j.,:, N...,--.15 N,.....,,i-,/ N,, ' N
/ - N
HN / ------- ss5) HN
0 =
---- ss-5, =
'WI HN
0 sSS:: N
\ N e r -.5.-.d , d N
NQ = N)r-...- N,ssS) N....1\1,ss.5: 1 , /12\17:
' N
/ ---- HN
HN Nit.-1' ,-- ss-5, /

trL0/tIOZSII/I3c1 6Z6Z81/1710Z OM

avvv, I
..rv-vv, _, NH N -----.,0 Y---- --.. .--k....., H

, , õivy,0 * ...
so Illy' i 0 , ,.

c.ss5 = .rs..55.
;5,55 0 :ss5 0 ,s_r.r = rsfY" . r;ssr it es.õ,- it r ,,,,, 11 =
41 110 c, 10 0 F, rp 0 ...-, 3 F , , -tivvN
401 10 :5155 0 , and F F OH 0 r- p.
...,, 3 , , .
[0033] In some compounds, one of R4a or R4b is H and the other is absent, that is, in some compounds R4a is H and R4b is absent, and in other compounds lea is absent and R41' is H. In other compounds, one of R4a and R4b is alkyl and the other is absent, that is, in some compounds R4a is alkyl and R41' is absent, and in other compounds R4a is absent and R4b is alkyl. In some compounds the alkyl is methyl.
[0034] In some compounds, R5 is -C(0)01e, -NHC(0)0R5, -NHS(0)2R5, or -S(0)2NRaRb, wherein Ra and Rb are described above. In some compounds, R5 is -C(0)0R5, -NHC(0)0Ra, -NHS(0)2Ra, or -S(0)2NRaRb, wherein each Ra and Rb is independently C1_10 alkyl or C5-10 aryl, each of which may be optionally substituted as described above. For example, in some compounds R5 is -NHC(0)0Ra, wherein Ra is methyl. In some compounds, R5 is -NHS(0)2Ra, wherein Ra is C140 alkyl or C5-10 aryl, each of which may be optionally substituted as described above. For example, in some compounds R5 is -NHS(0)2Ra, wherein Ra is cyclopropyl. In some compounds, R5 is selected from the group consisting of H, C1_10 alkyl, C1_10 haloalkyl, C1_10 alkoxy, amino, C5_10 aryl, C6_20 arylalkyl, C1_10 heteroalkyl, C5_10 heteroaryl, and C6_20 heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R2 groups, wherein R2 is described above. In some compounds, R5 is C1.10 alkyl optionally substituted as described above. In some compounds the C1_10 alkyl is a C1_10 cycloalkyl, e.g.

cyclopropyl. In other compounds, R5 is amino optionally substituted as described above.
For example, in some compounds R5 is -NH2, and in other compounds R5 is -NRYRz, wherein RY is H and Rz is alkyl, e.g. cyclopropyl. In other compounds, R5 is alkoxy, e.g.
methoxy.
[0035] In some compounds, Ria, Rib, R3, R4a, R4b and R5 are optionally substituted with from 1 to 5 (i.e. 1, 2, 3, 4 or 5) R2 groups as described above. In some compounds, Ra, Rib, R3, R4a, R4b and R5 are optionally substituted with 1, 2, or 3 R20 groups. In some compounds, each R2 is independently selected from the group consisting of alkyl, alkoxy, amino, cyano, halo, haloalkyl, heteroalkyl, hydroxy, and sulfonyl. In some comounds, each R2 is independently selected from the group consisting of aryl, alkylaryl, heteroaryl, and heteroalkylaryl. In some compounds, Ria, R1b, R3, R4a, R4b and R5 are not substituted. In some comounds, R2 is not substituted.
[00361 One subset of compounds of Formula (I) relates to compounds of Formula (Ia) /
R.a z Rib R4a 1101_N \
R4b R5 (Ia) wherein Ria and Rib are each independently C1_6 alkyl optionally substituted with from 1 to 5 1-1,20 groups;
R3 is boronic acid or halo; or -C(0)0Ra, -NHC(0)0Ra, -NHS (0)2Ra, or -S(0)2NRaRb; or selected from the group consisting of C1_10 alkyl, C1.10 alkoxy, amino, C5-10 aryl, C6_20 arylalkyl, C1_10 heteroalkyl, C5_10 heteroaryl, and C6_20 heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R2 groups;
one of R4a and R4b is selected from the group consisting of H and C1-6 alkyl optionally substituted with from 1 to 5 R2 groups, and the other is absent;
R5 is -C(0)0R5, -NHC(0)0Ra, -NHS(0)21e, or -S(0)2NR5Rb; or selected from the group consisting of H, C1_10 alkyl, C1_10 haloalkyl, C1_10 alkoxy, amino, C5-10 aryl, C6-20 arylalkyl, C1_10 heteroalkyl, C5-10 heteroaryl, and heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R2 groups;
each Ra and le is independently selected from the group consisting of H, C1_10 alkyl, C5_10 aryl, C6-20 arylalkyl, C1-10 heteroalkyl, C5-10 heteroaryl, and C6-20 heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R2 groups;
and each R2 is independently selected from the group consisting of acyl, C1_10 alkyl, C1 10alkoxy, amino, amido, amidino, C5_10 aryl, C6-20 arylalkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, C1_10 haloalkyl, C1_10 heteroalkyl, C5_10 heteroaryl, C6-20 heteroarylalkyl, hydroxy, hydrazino, imino, oxo, nitro, sulfinyl, sulfonic acid, sulfonyl, thiocyanate, thiol, and thione;
wherein the C1_10 alkyl, C5-10 aryl, C6-20 arylalkyl, C1_10 heteroalkyl, C5-10 heteroaryl, and C6-20 heteroarylalkyl groups are optionally substituted with from 1 to 3 substituents independently selected from C1_6 alkyl, C5_10 aryl, halo, haloalkyl, cyano, hydroxy, and Ci_6 alkoxy;
or a pharmaceutically acceptable salt thereof.
[0037] Another subset of compounds of Formula (I) relates to compounds of Formula (113) R .a V Rib R2a R2b N el R3 R5 (lb) wherein Ria and Rib are each independently C1_6 alkyl optionally substituted with from 1 to 5 groups;
R2a and R2b are each independently H or halo;
R3 is boronic acid or halo; or -C(0)0Ra, -NHC(0)0R.5, -NHS(0)2Ra, or -S(0)2NRaRb; or selected from the group consisting of C1_10 alkyl, C140 alkoxy, amino, C5-10 aryl, C6_20 arylalkyl, C1_10 heteroalkyl, C5_10 heteroaryl, and C6_20 heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R2 groups;
R5 is -C(0)0Ra, -NHC(0)0Ra, -NHS(0)2R5, or -S(0)2NRaRb; or selected from the group consisting of H, C1..10 alkyl, C1_10 haloalkyl, C1-10 alkoxy, amino, C5_10 aryl, C6-20 arylalkyl, C1_10 heteroalkyl, C540 heteroaryl, and C6-c heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R2 groups;
each Ra and Rb is independently selected from the group consisting of H, C1_10 alkyl, C5.10 aryl, C6-20 arylalkyl, Ci_io heteroalkyl, C5-10 heteroaryl, and C6-20 heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R2 groups;
and each R2 is independently selected from the group consisting of acyl, C1.10 alkyl, Cl-io alkoxy, amino, amido, arnidino, C5-10 aryl, C6.20 arylalkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, C1_10 haloalkyl, Ci_io heteroalkyl, C5_10 heteroaryl, C6-20 heteroarylalkyl, hydroxy, hydrazino, imino, oxo, nitro, sulfinyl, sulfonic acid, sulfonyl, thiocyanate, thiol, and thione;
wherein the C1.10 alkyl, C5-10 aryl, C6-20 arylalkyl, Ci_io heteroalkyl, C5-10 heteroaryl, and C6_20 heteroarylalkyl groups are optionally substituted with from 1 to 3 substituents independently selected from C1-6 alkyl, C5_10 aryl, halo, haloalkyl, cyano, hydroxy, and C1-6 alkOXY;
or a pharmaceutically acceptable salt thereof.
[0038] Another subset of compounds of Formula (I) relates to compounds of Formula (Ic) R V Rib HN el R3 R5 (Ic) wherein Rla and Rib are each independently C1_6 alkyl optionally substituted with from 1 to 5 groups;
R3 is boronic acid or halo; or -C(0)0R5, -NHC(0)0Ra, -NHS(0)2R', or -S(0)2NRaRb; or selected from the group consisting of Ci_10 alkyl, Ci_10 alkoxy, amino, C5_10 aryl, C6_20 arylalkyl, Ci_10 heteroalkyl, C5_10 heteroaryl, and C6_20 heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R2 groups;
R5 is -C(0)0Ra, -NHC(0)0Ra, -NHS(0)2Ra, or -S(0)2NRaRb; or selected from the group consisting of H, C1_10 alkyl, C1_10 haloalkyl, C1_10 alkoxy, amino, C5_10 aryl, C6_20 arylalkyl, C1_10 heteroalkyl, C5-10 heteroaryl, and heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R2 groups;
each Ra and Rb is independently selected from the group consisting of H, C1..10 alkyl, C5.10 aryl, C6-20 arylalkyl, C1_10 heteroalkyl, C5-10 heteroaryl, and C6-20 heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R2 groups;
and each R2 is independently selected from the group consisting of acyl, C1_10 alkyl, Ci-alkoxy, amino, amido, amidino, C5-10 aryl, C6-20 arylalkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, Ci_10 haloalkyl, C1_10 heteroalkyl, C5..10 heteroaryl, C6..20 heteroarylalkyl, hydroxy, hydrazino, imino, oxo, nitro, sulfinyl, sulfonic acid, sulfonyl, thiocyanate, thiol, and thione;
wherein the Ci_10 alkyl, C5-10 aryl, C6_20 arylalkyl, C1_10 heteroalkyl, C5-10 heteroaryl, and C6.20 heteroarylalkyl groups are optionally substituted with from 1 to 3 substituents independently selected from C1_6 alkyl, C5-10 aryl, halo, haloalkyl, cyano, hydroxy, and C1_6 alkoxy;
or a pharmaceutically acceptable salt thereof.
[00391 Another subset of compounds of Formula (I) relates to compounds of Formula (Id) R5 (Id) wherein R3 is boronic acid or halo; or -C(0)0Ra, -NHC(0)0R5, -NHS(0)2Ra, or -S(0)2NRaRb; or selected from the group consisting of C1_10 alkyl, C1.10 alkoxy, amino, C5-10 aryl, C6_20 arylalkyl, C1_10 heteroalkyl, C5_10 heteroaryl, and C6_20 heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R2 groups;
R5 is -C(0)0Ra, -NHC(0)01e, -NHS(0)2Ra, or -S(0)2NRaRb; or selected from the group consisting of H, C1_10 alkyl, C1_10 haloalkyl, Ci_io alkoxy, amino, C5-10 aryl, C6-20 arylalkyl, Ci_io heteroalkyl, C5-10 heteroaryl, and heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R2 groups;
each Ra and Rb is independently selected from the group consisting of H, C1_10 alkyl, C5_10 aryl, C6-20 arylalkyl, C1.10 heteroalkyl, C5-10 heteroaryl, and C6-20 heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R2 groups;
and each R2 is independently selected from the group consisting of acyl, C1_10 alkyl, C1_ io alkoxy, amino, amido, amidino, C5-10 aryl, C6_20 arylalkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, C1_10 haloalkyl, C1_10 heteroalkyl, C5-10 heteroaryl, C6-20 heteroarylalkyl, hydroxy, hydrazino, imino, oxo, nitro, sulfinyl, sulfonic acid, sulfonyl, thiocyanate, thiol, and thione;

wherein the Ci_io alkyl, C5-10 aryl, C6.20 arylalkyl, C1_10 heteroalkyl, C5-10 heteroaryl, and C6-20 heteroarylalkyl groups are optionally substituted with from 1 to 3 substituents independently selected from C1.6 alkyl, C5-10 aryl, halo, haloalkyl, cyano, hydroxy, and C1..6 alkoxy;
or a pharmaceutically acceptable salt thereof.
[0040] Another subset of compounds of Formula (I) relates to compounds of Formula (le) <ir N
(Ie) wherein R3 is boronic acid or halo; or -C(0)OR', -NHC(0)0Ra, -NHS(0)2R', or -S(0)2NRaRb; or selected from the group consisting of C1_10 alkyl, C1_10 alkoxy, amino, C5_10 aryl, C6_20 arylalkyl, C110 heteroalkyl, C5_10 heteroaryl, and C6..20 heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R2 groups;
each Ra and Rb is independently selected from the group consisting of H, C1.10 alkyl, C5..10 aryl, C6_20 arylalkyl, C1.10 heteroalkyl, C5_10 heteroaryl, and C6-20 heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R2 groups;
and each R2 is independently selected from the group consisting of acyl, C1.10 alkyl, C1_ io alkoxy, amino, amido, amidino, C5-10 aryl, C6..20 arylalkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, C1_10 haloalkyl, C1_10 heteroalkyl, C5-10 heteroaryl, C6-20 heteroarylalkyl, hydroxy, hydrazino, imino, oxo, nitro, sulfinyl, sulfonic acid, sulfonyl, thiocyanate, thiol, and thione;
wherein the C1_10 alkyl, C5-10 aryl, C6-20 arylalkyl, C1_10 heteroalkyl, C5-10 heteroaryl, and C6_20 heteroarylalkyl groups are optionally substituted with from 1 to 3 substituents independently selected from C1_6 alkyl, C5-10 aryl, halo, haloalkyl, cyano, hydroxy, and Ci_6 alkOXY;
or a pharmaceutically acceptable salt thereof.
[0041] Unless defined otherwise, all technical and scientific tern's used herein have the same meaning as commonly understood by one of ordinary skill in the art. It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise.
Thus, e.g., reference to "the compound" includes a plurality of such compounds and reference to "the assay" includes reference to one or more assays and equivalents thereof known to those skilled in the art, and so forth.
[0042] A dash at the front or end of a chemical group is a matter of convenience;
chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line drawn through a line in a structure indicates a point of attachment of a group. A dashed line indicates an optional bond. Unless chemically or structurally required, no directionality is indicated or implied by the order in which a chemical group is written. For instance, the group "-S02CH2-" is equivalent to "-CH2S02-" and both may be connected in either direction. The prefix "C"
indicates that the following group has from u to v carbon atoms, one or more of which, in certain groups (e.g. heteroalkyl, heteroaryl, heteroarylalkyl, etc.), may be replaced with one or more heteroatoms or heteroatomic groups. For example, "C1_6 alkyl" indicates that the alkyl group has from 1 to 6 carbon atoms.
[0043] Also, certain commonly used alternative chemical names may or may not be used. For example, a divalent group such as a divalent "alkyl" group, a divalent "aryl"
group, etc., may also be referred to as an "alkylene" group or an "alkylenyl"
group, an "arylene" group or an "arylenyl" group, respectively.
[0044] "Alkyl" refers to any aliphatic hydrocarbon group, i.e. any linear, branched, cyclic, or Spiro nonaromatic hydrocarbon group or an isomer or combination thereof. As used herein, the term "alkyl" includes terms used in the art to describe saturated and unsaturated aliphatic hydrocarbon groups with one or more points of attachment, including alkenyl (an aliphatic group containing at least one carbon-carbon double bond), alkylene (a divalent aliphatic group), alkynyl (an aliphatic group containing at least one carbon-carbon triple bond), cycloalkyl (a cyclic aliphatic group), alkylcycloalkyl (a linear or branched aliphatic group attached to a cyclic aliphatic group), and the like. Alkyl groups include, but are not limited to, methyl;
ethyl; propyls such as propan-1-yl, propan-2-y1 (iso-propyl), and cyclopropyls such as cyclopropan-l-yl, etc.; butyls such as butan-l-yl, butan-2-y1 (sec-butyl), 2-methyl-propan-1 -y1 (iso-butyl), 2-methyl-propan-2-y1 (t-butyl), cyclobutan-1-y1; butenes (e.g. (E)-but-2-ene, (Z)-but-2-ene); pentyls; pentenes; hexyls; hexenes; octyls; decyls; cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl, spiro[2.4Theptyl, and the like. An alkyl group comprises from 1 to about 10 carbon atoms, e.g., from 1 to 6 carbon atoms. In some embodiments, alkyl is a monovalent, linear or branched, saturated aliphatic hydrocarbon group comprising from 1 to about 10 carbon atoms, e.g., from 1 to 6 carbon atoms.
[0045] "Alkenyl" is a subset of "alkyl" and refers to an aliphatic group containing at least one carbon-carbon double bond and having from 2 to about 10 carbon atoms, e.g., from 2 to 6 carbon atoms or 2 to 4 carbon atoms and having at least one site of vinyl unsaturation (>C = C<). Alkenyl groups include ethenyl, propenyl, 1,3-butadienyl, and the like. Alkynyl may have from 2 to about 10 carbon atoms, e.g. from 2 to 6 carbon atoms or 2 to 4 carbon atoms.
100461 "Alkynyl" is a subset of "alkyl" and refers to an aliphatic group containing at least one carbon-carbon triple bond. The term "alkynyl" is also meant to include those groups having one triple bond and one double bond.
[0047] "Alkoxy" refers to the group -0-alkyl, wherein the alkyl group may be optionally substituted. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy.
[0048] "Acyl" refers to a group -C(=0)R, where R is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl or heteroarylalkyl as defined herein, each of which may be optionally substituted, as defined herein.
Representative examples include, but are not limited to fonnyl, acetyl, cylcohexylcarbonyl, cyclohexylmethyl-carbonyl, benzoyl, benzyloxycarbonyl and the like.
[0049] "Amido" refers to both a "C-amido" group which refers to the group -C(=0)NRYRz and an "N-amido" group which refers to the group -NRYC(=0)1e, wherein RY and Rz are independently selected from the group consisting of hydrogen, alkyl, aryl, heteralkyl, heteroaryl (each of which may be optionally substituted), and where RY and Rz are optionally joined together with the nitrogen or carbon bound thereto to form an optionally substituted heterocycloalkyl.
[0050] "Amino" refers to the group -NRYle wherein RY and Rz are independently selected from the group consisting of hydrogen, alkyl, aryl, heteralkyl, heteroaryl (each of which may be optionally substituted), and where R3' and Rz are optionally joined together with the nitrogen bound thereto to form a heterocycloalkyl or heteroaryl heteroaryl (each of which may be optionally substituted).
[0051] "Amidino" refers to the group -C(=NRx)NRYle where Rx, RY, and Rz are independently selected from the group consisting of hydrogen, alkyl, aryl, heteralkyl, heteroaryl (each of which may be optionally substituted), and where RY and Rz are optionally joined together with the nitrogen bound thereto to form a heterocycloalkyl or heteroaryl (each of which may be optionally substituted).
[0052] "Aryl" refers to a group with one or more aromatic rings. It may be a single aromatic ring or multiple aromatic rings which are fused together, linked covalently, or linked via one or more such as a methylene or ethylene moiety. Aryl groups include, but are not limited to, those groups derived from aeenaphthylene, anthracene, azulene, benzene, biphenyl, chrysene, cyclopentadienyl anion, diphenylmethyl, fluoranthene, fluorene, indane, indene, naphthalene, perylene, phenalene, phenanthrene, pyrene, triphenylene, and the like. An aryl group comprises from 5 to about 20 carbon atoms, e.g., from 5 to 20 carbon atoms, e.g. from 5 to 10 carbon atoms. In some embodiments, aryl is a a single aromatic ring or multiple aromatic rings which are fused together.
[0053] "Arylalkyl" (also "aralkyl") refers to an aryl group attached to an alkyl group.
Arylalkyl groups include, but are not limited to, benzyl, tolyl, dimethylphenyl, 2-phenylethan-1-yl, 2-naphthylmethyl, 2-naphthylethan-l-yl, naphthobenzyl, phenylvinyl, diphenylmethyl, and the like. For example, the "arylalkyl" may be attached to the rest of the compound of formula (I) through the aryl group. Alternatively, the "arylalkyl" may be attached to the rest of the compound of formula (I) through the alkyl group. Where specific alkyl moieties are intended, the nomenclature arylalkanyl, arylalkenyl and/or arylalkynyl may be used. An arylalkyl group comprises from 6 to about 30 carbon atoms, e.g. the alkyl portion of the arylalkyl group can comprise from 1 to about 10 carbon atoms and the aryl portion of the arylalkyl group can comprise from 5 to about 20 carbon atoms. In some instances an arylalkyl group comprises from 6 to about carbon atoms, e.g. the alkyl portion of the arylalkyl group can comprise from 1 to about carbon atoms and the aryl portion of the arylalkyl group can comprise from 5 to about 10 carbon atoms.
[0054] "Aryloxy" refers to the group -0-aryl, including by way of example, phenoxy and naphthoxy.
[0055] "Azido" refers to the group -N3.
[0056] "Boronic acid" refers to the group ¨B(OH)2.
[0057] "Boronic acid ester" refers to an ester derivative of a boronic acid compound.
Suitable boronic acid ester derivatives include those of the formula ¨B(OR)2 where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted. For example, boronic acid ester may be pinacol ester or catechol ester.
[0058] "Carbamoyl" refers to the group -C(0)NRYRz where RY and Rz are defined as in "amino" above.
[0059] "Carbonyl" refers to the divalent group -C(0)- which is equivalent to -C(=0)-.
[0060] "Carboxyl" or "carboxy" refers to -COOH or salts thereof.
[0061] "Carboxyl ester" or "carboxy ester" refers to the groups -C(0)0R, wherein R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted. In one embodiment, R is alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted.

[0062] "Cyano" or "carbonitrile" refers to the group -CN.
[0063] "Cycloalkyl" is a subset of "alkyl" and refers to a saturated or partially saturated cyclic group of from 3 to about 10 carbon atoms and no ring heteroatoms and having a single ring or multiple rings including fused, bridged, and Spiro ring systems. For multiple ring systems having aromatic and non-aromatic rings that have no ring heteroatoms, the term "cycloalkyl" applies when the point of attachment is at a non-aromatic carbon atom (e.g., 5,6,7,8,-tetrahydronaphthalene-5-y1). The term "cycloalkyl"
includes cycloalkenyl groups. Examples of cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and cyclohexenyl.
[0064] "Guanidino" refers to the group -NHC(=NH)NH2.
[0065] "Halo" or "halogen" refers to fluor , chloro, bromo and iodo.
[0066] "Haloalkyl" refers to substitution of alkyl groups with 1 to 5 or, in some embodiments, 1 to 3 halo groups, e.g., -CH2C1, -CH2F, -CH2Br, -CFC1Br, -CH2CH2C1, -CH2CH2F, -CF3, -CH2CF3, -CH2CC13, and the like, and further includes those alkyl groups such as perfluoroalkyl in which all hydrogen atoms are replaced by fluorine atoms.
[0067] "Haloaryl" refers to aryl groups with one or more halo or halogen substituents.
For example, haloaryl groups include phenyl groups in which from 1 to 5 hydrogens are replaced with a halogen. Haloaryl groups include, for example, fluorophenyl, difluorophenyl, trifluorophenyl, chlorophenyl, clorofluorophenyl, and the like.
[0068] "Heteroalkyl" refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatom or heteroatomic group. For example, heteroalkyl may include 1, 2 or 3 heteroatomic groups, e.g. 1 heteroatomic group. Heteroatoms include, but are not limited to, N, P, 0, S, etc. Heteroatomic groups include, but are not limited to, -NR-, -0-, -S-, -PH-, -P(0)2-, -S(0)-, -S(0)2-, and the like, where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or cycloheteroalkyl. The term "heteroalkyl" includes heterocycloalkyl (a cyclic heteroalkyl group), alkyl-heterocycloalkyl (a linear or branched aliphatic group attached to a cyclic heteroalkyl group), and the like.
Heteroalkyl groups include, but are not limited to, -OCH3, -CH2OCH3, -SCH3, -CH2SCH3, -NRCH3, -CH2NRCH3, and the like, where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted. A
heteroalkyl group comprises from 1 to about 10 carbon and hetero atoms, e.g., from 1 to 6 carbon and hetero atoms.
[0069] "Heteroaryl" refers to an aryl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatoms, as defined above. For example, heteroaryl may include 1, 2 or 3 heteroatomic groups, e.g. 1 heteroatomic group. Heteroaryl groups include, but are not limited to, groups derived from acridine, benzoimidazole, benzothiophene, benzofuran, benzoxazole, benzothiazole, carbazole, carboline, cinnoline, furan, imidazole, imidazopyridine, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like. A heteroaryl group comprises from 5 to about 20 carbon and hetero atoms in the ring or rings, e.g., from 5 to 20 carbon and hetero atoms, e.g. from 5 to 10 carbon and hetero atoms.
[0070] "Heteroarylalkyl" refers to an arylalkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatoms, as defined above. For example, heteroarylalkyl may include 1, 2 or 3 heteroatomic groups.Heteroarylalkyl groups include, but are no limited to, groups derived from heteroaryl groups with alkyl substituents (e.g. methylpyridine, dimethylisoxazole, etc.), hydrogenated heteroaryl groups (dihydroquinolines, e.g. 3,4-dihydroquinoline, dihydroisoquinolines, e.g. 1,2-dihydroisoquinoline, dihydroimidazole, tetrahydroimida7ole, etc.), isoindoline, isoindolones (e.g. isoindolin-1-one), dihydrophthalazine, quinolinone, spiro[cyclopropane-1,1'-isoindolin]-3'-one, di(pyridin-2-yl)methyl, di(pyridin-3-yl)methyl, di(pyridin-4-yl)methyl, and the like. A
heteroarylalkyl group comprises from 6 to about 30 carbon and hetero atoms, for example from 6 to about 20 carbon and hetero atoms.
[0071] "Heterocycloalkyl" is a subset of "heteroalkyl" and refers to a saturated or unsaturated cycloalkyl group in which one or more carbon atoms (and any associated 4.5 hydrogen atoms) are independently replaced with the same or different heteroatom.
Heteroatoms include, but are not limited to, N, P, 0, S, etc. A
heterocycloalkyl group may also contain a charged heteroatom or group, e.g., a quaternized ammonium group such as -N+(R)2- wherein R is alkyl, e.g., methyl, ethyl, etc.
Heterocycloalkyl groups include, but are not limited to, groups derived from epoxide, imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine, N-bromopyrrolidine, N-bromopiperidine, N-chloropyrrnlidine, N-chloropiperidine, an N,N-dialkylpyrrolidinium, such as N,N-dimethylpyrrolidinium, a N,N-dialkylpiperidinium such as N,N-dimethylpiperidium, and the like. The heterocycloalkyl group comprises from 3 to about 10 carbon and hetero atoms in the ring or rings. In some embodiments, heterocycloalkyl includes 1, 2 or 3 heteroatomic groups.
[0072] "Hydrazino" refers to the group -NHNF12.
10073] "Hydroxy" or "hydroxyl" refers to the group -OH.
[0074] "Imino" refers to the group -C(=NR)- wherein R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted.
[0075] "Nitro" refers to the group -NO2.
[0076] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
[0077] "Oxide" refers to products resulting from the oxidation of one or more heteroatoms. Examples include N-oxides, sulfoxides, and sulfones.
[0078] "Oxo" refers to a double-bonded oxygen (=0). In compounds where an oxo group is bound to an sp2 nitrogen atom, an N-oxide is indicated.
[0079] "Racemates" refers to a mixture of enantiomers.
[0080] "Stereoisomer" or "stereoisomers" refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiorners and diastereomers.
The compounds may exist in stereoisomeric form if they possess one or more asymmetric centers or a double bond with asymmetric substitution and, therefore, can be produced as individual stereoisomers or as mixtures. Unless otherwise indicated, the description is intended to include individual stereoisomers as well as mixtures. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see, e.g., Chapter 4 of Advanced Organic Chemistry, 4th ed., J.
March, John Wiley and Sons, New York, 1992).
[0081] "Substituted" (as in, e.g., "substituted alkyl") refers to a group wherein one or more hydrogens have been independently replaced with one or more substituents including, but not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, hydroxy, hydrazino, hydroxyl, imino, oxo, nitro, sulfinyl, sulfonic acid, sulfonyl, thiocyanate, thiol, thione, or combinations thereof. Polymers or similar indefinite structures arrived at by defining substituents with further substituents appended ad infinitum (e.g., a substituted aryl having a substituted alkyl which is itself substituted with a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.) are not intended for inclusion herein. Unless otherwise noted, the maximum number of serial substitutions in compounds described herein is three. For example, serial substitutions of substituted aryl groups with two other substituted aryl groups are limited to -substituted aryl-(substituted aryl)-substituted aryl. For example, in some embodiments, when a group described above as being "optionally substituted" is substituted, that substituent is itself unsubstituted.Similarly, it is understood that the above definitions are not intended to include impeanissible substitution patterns (e.g., methyl substituted with 5 fluoro groups or heteroaryl groups having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to the skilled artisan.
When used to modify a chemical group, the term "substituted" may describe other chemical groups defined herein. For example, the term "substituted aryl" includes, but is not limted to, "arylalkyl." Generally, substituted groups will have 1 to 5 substituents, 1 to substituents, 1 or 2 substituents or 1 substituent. Alternatively, the optionally substituted groups of the invention may be unsubstituted.
[0082] "Sulfonyl" refers to the divalent group -S(0)2-=
[0083] "Tautomer" refers to alternate forms of a compound that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups containing a ring atom attached to both a ring -NH- moiety and a ring =N- moiety such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.
[0084] "Thiocyanate" refers to the group -SCN.
[0085] "Thiol" refers to the group -SH.
[0086] "Thione" refers to a thioketone (=S) group.
[0087] "Pharmaceutically acceptable" refers to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.
[0088] "Pharmaceutically acceptable salt" refers to a salt of a compound that is pharmaceutically acceptable and that possesses (or can be converted to a form that possesses) the desired pharmacological activity of the parent compound. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like;
or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, lactic acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid, 2-napththalenesulfonic acid, oleic acid, palmitic acid, propionic acid, stearic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, and the like, and salts formed when an acidic proton present in the parent compound is replaced by either a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as diethanolamine, triethanolamine, N-methylglucamine and the like. Also included in this definition are ammonium and substituted or quatemized ammonium salts. Representative non-limiting lists of pharmaceutically acceptable salts can be found in S.M. Berge et al., J.
Pharina Sci., 66(1), 1-19 (1977), and Remington: The Science and Practice of Pharmacy, R.
Hendrickson, ed., 21st edition, Lippincott, Williams & Wilkins, Philadelphia, PA, (2005), at p. 732, Table 38-5.
[0089] The following abbreviations may also be used: AcOH: acetic acid; nBuLi:
n-butyllithium; CC: column chromatography; Cs2CO3: cesium carbonate; CH2C12 or DCM: dichloromethane; CH3MgI: methyl magnesium iodide; CuC12: copper chloride;

DAST: (diethylamino)sulfur trifluoride; DEAD: diethyl azodicarboxylate; DIBAL:

diisobutylaluminum hydride; DIPEA: diisopropylethylamine; DMF:
dimethylfoiniamide; DMSO: dimethyl sulfoxide; Et3N: triethylamine; Et0Ac:
ethyl acetate; Et0H: ethanol; g: gram(s); h: hour; H2: hydrogen; HBr: hydrogen bromide; HC1:
hydrogen chloride; H20: water; H202: hydrogen peroxide; HPLC: high perfoiniance liquid chromatography; KCN: potassium cyanide; LHMDS: lithium hexamethyldisilazide; LiA1H4: lithium aluminum hydride; LiOH: lithium hydroxide; M:
molar; MeCN: acetonitrile; Mel: methyl iodide; MeOH: methanol; MgSO4:
magnesium sulfate; MgCO3: magnesium carbonate; mg: millilgram; MsCI: mesyl chloride;
mmol:
millimoles mL: milliliter; sodium hydrogen sulfite; mCPBA: meta-chloroperoxybenzoic acid; N: noilliality; N2: nitrogen; Na2CO3: sodium carbonate; Na.HCO3: sodium bicarbonate; NaNO2: sodium nitrite; NaOH: sodium hydroxide; Na2S203: sodium bisulfate; Na2SO4: sodium sulfate; NBS: N-bromosuccinimide; NR4C1: ammonium chloride; NH40Ac: ammonium acetate; NMR: nuclear magnetic resonance; Pd/C:
palladium on carbon; PPh3: triphenyl phosphine; iPrOH: isopropyl alcohol; RT:
room temperature; SOC12: thionyl chloride; THF: tetrahydrofuran; TLC: thin layer chromatography; JAL: microliter.
[00901 It it understood that combinations of chemical groups may be used and will be recognized by persons of ordinary skill in the art. For instance, the group "hydroxyalkyl" would refer to a hydroxyl group attached to an alkyl group. A
great number of such combinations may be readily envisaged.
100911 Provided are also compounds in which from 1 to n hydrogen atoms attached to a carbon atom may be replaced by a deuterium atom or D, in which n is the number of hydrogen atoms in the molecule. As known in the art, the deuterium atom is a non-radioactive isotope of the hydrogen atom. Such compounds exhibit may increase resistance to metabolism, and thus may be useful for increasing the half-life of the compounds when administered to a mammal. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Phaiinacol. Sci., 5(12):524-527 (1984).
Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0092] Compounds of a given formula described herein encompasses the compound disclosed and all pharmaceutically acceptable salts, esters, stereoisomers, tautomers, prodrugs, solvates, and deuterated foims thereof, unless otherwise specified.
[0093] "Effective amount" or "therapeutically effective amount" means the amount of a compound described herein that may be effective to elicit the desired biological or medical response. These terms include the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The effective amount will vary depending on the compound, the disease and its severity and the age, weight, etc., of the subject to be treated.
[0094] "Subject" and "subjects" refers to humans, domestic animals (e.g., dogs and cats), farm animals (e.g., cattle, horses,sheep, goats and pigs), laboratory animals (e.g., mice, rats, hamsters, guinea pigs, pigs, rabbits, dogs, and monkeys), and the like.
[0095] "Treating" and "treatment" of a disease include the following: (I) preventing or reducing the risk of developing the disease, i.e., causing the clinical symptoms of the disease not to develop in a subject that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease,(2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms, and (3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms.
[0096] In some aspects, the disease or condition is chosen from an autoimmune disease, an inflammatory disease, a neurodegenerative disease, a cardiovascular disorder, a renal disorder, a viral infection, and obesity. In some aspects, the disease or condition is chosen from rheumatoid arthritis, osteoarthritis, atherosclerosis, psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, asthma, chronic obstructive airways disease, pneumonitis, denuatitis, alopecia, nephritis, vasculitis, atherosclerosis, Alzheimer's disease, hepatitis, primary biliary cirrhosis, sclerosing cholangitis, diabetes (including type I diabetes), and acute rejection of transplanted organs. In some aspects the disease or condition is cancer, including hematological cancers, lymphoma, multiple myelomas, leukemias, a neoplasm, cancer or tumor (for example a solid tumor). In some aspects the disease or condition is a neoplasm, cancer or tumor of the colon, rectum, prostate (for example castrate resistant prostate cancer), lung (for example non-small cell lung cancer, and small-cell lung cancer), pancreas, liver, kidney, cervix, uterus, stomach, ovary, breast (for example basal or basal-like breast cancer, and triple-negative breast cancer), skin (for example melanoma), the nervous system (including the brain, meninges, and central nervous system, including a neuroblastoma, a glioblastoma, a meningioma, and a medulloblastoma). In some aspects the disease or condition is a carcinoma. In some aspects, the disease or condition is hepatocellular carcinoma. In some aspects, the disease or condition is a lymphoma. In some aspects, the disease or condition is a B-cell lymphoma. In some aspects, the disease or condition is Burkitt's lymphoma. In some aspects, the disease or condition is diffuse large B-cell lymphoma. In some aspects, the disease or condition is multiple myeloma. In some aspects, the disease or condition is chronic lymphocytic leukemia. In some aspects the disease or condition is NUT midline cardinoma. In some aspects the subject is a human.
[00971 The pharmaceutical compositions may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, for example as described in those patents and patent applications incorporated by reference, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer.
[0098] In one aspect, the compounds described herein may be administered orally. Oral administration may be via, for example, capsule or enteric coated tablets. In making the pharmaceutical compositions that include at least one compound of Formula (I), or a pharmaceutically acceptable salt thereof, the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material (as above), which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.
[0099] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, ci mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include:

lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents;
emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
[00100] The compositions that include at least one compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the subject by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patent Nos. 3,845,770; 4,326,525; 4,902,514;
and 5,616,345. Another fonnulation for use in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of phaimaceutical agents is well known in the art. See, e.g., U.S. Patent Nos.
5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
[001011 The compositions may, in some embodiments, be formulated in a unit dosage form. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetetinined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient (e.g., a tablet, capsule, ampoule). The compounds are generally administered in a pharmaceutically effective amount. In some embodiments, for oral administration, each dosage unit contains from about 10 mg to about 1000 mg of a compound described herein, for example from about 50 mg to about 500 mg, for example about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, or about 300 mg. In other embodiments, for parenteral administration, each dosage unit contains from 0.1 to 700 mg of a compound a compound described herein. It will be understood, however, that the amount of the compound actually administered usually will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual subject, and the severity of the subject's symptoms.
[00102] In certain embodiments, dosage levels may be from 0.1 mg to 100 mg per kilogram of body weight per day, for example from about 1 mg to about 50 mg per kilogram, for example from about 5 mg to about 30 mg per kilogram. Such dosage levels may, in certain instances, be useful in the treatment of the above-indicated conditions. In other embodiments, dosage levels may be from about 10 mg to about 2000 mg per subject per day. The amount of active ingredient that may be combined with the vehicle to produce a single dosage foim will vary depending upon the host treated and the particular mode of administration. Dosage unit fauns may contain from 1 mg to 500 mg of an active ingredient.
[00103] Frequency of dosage may also vary depending on the compound used and the particular disease or condition treated. In some embodiments, for example, for the treatment of an autoimmune and/or inflammatory disease, a dosage regimen of 4 times daily or less is used. In some embodiments, a dosage regimen of 1 or 2 times daily is used. It will be understood, however, that the specific dose level for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease in the subject undergoing therapy.
[00104] For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
[00105] The tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
[00106] Kits that include a compound of Formula (I), or a pharmaceutically acceptable salt, thereof, and suitable packaging are provided. In one embodiment, a kit further includes instructions for use. In one aspect, a kit includes a compound of Formula (I), or a phatinaceutically acceptable salt thereof, and instructions for use of the compounds in the treatment of the diseases or conditions described herein.
[00107] Articles of manufacture that include a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a suitable container are provided. The container may be a vial, jar, ampoule, preloaded syringe, and intravenous bag.

[0008] Compounds of Formula (I) may be combined or administered with one or more additional anti-cancer or anti-inflammatory agents. For example, compounds of Formula (I) may be administered simultaneously with the one or more additional anti-cancer or anti-inflammatory agents, or may be administered sequentially (before or after) the one or more additional anti-cancer or anti-inflammatory agents.

[0009] Sequential administration or administered sequentially means that the inhibitors, compounds, or drugs are administered with a time separation of a few seconds, several minutes, hours, days, or weeks. Compounds may be administered with a time separation of up to 30 seconds, up to 15 minutes, up to 30 minutes, up to 60 minutes, or 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days, or 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks. When administered sequentially, the compounds or drugs may be administered in two or more administrations, and the compounds or drugs may be contained in separate compositions or dosage forms, which may be contained in the same or different package or packages.

[0010] Simultaneous administration or administered simultaneously means that the inhibitors, compounds, or drugs are administered with a time separation of no more than a few minutes or seconds. Compounds are administered with a time separate of no more than about 15 minutes, about 10 minutes, about 5 minutes, or 1 minute. When administered simultaneously, the inhibitors, compounds or drugs may be in separate compositions or dosage forms, or the same composition or dosage form.
[00108] In some aspects, compounds of Formula (I) may be combined with the additional anti-cancer or anti-inflammatory agents in a unitary dosage form (for example for oral administration). In other aspects, compounds of Formula (I) and the one or more additional anti-cancer or anti-inflammatory agents may be separate dosage foul's.
[00109] Suitable additional anti-cancer or anti-inflammatory agents include but are not limited to the following. Various kinase inhibitors are being used and are being developed to treat various cancers. For example, the activiation of the phosphatidylinositol 3-kinase (PI3K) pathway is observed in human cancer, and agents inhibiting PI3K are being investigated or developed as potential anti-cancer drugs and for the use in anti-cancer therapies. Additional kinase inhibitors include inhibitors of spleen tyrosine kinase (Syk) and Janus kinase (JAK). Other agents inhibiting related pathways are also of interest as anti-cancer or anti-inflammatory agents, including agents inhibiting the Ras/Raf/MEK/ERK pathway and the PI3KJPTEN/Akt/mTOR pathway.
As described herein, such inhibitors include agents that inhibit all subclasses of a target (e.g. PI3K alpha, beta, delta and gamma), agents that inhibit primarily one subclass, and agents that inhibit a subset of all subclasses. Compounds of Formula (I) may also be combined or administered with one or more additional anti-cancer or anti-inflammatory agents including inhibitors or antagonists of lysyl oxidase-like 2 (LOXL2), and inhibitors or antagonists of adenosine A2B receptor.
[00110] Further examples of kinase inhibitors include PI3K inhibitors, Syk inhibitors and JAK inhibitors. Examples of PI3K inhibitors include Compound A, Compound B, and Compound C:
si F 0 41) )1 N
HN
t-NH (Compound A) OF, HN N
NT
H (Compound B) N N
HN NT
H (Compound C).
[00111] Additional examples of PI3K inhibitors include XL147, BKM120, GDC-0941, BAY80-6946, PX-866, CH5132799, XL756, BEZ235, and GDC-0980, wortmannin, LY294002, PI3K II, TGR-1202, AMG-319, GSK2269557, X-339, X-414, RP5090, KAR4141, XL499, OXY111A, IPI-145, IPI-443, GSK2636771, BAY
10824391, buparlisib, BYL719, RG7604, MLN1117, WX-037, AEZS-129, PA799, AS252424, TGX221, TG100115, IC87114, and ZSTK474.
[00112] Inhibitors of mTOR include OSI-027, AZD2014, and CC-223.
[00113] Inhibitors of AKT include MK-2206, GDC-0068 and GSK795.

[00114] Examples of Syk inhibitors include compound D:
LN
NH
LN
===., 1.1 N--NH (Compound D).
[00115] Additional Syk inhibitors include R788 (fostamatinib), R-406 (tamatinib), and PRT062607.
Examples of JAK inhibitors include Compound E:

*
N H
N N
Lo N
N
(Compound E).
[00116] Compound E is described in U.S. Patent No. 8,486,941.
[00117] Additional JAK inhibitors include ruxolitinib (INCB018424), fedratinib (SAR302503, TG101348), tofacitinib, baricitinib, lestaurtinib, pacritinib (SB1518), XL019, AZD1480, INCB039110, LY2784544, BMS911543, and NS018.
[00118] In other aspects, compounds of Formula (I) may be combined or administered with one or more inhibitors or modulators (e.g. antagonists) of LOXL2, inhibitors or modulators of adenosine A2B receptor, or inhibitors or modulators of MMP-9.
[00119] In other aspects, compounds of Foimula (I) may be combined or administered with one or more agents that activate or reactivate latent human immunodeficiency virus (HIV). For example, compounds of Formula (I) may be combined or administered with a histone deacetylase (HDAC) inhibitor or a protein kinase C (PKC) activator. For example, compounds of Formula (I) may be combined or administered with romidepsin or panobinostat.
[00120] Compounds of Formula (I) may also be combined or administered with one or more anti-androgenic agents (for example, bicalutamide, flutamide, megestrol, and nilutamide).

[0011] Compounds of Formula (I) may also be combined or administered with one or more immunotherapeutic agents such as abagovomab, adecatumumab, afutuzumab, alemtuzumab, altumomab, amatuximab, anatumomab, arcitumomab, bavituximab, bectumomab, bevacizumab, bivatuzumab, blinatumomab, brentuximab, cantuzumab, catumaxomab, cetuximab, citatuzumab, cixutumumab, clivatuzumab, conatumumab, daratumumab, drozitumab, duligotumab, dusigitumab, detumomab, dacetuzumab, dalotuzumab, ecromeximab, elotuzumab, ensituximab, ertumaxomab, etaracizumab, farietuzumab, ficlatuzumab, figitumumab, flanvotumab, futuximab, ganitumab, gemtuzumab, girentuximab, glembatumumab, ibritumomab, igovomab, imgatuzumab, indatuximab, inotuzumab, intetumumab, ipilimumab, iratumumab, labetuzumab, lexatumumab, lintuzumab, lorvotuzumab, lucatumumab, mapatumumab, matuzumab, milatuzumab, minretumomab, mitumomab, moxetumomab, narnatumab, naptumomab, necitumumabõ nimotuzumab, nofetumomabn, ocaratuzumab, ofatumumab, olaratumab, onartuzumab, oportuzumab, oregovomab, panitumumab, parsatuzumab, patritumab, pemtumomab, pertuzuMab, pintumomab, pritumumab, racotumomab, radretumab, rilotumumab, rituximab, robatumumab, satumomab, sibrotuzumab, siltuximab, simtuzumab, solitomab, tacatuzumab, taplitumomab, tenatumomab, teprotumumab, tigatuzumab, tositumomab, trastuzumab, tucotuzumab, ublituximab, veltuzumab, vorsetuzumab, votumumab, zalutumumab, CC49 and 3F8. The exemplified therapeutic antibodies may be further labeled or combined with a radioisotope particle, such as indium In 111, yttrium Y 90, iodine 1-131.
EXAMPLES
[00121] Synthesis of certain compounds of Formula (I), and intermediates used to prepare them, is detailed in the following sections. Any compound numbers are listed for convenience.
[00122] All operations involving moisture and/or oxygen sensitive materials were conducted under an atmosphere of dry nitrogen in pre-dried glassware. Unless noted otherwise, materials were obtained from commercially available sources and used without further purification.
TM
[00123] Flash chromatography was performed on an Isco Combiflash Companion TM
using RediSep Rf silica gel cartridges by Teledyne Isco. Thin layer chromatography was performed using precoated plates purchased from E. Merck (silica gel 60 PF254, 0.25 mm) and spots were visualized with long-wave ultraviolet light followed by an appropriate staining reagent.
[00124] Nuclear magnetic resonance ("NMR") spectra were recorded on a Varian 400 MHz resonance spectrometer. 111 NMR chemical shifts are given in parts per million (5) downfield from tetramethylsilane ("TMS") using TMS or the residual solvent signal (CHC13 = 5 7.24, DMSO = ö 2.50) as internal standard. 11-1 NMR
information is tabulated in the following format: multiplicity (s, singlet; d, doublet; t, triplet; q, quartet;
m, multiplet), coupling constant(s) (J) in Hertz, number of protons. The prefix app is occasionally applied in cases where the true signal multiplicity was unresolved and hr indicates the signal in question was broadened.
TM
[00125] The compounds were named using ChemBioDraw Ultra Version 12Ø
TM
[00126] LCMS analysis was performed using a PE SCIEX API 2000 spectrometer TM
with a Phenomenex Luna 5 micron C18 column.
[00127] Preparatory HPLC was performed on a Gilson HPLC 215 or 271 liquid TM
handler with a Phenomenex column (Luna 5 u, C18, 100A or Gemini 10 u, C18, II0A) and a UV/VIS 156 detector.
[00128] When production of starting materials is not particularly described, the compounds are known or may be prepared analogously to methods known in the art or as disclosed in the Examples. One of skill in the art will appreciate that synthetic methodologies described herein are only representative of methods for preparation of the compounds described herein, and that other known methods and variants of methods described herein may be used. The methods or features described in various Examples may be combined or adapted in various ways to provide additional ways of making the compounds described herein.

[001291 Methods for obtaining the novel compounds described herein will be apparent to those of ordinary skill in the art, procedures described in, for example, the reaction schemes and examples below, and in the references cited herein.
Scheme 1 R1a N..õ....- Os, _.,_. N r-0 N-0 X B ____ \ 1 vz 4 / ,,, 4, Rla R1b 12 R .a v R,,, ,.
11101 Rib ..
________________________________________________ Yir ,..., , 1110 ,.., õ 1101 NH2 L,21,1 ....,21.1 I

(S1-1) (S1-2) (S1-3) SnCl2 I( i / õ i / . N-0 HO\0 R.a v R .. R.a v Rib 4 / ,, i, B-R3 p , a v R.,, le +X HO/
Si -* R5.CI

--NH ,--NH H2N I

(lc) (S1-5) (S1-4) halogenating agent ir R la v Rib R2a R2b N R-)\--NH

(lb) Step 1: Preparation of (S1-2) [00130] A compound of Foiniula (S1-2), wherein Ria and Rib are as defined for compounds of Formula (I), can be prepared by Suzuki coupling of a nitro aniline (S1-1) to a substituted isoxazole boronate ester in the presence of a base. It is understood that isoxazole boronic acids, other boronate esters, or other appropriate boron complexes hi) (e.g. -BF31( salts, etc.) may also be used in Suzuki coupling reactions.
Substituent X on nitro aniline (S1-1) may be any appropriate leaving group (e.g., Cl, Br, I, OTf), and X at each occurrence may be the same or different. Suitable catalysts include palladium catalysts, such as (1,3-bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridyl) palladium(II) dichloride (Peppsi-iPr). Suitable bases include, for example, cesium carbonate or 1,8-diazobicycloundec-7-ene. Suitable solvents include a combination of organic solvents and water, including, for example, dimethoxyethane and water.
The reaction is carried out in an appropriate solvent under nitrogen, at 70 to 150 C, for 30 minutes to 5 hours. When the reaction is substantially complete, the reaction is allowed to cool to room temperature. The reaction mixture can be partitioned between an aqueous phase and an organic phase. The aqueous phase is discarded, and the organic phase is purified by chromatography on silica gel. Alternatively, the compound of Formula (S1-2) may be used in the next step without purification.
Step 2: Preparation of (S1-3) [00131] A compound of Formula (S1-2) can then be iodinated in the presence of an appropriate iodine source, for example, elemental iodine. The reaction is typically conducted in the presence of a silver salt in an appropriate solvent.
Suitable, silver salts include, for example, silver nitrate. Suitable solvents include alcoholic solvents, including, for example, ethanol. The starting materials are typically combined at room temperature and allowed to react for 12-18 hours. When the reaction is substantially complete, the compound of Foimula (S1-3) is isolated by conventional means, such as by extraction using brine and an organic solvent such as ethyl acetate. The organic layer is dried and concentrated. The crude compound of Formula (S1-3) may be purified using chromatography on silica gel, or be used in the next step without purification.
Step 3: Preparation of (S1-4) [00132] The nitro group of compound (S1-3) can be reduced in the presence of an appropriate reducing agent, for example, stannous chloride, in an appropriate solvent, including alcoholic solvents such as ethanol. The starting materials are combined and brought to an elevated temperature such as 50 to 100 C, and kept at an elevated temperature for 3-10 hours. When the reaction is substantially complete, the compound of Foimula (S1-4) is isolated by conventional means, such as by extraction, and purified by chromatography on silica gel.
Step 4: Preparation of (S1-5) [00133] An appropriately substituted acyl chloride with substituent R5, as defined for compounds of Formula (I), is then reacted with the compound of Formula (S1-4) in an appropriate solvent, and allowed to react for a period of time such as 1-5 hours at a temperature near room temperature to form an acylated intermediate.
Appropriate solvents include basic organic solvents such as Pyridine. It is understood that in place of an acyl chloride, other appropriate acylating reagents may be used, such as acyl bromides or acid anhydrides. When reaction is sufficiently complete, solvent is removed under reduced pressure, and crude acylated intermediate is taken up into an appropriate acidic solvent, such as glacial acetic acid. Strong acid, such as concentrated hydrochloric acid, may then be added, and the reaction mixture is stirred at a refluxing temperature for

12-18 hours. When the reaction is substantially complete, the compound of Formula (51-5) is isolated by conventional means, such as by neutralization of acidic solvent followed by extraction, and either used without further purification or purified by chromatography on silica gel.
Alternative Step 4: Preparation of (S1-5) 0 4 õ
Ria Rib (31-4) ____________________________ HN

(S1-5) [00134] A substituted carboxylic acid with substituent R5, as defined for compounds of Fomula (I), or alternatively a mixture of acyl chloride bearing a substituent of R5 in a suitable acidic solvent such as glacial acetic acid, is reacted neat with the compound (S1-4) for 15 minutes to 24 hours at the refluxing temperature of the solvent acid. When the reaction is substantially complete, compound (S1-5) is isolated by conventional means, such as by neutralization of acidic solvent followed by extraction, and either used without further purification or purified by chromatography on silica gel.
Step 5: Preparation of (Ic) 1001351 A compound of Fonnula (Ic) can be prepared by Suzuki coupling of a compound (S1-5) to a boronic acid in the presence of a base. As shown above, boronic acid is substituted with carbon-linked aryl or heteroaryl R4 as defined for compounds of Formula (I). Boronate esters, or other appropriate boron complexes (e.g. -BF3K
salts, etc.) may also be used in place of a boronic acid. Suitable catalysts include palladium catalysts, such as (1,3-bis(2,6-diisopropylphenypimidazolidene)(3-chloropyridyl) palladium(II) dichloride (Peppsi-iPr). Suitable bases include, for example, cesium carbonate or 1,8-diazobicycloundec-7-ene. Suitable solvents include a combination of organic solvents and water, including, for example, dimethoxyethane or dimethylfonnamide and water. The reaction is carried out in an appropriate solvent under nitrogen, at 70 to 150 C, for 30 seconds to 5 hours. When the reaction is substantially complete, the reaction is allowed to cool to room temperature.
The reaction mixture can be partitioned between an aqueous phase and an organic phase. The aqueous phase is discarded, and the organic phase concentrated under reduced pressure, and the residue is purified by reverse phase high-performance liquid chromatography, eluting with an appropriate solvent mixture such as acetonitrile and water, to isolate compounds. Alternatively, the compound (Ic) may be purified by other conventional means, such as silica gel chromatography or recrystallization.
Step 6: Preparation of (Ib) [00136] A compound of Formula (lb) can be prepared by halogenation of a compound (Ic) with a halogenation agent such as NCS, NBS or NIS in an appropriate solvent such as THF, DMF, CH2C12 or CHC13. The reaction is carried out at 0 to 150 C, for 30 seconds to 5 hours. When the reaction is substantially complete, the reaction is allowed to cool to room temperature. The reaction mixture can be partitioned between an aqueous phase and an organic phase. The aqueous phase is discarded, and the organic phase concentrated under reduced pressure, and the residue is purified by reverse phase high-perfonnance liquid chromatography, eluting with an appropriate solvent mixture such as acetonitrile and water, to isolate compounds. Alternatively, the compound (lb) may be purified by other conventional means, such as silica gel chromatography or Aq recrystallization.
Scheme 2 [00137] Scheme 2 describes an exemplary method of preparing compounds of Formula (Id) wherein Rla, R1b and R5 are as described for compounds of Formula (Id), and R3 is aryl or heteroaryl, each of which may be optionally substituted as described for compounds of Formual (Id).

/õ / õ
'B-B' Ria RIIJ R1 a Rib \CYA
X¨R3 (S1-5)lel OH ______________________________________ HN B' HN R-OH

(S2-1) (Id) Step 1: Preparation of (S2-1) [00138] The compound (S2-1) can be prepared by borylation of compound (S1-5), described above, with a borylating reagent such as bis(pinacolato)diboron, shown, in the presence of a base such as potassium acetate, in a suitable solvent. Suitable catalysts include palladium catalysts, such as [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II). Suitable solvents include polar organic solvents such as dimethylfon-namide or dimethylsulfoxide. The reaction is carried out in an appropriate solvent under nitrogen, at about 70 to 130 C, for 1-18 hours. When the reaction is substantially complete, the reaction is allowed to cool to room temperature. The reaction mixture can be partitioned between an aqueous phase and an organic phase. The aqueous phase is discarded, the organic phase concentrated under reduced pressure, and the residue is purified by reverse phase high-perfoimance liquid chromatography, eluting with an appropriate solvent mixture such as acetonitrile and water with 0.1% TFA, with spontaneous boronic ester hydrolysis occurring under purification conditions, to isolate compound (S5-1) as a boronic acid.
Alternatively, compound (S5-1) may be used in Step 2 in its crude boronate ester font'.
Step 2: Preparation of (Id) [00139] The compound (Id) can be prepared by Suzuki coupling of compound hd (S5-1) in the presence of a base to X-R3, wherein X is a leaving group such as bromide or iodide and R3 is an aryl or heteroaryl, each of which may be optionally substituted as described for compounds of Formual (Id). Suitable catalysts include palladium catalysts, such as (1,3-bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridyl) palladium(II) dichloride (Peppsi-iPr). Suitable bases include, for example, cesium carbonate or 1,8-diazobicycloundec-7-ene. Suitable solvents include a combination of organic solvents and water, including, for example, dimethoxyethane or dimethylfoitnamide and water. The reaction is carried out in an appropriate solvent under nitrogen, at about 70 to 150 C, for 30 seconds to 5 hours. When the reaction is substantially complete, the reaction is allowed to cool to room temperature.
The reaction mixture can be partitioned between an aqueous phase and an organic phase. The aqueous phase is discarded, and the organic phase concentrated under reduced pressure, and the residue is purified by reverse phase high-performance liquid chromatography, eluting with an appropriate solvent mixture such as acetonitrile and water, to isolate compound (Ie), wherein R3 is aryl or heteroaryl, each of which may be optionally substituted as described for compounds of Formual (I). Alternatively, the compound (Ie) may be purified by other conventional means, as described above.
Scheme 3 1001401 Scheme 3 describes an exemplary method of preparing compounds of Formula (Ic) wherein RI', Rib and R5 are as described for compounds of Formula (I), and R3 is an optionally substituted amino group as described for compounds of Formula (I).

, Ri4 a R.b opt. sub. amine laS1-5 HN R-(Ic) [00141] Compound (S1-5) may be reacted with a primary or secondary amine NHRYle (see definition of "amino" above) or heterocycle bearing NH in the present of palladium or copper catalyst (eg, CuI , Cu0Ac, CuO, Cu20) and an appropriate ligand such as 4,7-dimethoxy-1,10-phenanthroline in the presence of a a suitable base, such as cesium carbonate, and PEG-3350 in a suitable solvent (e.g. butyronitrile, THF, DMF, DMA pyridine, toluene or 1,4- dioxane) to produce a compound (Id), wherein R3 is an optionally substituted amino group as described for compounds of Formula (Id).
The reaction mixture is carried out at 100 to 150 C for 24-96 hours. When the reaction is substantially complete, the reaction is allowed to cool to room temperature.
The reaction mixture can be concentrated and purified as described above to obtain the compound (Id).
Scheme 4 [00142] Scheme 4 describes a particular subset of the reaction described in Scheme 3 in which compound (S1-5) is reacted with a cyclic amine (e.g. an optionally substituted lactam, as shown) to yield compound of Formula (S4-1) wherein Rh, Rib and R5 are as described for compounds of Folinula (Id), and R3 is an optionally substituted heteroalkyl or heterarylalkyl, in this case an optionally substituted lactam group wherein each R2 is as described for compounds of Formula (Id) and n is from 0 to 5, e.g. 0, I, or 2.

/ R la Rib Ria õ- Rib HN

HN HN
¨N

(51-5) (S4-1) [00143] The compound of (S4-1) can be prepared by coupling an optionally substituted lactam to compound (S1-5) in the presence of a copper catalyst, an amino ligand, and a base. As shown above, R5 and R2 are defined above for compounds of Formula (I). As described there, each R2 may be independendly selected from the groups listed, and n is from 0 to 5. An appropriate copper catalyst could be copper halide, such as copper (I) iodide. The amino ligand could be a substituted amine, such as N,N)-dimethylethane-1,2-diamine. The base is an appropriate inorganic base, such as cesium carbonate. The reaction is carried out in an appropriate solvent, such as 1-methylpyrrolidin-2-one (NMP), at 50 to 200 C for 0.5-24 hours under conventional heating or microwave-assisted heating. When the reaction is substantially complete, the product (S4-1) is isolated by conventional means, such as by filtration, extraction, followed by purification by chromatography of the residue on silica gel.
Scheme 5 100144] Scheme 5 describes an exemplary method of preparing compounds of Formula (S5-5), (S5-6) and (S5-7), all subgenera of Formula (I), wherein R1a, Rib, Rs, and R2 are as described for compounds of Formula (I), and R3 is alkyl optionally substituted with 1 to 5 R2 groups, wherein each R2 is independently selected from the group described for compounds of Formula (I).

Br Rla V Rib Ria r/ Rib R2a R2b Scheme 1 )m. R2 a io R2b R2a le R2b õI
_________________________________________________ Ylio' 0 step 1 0, 0, (S5-1) (S5-2) (S5-3) Scheme 1 ., step 4 / , / y /
Ria .-- Rib Ria ..,, Rib Ria V Rib R2a 10 R2b R2a R2b .04( l l HN TFA R2o ___ RN R2o 4 _______ RN
R2o 2 eq. R20MgX
)---=""-N R2o .)---=N OH (R20 is same) ----=N 0 R5 R5 or 1 eq. R20MgX +
(S5-6) (S5-5) 1 eq. R20MgX (S5-4) (each R2 is NR = NBoc or NH
hydrogen ; DAST different) Ria V R lb /, /
Ria Rib Rla /- Rib NaCN

la R20 -Alio-101 R2o HN R2o R2o HN HN
R2o >=7---.N F )=-N CN

(S5-7) (S5-8) (S5-8) Step 1: Preparation of (S5-2) 1001451 Compound (S5-2) may be prepared by reacating (S5-1) with a substituted isoxazole boronate ester as described in Scheme 1, Step 1.
Step 2: Preparation of (S5-3) [00146] Compound (S5-3) may be prepared by reducing the nitro group in the presence of an appropriate reducing agent such as stannous chloride, as described in Scheme 1, Step 3. Other reducing agents such as palladium may also be used.
AR

Step 3: Preparation of (S5-4) [00147] Compound S5-4 may be prepared from (S5-3) in a similar manner as that described in Scheme 1, Step 4. Alternatively, this process can be carried out by treating with ethyl alkylcarbimidate hydrochloride in alcoholic solvent such as Me0H at elevated temperature for a few to several hours.
Step 4: Preparation of (S5-5) [00148] The compound (S5-5) can be prepared by coupling one or more Grignard reagents to (S5-4) in the presence of a base. In this example, each R2 may be the same or different, that is, each R2 may be independently selected from the group of substituents described for compounds of Foimula (I). Where each R2 is the same group, two equivalents of R20MgX can be used. Where each R2 is a different, one equivalent of R20MgX may be used followed by one equivalent of a different R20MgX. The reactions are carried out in an appropriate solvent, such as tetrahydrofuran (THF), at temperatures ranging from -78 C to ambient temperature from anywhere from an hour to 24 hours. The reaction mixture can be allowed to warm to room temperature.
When the reaction is substantially complete, it can be quenched with for example, water or methanol and the product of Formula 2 is isolated by conventional means, such as by extraction, followed by purification by chromatography of the residue on silica gel.
Alternatively, the compound (S5-5) can be prepared by reacting with alkyl lithium agent or lithium reagent generated from (hetero)aromatic compound or (hetero)aromatic halide with strong base such as LDA,LiHMP, n-BuLi, sec-BuLi, tert-BuLi in an appropriate solvent such as hexane, THF, diethyl ether, dichrolomethane at lower temperature if necessary.
[00149] This process can be carried out after protection of N on the benzimidazole with appropriate protectiong group such as Boc to impropve the chemical yield.
Step 5: Preparation of (S5-6) [00150] The compound (S5-5) can then undergo a dehydroxylation in the presence of an acid to obtain corresponding alkenes such as those of compound (S5-6).
It is understood that a large variety of both organic and inorganic acids can facilitate this reaction. Suitable solvents include as toluene or acetonitrile. The reaction may also be performed neat, that is using the reagent acid as the solvent. Examples of strong acid that can be used include sulfuric or phosphoric acid and also trifluoroacetic acid.
The reaction is carried out in an appropriate solvent under nitrogen, at an elevated temperature of about 70 to 150 C, for 30 minutes to 5 hours by conventional heating or by use of microwave irradiation. When the reaction is substantially complete, the reaction is allowed to cool to room temperature. The reaction mixture can be partitioned between an aqueous phase and an organic phase. The aqueous phase is discarded, and the organic phase is purified by chromatography on silica gel. Alternatively, compound (S5-6) may be used in the next step without purification.
Step 6: Preparation of (S5-7) [00151] Compound (S5-6) can then be reduced in the presence of an appropriate metal catalyst and hydrogen to furnish compound of (S5-7). The reaction is typically conducted in the presence of a catalyst like 10% palladium on carbon and a solvent such ethanol or ethyl acetate. When the reaction is substantially complete, the solid is filtered off and the filtrate is concentrated under vacuum. The reaction mixture can be partitioned between an aqueous phase and an organic phase. The aqueous phase is discarded, and the organic phase is purified by chromatography on silica gel.
It should be noted that the compound (S5-7) can also be made directly from compounds (S5-5) using methodology readily available to those skilled in the art.
Step 7: Preparation of (S5-8) [00152] Compound (S5-8) can then be prepared from (S5-5) by treating with a fluorinating agent such as DAST in inert solvent toward electrophilic fluorination such as dicloromethane at appropriate temperature from 0 C to rt.
Step 8: Preparation of (S5-9) [00153] Compound (S5-9) can then be prepared from (S5-8) by treating with a cyanide such as NaCN, KCN or CuCN in polar solvent such as water, acetonitrile, DMF.
THF, dioxane or mixed solvent system if necessary and at appropriate temperature from 0 C to elevated temperature desirably at rt.
-7n Alternative method for the preparation of (S5-5) Step 9: Preparation of (S5-10) [00154] Compound (S5-4) can be hydrolyzed to give the carboxylic acid (S5-10) by treating with Li0H, NaOH or KOH in water and polar solvent such as Me0H, Et0H,.
THF, dioxane or mixed solvent system if necessary and at appropriate temperature from rt to elevated temperature.
Step 10: Preparation of (S5-11) [00155] Compound (S5-11) can be obtained from the carboxylic acid (S5-10) by treating with N,0 dimethyl hydroxyl amine hydrochloride, organo tert-amine and appropriate coupling agent such as HATU, DCC or EDC in an appropriate solvent such as DMF, THF, dioxane or dichloromethane and at appropriate temperature from rt to elevated temperature.
Step 11: Preparation of (S5-12) [00156] Compound (S5-12) can be obtained from (S5-11) by protecting NH on the benzimidazole with Boc20 in the presence of organo tert-amine and DMAP if necessary at rt.
Step 12 and 13: Preparation of (S5-5) [00157] Compound (S5-12) was sequencially treated with organi lithium reagent or organo magnesium reagent in an appropriate solvent such as hexane, THF, diethyl ether, dioxane or dichloromethane at lower temperature to rt to install two same or different R2 onto the tert alchol. The protecting group on the N of benzimidazole falls off during the reaction in some cases. But the product has to be treated with TFA to remove Boc if it stays.

R.
4 ,,, / , Rib R. Rib , 4, H
aa ,--= HCI
HATU
NaOH DIPEA
meOH
_____________________________ 9 ____________ 9' OH
HN HN DMF
}-,---N 0 R5 step 9 R5 step 10 (S5-4) (S5-10) 4 / , 4, 4 i , 4, R.L, R.a , R,,, Boc20 DMAP
IP Et3N
e l I, HN k0 Boc-N 0 THE 0 1 ----=-N 0 I
R5 step 11 R5 (55-11) (S5-12) R20mgx R R'' 4,, R20mgX Rl , / Rib ia a , or or R20L1 R2oLi %
40 R20 _________________________________________ 01 R20 _______________ .
Boc-N RN R2o OH
--,----N 0 )------N
step 12 R5 step 13 (S5-13) (S5-5) NR = NH or NBoc Alternative method for the preparation of (S5-2) [00158] When the phenyl ring is mono-fluorinated at R2a or R2b position, compound (S5-15) can be prepared from (S5-14) in a similar manner as that described in Scheme 1, Step 1. And then, the compound (S5-15) can be nitrated under conditions generating NO2 + to afford (S5-2, R2a or R21 is F).

, Br /
R1a .., Rlb Rla ,Z. Rib R28, R2b Scheme 1 2+ / R2a 40 R2b _______________________________________________ OR, Step 1 TFA R2b C31 Ci (S5-14) (S5-15) (55-2) Alternative method for the preparation of (S5-13) [00159] The compound (S5-13) can be prepared from (S5-16) by means of lithiation using appropriate strong base such as BuLi, sec-BuLi or tert-BuLi at lower temperature such as -78 C in appropriate solvent such as hexane, THF or diethyl ether.
Generated lithium intermediate can be trapped with carbonyl derivative such as Wienreb amide to give (S5-13).

Ria V Rla n-BuLi Rla Ria THF

el Boc-N ,0 Boc-N 0 (S5-16) (S5-13) Alternative method for the preparation of (S5-13) [00160] When R2 on (S5-13) is a saturated ring system, the present keton can be prepared from the compound (S5-11) in 3 steps sequence.

/ k / k R R1a Rib R18 / Rib a 1110/-o )1.

Boc_N LiAIH4 1110 ________ H BOG-N

(S5-11) (S5-17) (S5-18) R .a Rib [0]

Boc_N
Y---=-N R2 (S5-13) Step 1: Preparation of (S5-17) [00161] The compound (S5-11) is reduced by an appropriate reducing agent such as LAB to give compound (S5-17).
'71 Step 2: Preparation of (S5-18) [00162] A saturated ring precursor can be treated with tert-butylhydroperoxide to generate radical intermediate (in case the ring prescursor is a cyclic ether) or strong base such as LDA to generate lithium enorate intermediate (in case the ring system is a cyclic ketone) in an appropriate solvent. The intermediate can react with the compound (S5-17) to give the alcohol (S5-18).
Step 3: Preparation of (S5-13) [00163] The alcohol (S5-18) can be oxidized by an appropriate oxidizer such as Dess-Martin reagent in an appropriate solvent such as dichloromethane or chloroform to give (S5-13).
Scheme 6 [00164] Scheme 6 describes an exemplary method of preparing compounds of Formula (Id) wherein Rea, Rib and R3 are as described for compounds of Folinula (I), and R5 is alkyl or heteroalkyl, each of which may be optionally as described for compounds of Folinula (Id).

/ / /
R R R 0 R,a Rib X

(S1-4) (S6-1) (Id) Step 1: Preparation of Foimula (S6-1) [00165] Compound (S6-1) can be prepared by Suzuki coupling of a compound (S1-4) to a boronic acid as described in Scheme 1, Step 5.
'7/1 Step 2: Preparation of (Id) [00166] A substituted acyl halide (R5C(0)X wherein X is a halide, e.g. Cl, and R5 is alkyl or heteroalkyl, each of which may be optionally as described for compounds of Formula (I)) is then reacted with compound (S6-1) in an appropriate solvent for 1-5 hours at room temperature to form an acylated intermediate. Appropriate solvents include basic organic solvents such as pyridine. It is understood that in place of an acyl chloride, other appropriate acylating reagents may be used, such as acyl bromides or acid anhydrides. Other acylation strategies, such as peptide coupling, can also be used to Rum such an acylated intermediate. When the reaction is sufficiently complete, solvent is removed under reduced pressure and crude acylated intermediate is taken up into an appropriate acidic solvent such as glacial acetic acid. Strong acid, such as trifluoroacetic acid, may then be added and the reaction mixture is stirred at refluxing temperature for 12-18 hours. When the reaction is substantially complete, the reaction mixture is subjected to= neutralization of acidic solvent followed by extraction, and purified by reverse phase high-performance liquid chromatography, eluting with an appropriate solvent mixture such as acetonitrile and water, to isolate compound (Id).
Scheme 7 001671 Scheme 7 describes an exemplary method of preparing compounds of Formula (S7-4) wherein Ri a, Rib, are as described for compounds of Formula (I) and R4b is an optionally substituted alkyl as described for compounds of Foimula (I) / 4õ, Ri4 a Rib Ria Rib /
Ria 7 Rib R4b_x SnCl2 0211m NH2 HN,R4b H2NI
HN,R4b (S1-3) (S7-1) (S7-2) , HOµ
/
R,a Rib B¨R3 Ria HO/
R-)\---N,R4b R5 µR4b (S7-4) 0 (S7-3) Step 1: Preparation of (S7-1) [00168] Compound (S7-1) wherein may be prepared by alkylating the compound (S1-3) with R4b-X, wherein R4b is an optionally substituted alkyl as defined for compounds of Formula (I) and X is an appropriate leaving group, e.g. iodo or triff ate, in a suitable organic solvent such as dimethylfonnamide in presence of a suitable base such as cesium carbonate. The starting materials are combined and allowed to react for 30 minutes to 5 hours. When the reaction is substantially complete, the compound of (S7-1) is isolated by conventional means, such as by extraction, and purified by chromatography on silica gel.
Step 2: Preparation of (S7-2) [00169] The nitro group of compound (S7-1) can then have reduced in the presence of an appropriate reducing agent, for example, stannous chloride, in an appropriate solvent, including alcoholic solvents such as ethanol. The starting materials are combined and brought to an elevated temperature such as 50 to 100 C, and kept at an elevated temperature for 3 to 10 hours. When the reaction is substantially complete, 'h the compound of (S7-2) is isolated by conventional means, such as by extraction, and purified by chromatography on silica gel.
Step 3: Preparation of (S7-3) [00170] An appropriately substituted acyl chloride with substituent R5, as defined in the specification for compounds of Formula (I), is then reacted with the compound (S7-2) in an appropriate solvent, and allowed to react for a period of time such as 1-5 hours at a temperature near room temperature to fowl an acylated intermediate.

Appropriate solvents include basic organic solvents such as Pyridine. It should be understood that in place of an acyl chloride, other appropriate acylating reagents may be used, such as acyl bromides or acid anhydrides. When reaction is sufficiently complete, solvent is removed under reduced pressure, and crude acylated intermediate is taken up into an appropriate acidic solvent, such as glacial acetic acid. Strong acid, such as concentrated hydrochloric acid, may then be added, and the reaction mixture is stirred at refluxing temperature for 12-18 hours. When the reaction is substantially complete, the compound (S7-3) is isolated by conventional means, such as by neutralization of acidic solvent followed by extraction, and either used without further purification or purified by chromatography on silica gel.
Step 4 ¨ Preparation of (S7-4) [00171] The compound (S7-4) can be prepared by Suzuki coupling of compound (S7-3) to commercially available boronic acid shown above in the presence of a base. As shown above, boronic acid is substituted with carbon-linked aryl or heteroaryl R3 as defined in the specification for compounds of Formula (I). It should be understood that boronate esters, or other appropriate boron complexes (i.e. -BF3K salts, etc.) may also be used in place of a boronic acid. Suitable catalysts may include palladium catalysts, such as (1,3-bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridyl) palladium(II) dichloride (Peppsi-iPr). Suitable bases may include, for example, cesium carbonate or 1,8-diazobicycloundec-7-ene. Suitable solvents may include a combination of organic solvents and water, including, for example, dimethoxyethane or dimethylfonuamide and water. The reaction is carried out in an appropriate solvent under nitrogen, at an elevated temperature of about 70 C to 150 C, for about 30 seconds to 5 hours. When the reaction is substantially complete, the reaction is allowed to cool to room temperature. The reaction mixture can be partitioned between an aqueous phase and an organic phase.
The aqueous phase is discarded, and the organic phase concentrated under reduced pressure, and the residue is purified by reverse phase high-performance liquid chromatography, eluting with an appropriate solvent mixture such as acetonitrile and water, to isolate compound (xiii). Alternatively, the compound (xiii) may be purified by other conventional means, such as silica gel chromatography or recrystallization.
Scheme 8 [00172] Scheme 8 describes an exemplary method of preparing compounds of Formula (S8-1) wherein Ria, RR3 and Ra are as described for compounds of Formula / /
R RILJ
R'a z Rib N - _______________________________ S
HN

HN
Ra (S6-1) (S8-1) [00173] An isothiocyanate substituted with substituent R20, as defined in this Scheme, is reacted with compound (S6-1) in an appropriate solvent, such as tetrahydrofuran, in presence of an appropriate base, such as triethylamine, for1-5 hours at 50 to 100 C, at which point an activating carbodiimide such as 1-ethy1-3-(3-dimethylaminopropyl)carbodiimide hydrogen chloride is added and the reaction is allowed to continue for an additional 1-5 hours. When the reaction is substantially complete, the solvent is removed under reduced pressure and the crude residue is purified by reverse phase high-perfaimance liquid chromatography, eluting with an appropriate solvent mixture such as acetonitrile and water, to isolate compound (S8-1).
Scheme 9 [00174] Scheme 9 describes an exemplary method of preparing compounds of Formula (S9-1) wherein Rla, R11', R3 and Ra are as described for compounds of Formula (I).
'72 / õ /
Ria R,aV Rib C(ORa)4 (S5-1) (S9-1) [00175] An orthocarbonate C(OW)4, (wherein Ra is described above, e.g.
alkyl, haloalkyl) is reacted with compound (S5-1) either neat or in the presence of an appropriate acid, such as acetic acid, and allowed to react for 30 minutes to 18 hours 25 to 150 C. When the reaction is substantially complete, the solvent is removed under reduced pressure and the crude residue is purified by reverse phase high-performance liquid chromatography, eluting with an appropriate solvent mixture such as acetonitrile and water, or by conventional means such as silica gel chromatography, to isolate compound (S9-1).
Scheme 10 [00176] Scheme 10 describes an exemplary method of preparing compounds of , ¨3 Formula (S10-3) wherein Rh,Riband Ra are as described for compounds of Formula r Rla R Ri a Rib CI
Lj Ri a R
S' BrCN l Ra 1101 ___________ el 0 (S1-4) (S10-1) (S10-2) HO
\B¨R3 R Rib Rib HN 1.1 R3 HN
k S
Ra 0 (S10-3) Step 1: Preparation of (S10-1) [001771 Compound (S1-4) in an appropriate solvent mixture such as ethanol, acetonitrile, and water, with an appropriate base, such as sodium bicarbonate, is cooled to a low temperature such as 0 C. An appropriate cyanogen halide, such as cyanogen bromide, shown, is added to the reaction mixture and the reaction mixture is allowed to warm to room temperature and to react for 12-18 hours. When the reaction is substantially complete, ethanol is added, the reaction mixture is filtered, solvents are removed under vacuum, and the crude residue is purified by conventional means such as silica gel chromatography, to isolate compound of (S10-1).
Step 2: Preparation of (S10-2) [001781 Compound of (510-1) is combined in an appropriate solvent, such as tetrahydrofuran, with an appropriate base, such as triethylamine. An appropriate sulfonylating reagent, such as cyclopropanesulfonyl chloride, is added to the reaction mixture and the reaction is allowed to react for a time of 12 to 18 hours.
When the R() reaction is substantially complete, the reaction mixture may be isolated by conventional means, such as extraction followed by removal of organic solvents, and the crude residue is purified by conventional means such as silica gel chromatography, to isolate compound of (S10-2).
Step 3: Preparation of (S10-3) [00179] The compound (S10-3) can be prepared by Suzuki coupling of a compound (S10-2) to a substituted boronic acid, as described in Scheme 1 above.
Scheme 11 [00180] Scheme 11 describes an exemplary method of preparing compound (S11-7) wherein Ra is as described for compounds of Formula (I).
Br Br Br F ____________________ S 40 ___________________ S' NO2 NO2 NO2 H\N
(S11-1) (S11-2) 0 / Z
la 9-0 110 9 (S11-3) \-__./ (S11-4) 0 / / S V
V V

1401 9, la 9,,o lel 9, n2-NI
- S'C) --,..õ-\ NH2 H,I\I --H0 Ra-NH
(S11-5) L----/ (S11-6) LI (S11-7) Step 1: Preparation of Foimula (S11-1) [00181] Compound (S11-1) can be prepared by coupling commercially available benzyl mercaptan to commercially available 4-bromo-2-fluoro-1-nitrobenzene in the presence of a base such as cesium carbonate. The reaction is carried out in an appropriate solvent, such as dimethylformamide (DMF), at a temperature of from 0 C to RT
for about 2 hours. When the reaction is substantially complete, the product (S11-1) is isolated by conventional means, such as by extraction, followed by purification by chromatography of the residue on silica gel. Alternatively, the compound (S11-1) may be used in the next step without purification.
Step 2: Preparation of Formula (S11-2) [00182] Compound (S11-1) can then be oxidized in the presence of an appropriately substituted haloimidazolidine-2,4-dione compound, for example, 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione. The reaction is typically conducted in the presence of an acid in an appropriate solvent. Suitable acids may include, for example, acetic acid. Suitable solvents may include a combination of solvents, including, for example, acetonitrile and water. The reaction was conducted at 0 C and then was allowed to warm to room temperature and stirred for 1 hour before being partitioned between brine and ethyl acetate. The organic layer was dried using sodium sulfate and evaporated. The crude sulfonyl chloride was used without further purification in the next step.
Step 3: Preparation of (S11-3) [00183] The compound (S11-2) can then be used in a Suzuki coupling reaction with a boronate ester, as described in Scheme 1, Step 1.
Step 4: Preparation of (S11 -4) [00184] Compound (S11-3) can be dissolved in solvent such as HOAc and reduced with Zn powder at RT. After stirring for about 25 mm, the Zn powder is filtered off. Volatiles are removed and the crude aniline in taken up in AcOEt, washed with carbonate solution, and purified by chromatography on silica gel to afford (S11-5).
Step 5: Preparation of (S11-5) [00185] Compound (S11-4) can be nitrated using NO2BF4 in solvents like DCM/acetonitrile. The reaction is conducted at 0 C and then the temperature is slowly raised to RT overnight. The solvent is then evaporated, the residue was dissolved in Et0Ac, washed with sat. NaHCO3 solution. The organic solvent is then evaporated and purified with chromatography on silica gel to afford (S11-5).
Step 6: Preparation of (S11-6) [00186] Compound (S11-5) can be reduced using catalytic hydrogenation. The reaction can be conducted in solvent such as Me0H and catalyst used was Pd (10% on carbon). The reaction is completed in 2h at RT. The reaction mixture is filtered and solvent is evaporated. The residue is then purified with chromatography on silica gel to afford (S11-6).
Step 7: Preparation of (S11-7) [00187] [0108] Compound (S11-6) can be reacted with an isothiocyanate derivative. The reaction can be conducted in solvent such as THF in the presence of base such as triethylamine. The reaction is heated to about 80 C for 3-5h before 1-ethy1-3-(3-dimethylaminopropy1)-carbodiimide hydrogen chloride is added and heated at for 30 mins. The solvent is then evaporated. The residue is then purified with prep-HPLC to afford (S11-7).
Scheme 12 [00188] Scheme 12 describes an exemplary method of preparing compounds of Folinula (12-1) wherein R5 is as described for compounds of Formula (I).

OH
1.1 9, o 0 H2N s-C) HN µe<-NH2 FIN)=7"-N HNO

(S11-6) (S12-1) Preparation of (S12-1) [00189] Compound (S11-6) can be reacted with a substituted carboxylic acid as described in Scheme 1, Alternative Step 4, to afford (S12-1).

Scheme 13 [00190] Scheme 13 describes an exemplary method of preparing compounds of Formula (13-2) wherein Ra is as described for compounds of Formula (I).

la 9 __________________ DN.
la 9 o H 2N SHN HN S-C) NH2 4,1 HNo HNID
HS RS
(S11-6) (S13-1) (S13-2) Step 1: Preparation of (S13-1) [00191] Compound (S11-6) can be reacted with 1,1'-thiocarbonyldiimidazole in a solvent such as DMF. The reaction is conducted at temperature of 90 C
overnight before the solvent is evaporated. The residue is then purified with prep-HPLC
to afford (S13-1).
Step 2: Preparation of (S13-2) [00192] Compound (S13-1) can be reacted with an iodide derivative (e.g. an optionally substituted alkyl iodide) in solvent such as Et0H in the presence of base such as KOH. The reaction is conducted at RT overnight before the solvent was evaporated.
The residue was then purified with prep-HPLC to afford (S13-2).
Scheme 14 [00193] Scheme 14 describes an exemplary method of preparing compounds of Formula (14-1) wherein 12a is as described for compounds of Founula (I).
A

9e0 le HN
HN S'C) HNID
o RaS HN
0=S, (S13-2) (S14-1) Step 1: Preparation of (S14-1) [00194] Compound (S13-2) can be reacted with 2,4,6-trichloro-1,3,5-triazine and H202 in a solvent such as acetonitrile. The reaction is conducted at RT
overnight before the solvent is evaporated. The residue is then purified with prep-HPLC to afford (S14-1).
Scheme 15 [00195] Scheme 15 describes an exemplary method of preparing compounds of Formula (15-1) wherein Ra is as described for compounds of Formula (I).

9e0. 9e0 HN HN
N H N
o, HNID
RaS rõ,:S
`Ra (S13-2) (S15-1) Preparation of (S15-1) [00196] Compound (S13-2) can be reacted with mCPBA or H202 in solvent such as DCM. The reaction is conducted at RT for 30 mins before the solvent is evaporated.
The residue is then purified with prep-HPLC to afford (S15-1).
[00197] Compounds of Foimula (I) also include the following:
RC

0 N/_:\ 0 N/__ HN
HN ,, HN ,, )=-N HO N
)=--"N HO N 7 X-=-N HO N
HN HN IAN
0=S=0 0=S=0 0=S=0 . , 6 , / / /

0 N/ \
0 N/_\ 0 N/_\
-HN HN HN
)--:--N HO I )-=---"N HO NI X----N HO NI

0=S=0 0=S=00,---i=0 , / I, HO / / OH
z7 7 * OH 1 1 O. OH 1 HN N
HN N HN N HN N
<
_<?:---- 1 -N ?.-,--N
<1tN N '',- NI '===
HO N
I I
HO .-- , v , / / / /

* OH --- i 101 OH ---- 1 1101 OH 1 0 OH 1 HN N HNN HN N HN N
(--N -----N 2----:-N -N
NN N '-= N
I7 `--I I I
7 7 , HO--"- 7 , , ' / / / /
/ 7 V 7 ir * OH 1 0 OH --- 1 0 OH %-'T HN 0 OH 0 HN N HN N HN -. ..J.
N
<(----=-N , <r N N , <rN N <rN
N .. '---I I ' N
I

I7 ..
Rh /

* HNa HN HN N3 1 110 OH-' 1 N N HN '''' N
<r-N
0 N (N
N N
I 1--- . 1 ' ' 1r ' ..-=
= N-0 N-0 z z /
V
* OH --- 1 1 * OH ---- 1 *

HN N HN N N
.---N y.--N -N
N N
H2N-"--I , HN
---i 0 OH i HN N HN N HN N
y---N
NN '' =-----N

I-IN 1 .
S, 7 \ 0 / 7. Z

F F F
F 7 , OHO
, * OH 1 *7 OH 1 lel N HN
HN N HN
.<---N N
i N
N j--N
<("-N -,' 1 l ' . , I
F

/ / / z le OH 11101 OH
HN * OH 0 HN HN
<r-N <rN <y-='N
N --- N , , --. -,.
F
R'7 I
P N -, N
W
zOS
-N={-----P
N N N NH N NH N NH
1 ; HO 0 1 HO 140 I HO le 7 X. y 41 / N 7zH / /
O-N O-N O-N
.---I
?
N c N - 9 A N.--7 N N--,---P
N N NH N NH N NH
I ; HO 0 I HO 10111 1 7, HO 0 4HN / / NzH
O-N O-N O-N
OcA
, , N N-N
I ---1NT 14=---( __PO
N N
,, rah NH / N
\ NH / \ NH / = \ NH
W

A -N HO lat -N HO 0 -N HO 0 --.
N2 N-,---P N- N.,---P---/ / \ NH
-N HO 4 -N HO el -N HO 4 -N HO 0 z / y 7 7 / / /

=
====== ,- I 1 I 7 ' NV 1 , 1----\s N---N---I
N--NH ))). S
NH

1 ...NH0 = tNi HO 0 A
. ,., . z VI
A .._'= 'i / O- O-N
U-N N
trL0/tIOZSI1IIDd 6Z6Z81/1710Z OM

z z z , -HN N HN N HN N
<(-N <IN I NN
N --= N I , and I .
[00198] Compounds of Foimula (I) also include the following:

/ / /
Z V z F 401 14/ \ F II" N / \
HN HN HN lir ---.
)--=----N HO NI ,.-- )--:-:14 HO NI ,.-- )'-=-----N
HO NI
HN HN HN
04=0 07--=0 I , , ----, ' /V / /
Z V
F 0 N./ , F . N / \ F is N/ \
HN , HN HN , =,, )-----:--N HO NI )------N HO tkj )_N HO N ,--HN HN HN
074=0 04=0 0--7-S=0 L./.
6 , L, , , N-0 I,/
Z
F 40 N/ \
F= N/ \
HN \
HN )----:"-N HO
);------N HO NI HN
HN 04=0 0--=-==0 A, and 6 .
[00199] The following examples illustrate further aspects, and provide additional compounds of Formula (I).
Example 1 N-Cyclopenty1-2-(cyclopropylmethylamino)-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazole-4-sulfonamide (1020-1) Step 1: Preparation of 1-bromo-3-benzylthio-4-nitrobenzene HS siBr Br Cs2CO3, DIVIF
S

[00200] Benzyl mercaptan (2.36 g, 19 mmol) was added dropwise to a mixture of 1-bromo-3-fluoro-4-nitrobenzene (5 g, 19 mmol), cesium carbonate (7.87 g, 57 mmol) at C in DMF (25 ml) under nitrogen. The reaction mixture was allowed to warn' to room temperature, stirred for 2 hours and partitioned between ethyl acetate and water.
The organic phase was washed with brine (4x), dried with sodium sulfate and concentrated. Crystallization from hot EtOAc afforded the product 1-bromo Step 2: Preparation of 5-bromo-N-cyclopenty1-2-nitrobenzenesulfonamide Br Br 1.
N
0 \CI I. 0 11.0 S' NO2 2. NH2 [00201] Solid 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (1.21 g, 6.19 mmol) was added to an ice-cold suspension of the 1-bromo-3-benzylthio-4-nitrobenzene (1 g, 3.09 mmol) in acetonitrile (25 mL), acetic acid (1 ml) and water (0.62 m1). The clear solution was allowed to warm to room temperature and stirred for 1 hour before being partitioned between brine and ethyl acetate. The organic layer was dried using sodium sulfate and evaporated. The crude sulfonyl chloride (rf = 0.23 in 9:1 hexanes/
ethyl acetate, starting material rf = 0.57) was used without further purification in the next 9(1 step.
[00202] To a solution of cyclopentyl amine (0.52 g, 6.18 mmol) in pyridine (5 ml) was added above sulfonyl chloride in DCM (5 mL) at 0 C. The reaction was stirred at room temperature for 15 minutes before being partitioned between brine and ethyl acetate. The organic layer was washed with brine, dil. HC1 and again brine, and dried over sodium sulfate. Purification on silica gel (rf = 0.33 in 9:1 hexanes/
ethyl acetate) afforded the product 5-bromo-N-cyclopenty1-2-nitrobenzenesulfonamide as an off-white powder.
Step 3: Preparation of N-cyclopenty1-5-(3,5-dimethylisoxazol-4-y1)-2-nitrobenzenesulfonamide Br PEPPSI-IPr, Cs2CO3 la 9. N 9 s-9 B

[00203] To a mixture of the 5-bromo-N-cyclopenty1-2-nitrobenzenesulfonamide (1.394 g, 4 mmol), 3,5-dimethylisoxazole-4-boronic acid pinacol ester (1.78 g, 8 mmol), PEPPSITm-IPr (Sigma-Aldrich Corporation) (0.271 g, 0.4 mmol) and cesium carbonate (3.90 g, 12 mmol) under nitrogen were added dimethoxyethane (20 mL) and water (10 mL). The reaction mixture was degassed with N2 and then heated to 90 C for 1 hour.
The mixture was partitioned between water and ethyl acetate, the organics concentrated and purified by silica gel chromatography (gradient DCM to DCM/ethyl acetate=
1/1) to give the product N-cyclopenty1-5-(3,5-dimethylisoxazol-4-y1)-2-nitrobenzenesulfonamide as a white powder.
Step 4: Preparation of 2-amino-N-cyclopenty1-5-(3,5-dimethylisoxazol-4-yl)benzenesulfonamide 11. Zn, AcOH
S' SO

NT() 2 HN
1002041 The N-cyclopenty1-5-(3,5-dimethylisoxazol-4-y1)-2-nitrobenzenesulfonamide (1.27 g, 3.5 mmol) was dissolved in AcOH with stirring and Zn powder (20 g) added in portions (5x, in 5 mm intervals) at RT. After stirring for 25 min., the Zn powder was filtered off. Volatiles were removed and the crude aniline taken up in Et0Ac, washed 4x with aq. carbonate solution, and purified by column chromatography ( rf = 0.2, hexane/Et0Ac : 1/1) to afford 2-amino-N-cyclopenty1-5-(3,5-dimethylisoxazol-4-yl)benzenesulfonamide as a white powder.
Step 5: Preparation of 2-amino-3-bromo-N-cyclopenty1-5-(3.5-dimethylisoxazol-4-yl)benzenesulfonamide NBS
1St 0 9,10 Br 11,0 NH2 Hisi NH2 Hirj [00205] The 2-amino-N-cyclopenty1-5-(3,5-dimethylisoxazol-4-yl)benzenesulfonamide (0.26g, 0.763 mmol) was taken up in DMF (5 ml) and cooled to 0 C. NBS (0.136 g, 0.763 mmol) was added and stirred for 10 min at 0 C
followed by 20 min at RT. The solution was diluted with Et0Ac (20 ml) and washed 5x with brine.
The product (rf= 0.5, hexane/ Et0Ac = 1/1) was purified by CC (loaded in DCM, gradient hexane to hexane/Et0Ac = 1/1) to afford 2-amino-3-bromo-N-cyclopenty1-(3,5-dimethylisoxazol-4-yl)benzenesulfonamide as a white powder.
Step 6: Preparation of 2-amino-N-cyclopenty1-5-(3,5-dimethylisoxazol-4-yl)benzenesulfonamide Pd/C, H2 Br 9õ0 40 9. Me0H
S'Cs Nn2 HN NH2Hrisi [00206] The 2-amino-3-bromo-N-cyclopenty1-5-(3,5-dimethylisoxazol-4-yl)benzenesulfonamide (4g) was dissolved in Me0H (150 ml) and DCM (10 mL). To the solution was added Pd/C (2g, 10% on carbon) and the flask was charged with H2.
The reaction was completed overnight. The reaction mixture was filtered and thesolvent was evaporated. The residue was purified by silica gel column chromatography (0-70%
Et0Ac/Hexane) to afford 2-amino-N-cyclopenty1-5-(3,5-dimethylisoxazol-4-yl)benzenesulfonamide.
Step 7: Preparation of 2-amino-N-cyclopenty1-5-(3,5-dimethylisoxazo1-4-y1)-3-nitrobenzenesulfonamide ___________________________________ )1, 140 9.
021v [00207] The 2-amino-N-cyclopenty1-5-(3,5-dimethylisoxazol-4-yl)benzenesulfonamide (336mg, immol)) was dissolved in DCM/acetonitrile (15/15 ml).
To the solution was added NO2BF4 (1.4 mmol, 2.8 mL(0.5M)) at 0 C. The temperature was slowly raised to RT. Reaction completed about 30% after lh. To the solution was added 0.1eq of NO2BF4. The reaction completed about 50% after 3h. To the solution was added another 0.2 eq of NO2BF4 and stirred at RT overnight. The solvent was then evaporated, the residue was dissolved in Et0Ac, washed with sat. NaHCO3 solution. The organic solvent was then evaporated and purified with silica gel column chromatography (0-60% Et0Ac/Hexane) to afford 2-amino-N-cyclopenty1-5-(3,5-dimethylisoxazol-4-y1)-3-nitrobenzenesulfonamide.

Step 8: Preparation of 2,3-diamino-N-cyclopenty1-5-(3,5-dimethylisoxazol-4-yl)benzenesulfonamide 7HHSIlo Pd/C, H2 0 Me0H 0 NH2Hfl N
ON

[00208] The 2-amino-N-cyclopenty1-5-(3,5-dimethylisoxazol-4-y1)-3-nitrobenzenesulfonamide (400mg) was dissolved in Me0H (20 m1). To the solution was added Pd/C (200 mg,10% on carbon) and then placed under a hydrogen atmosphere while stirring. When the reaction was completed the mixture was filtered and the solvent was evaporated. The residue was then purified by silica gel column chromatography (0-20% Me0H/DCM) to afford 2,3-diamino-N-cyclopenty1-5-(3,5-dimethylisoxazol-4-yl)benzenesulfonamide.
Step 9: Preparation of N-cyclopenty1-2-(cyclopropylmethylamino)-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazole-4-sulfonamide O-N N
S EDC s-HN
H2N ,õµ 0 THE NEt3, 80 C )--=N 0 0 H2N 0 0 <(-NH
[00209] 2,3-diamino-N-cyclopenty1-5-(3,5-dimethylisoxazol-4-yl)benzenesulfonamide (20 mg, 0.06 mmol) was dissolved in THF (1 mL) and to this solution was added cyclopropylmethyl isothiocyanate (8 mg, 0.07 mmol) and triethylamine (84 L). The reaction was heated at 80 C overnight before 1-ethy1-3-(3-dimethylaminopropy1)-carbodiimide hydrogen chloride (13 mg, 0.07 mmol) was added and heated at 80 C for 2h. The solvent was then evaporated under vacuum and the residue was purified by preparative HPLC (0-100% CH3CN/H20) to afford N-ALL

cyclopenty1-2-(cyclopropylmethylamino)-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazole-4-sulfonamide.
[00210] C211-127N503S. 430.2 (M+1). NMR
(400MHz, CD30D) 6 7.65 (s, 1H), 7.54 (s, 1H), 3.66-3.57 (m, 3H), 2.38(s, 3H), 2.25 (s, 3H), 2.00-1.51 (m, 4 H), 1.49-1.39 (m, 4H), 0.84-0.80 (m, 1H), 0.32-0.27 (m, 2H), 0.08-0.05 (m, 2H).
Example 2 N-Cyclopenty1-6-(3,5-dimethylisoxazol-4-y1)-2-(3-methoxypropylamino)-1H-benzo[d]imidazole-4-sulfonamide (1020-2) S

/
EDC

,N
H
H2N THF, NEt3, 80 C HN
H2N 0 µ0 NH
¨0 1002111 2,3-diamino-N-cyclopenty1-5-(3,5-dimethylisoxazol-4-yObenzenesulfonamide (25 mg, 0.07 mmol) (see Example 1, Step 8) was dissolved in THF (1 mL). To the solution was added 3-methoxypropyl isothiocyanate (11 mg, 0.09 mmol) and triethylamine (3001aL). The reaction was heated at 80 C for 4h before 1-ethy1-3-(3-dimethylaminopropy1)-carbodiimide hydrogen chloride (16 mg, 0.08 mmol) was added and heated at 80 C for 30 mins. The solvent was then evaporated under vacuum and the residue was purified with preparative HPLC (0-100% CH3CN/H20) to afford N-cyclopenty1-6-(3,5-dimethylisoxazol-4-y1)-2-(3-methoxypropylamino)-1H-benzo[d]imidazole-4-sulfonamide.
[00212] C211-129N504S. 448.2 (M+1). 11-1 NMR (400MHz, CD30D) 6 7.56 (s, 1H), 7.53 (s, 1H), 3.66-3.57 (m, 5H), 3.38 (s, 3H), 2.44 (s, 3H), 2.27 (s, 3H), 2.26-2.10 (m, 2H), 2.00-1.51 (m, 4 H), 1.49-1.39 (m, 4H).
QS

Example 3 N-Cyclopenty1-6-(3,5-dimethylisoxazol-4-y1)-2-mercapto-1H-benzo[d]imidazole-4-sulfonamide (1020-3) "

H2N s-HN)=-N HN
HS
[00213] 2,3-diamino-N-cyclopenty1-5-(3,5-dimethylisoxazol-4-yl)benzenesulfonamide (40 mg, 0.12 mmol) was dissolved in DMF (2 mL). To the solution was added 1,1'-Thiocarbonyldiimidazole (43 mg, 0.24 mmol). The reaction was heated at 90 C overnight before being evaporated under vacuum. The residue was purified by preparative HPLC (0-100% CH3CN/H20) to afford N-cyclopenty1-6-(3,5-dimethylisoxazol-4-y1)-2-mercapto-1H-benzo[d]imidazole-4-sulfonamide.
[00214] C17H20N403S2. 393.1 (M+1). 111NMR (400MHz, CD30D) 8 7.66 (s, 1H), 7.36 (s, 1H), 3.75-3.55 (m, 1H), 2.32 (s, 3H), 2.28 (s, 3H), 2.09-1.85 (m, 4 H), 1.64-1.47 (m, 4H).
Example 4 N-Cyclopenty1-6-(3,5-dimethylisoxazol-4-y1)-2-(methylthio)-1H-benzo[d]imidazole-4-sulfonamide (1020-4) Mel, KOH
40 le HS
[00215] N-cyclopenty1-6-(3,5-dimethylisoxazol-4-y1)-2-mercapto-1H-benzo[d]imidazole-4-sulfonamide (12 mg, 0.03 mmol) was dissolved in Et0H (2 mL).

To the solution was added methyliodide (5 mg, 0.037 mmol) and KOH (2.5mg, 0.045 mmol). The reaction was stirred overnight before being evaporated under vacuum. The residue was purified by preparative HPLC (0-100% CH3CN/H20) to afford N-cyclopenty1-6-(3,5-dimethylisoxazol-4-y1)-2-(methylthio)-1H-benzo[d]imidazole-sulfonamide.
[00216] C18H22N403S2. 407.0 (M+1). 114 NMR (400MHz, CD30D) 6 7.54 (s, 111), 7.35 (s, 1H), 3.62-3.48 (m, 111), 2.58 (s, 3H), 2.33 (s, 3H), 2.27 (s, 3H), 2.07-1.88 (m, 4 H), 1.68-1.45 (m, 4H).
Example 5 N-Cyclopenty1-6-(3,5-dimethylisoxazol-4-y1)-2-(methylsulfiny1)-1H-benzo[d]imidazole-4-sulfonamide (1020-5) 9 CI N 1.1 9 HN HN
N N N HO
>=N
0=S
ci [00217] N-cyclopenty1-6-(3,5-dimethylisoxazol-4-y1)-2-(methylthio)-1H-benzo[d]imidazole-4-sulfonamide (3.4 mg, 0.008 mmol) was dissolved in CH3CN (1 mL). To the solution was added 2,4,6-trichloro-1,3,5-triazine (1.5 mg, 0.008 mmol) and H202 (0.2 mL, 30% in water). The reaction was stirred overnight before being evaporated under vacuum. The residue was purified by preparative HPLC (0-100%
CH3CN/H20) to afford N-cyclopenty1-6-(3,5-dimethylisoxazol-4-y1)-2-(methylsulfiny1)-1H-benzo[d]imidazole-4-sulfonamide.
[00218] C18H22N404S2. 423.0 (M+1). 1H NMR (400MHz, CD30D) ö 7.68 (s, 1H), 7.42 (s, 1H), 3.71-3.52 (m, 1H), 2.98 (s, 3H), 2.34 (s, 3H), 2.29 (s, 3H), 2.11-1.92 (m, 4 H), 1.72-1.44 (m, 4H).

Example 6 N-Cyclopenty1-6-(3,5-dimethylisoxazol-4-y1)-2-(methylsulfony1)-1H-benzo[d]imidazole-4-sulfonamide (1020-6) Iv Iv mCPBA, H202 9s.0 le 9.
HN HN S' HN
C): S
o-[00219] N-cyclopenty1-6-(3,5-dimethylisoxazol-4-y1)-2-(methylsulfiny1)-1H-benzo[d]imidazole-4-sulfonamide (3.4 mg, 0.008 mmol) was dissolved in DCM (1 mL).
To the solution was added mCPBA (2.6 mg, 0.015 mmol) and H202 (1 mL, 30% in water). The reaction was stirred for 30 mins before being evaporated under vacuum. The residue was purified by preparative HPLC (0-100% CH3CN/H20) to afford N-cyclopenty1-6-(3,5-dimethylisoxazol-4-y1)-2-(methylsulfony1)-1H-benzo[d]imidazole-4-sulfonamide.
[00220] C18H22N405S2. 439.0 (M+1). ii NMR (400MHz, CD30D) 6 7.91 (s, 1H), 7.85 (s, 1H), 3.72-3.64 (m, 1H), 3.49 (s, 3H), 2.46 (s, 3H), 2.30 (s, 3H), 1.64-1.60 (m, 4H), 1.45-1.29 (m, 4H).
Example 7 N-Cyclopenty1-6-(3,5-dimethylisoxazol-4-y1)-2-(trifluoromethyl)-1H-benzo[d]imidazole-4-sulfonamide (1020-7) Iv FOH
IS 0 SI 9.
HN
HN S'C) NH2 HN 41\
FC
[00221] 2,3-diamino-N-cyclopenty1-5-(3,5-climethylisoxazo1-4-yl)benzenesulfonamide (20 mg, 0.06 mmol) was dissolved in 4N HC1 (2 mL). To the solution was added trifluoroacetic acid (65 mg, 0.6 mmol). The reaction was refluxed overnight before being evaporated under vacuum. The residue was purified by preparative HPLC (0-100% CH3CN/H20) to afford N-cyclopenty1-6-(3,5-dimethylisoxazol-4-y1)-2-(trifluoromethyl)-1H-benzo[d]imidazole-4-sulfonamide.
[00222] C18H19F3N403S. 429.0 (M+1). 1H NMR (400MHz, CD30D) 8 7.51 (s, 1H), 7.45 (s, 1H), 3.62-3.52 (m, 1H), 2.44 (s, 3H), 2.31 (s, 3H), 1.68-1.52 (m, 4 H), 1.42-1.25 (m, 4H).
Example 8 4-(2-Cyclopropy1-4-(3,5-dimethyl-1H-pyrazol-4-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-8) = Step 1:. Preparation of 4-(3,5-dimethylpyrazol-4-y1)-2-nitroaniline ¨N
O-N
B \ 6 Br /7-6 PEPPSI-IPr, Cs2CO3 DME/H20, M.W. 120 C
1002231 Starting material 4-bromo-2-nitroaniline (1 g, 4.6 mmol) and 3,5-dimethylisoxazole-4-boronic acid pinacol ester (2 g, 9.2 mmol) was added to a solvent mixture of 1,2-dimethoxyethane (12 ml) and water (6 m1). To the above mixture were added PEPPSI-IPr (312mg, 0.46 mmol) and Cs2CO3 (4.5g, 13.8 mmol). The reaction mixture was heated at 120 C for 30 mins. The reaction mixture was then diluted with Et0Ac (100 ml), washed with bring (50 mL X 2). The organic solvent was evaporated and the residue was dissolved in DCM and purified with silica gel chromatography (product came out at 50% Et0Ac/Hexane) to afford 4-(3,5-dimethylpyrazol-4-y1)-nitroaniline as a yellow solid.
100224] C11HIIN303. 234.3 (M+1).
Step 2: Preparation of 4-(3,5-dimethylisoxazol-4-y1)-2-iodo-6-nitroaniline O
O-N -N
12, AgNO3 Et0H
02N 1.1 1 N

[00225] Starting material compound 4-(3,5-dimethylpyrazol-4-y1)-2-nitroaniline (1g, 4.6 mmol) was added to Et0H (50 ml), to the mixture were added 12 (1.4g, 5.5 mmol) and AgNO3 (0.94g, 5.5 mmol). The reaction mixture was stirred at RT
overnight.
The solvent was evaporated and then the residue was dissolved in Et0Ac (50 ml) and washed with brine (30 mL X 2). The organics were evaporated and the residue was dissolved in DCM and purified by silica gel column chromatography (product came out at 35% Et0Ac/Hexane) to afford 4-(3,5-dimethylisoxazol-4-y1)-2-iodo-6-nitroaniline as an orange solid.
[00226] C11H10IN303. 360.2 (M+1).
Step 3: Preparation of 5-(3,5-dimethylisoxazol-4-y1)-3-iodobenzene-1,2-diamine O-N O-N
SnC12 1101 Et0H, 75 C

[00227] 4-(3,5-dimethylisoxazol-4-y1)-2-iodo-6-nitroaniline (0.9g, 2.5 mmol) was added to Et0H (50 ml), to the mixture were added SnC12 (2.4g, 12.5 mmol). The reaction mixture was stirred at 75 C for 7h. The solvent was evaporated and then the residue was dissolved in Et0Ac (100 ml) and washed with 1N NaOH (100 mL X 3).
The organic solvent was evaporated and the residue was dissolved in DCM and purified with silica gel column chromatography (product came out at 60% Et0Ac/Hexane) to afford 5-(3,5-dimethylisoxazol-4-y1)-3-iodobenzene-1,2-diamine as a brown solid.
[00228] Cl1H121N30 330.1 (M+1). 1H NMR (400 MHz, CD30D) 6 2.21 (s, 3H), 2.39 (s, 3H), 7.16 (d, 1H), 7.62 (d, 1H).

Step 4: Preparation of 4-(2-cyclopropy1-4-iodo-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole HCI
CI
Pyr. CH3000H, 100 C
HN

NH2 <y=---"=N
[00229] 5-(3,5-dimethylisoxazol-4-y1)-3-iodobenzene-1,2-diamine (0.92g, 2.8 mmol) was dissolved in pyridine (10 ml), to the solution was added cyclopropyl carbonyl chloride (0.29g, 2.8 mmol). The reaction was stirred at RT for 3h before solvent was evaporated. The residue was dissolved in acetic acid (5 ml) and to the solution was added hydrogen chloride (1 m1). The reaction mixture was then heated at 100 C overnight. The acid was then evaporated under reduced pressure and the residue was dissolved in DCM and purified by silica gel column chromatography (product came out at 70% Et0Ac/Hexane) to afford product 4-(2-cyclopropy1-4-iodo-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazoleas as a brown solid.
[00230] C151-1141N30. 380.1 (M+1).
Step 5: Preparation of 4-(2-cyclopropy1-4-(3,5-dimethyl-1H-pyrazol-4-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole O-N ¨N O-N
8 \
401 \
HN I HN N
<r-N
PEPPSI-IPr, Cs2003 DME/H20, M.W. 120 C <rN 141-1 [00231] 3,5-dimethylpyrazole-4-boronic acid, pinacol ester (29 mg, 0.13 mmol) was added to a solution of 4-(2-cyclopropy1-4-iodo-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (25 mg, 0.066 mmol) in 1,2-dimethoxyethane and water (2/1 mL). To the mixture was added cesium carbonate (65 mg, 0.2 mmol) and PEPPSI-IPr (5 mg, 0.0066 mmol). The reaction was put in microwave reactor and heated at 120 C
for 30 minutes before being evaporated under vacuum. The residue was purified by preparative HPLC (0-100% CH3CN/H20) to afford 4-(2-cyclopropy1-4-(3,5-dimethyl-1H-pyrazol-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole.
[00232] C20H211\150. 348.2 (M+1). H NMR (400MHz, CD30D) 6 7.56 (s, 1H), 7.32 (s, 1H), 2.46 (s, 3H), 2.45-2.44 (m, 1H), 2.30 (s, 3H), 2.21 (s, 6H), 1.53-1.51 (m, 2 H), 1.41-1.39 (m, 2H).
Example 9 4-(2-Cyclopropy1-7-(2-methylpyridin-3-y1)-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole (1020-9) O¨N O¨N
HO
HOBs's ______________________________________ N
<2--NH
[00233] To a 0.5 to 2 mL Smith process vial equipped with a stir bar was added 2-methylpyridin-3-ylboronic acid (0.45 mmol, 62 mg), 4-(2-cyclopropy1-4-iodo-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (37.9 mg, 0.1 mmol) (Example 8, Step 4), potassium carbonate (0.90 mmol, 125 mg), and PEPPSI-IPr catalyst (0.01 mmol, 6.8mg).
The reaction vessel was capped with a rubber septum, evacuated and backfilled three times with N2, followed by the addition of 1,4-dioxane (0.4 mL) and water (0.1 mL). The reaction mixture was then heated in a microwave reactor for 30 minutes at 130 C. The organic layer was then removed by syringe, filtered, and directly injected for purification by preparative reverse phase high performance liquid chromatography (Phenomenex TM
Gemini C18 column, 5% to 50% gradient acetonitrile in water with 0.1% TFA) to give 4-(2-cyclopropy1-7-(2-methylpyridin-3-y1)-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole as a TFA salt.
[00234] C211-120N40. 345.2 (M+1). 1H NMR (400 MHz, CD30D) 6 8.81 (dd, J =
5.7, 1.5 Hz, 1H), 8.43 (dd, J = 7.9, 1.5 Hz, 1H), 7.93 (dd, J= 7.8, 5.8 Hz, 1H), 7.70 (d, J

= 1.4 Hz, 1H), 7.42 (d, J= 1.5 Hz, 1H), 2.62 (s, 3H), 2.47 (s, 3H), 2.45 ¨
2.34 (m, 1H), 2.31 (s, 3H), 1.53 ¨ 1.42 (m, 2H), 1.39¨ 1.31 (m, 2H).
Example 10 4-(2-Cyclopropy1-7-(3-methylpyridin-4-y1)-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole (1020-10) O-N O-N
HO
HOAil O

___________________________________________ N \
NH <2--NH I N
1002351 4-(2-cyclopropy1-7-(3-methylpyridin-4-y1)-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole (5.8 mg, 13%) was prepared as a TFA salt in a manner similar to that of Example 9 substituting 3-methylpyridin-4-ylboronic acid for 2-methylpyridin-3-ylboronic acid.
[00236] C211-120N40. 345.2 (M+1). 1H NMR (400 MHz, CD30D) 6 8.77 (s, 1H), 8.68 (d, J= 5.6 Hz, 1H), 7.81 (d, J= 5.5 Hz, 1H), 7.63 (d, J= 1.5 Hz, 1H), 7.32 (d, J=
1.5 Hz, 1H), 2.45 (s, 3H), 2.35 (s, 3H), 2.35 ¨2.29 (m, 1H), 2.29 (s, 3H), 1.44 ¨ 1.34 (m, 2H), 1.34 ¨ 1.24 (m, 2H).
Example 11 4-(2-Cyclopropy1-7-(4-methylpyridin-3-y1)-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole (1020-11) O-N O-N
HO
HO N

N N
NH
.<\-NH I
[002371 4-(2-cyclopropy1-7-(4-methylpyridin-3-y1)-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole (4.4 mg, 9.9%) was prepared as a TFA salt in a manner similar to (-11 that of Example 9 substituting 4-methylpyridin-3-ylboronic acid for 2-methylpyridin-3-ylboronic acid.
[00238] C211-120N40. 345.2 (M+1). 11-1NMR (400 MHz, CD30D) &8.68 (d, ./=
4.4 Hz, 1H), 7.83 (d, J= 5.5 Hz, 1H), 7.64 (d, J= 1.4 Hz, 1H), 7.35 (d, J= 1.4 Hz, 1H), 2.47 (s, 3H), 2.43 (s, 3H), 2.39 - 2.33 (m, 1H), 2.31 (s, 3H), 1.46 - 1.36 (m, 2H), 1.36 -1.25 (m, 2H).
Example 12 4-(2-Cyclopropy1-7-(1,4-dimethyl-1H-pyrazol-5-y1)-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole (1020-12) O-N O-N

/
0-BN--N\
N
la Ili N \ N
/
[00239] 4-(2-cyclopropy1-7-(1,4-dimethyl-1H-pyrazol-5-y1)-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole (21 mg, 46%) was prepared as a TFA salt in a manner to Example 9 substituting 1,4-dimethy1-5-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-1H-pyrazole for 2-methylpyridin-3-ylboronic acid.
[00240] C20H211\150. 348.1 (M+1). 1H NMR (400 MHz, CD30D) 6 7.75 (d, J= 1.4 Hz, 1H), 7.53 (s, 1H), 7.46 (d, J = 1.4 Hz, 1H), 3.74 (s, 3H), 2.59 - 2.40 (m, 4H), 2.31 (s, 3H), 2.00 (s, 3H), 1.65- 1.51 (m, 2H), 1.51 - 1.35 (m, 2H).
Example 13 4-(2-Cyclopropy1-7-(imidazo[1,2-a]pyridin-3-y1)-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole (1020-13) 1n,a O-N O-N

-N
I /
NO
N
__________________________________________ N
/
[00241] 4-(2-cyclopropy1-7-(imidazo[1,2-a]pyridin-3-y1)-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole (10 mg, 20%) was prepared as a TFA salt in a manner similar to that of Example 9 substituting 3-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine for 2-methylpyridin-3-ylboronic acid.
[00242] C22H19N50. 370.1 (M+1). 1H NMR (400 MHz, CD30D) 6 8.42 (dd, J =
6.9, 1.0 Hz, 1H), 8.34 (d, J = 1.3 Hz, 1H), 8.06 -8.01 (m, 2H), 7.83 -7.77 (m, 1H), 7.68 - 7.63 (m, 1H), 7.47 (ddd, J= 7.0, 4.9, 3.3 Hz, 1H), 2.46 -2.33 (m, 4H), 2.26 (s, 3H), 1.50- 1.37 (m, 2H), 1.32 (dd, J= 8.2, 3.7 Hz, 2H).
Example 14 4-(2-Cyclopropy1-7-(quinolin-8-y1)-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole (1020-14) O-N O-N

-N
__________________________________________ N
[00243] 4-(2-cyclopropy1-7-(quinolin-8-y1)-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole (1.7 mg, 2.8%) was prepared as a TFA salt in a manner similar to that of Example 9 substituting quinolin-8-ylboronic acid for 2-methylpyridin-3-ylboronic acid.
[00244] C24H201\140. 381.1 (M+1). 1H NMR (400 MHz, CD30D) 6 8.82 (dd, J=
4.3, 1.7 Hz, 1H), 8.54 (dd, J= 8.3, 1.7 Hz, 1H), 8.18 (dd, J= 8.2, 1.3 Hz, 1H), 7.97 (dd, J= 7.1, 1.4 Hz, 1H), 7.82 (dd, J= 8.0, 7.3 Hz, 2H), 7.69 - 7.63 (m, 2H), 2.48 (s, 3H), 1 fl<

2.40 ¨ 2.33 (m, 1H), 2.32 (s, 3H), 1.53 ¨ 1.42 (m, 2H), 1.39 ¨ 1.27 (m, 2H).
Example 15 4-(2-Cyclopropy1-7-(quinolin-5-y1)-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole (1020-15) O-N O-N

HO-B N
N
NH
[00245] 4-(2-cyclopropy1-7-(quinolin-5-y1)-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole (30 mg, 49%) was prepared as a TFA salt in a manner similar to that of Example 9 substituting quinolin-5-ylboronic acid for 2-methylpyridin-3-ylboronic acid.
[00246] C24H20N40. 381.1 (M+1). 1H NMR (400 MHz, CD30D) 6 9.08 (dd, J=
4.7, 1.5 Hz, 1H), 8.35 (dd, J= 18.7, 8.5 Hz, 2H), 8.11 (dd, J= 8.6, 7.2 Hz, 1H), 7.93 (dd, J= 7.1, 1.0 Hz, 1H), 7.79 ¨ 7.69 (m, 2H), 7.53 (d, J= 1.5 Hz, 1H), 2.48 (s, 3H), 2.36 (tt, J= 8.5, 5.1 Hz, 1H), 2.32 (s, 3H), 1.53 ¨ 1.42 (m, 2H), 1.40¨ 1.29 (m, 2H).
Example 16 4-(2-Cyclopropy1-7-(isoquinolin-5-y1)-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole (1020-16) X
-HOB
'r __________________________________________ N
NH a 4-(2-cyclopropy1-7-(isoquinolin-5-y1)-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole (26.7 mg, 44%) was prepared as a TFA salt in a manner similar to that of Example 9 substituting isoquinolin-5-ylboronic acid for 2-methylpyridin-3-ylboronic acid.
[00247] C24H20N40. 381.1 (M+1). 11-1 NMR (400 MHz, CD30D) 6 9.82 (s, 1H), 8.62 (d, J= 8.3 Hz, 1H), 8.53 (d, J= 6.6 Hz, 1H), 8.29 (dd, J= 7.2, 1.0 Hz, 1H), 8.14 (dd, J= 8.2, 7.3 Hz, 1H), 7.98 (d, J= 6.6 Hz, 1H), 7.77 (d, J= 1.4 Hz, 1H), 7.55 (d, J=
1.4 Hz, 1H), 2.48 (s, 3H), 2.37 (tt, J= 8.4, 5.0 Hz, 1H), 2.32 (s, 3H), 1.52¨
1.42 (m, 2H), 1.41 ¨ 1.29 (m, 2H).
Example 17 4-(2-Cyclopropy1-7-(isoquinolin-4-y1)-1H-benzo[d]imidazo1-5-y1)-3,5-dimethylisoxazole (1020-17) O-N O-N

HO-B

__________________________________________ N
[00248] 4-(2-cyclopropy1-7-(isoquinolin-4-y1)-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole (10.2 mg, 17%) was prepared as a TFA salt in a manner similar to that of Example 9 substituting isoquinolin-4-ylboronic acid for 2-methylpyridin-3-ylboronic acid.
[00249] C24H20N40. 381.1 (M+1). IFINMR (400 MHz, CD30D) 6 9.86 (s, 1H), 8.78 (s, 1H), 8.61 (d, J= 8.0 Hz, 1H), 8.14 (ddd, J= 8.4, 7.0, 1.3 Hz, 1H), 8.06 (ddd, J=
8.2, 7.0, 1.1 Hz, 1H), 7.88 (d, J= 8.4 Hz, 1H), 7.84 (d, J= 1.5 Hz, 1H), 7.64 (d, J= 1.4 Hz, 1H), 2.50 (s, 3H), 2.41 (tt, J= 8.4, 5.0 Hz, 1H), 2.34 (s, 3H), 1.56¨ 1.45 (m, 2H), 1.43 ¨ 1.33 (m, 2H).
Example 18 4-(2-Cyclopropy1-7-(6-methylquinolin-5-y1)-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole (1020-18) 1 (Y7 O-N HO O-N

13 HO_ N
3 ' N
NH
=
[002501 To a 2 to 5 mL Smith process vial equipped with a stir bar was added 6-methylquinolin-5-ylboronic acid (3 mmol, 561 mg), 4-(2-cyclopropy1-7-iodo-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole (379 mg, 1 mmol), potassium carbonate TM
(10 mmol, 1.38 g), and PEPPSI-IPr catalyst (0.1 mmol, 68 mg). The reaction vessel was capped with a rubber septum, evacuated and backfilled three times with N2, followed by the addition of 1,4-dioxane (4 mL) and water (1 mL). The reaction mixture was then heated in a microwave reactor for 1 hour at 135 C. The organic layer was then removed by syringe, filtered, and directly injected for purification by preparative reverse phase TM
high performance liquid chromatography (Phenomenex Gemini C18 column, 5% to 50% gradient acetonitrile in water with 0.1% TFA). The eluting fraction containing the desired product was then concentrated under reduced pressure and purified again using silica gel chromatography (0% to 20% gradient methanol in ethyl acetate) to give 4-(2-cyclopropy1-7-(6-methylquinolin-5-y1)-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole.
[00251] C25H22N40. 395.2 (M+1). 1H NMR (400 MHz, CD30D) 6 8.48 (dd, .1=
6.9, 1.0 Hz, 1H), 8.39 (d, .1= 1.3 Hz, 1H), 8.12 ¨ 8.07 (m, 2H), 7.89 ¨ 7.83 (m, 1H), 7.74 ¨7.68 (m, 1H), 7.52 (ddd, J= 7.0, 4.9, 3.3 Hz, 1H), 2.51 ¨2.38 (m, 4H), 2.31 (s, 3H), 1.55 ¨ 1.43 (m, 2H), 1.42 ¨ 1.29 (m, 2H).
Example 19 4-(2-Cyclopropy1-4-(2-phenylpyridin-3-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-19) (H0)2B -N
PEPPSI-iPr (5 mol%) N
HNI ___________________________________ HN
<rN Cs2C 03 dioxane H20 <r-N
1002521 4-(2-cyclopropy1-4-iodo-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (50.0 mg, 0.132 mmol) was treated with 2-phenylpyridin-3-ylboronic acid (39.4 mg, 0.198 mmol, 1.5 equiv.), 2M Na2CO3 (aq) (1 mL) in the presence of PEPPSI-IPr (4.5 mg, 0.0066 mmol, 0.05 equiv) in 1,4-dioxane (3 mL) at 15 C
for 10 mm in microwave reactor. To the reaction mixture was added water (30 mL) and Et0Ac (70 mL), then the mixtured was filtered through Celite (3 g) and then organic layer was separated from the filtrate. The organic layer was washed with brine (30 mL) and dried over Na2SO4. The solvent was removed under a reduced pressure to give the crude product. The crude product was purified by a preparative HPLC (5-95%
acetonitrile:
water with 0.05% trifluoroacetic acid, on a Phenomenex Luna C18 column) to give 4-(2-cyclopropy1-4-(2-phenylpyridin-3-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole.
[002531 C26H22N40. MS. 407.2 (M+1). 1H NMR (Me0H-d4) 6 8.87 (dd, J= 5.0, 1.7 Hz, 1H), 8.35 (dd, J= 8.3, 1.7 Hz, 1H), 7.83 (dd, J= 8.3, 5.0 Hz, 1H), 7.56 (d, J-1.7 Hz, 1H), 7.42-7.28 (m, 5H), 7.22 (d, J= 1.7 Hz, 1H), 2.43-2.34 (m, 1H), 2.22 (s, 3H), 2.05 (s, 3H), 1.52-1.46 (m, 2H), 0.36-1.30 (m, 2H).
Example 20 4-(2-Cyclopropy1-4-(5-(4-fluoropheny1)-1H-pyrazol-4-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-20) Iv HN NH

[00254] 4-(2-cyclopropy1-4-(5-(4-fluoropheny1)-1H-pyrazol-4-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole was synthsized in a manner similar to that of Example 19 using 5-(4-fluoropheny1)-1H-pyrazol-4-ylboronic acid.
[00255] C24H20FN50. MS. 414.1 (M+1). 1H NMR (Me0H-d4) 6 8.03 (s, 1H), 7.53 (d, J= 1.5 Hz, 1H), 7.41 (dd, J= 8.8, 5.3 Hz, 2H), 7.20 (d, J= 1.5 Hz, 1H), 7.07 (t, J= 8.8 Hz, 2H), 2.42 (tt, 8.5, 5.1 Hz, 1H), 2.29 (s, 3H), 2.12 (s, 3H), 1.56 ¨ 1.46 (m, 2H), 1.35 (dt, J=7.5, 4.7 Hz, 2H).
Example 21 4-(4-(Biphenyl-2-y1)-2-cyclopropy1-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-21) H<:NrN
[00256] 4-(4-(bipheny1-2-y1)-2-cyclopropy1-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole was synthsized in a manner similar to that of Example 19 using biphenyl-2-ylboronic acid.
[00257] C27H23N30. MS. 406.2 (M+1). 1H NMR (Me0H-d4) 6 7.66 ¨ 7.09 (m, 11H), 2.43 ¨ 2.32 (m, 1H), 2.20 (s, 3H), 2.03 (s, 3H), 1.54 ¨ 1.44 (m, 2H), 1.38 ¨ 1.27 (m, 2H).
Example 22 4-(4-(2-Benzylpheny1)-2-cyclopropyl-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-22) 11 n is [00258] 4-(4-(2-benzylpheny1)-2-cyclopropy1-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole was synthsized in a manner similar to that of Example 19 using 2-benzylphenylboronic acid.
[00259] C28H25N30. MS. 420.2 (M+1). NMR (Me0H-d4) 5 7.60 - 7.50 (m, 3H), 7.45 (td, J= 7.2, 2.0 Hz, 1H), 7.38 - 7.31 (m, 1H), 7.21 (d, J= 1.4 Hz, 1H), 7.02 -6.93 (m, 3H), 6.67 - 6.60 (m, 2H), 3.92 (d, J= 11.5 Hz, 1H), 3.87 (d, J= 11.5 Hz, 1H), 2.40 (s, 1H), 2.25 (s, 1H), 2.30 - 2.22 (m, 1H), 1.53 - 1.45 (dt, J= 8.1, 3.5 Hz, 1H), 1.35 - 1.27(m, 1H).
Example 23 4-(2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yebenzamide (1020-23) HN
<r-N Si NH2 [00260] 4-(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-yObenzamide was synthsized in a manner similar to that of Example 19 using 4-carbamoylphenyl-boronic acid.
[00261] C22H20N402. MS. 373.1 (M+1). 1H NMR (Me0H-d4) 6 8.1 (d, J= 8.3 Hz, 2H), 7.80 (d, J= 8.3 Hz, 2H), 7.62 (d, J= 1.5 Hz, 1H), 7.52 (d, J= 1.5 Hz, 1H), 2.56 - 2.48 (tt, J= 8.5, 5.0 Hz, 1H), 2.46 (s, 3H), 2.30 (s, 3H), 1.61 - 1.50 (m, 2H), 1.50 -1.41 (m, 2H).

Example 24 3-(2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[djimidazol-4-yl)benzamide (1020-24) <r-N
[002621 3-(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-yl)benzamide was synthsized in a manner similar to that of Example 19 using 3-carbamoylphenyl-boronic acid.
1002631 C22H20N402. MS. 373.1 (M+1). 1H NMR (Me0H-d4) 6 8.16 (t, J= 1.4 Hz, 1H), 8.02 (dt, J= 7.7, 1.4 Hz, 1H), 7.88 (dt, J= 7.7, 1.4 Hz, 1H), 7.71 (t, J= 7.7 Hz, 1H), 7.61 (d, J= 1.4 Hz, 1H), 7.54 (d, J= 1.4 Hz, 1H), 2.56 -2.47 (m, 1H), 2.46 (s, 3H), 2.30 (s, 3H), 1.58 - 1.50 (m, 2H), 1.49- 1.42 (m, 2H).
Example 25 4-(2-Cyclopropy1-4-(2-methoxy-4-methylpyridin-3-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-25) HN
<r-N

[002641 4-(2-cyclopropy1-4-(2-methoxy-4-methylpyridin-3-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole was synthsized in a manner similar to that of Example 19 using 2-methoxy-4-methylpyridin-3-ylboronic acid.

[00265] C22H22N402. MS. 374.9 (M+1). 11-1 NMR (Me0H-d4) 8 8.17 (d, J= 5.3 Hz, 1H), 7.62 (d, J= 1.5 Hz, 1H), 7.34 (d, J= 1.5 Hz, 1H), 7.07 (d, J= 5.3 Hz, 1H), 3.86 (s, 3H), 2.50 ¨ 2.38 (m, 2H), 2.46 (s, 3H), 2.29 (s, 3H), 2.19 (s, 3H), 1.56-1.49 (m, 2H), 1.46 ¨ 1.35 (m, 2H).
Example 26 4-(2-Cyclopropy1-4-(2-ethoxy-4-methylpyridin-3-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-26) Iv HN

[00266] 4-(2-cyclopropy1-4-(2-ethoxy-4-methylpyridin-3-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole was synthsized in a manner similar to that of Example 19 using 2-ethoxy-4-methylpyridin-3-ylboronic acid.
[00267] C23H24N402. MS. 388.9 (M+1). IFINMR (Me0H-d4) 6 8.14 (d, J= 5.3 Hz, 1H), 7.62 (d, J= 1.4 Hz, 1H), 7.34 (d, J= 1.4 Hz, 1H), 7.04 (d, J= 5.3 Hz, 1H), 4.40 ¨4.23 (m, 2H), 2.46 (s, 3H), 2.46 ¨ 2.38 (m, 1H), 2.29 (s, 3H), 2.19 (s, 3H), 1.60¨ 1.47 (m, 2H), 1.45 ¨ 1.34 (m, 2H), 1.15 (t, J= 7.0 Hz, 3H).
Example 27 3-(2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)-4-methylpyridin-2-ol (1020-27) Iv Iv TFA
H
HN
N
MW, 160 C
0 Ho 60 min 100268] A solution of 4-(2-cyclopropy1-4-(2-methoxy-4-methylpyridin-3-y1)-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (40.0 mg, 0.08189 mmol) in TFA (3 mL) was heated at 160 C for 1 h in microwave reactor. The solvent was removed under a reduced pressure to give the crude material. The crude material was purified by a preparative HPLC (5-95% acetonitrile: water with 0.05% trifluoroacetic acid, on a Phenomenex Luna C18 column) to give 3-(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)-4-methylpyridin-2-ol.
100269] C21F120N402. MS. 361.1 (M+1). 1H NMR (Me0H-d4) 6 7.59 (d, J= 1.4 Hz, 1H), 7.50 (d, J= 6.8 Hz, 1H), 7.34 (d, J= 1.5 Hz, 1H), 6.50 (d, Jr 6.8 Hz, 1H), 2.47 ¨2.39 (m, 1H), 2.45 (s, 3H), 2.28 (s, 3H), 2.18 (s, 3H), 1.57¨ 1.47 (m, 2H), 1.44¨ 1.37 (m, 2H).
Example 28 (E)-4-(2-Cyclopropy1-4-(hex-3-en-3-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-28) lei 00 HN I PEPPSI-IPr HN
cir N DME : H20 Cs2CO3 110 C, 90min [00270] A suspension of 4-(2-cyclopropy1-4-iodo-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (100 mg, 0.265 mmol) (Example 8, Step 4), (Z)-3-Hexeny1-3-boronic acid catechol ester (81 mg, 0.400 mmol), caesium carbonate (260 mg, 0.8 mmol) and PEPPSI-IPrTM (18 mg, 0.026 mmol) in 10 mL DME : F120 (2:1) was heated by microwave in a sealed vessel at 110 C for 90 minutes. The reaction was then cooled and partitioned between water and ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. Purification on silica gel (rf = 0.5 in 60% ethyl acetate in hexanes) afforded (E)-4-(2-cyclopropy1-4-(hex-3-en-3-y1)-1H-benzo [d]imidazol-6-y1)-3,5-dimethylisoxazole as an off-white solid.
[00271] C211-125N30. 336.2 (M+1). 1H NMR (400 MHz, Methanol-d4) 6 7.28 (d, J
lid = 1.5 Hz, 1H), 6.92 (d, ./= 1.6 Hz, 1H), 5.68 (t, J= 7.2 Hz, 1H), 2.66 (q, J=
7.5 Hz, 2H), 2.47 ¨ 2.17 (m, 9H), 1.38¨ 1.24 (m, 1H), 1.20¨ 1.08 (m, 7H), 0.95 (t, J=
7.5 Hz, 3H).
Example 29 4-(2-Cyclopropy1-4-(2,6-dimethylpheny1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-29) lB
HN I HN
tN PEPPSI-IPr, Cs2003 DME/H20, MW 120 C
[00272] 2,6-Dimethylphenylboronic acid, pinacol ester (33 mg, 0.22 mmol) was added to a solution of 4-(2-cyclopropy1-4-iodo-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (40 mg, 0.11 mmol) (Example 8, Step 4) in 1,2-dimethoxy ethane and water (2/1 mL). To the mixture was added cesium carbonate (107 mg, 0.33 mmol) and PEPPSI-IPr (8 mg, 0.011 mmol). The reaction was put in microwave reactor and heated at 120 C for 30 minutes before being evaporated under vacuum. The residue was purified by preparative HPLC (0-100% CH3CN/H20) to afford 4-(2-cyclopropy1-4-(2,6-dimethylpheny1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole.
[00273] C23H23N30. 358.3 (M+1). 1H NMR (400MHz, CD30D) 6 7.58 (s, 1H), 7.33-7.31 (m, 1H), 7.29-7.21 (m, 2H), 7.06-7.02 (m, 1H), 6.93-6.90 (m, 2H), 2.45 (s, 3H), 2.39-2.33 (m, 1H), 2.29 (s, 3H), 2.28 (s, 3H), 1.50-1.45 (m, 2 H), 1.38-1.35 (m, 2H).
Example 30 4-(2-Cyclopropy1-4-o-toly1-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-30) O-N

[002741 4-(2-cyclopropy1-4-o-toly1-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole was synthesized by reacting 4-(2-cyclopropy1-4-iodo-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (Example 8, Step 4) with 2-methylphenylboronic acid in a manner similar to that of Example 29.
[00275] C22H21N30. 344.3 (M+1). 1FINMR (400MHz, CD30D) 6 8.75 (dd, J-5.0, 1.3 Hz, 1H), 8.33 (d, J= 8.5 Hz, 1H), 8.08 (d, J= 8.6 Hz, 1H), 7.82 ¨
7.74 (m, 1H), 7.65 ¨ 7.62 (m, 1H), 7.20 (s, 1H), 2.74-2.71 (m, 1H), 2.35 (s, 3H), 2.26 (s, 3H), 2.19 (s, 3H), 1.14-1.10 (m, 2H), 0.97-0.82 (m, 2H).
Example 31 4-(2-Cyclopropy1-4-phenyl-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-31) O-N

(NS
[00276] 4-(2-Cyclopropy1-4-pheny1-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (40 mg, 46%) was synthesized by reacting 4-(2-cyclopropy1-4-iodo-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (Example 8, Step 4) with phenylboronic acid in a manner similar to that of Example 29.
[00277] C21Hi9N30. 330.2 (M+1). 1H NMR (400 MHz, Methanol-d4) 6 7.78 (d, J
= 53.8 Hz, 2H), 7.54 (t, J= 7.0 Hz, 2H), 7.45 (d, J= 9.1 Hz, 2H), 7.16 (s, 1H), 2.46 (s, 3H), 2.31 (s, 4H), 1.25¨ 1.07 (m, 4H).
Example 32 4-(2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)phenol (1020-32) O-N
7.1%,1 OH
[00278] 4-(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-yl)phenol was synthesized by reacting 4-(2-cyclopropy1-4-iodo-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (Example 8, Step 4) with 4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-yl)phenol in a manner similar to that of Example 29.
[00279] C21Hi9N302. 346.2 (M+1). 1H NMR (400 MHz, Methanol-d4) 6 7.47 (s, 2H), 7.31 (s, 1H), 7.05 (s, 1H), 6.99 ¨ 6.87 (m, 2H), 2.41 (s, 3H), 2.26 (s, 3H), 2.19 (d, J
= 6.2 Hz, IH), 1.20¨ 1.06 (m, 4H).
Example 33 4-(2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)-2,6-dimethylphenol (1020-33) O-N
HN

OH
[00280] 4-(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-y1)-2,6-dimethylphenol was synthesized by reacting 4-(2-cyclopropy1-4-iodo-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (Example 8, Step 4) with 4-hydroxy-3,5-dimethylphenylboronic acid pinacol ester in a manner similar to that of Example 29.
[00281] C23H23N302. 374.2 (M+1). 1H NMR (400 MHz, Methanol-d4) 6 7.31 (d, J
= 1.5 Hz, 1H), 7.28 (s, 2H), 7.06 (d, J= 1.6 Hz, 1H), 2.44 (s, 3H), 2.33 (s, 6H), 2.29 (s, 3H), 2.27 ¨ 2.21 (m, 1H), 1.17 (ddd, J= 7.6, 4.0, 2.5 Hz, 4H).
Example 34 4-(2-Cyclopropy1-4-(3,5-dimethylpheny1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-34) O-N

40, [00282] 4-(2-Cyclopropy1-4-(3,5-dimethylpheny1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole was synthesized by reacting 4-(2-cyclopropy1-4-iodo-1H-benzo[d]imidazol-6-y1)-3,5-dirnethylisoxazole (Example 8, Step 4) with 3,5-dimethylphenylboronic acid in a manner similar to that of Example 29.
[00283] C23H23N30. 358.2 (M+1). 1H NMR (400 MHz, Methanol-d4) 6 7.34 (d, J
= 29.8 Hz, 3H), 7.11 (d, J= 8.2 Hz, 2H), 2.44 (d, J= 13.2 Hz, 9H), 2.31 (s, 3H), 2.24 (p, J= 6.8 Hz, 1H), 1.23 ¨ 1.07 (m, 4H).
Example 35 4-(2-Cyclopropy1-4-(2,3-dimethylpheny1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-35) O-N

H71,N
[00284] 4-(2-cyclopropy1-4-(2,3-dimethylpheny1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole was synthesized by reacting 4-(2-cyclopropy1-4-iodo-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (Example 8, Step 4) with 2,3-dimethylphenylboronic acid in a manner similar to that of Example 29.
[00285] C23H23N30. 358.2 (M+1). NMR (400 MHz, Methanol-d4) 6 7.41 (s, 1H), 7.31 ¨ 7.08 (m, 3H), 6.94 (d, J= 1.6 Hz, 1H), 2.45 (s, 3H), 2.40 (s, 3H), 2.30 (s, 3H), 2.10 (s, 4H), 1.24 ¨ 1.04 (m, 4H).
Example 36 4-(2-cyclopropy1-4-(3,5-dimethoxypheny1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-36) O-N
HN
(3 [00286] 4-(2-cyclopropy1-4-(3,5-dimethoxypheny1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole was synthesized by reacting 4-(2-cyclopropy1-4-iodo-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (Example 8, Step 4) with 243,5-dimethoxy)-pheny1-4,4,5,5-tetramethyl-(1,3,2)-dioxaborolane in a manner similar to that of Example 29.
[00287] C23H23N303. 390.3 (M+1). NMR (400 MHz, Methanol-d4) 6 7.45 ¨
7.30 (m, 1H), 7.15 (d, J= 1.7 Hz, 1H), 6.87 (s, 2H), 6.65 ¨6.48 (m, 1H), 3.87 (s, 6H), 2.46 (s, 3H), 2.30 (s, 4H), 1.24 ¨ 1.05 (m, 4H).
Example 37 (E)-4-(2-cyclopropy1-4-styry1-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-37) O-N

[00288] (E)-4-(2-cyclopropy1-4-styry1-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole was synthesized by reacting 4-(2-cyclopropy1-4-iodo-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (Example 8, Step 4) with trans-2-phenylvinylboronic acid in a manner similar to that of Example 29.
[00289] C23H21N30. 356.2 (M+1). 1H NMR (400 MHz, Methanol-d4) 6 7.77 ¨
7.64 (m, 3H), 7.50 ¨ 7.35 (m, 4H), 7.33 ¨7.24 (m, 2H), 2.45 (s, 3H), 2.30 (s, 4H), 1.33 ¨
1.16 (m, 4H) Example 38 4-(2-Cyclopropy1-4-(1-phenylviny1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-38) HOB

HN PEPPSI-1Pr 40, HN
<r-N DME : H20 <(-N
Cs2CO3 [00290] A suspension of 4-(2-cyclopropy1-4-iodo-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (100 mg, 0.265 mmol) (Example 8, Step 4), 1-phenylvinylboronic acid (59 mg, 0.400 mmol), caesium carbonate (260 mg, 0.8 mmol) and PEPPSIIPrTM

(18 mg, 0.026 mmol) in 10 mL DME : H20 (2:1) was heated by microwave in a sealed vessel at 110 C for 90 minutes. The reaction was then cooled and partitioned between water and ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. Purification on silica gel (rf = 0.6 in 60% ethyl acetate in hexanes) afforded 4-(2-cyclopropy1-4-(1-phenylviny1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole.
[00291] C23H2IN30. 356.2 (M+1). 1H NMR (CDC13) 6 7.48 (s, 1H), 7.39 (m, 5H), 7.04 (s, 1H), 5.73 (s, 1H), 5.59 (br, 1H), 3.69 (s, 1H), 2.39 (s, 3H), 2.26 (s, 3H), 1.87 (br, 1H), 1.14-1.03 (m, 4H).
Example 39 4-(2-Cyclopropy1-4-(1-(4-fluorophenyl)viny1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-39) O-N
F
HN
<rN
[00292] 4-(2-Cyclopropy1-4-(1-(4-fluorophenyeviny1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole was synthesized by reacting 4-(2-cyclopropy1-4-iodo-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (Example 8, Step 4) with 1-(4-fluorophenyl)vinylboronic acid, pinacol ester in a manner similar to that of Example 38.
[00293] C23H20FN30. 374.2 (M+1). NMR (400 MHz, Methanol-d4) 6 7.61 ¨
7.24 (m, 3H), 7.09 (t, J= 8.8 Hz, 2H), 6.93 (d, J= 1.5 Hz, 1H), 5.93 (d, J=
0.9 Hz, 1H), 5.63 (s, 1H), 2.40 (s, 3H), 2.33 ¨2.10 (m, 4H), 1.27¨ 1.07 (m, 4H). 19F NMR
(376 MHz, Methanol-d4) 6 -116.27.
Example 40 4-(2-Cyclopropy1-4-(1-(3-fluorophenypviny1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-40) O-N
la HN
<rN
[00294] 4-(2-Cyclopropy1-4-(1-(3-fluorophenyl)viny1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole was synthesized by reacting 4-(2-cyclopropy1-4-iodo-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (Example 8, Step 4) with 1-(3-fluorophenyl)vinylboronic acid, pinacol ester in a manner similar to that of Example 38.
[00295] C23H20FN30. 374.2 (M+1). NMR (400 MHz, Methanol-d4) 6 7.46 ¨
7.30 (m, 2H), 7.23 ¨7.01 (m, 3H), 6.89 (d, J= 1.6 Hz, 1H), 5.99 (d, Jr 1.0 Hz, 1H), 5.70 (s, 1H), 3.67 (s, 1H), 2.39 (s, 3H), 2.26 ¨ 2.12 (m, 4H), 1.19 ¨ 1.09 (m, 4H). '9F
NMR (376 MHz, Methanol-d4) 6 -116.09.
Example 41 4-(4-(1-(4-Chlorophenyl)viny1)-2-cyclopropy1-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-41) O-N
CI
HN
<r-N
[00296] 4-(4-(1-(4-Chlorophenyl)viny1)-2-cyclopropyl-1H-benzokliimidazol-6-y1)-3,5-dimethylisoxazole was synthesized by reacting 4-(2-cyclopropy1-4-iodo-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (Example 8, Step 4) with 1-(4-chlorophenyl)vinylboronic acid, pinacol ester in a manner similar to that of Example 38.
[00297] C23H20C1N30. 390.2 (M+1). IFINMR (400 MHz, Methanol-d4) 6 7.44 ¨
7.32 (m, 5H), 6.91 (d, J= 1.6 Hz, 1H), 5.97 (d, J= 0.9 Hz, 1H), 5.67 (d, J=
0.9 Hz, 1H), 2.40 (s, 3H), 2.27 ¨ 2.13 (m, 4H), 1.42 (s, 1H), 1.17 (d, J= 6.7 Hz, 4H).
i??

Example 42 4-(2-Cyclopropy1-4-(1-(4-(trifluoromethyl)phenyeviny1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-42) O-N
tio .,3 HN
4-(2-Cyclopropy1-4-(1-(4-(trifluoromethyl)phenyl)viny1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole was synthesized by reacting 4-(2-cyclopropy1-4-iodo-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (Example 8, Step 4) with 1-(4-trifluoromethylpheny1)-vinylboronic acid, pinacol ester in a manner similar to that of Example 38.
C24H20F3N30. 424.2 (M+1). 1HNMR (400 MHz, Methanol-d4) 6 7.63 (d, I = 8.4 Hz, 2H), 7.54 (d, J= 8.6 Hz, 2H), 7.41 (s, 1H), 6.86 (s, 1H), 6.04 (s, 1H), 5.77 (d, J= 48.9 Hz, 1H), 2.36 (s, 3H), 2.20 (s, 4H), 1.18 ¨ 1.00 (m, 4H). 19F NMR (376 MHz, Methanol-d4) 6 -64.6.
Example 43 4-(2-Cyclopropy1-4-(1-phenylethyl)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-43) O-N O-N
10% Pd/C, H2 Et0H _____________________________________ 0. 40 40 HN HN
<r-N <r-N
A suspension of 4-(2-cyclopropy1-4-(1-phenylviny1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (50 mg, 0.141 mmol) (Example 38) and 10% palladium on carbon (10 mg) in 5 mL ethanol was purged with hydrogen gas and allowed to stir for 2 hours. The reaction was then filtered and the solvents evaporated. Purification on silica gel (rf = 0.6 in 60% ethyl acetate in hexanes) afforded 4-(2-cyclopropy1-4-(1-phenylethyl)-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole.
[00298] C23H23N30. 358.2 (M+1). 11-1NMR (CDC13) 6 7.4-7.2 (m, 6H), 6.96 (s, 1H), 4.41 (br, 1H), 2.38 (s, 3H), 2.21 (s, 3H), 1.85 (br, 1H), 1.74 (d, 3H, J
= 7.2 Hz), 1.24 (br, 1H), 1.05 (m, 4H).
Example 44 4-(2-Cyclopropy1-4-(1-(4-fluorophenyl)ethyl)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-44) O-N
le el FIN
[00299] 4-(2-Cyclopropy1-4-(1-(4-fluorophenypethyl)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole was obtained by reducing 4-(2-cyclopropy1-4-(1-(4-fluorophenyl)viny1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (Example 39) in a manner similar to that of Example 43.
[00300] C23H22FN30. 376.2 (M+1). 1H NMR (400 MHz, Methanol-d4) 6 7.45 ¨
7.25 (m, 2H), 7.20 (s, 1H), 6.99 (t, J= 8.8 Hz, 2H), 6.80 (s, 1H), 2.32 (s, 3H), 2.16 (d, J
= 3.2 Hz, 4H), 1.70 (d, J= 7.2 Hz, 3H), 1.38 (s, 1H), 1.20¨ 1.06 (m, 3H). '9F
NMR (376 MHz, Methanol-d4) 6 -119.6.
Example 45 4-(2-Cyclopropy1-4-(1-(3-fluorophenypethyl)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-45) 1 la O-N
HN SF
<rN
[003011 4-(2-Cyclopropy1-4-(1-(3-fluorophenyl)ethyl)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole was obtained by reducing 4-(2-cyclopropy1-4-(1-(3-fluorophenyl)viny1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (Example 40) in a manner similar to that of Example 43.
[003021 C23H22FN30. 376.2 (M+1).11-1NMR (400 MHz, Methanol-d4) 6 7.34 ¨
7.23 (m, 2H), 7.20 ¨ 7.13 (m, 1H), 7.13 ¨ 7.06 (m, 1H), 6.93 (dt, J= 8.6, 4.5 Hz, 1H), 6.87 (s, 1H), 2.36 (s, 3H), 2.20 (s, 4H), 1.75 (d, J= 7.2 Hz, 3H), 1.41 (s, 1H), 1.22¨ 1.13 (m, 4H). 19F NMR (376 MHz, Methanol-d4) 6 -116.1 .
Example 46 4-(2-Cyclopropy1-4-(1-(4-(trifluoromethyl)phenyl)ethyl)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-46) io CF3 HN
<r-N
[00303] 4-(2-cyclopropy1-4-(1-(4-(trifluoromethyl)phenyl)ethyl)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole was obtained by reducing 4-(2-cyclopropy1-4-(1-(4-(trifluoromethyl)phenyl)viny1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (Example 42) in a manner similar to that of Example 43.
[003041 C24H22F3N30. 426.2 (M+1). 1H NMR (400 MHz, Methanol-d4) 6 7.60 ¨
7.47 (m, 4H), 7.23 (d, J= 1.5 Hz, 1H), 6.86 (d, J= 1.5 Hz, 1H), 2.32 (s, 3H), 2.24 ¨ 2.13 (m, 4H), 1.76 (d, J= 7.2 Hz, 3H), 1.20¨ 1.11 (m, 4H). '9F NMR (376 MHz, Methanol-4) 8 -64.6.
Example 47 4-(2-Cyclopropy1-4-(2,4-dimethylthiazol-5-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-47) PEPPSI-IPr, DBU, NP _________________________ DMF/H20, 130 C
S\
HN ZL'S
HN
<rN
[00305] To a mixture of 2-cyclopropy1-4-iodo-6-(3,5-dimethylisoxazol-4-yl)benzimidazole (30 mg, 0.079 mmol) (Example 8, Step 4), 2,4-dimethy1-5-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-1,3-thiazole (38 mg, 0.158 mmol) and DBU
(75 0.50 mmol) under nitrogen was added DMF (1.6 mL) and water (0.8 hiL), followed TM
by PEPPSI-IPr Pd catalyst (6 mg, 0.008 mmol). The reaction mixture was capped, heated to 130 C for 30 min in a microwave reactor. The mixture partitioned between water and ethyl acetate, the aqueous phase was extracted with ethyl acetate twice, and the combined organic phase was washed with 1M aqueous K2CO3, brine, dried, filtered through a layer of celite and concentrated. The crude product was purified by reverse phase HPLC eluting with 0.1% TFA-containing acetonitrile/water to give 4-(2-cyclopropy1-4-(2,4-dimethylthiazol-5-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole.
[00306] C201-120N40S. 365.1 (M+1). 1HNMR (DMSO-d6) 8 7.59 (s, 1H), 7.29 (s.
1H), 2.73 (m, 4H), 2.47 (s, 3H), 2.36 (m, 4H), 2.29 (s, 314), 1.27 (m, 4H), Example 48 4-(2-Cyclopropy1-4-(4,5-dim ethy1-1H-imidazol-1-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-48) o-r HNNN-0 HN HN
<rN
[00307] A suspension of 4-(2-cyclopropy1-4-iodo-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (35 mg, 0.13 mmol) (Example 8, Step 4), 4,5-dimethylimidazole (50 mg), Cu20 (1 mg, 0.007 mmol), 4,7-dimethoxy-1,10-phenanthroline (3 mg, 0.012 mmol), cesium carbonate (41 mg, 0.126 mmol), and PEG-3350 (20 mg) in butyronitrile (1 mL) was heated at 120 C for 72 hours. The solvent was removed and the residue was purified by preparative HPLC to give 4-(2-cyclopropy1-4-(4,5-dimethyl-1H-imidazol-1-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole.
[00308] C201-121N50. 348.1 (M+1). 11-1NMR (DMSO) 69.34 (s, 1H), 7.64 (s, 1H), 7.39 (s, 1H), 2.45 (s, 3H), 2.36 (s, 3H), 2.27 (s, 3H), 2.18 (m, 1H), 2.13 (s, 3H), 1.12 (m, 2H), 1.04 (m, 2H).
[00309] Compounds (1020-49), (1020-50), (1020-51), (1020-52), (1020-53), (1020-54), (1020-55) and (1020-56) were prepared in a similar manner as Example 48 by substituting the appropriate commercially available heterocycle for 4,5-dimethylimidazole:
Example 49 4-(2-Cyclopropy1-4-(3,5-dimethyl-1H-1,2,4-triazol-1-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-49) <r-14 [00310] C19H20N60. 349.1 (M+1). NMR
(DMSO) 6 7.62 (s, 1H), 7.38 (s, 1H), 2.42 (s, 3H), 2.37 (s, 3H), 2.32 (s, 3H), 2.30 (m, 1H), 2.23 (s, 3H), 1.21 (m, 4H).

Example 50 N-Cyclopenty1-2-eyelopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-amine (1020-50) SN
HN
<r-N
[00311] C201-124N40. 337.1 (M+1). 1H NMR (DMSO) 6 6.76 (s, 1H), 6.43 (s, 1H), 5.75 (br, 1H), 3.95 (br, 1H), 2.40 (s, 3H), 2.39 (m, 1H), 2.22 (s, 3H), 2.03 (m, 2H), 1.8-1.2 (m, 12H).
Example 51 4-(2-Cyclopropy1-4-(3,5-dimethyl-4H-1,2,4-triazol-4-y1)-1H-benzokilimidazol-6-y1)-3,5-dimethylisoxazole (1020-51) <r-N ),N
[00312] C191-120N60. 349.1 (M+1). 1H NMR (DMSO) 6 10.19 (s, I H), 7.41 (s, 1H), 7.33 (s, 1H), 2.50 (s, 3H), 2.43 (m, 1H), 2.39 (s, 3H), 2.21 (s, 3H), 2.16 (s, 3H), 1.29 (m, 4H).
Example 52 4-(2-Cyclopropy1-4-(2,5-dimethy1-1H-imidazol-1-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-52) <r_HN *IN %4N
[00313] C20H21N50. 348.1 (M+1). 1H NMR (DMSO) 6 7.66 (s, 1H), 7.58 (s, 1H), 7.40 (s, 1H), 2.45 (s, 3H), 2.40 (s, 3H), 2.27 (s, 3H), 2.18 (m, 1H), 2.06 (s, 3H), 1.2-1.0 (m, 4H).
Example 53 4-(2'-Cyclopropy1-2-methyl-1'H-1,4'-bibenzo[d]imidazol-6'-y1)-3,5-dimethylisoxazole (1020-53) /

[00314] C23H21N50. 384.1 (M+1). 1H NMR (DMSO) 6 7.91 (d, J = 8.4 Hz, 1H), 7.75 (s, 1H), 7.6-7.4 (m, 3H), 7.32 (d, J = 8.0 Hz, 1H), 2.67 (s, 3H), 2.48 (s, 3H), 2.30 (s, 3H), 2.17 (m, 1H), 1.2-1.0 (m, 4H).
Example 54 4-(2-Cyclopropy1-4-(2-methyl-1H-imidazol-l-yl)-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole (1020-54) HN N
\ N
.(p-N

[00315] C19H19N50. 334.1 (M+1). 1H NMR (DMSO) 6 7.95 (s, 1H), 7.83 (s, 1H), 7.65 (s, 1H), 7.40 (s, 1H), 2.54 (s, 3H), 2.45 (s, 3H), 2.27 (s, 3H), 2.19 (m, 1H), 1.13-1.06 (m, 4H).
Example 55 4-(2'-Cyclopropy1-4,5,6,7-tetrahydro-1'H-1,4'-bibenzo[d]imidazol-6'-y1)-3,5-dimethylisoxazole (1020-55) HN
<1=-N
[00316] C22H23N50. 374.1 (M+1). 1H NMR (DMSO) 6 9.38 (s, 1H), 7.64 (s, 1H), 7.41 (s, 1H), 2.74 (m, 2H), 2.56 (m, 2H), 2.44 (s, 3H), 2.27 (s, 3H), 2.20 (m, 111), 1.80 (m, 4H), 1.2-1.0 (m, 4H).
Example 56 4-(2'-Cyclopropy1-1'H-1,4'-bibenzo[d]imidazol-6'-y1)-3,5-dimethylisoxazole (1020-56) HN NN
<rN =
[00317] C221119N50. 370.1 (M+1). 1H NMR (DMSO) 6 9.09 (s, 1H), 7.88 (d, J
=
8.0 Hz, 1H), 7.63 (s, 1H), 7.6-7.4 (m, 4H), 2.47 (s, 3H), 2.30 (s, 3H), 2.20 (m, 1H), 1.2-1.0 (m, 4H).
Example 57 1 "111 4-(2-Cyclopropy1-7-(2,4-dimethylpyridin-3-y1)-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole (1020-57) B
40 r ____________________________ N N N
NH
NH P
<INN i [00318] To a 10 mL Smith process vial equipped with a stir bar was added 4-(2-cyclopropy1-4-iodo-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (758 mg, 2 mmol), (Example 8, Step 4) bis(pinacolato)diboron (2.54 g, 10 mmol), [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (146 mg, 0.2 mmol), and potassium acetate (1.96 g, 20 mmol). 1,4-dioxane was then added, and the reaction vessel was capped with a rubber septum, and evacuated and backfilled with N2 three times. The reaction mixture was then heated for 18 hours at 100 C, followed by 6 hours at 110 C. The reaction mixture was then diluted with ethyl acetate (100 mL), filtered, washed with water (100 mL) followed by brine (50 mL), and dried over anhydrous magnesium sulfate. This mixture was then concentrated to dryness to give crude 4-(2-cyclopropy1-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y1)-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole. C15H17BN303. 298.1 ((M-Pinacol)+1).
[00319] Crude 4-(2-cyclopropy1-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y1)-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole (280 mg crude mixture, ¨0.2 mmol) from the previous step was added to a 0.5 to 2 mL Smith process vial equipped with a stir bar. To the reaction vessel was added 3-bromo-2,4-dimethylpyridine (112 mg, 0.6 mmol), potassium carbonate (276 mg, 2 mmol), PEPPSI-IPr catalyst (13.6 mg, 0.02 mmol), 1,4-dioxane (0.8 mL) and water (0.2 mL). The reaction mixture was heated in a microwave reactor for 45 minutes at 135 C, then the organic layer was removed by syringe, filtered, and directly injected onto preparative reverse phase high performance liquid chromatography (Phenomenex Gemini C18 column, 5% to 50% gradient acetonitrile in water with 0.1% TFA) to give 4-(2-cyclopropy1-7-(2,4-dimethylpyridin-3-y1)-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole (34 mg) as a TFA salt.
[00320] C22H22N40. 359.2 (M+1). 1H NMR (400 MHz, CD30D) 6 8.69 (d, J= 6.2 Hz, 1H), 7.94 (d, J= 6.2 Hz, 1H), 7.79 (d, J= 1.4 Hz, 1H), 7.44 (d, 1= 1.4 Hz, 1H), 2.50 (s, 3H), 2.49 - 2.40 (m, 4H), 2.36 (s, 3H), 2.30 (s, 3H), 1.57 - 1.46 (m, 2H), 1.46 - 1.37 (m, 2H).
Example 58 4-(2-Cyclopropy1-7-(3-cyclopropy1-5-methy1-1H-pyrazol-4-y1)-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole (1020-58) O-N O-N
Br \ N

p5,0 _______________________________________ N
<!-NHN'11-11 [00321] Crude 4-(2-cyclopropy1-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y1)-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole (729 mg crude mixture, -0.5 mmol) (Example 57) was added to a 2 to 5 mL Smith process vial equipped with a stir bar. To the reaction vessel was added 4-bromo-3-cyclopropy1-5-methy1-11-1-pyrazole hydrochloride (355.5 mg, 1.5 mmol), potassium carbonate (690 mg, 5 mmol), TM
1Pr catalyst (34 mg, 0.05 mmol), 1,4-dioxane (2 mL) and water (0.5 mL). The reaction mixture was heated in a microwave reactor for 1 hour at 135 C, then the organic layer was removed by syringe, filtered, and directly injected onto preparative reverse phase TM
high performance liquid chromatography (Phenomenex Gemini C18 column, 5% to 50%
gradient acetonitrile in water with 0.1% TFA) to give 4-(2-cyclopropy1-7-(3-cyclopropy1-5-methy1-1 H-pyrazol-4-y1)-1H-benzo [d]imi d az ol-5-y1)-3 ,5-dimethylisoxazole as a TFA salt.
[00322] C22H23N50. 374.2 (M+1). 1HNMR (400 MHz, CD30D) 6. 7.64 (d, J= 1.4 Hz, 1H), 7.39 (d, J= 1.5 Hz, 1H), 2.53 - 2.39 (in, 4H), 2.29 (s, 3H), 2.23 (s, 3H), 1.87 -1.70 (m, 1H), 1.58 - 1.48 (in, 2H), 1.48 - 1.40 (m, 2H), 1.02- 0.73 (m, 4H).
Example 59 4-(2-Cyclopropy1-4-(3-methyl-5-pheny1-1H-pyrazol-4-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-59) O-N N-NH O-N
/
Ph le B..0 Br, \
HN HN N
<-..=-1µ1 6 PEPPSI-IPr, Cs2CO3, DME/H20N
Ph M.W. 12000 [00323] Crude 4-(2-eyelopropy1-7-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole (74 mg ,0.05 mmol) (Example 57) and 4-bromo-3-methyl-5-phenyl-1H-pyrazole (36 mg, 0.15 mmol) was added to a solvent mixture of 1,2-dimethoxyethane (2 mL) and water (1 mL). To the above mixture were added PEPPSI-1Pr (4 mg, 0.005 mmol) and Cs2CO3 (72 mg, 0.2 mmol). The reaction mixture was heated at 120 C for 30 mins in microwave reactor. The reaction mixture was evaporated and the residue was purified by preparative HPLC (0-100%
CH3CN/H20) to afford 4-(2-cyclopropy1-4-(3-methyl-5-pheny1-1H-pyrazol-4-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole.
[00324] C25H23N50. 410.3 (M+1). 1H NMR (400MHz, CD30D) 6 7.61 (d, J=1.2 Hz, 1H), 7.35-7.28 (m, 5H), 7.26 (d, J1.2 Hz, 1H), 2.41-2.39 (m, 1H), 2.33 (s, 3H), 2.31 (s, 3H), 2.13 (s, 3H), 1.51-1.48 (m, 2H), 3.34 (s, 2H).
Example 60 4-(2-Cyclopropy1-4-(3,5-dicyclopropy1-1H-pyrazol-4-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-60) __________________ H \ \ Br -->" io NJ
\

HN --- NH
Step 1 [00325] 1,3-Dicyclopropylpropane-1,3-dione (1.1g, 7.23 mmol) was stirred at 0 C in Et0H (25 mL) and hydrazine (0.232g, 7.23 mmol) added slowly. After stirring at RT for 2 h, volatiles were remove, the residue taken up in Et0Ac and the organic layer washed with brine and dried over sodium sulfate. Purification on silica gel (hexanes ethyl acetate 0-100%) afforded 3,5-dicyclopropy1-1H-pyrazole.
Step 2 [00326] 3,5-Dicyclopropy1-1H-pyrazole (1.0g, 6.79 mmol) was dissolved in acetic acid (10 ml) and reacted with NBS (1.209 g, 6.79 mmol). After stirring for 1 h, volatiles were removed, the residue taken up in Et0Ac and the organic layer washed with brine and dried over sodium sulfate. Purification on silica gel (hexanes ethyl acetate 0-100%) afforded 4-bromo-3,5-dicyclopropy1-1H-pyrazole.
Step 3 [00327] 4-Bromo-3,5-dicyclopropy1-1H-pyrazole was reacted under standard Suzuki conditions with 4-(2-cyclopropy1-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y1)-1H-benzo[d]imidazol-6-y1)-3-methylisoxazole (see Example 59) to afford 4-(2-cyclopropy1-4-(3,5-dicyclopropy1-1H-pyrazol-4-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole.
[00328] C24H25N50. 400.2 (M+1). 1H NMR (400 MHz, dmso) 6 7.61 (s, 1H), 7.34 (s, 1H), 2.45 (s, 3H), 2.26 (s, 3H), 1.71 ¨ 1.59 (m, 1H), 1.48 ¨ 1.33 (m, 8H), 0.74 (m, 6H).
Example 61 5-(2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)quinolin-2(1H)-one (1020-61) Step 1: Preparation of 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-ylboronic acid 1 1 d O13-130f-Pc1C12clopf (5 mol%) HN HN B(OH)2 <rN KOAc DMSO
[00329] 4-(2-Cyclopropy1-4-iodo-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (300.0 mg, 0.791 mmol) (Example 8, Step 4) was treated with 4,4,4',4',5,5,5',5'-octamethy1-2,2'-bi(1,3,2-dioxaborolane) (301.3 mg, 1.1865 mmol, 1.5 equiv.), KOAc (232.9 mg, 2.373 mmol, 3.0 equiv.) in the presence of PdC12dppf (28.9 mg, 0.03955 mmol, 0.05 equiv) in DMSO (5 mL) at 170 C for 30 min. in an oil bath.
To the reaction mixture were added water (30 mL) and Et0Ac (70 mL). The whole was filtered through Celite (3 g) and then organic layer was separated from the filtrate. The organic layer was washed with brine (30 mL) and dried over Na2504. The solvent was removed under a reduced pressure to give the crude product. The crude product was purified by a preparative HPLC (5-95% acetonitrile: water with 0.05%
trifluoroacetic acid, on a Phenomenex Luna C18 column) to give 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-ylboronic acid.
[00330] C15H16BN303: MS. ink 297.9 (M+1).
Step 2: Preparation of 5-(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yflisoquinolin-1(2H)-one N-0 Br, PEPPSI-iPr (5 mol%) B(OH)2 HN HN
Na2CO3 dioxane [00331] 2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-ylboronic acid (47.1 mg, 0.1585 mmol) was treated with 5-bromoquinolin-2(1H)-one (106.5 mg, 0.4755 mmol, 3.0 equiv.), 2M-Na2CO3 (aq) (1 mL) in the presence of PEPPSI-IPr (5.3 mg, 0.007925 mmol, 0.05 equiv) in 1,4-dioxane (3 mL) at 150 C
for 10 min in microwave reactor. To the reaction mixture were added water (30 mL) and Et0Ac (70 mL). The whole was filtered through Celite (3 g) and then organic layer was separated from the filtrate. The organic layer was washed with brine (30 mL) and dried over Na2SO4. The solvent was removed under a reduced pressure to give the crude product. The crude product was purified by a preparative HPLC (5-95%
acetonitrile:
water with 0.05% trifluoroacetic acid, on a Phenomenex Luna C18 column) and a silica gel chromatography (MeOH:CH2C12= 3:97-10:90) to give 5-(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-371)isoquinolin-1(2H)-one.
100332] C24H20N402. MS. m/z 396.9 (M+1). NMR (Me0H-d4) 8 8.45 (d, J-7.3 Hz, 1H), 7.81 (d, J= 7.3 Hz, 1H), 7.66 (t, J= 7.3, 1.5 Hz, 1H), 7.48 (s, 1H), 7.13 (d, J= 7.3, 1H), 7.07 (s, 1H), 6.35 (d, J= 7.3, 1H), 2.45 (s, 3H), 2.30 (s, 3H), 2.15 - 2.05 (m, 1H), 1.17 - 1.05 (m, 4H).
Example 62 5-(2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)-3,4-dihydroisoquinolin-1(2H)-one (1020-62) HN
_N

[00333] 5-(2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-y1)-3,4-dihydroisoquinolin-1(2H)-one was synthsized in a similar manner as that of Example 61, Step 2, using 5-bromo-3,4-dihydroisoquinolin-1(2H)-one.
[00334] C24HnN402. MS. 399.2 (M+1). 11-1 NMR (Me0H-d4) 8 8.07 (dd, J= 7.7, 1.4 Hz, 1H), 7.60 (dd, J= 7.7, 1.4 Hz, 1H), 7.50 (t, J= 7.7 Hz, 1H), 7.43 (d, J= 1.5 Hz, 1H), 7.01 (d, J= 1.5 Hz, 1H), 3.41 (t, J= 6.7 Hz, 2H), 2.96 - 2.64 (m, 2H), 2.44 (s, 3H), 2.29 (s, 3H), 2.20 -2.07 (quin, J= 7.0 Hz, 1H), 1.20 - 1.07 (d, J= 7.0 Hz, 4H).

Example 63 5-(2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)quinolin-2(1H)-one (1020-63) HN
N
NH

[00335] 5-(2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-yl)quinolin-2(1H)-one was synthsized in a similar manner as that of Example 61, Step 2, using 5-bromoquinolin-2(1H)-one.
[00336] C24H20N402. MS. 397.1 (M+1). 1H NMR (Me0H-d4) 8 7.68 (t, J= 8.0 Hz, 1H), 7.67 (d, J= 8.0 Hz, 1H), 7.49 (s, 1H), 7.47 (d, J= 8.0 Hz, 1H), 7.35 (d, J= 8.0 Hz, 1H), 7.08 (s, 1H), 6.55 (d, J= 8.0 Hz, 1H), 2.46 (s, 3H), 2.30 (s, 3H), 2.11 (quin, J=
7.0 Hz, 1H), 1.13 (d, J= 7.0 Hz, 4H).
Example 64 5-(2-Cyelopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]irnidazol-4-y1)-3,4-dihydroquinolin-2(1H)-one (1020-64) 1.1 NH

[00337] 5-(2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-y1)-3,4-dihydroquino1in-2(1H)-one was synthsized in a similar manner as that of Example 61, Step 2, using 5-bromo-3,4-dihydroquinolin-2(1H)-one.
[00338] C24H22N402. MS. 399.1 (M+1). 1H NMR (Me0H-d4) 6 7.41 (br s, 1H), 7.29 (br t, J= 8.0 Hz, 1H), 7.08 (d, J= 8.0 Hz, 1H), 7.01 ¨ 6.95 (m, 2H), 2.91 ¨2.60 (m, 2H), 2.55 ¨2.45 (br m, 1H), 2.43 (s, 3H), 2.28 (s, 3H), 2.16 ¨ 2.07 (m, 1H), 1.12 (d, J=
7.4 Hz, 4H).
Example 65 5-(2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)-4,6-dimethylpyrimidin-2-ol (1020-65) el N
HN
' NOH
[00339] 5-(2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-y1)-4,6-dimethylpyrimidin-2-ol was synthsized in a similar manner as that of Example 61, Step 2, using 5-bromo-4,6-dimethylpyrimidin-2-ol.
[00340] C211-121N502. MS. 376.1 (M+1). 1H NMR (CD3CN) 6 7.81 (d, J= 1.4 Hz, 1H), 7.28 (d, J= 1.4 Hz, 1H), 2.56 ¨ 2.45 (m, 1H), 2.42 (s, 3H), 2.26 (s, 3H), 2.15 - 2.05 (m, 6H), 1.57 - 1.52 (m, 2H), 1.50-1.40 (m, 2H).
Example 66 542-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)-4-methylpyrimidin-2-ol (1020-66) HN N
N OH
[00341] 5-(2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-y1)-4-methylpyrimidin-2-ol was synthsized in a similar manner as that of Example 61, Step 2, using 5-bromo-4-methylpyrimidin-2-ol.
[00342] C20Hi9N502. MS. 362.1 (M+1). 1H NMR (CD3CN) 8 8.29 (s, 1H), 7.75 (d, J= 1.4 Hz, 1H), 7.34 (d, J= 1.4 Hz, 1H), 2.49 (quin, J= 6.7 Hz, 1H), 2.42 (s, 3H), 2.29 (s, 3H), 2.26 (s, 3H), 1.49 (d, J= 6.7 Hz, 4H).
Example 67 4-(2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)phthalazin-1(2H)-one (1020-67) HN --'N,NH
<r-N

[00343] 4-(2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-yl)phthalazin-1(2H)-one was synthsized in a similar manner as that of Example 61, Step 2, using 4-bromophthalazin-1(2H)-one.
[00344] C23Hi9N502. MS. 398.1 (M+1). 1H NMR (Me0H-d4) 6 8.51 (dd, J= 7.5, 1.4 Hz, 1H), 7.95 (td, J= 7.5, 1.4 Hz, 2H), 7.92 (td, J= 7.5, 1.4 Hz, 1H), 7.77 (d, J= 1.4 Hz, 1H), 7.67 (dd, J= 7.5, 1.4 Hz, 1H), 7.66 (d, 1.4 Hz, 1H), 2.49 (s, 3H), 2.48 -2.40 (m, 1H), 2.33 (s, 3H), 1.58 - 1.49 (m, 2H), 1.44 - 1.35 (m, 2H).
Example 68 51-(2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yespiro[cyclopropane-1,11-isoindolin]-3'-one (1020-68) HN SI NH
Pk' [00345] 51-(2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)spiro[cyclopropane-1,11-isoindo1in]-31-one was synthsized in a similar manner as that of Example 61, Step 2, using 31-oxospiro[cyclopropane-1,11-isoindoline]-51-y1 trifluoromethanesulfonate.
[003461 C25H22N402. MS. 411.1 (M+1). 11-1 NMR (Me0H-d4) 8 8.05 (br s, 1H), 7.90 (d, J= 8.6 Hz, 1H), 7.30 (d, J= 1.5 Hz, 1H), 7.27 (d, J= 8.6 Hz, 1H), 7.10 (d, J=
1.5 Hz, 1H), 2.35 (s, 3H), 2.20 (s, 3H), 2.08 - 2.16 (s, 1H), 1.58 - 1.50 (m, 2H), 1.50 -1.47 (m, 2H), 1.11 - 1.02 (m, 4H).
Example 69 5-(2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)-1-methyl-3,4-dihydroquinolin-2(1H)-one (1020-69) Step 1 Br Br Mel NH THF N,Me [00347] 5-Bromo-3,4-dihydroquinolin-2(1H)-one (300.0 mg, 1.327 mmol) was treated with KHMDS (1.33 mL, 1.327 mmol, 1.0 equiv., 1M solution in THF) in THF (3 mL) under a nitrogen atmosphere at -78 C for 30 min. To the reaction mixture was added a solution of Mel (367.7 mg, 2.654 mmol, 2.0 equiv.) in THF (1 mL) at the same temperature. And then the reaction was allowed to warm to room temperature and stirred for 45 mm. To the reaction mixture was added water (30 mL). The whole was extracted with CH2C12 (30 mL x 3). Obtained organic layer was washed with brine (30 mL) and dried over Na2SO4. The solvent was removed under a reduced pressure to give a crude product. The crude product was purified a silica gel column chromatography (MeOH:CH2C12= 0:100 - 1:99) to give 5-bromo-1-methy1-3,4-dihydroquinolin-2(1H)-one.
[00348] CioHioBrNO: MS. m/z 240.0 (M-1), 242.0 (M+1).
Step 2: Preparation of 5-(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)-1-methyl-3,4-dihydroquinolin-2(1H)-one Iv HN
N, Me [00349] 5-(2-Cyc1opropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-y1)-1-methyl-3,4-dihydroquinolin-2(1H)-one was synthsized in a similar manner as that of Example 61, Step 2, using 4-bromo-2-tert-butoxypyridine.
[00350] C25H24N402. MS. m/z 413.2 (M+1). 1H NMR (Me0H-d4) 6 7.63 (d, J=
1.5 Hz, 1H), 7.50 (t, J= 7.9 Hz, 1H), 7.36 (d, J= 1.5 Hz, 1H), 7.35 (d, J= 7.9 Hz, 1H), 7.19 (d, J= 7.9 Hz, 1H), 3.45 (s, 3H), 2.72 (t, J= 7.3 Hz, 2H), 2.55 (br t, J=
7.3 Hz, 2H), 2.46 (s, 3H), 2.46 - 2.39 (m, 1H), 2.30 (s, 3H), 1.56- 1.47 (m, 2H), 1.42-1.35 (m, 2H).
Example 70 4-(4-(2-tert-Buto xypyridin-4-y1)-2-cycl opropy1-1H-b enzo [d] imidazol-6-y1)-3 ,5-dimethylisoxazole (1020-70) Iv 0, HN
[00351] 4-(4-(2-tert-butoxypyridin-4-y1)-2-cyclopropy1-1H-benzo[d]imidazol-34)-3,5-dimethylisoxazole was synthsized in a similar manner as that of Example 61, Step 2, using 4-bromo-2-tert-butoxypyridine.
[00352] C24H26N402. MS. 403.2 (M+1). NMR (Me0H-d4) 8 8.21 (br s, 1H), 7.50 - 7.30 (br m, 2H), 7.30 - 7.10 (br m, 2H), 2.43 (s, 2H), 2.28 (s, 2H), 2.22 (quin, J=
7.0 Hz, 1H), 1.61 (s, 9H), 1.16 (d, J= 7.0 Hz, 4H).
Example 71 4-(2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)pyridin-2-ol (1020-71) Iv Iv HN
o.< TFA

N NH
[00353] 4-(4-(2-tert-Butoxypyridin-4-y1)-2-cyclopropy1-1H-benzo[d]imidazol-y1)-3,5-dimethylisoxazole (10.1 mg, 0.0251 mmop was dissolved into TFA (2 mL) at room temperature. The reaction mixture was stirred at the same temperature for 1 h. The solvent was removed under a reduced pressure to give 4-(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)pyridin-2-ol.
[00354] C20H18N402. MS. m/z 347.1 (M+1). 1H NMR (Me0H-d4) 6 7.67 (d, J-1.4 Hz, 1H), 7.65 (d, J= 6.8 Hz, OH), 7.55 (d, J= 1.4 Hz, 1H), 6.83 (d, J= 1.7 Hz, 1H), 6.70 (dd, J= 6.8, 1.7 Hz, 1H), 2.49 - 2.57 (m, 1H), 2.45 (s, 3H), 2.29 (s, 3H), 1.60- 1.52 (m, 1H), 1.49 - 1.41 (m, 1H).
1 A') Example 72 N-(4-(3,5-Dimethylisoxazol-4-y1)-2-iodo-6-nitropheny1)-N-methylcyclopropanecarboxamide (1020-72) Step 1: Preparation of 4-(3,5-dimethylisoxazol-4-y1)-2-iodo-N-methy1-6-nitroaniline Mel, Cs2003 DMF

L,21N

[00355] Into a flask containing 4-(3,5-dimethylisoxazol-4-y1)-2-iodo-6-nitroaniline (1000 mg, 2.78 mmol, 1 equiv) (see Example 8, Step 2) was added DMF (15 mL, 0.2 M) before adding cesium carbonate (1.4 gm, 4.17 mmol, 1.5 equiv.) and idomethane (260 tiL, 4.17 mmol, 1.5 equiv). After an hour, the reaction was quenched with water and the reaction was partitioned between water and ethyl acetate.
The organic layer was washed with brine and dried over sodium sulfate. Purification was carried out by flash column chromatography to furnish 4-(3,5-dimethylisoxazol-4-y1)-2-iodo-N-methy1-6-nitroaniline.
[00356] LCMS (m/z +1) 373.85. 1H NMR (400 MHz, cdc13) 8 7.81 (t, J = 3.0 Hz, 1H), 7.70 (d, J = 2.1 Hz, 1H), 2.97 (s, 3H), 2.40 (d, J = 16.8 Hz, 3 H), 2.26 (d, J = 14.2 Hz, 3H).
Step 2: Preparation of N-(4-(3,5-dimethylisoxazol-4-y1)-2-iodo-6-nitropheny1)-N-methylcyclopropaneearboxamide >4c1 TEA, CH2Cl2 %/21,1 HN
Ox [00357] To a flask containing 4-(3,5-dimethylisoxazol-4-y1)-2-iodo-N-methy1-6-1 t1.1 nitroaniline (300 mg, 0.8 mmol, 1 equiv.) was added methylene dichloride (8 ml, 0.1M) and TEA (335 L, 2.42 mmol, 3 equiv.). At 0 C, cyclopropanecarbonyl chloride (110 1.21mmol, 1.5 equiv) was added. After an hour, the reaction was complete. The reaction was extracted with Et0Ac and washed with water, saturated NH4C1.
After drying with MgSO4, it was filtered and concentrated to dryness. The product was purified by flash column chromatography to furnish N-(4-(3,5-dimethylisoxazol-4-y1)-2-iodo-6-nitropheny1)-N-methylcyclopropanecarboxamide.
[00358] LCMS (m/z +1) 442.06 Step 3: Preparation of 4-(2-cyclopropy1-7-iodo-1-methy1-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole õ SnCl2, AcOH
N
Ox [00359] Into a microwave vial containing N-(4-(3,5-dimethylisoxazol-4-y1)-iodo-6-nitropheny1)-N-methylcyclopropanecarboxamide (110 mg, 0.23 mmol, 1 equiv) was added AcOH (5mL, 0.25M) and tin (II) chloride (86 mg, 0.45 mmol, 2 equiv).
The reaction was heated for 90 min at 120 C. The reaction was then stirred in 2N
NaOH
solution for 20 minutes before being partitioned between water and ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The product was purified by flash column chromatography to furnish 4-(2-cyclopropy1-7-iodo-1-methy1-1H-benzo[djimidazol-5-y1)-3,5-dimethylisoxazole.
LCMS (m/z +1) 394.05.
Step 4: Preparation of 4-(2-cyclopropy1-7-(3,5-dimethyl-1H-pyrazol-4-y1)-1-methyl-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole ¨1\\J
B \ NH

I - NH
op-ir, r, 0s2003 N
DME/H20, M.W. 12000 [00360] To a microwave vial containing 4-(2-cyclopropy1-7-iodo-1-methy1-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole (4 mg, 0.01 mmol, 1 equiv.) was added 3,5-dimethy1-4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-1H-pyrazole (6 mg, 0.025 mmol, 2.5 equiv.), Cs2CO3 (13 mg, 0.04 mmol, 4 equiv.) and PEPPSITm-IPr catalyst (0.8 mg, 0.02 mmol, 0.1 equiv.) and dissolved in DME-H20 (20 mL, 0.2 M, 2/1, v/v).
The mixture was heated to 120 C. After 1 hr, the reaction was complete. The reaction was concentrated in yam and purification was then carried out by reverse phase HPLC to furnish 4-(2-cyclopropy1-7-(3 ,5-dimethy1-1H-pyrazol-4-y1)-1-m ethyl-1H-benzo [d]imidazol-5-y1)-3 ,5-dimethylisoxazole.
[00361] LCMS (m/z +1) 362.22. 1H NMR (400 MHz, cd3od) 6 7.44 (d, J= 1.6 Hz, 1H), 6.87 (d, J= 1.6 Hz, 1H), 3.54 (s, 3H), 2.40 (s, 3H), 2.25 (s, 3H), 2.15 (s, 1H), 2.10 (s, 6H), 1.37 (s, 2H), 1.19 - 1.07 (m, 2H).
Example 73 4-(2-Cyclopropy1-7-(1,4-dimethy1-1H-pyrazol-5-y1)-1-methyl-1H-benzo[d]imidazol-y1)-3,5-dimethylisoxazole (1020-73) / \ 9 /
N
NSI _____________________________________________ N PEPPSI-Pr, Cs2003 /N
DME/H20, M.W. 120 00 [00362] To a microwave vial containing 4-(2-cyclopropy1-7-iodo-1-methy1-1H-benzo [d] imidazol-5 -y1)-3 ,5-dim ethylisoxazole (22 mg, 0.056 mmol, 1 equiv.) was added 1,4-dimethy1-5-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-1H-pyrazole (31 mg, 0.14 mmol, 2.5 equiv.), Cs2CO3 (72 mg, 0.22 mmol, 4 equiv.) and PEPPSITm-IPr catalyst (4 mg, 0.006 mmol, 0.1 equiv.) and dissolved in DME-H20 (4 mL, 0.2 M, 2/1, v/v).
The mixture was heated to 120 C. After 1 hr, the reaction was complete. The reaction was concentrated in vacuo and purification was then carried out by reverse phase HPLC to furnish 4-(2-cyclopropy1-7-(1,4-dimethyl-1H-pyrazol-5-y1)-1-methy1-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole.
[003631 LCMS (m/z +1) 362.24. 1H NMR (400 MHz, cd3od) 6 7.57 (d, J= 1.6 Hz, 1H), 7.46 (s, 1H), 7.02 (d, J= 1.6 Hz, 1H), 3.70¨ 3.58 (m, 3H), 3.40 (s, 3H), 2.42 (s, 3H), 2.26 (s, 3H), 2.24 ¨ 2.12 (m, 1H), 1.93 (s, 3H), 1.20¨ 1.04 (m, 4H).
Example 74 4-(2-Cyclopropy1-1-methyl-7-(6-methylquinolin-5-y1)-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole (1020-74) N, 40 HO B.OH
= 1 PEPPSI-IPr, Cs2003, [00364] To a microwave vial containing 4-(2-cyclopropy1-7-iodo-1-methy1-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole (22 mg, 0.056 mmol, 1 equiv.) was added 3,5- 6-methylquinolin-5-ylboronic acid (26 mg, 0.14 mmol, 2.5 equiv.), Cs2CO3 (72 mg, 0.22 mmol, 4 equiv.) and PEPPSITm-IPr catalyst (4 mg, 0.006 mmol, 0.1 equiv.) and dissolved in DME-H20 (4 mL, 0.2 M, 2/1, v/v). The mixture was heated to 120 C. After 1 hr, the reaction was complete. The reaction was concentrated in vacuo and purification was then carried out by reverse phase HPLC to furnish 4-(2-cyclopropy1-1-methy1-7-(6-methylquinolin-5-y1)-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole.
[00365] LCMS (m/z +1) 409.52. 1H NMR (400 MHz, cd3od) 6 8.73 (d, J= 4.3 Hz, 1H), 8.02 (d, J= 8.6 Hz, 1H), 7.75 (d, J= 8.8 Hz, 1H), 7.64 (d, .1= 8.4 Hz, 1H), 7.51 (d, J= 1.6 Hz, 1H), 7.34 (dd, J= 8.6, 4.3 Hz, 1H), 6.87 (d, J= 1.5 Hz, 1H), 2.97 (s, 3H), 1,e1A

2.34 (s, 3H), 2.20 (d, J = 9.3 Hz, 6H), 1.99 (d, J= 8.6 Hz, 1H), 1.07 ¨0.93 (m, 4H).
Example 75 4-(2-Cyclobuty1-4-(3,5-dimethy1-1H-pyrazol-4-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-75) Step 1: Preparation of 3-(3,5-dimethy1-1H-pyrazol-4-y1)-5-(3,5-dimethylisoxazol-4-yObenzene-1,2-diamine O-N
O-N ¨N
B
NH
1.1 \ N
H2N H2N PEPPSI-1Pr, Cs2CO3 NH2 NI-I
NH2 DME/H20, M.W. 130 C
[00366] 3,5-Dimethylpyrazole-4-boronic acid, pinacol ester (1.35g, 6.08 mmol) was added to a solution of 5-(3,5-dimethylisoxazol-4-y1)-3-iodobenzene-1,2-diamine (500 mg, 1.52 mmol) in 1,2-dimethoxy ethane and water (8/4 mL). To the mixture was added cesium carbonate (2.5g, 7.6 mmmol) and PEPPSI-IPr (103 mg, 0.15 mmol).
The reaction was put in microwave reactor and heated at 130 C for 60 minutes before being evaporated under vacuum. The residue was purified by preparative HPLC (0-100%
CH3CN/H20) to afford 3-(3,5-dimethy1-1H-pyrazol-4-y1)-5-(3,5-dimethylisoxazol-y1)benzene-1,2-diamine.
[00367] C16H19N50. 298.4 (M+1).
Step 2: Preparation of 4-(2-cyclobuty1-4-(3,5-dimethy1-1H-pyrazol-4-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole 0-r U

TEA
O
Pyr ___________________________ )1, \ N

\ N NH

[00368] 3-(3,5-dimethy1-1H-pyrazol-4-y1)-5-(3,5-dimethylisoxazol-4-y1)benzene-1,2-diamine (50 mg, 0.17 mmol) was dissolved in pyridine (1 mL). To the solution was added cyclobutyl carbonyl chloride (20 mg, 0.17 mmol). The reaction was stirred at RT
for lh before the solvent was evaporated under vacuum and TFA (1 mL) was added and the reaction mixture was heated at 80 C overnight. The solvent was removed under vacuum and the residue was purified by preparative HPLC (0-100% CH3CN/H20) to afford 4-(2-cyclobuty1-4-(3,5-dimethy1-1H-pyrazol-4-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole.
[00369] C211123N50. 362.3 (M+1). 1H NMR (400MHz, CD30D) 8 7.77 (d, J =1.6 Hz, 1H), 7.47 (d, J=1.6 Hz, I H), 4.14-4.10 (m, 1H), 2.64-2.58 (m, 4H), 2.48 (s, 3H), 2.33(s, 6H), 2.31 (s, 3H), 2.12-2.10 (m, 2H).
Examples 76 and 77 4-(2-(Difluoromethyl)-7-(3,5-dimethy1-1H-pyrazol-4-y1)-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole (1020-76); and 4-(7-(3,5-Dirnethyl-1H-pyrazol-4-y1)-2-methyl-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole (1020-77) O-N O-N O-N

FJLQAF
.2N
\ N NH NH
NH2 NH -14 )\--NH -t4 [00370] To a stirred round-bottomed flask was added 3-(3,5-dimethy1-1H-pyrazol-4-y1)-5-(3,5-dimethylisoxazol-4-y1)benzene-1,2-diamine (52.5 mg, 0.18 mmol) (see Example 75, Step 1) and methylene chloride (1 mL). To this solution was added difiuoroacetic anhydride (25 'IL, 0.198 mmol). This solution was allowed to stir at room temperature for 1 hour before adding 5 mL TFA. Resulting solution was refluxed hours, then concentrated in vacuo. Residue was then taken up in methanol, and injected onto preparative reverse phase high performance liquid chromatography (Phenomenex TM
Gemini C18 column, 5% to 50% gradient acetonitrile in water with 0.1% TFA) to give two products:

[00371] 4-(2-(Difluoromethyl)-7-(3,5-dimethy1-1H-pyrazol-4-y1)-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole: C18Hi7F2N50. 358.1 (M+1). 1H NMR

(400 MHz, cd3od) 6 7.67 (d, J= 1.6 Hz, 1H), 7.27 (d, J= 1.6 Hz, 1H), 7.05 (td, J= 53.4, 0.8 Hz, 1H), 2.47 (s, 3H), 2.38 - 2.35 (m, 6H), 2.32 (s, 3H).
[00372] 4-(7-(3,5-Dimethy1-1H-pyrazol-4-y1)-2-methy1-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole: Ci8Hi9N50. 322.1 (M+1). 1H NMR (400 MHz, cd3od) ö
7.72 (d, J= 1.1 Hz, 1H), 7.40 (d, J= 1.4 Hz, 1H), 2.87 (s, 3H), 2.47 (s, 3H), 2.31 (s, 3H), 2.27 (s, 6H).
Example 78 4-(2-(2,2-Difluorocyclopropy1)-7-(3,5-dimethyl-1H-pyrazol-4-y1)-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole (1020-78) \ _____________________________________ NH
NH2 NN H _F_\< \(-NH
[00373] To a stirred solution of 3-(3,5-dimethy1-1H-pyrazol-4-y1)-5-(3,5-dimethylisoxazol-4-y1)benzene-1,2-diamine (52.5 mg, 0.18 mmol) (see Example 75, Step 1) in DMF (1 mL) was added 2,2-difluorocyclopropanecarboxylic acid (24.2 mg, 0.198 mmol), DIPEA (157 [IL, 0.9 mmol), and HATU (150 mg, 0.396 mmol). This solution was allowed to stir 1 hr at room temperature, then 2 mL TFA was added and the solution was heated to 80 C for 18 hours. Resulting solution was concentrated in vacuo, filtered, and purified by preparative reverse phase HPLC (Phenomenex Gemini column, 5% to 50% gradient acetonitrile in water with 0.1% TFA) to give 44242,2-difluorocyclopropy1)-7-(3,5-dimethyl-1H-pyrazol-4-y1)-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole.
[00374] C20F119F2N50. 384.2 (M+1). 1H NMR (400 MHz, CD30D) 6 7.66 (d, J=
1.4 Hz, 1H), 7.35 (d, J= 1.4 Hz, 1H), 3.50 -3.34 (m, 1H), 2.47 (s, 3H), 2.47 -2.38 (m, 2H), 2.31 (s, 3H), 2.28 (s, 6H).

Example 79 N-(Cyclopropylmethyl)-4-(3,5-dimethy1-1H-pyrazol-4-y1)-6-(3,5-dimethylisoxazol-y1)-1H-benzo[d]imidazol-2-amine (1020-79) O-N
O-N
S EDC
HN
N
H2N N THE, NEt3, 80 C )=-*N NH
H2N ' NH
1003751 3-(3,5-Dimethy1-1H-pyrazol-4-y1)-5-(3,5-dimethylisoxazol-4-yObenzene-1,2-diamine (20 mg, 0.07 mmol) (Example 75, Step 1) was dissolved in THF (1 mL).
To the solution was added cyclopropylmethyl isothiocyanate (9 mg, 0.08 mmol) and triethylamine (93 uL). The reaction was heated at 80 C for 3h before 1-ethy1-3-(3-dimethylaminopropy1)-carbodiimide hydrogen chloride (30 mg, 0.16 mmol) was added and heated at 80 C for 4h. The solvent was then evaporated under vacuum and the residue was purified by preparative HPLC (0-100% CH3CN/H20) to afford N-(cyclopropylmethyl)-4-(3,5-dimethy1-1H-pyrazol-4-y1)-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-2-amine.
[003761 C21F124N60. 377.3 (M+1). 1H NMR (400MHz, CD30D) 6 7.04 (s, 1H), 6.80 (s, 1H), 2.52-2.51 (m, 2H), 2.09(s, 3H), 1.99 (s, 6H), 1.91 (s, 3H), 0.95-0.85 (m, 1H), 0.30-0.27 (m, 2H), 0.15-0.05 (m, 2H).
Example 80 4-(4-(3,5-Dimethy1-1H-pyrazol-4-y1)-2-(1-fluorocyclopropyl)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-80) 1) HATU
i-Pr2NEt DMF, rt H2N NH 2) TFA, 100001. HN NH

[00377] 3-(3,5-Dimethy1-1H-pyrazol-4-y1)-5-(3,5-dimethylisoxazol-4-y1)benzene-1,2-diamine (20.0 mg, 0.0673 mmol) (see Example 75, Step 1) was treated with 1-fluorocyclopropanecarboxylic acid (7.0 mg, 0.0673 mmol, 1.0 equiv.), HATU
(30.7 mg, 0.0808 mmol, 1.2 equiv) and i-Pr2NEt (0.3 mL) in DMF (1 mL) at room temperature for 2 h. To the reaction mixture was added TFA (3 mL) and the mixture was heated at 100 C for 15 min. After removal of TFA under a reduced pressure, the reaction mixture was quenched with brine (30 mL). The whole was extracted with AcOEt (30 mL x 3).
Organic layer was washed with brine (30 mL) and dried over Na2SO4. The solvent was removed under a reduced pressure to give the crude product. The crude product was purified by a silica gel chromatography (Et0Ac:Me0H = 100:0 to 90:10).
[00378] C20H21FN50. 366.2 (M+1). 1H NMR (Me0H-d4) 6 7.47 (d, .1= 1.0 Hz, 1H), 7.05 (d, J= 1.0 Hz, 1H), 2.46 (s, 3H), 2.31 (s, 3H), 2.22 (s, 6H), 1.70-1.60 (m, 2H), 1.54-1.45 (m, 2H).
Example 81 N-Cyclopropy1-4-(3,5-dimethy1-1H-pyrazol-4-y1)-6-(3,5-dimethylisoxazol-4-y1)-benzo[d]imidazol-2-amine (1020-81) HN
NH
1j¨NH
[00379] N-Cyclopropy1-4-(3,5-dimethy1-1H-pyrazol-4-y1)-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-2-amine was prepared in a similar manner as Example 79, substituting isothiocyanatocyclopropane for cyclopropy1methyl ici isothiocyanate.
[003801 C20H22N60. 363.1 (M+1). 1H NMR (400MHz, CD30D) 6 7.45 (d, J= 1.6 Hz, 1H), 7.20 (d, J= 1.6 Hz, 1H), 2.84-2.80 (m, 1H), 2.45 (s, 3H), 2.36 (s, 6H), 2.29 (s, 3H), 1.05-0.98 (m, 2H), 0.84-0.80 (m, 2H).
Example 82 4-(4-(3,5-Dimethy1-1H-pyrazol-4-y1)-2-methoxy-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-82) O-N ON
¨0 CH3COON HN ",N
H2N \ N NH

[00381] 3-(3,5-Dimethy1-1H-pyrazol-4-y1)-5-(3,5-dimethylisoxazol-4-yObenzene-1,2-diamine (60 mg, 0.2 mmol) was dissolved in acetic acid (2 mL). To the solution was added tetramethyl ortho carbonate (55 mg, 0.4 mmol). The reaction was stirred at RT for 3h before the solvent was evaporated under vacuum and the residue was purified by preparative HPLC (0-100% CH3CN/H20) to afford 4-(4-(3,5-dimethy1-1H-pyrazol-4-y1)-2-methoxy-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (8 mg, 12%).
[00382]
CI8F119N502. 338.3 (M+1). 1H NMR (400MHz, CD30D) 6 7.08 (d, J=1.6 Hz, 1H), 6.91 (d, J=1.6 Hz, 1H), 2.42 (s, 3H), 2.35 (s, 6H), 2.34 (s, 3H), 2.27 (s, 3H).

Example 83 3,5-Dimethy1-4-(4-(6-methylquinolin-5-y1)-1H-benzo[d]imidazol-6-yDisoxazole (1020-83) O-N O-N
O-N

HN HN
I

N
Step 1 [00383] 5-(3,5-Dimethylisoxazol-4-y1)-3-iodobenzene-1,2-diamine (1.39g) was dissolved in formic acid and heated to reflux for 15 min. Volatiles were removed, the residue taken up in Et0Ac and the organic layer washed with brine and dried over sodium sulfate. Purification on silica gel (hexanes ethyl acetate 0-100%) afforded 4-(4-iodo-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole.
Step 2 [00384] 4-(4-Iodo-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (0.1g, 0.3 mmol) was reacted with (6-methylquinolin-5-yl)boronic acid (0.275g, 1.47 mmol), PEPPSI-IPr catalyst (0.02g, 0.03 mmol) and Cs2CO3 (0.3g, 0.9 mmol) in dioxane/
water (4/ 2 ml, degassed with Argon) at 130 C for 30 min in a Microwave reactor. The aqueous layer was discarded, volatiles were removed and the residue was purified via preparatory HPLC (5-100%, H20-MeCN, 0.1% HC1) to afford 3,5-dimethy1-4-(4-(6-methylquinolin-5-y1)-1H-benzo[d]imidazol-6-ypisoxazole.
[00385] C22E118N40. 355.1 (M+1). 1H NMR (400 MHz, dmso) 6 9.41 (s, 1H), 9.07 (d, J = 3.7 Hz, 1H), 8.32 (d, J = 8.8 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.96 (d, J =-1.4 Hz, 1H), 7.65 (dd, J = 8.5, 4.8 Hz, 1H), 7.50 (d, J = 1.2 Hz, 1H), 2.46 (s, 3H), 2.28 (d, J = 3.0 Hz, 6H).

Example 84 4-(4-(2,4-Dimethylpyridin-3-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-84) HN 'N
I
[00386] Compound (1020-84) was synthesized in a similar manner as that of Example 83, Step 2, using (2,4-dimethylpyridin-3-yl)boronic acid.
[00387] C19H18N40. 319.2.1 (M+1). 1H NMR (400 MHz, dmso) 9.43 (s, 1H), 9.09 (d, J = 3.7 Hz, 1H), 8.34 (d, J = 8.8 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.98 (d, J =-1.4 Hz, 1H), 7.67 (dd, J = 8.5, 4.8 Hz, 1H), 7.52 (d, J = 1.2 Hz, 1H), 2.48 (s, 3H), 2.30 (d, J = 3.0 Hz, 6H).
Example 85 4-(4-(1,4-Dimethy1-1H-pyrazol-5-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-85) HN
/N
[00388] Compound (1020-85) was synthesized in a similar manner as that of Example 83, Step 2, using (1,4-dimethy1-1H-pyrazol-5-y1)boronic acid, pinacol ester.
[00389] C17H17N50. 308.1 (M+1) 1H NMR (400 MHz, dmso) 8 9.09 (s, 1H), 9.09 (s, 1H), 7.83 (s, 1H), 7.83 (s, 1H), 7.45 (s, 1H), 7.45 (s, 1H), 7.40 (s, 1H), 7.40 (s, 1H), 3.70 (s, 3H), 2.47 (s, 3H), 2.29 (s, 3H), 1.95 (s, 3H).

Example 86 3,5-Dimethy1-4-(2-methyl-4-(6-methylquinolin-5-y1)-1H-benzo[d]imidazol-6-yl)isoxazole (1020-86) O-N O-N
O-N
HN
H2N Si NH2 I HN7N
)=-N
N
Step 1 [00390] 4-(4-Iodo-2-methyl-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1.43g, >95%) was foimed using acetic acid in Example 83, Step 1, and refluxing for 12 h.
Step 2 [00391] The product of Step 1 was used in the same procedure as that of Example 83, Step 2 to afford 3,5-dimethy1-4-(2-methy1-4-(6-methylquinolin-5-y1)-1H-benzo[d]imidazol-6-ypisoxazole.
[00392] C23H20N40. 368.8. (M+1) 1H NMR (400 MHz, cd3cn) 6 9.56 (d, J = 5.2 Hz, 1H), 8.93 (d, J = 8.9 Hz, 1H), 8.84 (d, J = 8.5 Hz, 1H), 8.63 (d, J = 8.8 Hz, 1H), 8.49 (d, J = 1.4 Hz, 1H), 8.31 (dd, J = 8.6, 5.2 Hz, 1H), 7.98 (d, J = 1.4 Hz, 1H), 3.28 (s, 3H), 3.01 (s, 3H), 2.91 (s, 3H), 2.85 (s, 3H).

Example 87 4-(4-(2,4-Dimethylpyridin-3-y1)-2-methyl-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-87) HN N
[00393] Compound (1020-87) was prepared by following Example 86, Step 1, to make the intermediate compound and using that compound in a similar manner as that of Example 84 to make the final product.
[00394] C20H20N40. 332.1 (M+1). 1H NMR (400 MHz, cd3cn) 69.10 (s, 1H), 8.84 (d, J = 1.6 Hz, 1H), 8.35 (d, J = 1.3 Hz, 1H), 7.94 (d, J = 1.4 Hz, 1H), 4.74 (s, 5H), 3.31 (s, 3H), 3.05 (s, 6H), 2.96 (s, 3H), 2.79 (s, 3H).
Example 88 3 ,5-Dimethy1-4-(2-(1-methy1-1H-pyrazol-4-y1)-4-(6-methylquinolin-5-y1)-1H-benzo [d]imidazol-6-yl)isoxazole (1020-88) O-N O-N
O-N
HN I

NH2 2--"N HN
1=N
N
N
Step 1 [00395] 5-(3,5-Dimethylisoxazol-4-y1)-3-iodobenzene-1,2-diamine (0.1g, 0.336 mmol) ) was dissolved in acidic acid (4 ml) and stirred at RT with 1-methy1-1H-pyrazole-4-carbonyl chloride (0.048g, 0.336 mmol) for 24 h. Volatiles were remove and the residue purified via preparatory HPLC (5-100%, H20-MeCN, 0.1% HC1) to afford 1;

the 4-(4-iodo-2-(1-methy1-1H-pyrazol-4-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole.
Step 2 [00396] Compound (1020-88) was made by using the product of Step 1 and (6-methylquinolin-5-yl)boronic acid in a manner similar to that of Example 83, Step 2.
[00397] C26H22N60. 435.21 (M+1). 1H NMR (400 MHz, dmso) 6 8.94 (d, J = 4.2 Hz, 1H), 8.43 (s, 1H), 8.15 (d, J = 4.3 Hz, 2H), 7.93 (d, J = 8.7 Hz, 1H), 7.81 (d, J = 7.0 Hz, 2H), 7.50 (dd, J = 8.6, 4.4 Hz, 1H), 7.27 (s, 1H), 3.92 (s, 3H), 2.47 (s, 17H), 2.47 (s, J = 12.2 Hz, 3H), 2.30 (s, 3H), 2.29 (s, 3H).
Example 89 1-(6-(3,5-dimethylisoxazol-4-y1)-4-(6-methylquinolin-5-y1)-1H-benzo[d]imidazol-yl)propane-1,3-diol (1020-89) O-N O-N
O-N

HN HN
H2N I. I ¨N

HO
N
OH
Step 1 [00398] 2-0xetane carboxylic acid (0.77g, 2.36 mmol) and CDI (0.858g, 3.45 mmol) were dissolved in MeCN (4 ml) and stirred for 30 min at RT. 543,5-dimethylisoxazol-4-y1)-3-iodobenzene-1,2-diamine (0.77g, 2.36 mmol) in MeCN (4 ml) was added at the solution stirred for 4 days at RT and 1 days at 70 C.
Volatiles were remove and the residue purified via preparatory HPLC (5-100%, H20-MeCN, 0.1%
HC1) to afford 4-(4-iodo-2-(oxetan-2-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole.
Step 2 [00399] The method described in Example 83, Step 2, using the product of Step 1 and (6-methylquinolin-5-yl)boronic acid was used to afford compound (1020-89).
[00400] C25H2AN403. 429.2 (M+1). 1H NMR (400 MHz, dmso) 6 9.09 (d, J = 4.7 Hz, 1H), 8.22 (d, J = 8.9 Hz, 1H), 8.07 (d, J = 8.1 Hz, 1H), 8.01 (d, J = 8.7 Hz, 1H), 7.80 ¨ 7.71 (m, 1H), 7.30 (s, 1H), 6.87 (s, 1H), 2.48 ¨ 2.45 (m, 2H), 2.39 (s, 3H), 2.32 (s, 3H), 2.30 ¨ 2.25 (m, 3H), 2.23 (s, 3H).
Example 90 5-(3,5-Dimethylisoxazol-4-y1)-3-(6-methylquinolin-5-yObenzene-1,2-diamine (1020-90) Step 1: Preparation of 5-(3,5-dimethylisoxazol-4-y1)-3-(6-methylquinolin-5-ypbenzene-1,2-diamine \ N
HO
O-N
O-N HO
140 \N
110 PEPPSI-IPr, Cs2CO3 H2N

DME/H20, M.W. 130 C NH2 [00401] (6-Methyl-5-quinolinyl)boronic acid (0.91g, 4.8 mmol) was added to a solution of 5-(3,5-dimethylisoxazol-4-y1)-3-iodobenzene-1,2-diamine (1g, 3 mmol) in 1,2-dimethoxy ethane and water (10/5 mL). To the mixture was added cesium carbonate (2.9g, 9 mmol) and PEPPSI-IPr (200 mg, 0.3 mmol). The reaction was put in microwave reactor and heated at 130 C for 120 minutes before the solvent was evaporated under vacuum. The residue was purified by preparative HPLC (0-100% CH3CN/H20) to afford 5-(3,5-dimethylisoxazol-4-y1)-3-(6-methylquinolin-5-yl)benzene-1,2-diamine.
[00402] C21F120N40. 345.18 (M+1).

Step 2: Preparation of 4-(2-methoxy-4-(6-methylquinolin-5-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole --0\ /0, 001 \N HN \N

NH2 11Pe ¨0 [00403] 5-(3,5-Dimethylisoxazol-4-y1)-3-(6-methylquinolin-5-yl)benzene-1,2-diamine (60 mg) was dissolved in acetic acid (1 mL) and to the solution was added tetramethyl orthocarbonate (1 m1). The reaction was stirred at RT for 30 mins.
The solvent was then evaporated under vacuum and the residue was purified by preparative HPLC (0-100% CH3CN/H20) to afford 4-(2-methoxy-4-(6-methylquinolin-5-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole.
1004041 C23H20N402. 385.2 (M+1). IFINMR (400 MHz, CD30D) 6 9.09 (dd, J-5.1, 1.3 Hz, 1H), 8.45 (t, J= 8.6 Hz, 1H), 8.24 (d, .1= 8.8 Hz, 1H), 8.18 ¨
8.12 (m, 1H), 7.88 ¨7.77 (m, 1H), 7.51 (t, J= 1.7 Hz, 1H), 7.05 (dd, J¨ 7.4, 1.6 Hz, 1H), 4.06 (s, 3H), 2.53 (s, 3H), 2.44 (s, 3H), 2.34 (s, 3H).
Example 91 4-(2-Ethoxy-4-(6-methylquinolin-5-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-91) \,0\
\N

[00405] 5-(3,5-Dimethylisoxazol-4-y1)-3-(6-methylquinolin-5-yl)benzene-1,2-diamine (100 mg) was added to tetraethyl orthocarbonate (1.2 ml). The reaction was stirred at 130 C overnight. The solvent was then evaporated under vacuum and the residue was purified by preparative HPLC (0-100% CH3CN/H20) to afford 4-(2-ethoxy-4-(6-methylquinolin-5-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole.
[00406] C24H221\1402. 399.2 (M+1). NMR (400 MHz, CD30D) 6 8.77 (dd., J =
2.8Hz, 1H), 8.05 (d, J= 8.4 Hz, I H), 7.83-7.80 (m, 2H), 7.42 ¨7.38 (m, 2H), 6.92 (s, 1H), 4.46 (bs, 2H), 2.45 (s, 3H), 2.32 (s, 3H), 2.29 (s, 3H), 1.39 (s, 3H).
Example 92 3,5-Dimethy1-4-(4-(6-methylquinolin-5-y1)-2-(trifluoromethyl)-1H-benzo[d]imidazol-6-ypisoxazole (1020-92) Step 1 O-N
O-N
TEA
=

HN
H2N I.

[00407] 5-(3,5-Dimethylisoxazol-4-y1)-3-iodobenzene-1,2-diamine (500 mg) was dissolved in TFA (5 m1). The reaction was stirred at 60 C overnight before solvent was evaporated. The residue was used as crude material (4-(4-iodo-2-(trifluoromethyl)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole.
CI3H9F3IN30. 408.1 (M+1).
Step 2 HN

[00408] (6-Methyl-5-quinolinyl)boronic acid (90 mg, 0.48 mmol) was added to a solution of 4-(4-iodo-2-(trifluoromethyl)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (50 mg, 0.12 mmol) in 1,2-dimethoxy ethane and water (2/1 mL). To TM
the mixture was added cesium carbonate (196 mg, 0.6 mmol) and PEPPSI-IPr (8 mg, 0.012 mmol). The reaction was put in microwave reactor and heated at 130 C
for 120 minutes before the solvent was evaporated under vacuum. The residue was purified by preparative HPLC (0-100% CH3CN/H20) to afford 3,5-dimethy1-4-(4-(6-methylquinolin-5-y1)-2-(trifluoromethyl)-1H-benzo[d]imidazol-6-y1)isoxazole.
[00409] C23H17F3N40. 423.1 (M+1). 1H NMR (400 MHz, CD30D) 6 9.04 (d, J-4.4 Hz, 1H), 8.28 (d, J 8.4 Hz, 1H), 8.24 (d, J= 8.8 Hz, 1H), 8.12 (d, J= 8.8 Hz, 1H), 7.84 (s, 1H), 7.75 (dd, J= 8.5, 5.0 Hz, 1H), 7.35 (d, J= 1.3 Hz, 1H), 2.49 (s, 3H), 2.37 (s, 3H), 2.33 (s, 3H).
[00410] Compounds (1020-93), (1020-94), and (1020-95) were prepared in a similar manner as that of Example 92, substituting the appropriate commercial boronic acid or boronate ester for (6-Methyl-5-quinolinyl)boronic acid:
Example 93 5-(6-(3,5-Dimethylisoxazol-4-y1)-2-(trifluoromethyl)-1H-benzo[d]imidazol-4-y1)-3,4-dihydroquinolin-2(1H)-one (1020-93) O-N
HN
)---=-N

NH

1004111 C221117F3N402. 427.1 (M+1). IHNMR (400 MHz, CD30D) 8 7.68 (d, .1=
1.5 Hz, 1H), 7.32 (t, J= 7.8 Hz, 1H), 7.25 (d, J= 1.5 Hz, 1H), 7.11 (d, J= 6.8 Hz, 1H), 7.01 (d, J= 7.2 Hz, 1H), 2.76 (s, 2H), 2.50 (d, J= 7.5 Hz, 2H), 2.47 (s, 3H), 2.32 (s, 3H).
Example 94 4-(4-(1,4-Dimethy1-1H-pyrazo1-5-y1)-2-(trifluoromethyl)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-94) O-N
HN
Y=-N /NN

[00412]
Ci8H16F3N50. 376.1 (M+1). 1H NMR (400 MHz, CD30D) 6 7.86 (s, 1H), 7.80 (s, 1H), 7.43 (s, 1H), 3.30 (s, 3H), 2.47 (s, 3H), 2.31 (s, 3H), 2.07 (s, 3H).
Example 95 3,5-Dimethy1-4-(4-(quinolin-5-y1)-2-(trifluoromethyl)-1H-benzo[d]imidazol-6-y1)isoxazole (1020-95) O-N

HN

[00413] C221-115F3N40. 409.1 (M+1). 1H NMR (400 MHz, CD30D) 6 9.03 (dd, J=
5.0, 1.3 Hz, 1H), 8.49 (d, J= 8.5 Hz, 1H), 8.21 (d, J= 8.6 Hz, 1H), 8.12 ¨
8.04 (m, 1H), 7.90 (d, J= 7.2 Hz, 1H), 7.75 ¨7.72 (m, 1H), 7.71 (d, J= 1.4 Hz, 1H), 7.38 (d, J=1.5 Hz, 1H), 2.40 (s, 3H), 2.24 (s, 3H).
Example 96 4-(3,5-Dimethy1-1H-pyrazol-4-y1)-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-2-amine (1020-96) Step 1: Preparation of 6-(3,5-dimethylisoxazol-4-y1)-4-iodo-1H-benzotd]imidazol-2-amine O-N
O-N N
BrCN

________________________________________ )1.
Et0H, ACN, H20, HN I
H2N 101 I NaHCO3, 0 C to it [00414] 5-(3,5-dimethylisoxazol-4-y1)-3-iodobenzene-1,2-diamine (1.5g, 4.6 mmol) was dissolved in a mixture of ethanol (10 mL) and acetonitrile (10 mL).
To this solution was then added water (10 mL) followed by solid sodium bicarbonate (0.77 g, 9.2 mmol). Mixture was then stirred under nitrogen and cooled to 0 C before adding cyanogen bromide ( 0.97 g, 9.2 mmol). Reaction was allowed to then warm to room temperature and stir overnight. Next day reaction solvents were removed and ethanol (100 mL) was added. Suspension was sonicated, then the solids fitered off.
Solution was rotavapped dry then purified by silica gel chromatography (rf = 0.5 in 10%

methanol in dichloromethane) affording 6-(3,5-dimethylisoxazol-4-y1)-4-iodo-1H-benzo[d]imidazol-2-amine as a brown solid.
[0041.5] C12Fl111N40. 355.0 (M+1). 1H NMR (400 MHz, DMSO-d6) 8 11.03 (s, 1H), 7.21 (s, 1H), 7.06 (d, J= 1.5 Hz, 1H), 6.56 (s, 2H), 2.37 (s, 3H), 2.19 (s, 3H).
Step 2 O-N N¨ O-N
B
HN
PEPPSI-1Pr \
HN HN N
DME : H20 Cs2CO3 N NH
H2N 110 C, 90min H2N
[00416] A suspension of 6-(3,5-dimethylisoxazol-4-y1)-4-iodo-1H-benzo[d]imidazol-2-amine (150 mg, 0.425 mmol), 3,5-dimethy1-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y1)-1H-pyrazole (170 mg, 0.765 mmol), caesium carbonate (415 mg, 1.28 mmol) and PEPPSI-IPrTM (30 mg, 0.043 mmol) in 12 mL DME : H20 (2:1) was heated by microwave in a sealed vessel at 110 C for 90 minutes. The reaction was then cooled and partitioned between water and ethyl acetate. The organic layer was 1 Al washed with brine and dried over sodium sulfate. Purification on silica gel (rf = 0.5 in 25% methanol in dichloromethane) afforded 4-(3,5-dimethy1-1H-pyrazol-4-y1)-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-2-amine as an off-white solid.
[00417] C171-118N60. 323.2 (M+1). 1H NMR (DMSO) 6 6.99 (s, 1H), 6.63 (s, 1H), 6.09 (br, 2H), 2.38 (s, 3H), 2.21 (s, 3H), 2.11 (s, 6H).
Example 97 6-(3,5-Dimethylisoxazol-4-y1)-4-(1-phenylviny1)-1H-benzo[d]imidazol-2-amine (1020-97) O-N O-N

OH
40 PEPPSI-IPA Si HN HN
DME : H20 Cs2CO3 )=-N

[00418] A suspension of 6-(3,5-dimethylisoxazol-4-y1)-4-iodo-1H-benzo[d]imidazol-2-amine (100 mg, 0.265 mmol), 1-phenylvinylboronie acid (59 mg, 0.400 mmol), caesium carbonate (260 mg, 0.8 mmol) and PEPPSIIPrTM (18 mg, 0.026 mmol) in 10 mL DME : H20 (2:1) was heated by microwave in a sealed vessel at 'V for 90 minutes. The reaction was then cooled and partitioned between water and ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate.
Purification on silica gel (rf = 0.5 in 20% methanol in dichloromethane) afforded 643,5-dimethylisoxazol-4-y1)-4-(1-phenylviny1)-1H-benzo[d]imidazol-2-amine as an off-white solid.
[00419] C20H18N40. 331.2 (M+1). 1H NMR (Me0D) 6 7.36-7.31 (m, 4H), 7.10 (s, 1H), 6.69 (s, 1H), 5.79 (s, 1H), 5.55 (s, 1H), 2.35 (s, 3H), 2.20 (s, 3H).

Example 98 6-(3,5-Dimethylisoxazol-4-y1)-4-(1-phenylethyl)-1H-benzo[d]imidazol-2-amine (1020-98) O-N O-N
10% Pd/C, H2 =Et0H 40 HN HN

[00420] A suspension of 6-(3,5-dimethylisoxazol-4-y1)-4-(1-phenylviny1)-1H-benzo [d]imidazol-2-amine (40 mg, 0.121 mmol) and 10% palladium on carbon (10 mg) in 5 mL ethanol was purged with hydrogen gas and allowed to stir for 2 hours.
The reaction was then filtered and the solvents evaporated. Purification on silica gel (rf = 0.5 in 20% methanol in dichloromethane) afforded 6-(3,5-dimethylisoxazol-4-y1)-4-(1-phenylethyl)-1H-benzo[d]imidazol-2-amine as a pale solid.
1004211 C20H20N40. 333.2 (M+1). 1H NMR (Me0D) 6 7.31-7.23 (m, 5H), 6.97 (s, 1H), 6.68 (s, 1H), 4.56 (q, 1Hõ J = 7.2 Hz), 2.31 (s, 3H), 2.15 (s, 3H), 1.67 (d, 3H, J
= 7.2 Hz).
Example 99 4-(4-(1,4-Dimethy1-1H-pyrazol-5-y1)-2-methoxy-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-99) Step 1: 4-(4-Iodo-2-methoxy-1H-benzoidlimidazol-6-y1)-3,5-dimethylisoxazole -- 0\/0 ¨0 [00422] 5-(3,5-Dimethylisoxazol-4-y1)-3-iodobenzene-1,2-diamine (100 mg) was dissolved in acetic acid (2 ml) and to the solution was added to tetramethyl orthocarbonate (0.08 m1). The reaction was stirred at RT for 30 mins. The solvent was then evaporated under vacuum and the residue was purified by silica gel column chromatography (0-60% Et0Ac/Hexane) to afford 4-(4-iodo-2-methoxy-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole.
1004231 C13H121N302. 370.1 (M+1). 1H NMR (400 MHz, CD30D) 6 7.41 (s, 1H), 7.22 (s, 1H), 4.19 (s, 3H), 2.41 (s, 3H), 2.23 (s, 3H).
Step 2 O-N

HN
/NN

[004241 4-(4-(1,4-Dimethy1-1H-pyrazol-5-y1)-2-methoxy-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole was synthesized by reacting 4-(4-iodo-2-methoxy-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole with 3,5-dimethylpyrazole-4-boronic acid, pinacol ester using similar conditions as described in Example 75, Step 1.
1004251 Ci8H19N502. 338.1 (M+1). NMR (400 MHz, CD30D) 6 7.32-7.25 (m, 2H), 6.89 (d, J= 1.3 Hz, 1H), 4.03 (s, 3H), 3.63 (s, 3H), 2.34 (s, 3H), 2.19 (s, 3H), 1.89 (s, 3H).
Example 100 N-(Cyclopropylmethyl)-4,6-bis(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-2-amine (1020-100) Step 1: Preparation of 2,4-bis(3,5-dimethylisoxazol-4-y1)-6-nitroaniline Br / B\c, 02N PEPPSI-Ipr, Cs2003 2r4 ia \N
H2N DME/H20, 120 C H2N

1004261 4-bromo-2-iodo-6-nitroaniline (150mg, 0.44 mmol) and 3,5-Dimethylisoxazole-4-boronic acid pinacol ester (390g, 1.75mmol) was added to a solvent mixture of 1,2-dimethoxyethane (2 ml) and water (1 m1). To the above mixture were added PEPPSI-Ipr (30mg, 0.04 mmol) and Cs2CO3 (0.86g, 2.64 mmol). The reaction mixture was heated at 120 C in microwave reactor for 2hs. The reaction mixture was then diluted with Et0Ac (100 ml), washed with bring (50 ml, 2 times). The organic solvent was evaporated and the residue was dissolved in DCM and purified with combi-flash column chromatography (product came out at 25% Me0H/DCM) to afford 2,4-bis(3,5-dimethylisoxazol-4-y1)-6-nitroaniline.
[00427] C16H16N404. 329.2 (M+1).
Step 2: Preparation of 3,5-bis(3,5-dimethylisoxazol-4-yl)benzene-1,2-diamine H2, Pd 401 Me0H
\ N H2N
H2N H2N \ N
[00428] 2,4-Bis(3,5-dimethylisoxazol-4-y1)-6-nitroaniline (0.1g, 0.3 mmol) was added to Me0H (5 ml), To the solution was added Pd (10% on carbon, 100mg).
Then the flask was charged with H2 balloon. The reaction was completed in 2h. The reaction mixture was filtered, solvent was evaporated. The residue was then purified with Prep HPLC (0-100% CH3CN/H20) to afford 3,5-bis(3,5-dimethylisoxazol-4-yl)benzene-1,2-diamine.
[00429] C16H18N402 299.1 (M+1).
Step 3: Preparation of N-(cyclopropylmethyl)-4,6-bis(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-2-amine O-N N
.
N=
S EDC
, HN N
H2N 'N THF, NEt3, 80 C 80 C
H2N d [00430] 3,5-bis(3,5-dimethylisoxazol-4-yl)benzene-1,2-diamine (27 mg, 0.07 mmol) was dissolved in THF (1 mL). To the solution was added cyclopropylmethyl isothiocyanate (12 mg, 0.08 mmol) and triethylamine (130 uL). The reaction was heated at 80 C for 3h before 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrogen chloride (20 mg, 0.08 mmol) was added and heated at 80 C for 4h. The solvent was then evaporated under vacuum and the residue was purified with Prep HPLC (0-100%
CH3CN/H20) to afford compound (1020-106).
[00431] C211-123N502. 378.2 (M+1). 1H NMR (400MHz, CD30D) 6 7.00 (s, 1H), 6.78 (s, 1H), 2.98-2.96 (m, 2H), 2.08 (s, 3H), 2.01 (s, 3H), 1.92 (s, 6H), 1.85 (s, 3H), 0.85-0.75 (m, 1H), 0.32-0.27 (m, 2H), 0.03-0.01 (m, 2H).
Example 101 Methyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazole-4-carboxylate (1020-101) Step 1 Br isoxazole pinacol ester 0 01 0 _________________________ 401 PEPPSI, Cs2CO3, DME / H20 [00432] To a flask containing methyl 2-amino-5-bromo-3-nitrobenzoate (4.0 g,

14.5 mmol, lequiv.) was added 3,5-Dimethylisoxazole-4-boronic acid pinacol ester (4866 mg, 21.8 mmol, 1.5 equiv.), Cs2CO3 (14.2 gm, 43.6 mmol, 3 equiv.) and PEPPSITm-IPr catalyst (495 mg, 0.72 mmol, 0.05 equiv.) and dissolved in DME-H20 (70 mL, 0.2 M, 2/1, v/v). The mixture was heated to 105 C. After 3 hr, the reaction was complete. After cooling, the reaction was extracted with Et0Ac and washed with water, saturated NH4C1. After drying with MgSO4, it was filtered and concentrated to dryness.
The resulting solid was washed with Et0Ac. A mustard yellow solid was obtained as methyl 2-amino-5-(3,5-dimethylisoxazol-4-y1)-3-nitrobenzoate.
[00433] LCMS (m/z+1) 291.96. 1H NMR (400 MHz, dmso) 6 8.34 (s, 2H), 8.24 (d, J= 2.2 Hz, 1H), 8.11 (d, J= 2.2 Hz, 1H), 3.84 (s, 3H), 2.35 (s, 3H), 2.17 (s, 3H).
Step 2 10% Pd-C, Et0H
Pd-C

[00434] To a flask containing methyl 2-amino-5-(3,5-dimethylisoxazol-4-y1)-nitrobenzoate (1.55 gm, 5.32 mmol, 1 equiv) was added 10% Pd-C (600 mg) and Et0H
(40 mL) and stirred under hydrogen. After 2 hr, the reaction appears complete.
The reaction was degassed and the reaction filtered and washed with methanol. The filtrate was concentrated in vacuo to furnish methyl 2,3-diamino-5-(3,5-dimethylisoxazo1-4-yl)benzoate. It was used in Step 3 without further purification.
[00435] LCMS (m/z+1) 262.03. 111 NMR (400 MHz, dmso) 8 6.99 (d, .1=2.0 Hz, 1H), 6.66 (d, J= 2.0 Hz, 1H), 6.31 (s, 2H), 4.91 (s, 2H), 3.74 (s, 3H), 2.30 (s, 3H), 2.12 (s, 3H).
Step 3 1>rio 0 TEA, CH2Cl2 LN
la [00436] To a flask containing methyl 2,3-diamino-5-(3,5-dimethylisoxazol-4-yl)benzoate (750 mg, 2.9 mmol, 1 equiv.) was added THF (30 ml, 0.1M) and TEA
(1.2 mL, 8.6 mmol, 3 equiv.). At 0 C, cyclopropanecarbonyl chloride (315 uL, 3.4 mmol, 1.1 equiv) was added. After an hour, the reaction was complete. The reaction was extracted with Et0Ac and washed with water, saturated NH4C1. After drying with MgSO4, it was filtered and concentrated to dryness and used in the next reaction as crude methyl 2-amino-3-(cyclopropanecarboxamido)-5-(3,5-dimethylisoxazol-4-yebenzoate.
Step 4 150 C, AcOH

microwave HN
c?---"H NH2 0 <1=---N
[00437] Into a microwave vial was placed methyl 2-amino-3-(cyclopropanecarboxamido)-5-(3,5-dimethylisoxazol-4-yObenzoate was added acetic acid (10 mL) and heated in the microwave for 150 C for 30 minutes. The reaction was concentrated down and extracted with Et0Ac and washed with water (3x), saturated NaHCO3 and brine. After drying with Mg504, it was filtered and concentrated to dryness and used in the next reaction as crude. The product was purified by silica gel chromatography with hexanes-Et0Ac, resulting in a light-brown powder.
[00438] LCMS (m/z+1) 312.04. IHNMR (400 MHz, dmso) 6 12.47 (s, 1H), 7.71 (d, J= 1.4 Hz, 1H), 7.58 (d, J= 1.6 Hz, 1H), 3.93 (s, 3H), 2.35 (s, 3H), 2.17 (s, 3H), 1.06 (t, J= 6.9 Hz, 5H).
Example 102 (2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzokliimidazol-4-yDdiphenylmethanol (1020-102) 17n 0 BrMg * Si _______________________________________ HN
HN THE
<r" N HO 01 [00439] Methyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazole-4-carboxylate (Example 101, Step 4) was treated with PhMgBr (2.9 M MeTHF solution, Aldrich, 1.24 mL, 3.531 mmol, 11 equiv.) in THF (3 mL) at 0 C to room temperature for 20 h. The reaction mixture was quenched with brine (30 mL). The whole was extracted with AcOEt (30 mL x 3). Organic layer was washed with brine (30 mL) and dried over Na2SO4. The solvent was removed under a reduced pressure to give the crude product. The crude product was purified by a silica gel chromatography (hexane:Et0Ac = 1:1).
[00440] C28H26N302. 436.2 (M+1). 11-1 NMR (Me0H-d4) 6 7.40-7.24 (m, 12H), 2.60 (s, 3H), 2.24-2.14 (m, 1H), 2.08 (s, 3H), 1.14-1.06 (m, 4H).
Example 103 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)di(thiazol-2-y1)methanol (1020-103) Iv Iv >0 N S
\¨/
[00441] Thiazole (62mg, 0.73 mmol) was dissolved in 5m1 THF, the reaction flask was then put in dry ice-acetone bath to lower temperature to -78 C, to the clear solution was added nBuLi (0.29m1, 2.5 M in hexane). The reaction mixture was stirred at for lh, then to the reaction mixture was added 1-tert-butyl 4-methyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazole-1,4-dicarboxylate in 2m1 THF
at-78 1 '71 C. Reaction temperature was slowly raised to RT and stirred overnight. The reaction was quenched with water, solvent was evaporated, the residue was purified with Prep HPLC with 0.1% TFA modifier to afford 10mg product (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)di(thiazol-2-yl)methanol.
[00442] C2211oN502S2. 450.0 (M+1). 111 NMR (400MHz, CD30D) 6 7.75 (d, J=
2.8 Hz, 2H), 7.58 (d, J= 3.2 Hz, 2H), 7.43 (s, 2H), 2.58-2.54 (m, 1H), 2.26 (s, 3H), 2.08 (s, 3H), 1.47-1.42 (m, 2H), 1.32-1.29 (m, 2H).
Example 104 (2-eyelopropy1-643,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)di(pyridin-2-yemethanol (1020-104) OOH_ <r-N
N'\
[00443] Compound (1020-104) was made in a similar manner as that of Example 103, using 3-bromopyridine in 2-methylTHF.
[00444] C26H23N502 438.1 (M+1). 11-1 NMR (400 MHz, DMSO-d6) 8 8.55 (ddd, J
= 5.0, 1.8, 0.9 Hz, 2H), 7.91 (td, J= 7.8, 1.8 Hz, 2H), 7.66 (dt, Jr 8.1, 1.0 Hz, 2H), 7.54 (d, J=1.5 Hz, 1H), 7.40 (ddd, J= 7.6, 4.9, 1.1 Hz, 2H), 7.06 (d, J=1.5 Hz, 1H), 2.70 ¨
2.55 (m, 111), 2.31 (s, 3H), 2.11 (s, 3H), 1.48 ¨ 1.22 (m, 441).
Example 105 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)di(pyrazin-2-yl)methanol (1020-105) 1 '71 HN N N
<r-N
\
[00445] Butyllithium (1.6 M in hexanes, 0.61 mL, 1 mmol) was added to a solution of 2,2,6,6-tetramethylpiperidine (0.18 mL, 1.1 mmol) in THF (5 mL) at 0 C.
After stirring for 5 minutes, the reaction was cooled to -78 C and pyrazine (78 mg) was added. The reaction mixture was stirred for 5 minutes and a solution of 1-tert-butyl 4-methyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[djimidazole-1,4-dicarboxylate (80 mg, 0.19 mmol) was added The reaction mixture was allowed to waim to room temperature and quenched with 1M HC1, neutralized with sodium bicarbonate solution, extracted with ethyl acetate and purified by reverse-phase HPLC to give the desired product.
[00446] C24H21N702 440.2 (M+1).1H NMR (400 MHz, DMSO-d6) 6 8.90 (d, J=
1.5 Hz, 2H), 8.61 (d, J= 2.5 Hz, 2H), 8.56 (dd, J= 2.5, 1.5 Hz, 2H), 7.54 (s, 1H), 6.94 (s, 1H), 2.55 (m, 1H), 2.29 (s, 3H), 2.09 (s, 3H), 1.27 (m, 4H).
Example 106 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyridin-y1)(thiazol-2-yl)methanol (1020-106) Step 1:

n-BuLi N
Me-THE THE Boc-N
4r---"N 0 I <?---:"-N 0 [00447] 2-bromopyridine (0.87 mL, 9.0 mmol) was dissolved in MeTHF (30 mL) and cooled to -78 C. n-BuLi (6.2 mL, 10.0 mmol, 1.6 M) was added dropwise and the 1 '7 2 reaction was allowed to stir for 1 hour at -78 C. tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(methoxy(methyl)carbamoy1)-1H-benzo[d]imidazole-l-carboxylate (2.0 g, 5.0 mmol) in MeTHF was added and the reaction was allowed to come to 0 C and stir for 15 minutes before being quenched with water.
Reaction was diluted with Et0Ac, washed twice with brine, concentrated, and purified by silica gel chromatography to give tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-picolinoy1-1H-benzo[d]imidazole-1-carboxylate (1.2g, 57%) as a pale yellow powder.
Step 2:

>0 110 40 N N N OHS

Thiazole (39mg, 0.46 mmol) was dissolved in 5m1THF, the reaction flask was then put in dry ice-acetone bath to lower temperature to -78 C, to the clear solution was added nBuLi (0.18m1, 2.5 M in hexane). The reaction mixture was stirred at for lh, then to the reaction mixture was added tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-picolinoy1-1H-benzo[d]imidazole-1-carboxylate (35mg, 0.076 mmol) in 2m1 THF at -78 C. Reaction temperature was slowly raised to RT and stirred overnight. The reaction was quenched with water, solvent was evaporated, the residue was purified with Prep HPLC with 0.1% TFA modifier to afford 20mg product (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyridin-2-yl)(thiazol-2-y1)methanol.
1004491 C24H211\1502S. 444.1 (M+1). 1HNMR (400MHz, CD30D) 8 8.56 (d, .1=
3.2 Hz, 1H), 7.80 (t, J= 4.8 Hz, 2H), 7.78 (d, J= 2.8 Hz, 1H), 7.70 (d, J= 3.2 Hz, 1H), 7.60 (d, J= 2.8 Hz, 1H), 7.42 (d, J= 2.8 Hz, 1H), 7.38-7.35 (m, 1H), 2.68-2.56 (m, 1H), 2.33 (s, 3H), 2.15 (s, 3H), 1.48-1.42 (m, 2H), 1.38-1.30 (m, 2H).
Example 107 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyridin-y1)(pyridin-3-yl)methanol (1020-107) la OH -N
HN \
<rN
N \
[00450] Compound 1020-107 was made in a similar manner as that of Example 106, using 3-bromopyridine as the aryl bromide.
[00451] C26H23N502 438.2 (M+1). 1H NMR (400 MHz, DMSO-d6) 6 8.78 ¨ 8.59 (m, 2H), 8.59¨ 8.50 (m, 1H), 8.02 (d, J= 8.2 Hz, 1H), 7.96 (td, J= 7.8, 1.8 Hz, 1H), 7.85 (d, J= 8.1 Hz, 1H), 7.78 (br, 1H), 7.64 (t, J= 6.7 Hz, 1H), 7.56 (d, J=
1.5 Hz, 1H), 7.41 (ddd, J= 7.4, 4.8, 1.1 Hz, 1H), 6.85 (d, J= 1.5 Hz, 1H), 2.57 (s, 1H), 2.29 (s, 3H), 2.09 (s, 3H), 1.48 ¨ 1.10 (m, 4H).
Example 108 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyridin-y1)(pyrimidin-2-yl)methanol (1020-108) HN
N \
[00452] Butyllithium (1.6 M in hexanes, 0.2 mL, 0.32 mmol) was added dropwise to a solution 2-bromopyrimidine (47 mg, 0.3 mmol) in dichloromethane (5 mL) at C. After stirring for 15 minutes a solution of tert-butyl 6-(3,5-dimethylisoxazol-4-y1)-2-ethoxy-4-picolinoy1-1H-benzo[d]imidazole-1-carboxylate (45 mg, 0.1 mmol) in dichloromethane (1 mL) was added. The reaction mixture was allowed to warm to room temperature and quenched with 1M HC1, neutralized with sodium bicarbonate solution, extracted with ethyl acetate and purified by reverse-phase HPLC to give the desired product.
[00453] C25H22N602 439.1 (M+1). 1H NMR (400 MHz, DMSO-d6) ö 8.82 (d, J=
4.9 Hz, 2H), 8.55 ¨ 8.35 (m, 1H), 7.91 (td, J= 7.6, 1.6 Hz, 1H), 7.78 (d, J=
8.0 Hz, 1H), 7.54 (d, J= 1.5 Hz, 1H), 7.49 (t, J= 4.9 Hz, 1H), 7.41 ¨7.31 (m, 1H), 7.09 (d, J=1.5 Hz, 1H), 2.69 ¨ 2.58 (m, 1H), 2.31 (s, 3H), 2.11 (s, 3H), 1.52¨ 1.19 (m, 4H).
Example 109 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyridin-yl)(pyrimidin-5-yl)methanol (1020-109) le OH
HN N
<r-N
N
[00454] Compound 1020-109 was made in a similar manner as that of Example 108, using 5-bromopyrimidine in place of 2-bromopyrimidine, and in 2-methylTHF

instead of dichloromethane.
[00455] C25H22N602 439.1 (M+1).1H NMR (400 MHz, DMSO-d6) 6 9.09 (s, 1H), 8.72 (s, 2H), 8.59¨ 8.55 (m, 1H), 7.93 (dd, J=7.7, 1.8 Hz, 1H), 7.86 (d, .1=
8.0 Hz, 1H), 7.52 (d, J= 1.6 Hz, 1H), 7.39 (dd, J= 7.6, 4.9 Hz, 1H), 6.84 (s, 1H), 2.55 (s, 1H), 2.27 (s, 3H), 2.07 (s, 3H), 1.31 (m, 4H).
Example 110 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyridazin-3-yl)(pyridin-2-yl)methanol (1020-110) 1 lIZ

HN \
<r-N
N
[00456] Butyllithium (1.6 M in hexanes, 2.15 mL, 3.4 mmol) was added to a solution of 2,2,6,6-tetramethylpiperidine (0.68 mL, 4.0 mmol) in MeTHF (20 mL) at 0 C. After stirring for 5 minutes, the reaction was cooled to -78 C and pyridazine (275 mg, 3.4 mmol) was added. The reaction mixture was stirred for 5 minutes and a solution of tert-butyl 6-(3,5-dimethylisoxazol-4-y1)- 4-picolinoy1-1H-benzo[d]imidazole-carboxylate (525 mg, 1.15 mmol) in MeTHF (5 mL) was added. The reaction mixture was allowed to waim to room temperature and quenched with 1M HC1, neutralized with sodium bicarbonate solution, extracted with ethyl acetate and purified by reverse-phase HPLC to give the desired product.
[00457] C25H22N602 439.1 (M+1). 1HNMR (400 MHz, DMSO-d6) 6 9.18 (dd, 4.7, 1.8 Hz, 1H), 8.63 ¨ 8.46 (m, 1H), 7.93 (td, J= 7.8, 1.8 Hz, 1H), 7.87 ¨
7.66 (m, 3H), 7.57 (d, J= 1.5 Hz, 1H), 7.40 (ddd, J= 7.5, 4.8, 1.1 Hz, 1H), 6.99 (d, J= 1.9 Hz, 1H), 2.62 (t, J= 4.9 Hz, 1H), 2.29 (s, 3H), 2.09 (s, 3H), 1.54¨ 1.25 (m, 4H).
Example 111 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyrazin-y1)(pyridin-2-yOmethanol (1020-111) 40, OH N-Th HN N
<re-N
N
[00458] Compound 1020-111 was made in a similar manner as that of Example 108, using pyrazine in place of pyridazine.

[00459] C25H22N602 439.1 (M+1). 1H NMR (400 MHz, DMSO-d6) 6 8.79 (d, J=
1.5 Hz, 1H), 8.59 (d, J= 2.5 Hz, 1H), 8.57¨ 8.55 (m, 1H), 8.53 (d, J= 4.7 Hz, 1H), 7.91 (t, J= 7.7 Hz, 1H), 7.72 (d, Jr 8.0 Hz, 1H), 7.53 (d, J= 1.5 Hz, 1H), 7.39 (dd, J= 7.4, 4.9 Hz, 1H), 6.97 (s, 1H), 2.60 (m, 1H), 2.30 (s, 3H), 2.10 (s, 3H), 1.33 (d, J= 25.6 Hz, 4H).
Example 112 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(phenyl)(pyridin-3-y1)methanol (1020-112) IN
HN
HO it Step 1:
[00460] Phenylmagnesium chloride in THF (2M, 3 mL) was added to a solution of 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-N-methoxy-N-methyl-1H-benzo[dJimidazole-4-carboxamide in NMP (6 mL) and the reaction mixture was stiffed for 15 min, quenched with sodium bicarbonate solution and extracted using ethyl acetate.
Purification by silica gel chromatography gave (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(phenyl)methanone.
Step 2:
[00461] A solution of 3-pyridylmagnesium bromide (2 equiv) and (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(phenyl)methanone (30 mg) was stirred at room temperature for 15 min. The reaction mixture was quenched with 1M HC1 solution, concentrated and purified by reverse-phase HPLC to give the desired product.
[00462] C27H24N402 437.1 (M+1). 1H NMR (400 MHz, DMSO-d6) 6 8.67 ¨ 8.50 (m, 2H), 7.81 (s, 1H), 7.53 (d, J= 7.4 Hz, 3H), 7.49 ¨ 7.21 (m, 5H), 6.62 (s, 1H), 2.25 (s, 3H), 2.05 (s, 3H), 1.31 (m, 5H).
Example 113 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(phenyl)(pyridin-2-yOmethanol (1020-113) OH --\
HN
<(--N
[00463] Compound 1020-113 was made in a similar manner as that of Example 112, using 2-pyridylmagnesium bromide in place of 3-pyridylmagnesium bromide.
[00464] C271124N402 437.1 (M+1). NMR (400 MHz, DMSO-d6) 8 8.59 ¨ 8.47 (m, 1H), 7.89 (dd, .1= 7.6, 1.8 Hz, 1H), 7.79 ¨ 7.59 (m, 1H), 7.53 ¨ 7.46 (m, 1H), 7.39 ¨
7.23 (m, 5H), 6.83 (d, J= 1.4 Hz, 1H), 2.27 (s, 3H), 2.07 (s, 3H), 1.47¨ 1.17 (m, 5H).
Example 114 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(6-methylpyridin-2-y1)(tetrahydrofuran-2-yl)methanol (1020-114) Step 1 triethylborane, THF
110 H t-butylhydroperoxide 40 0 BocN BocN
j---=-N 0 j=---N OH
0 C tort [00465] Into a flask containing tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-formy1-1H-benzo[d]imidazole-1-carboxylate (280 mg, 0.73 mmol, 1 equiv.) is added THF (10 mL) and cooled to 0 C before adding triethylborane (8.8 mL, 8.8 mmol, 12 equiv., 1 M THF). Tert-butylhydroperoxide (0.8 mL, 4.4 mmol, 6 equiv., 6 M
decanes) is added slowly to the reaction mixture and the reaction allowed to waiiii up slowly to room temperature. After completion, the reaction was quenched with solution (5 mL) and extracted with Et0Ac and washed with water (spiked with a solution of FeSO4.H2SO4.H20 (2 mL)) and then with saturated NH4C1. After drying with MgSO4, it was filtered and concentrated to dryness. Purification was carried out by flash column chromatography to furnish tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(hydroxy(tetrahydrofuran-2-yl)methyl)-1H-benzo[d]imidazole-1-carboxylate (175 mg, y.53%, dr 3:2).
[00466] LCMS (m/z +1) 454.34.
Step 2:
N
N-0 ¨0 SoIv 7 Dess-Martin Perioiodina,ne CH20I2 BocN
BocN
<rN OH
[00467] Into a flask containing tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(hydroxy(tetrahydrofuran-2-y1)methyl)-1H-benzo[d]imidazole-1-carboxylate (660 mg, 1.82 mmol, 1 equiv.) is added DCM (40 mL) and Dess-Martin periodinane (802 mg, 2.4 mmol, 1.3 equiv.). After completion, the reaction was quenched with sodium thiosulfate solution and allowed to stir for several minutes. It was extracted with DCM and washed with water and saturated NH4C1. After drying with Mg504, it was filtered and concentrated to dryness. Purification was carried out by flash column chromatography to furnish tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(hydroxy(tetrahydrofuran-2-yl)methyl)-1H-benzo[d]imidazole-1-carboxylate (175 mg, y.53%).
[00468] LCMS (m/z +1) 452.23.
Step 3:
1 52(1 BocN 0 THE N

j---=N 0 HN
/ N\
2. TFA HO
[00469] Into a flask containing tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(hydroxy(tetrahydrofuran-2-yl)methyl)-1H-benzo[d]imidazole-1-carboxylate(60 mg, 0.13 mmol, 1 equiv.) is added THF (5 mL) and to it is added (6-methylpyridin-2-yl)magnesium bromide (3.2 mL, 0.80 mmol, 6 equiv., 0.25 M THF, Rieke Metals).
After completion, the reaction was quenched and extracted with Et0Ac and washed with water, saturated NH4C1. After drying with MgSO4, it was filtered and concentrated to dryness. To the crude material is added TFA (5 mL) and allowed to stir for 30 min. After the reaction was complete, it was concentrated in vacua. Purification was carried out by reverse phase HPLC to furnish (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(6-methylpyridin-2-y1)(tetrahydrofuran-2-yl)methanol as a mixture of enantiomers.
[00470] 1H NMR (400 MHz, Methanol-d4) 6 7.62 (d, J = 5.2 Hz, 1H), 7.37 (t, J =
1.6 Hz, 1H), 7.28 (s, OH), 7.11 (dd, J = 6.1, 2.9 Hz, 1H), 5.34 (t, J = 7.2 Hz, 1H), 3.89 (q, J = 6.9 Hz, 1H), 3.79 (t, J = 6.8 Hz, 1H), 2.58 (s, 2H), 2.38 (d, J = 1.4 Hz, 2H), 2.34 -2.26 (m, 1H), 2.22 (d, J = 1.4 Hz, 2H), 2.01 - 1.69 (m, 3H), 1.16 (t, J = 5.7 Hz, 2H).
[00471] LCMS (m/z +1) 445.23 Example 115 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyridazin-3-y1)(tetrahydrofuran-2-yOmethanol (1020-115) 1. a) -78 C, TMP, n-BuLi THF
I,0 b) Pyridazine OH

Boc¨N 3.
HN
<2=-N 2. TFA

I
.1\1 [00472] In a flame-dried flask containing THF and 2,2,6,6-Tetramethylpiperidine (0.12 mL, 4.4 equiv.) at -78 C, n-BuLi (0.42 mL, 4.0 equiv.) was added dropwise. After

15 minutes of stirring, Pyridazine (0.07 mL, 6 equiv.) was added. The solution was allowed to stir for 15 minutes, followed by the addition of tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(tetrahydrofuran-2-carbony1)-1H-benzo[d]imidazole-1-carboxylate (75 mg, 1 equiv.). The reaction was allowed to stir for 30 minutes at -78 C, then removed from cold bath and allowed to waim to room temperature. Once complete, the solution was quenched with DI H20 and extracted three times with Et0Ac.
The combined organic layers were washed with saturated NaC1, dried over sodium sulfate, filtered and concentrated in vacuo. To the crude material was added TFA (5 mL) and allowed to stir for 30 minutes. Once complete, the solution was concentrated in vacuo.
Purification was carried out by reverse phase HPLC to afford (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyridazin-3-y1)(tetrahydroftiran-2-yl)methanol (23 mg, 33% yield as a mixture of enantiomers). Enantiomers were resolved using a Chiralpak AD-H column (Heptane:IPA, 70:30) [00473] C24H25N503. M.S 432.2 (M 1) 'HNMR (400 MHz, Me0H-d4) 8 9.02 (d, J= 4.9 Hz, 1H), 8.16 (d, J= 8.5 Hz, 1H), 7.65 (dd, J= 8.7, 4.9 Hz, 1H), 7.29 (s, 2H), 5.48 (t, J= 7.2 Hz, 1H), 3.99 ¨ 3.87 (m, 2H), 3.78 (dd, J= 13.6, 7.2 Hz, 1H), 3.34¨ 3.27 (m, 1H), 2.33 (s, 3H), 2.27 (dd, J= 13.0, 6.6 Hz, 1H), 2.17 (s, 3H), 1.95 (dqd, J= 26.1, 11.6, 7.5 Hz, 4H), 1.78 (qd, J= 11.3, 5.6 Hz, 1H), 1.14 (d, J= 6.1 Hz, 2H).
Example 116 (2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yOdipyridin-ylmethanol (1020-116) BrMg-0 () __________________________________ HN THF HN = N
0 <1-N HO
[00474] Methyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazole-4-carboxylate (Example 107, Step 4) was treated with 3-pyridine magnesiumbromide (0.25 M MeTHF solution, Novel, 5.6 mL, 1.42 mmol, 8.8 equiv.) in THF (3 mL) at room temperature for 16 h. The reaction mixture was quenched with water (30 mL). The whole was extracted with AcOEt (30 mL x 3). Organic layer was washed with brine (30 mL) and dried over Na2SO4. The solvent was removed under a reduced pressure to give the crude product. The crude product was purified by a preparative HPLC (5-95% acetonitrile: water with 0.05% trifluoroacetic acid, on a Phenomenex Luna C18 column).
[00475] C26H24N502. 438.2 (M+1). 1H NMR (Me0H-d4) 6 8.81 (s, 2H), 8.77 (d, J
= 5.0 Hz, 2H), 8.27 (d, J= 8.3 Hz, 2H), 7.84 (dd, J= 8.3, 5.0 Hz, 2H), 7.62 (d, J= 1.0 Hz, 1H), 6.94 (d, J= 1.0 Hz, 1H), 2.60-2.50 (m, 1H), 2.31 (s, 3H), 2.13 (s, 3H), 1.55-1.47 (m, 2H), 1.40-1.34 (m, 2H).
Examples 117-118 1-(2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)propan-1-ol (1020-117); and 3-(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)pentan-3-ol (1020-118) EtMgBr, THF
110 C) 0 C to rt HN HN HN
OH <2=-N HO

[00476] Into a flask containing methyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazole-4-carboxylate (60 mg, 0.19mmol, 1 equiv) (Example 107, Step 4) was added THF (4 mL, 0.05 M) before being cooled to 0 C.
Ethylmagnesium bromide (0.39 mL, 1.15 mmol, 6 equiv., 3M Hexanes) was added slowly and the reaction was allowed to warm up to room temperature. After the starting material was consumed, the reaction was partitioned between water and ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. Purification was carried out by reverse phase HPLC to give two products:
[00477] 1-(2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-yl)propart-1-ol: LCMS (m/z+1) 312.03. 1H NMR (400 MHz, cd3od) 8 7.74 (d, J-1.5 Hz, 1H), 7.64 (s, 1H), 4.83 (s, 14H), 4.01 (s, 4H), 3.29 (dt, J= 3.2, 1.6 Hz, 26H), 3.11 (s, 2H), 2.42 ¨ 2.20 (m, 10H), 1.22¨ 1.10 (m, 6H);
[00478] 3-(2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-yl)pentan-3-ol: LCMS (m/z+1) 339.07. 1H NMR (400 MHz, cdc13) 6 7.38 (s, 1H), 6.71 (s, 1H), 2.38 (d, J= 5.8 Hz, 3H), 2.24 (d, J= 7.2 Hz, 3H), 2.10 (s, 1H), 1.99 (dd, J-14.4, 7.4 Hz, 2H), 1.90 (td, J= 14.7, 7.4 Hz, 2H), 1.46 (s, 2H), 1.30 (s, 2 H), 1.17 (s, 1H), 0.84 (t, J= 7.4 Hz, 6H).
Example 119 4-(2-Cyclopropy1-4-(pent-2-en-3-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-119) TFA, 150 C

HN HN
HO <r-N
[00479] Into a microwave vial was placed 3-(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)pentan-3-ol (25 mg, 0.074 mmol, 1 equiv) (Example 111) and TFA (4 ml). The reaction was subjected to microwave irradiation at 150 C for 30 minutes. Following completion of reaction, the mixture was 1 Rd concentrated in vacuo and the reaction was partitioned between water and ethyl acetate.
The organic layer was washed with saturated NaHCO3 solution and brine and dried over sodium sulfate. Purification was carried out by reverse phase HPLC to furnish 4-(2-cyclopropy1-4-(pent-2-en-3-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (10.
3mg, 44%). This compound was isolated as a mixture of E/Z isomers.
[00480] LCMS (m/z+1) 322.20. 1H NMR (400 MHz, cdc13) 7.34 (s, 1H), 6.91 (s, 1H), 5.82 (dd, J=2.2, 6.8 Hz,1H), 2.58 (d, J= 7.6 Hz, 2H), 2.38 (s, 3H), 2.25 (s, 3H), 2.08 (m, 1H), 1.87 (d, J=6.8Hz, 1H), 1.26 (m, 2H), 1.15 (m, 2 H), 0.97 (m, 4H).
Example 120 4-(2-C yclopropy1-4-(pentan-3-y1)-1H-b enzo [d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-120) 10% Pd-C, H2 Et0H __________________________________ =
HN HN
<p-N
[00481] Into a flask containing 4-(2-cyclopropy1-4-(pent-2-en-3-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (20 mg, 0.062 mmol, 1 equiv.) (Example 112) was added Pd-C (30mg, 10%) and ethanol (5 mL). The suspension was stirred under a hydrogen atmosphere for an hour. After the solid was filtered off and the filtrate was concentrated in vacuo. Purification was carried out by reverse phase HPLC
to furnish 4-(2-cyclopropy1-4-(pentan-3-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole.
[00482] LCMS (m/z+1) 324.22. 1H NMR (400 MHz, cd3od) 6 7.21 (s, 1H), 6.88 (s, 1H), 2.38 (s, 3H), 2.23 (s, 3H), 2.18 (s, 1H), 1.93 ¨ 1.78 (m, 3H), 1.78 ¨
1.63 (m, 3H), 1.13 (d, J= 7.4 Hz, 5H), 0.80 (t, J= 7.4 Hz, 7H).
Examples 121-122 Cyclopenty1(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yOmethanol (1020-121); and Dicyclopenty1(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-yOmethanol (1020-122) CyclopentylMgBr, THF
0040 +=OH.
0 C to rt HN HN HN
<--=-N 0ci--=N OH <c)-=-N *
[00483] Into a flask containing methyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazole-4-carboxylate (45 mg, 0.14mmol, 1 equiv) (Example 107, Step 4) was added THF (4 mL, 0.05 M) before being cooled to 0 C.
Cyclopentylmagnesium bromide (0.29 mL, 1.15 mmo1,4 equiv., 2M Diethyl ether) was added slowly and the reaction was allowed to warm up to room temperature.
After the starting material was consumed, the reaction was partitioned between water and ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate.
Purification was carried out by reverse phase HPLC to furnish two products:
[00484] Cyclopenty1(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)methanol: LCMS (m/z+1) 352.02. iff NMR (400 MHz, cd3od) 7.26 (s, 1H), 6.88 (s, 1H), 2.57 (s, 2H), 2.38 (s, 3H), 2.22 (s, 5H), 1.83 (s, 3H), 1.47 (s,5H), 1.12 (d, J= 7.2 Hz, 5H).
[00485] Dicyclopenty1(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)methanol: LCMS (m/z+1) 420.03. 1H NMR (400 MHz, cd3od) 6 7.26 (s, 1H), 7.08 (s, 1H), 2.46 ¨ 2.31 (m, 4H), 2.31 ¨2.15 (m, 4H), 1.84 (s, 1H), 1.77 ¨
1.45 (m, 58H), 1.33 (dd, J= 19.7, 11.9 Hz, 7H), 1.13 (d, J= 7.8 Hz, 6H).
Examples 123-124 (S)-Cyclopenty1(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)methanol (1020-123) and (R)-Cyclopentyl(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imida7o1-4-yl)methanol (1020-124) chiral separation la = ___________________________________________ + 140 =
HN HN = HN
OH <r-N OH <rN OH
[00486] The enantiomers of compound 1020-121 were separated by chiral column (DAICEL Chirapak-IC, heptane:Et0H (80:20)).
[00487] (S)-Cyclopenty1(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yemethanol: LCMS (m/z+1) 352.02. 1H NMR (400 MHz, cd3od) 6 7.26 (s, 1H), 6.88 (s, 1H), 2.57 (s, 2H), 2.38 (s, 3H), 2.22 (s,5H), 1.83 (s, 3H), 1.47 (s,5H), 1.12 (d, J= 7.2 Hz, 5H).
[00488] (R)-Cyclopenty1(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yemethanol: LCMS (m/z+1) 352.02. ill NMR (400 MHz, cd3od) 6 7.26 (s, 1H), 6.88 (s, 1H), 2.57 (s, 2H), 2.38 (s, 3H), 2.22 (s, 5H), 1.83 (s, 3H), 1.47 (s,5H), 1.12 (d, J= 7.2 Hz, 5H).
Examples 125-126 1-(2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzokilimidazol-4-y1)-2-methylpropan-1-ol (1020-125); and 3-(2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)-2,4-dimethylpentan-3-ol (1020-126) IsopropylMgBr, THF
0 0 C to rt 40 401 OH
HN HN HN
<IN 0 4>Z---N OH
1 R'7 [00489] Into a flask containing methyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazole-4-carboxylate (40 mg, 0.13mmol, 1 equiv) (Example 107, Step 4) was added THF (4 mL, 0.05 M) before being cooled to 0 C.
Isopropylmagnesium bromide (0.60 mL,0.77 mmol, 6 equiv., 2M Diethyl ether) was added slowly and the reaction was allowed to warm up to room temperature.
After the starting material was consumed, the reaction was partitioned between water and ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate.
Purification was carried out by reverse phase HPLC to furnish two products:
[00490] 1-(2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-y1)-2-methylpropan-1-ol: LCMS (m/z+1) 326.01. NMR (400 MHz, cdc13) 6 7.36 (s, 1H), 6.81 (s, 1H), 4.70 (d, J= 6.6 Hz, 1H), 2.36 (s, 3H), 2.22 (s, 3H), 2.14 (dd, J= 13.2, 6.9 Hz, 3H), 1.26 (d, J= 18.0 Hz, 4H), 1.15 (d, J= 6.7 Hz, 2H), 1.05 (d, J=
6.6 Hz, 4H), 0.88 (d, J= 6.8 Hz, 5H).
[00491] 3-(2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-y1)-2,4-dimethylpentan-3-ol: LCMS (m/z+1) 368.03. 1H NMR (400 MHz, cdc13) 6 7.45 (s, 1H), 6.80 (s, 1H), 2.49 - 2.28 (m, 6H), 2.21 (d, J= 15.9 Hz, 4H), 1.36 (s, 2H), 1.27 -1.10 (m, 3H), 0.85 (dt, J= 18.2, 9.1 Hz, 12H).
Example 127 4-(2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-ypheptan-4-ol (1020-127) PrMgBr, THE
0 0 C to rt HN HN
<-="-N 0 HO
[00492] Into a flask containing methyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazole-4-carboxylate (50 mg, 0.16 mmol, 1 equiv) (Example 101, Step 4) was added THF (3 mL, 0.05 M) before being cooled to 0 C.
Isopropylmagnesium bromide (0.53 mL, 1.15 mmol, 6 equiv., 27% THF) was added slowly and the reaction was allowed to warm up to room temperature. After the starting material was consumed, the reaction was partitioned between water and ethyl acetate.
The organic layer was washed with brine and dried over sodium sulfate.
Purification was carried out by reverse phase HPLC to furnish 4-(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)heptan-4-ol.
[00493] LCMS (m/z+1) 368.22. 1H NMR (400 MHz, cdc13) 6 7.38 (s, 1H), 6.71 (s, 1H), 2.38 (d, J.= 5.8 Hz, 3H), 2.24 (d, J= 7.2 Hz, 3H), 2.10 (s, 1H), 1.99 (dd, J=
14.4, 7.4 Hz, 2H), 1.90 (td, J= 14.7, 7.4 Hz, 2H), 1.46 (s, 2H), 1.30 (s, 2 H), 1.17 (s, 1H), 0.84 (t, J= 7.4 Hz, 6H).
Example 128 4-(2-Cyclopropy1-4-(hept-3-en-4-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-128) TFA, 150 C
HN HN
HO
[00494] Into a microwave vial was placed 4-(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-ypheptan-4-ol (24 mg, 0.068 mmol, equiv) (Example 120) and TFA (4 ml). The reaction was subjected to microwave irradiation at 150 C for 30 minutes. Following completion of reaction, the mixture was concentrated in vacuo and the reaction was partitioned between water and ethyl acetate.
The organic layer was washed with saturated NaHCO3 solution and brine and dried over sodium sulfate. Purification was carried out by reverse phase HPLC to furnish 4-(2-cyclopropy1-4-(hept-3-en-4-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole as a mixture of E/Z isomers.
[00495] LCMS (m/z+1) 350.21. 1H NMR (400 MHz, cd3od) 6 7.28 (s, 1H), 7.24 (d, J= 1.4 Hz, 1H), 6.88 (d, J= 1.5 Hz, 1H), 6.77 (d, J= 1.5 Hz, 1H), 5.68 (dd, J= 15.7, 8.5 Hz, 2H), 2.61 (t, J= 7.4 Hz, 2H), 2.55 ¨2.39 (m, 2H), 2.39 ¨ 2.28 (m, 4H), 2.28 ¨

2.10 (m, 511), 1.85 (dd, J= 15.0, 7.6 Hz, 1H), 1.31 (dt, J= 14.9, 7.4 Hz, 3H), 1.20 ¨ 1.01 (m, 7H), 0.88 (dt, J= 13.1, 7.5 Hz, 5H).
Example 129 4-(2-Cyclopropy1-4-(heptan-4-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-129) 1101 10% Pd-C, H2 HN Et0H
HN
[00496] Into a flask containing 4-(2-cyclopropy1-4-(hept-3-en-4-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (16 mg, 0.045 mmol, 1 equiv.) (Example 121) was added Pd-C (30mg, 10% Pd-C) and ethanol (5 mL). The suspension was stirred under a hydrogen atmosphere for an hour. After the solid was filtered off and the filtrate was concentrated in vacuo. Purification was carried out by reverse phase HPLC
to furnish 4-(2-cyclopropy1-4-(heptan-4-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole.
[00497] LCMS (m/z+1) 352.26. 1H NMR (400 MHz, cd3od) ö 7.19 (s, 1H), 6.89 (s, 1H), 3.18 (s, 1H), 2.39 (s, 311), 2.21 (d, J= 10.4 Hz, 3H), 2.18 (d, J=
7.0 Hz, 1H), 1.72 (dd, J= 15.2, 7.4 Hz, 4H), 1.37¨ 1.17 (m, 3H), 1.12 (dd, J= 14.5, 6.7 Hz, 611), 0.84 (t, J= 7.4 Hz, 7H).
Example 130-131 Methyl 2-cyclopropy1-6-(3 ,5-dimethylisoxazol-4-y1)-1 -methyl-1H-benzo [d]
imidazole-4-carboxylate (1020-130); and Methyl 2-cyclopropy1-5-(3,5-dimethylisoxazol-4-y1)-1-methyl-1H-benzo[d]imidazole-7-carboxylate (1020-131) 1 on 0 Mel, K2CO3 o o HN DIVIF
0 (2--N 0 [00498] Into a flask containing methyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazole-4-carboxylate (500 mg, 1.60 mmol, 1 equiv.) (Example 107, Step 4) was added DMF (16, 0.1 M) and cesium carbonate (1560 mg, 4.81 mmol, 3 equiv.). To this was then added iodomethane (0.30 mL, 4.81 mmol, 3 equiv.).
The reaction was allowed to stir overnight and showed consumption of starting material.
After the starting material was consumed, the reaction was partitioned between water and ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. Purification on silica gel (rf = 0.3 in 20% ethyl acetate in hexanes) separated the two isomers (1:1 ratio):
[00499] Methyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1-methyl-1H-benzo[d]imidazole-4-carboxylate: LCMS (m/z+1) 326.16. 1H NMR (400 MHz, cd3od) 8 7.72 (d, J = 1.6 Hz, 9H), 7.64 (d, J = 1.6 Hz, 8H), 3.95 (d, J = 4.2 Hz, 52H), 2.41 (s, 27H), 2.34 - 2.16 (m, 37H), 1.34- 1.22 (m, 19H), 1.22 - 1.08 (m, 22H).
[00500] Methyl 2-cyclopropy1-5-(3,5-dimethylisoxazol-4-y1)-1-methyl-1H-benzo[d]imidazole-7-carboxylate: LCMS (m/z+1) 326.16. 1H NMR (400 MHz, cd3od) 6 7.63 (d, J= 1.6 Hz, 1H), 7.61 (d, J= 1.6 Hz, 1H), 4.03 (s, 3H), 3.97 (s, 3H), 2.41 (d, J
= 15.6 Hz, 3H), 2.31 -2.17 (m, 4H), 1.19 (dt, J= 8.2, 2.9 Hz, 2H), 1.16 - 1.08 (m, 2H).
Example 132 3-(2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1-methy1-1H-benzo[d]imidazol-4-yOpentan-3-ol (1020-132) EtMgBr, THF
N 1. ON.

[00501] Into a flask containing methyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1-methyl-1H-benzo[d]imidazole-4-carboxylate (35 mg, 0.11 mmol, 1 equiv) (Example 130) was added THF (4 mL, 0.05 M) before being cooled to 0 C.
Ethylmagnesium bromide (0.22 mL, 1.15 mmol, 6 equiv., 3M hexanes) was added slowly and the reaction was allowed to warm up to room temperature. After the starting material was consumed, the reaction was partitioned between water and ethyl acetate.
The organic layer was washed with brine and dried over sodium sulfate.
Purification was carried out by reverse phase HPLC to afford the title compound.
[00502] LCMS (m/z+1) 354.00. 1HNMR (400 MHz, cd3od) 6 7.22 (d, J= 1.3 Hz, 1H), 6.92 (d, J= 1.3 Hz, 1H), 3.88 (s, 3H), 2.40 (s, 3H), 2.23 (d, J= 10.0 Hz, 3H), 2.18 (td, J= 8.0, 4.0 Hz, 1H), 2.08 (dq, J= 14.8, 7.4 Hz, 2H), 1.86 (dq, J=
14.6, 7.4 Hz, 2H), 1.23 ¨0.99 (m, 4H), 0.72 (t, J= 7.4 Hz, 6H).
Example 133 1-(2-Cyclopropy1-5-(3,5-dimethylisoxazol-4-y1)-1-methyl-1H-benzo[d]imidazol-7-yl)propan-1-ol (1020-133) 401 EtMgBr, THF
0 Ctort N OH
[00503] Into a flask containing methyl 2-cyclopropy1-5-(3,5-dimethylisoxazol-4-y1)-1-methyl-1H-benzo[d]imidazole-7-carboxylate (39 mg, 0.12 mmol, 1 equiv) (Example 124) was added THF (4 mL, 0.05 M) before being cooled to 0 C.

Ethylmagnesium bromide (0.24 mL, 1.15 mmol, 6 equiv., 3M hexanes) was added slowly and the reaction was allowed to warm up to room temperature. After the starting material was consumed, the reaction was partitioned between water and ethyl acetate.
The organic layer was washed with brine and dried over sodium sulfate.
Purification was carried out by reverse phase HPLC to afford the title compound.
[005041 LCMS (m/z +1) 326.22. 1H NMR (400 MHz, cd3od) 6 7.35 (d, J= 1.6 Hz, 7H), 7.23 (d, J= 1.4 Hz, 8H), 5.30 (dd, J= 7.4, 5.8 Hz, 9H), 4.17 (s, 22H), 2.39 (s, 20H), 2.31 ¨2.20 (m, 23H), 2.20¨ 2.13 (m, 7H), 2.02¨ 1.80 (m, 18H), 1.23 ¨0.97 (m, 53H).
Example 134 3-(2-Amino-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)pentan-3-ol (1020-134) Step 1 BrCN
Et0H/CH3CN/H20 401 0 [005051 Into a flask containing methyl 2,3-diamino-5-(3,5-dimethylisoxazol-yl)benzoate (155 mg, 0.59 mmol, 1 equiv.) was added Et0H (2 mL), H20 (2 mL) and CH3CN (2 mL) before cyanogen bromide (75 mg, 0.71 mmol, 1.2 equiv.) was added.

After an hour, at room temperature, the reaction was then warmed 65 C. After the reaction was complete, it was concentrated in vacuo and then washed with dilute sodium bicarbonate solution. A precipitate formed and was filtered and washed with water and warm ethanol to afford the product.
[005061 LCMS (m/z+1) 286.96. 1H NMR (400 MHz, cd3od) 6 7.41 (d, J= 1.4 Hz, 1H), 7.25 (d, J= 1.4 Hz, 1H), 3.90 (s, 31-1), 2.31 (s, 3H), 2.15 (s, 3H), 1.94 (s, 1H).
Step 2 EtMgBr, THF
NO 0 C to rt HN

[00507] Into a flask containing methyl 2-amino-5-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazole-7-carboxylate (30 mg, 0.09 mmol, 1 equiv) (Example 127) was added THF (4 mL, 0.05 M) before being cooled to 0 C. Ethylmagnesium bromide (0.29 mL, 0.88 mmol, 10 equiv., 3M Hexanes) was added slowly and the reaction was allowed to warm up to room temperature. After the starting material was consumed, the reaction was partitioned between water and ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. Purification was carried out by reverse phase HPLC
to affored the title compound.
[00508] LCMS (m/z +1) 314.91. 1H NMR (400 MHz, ed3od) 5 7.00 (d, J= 1.4 Hz, 2H), 6.67 (d, J= 1.3 Hz, 2H), 2.38 (d, J= 2.9 Hz, 6H), 2.22 (d, J= 3.1 Hz, 6H), 2.05 - 1.91 (m, 4H), 1.91 - 1.72 (m, 5H), 0.79 (dd, J= 9.1, 5.7 Hz, 13H).
Example 135 4,4'(2-Cyclopropy1-1H-benzo[d]imidazole-4,6-diyObis(3,5-dimethylisoxazole) (1020-135) O isoxazole pinacol ester - __________________________________________ PEPPSI-IPr, Cs2CO3, DME / H20 HN HN
N
[00509] Toa flask containing 4-(2-cyclopropy1-4-iodo-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (650 mg, 1.7 mmol, 1 equiv.) (Example 8, Step 5) was added 3,5-Dimethylisoxazole-4-boronic acid pinacol ester (840 mg, 3.8 mmol, 2.2 equiv.), Cs2CO3 (1.67 gm, 5.1 mmol, 3 equiv.) and PEPPSITm-IPr catalyst (120 mg, 0.2 mmol, 0.1 equiv.) and dissolved in DME-H20 (20 mL, 0.2 M, 2/1, v/v). The mixture was heated to 125 C. After 3 hr, the reaction was complete. After cooling, the reaction was extracted with Et0Ac and washed with water, saturated NH4C1. After drying with MgSO4, it was filtered and concentrated to dryness. The resulting solid was washed with Et0Ac. A
mustard yellow solid was obtained as the title compound.
[00510] LCMS (m/z+1) 349.13. 1H NMR (400 MHz, cd3od) 6 7.39 (s, 2H), 6.99 (d, 1.5 Hz, 2H), 3.64 (s, 2H), 2.42 (s, 6H), 2.35 (s, 6H), 2.26 (s, 6H), 2.20 (s, 6H), 2.15 (s, 3H), 1.15 (s, 9H).
Example 136 1-(2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)-5-methylpyrrolidin-2-one (1020-136) Cul, Cs2CO3, dioxane, mw 140 C,40min +
HN I
HN
<1-"N

[00511] To a mixture of 4-(2-cyclopropy1-4-iodo-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (30 mg, 0.08 mmol) (Example 8, Step 4), 5-methylpyrrolidin-2-one (100 mg, 1.00 mmol), copper(I) iodide (15 mg, 0.08 mmol), cesium carbonate (163 mg, 0.50 mmol) in 1,4-dioxane (2 mL) under nitrogen was added N,N-dimethylethane-1,2-diamine (14 mg, 0.16 mmol). The reaction mixture in a microwave vial was purged with dry nitrogen, capped, heated to 140 C in a microwave reactor for about 40 minutes.
The mixture was cooled, diluted with ethyl acetate (10 mL), filtered through a layer of TM
celite, then partitioned between water and ethyl acetate, the aqueous phase was extracted with ethyl acetate twice, and the combined organic phase was washed with I M
aqueous K2CO3, 30% aqueous ammonium chloride, brine, dried and concentrated. The crude product was purified by reverse phase HPLC eluting with 0,1% TFA-containing acetonitrile/water to afford the title compound.
[00512] C20H22N402. 351.2 (M+1). 11-INMR (DMSO-d6) 6 7.54 (s, 1H), 7.32 (s, 1H), 4.55 (m, 1H), 2.59 (m, 2H), 2.40-2.51 (m, 6H), 2.28 (s, 3H), 1.83 (m, 1H), 1.39 (m, 4H), 1.14 (d, J = 6.2 Hz, 3H).
Example 137 1-(2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)-5-ethylpyrrolidin-2-one (1020-137) HN
<r-N

[00513] Compound 1020-137 was synthesized from 4-(2-cyclopropy1-4-iodo-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole and 5-ethylpyrrolidin-2-one, using similar conditions as described in Example 136.
[00514] C211124N402. 365.2 (M+1). IFINMR (DMSO-d6) 8 7.47 (s, 1H), 7.25 (s, 1H), 4.87 (m, 1H), 2.59 (m, 2H), 2.45 (s, 3H), 2.30-2.43 (m, 3H), 2.27 (s, 3H), 1.80-2.00 (m, 1H), 1.54 (m, 1H), 1.20-1.45 (m, 5H), 0.85 (t, J = 7.4 Hz, 3H).
Example 138 (S)-1-(2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)-5-(trifluoromethyl)pyrrolidin-2-one (1020-138) HN
F F
[00515] Compound 1020-138 was synthesized from 4-(2-cyclopropy1-4-iodo-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole and 5-trifluoromethylpyrrolidin-2-one using similar conditions as described in Example 136.
[00516] C20E119F3N402. 405.1 (M+1). IFINMR (DMSO-d6) 6 7.47 (s, 1H), 7.32 (s, 1H), 5.60 (m, 1H), 2.52-2.80 (m, 2H), 2.48-2.50 (m, 4H), 2.40-2.47 (m, 6H), 1.23 (m, 4H).
Example 139 2-Amino-N-cyclopenty1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazole-4-sulfonamide (1020-139) O-N O-N
BrCN
fql CH3CRI/Me0H/H20 HN

y---=-N 00 \c) [00517] 2,3-diamino-N-cyclopenty1-5-(3,5-dimethylisoxazol-4-yObenzenesulfonamide (17 mg, 0.05 mmol) (Example 1, Step 8) was dissolved in Me0H (1 mL). The solution was added slowly to a stirred solution of 5M BrCN in acetonitrile (11u1) in water (1 mL). The reaction was stirred at RT for lh before being evaporated under vacuum. The residue was purified with Prep HPLC (0-100%
CH3CN/H20) to afford the title compound.
[00518] Ci7H2IN503S. 376.0 (M+1). 1H NMR (400MHz, CD30D) 6 7.57 (s, 1H), 7.53 (s, 1H), 3.67-3.63 (m, 1H), 2.42 (s, 3H), 2.21 (s, 3H), 1.78-1.61 (m, 4 H), 1.50-1.38 (m, 4H).
Example 140 N-Cyclopenty1-6-(3,5-dimethylisoxazol-4-y1)-2-(hydroxymethyl)-1H-benzo[d]imidazole-4-sulfonamide (1020-140) -II reflux)1' HN la II

-N

[00519] 2,3-Diamino-N-cyclopenty1-5-(3,5-dimethylisoxazol-4-yObenzenesulfonamide (20 mg, 0.06 mmol) (Example 1, Step 8) was dissolved in HC1 (2 mL). To the above solution was added glycolic acid (13mg, 017 mmol).
The reaction was refluxed overnight before being evaporated under vacuum. The residue was purified with Prep HPLC (0-100% CH3CN/H20) to afford the title compound.
[00520] C18H22N404S. 391.1 (M+1). NMR
(400MHz, CD30D) 6 7.88 (s, 1H), 7.81 (s, 1H), 5.08 (s, 2H), 3.68-3.65 (m, 1H), 2.46 (s, 3H), 2.29 (s, 3H), 1.73-1.61 (m, 4 H), 1.49-1.46 (m, 4H).
Example 141 2-Benzyl-N-cyclopenty1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazole-4-sulfonamide (1020-141) HN
-N b [00521] Compound 1020-141 was prepared in a similar manner as that of Example 7 by reacting 2,3-diamino-N-cyclopenty1-5-(3,5-dimethylisoxazol-4-yObenzenesulfonamide (20 mg, 0.06 mmol) (Example 1, Step 8) with 2-phenylacetic acid.
[00522]
C24H26N403S. 451.2 (M+1). 1H NMR (400MHz, CD30D) 6 7.66 (s, 1H), 7.58 (s, 1H), 7.49-7.32 (m, 5H), 3.85 (s, 2H), 3.64-3.62 (m, 1H), 2.44 (s, 3H), 2.24 (s, 3H), 1.75-1.62 (m, 4 H), 1.58-1.44 (m, 4H).

[00523] Compounds 1020-142, 1020-143, 1020-144, 1020-145, 1020-146, 1020-147, and 1020-148, were prepared in a similar fashion as N-cyclopenty1-2-(cyclopropylmethylamino)-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazole-4-sulfonamide (Example 1) by substituting the appropriate commercial isothiocyanate in Example 1, Step 9:
Example 142 N-Cyclopenty1-6-(3,5-dimethylisoxazol-4-y1)-2-(phenylamino)-1H-benzo[d]imidazole-4-sulfonamide (1020-142) OH
HN

\O

[00524] C23H25N503S. 452.2 (M+1). 1H NMR (400MHz, CD30D) 6 7.57-7.51 (m, 6H), 7.40-7.36 (m, 1H), 3.68-3.65 (m, 1H), 2.42 (s, 3H), 2.26 (s, 3H), 1.79-1.62 (m, 4 H), 1.52-1.44 (m, 4H).
Example 143 2-(Benzylamino)-N-cyclopenty1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazole-4-sulfonamide (1020-143) fr`i HN

NH
[00525] C24H27N503S. 466.2 (M+1). 1H NMR (400MHz, CD30D) 6 7.56 (s, 1H), 7.51 (s, 1H), 7.48-7.34 (m, 5H), 4.74 (s, 2H), 3.65-3.62 (m, 1H), 2.42 (s, 3H), 2.24 (s, 3H), 1.79-1.64 (m, 4 H), 1.58-1.48 (m, 4H).

Example 144 N-Cyclopenty1-6-(3,5-dimethylisoxazol-4-y1)-2-(2-morpholinoethylamino)-1H-benzo[d]imidazole-4-sulfonamide (1020-144) O-N
401 ,N
Cs %H
HN
0/ / __ NH
\ __ /
100526] C23H32N604S. 489.2 (M+1). 1H NMR (400MHz, CD30D) 6 7.61 (s, 1H), 7.59 (s, 1H), 4.74 (s, 2H), 4.08-4.01 (m, 6H), 3.67-3.64 (m, 1H), 3.60-3.48 (m, 6H), 2.44 (s, 3H), 2.27 (s, 3H), 1.74-1.64 (m, 4 H), 1.51-1.42 (m, 4H).
Example 145 N-Cyclopenty1-2-(cyclopropylamino)-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazole-4-sulfonamide (1020-145) O-N
,FNII
HN

[00527] C201-125N503S. 416.1 (M+1). 1H NMR (400MHz, CD30D) 6 7.68 (s, 1H), 7.52 (s, 1H), 3.68-3.57 (m, 1H), 2.42 (s, 3H), 2.28 (s, 3H), 2.05-1.58 (m, 4 H), 1.49-1.39 (m, 4H), 1.35-1.20 (m, 1H). 0.35-0.24 (m, 2H), 0.18-0.15 (m, 2H).
Example 146 N-Cyclopenty1-6-(3,5-dimethylisoxazol-4-y1)-2-((tetrahydrofuran-2-yOmethylamino)-1H-benzo[d]imidazole-4-sulfonamide (1020-146) win O-N
Si AI
HN

HN

[00528] C22H29N504S. 460.1 (M+1). 1H NMR (400MHz, CD30D) 6 7.67 (s, 1H), 7.58 (s, 1H), 3.81-3.75 (m, 2H), 3.45-3.37 (m, 2H), 3.00-2.95 (m, 1H), 2.43 (s, 3H), 2.28 (s, 3H), 2.05-1.58 (m, 8 H), 1.49-1.39 (m, 4H).
Example 147 N-Cyclopenty1-6-(3,5-dimethylisoxazol-4-y1)-2-(2-methoxyethylamino)-1H-benzo[d]imidazole-4-sulfonamide (1020-147) O-N
Al HN

\O.
/NH

[00529] C20H27N504S. 434.2 (M+1). 1H NMR (400MHz, CD30D) 6 7.78 (s, 1H), 7.62 (s, 1H), 3.81-3.48 (m, 5H), 2.45(s, 3H), 2.27 (s, 3H), 2.02-1.59 (m, 4 H), 1.48-1.39 (m, 4H).
Example 148 N-Cyclopenty1-6-(3,5-dimethylisoxazol-4-y1)-2-(2,2,2-trifluoroethylamino)-1H-benzo[d]imidazole-4-sulfonamide (1020-148) O-N
HN

\CD
r¨NH

[005301 Ci9H22F3N503S. 458.1 (M+1). NMR (400MHz, CD30D) 6 7.72 (s, 1H), 7.58 (s, 1H), 3.60-3.58 (m, 3H), 2.43(s, 3H), 2.25 (s, 3H), 2.08-1.54 (m, 4 H), 1.48-1.32 (m, 4H).
Examples 149 and 150 (R)-4-(2-cyclopropy1-4-(6-methylquinolin-5-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-149) and (S)-4-(2-cyclopropy1-4-(6-methylquinolin-5-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-150) O-N O-N O-N
HNHN _N HN
7N 5(.<14 N
I I ,N
racemate (R) (S) [005311 4-(2-cyclopropy1-4-(6-methylquinolin-5-y1)-1H-benzo[d]imidazol-6-y1)-TM
I M
3,5-dimethylisoxazole from Example 18 was optically resolved by DAICEL, Chiralapk IC, Et0Ac / hexane / diethylamine = 70 : 30: 0.1.
[005321 (R)-4-(2-cyclopropy1-4-(6-methylquinolin-5-y1)-1H-benzo[d]imidazol-y1)-3,5-dimethylisoxazole (1020-149): retention time 5.46 min, 99.8% e.e.
(entantiomeric excess).

(S)-4-(2-cyclopropy1-4-(6-methylquinolin-5-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-150): retention time 5.87 mm, 99.2% e.e.
Example 151 (S)-5 -(2-cyclopropy1-6-(3 ,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)-methylquinoline 1-oxide (1020-151) 0¨N 0-N
N
H
HN N
INS tNS
I N N
'0 [00533] (S)-4-(2-Cyclopropy1-4-(6-methylquinolin-5-y1)-1H-benzo [d]imidazol-6-y1)-3,5-dimethylisoxazole (0.015g) was subjected to MCPBA (0.016g) in Me0H/
DCM
(1/1 ml) and stirred at RT for 24 h. Volatiles were removed and the residue purified by reverse phase HPLC (5-95% MeCN in water, 0.1% TFA) to afford (S)-5-(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)-6-methylquinoline 1-oxide.
[00534] LCMS (m/z +1) 411.22. IFINMR (400 MHz, DMSO-d6) 6 8.58 (d, J =
8.9 Hz, 1H), 8.53 (d, J 6.0 Hz, 1H), 7.84 (d, J = 9.1 Hz, 2H), 7.55 (s, 2H), 7.35¨ 7.23 (m, 1H), 7.11 (d, J = 8.8 Hz, 1H), 7.01 (s, 1H), 2.42 (s, 3H), 2.24 (s, 2H), 2.21 (s, 2H).
Example 152 5-(2-cyclopropy1-5-(3,5-dimethylisoxazol-4-y1)-1 -methyl-1H-benzo [d] imidazol-7-ye -6-methylquinoline 1-oxide (1020-152) / z mCPBA
(40 DCM

N <ri N+
N
[00535] Into a flask containing 4-(2-cyclopropy1-1-methyl-7-(6-methylquinolin-5-y1)-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole (120 mg, 0.29 mmol, 1 equiv.
from Example 74) in DCM (5 mL) is added mCPBA (130 mg, 0.59 mmol, 2 equiv., 77%). After completion, the reaction was quenched with water and extracted with DCM
and washed with water, saturated NH4C1. After drying with MgSO4, it was filtered and concentrated to dryness. Purification was carried out by reverse phase HPLC to cyclopropy1-5-(3,5-dimethylisoxazol-4-y1)-1-methyl-1H-benzo[d]imidazol-7-y1)-6-methylquinoline 1-oxide.
[00536] LCMS (m/z+1) 425.34. 1H NMR (400 MHz, Methanol-d4) 6 8.75 (d, J =
6.8 Hz, 1H), 8.62 (d, J = 4.2 Hz, 1 H), 7.90 (d, J = 5.2 Hz, 1 H), 7.60 (s, 1H), 7.55 - 7.40 (M, 2H), 7.00 (s, 1H), 3.29 (s, 3 H), 2.32 (s, 3H), 2.27 (s, 3H), 2.15 -2.00 (m, 1H), 1.19 -1.02 (m, 4H).
Example 153 5-(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)-6-methylquinolin-2(1H)-one (1020-153) HN

NH

[00537] 5-(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-y1)-6-methylquinolin-2(1H)-one was synthsized in a similar manner as that of Example 61, Step 2, using 5-bromo-6-methylquinolin-2(1H)-one.
[00538] C25H22N402. MS. 411.1 (M+1). 1H NMR (Me0H-d4) 6 7.59 (d, J= 8.5 Hz, 1H), 7.50 (s, 1H), 7.41 (d, J= 8.5 Hz, 1H), 7.405 (d, J= 9.8 Hz, 1H), 6.96 (d, J= 1.5 Hz, 1H), 6.47 (d, J= 9.8 Hz, 1H), 2.45 (s, 3H), 2.30 (s, 3H), 2.15 (s, 3H), 2.09 (quin, J=
6.7 Hz, 1H), 1.18¨ 1.06 (m, 4H).
Example 154 5-(2-eyelopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)-4-methylpyridin-2(1H)-one (1020-154) HN

[00539] 5-(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-y1)-4-methylpyridin-2(1H)-one was synthsized in a similar manner as that of Example 61, Step 2, using 5-bromo-4-methylpyridin-2(1H)-one.
[00540] C211-120N402. MS. 361.1 (M+1). NMR
(Me0H-d4) 6 7.33 (s, 1H), 7.32 (d, J= 1.5 Hz, 1H), 6.89 (d, J= 1.5 Hz, 1H), 6.48 (hr s, 1H), 2.33 (s, 3H), 2.17 (s, 3H), 2.11-2.01 (m, 1H), 2.01 (s, 3H), 1.11 ¨ 1.00 (m, 4H).
Example 155 4-(2-eyelopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)-5-methylpyridin-2(1H)-one (1020-155) HN

[00541] 4-(2-eyelopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-y1)-5-methylpyridin-2(1H)-one was synthsized in a similar manner as that of Example 61, Step 2, using 4-bromo-5-methylpyridin-2(1H)-one.
[00542] C211-120N402. MS. 361.1 (M+1). 11-1 NMR (Me0H-d4) 6 7.33 (s, 1H), 7.32 (d, J= 1.5 Hz, 111), 6.89 (d, J= 1.5 Hz, 1H), 6.48 (br s, 1H), 2.33 (s, 3H), 2.17 (s, 311), 2.11-2.01 (m, 1H), 2.01 (s, 3H), 1.11 ¨ 1.00 (m, 4H).
Example 156 5-(2-eyelopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)-6-methylpyridin-2(1H)-one (1020-156) HN / NH

[00543] 5-(2-eyelopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-y1)-6-methylpyridin-2(1H)-one was synthsized in a similar manner as that of Example 61, Step 2, using 5-bromo-6-methylpyridin-2(1H)-one.
[00544] C21H20N402. MS. 361.1 (M+1). 1H NMR (Me0H-d4) 6 7.61 (d, J= 9.2 Hz, 1H), 7.41 (d, J= 1.5 Hz, 1H), 7.01 (d, J= 1.5 Hz, 1H), 6.51 (d, .1= 9.2 Hz, 1H), 2.43 (s, 3H), 2.28 (s, 3H), 2.21 (s, 3H), 2.19 ¨2.14 (m, 1H), 1.20 ¨ 1.13 (m, 4H).
Example 157 3,5-dimethy1-4-(4-(6-methylquinolin-5-y1)-2-(oxetan-3-y1)-1H-benzo[d]imidazol-ypisoxazole (1020-157) O-N O-N O-N
tel _________________________________________ )11, [00545] 3,5-Dimethy1-4-(4-(6-methylquinolin-5-y1)-2-(oxetan-3-y1)-1H-benzo[d]imidazol-6-yl)isoxazole was synthsized in a similar fasion as that of Example 88, Steps 1-2 replacing 1-methyl-1H-pyrazole-4-carbonyl chloride with oxetane-carbonyl chloride.
Step 1: 4-(4-iodo-2-(oxetan-3-y1)-1H-benzo[djimidazo1-6-y1)-3,5-dimethylisoxazole [00546] LCMS (m/z +1) 396Ø
Step 2: 3,5-Dimethy1-4-(4-(6-methylquinolin-5-y1)-2-(oxetan-3-y1)-benzo[d]imidazol-6-ypisoxazole [00547] LCMS (m/z +1) 411.1.
Example 158 3,5-dimethy1-4-(1-methy1-7-(6-methylquinolin-5-y1)-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-y1)isoxazole Si S
F\--N
F)--N
\
F
N
n7 [00548] To a microwave vial containing 4-(7-iodo-l-methy1-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole (80 mg, 0.19 mmol, 1 equiv.) was added 3,5- 6-methylquinolin-5-ylboronic acid (106 mg, 0.57 mmol, 3 equiv.), Cs2CO3 (371 mg, 1.14 mmol, 6 equiv.) and PEPPSITm-IPr catalyst (51 mg, 0.076 mmol, 0.4 equiv.) and dissolved in DME-H20 (10 mL, 0.2 M, 2/1, v/v). The mixture was heated to 140 C for 30 min. The reaction was extracted with Et0Ac and washed with water, saturated NH4C1. After drying with MgSO4, it was filtered and concentrated to dryness.
The resulting solid was washed with Et0Ac. Purification was carried out by reverse phase HPLC to furnish 3,5-dimethy1-4-(1-methy1-7-(6-methylquinolin-5-y1)-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yeisoxazole.
[00549] LCMS (m/z+1) 437.50. IHNMR (400 MHz, Methanol-d4) 6 8.85 (d, 1H), 8.10 (d, J = 5.8 Hz, 1 H), 7.90 (d, J = 5.2 Hz, 1 H), 7.82 (d, J = 5.8 Hz, 1 H), 7.78 (d, J = 8.2 Hz, 1H), 7.43 (d, J = 8.2 Hz, 1H), 7.20 (d, J = 4.8 Hz, 1 H), 3.29 (s, 3 H), 2.46 (s, 3H), 2.30 (s, 3H).
Example 159 4-(2-cyclopropy1-4-(3,5-dimethyl-1H-pyrazol-4-y1)-1-methyl-1H-benzo[d]imidazol-y1)-3,5-dimethylisoxazole (1020-159) N

[00550] To a microwave vial containing 4-(2-cyclopropy1-4-iodo-l-methyl-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (125 mg, 0.32 mmol, 1 equiv.) was 3,5-dirnethy1-4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-1H-pyrazole (140 mg, 0.64 mmol, 2 equiv.), Cs2CO3 (310 mg, 0.95 mmol, 3 equiv.) and PEPPSITm-IPr catalyst (22 mg, 0.031 mmol, 0.1 equiv.) and dissolved in DME-H20 (5 mL, 0.2 M, 2/1, v/v).
The mixture was heated to 140 C for 30 mm. The reaction was extracted with Et0Ac and washed with water, saturated NH4C1. After drying with MgSO4, it was filtered and concentrated to dryness. The resulting solid was washed with Et0Ac.
Purification was carried out by reverse phase HPLC to furnish 4-(2-cyclopropy1-4-(3,5-dimethyl-pyrazol-4-y1)-1-methyl-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole.
[00551] LCMS (m/z+1) 362.21. 1H NMR (400 MHz, Methanol-d4) 6 7.73 (d, J =
1.2Hz, 1H), 6.95 (d, J 1.2 Hz, 1 H), 3.92 (s, 3H), 2.43 (s, 3H), 2.29 (s, 311), 2.18 (S,3), 2.19 (s, 3H), 2.20 -2.15 (m, 1H), 1.15 -1.05 (m, 4H).
Example 160 4-(2-eyelopropy1-4-(prop-1-yn-1-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole V
HN I HN
[00552] To a microwave vial containing 4-(2-eyelopropy1-4-iodo-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (200 mg, 0.53 mmol, 1 equiv.) was added tributyl(prop-1-yn-l-ypstannane (245 p,L, 0.79 mmol, 1.5 equiv.), Pd(PPh3)4 (61 mg, 0.051 mmol, 0.1 equiv.) and dissolved in THF (10 mL).. The mixture was heated to 120 C for 30 mm. The reaction was extracted with Et0Ac and washed with water, saturated NH4C1. After drying with MgSO4, it was filtered and concentrated to dryness.
Purification was carried out by reverse phase HPLC to furnish 4-(2-cyclopropy1-4-(prop-1-yn-1-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole.
[00553] LCMS (m/z+1) 292.11. IFINMR (400 MHz, Methanol-d4) 6 7.23 (s, 1H), 7.05 (d, J = 1.2 Hz, 1 H), 2.37 (s, 3H), 2.21 (s, 3H), 2.20 -2.15 (m, 1H), 2.13 (s, 311), 1.15 -1.05 (m, 4H).
Example 161 N-(6-(3,5-dimethylisoxazol-4-y1)-4-(6-methylquinolin-5-y1)-1H-benzo[d]imidazol-yl)cyclopropanesulfonamide (1020-161) Step 1: Preparation of N-cyanocyclopropanesulfonamide calcium salt N= ______ N-2Ca+2 + ij--g CI=N Ca+2 [00554] Cyclopropanesulfonyl Chloride (1.09 ml, 10.14 mmol) was added dropwise to a suspension of Calcium Cyanamide (0.89 g, 11.15 mmol) in 25 mL of distilled water under stirring at 45 C. The mixture was stirred for 3 hours at that temperature and filtered, collecting the filtrate for subsequent use.
Step 2: Preparation of N-(6-(3,5-dimethylisoxazol-4-y1)-4-iodo-1H-benzoldlimidazol-2-y1)cyclopropanesulfonamide.

IPA, AcOH, HCI
-JO ¨8S-N __ =N
H2N + (1 /2 Ca+2 90 C HN

HN
0=S=0 .2\
[00555] 5-(3,5-dimethylisoxazol-4-y1)-3-iodobenzene-1,2-diamine (750 mg, 2.28 mmol) in 15 mL of solvent (2-Propanol : acetic acid, conc (36%) HC1 - 10:1:1) was added 25 mL of aqueous calcium sulfonyl cyanamide salt. Reaction was heated to for 2 days in a sealed tube.
[00556] After 2 days reaction was cooled and diluted lx with water then placed on ice. Precipitates formed which were subsequently filtered and collected to afford N-(6-(3,5-dimethylisoxazol-4-y1)-4-iodo-1H-benzo[d]imidazol-2-yl)cyclopropanesulfonamide (215mg, 21%).
LCMS (m/z + 1) 459.1 Step 3: Preparation of N-(6-(3,5-dimethylisoxazol-4-y1)-4-(6-methylquinolin-5-y1)-1H-benzo[djimidazol-2-y1)cyclopropanesulfonamide 71(1 PEPPSI-IPr 1 HN I + HO 1110 N HN
>---=-N
NMP, H20 DBU
N 135 C, 45 min HN
0=S=0 0=S=0 N
[00557] In a microwave vial were combined N-(6-(3,5-dimethylisoxazol-4-y1)-iodo-1H-benzo[d]imidazol-2-yl)cyclopropanesulfonamide (50 mg, 0.11 mmol), (6-methylquinolin-5-yOboronic acid (61.21 mg, 0.33 mmol), 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.1 ml, 0.65 mmol), PEPPSI-IPr catalyst (2.48 mg, 0.005 mmol) and 9 mL
NMP /
H20 (2:1 by volume) and heated to 135 C for 45 minutes. After cooling, the reaction diluted in EtAc and aqueous ammonium chloride, was then extracted 3x with EtAc, organics were washed with water and then brine. Organics were then dried over sodium sulphate, filtered and concentrated to dryness. Purification was carried out first by silica gel chromatography (DCM/EtAc as the eluent) followed by reverse phase HPLC to furnish N-(6-(3,5-dimethylisoxazol-4-y1)-4-(6-methylquinolin-5-y1)-1H-benzo[d]imidazol-2-yl)cyclopropanesulfonamide.
[00558] LCMS (m/z +1) 474.3. 1H NMR (400 MHz, DMSO-d6) 8 11.74 (s, 1H), 8.87 (dd, J = 4.1, 1.6 Hz, 1H), 8.06 (d, J = 8.5 Hz, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.72 -7.59 (m, 1H), 7.53 -7.32 (m, 2H), 7.03 (d, J = 1.6 Hz, 1H), 2.63 -2.58 (m, 1H), 2.46 (s, 3H), 2.28 (s, 6H), 1.38 (d, J = 3.8 Hz, 1H), 0.94 (dt, J = 5.2, 2.9 Hz, 2H), 0.88 (dt, J =
8.1, 3.0 Hz, 3H).
Example 162 N-(4-(3,5-dimethy1-1H-pyrazol-4-y1)-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-2-yl)cyclopropanesulfonamide (1020-162) 0,B4O PEPPSI-IPr HN I HN NH
NMP, H20 DBU ¨N' HN N¨NHHI
135 C, 45 min 0=S=0 0=S=0 ,2\ 21\.
[00559] N-(4-(3,5-dimethy1-1H-pyrazol-4-y1)-6-(3,5-dimethylisoxazol-4-y1)-benzo[d]imidazol-2-yl)cyclopropanesulfonamide was prepared using 3,5-dimethy1-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-1H-pyrazole in a similar fashion to N-(6-(3,5-dimethylisoxazol-4-y1)-4-(6-methylquinolin-5-y1)-1H-benzo[d]imidazol-2-ypeyelopropanesulfonamide Example 161, step 3.
[00560] LCMS (m/z +1) 427.2. 1H NMR (400 MHz, DMSO-d6) 8 12.39 (s, 1H), 11.66 (s, 2H), 7.30 (d, J = 1.6 Hz, 1H), 6.92 (d, J = 1.6 Hz, 1H), 2.68 ¨2.59 (m, 1H), 2.45 (s, 3H), 2.27 (s, 3H), 2.13 (s, 6H), 1.01 ¨ 0.84 (m, 4H).
Example 163 N-(6-(3,5-dimethylisoxazol-4-y1)-4-(2-phenylppidin-3-y1)-1H-benzo[d]imidazol-2-Acyclopropanesulfonamide (1020-163) OHS PEPPSI-IPr 01 HN B __________________ ar. HN N
HO" N
NMP, H20 DBU HN -135 C, 45 min HN
0=S=0 O=i=0 [00561] N-(6-(3,5-dimethylisoxazol-4-y1)-4-(2-phenylpyridin-3-y1)-1H-benzo[d]imidazol-2-yl)cyclopropanesulfonamide was prepared using (2-phenylpyridin-3-yl)boronic acid in a similar fashion to N-(6-(3,5-dimethylisoxazol-4-y1)-4-(6-methylquinolin-5-y1)-1H-benzo[d]imidazol-2-ypcyclopropanesulfonamide Example 161, step 3.

[00562] LCMS (mtz +1) 486.3. 1H NMR (400 MHz, DMSO-d6) 6 11.95 (d, J =
4.8 Hz, 1H), 11.65 (s, OH), 8.74 (dd, J = 4.7, 1.7 Hz, 1H), 7.94 (dd, J = 7.8, 1.7 Hz, 1H), 7.51 (dd, J = 7.7, 4.8 Hz, 1H), 7.39 ¨ 7.31 (m, 2H), 7.26 (dt, J = 4.3, 2.9 Hz, 4H), 6.71 (d, J = 1.6 Hz, 1H), 2.66 ¨ 2.57 (m, 1H), 2.14 (s, 3H), 1.97 (s, 3H), 1.00 ¨
0.84 (m, 4H).
Example 164 N-(6-(3,5-dimethy1isoxazo1-4-y1)-4-(6-methy1quinolin-5-y1)-1H-benzo[d]imidazol-ypethanesulfonamide (1020-164) Step 1: Preparation of N-(6-(3,5-dimethylisoxazol-4-y1)-4-iodo-1H-benzo[d]imidazol-2-ypethanesulfonamide HN
HN
0=SQ-0 [00563] Preparation of N-(6-(3,5-dimethylisoxazol-4-y1)-4-iodo-1H-benzo[d]imidazol-2-ypethanesulfonamide was accomplished in a similar fashion as N-(6-(3,5-dimethylisoxazol-4-y1)-4-iodo-1H-benzo[d]imidazol-2-yl)cyclopropanesulfonamide by using ethanesulfonyl chloride, Example 161, steps 1-2.
[00564] LCMS (m/z +1) 447Ø
Step 2: Preparation of N-(6-(3,5-dimethylisoxazol-4-y1)-4-(6-methylquinolin-5-y1)-1H-benzo[d]imidazol-2-yl)ethanesulfonamide OH
HO" PEPPSI-IPr HN I + HN
NMP, H20 1401 DBU
HN N
135 C, 45 min N
0=S=0 0=S=0 [00565] In a microwave vial were combined N-(6-(3,5-dimethylisoxazol-4-y1)-iodo-1H-benzo[d]imidazol-2-ypethanesulfonamide (50 mg, 0.11 mmol), 6-methylquinolin-5-ylboronic acid (83.81 mg, 0.45 mmol), 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.1 ml, 0.67 mmol), PEPPSI-IPr catalyst (7.64 mg, 0.01 mmol) and 9 mL
NMP /
H20 (2:1 by volume) and heated to 135 C for 45 minutes. After cooling, the reaction diluted in EtAc and aqueous ammonium chloride, was then extracted 3x with EtAc, organics were washed with water and then brine then dried over sodium sulfate, filtered and concentrated to dryness. Purification was canied out first by silica gel chromatography (DCM/EtAc as the eluent) followed by reverse phase HPLC to furnish N-(6-(3,5-dimethylisoxazol-4-y1)-4-(6-methylquinolin-5-y1)-1H-benzo[d]imidazol-yl)ethanesulfonamide.
[00566] LCMS (m/z +1) 462.3. IHNMR (400 MHz, DMSO-d6) 6 11.60 (s, 2H), 8.83 (dd, J = 4.2, 1.6 Hz, 1H), 8.01 (d, J= 8.7 Hz, 1H), 7.75 (d, J = 8.7 Hz, 1H), 7.64 (ddd, J = 8.5, 1.6, 0.9 Hz, 1H), 7.47 ¨ 7.36 (m, 2H), 6.98 (d, J = 1.6 Hz, 1H), 2.95 (q, J =
7.3 Hz, 2H), 2.41 (s, 3H), 2.24 (s, 6H), 1.18 (t, J = 7.3 Hz, 3H).
Example 165 N-(4,6-bis(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-2-yl)ethanesulfonamide (1020-165) 0,B'0 PEPPSI-IPr 10 HN HN n N NMP, H20 DBU ¨Nr 135 C, 45 min [00567] N-(4,6-bis(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-2-yl)ethanesulfonamide was prepared using 3,5-dimethy1-4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-ypisoxazole in a similar fashion to N-(6-(3,5-dimethylisoxazol-4-y1)-4-(6-methylquinolin-5-y1)-1H-benzo[d]imidazol-2-ypethanesulfonamide, Example 164, step 2.
[00568] LCMS (m/z 1)416.2. Ili NMR (400 MHz, DMSO-d6) 6 11.97 (s, 1H), 11.70 (s, 1H), 7.37 (d, J = 1.6 Hz, 1H), 7.03 (d, J = 1.6 Hz, 1H), 3.02 (q, J
= 7.3 Hz, 2H), 2.43 (s, 3H), 2.31 (s, 3H), 2.25 (s, 3H), 2.15 (s, 3H), 1.23 (t, J = 7.3 Hz, 3H).
Example 166 N-(6-(3,5-dimethylisoxazol-4-y1)-4-(2-phenylpyridin-3-y1)-1H-benzo[d]imidazol-ypethanesulfonamide (1020-166) HN
9Fi PEPPSI-IPr B
HN N
HO" N
NMP, H20X---N I
DBU
HN- HN
135 C, 45 min [00569] N-(6-(3,5-dimethylisoxazol-4-y1)-4-(2-phenylpyridin-3-y1)-1H-benzo[d]imidazol-2-ypethanesulfonamide was prepared using (2-phenylpyridin-3-yOboronic acid in a similar fashion to N-(6-(3,5-dimethylisoxazol-4-y1)-4-(6-methylquinolin-5-y1)-1H-benzo[d]imidazol-2-yl)ethanesulfonamide, Example 164, step 2.

[00570] LCMS (m/z +1) 474.3.
1005711 1H NMR (400 MHz, DMSO-d6) 8 11.84 (s, OH), 11.67¨ 11.60 (m, 1H), 8.71 (dd, J = 4.8, 1.6 Hz, 1H), 7.91 (dd, J = 7.8, 1.7 Hz, 1H), 7.48 (dd, J =
7.7, 4.8 Hz, 1H), 7.35 ¨7.28 (m, 2H), 7.26 ¨ 7.19 (m, 4H), 6.70 (d, J = 1.6 Hz, 1H), 2.97 (q, J = 7.3 Hz, 2H), 2.12 (s, 3H), 1.95 (s, 3H), 1.20 (t, J = 7.4 Hz, 3H).
Example 167 N-(6-(3,5-dimethylisoxazol-4-y1)-4-(6-methylquinolin-5-y1)-1H-benzo[d]imidazol-yl)propane-2-sulfonamide (1020-167) Step 1: Preparation of N-(6-(3,5-dimethylisoxazol-4-y1)-4-iodo-1H-benzo[d]imidazol-2-yl)propane-2-sulfonamide HN
HN
[00572] Preparation of N-(6-(3,5-dim ethylisoxazol-4-y1)-4-iodo-1H-benzo[d]imidazol-2-yl)propane-2-sulfonamide was accomplished in a similar fashion to N-(6-(3,5-dimethylisoxazol-4-y1)-4-iodo-1H-benzo[d]imidazol-2-yl)cyclopropanesulfonamide by using propane-2-sulfonyl chloride, Example 161, steps 1-2.
[00573] LCMS (m/z +1) 461.1.
Step 2: Preparation of N-(6-(3,5-dimethylisoxazol-4-y1)-4-iodo-1H-benzo[d]imidazol-2-yl)propane-2-sulfonamide HN I .4. HOB, PEPPSI-IPr HN
N NMP, H20 DBU
HI\11 135 C, 45 min HN
0=8=0 0=S=0 N
[005741 In a microwave vial were combined N-(6-(3,5-dimethylisoxazol-4-y1)-iodo-1H-benzo[d]imidazol-2-yl)propane-2-sulfonamide (50 mg, 0.11 mmol), 6-methylquinolin-5-ylboronic acid (81.25 mg, 0.43 mmol), 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.1 ml, 0.67 mmol), PEPPSI-IPr catalyst (7.64 mg, 0.01 mmol) and 9 mL
NMP /
H20 (2:1 by volume) and heated to 135 C for 45 minutes. After cooling, the reaction diluted in EtAc and aqueous ammonium chloride, was then extracted 3x with EtAc, organics were washed with water and then brine. Organics were then dried over sodium sulphate, filtered and concentrated to dryness. Purification was carried out first by silica gel chromatography (DCM/EtAc as the eluent) followed by reverse phase HPLC to furnish N-(6-(3,5-dimethylisoxazol-4-y1)-4-(6-methylquinolin-5-y1)-1H-benzo[d]imidazol-2-yl)propane-2-sulfonamide.
[005751 LCMS (m/z +1) 476.2. 1H NMR (400 MHz, DMSO-d6) 8 11.69 (s, 2H), 8.87 (dd, J = 4.1, 1.6 Hz, 1H), 8.05 (d, J = 8.7 Hz, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.72 -7.65 (m, 1H), 7.51 -7.40 (m, 2H), 7.02 (d, J = 1.7 Hz, 1H), 3.09 (p, J = 6.7 Hz, 1H), 2.45 (s, 3H), 2.28 (s, 6H), 1.24 (d, J = 6.8 Hz, 6H).
Example 168 N-(4,6-bis(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-2-yl)propane-2-sulfonamide (1020-168) 0, 0 IFY PEPPSI-IPr ___________________________________________ )1, HN 1 + P HN
NMP, H20 DBU N

135 C, 45 min 0=S=0 0=S=0 [00576] N-(4,6-bis(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-2-yl)propane-2-sulfonamide was prepared using 3,5-dimethy1-4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-yl)isoxazole in a similar fashion to N-(6-(3,5-dimethylisoxazol-4-y1)-4-(6-methylquinolin-5-y1)-1H-benzo[d]imidazol-2-yl)propane-2-sulfonamide, Example 167, step 2.
[00577] LCMS (m/z +1) 430.2. NMR (400 MHz, DMSO-d6) 6 11.97 (s, 1H), 11.67 (s, 1H), 7.37 (d, J = 1.6 Hz, 1H), 7.03 (d, J = 1.6 Hz, 1H), 3.13 (p, J
= 6.7 Hz, 1H), 2.43 (s, 3H), 2.31 (s, 3H), 2.25 (s, 3H), 2.15 (s, 3H), 1.26 (d, J = 6.7 Hz, 6H).
Example 169 N-(6-(3,5-dimethylisoxazol-4-y1)-4-(2-phenylpyridin-3-y1)-1H-benzo[d]imidazol-yl)propane-2-sulfonamide (1020-169) 1101 OHS PEPPSI-1Pr HN HN N
+
HO N
NMP, H20 X=N
DBU
HN- HN
135 C, 45 min 0= =0 0= =0 [00578] N-(6-(3,5-dimethylisoxazol-4-y1)-4-(2-phenylpyridin-3-y1)-1H-benzo[d]imidazol-2-yl)propane-2-sulfonamide was prepared using (2-phenylpyridin-3-yeboronic acid in a similar fashion to N-(6-(3,5-dimethylisoxazol-4-y1)-4-(6-methylquinolin-5-y1)-1H-benzo[d]imidazol-2-yl)propane-2-sulfonamide, Example 167, step 2.

[005791 LCMS (m/z +1) 488.4. 1H NMR (400 MHz, DMSO-d6) 6 11.85 (s, 1H), 11.61 (s, 1H), 8.75 (dd, J = 4.8, 1.7 Hz, 1H), 7.95 (dd, J = 7.8, 1.7 Hz, 111), 7.52 (dd, J =
7.7, 4.8 Hz, 1H), 7.38 ¨7.31 (m, 2H), 7.25 (dt, J = 5.7, 2.2 Hz, 4H), 6.76 (d, J = 1.7 Hz, 1H), 3.10 (p, J = 6.8 Hz, 1H), 2.17 (s, 3H), 2.00 (s, 3H), 1.25 (d, J = 6.7 Hz, 6H).
Example 170 N-(6-(3,5-dimethylisoxazol-4-y1)-4-(6-methylquinolin-5-y1)-1H-benzo[d]imidazol-yl)methanesulfonamide (1020-170) Step 1: Preparation of N-(6-(3,5-dimethylisoxazol-4-y1)-4-iodo-1H-benzo[d]imidazol-2-yl)methanesulfonamide HN
HN
[00580] Preparation of N-(6-(3,5-dimethylisoxazol-4-y1)-4-iodo-1H-benzo[d]imidazol-2-yl)methanesulfonamide was accomplished in a similar fashion to N-(6-(3,5-dimethylisoxazol-4-y1)-4-iodo-1H-benzo[d]imidazol-2-yl)cyclopropanesulfonamide by using methanesulfonyl chloride, Example 161, steps 1-2.
[00581] LCMS (m/z +1) 433Ø
Step 2: N-(6-(3,5-dimethylisoxazol-4-y1)-4-(6-methylquinolin-5-y1)-1H-benzoldjimidazol-2-yl)methanesulfonamide OH
1401 1 HO-13 PEPPSI-IPr 10 HN I 4. H14)______N
NMP, H20 DBU
HN N
135 C, 45 min FIN N
0=S=0 0=S=0 [00582] In a microwave vial were combined N-(6-(3,5-dimethylisoxazol-4-y1)-iodo-1H-benzo[d]imidazol-2-yl)methanesulfonamide (90 mg, 0.21 mmol), 6-methylquinolin-5-ylboronic acid (116.81 mg, 0.62 mmol), 1,8-Diazabicyclo[5.4.0]undec-7-ene, PEPPSI-IPr catalyst (4.73 mg, 0.01 mmol) and 15 mL
NMP / H20 (2:1 by volume) and heated to 135 C for 45 minutes. After cooling, the reaction diluted in EtAc and aqueous ammonium chloride, was then extracted 3x with EtAc, organics were washed with water and then brine. Organics were then dried over sodium sulphate, filtered and concentrated to dryness. Purification was carried out first by silica gel chromatography (DCM/EtAc as the eluent) followed by reverse phase HPLC to furnish N-(6-(3,5-dimethylisoxazol-4-y1)-4-(6-methylquinolin-5-y1)-1H-benzo[d]imidazol-2-yl)methanesulfonamide.
[00583] LCMS (m/z +1) 448.2. NMR (400 MHz, DMSO-d6) 6 11.64 (s, 2H), 8.84 (dd, J = 4.2, 1.6 Hz, 1H), 8.03 (d, J = 8.7 Hz, 1H), 7.76 (d, J = 8.7 Hz, 1H), 7.70 -7.60 (m, 1H), 7.41 (dd, J = 8.5, 4.0 Hz, 2H), 6.95 (s, 1H), 2.90 (s, 3H), 2.43 (s, 3H), 2.26 (d, J = 1.4 Hz, 6H).
Example 171 N-(6-(3,5-dimethylisoxazol-4-y1)-4-(2-phenylpyridin-3-y1)-1H-benzo[d]imidazol-yOmethanesulfonamide (1020-171) 77n OHS PEPPSI-IPr HN HN N
+ HO- N
NMP, H20 DBU
FIN
135 C, 45 min HN
0=S=0 0=S=0 [00584] N-(6-(3,5-dimethylisoxazol-4-y1)-4-(2-phenylpyridin-3-y1)-1H-benzo[d]imidazol-2-yOmethanesulfonamide was prepared using (2-phenylpyridin-3-yl)boronie acid in a similar fashion to N-(6-(3,5-dimethylisoxazol-4-y1)-4-(6-methylquinolin-5-y1)-1H-benzo[d]imidazol-2-yOmethanesulfonamide, Example 170, step 2.
[00585] LCMS (m/z +1) 460.3. 1H NMR (400 MHz, DMSO-d6) 6 11.90 (s, 1H), 11.72 (s, 1H), 8.75 (dd, J = 4.8, 1.6 Hz, 1H), 7.94 (dd, J = 7.8, 1.7 Hz, 1H), 7.52 (dd, J
7.8, 4.8 Hz, 1H), 7.39 - 7.23 (m, 7H), 6.70 (d, J = 1.6 Hz, 1H), 2.95 (s, 3H), 2.13 (s, 3H), 1.96 (s, 3H).
Example 172 N-(443,5-dimethy1-1H-pyrazol-4-y1)-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-2-y1)methanesulfonamide (1020-172) 0-13 PEPPSI, Cs2CO3 HN I / \ DME, H20 HN N
N
NH
HN HN
&--C) -S(3 0' \ 0' \
[00586] In a microwave vial containing N-(6-(3,5-dimethylisoxazol-4-y1)-4-iodo-1H-benzo[d]imidazol-2-yl)methanesulfonamide (50 mg, 0.12 mmol), PEPPSI (16 mg, 0.023 mmol), 3,5-dimethy1-4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-1H-pyrazole (77 mg, 0.35 mmol), and cesium carbonate (226 mg, 0.69 mmol) was added 2 mL of DME and 1 mL of DI water. The vial was placed in a microwave and heated to 130 C

for 30 minutes. Once complete, Once complete, the solution was quenched with and extracted three times with Et0Ac. The combined organic layers were washed with saturated NaC1, dried over sodium sulfate, filtered and concentrated in vacua Purification was carried out by reverse phase HPLC to afford N-(4-(3,5-dimethy1-1H-pyrazol-4-y1)-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-2-y1)methanesulfonamide.
[00587] Ci8H20N603S. MS. m/z 401.5 (M+1). 1H NMR (400 MHz, cd3od) 6 7.25 (d, J= 1.5 Hz, 1H), 6.94 (s, 1H), 3.02 (s, 3H), 2.44 (s, 3H), 2.28 (s, 3H), 2.19 (s, 6H).
Example 173 Preparation of N-(4,6-bis(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-2-yOmethanesulfonamide (1020-173) HN N
Xez"-N d HN
0' \
[00588] N-(4,6-bis(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]iinidazol-2-yOmethanesulfonamide was synthesized in a similar fashion as that of Example 172, substituting 3,5-dimethy1-4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-1H-pyrazole for 3,5-dimethy1-4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-ypisoxazole.
[00589] Ci8Hi9N5045. MS m/z 402.1 (M+1).1H NMR (400 MHz, cd3od) 6 7.30 (d, J= 1.4 Hz, 1H), 6.97 (d, J= 1.3 Hz, 1H), 3.03 (s, 3H), 2.43 (s, 3H), 2.36 (s, 3H), 2.28 (s, 3H), 2.21 (s, 3H).
Example 174 N-(6-(3,5-dimethylisoxazol-4-y1)-4-(6-methylquinolin-5-y1)-1H-benzo[d]imidazol-yl)benzenesulfonamide (1020-174) Step 1: Preparation of N-(6-(3,5-dimethylisoxazol-4-y1)-4-iodo-1H-benzo[d]imidazol-2-yl)benzenesulfonamide HN
HN
O=B=0 [00590] Preparation of N-(6-(3,5-dimethylisoxazol-4-y1)-4-iodo-1H-benzo[d]imidazol-2-yl)benzenesulfonamide was accomplished in a similar fashion to N-(6-(3,5-dimethylisoxazol-4-y1)-4-iodo-1H-benzo[d]imidazol-2-yl)cyclopropanesulfonamide by using benzenesulfonyl chloride, Example 161, steps 1-2.
[005911 LCMS (m/z +1) 495.1.
Step 2: N-(6-(3,5-dimethylisoxazo1-4-y1)-4-(6-methylquinolin-5-y1)-1H-benzo[d]imidazol-2-yl)benzenesulfonamide OH
HN
HOB, PEPPSI-IPr HN
HN
NMP, H20 N DBU
HN
135 C, 45 min 1%1 O=B=0 O=B=0 1005921 In a microwave vial were combined N-(6-(3,5-dimethylisoxazol-4-y1)-iodo-1H-benzo[d]imidazol-2-yl)benzenesulfonamide (50 mg, 0.11 mmol), 6-methylquinolin-5-ylboronic acid (83.81 mg, 0.45 mmol), 1,8-Diazabicyclo[5.4.0jundec-7-ene (0.1 ml, 0.67 mmol), PEPPSI-IPr catalyst (7.64 mg, 0.01 mmol) and 9 mL
NMP /
H20 (2:1 by volume) and heated to 135 C for 45 minutes. After cooling, the reaction diluted in EtAc and aqueous ammonium chloride, was then extracted 3x with EtAc, organics were washed with water and then brine. Organics were then dried over sodium sulphate, filtered and concentrated to dryness. Purification was carried out first by silica gel chromatography (DCM/EtAc as the eluent) followed by reverse phase HPLC to furnish N-(6-(3,5-dimethylisoxazol-4-y1)-4-(6-methylquinolin-5-y1)-1H-benzo[djimidazol-2-yObenzenesulfonamide.
[00593] LCMS (m/z +1) 510.3. 114 NMR (400 MHz, DMSO-d6) 6 11.90 (s, 2H), 8.84 (dd, J = 4.2, 1.6 Hz, 1H), 8.03 (d, J = 8.7 Hz, 1H), 7.91 ¨ 7.79 (m, 2H), 7.76 (d, J
8.7 Hz, 1H), 7.64 (dt, J = 8.4, 1.3 Hz, 1H), 7.60 ¨ 7.44 (m, 4H), 7.39 (dd, J
= 8.6, 4.2 Hz, 1H), 7.02 (s, 1H), 2.44 (s, 3H), 2.27 (s, 3H), 2.23 (s, 3H).
Example 175 N-(6-(3,5-dimethylisoxazol-4-y1)-4-(6-methylquinolin-5-y1)-1H-benzo[d]imidazol-2-y1)-3,3,3-trifluoropropane-1-sulfonamide (1020-175) Step 1: Preparation of N-(6-(3,5-dimethylisoxazol-4-y1)-4-iodo-1H-benzo[d]imidazol-2-y1)-3,3,3-trifluoropropane-1-sulfonamide HN
HN
0==0 [00594] Preparation of N-(6-(3,5-dimethylisoxazol-4-y1)-4-iodo-1H-benzo[d]imidazol-2-y1)-3,3,3-trifluoropropane-1-sulfonamide was accomplished in a similar fashion to N-(6-(3,5-dimethylisoxazol-4-y1)-4-iodo-1H-benzo[d]imidazol-yl)cyclopropanesulfonamide by using 3,3,3-trifluoropropane-1-sulfonyl chloride, Example 161, steps 1-2.
[00595] LCMS (m/z +1) 515Ø

Step 2: Preparation of N-(6-(3,5-dimethylisoxazol-4-y1)-4-(6-methylquinolin-5-y1)-1H-benzofdlimidazol-2-y1)-3,3,3-trifluoropropane-1-sulfonamide OH
HN HO_B PEPPSI-IPr HN

NMP, H20 40, DBU
HN N HN
135 C, 45 min 0=5=0 0=5 N
=0 [00596] In a microwave vial were combined N-(6-(3,5-dimethylisoxazol-4-y1)-iodo-1H-benzo[d]imidazol-2-y1)-3,3,3-trifluoropropane-1 -sulfonamide (50 mg, 0.1 mmol), 6-methylquinolin-5-ylboronic acid (72.73 mg, 0.39 mmol),T1,8-Diazabicyclo[5.4.0]undec-7-ene (0.09 ml, 0.58 mmol), PEPPSI-IPr catalyst (6.63 mg, 0.01 mmol) and 9 mL NMP / H20 (2:1 by volume) and heated to 135 C for 45 minutes.
After cooling, the reaction diluted in EtAc and aqueous ammonium chloride, was then extracted 3x with EtAc, organics were washed with water and then brine.
Organics were then dried over sodium sulphate, filtered and concentrated to dryness.
Purification was carried out first by silica gel chromatography (DCM/EtAc as the eluent) followed by reverse phase HPLC to furnish N-(6-(3,5-dimethylisoxazol-4-y1)-4-(6-methylquinolin-5-y1)-1H-benzo[d]imidazol-2-y1)-3,3,3-trifluoropropane-1-sulfonamide.
[00597] LCMS (m/z +1) 530.3. IFINMR (400 MHz, DMSO-d6) 6 11.87 (s, 1H), 11.81 (s, 1H), 8.83 (dd, J = 4.3, 1.6 Hz, 1H), 8.02 (d, J = 8.7 Hz, 1H), 7.75 (d, J = 8.7 Hz, 1H), 7.68 -7.60 (m, 1H), 7.47 - 7.35 (m, 2H), 7.01 (s, 1H), 3.25 -3.16 (in, 2H), 2.71 - 2.59 (m, 2H), 2.42 (s, 3H), 2.24 (s, 6H). 19F NMR (376 MHz, DMSO-d6) 6 -64.98 (t, J = 11.1 Hz).
Example 176 N-(5-(3,5-dimethylisoxazol-4-y1)-1-methy1-7-(6-methylquinolin-5-y1)- 1H-benzo[d]imidazol-2-yl)methanesulfonamide (1020-176) Step 1: Preparation of 2-chloro-4-(3,5-diniethylisoxazol-4-y1)-N-methyl-6-nitroaniline MeNH2-HCI SnCl2, Et0H
NMP, 120 C 120 C
02N CI 02N lel CI
HNN

-1110/ 0 IPA, AcOH, HCI
H
N ___________________________ N Ca+2 _________________ CI
\ 0 /2 80 C N

HN HN
0=S=0 [00598] 4-(3-chloro-4-iodo-5-nitropheny1)-3,5-dimethylisoxazole (4 g, 10.57 mmol) was taken up in 1-methy1-2-prro1idinone (10 ml) in a sealed vessel. To this was added methylamine hydrochloride (1.43 g, 21.13 mmol) and triethylamine (5.89 ml, 42.27 mmol). The vessel was capped and stirred at 120 C for 1 day. Reaction was then cooled to room temperature and the crude mixture was diluted in EtAc and aqueous ammonium chloride and extracted 3x with EtAc. Organics were washed with ammonium chloride, water then brine, dried over sodium, sulfate and evaporated to dryness under reduced pressure to afford 2-chloro-4-(3,5-dimethylisoxazol-4-y1)-N-methy1-6-nitroaniline as a very dark red oil.
[00599] LCMS (m/z +1) 281.9 Step 2: Preparation of 6-chloro-4-(3,5-dimethylisoxazol-4-y1)-N1-methylbenzene-1,2-diamine [00600] 2-chloro-4-(3,5-dimethylisoxazol-4-y1)-N-methyl-6-nitroaniline (3.3 g, 11.7 mmol), stannous chloride (6.66 g, 35.1 mmol) were mixed in 100mL ethanol in a pressure sealed vessel and heated to 120 C for 1 hour. Reaction was then cooled to room temperature before being poured into stirring EtAc/1N NaOH for 20 minutes.
Reaction was then extracted 3x with EtAc, washed with 1N NaOH, water 2x and brine. Organics were then dried over sodium sulfate and solvents removed under reduced pressure. Crude material was purified by silica gel chromatography, with Hex /

EtAc as the eluent to provide 6-chloro-4-(3,5-dimethylisoxazol-4-y1)-N1-methylbenzene-1,2-diamine as a dark yellow solid.
1006011 LCMS (m/z +1) 252.2 Step 3: Preparation of N-(7-chloro-5-(3,5-dimethylisoxazol-4-y1)-1-methy1-1H-benzo[d]imidazol-2-yl)methanesulfonamide from 6-chloro-4-(3,5-dimethylisoxazol-y1)-N1-methylbenzene-1,2-diamine 1006021 Preparation of N-(7-chloro-5-(3,5-dimethylisoxazol-4-y1)-1-methy1-benzo[d]imiclazol-2-y1)methanesulfonamide from 6-chloro-4-(3,5-dimethylisoxazol-4-y1)-N1-methylbenzene-1,2-diamine (420 mg, 1.67 mmol) was accomplished in a similar fashion to N-(6-(3,5-dimethylisoxazol-4-y1)-4-iodo-1H-benzo[d]imidazol-2-yl)cyclopropanesulfonamide by using methanesulfonyl cyanamide, Example 161, steps 1-2.
[00603] LCMS (m/z +1) 355.1 Step 4: Preparation of N-(5-(3,5-dimethylisoxazol-4-y1)-1-methy1-7-(6-methylquinolin-5-y1)-1H-benzo[d]imidazol-2-yl)m ethanesulfonarnide OH
HO" PEPPSI-IPr N Cl NMP, H20 N
N DBU
160 C, 45 min HN
HN N
0=6=0 0=6=0 [00604] Preparation of N-(5-(3,5-dimethylisoxazol-4-y1)-1-methy1-7-(6-methylquinolin-5-y1)-1H-benzo[d]imidazol-2-yOmethanesulfonamide was done in a similar manner as the preparation of N-(6-(3,5-dimethylisoxazol-4-y1)-4-(6-methylquinolin-5-y1)-1H-benzo[d]imidazol-2-yl)cyclopropanesulfonamide by using N-(7-chloro-5-(3,5-dimethylisoxazol-4-y1)-1-methy1-1H-benzo[d]imidazol-2-yOmethanesulfonamide as the starting material and heating the reaction to 160 C for 45 minutes.

[00605] LCMS (m/z +1) 462.3. 1H NMR (400 MHz, DMSO-d6) 6 11.96 (s, 1H), 8.90 (dd, J = 4.2, 1.6 Hz, 1H), 8.11 (d, J = 8.7 Hz, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.68 (dt, J = 8.5, 1.2 Hz, 1H), 7.58 (d, J = 1.6 Hz, 1H), 7.47 (dd, J = 8.5, 4.2 Hz, 1H), 6.99 (d, J =
1.6 Hz, 1H), 2.99 (s, 3H), 2.57 (s, 3H), 2.45 (s, 3H), 2.28 (d, J = 8.4 Hz, 6H).
Example 177 N-benzy1-6-(3,5-dimethylisoxazol-4-y1)-4-iodo-1H-benzo[d]imidazol-2-amine (1020-177) Step 1: Preparation of 6-(3,5-dimethylisoxazol-4-y1)-4-iodo-1H-benzokiiimidazol-2(3H)-one CD!, THE POCI3 ION=

[00606] 5-(3,5-dimethylisoxazol-4-y1)-3-iodobenzene-1,2-diamine (2.5 g, 7.6 mmol) and 1,1'-carbonyldiimidazole (2.71 g, 16.72 mmol) were added to tetrahydrofuran (75 ml) in a sealed vessel and heated to 105 C overnight white stirring.
Reaction was cooled then diluted in EtAc / H20 and extracted 4x with EtAc. Organics were washed with water, brine and dried over sodium sulfate. Solvents were removed under reduced pressure, then triturated with minimal EtAc and filtered to provide solids.
Process was repeated and solids combined to afford 6-(3,5-dimethylisoxazol-4-y1)-4-iodo-1H-benzo[d]imidazol-2(3H)-one.
[00607] LCMS (m/z +1) 356Ø
Step 2: Preparation of 442-chloro-4-iodo-1H-benzo[djimidazol-6-y1)-3,5-dimethylisoxazole [00608] 6-(3,5-dimethylisoxazol-4-y1)-4-iodo-1H-benzo[d]imidazol-2(3H)-one (4.5 g, 12.67 mmol) was taken up in 100 mL POC13 and heated to 105 C
overnight. Next day POC13 was removed under reduced pressure. Resulting residue was azeoptroped 2x with DCM then to afford a yellowish brown solid. Crude mixture was diluted in EtAc and water and extracted 3x with EtAc. Organics were washed with water then aq. sodium bicarbonate, brine. Organics were then dried over sodium sulfate and evaporated to dryness under reduced pressure to afford 4-(2-chloro-4-iodo-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole.
[00609] LCMS (m/z +1) 374.0 / 376Ø
Step 3: N-benzy1-6-(3,5-dimethylisoxazol-4-y1)-4-iodo-1H-benzo[d]imidazol-2-amine 13nNH2 NMP, TEA ________________________________ )1%
HN
HN
HN
CI
[00610] 4-(2-chloro-4-iodo-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (800 mg, 2.14 mmol) was dissolved in 1-methyl-2-pyrrolidinone (25 ml) and to this was added benzylamine (1.88 ml, 17.14 mmol) and triethylamine (1 mL, 7.17 mmol. Reaction was sealed in a pressure vessel and heated to 120 C for 1 day.
Ath this point reaction was cooled, then diluted in EtAc / aq. ammonium chloride, extracted 3x with EtAc, washed with ammoium chloride 2x, water 2x, brine, then dried over sodium sulfate before evaporating to dryness under reduced pressure. Residue was purified by flash chromatography using Hex / EtAc as the eluent to afford N-benzy1-6-(3,5-dimethylisoxazol-4-y1)-4-iodo-1H-benzo[d]imidazol-2-amine.
[00611] .LCMS (m/z +1) 445.1. 11-1 NMR (400 MHz, Methanol-d4) 6 7.34 (ddd, J = 33.2, 23.7, 7.0 Hz, 5H), 7.13 ¨7.06 (m, 1H), 4.63 (s, 2H), 2.39 (s, 3H), 2.23 (s, 3H).
Example 178 4-(2-ethoxy-4-(1-methy1-4-pheny1-1H-pyrazol-5-y1)-1H-benzo [d] imidazol-6-y1)-3,5-dimethylisoxazol e (1020-178) Step 1:

HN I

[00612] 543 ,5-dim ethylisoxazol-4-y1)-3 -iodobenzene-1,2 -diamine (1g, 3 mmol) was dissolved in tetraethylorthocarbonate (2 mL). The reaction mixture was then heated at 130 C overnight. The solvent was then evaporated and the residue was purified with combi-flash column chromatography to afford 1.1g of 4-(2-ethoxy-4-iodo-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole.
[00613] C14H14N302. 384.1 (M+1).
Step 2:

Br 0 ,F13 1006141 5-Bromo-1-methyl-4-phenyl-1H-pyrazole (87 mg, 0.37 mmol) and 3,5-Dimethylisoxazole-4-boronic acid pinacol ester (373 mg, 1.47 mmol) was added to a 1,4-dioxane (2 ml). To the above mixture were added Pd(dppf)C12 (27 mg, 0.037 mmol) and potassium acetate (181 mg, 1.85 mmol). The reaction mixture was heated at for 2h. The reaction mixture was then diluted with Et0Ac (100 ml), washed with bring (50m1X2). The organic solvent was evaporated and the residue was dissolved in DCM

and purified with combi-flash column chromatography (product came out at 45%
Et0Ac/Hexane) to afford 1-methy1-4-pheny1-5-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-1H-pyrazole.
[00615] C16H2113N202. 285.3 (M+1).
Step 3:

N

HN
HN
N-N

1006161 4-(2-ethoxy-4-iodo-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (100 mg , 0.26 mmol) and 1-methy1-4-pheny1-5-(4,4,5,5-tetramethyl- I ,3,2-dioxaborolan-2-y1)-1H-pyrazole (37 mg, 0.13 mmo1) were added to a solvent mixture of 1,2-T
dimethoxyethane (2 ml) and water (1 m1). To the above mixture were added PEPPSI-Ipr (18 mg, 0.026 mmol) and Cs2CO3 (127 mg, 0.39 mmol). The reaction mixture was heated at 130 C in microwave reactor for 30mins. The reaction mixture was then filtered and organic solvent was evaporated and the residue was purified with Prep HPLC
(0-100% CH3CN/H20) to afford 4-(2-ethoxy-4-(1-methy1-4-pheny1-1H-pyrazol-5-y1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole.
[00617] C24H23N502. 414.5 (M+1). IHNMR (400MHz, CD30D) 8.20 (s, 1H), 7.91 (s, 1H), 7.64 (d, J= 7.6 Hz, 2H), 7.55 (d, J = 7.6 Hz, 2H), 6.94 (s, 1H), 6.86 (s, 1H), 3.87 (s, 3H), 4.18 (q, J = 8.0 Hz, 2H), 2.39 (s, 3H), 2.22 (s, 3H), 1.22 (t, J
= 8.0 Hz, 3H).
Example 179 4-(2-isopropoxy-1-methy1-7-(6-methylquinolin-5-y1)-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole (1020-179) Step 1:

HN
)7¨N
\
Cl/ \

[00618] 5-(3,5-dimethylisoxazol-4-y1)-7-iodo-1-methy1-1H-benzo[d]imidazol-2(3H)-one (48mg, 0.13 mmol) was added to POC13 (0.1 mL) in round bottom flask and heated at 80 C overnight. POC13 was then evaporated; the residue was dissolved in Et0Ac, washed with NaHCO3, dried organic layer over MgSO4, filtered, and then evaporated. The residue was dried over high vacuum pump to afford 69mg of crude 4-(2-chl oro-7-iodo-l-methy1-1H-benzo [d]imidaz o1-5-y1)-3 ,5 -dimethylisoxazole.
[00619] Ce3H11C1N30. 388.1 (M+1).
Step 2:
O-N O-N
____________________________________ ).
Cl/ \

[00620] 4-(2-Chloro-7-iodo-l-methy1-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole (46mg, 0.12 mmol) was dissolved in isopropanol (2 mL), to the solution was added sodium isoproponoxide (195mg, 2.4 mmol) and the reaction mixture was heated at 80 C for 2h. The solvent was then evaporated and the residue was purified with Prep HPLC to afford 14mg of 4-(7-iodo-2-isopropoxy-l-methy1-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole.
[00621] C16H18IN302. 412.1 (M+1).
Step 3:

O-N O-N
_________________________________ )1. la la:, \
0 o1 100622] 4-(7-iodo-2-isopropoxy-1-methy1-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole (13mg, 0.03 mmol) and (6-methylquinolin-5-yl)boronic acid (26 mg, 0.14 mmol) were added to a solvent mixture of 1,2-dimethoxyethane (2 ml) and water (1 ml). To the above mixture were added PEPPSI-Ipr (3 mg, 0.004 mmol) and Cs2CO3 (52 mg, 0.16 mmol). The reaction mixture was heated at 130 C in microwave reactor for 30mins. The reaction mixture was then filtered and organic solvent was evaporated and the residue was purified with Prep HPLC (0-100% CH3CN/H20) to afford 4-(2-isopropoxy-1-methy1-7-(6-methylquinolin-5-y1)-1H-benzo[d]imidazol-5-y1)-3,5-dimethylisoxazole.
1006231 C26H26N402. 427.5 (M+1). 1H NMR (400MHz, CD30D) 6 8.72 (d, J=
4.0 Hz, 1H), 8.00 (d, J= 8.8 Hz, 1H), 7.73 (d, J= 8.4 Hz, 1H), 7.68 (d, J= 8.0 Hz, 1H), 7.41 (s, 1H), 7.35 (d, J= 4.0, 8.4 Hz, 1H), 6.78 (s, 1H), 5.20-5.16 (m, 1H), 2.62 (s, 3H), 2.35 (s, 3H), 2.22 (s, 3H), 2.19 (s, 3H), 1.37-1.34 (m, 6H).
Example 180 (4-chlorophenyl)(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyridin-3-y1)methanol (1020-180) H = HCI
NaOH HATU, DIPEA
*O Me0H SI OH __________ DMF
HN HN
0 <r-N 0 Boc20, DMAP
Et3N
=THFBoc¨N 11\1'0 HN '0 <r-N 0 I
Step 1:
[00624] From Example 101, step 4, methyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzokliimidazole-4-carboxylate (500 mg, 1.61 mmol) was dissolved in Me0H (5 mL) and NaOH (2M, 1.6 mL). Reaction was allowed to stir at room temperature overnight. The reaction was then neutralized to pH-7 with 1N

and precipitate was collected by vacuum filtration to give 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazole-4-carboxylic acid (329 mg, 69%) as a white powder.
Step 2:
[00625] 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazole-4-carboxylic acid (284mg, 0.95mmol) in DMF (10 mL) with HATU (581mg, 2 mmol) for 15mins, then added N,0-dilmethylhydroxylamine HC1 salt (0.28g, 3 mmol) and triethylamine.(0.53m1, 4 mmol), stirred at RT overnight. Diluted with Et0Ac, washed with brine, backextracted with Et0Ac 4 times, evaporated organic solvent, purified with Combi-Flash column, product came out at 100% Et0Ac, quantitative yield of 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-N-methoxy-N-methyl-1H-benzo[d]imidazole-4-earboxamide.
Step 3:

[00626] 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-N-methoxy-N-methyl-1H-benzo[d]imidazole-4-carboxamide (500mg, 1.47mmol) was dissolved in THF, to the solution was added Di-tert-butyl dicarbonate (64 lmg, 2.94 mmol), N,N-Diisopropylethylamine (0.77m1, 4.14 mmol) and 4-(Dimethylamino)pyridine (36mg, 0.29 mmol). After stirring at RT for 30mins, reaction was completed. Diluted with Et0Ac, washed with brine, evaporated organic solvent, purified with Combi-Flash column. Product came out at 70% Et0Ac/Hexane to give tert-butyl 2-cyclopropy1-(3,5-dimethylisoxazol-4-y1)-4-(methoxy(methyl)carbamoy1)-1H-benzo[d]imidazole-carboxylate (563 mg, 87%) as a white solid.
Steps 4 and 5:

100 examplo 118 HN 40, OH --N
Boc-N 0 CI
[00627] (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)(phenyl)(pyrimidin-5-y1)methanol was synthesized in similar fashion to Example 112 using 4-chlorophenylmagnesium chloride in place of phenylmagnesium chloride.
C27H23C1N402 471.2 (M+1). 1H NMR (400 MHz, DMSO-d6) 8 8.61 (dd, J= 15.4, 3.5 Hz, 2H), 7.85 (s, 1H), 7.58 (d, J= 8.6 Hz, 2H), 7.47 (d, J= 8.6 Hz, 2H), 7.39 -7.26 (m, 2H), 6.69 (s, 1H), 2.27 (s, 3H), 2.07 (s, 3H), 1.31 (d, J= 27.1 Hz, 5H).
Example 181 (2-cyclopropy1-6-(3 ,5 -dimethylisoxazol-4-y1)-1H-benz o [d]imidazol-4-y1)(pyri din-3 -yl)(pyrimidin-2-yemethanol (1020-181) SI OH N"--\
HN
/
N¨
[00628] (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(phenyl)(pyrimidin-5-yOmethanol was synthesized in similar fashion to Example 112 using 3-pyridylmagneisum bromide in place of phenylmagnesium chloride in step 1 and 2-pyrimidynyllithium in step 2.
[00629] C25H22N602 439.1 (M+1). 1H NMR (400 MHz, DMSO-d6) 6 8.90 (d, J =
4.9 Hz, 2H), 8.73 (s, 1H), 8.69 ¨ 8.57 (m, 1H), 8.00 (m, 1H), 7.54 (dd, J=
10.6, 5.7 Hz, 4H), 6.84 (s, 1H), 2.29 (s, 3H), 2.09 (s, 3H), 1.28 (d, J= 28.3 Hz, 4H).
Example 182 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(phenyl)(pyridazin-3-y1)methanol (1020-182) 1110 OH N'"--N
HN \
[00630] (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(phenyl)(pyrimidin-5-yOmethanol was synthesized in similar fashion to Example 112 using 2-pyridazinelithium in Step 2.
[00631] C26H23N502 438.2 (M+1). IHNMR (400 MHz, DMSO-d6) 6 9.32 ¨ 9.14 (m, 2H), 7.69 (s, 1H), 7.55 (s, 1H), 7.50 ¨ 7.36 (m, 3H), 7.36 ¨ 7.23 (m, 2H), 6.66 (s, 1H), 2.27 (s, 3H), 2.07 (s, 3H), 1.31 (s, 4H).
Example 183 (2-eyelopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(phenyl)(pyrazin-2-y1)methanol (1020-183) 1110 OH N"----\
HN \ N
<r-N
[00632] (2-eyelopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(phenyl)(pyrimidin-5-yOmethanol was synthesized in similar fashion to Example 112 using 2-pyrazinelithium in Step 2.
[00633] C26H23N502 438.2 (M+1). 1H NMR (400 MHz, DMSO-d6) 6 9.05 (d, J=
1.5 Hz, 1H), 8.64 ¨ 8.52 (m, 2H), 7.64 (s, 1H), 7.53 (s, 1H), 7.41 ¨7.24 (m, 6H), 6.78 (d, J= 1.8 Hz, 1H), 2.60 (br, 1H), 2.28 (s, 3H), 2.07 (s, 3H), 1.34 (d, J= 24.7 Hz, 4H).
Example 184 (2-eyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(phenyl)(pyridin-4-y1)methanol (1020-184) [00634] (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(phenyl)(pyrimidin-5-yOmethanol was synthesized in similar fashion to Example 112 using 4-pyridinyllithium in Step 2.
[00635] C27E124N402 438.2 (M+1). 1H NMR (400 MHz, DMSO-d6) 6 8.70 ¨ 8.64 (m, 2H), 7.61 (s, 1H), 7.54 (s, 3H), 7.45 ¨ 7.34 (m, 3H), 7.32 ¨ 7.25 (m, 2H), 6.61 (s, 1H), 2.55 (m, 1H) 2.26 (s, 3H), 2.06 (s, 3H), 1.32 (br, J= 8.4 Hz, 2H), 1.25 (br, 2H).

Example 185 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(phenyl)(pyrimidin-5-yOmethanol (1020-185) HN N
<r-N
[00636] (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(phenyl)(pyrimidin-5-yOmethanol was synthesized in similar fashion to Example 112 using 5-pyrimidinyllithium in Step 2.
[00637] C26H23N502 438.2 (M+1).1H NMR (400 MHz, DMSO-d6) 6 9.15 (s, 1H), 8.67 (s, 2H), 7.55 (d, J= 1.8 Hz, 2H), 7.47 ¨7.23 (m, 6H), 6.72 (d, J= 1.5 Hz, 1H), 2.58 (m, 1H), 2.25 (s, 3H), 2.05 (s, 3H), 1.32 (d, J= 24.4 Hz, 4H).
Example 186 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[djimidazol-4-y1)di(pyridin-4-yOmethanol (1020-186) 1.

N
n-BuLi Br n-BuLi 0 - E t2 0 40 78 C to rt Et20 N 2T FA HN OH
0 -78 C to rt 0 ¨N 0 <2=---=N
[00638] (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)di(pyridin-4-yl)methanol was synthesized using 4-bromopyridine in ether in a similar fashion to Example 112, steps 1-2.
[00639] C26H23N502. MS. 438.1 (M+1). 1H NMR (Me0H-d4) 6 8.82 (d, J= 6.4 Hz, 2H), 7.90 (d, J = 5.2 Hz, 2H), 7.64 (s, 1H), 6.95 (s, 1H), 2.56 (td, J=
8.6, 4.3 Hz, 1H), 2.33 (s, 3H), 2.14 (s, 3H), 1.57¨ 1.47 (m, 2H), 1.42¨ 1.34 (m, 2H).
Example 187 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyridazin-3-y1)(thiazol-2-yl)methanol (1020-187) Step 1:

>10 'ZI) NN. NH
<1----N 0 N'S
\¨/
[00640] Thiazole (0.35g, 4mmol) was dissolved in 5m1 THF, put the reaction flask in dry ice-acetone bath at -78 C, to the clear solution was added nBuLi (2.55m1, 1.6 M in Hexanethe reaction mixture was stirred at -78 C for lh, then added the solution of tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(methoxy(methyl)carbamoy1)-benzo[d]imidazole-1-carboxylate in 2m1 THF to the above reaction mixture at-78 C.
Temperature was slowly raised to RT, stirred at RT for 3h. The reaction was quenched with water, solvent was evaporated, the residue was purified with combi-flash to afford 500mg of (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(thiazol-2-yOmethanone.
Step 2:

01 0 _____________________________ NH NH
S
\

[00641] Pyridazine (52mg, 0.65 mmol) was dissolved in 2m1 THF, put the reaction flask in dry ice-acetone bath at -78 C, to the clear solution was added TMP-MgC1-LiC1 (0.365 ml, 1.0 M in Hexane/toluene), let Temperature warm up to 0 C.
The reaction mixture was stirred at 0 C for 30mins, to the reaction mixture was added (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(thiazol-2-yl)methanone (50mg, 0.1 mmol) in THF at 0 C and stirred for lh and then stirred at RT
overnight. The reaction was quenched with water, extracted with Et0Ac, evaporated organic solvent, then purified with Prep HPLC. Then added lml TFA to the pure HPLC
fraction of product and evaporated solvent at 50 C, the residue was purified again with Prep HPLC to afford 13mg of (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyridazin-3-y1)(thiazol-2-yl)methanol.
[00642] C23H20N602S. 445.1 (M+1). 1H NMR (400 MHz, CD30D) 6 9.44 (d, J =
2.4 Hz, 1H), 9.29-9.17 (m, 1H), 8.07-7.82 (m, 2H), 7.73 (d, J = 3.2 Hz, 1H), 7.58 (d, J =
1.6 Hz, 1H), 7.41 (d, J = 1.6 Hz, 1H), 2.63 (tt, J = 8.4, 6.0 Hz, 1H), 2.35 (s, 3H), 2.17 (s, 3H), 1.64-1.47 (m, 2H), 1.50-1.32 (m, 2H).
Example 188 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(3,5-dimethylisoxazol-4-y1)(pyridin-3-yl)methanol (1020-188) Step 1: tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-nicotinoy1-1H-benzo[d]imidazole-1-carboxylate O-N

Boc-N 110 Boc_N 1110 j=---N 0 <r-N
NI
[00643] To a solution of tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(methoxy(methyl)carbamoy1)-1H-benzo[d]irnidazole-1-carboxylate (300 mg, 0.68 mmol) in THF (30 mL) was added a solution of 3-pyridinylMgC1 (2eq) and the solution was stirred at room temperature for lh. To the solution was added 3-pyridinylMgC1 ?AA

(2eq) and the solution was stirred at room temperature for 20 min. Additional 0.25 mmol of 3-pyridinylMgC1 was added and the solution was stirred at room temperature for 1.5 h. Aq. NH4C1 was added and the mixture was extracted with Et0Ac (200 mL). The organic solution was washed with brine and dried over Na2SO4. Solvent was removed and the residue was purified by silica gel column chromatography (0-100% Et0Ac in hexane) to give tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-nicotinoy1-1H-benzo[d]imidazole-1-carboxylate.
[00644] C26H26N404. MS. ink 459Ø 1H NMR (Chlorofona-d) 6 8.92 (dd, J=
2.2, 0.9 Hz, 1H), 8.79 (dd, J= 5.0, 1.7 Hz, 1H), 8.25 (d, J= 8.0 Hz, 1H), 8.07 (d, J= 1.6 Hz, 1H), 7.57 (d, J= 1.6 Hz, 1H), 7.50 (m, 1H), 2.76 (ddd, J= 8.0, 5.0, 2.8 Hz, 1H), 2.46 (s, 3H), 2.32 (s, 3H), 1.73 (s, 9H), 1.08 -0.95 (m, 4H).
Step 2: (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(3,5-dimethylisoxazol-4-y1)(pyridin-3-y1)methanol O-N
O-N
Boc- 0N * OH

j=r-N HN
<r-N
N
N
[00645] To a solution of 3,5-dimethylisooxazole (446 mg, 2 mmol) in THF (5 mL) was added butyllithium ( 96 mg, 1.5 mmol, 1.6 M in THF) and the solution was stirred at -78 C for lh. To the solution was added a solution of tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-nicotinoy1-1H-benzo[d]imidazole-1-carboxylate (69 mg, 0.15 mmol) in THF (3 mL) at -78 C and the solution was stirred at room temperature for 5h. H20 (0.5 mL) was added and the solution was stirred at room temperature for 20h.
Et0Ac (100 mL) was added. The organic solution was washed with brine and dried over Na2SO4. Solvent was removed and the residue was purified by silica gel column chromatography (0-5% Me0H/CH2C12) to give (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(3,5-dimethylisoxazol-4-y1)(pyridin-3-yl)methanol.
[00646] C26H25N503. MS m/z 456.2 (M+1). 1H NMR (Methanol-d4) 6 8.59 (d, J=

2.6 Hz, 1H), 8.52 (dd, J= 5.0, 1.5 Hz, 1H), 7.85 (ddd, J= 8.1, 2.3, 1.5 Hz, 1H), 7.51 ¨
7.34 (m, 2H), 6.43 (d, J= 1.5 Hz, 1H), 2.28 (s, 3H), 2.25 ¨2.15 (m, 1H), 2.11 (s, 3H), 1.92 (s, 3H), 1.53 (s, 3H), 1.17¨ 1.06 (m, 4H).
Example 189 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyridin-y1)(thiazol-2-yOmethanol (1020-189) O-N
(el OH N
HN /
N
[006471 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyridin-3-y1)(thiazol-2-yl)methanol was synthesized using thiazole in a similar fashion as Example 188.
[00648] (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyridin-3-y1)(thiazol-2-yl)methanol: C24H2 1N502 S . MS M/Z 444.1 (M+1).

(Methanol-d4) 6 8.64 (d, J= 2.3 Hz, 1H), 8.44 (dd, J= 4.6, 1.6 Hz, 1H), 7.92 (dt, J = 8.4, 1.9 Hz, 1H), 7.81 (d, J= 3.0 Hz, 1H), 7.59 (d, J= 3.3 Hz, 1H), 7.39 (dd, J=
8.1, 4.8 Hz, 2H), 6.94 (s, 1H), 2.32 (s, 3H), 2.20 (s, 1H), 2.15 (s, 3H), 1.10 (d, J= 8.1 Hz, 4H).
Example 190 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(oxazol-y1)(pyridin-3-yl)methanol (1020-190) O-N
OH
HN /
N

[00649] (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)(oxazol-2-y1)(pyridin-3-y1)methanol was synthesized using oxazole in a similar fashion as Example 188.
[00650] (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(oxazol-2-y1)(pyridin-3-yOmethanol: C24H2IN503. MS m/z 428.1 (M+1). 1H NMR
(Methanol-d4) 6 8.66 (t, J= 1.6 Hz, 1H), 8.52¨ 8.41 (m, 1H), 8.10 ¨ 7.84 (m, 2H), 7.42 (dd, J= 8.1, 4.8 Hz, 2H), 7.22 (s, 1H), 6.56 (s, 1H), 2.32 (s, 3H), 2.19 (s, 1H), 2.15 (s, 3H), 1.09 (d, J= 7.9 Hz, 4H).
Example 191 1-(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)-1,2-di(pyridin-3-yl)ethanol (1020-191) O-N

HN N
<r-N
N
[00651] 1-(2-cyclopropy1-643,5-dimethylisoxazol-4-y1)-1H-benzordlimida7o1-y1)-1,2-di(pyridin-3-ypethanol was synthesized using 3-picoline in a similar fashion as Example 188.
[00652] 1-(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-y1)-1,2-di(pyridin-3-ypethanol: C27H25N502. MS m/z 452.1 (M+1). 1E1 NMR
(Methanol-d4) 6 8.93 (d, J= 2.2 Hz, 1H), 8.77 ¨ 8.63 (m, 2H), 8.55 ¨ 8.44 (m, 2H), 8.14 (dd, J=
8.1, 1.7 Hz, 1H), 7.84 (ddd, J-15.5, 8.2, 5.4 Hz, 2H), 7.55 (dd, J = 10.0, 1.3 Hz, 2H), 4.14 (d, J= 2.2 Hz, 2H), 2.50 (dd, J= 8.8, 1.9 Hz, 1H), 2.40 (s, 3H), 2.23 (s, 3H), 1.56 ¨
1.42 (m, 2H), 1.32 (td, i= 6.9, 6.3, 3.9 Hz, 2H).
Example 192 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(6-methylpyridin-2-y1)(pyridazin-3-yOmethanol (1020-192) Step 1: Preparation of tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-(pyridazine-3-carbony1)-1H-benzo[d]imidazole-1-carboxylate N -78 C, TMP, n-BuLi 0._11 + o 7o <1=-N N /-0 N
N
[00653] To a flame dried flask containing THF and 2,2,6,6-Tetramethylpiperidine (1.6 mL, 9.6 mmol.) at -78 C, n-BuLi (5.9 mL, 9.5 mmol, 1.6 M) was added dropwise.
After 15 minutes of stirring, Pyridazine (0.66 mL, 9.1 mmol) was added. The solution was allowed to stir for 15 minutes, followed by the addition of tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(methoxy(methyl)carbamoy1)-1H-benzo[d]imidazole-1-carboxylate (500 mg, 1.1 mmol). The solution was allowed to stir for 30 minutes, then was removed from the cold bath to waim to room temperature. Once complete, the solution was quenched with DI H2O and extracted three times with Et0Ac. The combined organic layers were washed with saturated NaC1, dried over sodium sulfate, filtered and concentrated in vacuo. To the crude product was added 5 mL of TFA
and was allowed to stir for 30 minutes. The solution was concentrated in yam) and was purified via flash column chromatography to afford tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(pyridazine-3-carbonyl)-1H-benzo[d]imidazole-1-earboxylate (270 mg, 52% yield).
[00654] C25H25N504. MS. m/z 460.5 (M+1).
Step 2: Preparation of (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(6-methylpyridin-2-y1)(pyridazin-3-yl)methanol MgBr 0 la 1) THF

2) TFA OFP
HN
/ N
II N N

[00655] To a flame dried flask containing tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(pyridazine-3-carbony1)-1H-benzo[d]imidazole-1-carboxylate (50 mg, 0.11 mmol) was added (6-methylpyridin-2-yl)magnesium bromide (1.3 mL, 0.33 mmol, 0.25 M). The reaction was allowed to stir for 30 minutes. Once complete, the solution was quenched with DI H20 and extracted three times with Et0Ac. The combined organic layers were washed with saturated NaCl, dried over sodium sulfate, filtered and concentrated in vacuo. To the crude product was added 5 mL of TFA
and was allowed to stir for 30 minutes. The solution was concentrated in vacuo and was purified via flash column chromatography to afford (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(6-methylpyridin-2-y1)(pyridazin-3-yl)methanol.
1006561 C26H24N602. MS. m/z 443.5 (M+1). 11-1 NMR (400 MHz, cd3od) 6 9.09 (d, J= 3.9 Hz, 1H), 8.03 (d, J= 7.6 Hz, 1H), 7.76 ¨ 7.63 (m, 2H), 7.37 (d, J=
8.6 Hz, 2H), 7.20 (d, J= 7.6 Hz, 1H), 6.73 (d, J= 1.3 Hz, 1H), 2.51 (s, 3H), 2.31 (s, 3H), 2.16 (d, J= 9.4 Hz, 1H), 2.14 (s, 3H), 1.09 (d, J= 7.1 Hz, 4H).
Example 193 Preparation of (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(3-methylpyridin-2-y1)(phenyl)methanol (1020-193) Br 1) -78 C, n-BuLi, THF
0 la OHO
2) TFA HN
OIN
N

[006571 Using the intermediate from Example 112, step 1, to a flame dried flask containing THF and 2-bromo-3-methylpyridine (56 mg, 0.33 mmol) was added n-BuLi (0.41 mL, 6.6 mmol) dropwise at -78 C. The solution was allowed to stir for 15 minutes, followed by the addition of tert-butyl 4-benzoy1-2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazole-l-carboxylate (50 mg, 0.11 mmol) in 2 mL of THF. The solution was allowed to wairn to room temperature. Once complete, the solution was quenched with DI H20 and extracted three times with Et0Ac. The combined organic layers were washed with saturated NaC1, dried over sodium sulfate, filtered and concentrated in vacuo. To the crude product was added 5 mL of TFA
and was allowed to stir for 30 minutes. The solution was concentrated in vacuo and was purified via reverse phase HPLC to afford (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(3-methylpyridin-2-y1)(phenyemethanol.
[00658] C28H26N402. MS. m/z 451.5 (M+1). 1H NMR (400 MHz, cd3od) 6 8.39 (s, 1H), 7.62 (d, J= 7.5 Hz, 1H), 7.46 ¨ 7.27 (m, 6H), 7.22 (s, 2H), 6.32 (s, 1H), 2.25 (s, 3H), 2.12 (d, J= 18.5 Hz, 2H), 2.06 (s, 3H), 1.92 (s, 3H), 1.08 (d, J= 8.1 Hz, 4H).
Example 194 Preparation of (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(phenyl)methanone (1020-194) <IN
[00659] (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(phenyemethanone was obtained from Example 193. In this case, deprotected starting material was recovered and characterized.
[00660] C221.119N302. MS. m/z 358.4 (M+1). 1HNMR (400 MHz, cd3od) 8 7.83 (d, J= 7.2 Hz, 2H), 7.67 (dd, J= 18.5, 11.1 Hz, 2H), 7.56 (t, J= 7.6 Hz, 2H), 7.37 (s, 1H), 2.40 (s, 3H), 2.34 (s, 1H), 2.24 (s, 3H), 1.21 (d, J= 8.1 Hz, 4H).

Example 195 Preparation of (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(4-methylpyridin-2-y1)(phenyl)methanol (1020-195) OHO
HN =
[00661] (2-eyelopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(4-methylpyridin-2-y1)(phenyl)methanol was synthesized in a similar fashion as Example 193, substituting 2-bromo-3-methylpyridine for 2-bromo-4-methylpyridine.
[00662] C28H26N402. MS. miz 451.5 (M+1). NMR (400 MHz, dmso) 8 8.33 (d, J= 37.9 Hz, 1H), 7.77 (d, J= 51.4 Hz, 1H), 7.49 ¨ 7.03 (m, 8H), 6.78 (d, J=
63.4 Hz, 1H), 6.44 (s, 1H), 2.09 (s, 1H), 0.95 (s, 4H).
Example 196 Preparation of (2-eyelopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(5-methylpyridin-2-y1)(phenyl)methanol (1020-196) OH*
HN
<r-N
N
[00663] (2-eyelopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(5-methylpyridin-2-y1)(phenyl)methanol was synthesized in a similar fashion as Example 193, substituting 2-bromo-3-methylpyridine for 2-bromo-5-methylpyridine.
[00664] C28H26N402. MS. m/z 451.5 (M+1). 1H NMR (400 MHz, ed3od) 5 8.33 (s, 1H), 7.61 (dd, J= 8.2, 2.3 Hz, 1H), 7.45 ¨7.19 (m, 7H), 6.33 (s, 1H), 2.52 (s, 3H), 2.26 (s, 3H), 2.17 (d, J= 8.2 Hz, 1H), 2.08 (s, 3H), 2.00 (s, 1H), 1.11 (dd, J=
18.3, 7.0 Hz, 4H).
Example 197 Preparation of (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(2-methylpyridin-3-y1)(phenyl)methanol (1020-197) OHO

HN
<r-N
N
[00665] (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(2-methylpyridin-3-y1)(phenyl)methanol was synthesized in a similar fashion as Example 193, substituting 2-bromo-3-methylpyridine for 3-bromo-2-methylpyridine.
[00666] C28H26N402. MS. m/z 451.5 (M+1). 1H NIVIR (400 MHz, dmso) 6 8.33 (d, J= 3.6 Hz, 1H), 7.65 (s, 1H), 7.31 (dt, J= 16.0, 7.6 Hz, 5H), 7.02 (s, 1H), 6.78 (s, 1H), 6.15 (s, 1H), 2.28 (s, 3H), 2.19 (s, 3H), 1.98 (s, 3H), 1.10 ¨0.89 (m, 4H).
Example 198 1-(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)-1-(5-fluoro-6-methylpyridin-2-y1)-2-methylpropan-1-o1 (1020-198) or 0-N
\N 401 OH
BOG-N '0 HN
<r-NO
NN-\ I
Step 1:
[00667] To a solution of 2-bromo-5-fluoro-6-methyl-pyridine (345 mg, 1.82 mmol) in toluene (4 mL) was added iPrMgCl/LiC1 (0.187 g, 1.8 mmol, 1M in THF) and the solution was stirred at room temperature for 4h. To the solution was added tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(methoxy(methyl)carbamoy1)-1H-benzo[d]imidazole-1-carboxylate (100 mg, 0.227 mmol) in THF (2 mL) and the solution was stirred at room temperature for 1h. Et0Ac (100 mL) was added and the solution was washed with aq NH4C1 and brine, dried over Na2SO4. Solvent was removed and the residue was purified by silica gel column chromatography (0-10% Me0H in CH2C12), then 0-60% Et0Ac in hexane) to give ketone intermediate (30 mg) which was dissolved in 2-methyl-THF (2 mL) for the next reaction.
Step 2:
[00668] To a solution of 2-bromo-5-fluoro-6-methyl-pyridine (93 mg, 0.49 mmol) in toluene (4 mL) was added iPrMgCl/LiC1 (50 mg, 0.49 mmol, 1M in THF) and the solution was stirred at room temperature for 4h. To the solution was added a solution of ketone prepared above and the solution was stirred at room temperature for lh.
Et0Ac (100 mL) was added and the solution was washed with aq NH4C1 and dried over Na2SO4. Solvent was removed and the residue was purified by silica gel column chromatography (0-10% Me0H in CH2C12 then 0-60% Et0Ac in hexanes) to give N-Boc protected product which was dissolved in THF (2 mL), TFA (2 mL) and waster (0.1 mL). The solution was heated at 50 C for lh. Solvent was removed and the residue was purified by HPLC to give 1-(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)-1-(5-fluoro-6-methylpyridin-2-y1)-2-methylpropan-1-01.
[00669] C25H27FN402. MS m/z 435.2 (M+1). 1H NMR (Methanol-d4) 6 7.72 (ddd, J= 8.7, 3.6, 0.8 Hz, 1H), 7.65 (d, J= 1.4 Hz, 1H), 7.48 (t, J= 8.9 Hz, 1H), 7.40 (d, J=
1.4 Hz, 1H), 3.18 (p, J= 6.7 Hz, 1H), 2.67 (tt, J= 8.5, 5.0 Hz, 1H), 2.51 (d, J= 2.9 Hz, 3H), 2.40 (s, 3H), 2.24 (s, 3H), 1.61 - 1.49 (m, 2H), 1.40 (dddd, J= 14.2, 7.4, 5.6, 3.9 Hz, 2H), 0.94 (d, J= 6.8 Hz, 3H), 0.81 (d, J= 6.6 Hz, 3H).
Example 199 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyridazin-3-y1)(thiazol-2-yl)methanol (1020-199) NHS0H) NH
N s N
\--i [00670] (2-eyelopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyridazin-3-y1)(thiazol-2-yOmethanol was synthesized in a similar fashion to Example 198.
[00671] C23H20N602S. 445.1 (M+1). 11-1 NMR (400 MHz, CD30D) 6 8.86 (d, J =
2.4 Hz, 1H), 7.79-7.77 (m, 1H), 7.74-7.72 (m, 1H), 7.64 (d, J = 2.8 Hz, 1H), 7.58 (d, J =
1.6 Hz, 1H), 7.51 (d, J = 1.6 Hz, 1H), 7.44-7.42 (m, 1H), 5.68 (s, 1H), 2.58-2.47 (m, 1H), 2.38 (s, 3H), 2.21 (s, 3H), 1.55-1.53 (m, 2H), 1.44-1.42 (m, 2H).
Example 200 (2-cyc1opropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(2,6-dimethylpyridin-3-y1)(pyridin-3-ypmethanol (1020-200) O-N
HN
JNH0 c:1 [00672] (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(2,6-dimethylpyridin-3-y1)(pyridin-3-yl)methanol was synthesized in a similar fashion to Example 198.
[00673] C28H27N502. 466.2 (M+1). 1H NMR (400MHz, CD30D) 6 8.41 (d, J=
3.6 Hz, 2H), 7.69 (d, J= 8.0 Hz, 1H), 7.38-7.35 (m, 1H), 7.31 (bs, 1H), 6.88 (bs, 2H), 6.18 (d, J= 1.6 Hz, 1H), 2.41 (s, 3H), 2.33 (s, 3H), 2.17 (s, 3H), 2.13-2.04 (m, 1H), 1.98 (s, 3H), 1.13-1.01 (m, 4H).
Example 201 eyelopropyl (2- cyclopropy1-6-(3 ,5-dim ethyli sox azol-4-y1)-1H-b enzo [d]
imidazol-4-yl)(pyridin-3-yl)methanol (1020-201) O-N

HN
[00674] eyelopropy1(2-cyclopropyl-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyridin-3-yl)methanol was synthesized in a similar fashion to Example 198.
[00675] C24H24N402. 401.1 (M+1). 1H NMR (400MHz, CD30D) 6 8.97 (d, J=
2.0 Hz, 1H), 8.70 (dd, J= 1.2, 6.4 Hz, 1H), 8.42 (tt, J= 1.6, 8.0 Hz, 1H), 7.84 (dd, J=
1.6, 8.4 Hz, 1H), 7.55-7.52 (m, 2H), 2.58-2.51 (m, 1H), 2.41 (s, 3H), 2.24 (s, 3H), 1.88-1.83 (m, 1H), 1.53-1.49 (m, 2H), 1.38-1.36 (m, 2H), 0.74-0.65 (m, 4H).
Example 202 (2-eyelopropy1-6-(3 ,5-dimethyli soxazol-4-y1)-1H-b enzo [d]imidazol-4-y1)(6-m ethylpyridin-2-y1)(phenyl)m ethanol (1020-202) BocN HN
HO /
[00676] Into a flask containing tert-butyl 4-benzoy1-2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazole-1-carboxylate (50 mg, 0.11 mmol, 1 equiv.) is added THF (5 mL) and to it is added (6-methylpyridin-2-yOmagnesium bromide (2.6 mL, 0.66 mmol, 6 equiv., 0.25 M THF, Rieke Metals). After completion, the reaction was quenched and extracted with Et0Ac and washed with water, saturated NH4C1. After drying with MgSO4, it was filtered and concentrated to dryness.
To the crude material is added TFA (5 mL) and allowed to stir for 30 min. After the reaction was complete, it was concentrated in vacuo. Purification was carried out by reverse phase HPLC to (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-y1)(6-methylpyridin-2-y1)(phenyl)methanol (as a racemate).
[00677] LCMS (m/z +1) 467.23 Example 203 Preparation of (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(3-methylpyridin-2-y1)(pyridin-2-yOmethanol (1020-203) Iv Iv MgBr 1) THF lel Or =

2) TFA HN

N N
[00678] To a flame dried flask containing THF and tert-butyl 2-cyclopropy1-(3,5-dimethylisoxazol-4-y1)-4-(6-methylpicolinoy1)-1H-benzo[d]imidazole-1-carboxylate (45 mg, 0.095 mmol) was added (pyridin-2-yl)magnesium bromide (2.3 mL, 0.57 mmol). The solution was allowed to stir for 1 hour. Once complete, the solution was quenched with DI H20 and extracted three times with Et0Ac. The combined organic layers were washed with saturated NaCl, dried over sodium sulfate, filtered and concentrated in vacuo . To the crude product was added 5 mL of TFA and was allowed to stir for 30 minutes. The solution was concentrated in vacuo and was purified via reverse phase HPLC to afford (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(6-methylpyridin-2-y1)(pyridin-2-yl)methanol.
[00679] C271125N502. MS. m/z 452.5 (M+1). 11-1 NMR (400 MHz, cd3od) 8 8.51 (d, J= 4.3 Hz, 1H), 7.80 (td, J= 7.8, 1.7 Hz, 1H), 7.67- 7.60 (in, 2H), 7.36 (s, 1H), 7.33 -7.28 (m, 1H), 7.24 (d, J= 7.8 Hz, 1H), 7.18 (d, J= 7.7 Hz, 1H), 6.68 (d, J=
1.4 Hz, 1H), 2.52 (s, 3H), 2.29 (d, J= 6.8 Hz, 3H), 2.18 (dd, J= 13.4, 7.0 Hz, 1H), 2.13 (s, 3H), 1.09 (d, J= 7.9 Hz, 4H).
Example 204 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(6-methoxypyridin-3-y1)(pyridin-2-yl)methanol (1020-204) Step 1: Tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(6-methoxynicotinoy1)-1H-benzo[d]imidazole-1-carboxylate '0 BocN
BocN
0 <r-N 0 <r-N
[00680] A flask containing 5-bromo-2-methoxypyridine (705 uL, 5.45 mmol, 4 equiv.) and MeTHF (10 mL) was cooled to -78 C before BuLi (3.41 mL, 5.45 mmol, equiv.) was added. After 30 min, tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(methoxy(methyl)carbamoy1)-1H-benzo[d]imidazole-1-carboxylate (600 mg, 1.36 mmol, 1 equiv.) dissolved in MeTHF (4 mL) was added to the reaction mixture.
After completion, the reaction was quenched and extracted with Et0Ac and washed with water, saturated NH4C1. After drying with MgSO4, it was filtered and concentrated to dryness. Flash column chromatography was carried out to tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(6-methoxynicotinoy1)-1H-benzo[d]imidazole-1-carboxylate (325 mg, 49%, 7/3 Et0Ac/ Hex).
[00681] LCMS (m/z+1) 489.48 Step 2: (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzoid]imidazol-4-y1)(6-methoxypyridin-3-y1)(pyridin-2-yOmethanol \ N

HN
BocN HO N
<r-N
[00682] Into a flask containing 2-bromopyridine (110 tL, 1.15 mml, 8 equiv.) was added MeTHF (5 mL) and to it is added BuLi (720 p,L, 1.15 mmol, 8 equiv.) slowly at -78 C. After 45 minutes, tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(6-methoxynicotinoy1)-1H-benzo[d]imidazole-1-carboxylate (70 mg, 0.14 mmol, 1 equiv.) dissolved in MeTHF (2 ML) was added slowly to the reaction. After completion, the reaction was quenched and extracted with Et0Ac and washed with water, saturated NH4C1. After drying with Mg504, it was filtered and concentrated to dryness.
To the crude material is added TFA (5 mL) and allowed to stir for 30 min. After the reaction was complete, it was concentrated in vacuo. Purification was carried out by reverse phase HPLC to (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-y1)(6-methoxypyridin-3-y1)(pyridin-2-yl)methanol (as a racemate).
[00683] LCMS (m/z +1) 468.23. 1H NMR (400 MHz, Methanol-d4) 8 8.62 (ddd, J = 4.9, 1.8, 0.9 Hz, 1H), 7.99¨ 7.80 (m, 2H), 7.72 (dt, J = 8.1, 1.0 Hz, 1H), 7.64 (dd, J =
8.8, 2.6 Hz, 1H), 7.52 (d, J = 1.5 Hz, 1H), 7.42 (ddd, J = 7.6, 4.9, 1.1 Hz, 1H), 7.04 (d, J
= 1.4 Hz, 1H), 6.83 (dd, J = 8.8, 0.7 Hz, 1H), 3.91 (s, 3H), 2.67 ¨2.49 (m, 1H), 2.33 (s, 3H), 2.15 (s, 3H), 1.52 (dd, J = 8.4, 2.8 Hz, 2H), 1.45 ¨ 1.26 (m, 2H). 19F
NMR (377 MHz, Methanol-d4) 6 -78.08.
Example 205 54(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(hydroxy)(pyridin-2-yOmethyppyridin-2-ol (1020-205) HN HN
N IN
OH

[006841 Into a microwave vial containing (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(6-methoxypyridin-3-y1)(pyridin-2-yl)methanol (35 mg, 0.075 mmol, 1 equiv.) is added THF (5 mL) and to it is added HCI (1 mL, 1N).
The reaction was heated to 100 *C for 30 min. After completion, the reaction was concentrated to dryness. Purification was carried out by reverse phase HPLC to furnish 54(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(hydroxy)(pyridin-2-yl)methyppyridin-2-ol (as a racemate).
[00685] 1H NMR (400 MHz, Methanol-d4) 6 8.61 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 7.92 (td, J = 7.8, 1.8 Hz, 1H), 7.78 (dt, J = 8.1, 1.0 Hz, 1H), 7.58 (dd, 3 9.6, 2.8 Hz, 1H), 7.52 (d, J = 1.4 Hz, 1H), 7.40 (ddd, 3 = 7.6, 4.8, 1.1 Hz, 1H), 7.18 ¨
7.06 (m, 2H), 6.54 (d, J = 9.6 Hz, 1H), 3.89 (s, 1H), 2.98 (s, 1H), 2.65 (s, 2H), 2.63 ¨
2.57 (m, 1H), 2.35 (s, 3H), 2.17 (s, 3H), 1.63 ¨ 1.45 (m, 2H), 1.45 ¨ 1.17 (m, 2H). 19F NMR
(377 MHz, Methanol-d4) -77.94.
Example 206 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)bis(6-fluoropyridin-3-y1)methanol (1020-206) Step 1: Preparation of methyl 2-cyclopropy1-5-(3,5-dimethylisoxazol-4-y1)-1H-benzo[djimidazole-7-carboxylate HCI
HN r Me0H
+ 2-0 ______________________________________ H2N .<¨NH 0 [00686] Methyl 2,3-diamino-5-(3,5-dimethylisoxazol-4-yl)benzoate (10 g, 0.038 mol) was added to Me0H (50 ml) and to this was added ethyl cyclopropanecarbimidate hydrochloride (8.6 g, 0.057 mol) and heated to 50 C for 3 hours. Solvents were then removed under reduced pressure and residue co-evaporated with toluene (2x), dissolved in EtAc, solids filtered off and organics washed with water and then solvents removed under reduced pressure to afford methyl 2-cyclopropy1-5-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazole-7-carboxylate (11.3g, 94%).
[00687] .LCMS (m/z +1) 312.1 Step 2: Preparation of 1-tert-butyl 4-methyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazole-1,4-dicarboxylate is (Boc)20, TEA, DMAP

_________________________________________ )0.
THF
Boc-N
0 <--=-N 0 [00688] Methyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazole-4-carboxylate (24 g, 77.09 mmol) was taken up in tetrahydrofuran (500 ml) and to this was added di-tert-butyl dicarbonate (33.65 g, 154.17 mmol), 4-(dimethylamirio)pyridine (1.88 g, 15.42 mmol) and finally triethylamine (32.23 ml, 231.26 mmol). Reaction was stirred at room temperature for 2 hours under nitrogen. At this point solvents were removed under reduced pressure and the residue was diluted in EtAc / aq. ammonium chloride. Material was extracted 3x with EtAc, washed with ammonium chloride, water, brine then dried over sodium sulfate. Solvents were removed under reduced pressure and the residue purified by silica gel chromatography using Hex / EtAc as the eluent. Solvents were removed under reduced pressure to give a yellowish solid. Material was triturated in minimal Et20 and filtered and air dried to provide 1-tert-butyl 4-methyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazole-1,4-dicarboxylate a pure white solid. (28.0 g, 88%).
[00689] LCMS (m/z +1) 411.7. 1HNMR (400 MHz, DMSO-d6) 6 8.00 (d, J =
1.7 Hz, 1H), 7.69 (d, J = 1.7 Hz, 1H), 3.87 (s, 3H), 2.80 (ddd, J = 8.2, 5.7, 3.1 Hz, 1H), 2.40 (s, 3H), 2.21 (s, 3H), 1.24- 1.00 (m, 4H).
Step 3: Preparation of tert-butyl 4-(bis(6-fluoropyridin-3-y1)(hydroxy)methyl)-2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazole-1-carboxylate OMe ,F
BrMg----"N 40 OH I
N
Me-THF
0 0 <irN
rt N
[00690] 1-tert-butyl 4-methyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-benzo[d]imidazole-1,4-dicarboxylate was treated with 2-fluoropyridine-5-magnesium bromide (0.062M in Me-THF, 3.8 mL, 3.0 equiv.) at room temperature for 16 h.
After an aqueous work-up, the crude material was purified by an HPLC purification to give 1-tert-butyl 4-(bis(6-fluoropyridin-3-y1)(hydroxy)methyl)-2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazole-1-carboxylate.
C311129F2N504. MS. 574.2 (M+1).
Step 4:
Preparation of (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)bis(6-fluoropyridin-3-yOmethanol c7 , :TFA
OH I
, rt le F
l OH I
N
HN
0 <r-N
, N N
[00691] 1-tert-butyl 4-(bis(6-fluoropyridin-3-y1)(hydroxy)methyl)-2-cyclopropyl-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazole-1-carboxylatem was then treated with TFA at room temperature for 1 h and 15 min. After removing TFA under a reduced pressure, the material was purified by an HPLC to give the (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)bis(6-fluoropyridin-3-yl)methanol.
[00692] 1H NMR (Me0H-d4) 6 8.22 (d, J= 2.6 Hz, 2H), 7.95 (td, J= 8.0, 2.6 Hz, 2H), 7.57 (d, J= 1.6 Hz, 1H), 7.13 (dd, J= 8.0, 2.6 Hz, 2H), 6.88 (d, J= 1.6 Hz, 1H), 2.64-2.56 (m, 1H), 2.32 (s, 3H), 2.14 (s, 3H), 1.58 ¨ 1.50 (m, 2H), 1.42 ¨
1.36 (m, 2H).
Example 207 and 208 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)bis(4-fluorophenyl)methanol (1020-207) and (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(4-fluorophenyemethanone (1020-208) [00693] The above two compounds were synthesized in a similar manner as that of Example 206, Steps 3-4, using 4-fluorophenyl magnesium bromide.

le OHO F
HN
[00694] (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-',SR

yl)bis(4-fluorophenyl)methanol: C281{23F2N302. MS. 472.1 (M+1). 1HNMR (Me0H-d4) 6 7.50 (d, J= 1.6 Hz, 1H), 7.34 (dd, J= 9.6, 6.1 Hz, 4H), 7.11 (t, J= 9.6 Hz, 4H), 6./0 (d, J= 1.6 Hz, 1H), 2.62-2.53 (m, 1H), 2.30 (s, 3H), 2.11 (s, 3H), 1.52 - 1.46 (m, 2H), 1.38 - 1.32 (m, 2H).

HN
[00695] (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(4-fluorophenyl)methanone: C22Hi8FN302. MS. 376.1 (M+1). 1H NMR (Me0H-d4) 6 7.99 (dd, J= 9.6, 6.1 Hz, 2H), 7.85 (d, J= 1.6 Hz, 1H), 7.68 (d, J= 1.6 Hz, 1H), 7.35 (t, J= 9.6 Hz, 2H), 2.56-2.64 (m, 1H), 2.44 (s, 3H), 2.28 (s, 3H), 1.61 - 1.54 (m, 2H), 1.50 -1.44 (m, 2H).
Example 209 (2-eyelopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(6-methylpyridazin-3-yl)methanone (1020-209) Step 1: Preparation of tert-butyl 2-eyelopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(6-methylpyridazine-3-earbony1)-1H-benzord]imidazole-1-earboxylate OMe LVNN 0 lel N,N1 Me-THF
0 0 <r-N

[00696] To a solution of tetramethylpiperidine (68.7 mg, 0.486 mmol, 4 equiv) in Me-THF (1 mL) was treated with BuLi (1.4 M in hexane, 0.49 mL, 0.486 mmol, 4 equiv) at -78 C. After 15 min to the solution was added 3-methylpyridazine (57.2 mg, 0.608 mmol, 5 equiv) in Me-THF (3 mL). After 1 h stirring, 1-tert-butyl 4-methyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazole-1,4-dicarboxylate (50.0 mg, 0.122 mmol) was added at -78 C. After an aqueous work-up, The crude mixture was purified by a column chromatography and Preparative HPLC to give ten'-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(6-methylpyridazine-3-carbony1)-1H-benzo[d]imidazole-1-carboxylate. C26H27N504. MS. 474.2 (M+1).
Step 2: Preparation of (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(6-methylpyridazin-3-yl)methanone -)--0 _NI TFA, rt -IN
HN
0 <r-N 0 [00697] tert-Butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(6-methylpyridazine-3-carbony1)-1H-benzo[d]imidazole-1-carboxylate was treated with TFA at rt for 30 min to give (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(6-methylpyridazin-3-yOmethanone.
[00698] C21H19FN502. MS. 374.2 (M+1). 1H NMR (Me0H-d4) 6 8.48 (s, 1H), 8.30 (d, J= 8.0 Hz, 1H), 7.90 (d, J= 8.0 Hz, 1H), 7.88 (s, 1H), 2.84 (s, 3H), 2.64-2.56 (m, 1H), 2.49 (s, 3H), 2.33 (s, 3H), 1.60¨ 1.40 (m, 4H).
Example 210 34(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(hydroxy)(pyridin-3-yl)methyppyridine 1-oxide (1020-210) Step 1 O-N O-N
0 * 0 01 OH -"N
0 ---11"- N
/\
<1-N 0 N
[00699] 1-tert-Butyl 4-methyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-benzo[d]imidazole-1,4-dicarboxylate (0.15g) was reacted with 3-MgCl-pyrdine (excess, Novel, 0.25 M) in THF (3 ml) at RT and stirred for 20 min. After adding Me0H
(1 mL), volatiles were removed and the residue purified by reverse phase HPLC (5-95%
MeCN
in water, 0.1% TFA) to afford tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(hydroxydi(pyridin-3-yl)methyl)-1H-benzo[d]imidazole-1-carboxylate.
[00700] LCMS (m/z +1) 438.2 (fragment parent ¨ Boc) Step 2 O-N O-N
N

NI
0 lel N \ HN \
<1.-N
N N
[00701] The substrate (0.057g) was subjected to MCPBA (0.037g) in Me0H/
DCM (1/1 ml) and stirred at RT for 3 h. Volatiles were removed, the residue dissolved in TFA and stirred for 1 h. Volatiles were removed and the residue purified by reverse phase HPLC (5-95% MeCN in water, 0.1% TFA) to afford 34(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(hydroxy)(pyridin-3-yl)methyppyridine 1-oxide. The bis-N-oxide was also isolated, see below.
[00702] LCMS (m/z +1) 454Ø Ili NMR (400 MHz, Methanol-d4) 6 8.63 ¨ 8.53 (m, 1H), 8.35 (d, J = 1.9 Hz, 1H), 8.31 ¨ 8.23 (m, 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.61 ¨
7.40 (m, 2H), 6.85 (d, J = 1.4 Hz, 1H), 2.49 (s, 1H), 2.24 (s, 1H), 2.06 (s, 1H), 1.43 (dd, J

= 8.4, 2.9 Hz, 3H), 1.32¨ 1.23 (m, 3H).
Example 211 3,3`4(2-cyc1opropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(hydroxy)methylene)bis(pyridine 1-oxide) (1020-211) 0¨N 0¨N
N

o OH _N

N HN
NI I C) N e -c) [00703] LCMS (m/z +1) 569.8. 1H NMR (400 MHz, Methanol-d4) 6 8.42 (t, J =
1.5 Hz, 1H), 8.36 (dt, J = 6.1, 1.5 Hz, 1H), 7.63¨ 7.48 (m, 3H), 7.00 (d, J =
1.4 Hz, 1H), 2.58 (s, 1H), 2.34 (s, 2H), 2.17 (s, 2H), 1.52 (dd, J = 8.3, 3.0 Hz, 2H), 1.43 ¨ 1.29 (m, 2H).
Example 212 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(6-methylpyridazin-3-ypmethanone (1020-212) Step 1: Preparation of tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(2-methylisonicotinoy1)-1H-benzo[d]imidazole-1-carboxylate N
0 1.1N
t-BuLi oMe ________________________________ Me-THF

[007041 To a solution of 4-bromo-2-methylpyridine (41.8 mg, 0.243 mmol, 4 equiv) in Me-THF (1 mL) was treated with t-BuLi (1.7 M in hexane, 0.14 mL, 0.243 mmol, 4 equiv) at -78 C. After 10 mm to the solution was added 1-tert-butyl 4-methyl 2-9h7 cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazole-1,4-dicarboxylate (25.0 mg, 0.061 mmol) in Me-THF (2 mL). After 1 h stirring, the reaction mixture was worked-up. The crude mixture was purified by a column chromatography (35% to 60%
Et0Ac/hexane) to give tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(2-methylisonicotinoy1)-1H-benzo[d]imidazole-1-carboxylate. C27H28N404. MS. 473.2 (M+1).
Step 2: Preparation of (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)bis(2-methylpyridin-4-y1)methanol N Br 7O I t-BuLi 0 OH 11ON 4 HN
0 Me-THF

[00705] tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(2-methylisonicotinoy1)-1H-benzo[d]imidazole-1-carboxylate was re-sbjeeted to the similar conditions to the preparation of present intermediate to give (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[dlimidazol-4-y1)bis(2-methylpyridin-4-yOmethanol.
C28H27N502. MS. 466.2 (M+1). IFI NMR (Me0H-d4) 6 8.71 (d, J= 6.4 Hz, 2H), 7.93 (s, 2H), 7.84 (d, J= 6.4 Hz, 2H), 7.64 (d, J=1.0 Hz, 1H), 7.00 (d, J= 1.0 Hz, 1H), 2.76 (s, 6H), 2.60-2.50 (m, 1H), 2.35 (s, 3H), 2.17 (s, 3H), 1.56 ¨ 1.47 (m, 2H), 1.40 ¨ 1.35 (m, 2H).
Example 213 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yObis(3-methylpyridin-4-yOmethanol (1020-213) Step 1: Preparation of tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-(hydroxybis(3-methylpyridin-4-yl)methyl)-1H-benzoldjimidazole-1-carboxylate 7r,1 OMe Br N
t-BuLi el OH
Me-THF
0 0 <(----N

[00706] To a solution of 4-bromo-3-methylpyridine (167.2 mg, 0.972 mmol, 8 equiv) in Me-THF (1 mL) was treated with t-BuLi (1.42 M in hexane, 0.68 mL, 0.972 mmol, 8 equiv) at -78 C. After 10 min to the solution was added 1-tert-butyl 4-methyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazole-1,4-dicarboxylate (50.0 mg, 0.122 mmol) in Me-THF (2 mL). After 1 h stirring at rt, the reaction mixture was worked-up. The crude mixture was purified by a prep-HPLC to give tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(hydroxybis(3-methylpyridin-4-yl)methyl)-1H-benzo[d]imidazole-1-carboxylate. C33H35N504. MS. 566.3 (M+1).
Step 2: Preparation of (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)bis(3-methylpyridin-4-y1)methanol N
OH I TFA, rt el OH j\I
HN
0 <1.-7--N
, [00707] tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(hydroxybis(3-methylpyridin-4-ypmethyl)-1H-benzo[d]imidazole-1-carboxylate was treated with TFA
at rt to give (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-yl)bis(3-methylpyridin-4-yl)methanol.
[00708] C28H27N502. MS. 466.2 (M+1). NMR (Me0H-d4) 6 8.70 (br s, 1H), 8.58 (br s, 1H), 7.64 (d, J= 1.0 Hz, 1H), 7.48 (br s, 1H), 6.61 (d, J= 1.0 Hz, 1H), 2.40 (m, 1H), 2.30 (s, 6H), 2.30 (s, 3H), 2.09 (s, 3H), 1.45 ¨ 1.26 (m, 4H).
Example 214 Azi.

(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[cl]imidazol-4-y1)(2,5-dimethylpyridin-4-yl)methanone (1020-214) [00709] (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(2,5-dimethylpyridin-4-yl)methanone was synthesized in a similar fashion to Example 209, steps 1-2.
Step 1:

OMe t-BuLi -7-0 el N
Me-THF
0 0<N 0 [00710] C33H35N504. MS. 566.3 (M+1).
Step 2: Preparation of (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[djimidazol-4-y1)(2,5-dimethylpyridin-4-Amethanone -)--O N TFA, rt ______________________________________ w N
HN
0 0 <r-N 0 [00711] C23H22N402. MS. 378.2 (M+1). 1H NMR (Me0H-d4) 6 8.72 (s, 1H), 7.92 (s, 1H), 7.87 (s, 1H), 7.42 (s, 1H), 2.75 (s, 3H), 2.65-2.56 (m, 1H), 2.42 (s, 3H), 2.37 (s, 3H), 2.20 (s, 3H), 1.56 ¨ 1.40 (m, 4H).
Example 215 (2-eyelopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(6-(trifluoromethyppyridazin-3-yl)methanone (1020-215) [00712] (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)(6-(trifluoromethyppyridazin-3-yl)methanone was synthesized in a similar fashion to Example 209, steps 1-2.

/

F
F
/ F
Si ' IN
HN
0 NI"
<1----N
[00713] C21H16F3N502. MS. 428.1 (M+1). 1H NMR (Me0H-d4) 8 8.62 (d, J= 8.0 Hz, 1H), 8.49 (s, 1H), 8.44 (d, J= 8.0 Hz, 1H), 7.94 (s, 1H), 2.70-2.62 (m, 1H), 2.50 (s, 3H), 2.33 (s, 3H), 1.64¨ 1.44 (m, 4H).
Example 216 (2-eyelopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyridazin-3-yl)methanone (2010-216) [00714] (2-eyelopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyridazin-3-yl)methanone was synthesized in a similar fashion to Example 209, steps 1-2.

/
el ' IN
HN N"
<--------N 0 [00715] C201-117F3N502. MS. 360.1 (M+1). 1H NMR (Me0H-d4) 8 9.44 (d, J=
5.2 Hz, 1H), 8.52 (s, 1H), 8.43 (d, J= 9.0 Hz, 1H), 8.04 (dd, J= 8.6, 5.1 Hz, 2H), 7.93 (s, 1H), 2.73 ¨2.62 (m, 1H), 2.50 (s, 3H), 2.33 (s, 3H), 1.65 ¨ 1.44 (m, 4H) Example 217 ?AA

(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)bis(5-fluoropyridin-2-yl)methanol (2010-217) Step 1: Preparation of tert-butyl 4-(bis(5-fluoropyridin-2-y1)(hydroxy)methyl)-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzoldlimidazole-1-carboxylate Br IµV F
OMe IPrMgBr -7\---0 Of OH
N
0 toluene 0 <I rt N
[00716] 4-Fluruolo-2-bromopyridine (128.3 mg, 0.729 mmol, 10 equiv) was treated with isopropyl magnesiumbromide (2M, THF, 0.33 mL, 0.656 mmol, 9 equiv) in toluene (2 mL) at room temperature for 1 h. To the reation mixture was added 643,5-dimethylisoxazol-4-y1)-2-methy1-1H-benzo[d]imidazole-4-carboxylate (50.0 mg, 0.175 mmol) in toluene (1 mL) at room temperature. After 18 h stirring, the reaction mixture was worked-up. The crude mixture was purified by a prep-HPLC to give tert-butyl 4-(bis(5-fluoropyridin-2-y1)(hydroxy)methyl)-2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazole-1-carboxylate. C3 11429F2N502. MS. 574.2 (M+1).
Step 2: Preparation of (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yObis(5-fluoropyridin-2-yOmethanol N
OH I TFA
le OH NV
rt -N HN
N N
[00717] tert-Butyl 4-(bis(5-fluoropyridin-2-y1)(hydroxy)methyl)-2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazole-1-carboxylate was treated with TFA
(3 mL) at room temperature for 1 h. After removing of TFA, the mixture was purified by a prep-HPLC and a silica gel column chromatography (50 to100% Et0Ac/hexane) to give (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)bis(5-fluoropyridin-2-yOmethanol.
[00718] C26H21F2N502. MS. 474.1 (M+1). NMR (Me0H-d4) 6 8.43 (d, J= 2.8 Hz, 1H), 7.72 (dd, J= 8.6, 4.3 Hz, 1H), 7.64 (td, J= 8.6, 2.9 Hz, 1H), 7.50 (d, J= 1.5 Hz, 1H), 7.21 (d, J= 1.5 Hz, 1H), 2.62-2.54 (m, 1H), 2.35 (s, 3H), 2.17 (s, 3H), 1.56 ¨
1.48 (m, 2H), 1.42-1.34 (m, 2H).
Example 218 (6-(3,5-dimethylisoxazol-4-y1)-2-methy1-1H-benzo[d]imidazol-4-y1)bis(5-fluoropyridin-2-yOmethanol (1020-218) Step 1: Preparation of N4(3-methylisoxazol-5-y1)methyl)acetamide O¨N O¨N
NH HCI
AO
OMe ______________________________________ 11101 OMe H2N Me0H HN
NH2 0 70 C, 1 h 0 [00719] Methyl 2,3-diamino-5-(3,5-dimethylisoxazol-4-yl)benzoate (351.8 mg, 1.346 mmol) was treated with ethyl acetimidate hydrochloride in Me0H at 70 C
for 1 h.
After an aqueours work-up, the crude mixture was purified by a silica-gel column chromatography (20 to 40% Et0Ac/hexane) to give methyl 6-(3,5-dimethylisoxazol-y1)-2-methyl-1H-benzo[d]imidazole-4-carboxylate. Ci5Hi5N303. MS. 286.1 (M+1).
Step 2: Preparation of (6-(3,5-dimethylisoxazol-4-y1)-2-methy1-1H-benzo[d]imidazol-4-yl)bis(5-fluoropyridin-2-y1)methanol 7hR

O-N

O-N
Br 'LF F
OH INV I
1PrNigBr OMe _________________________________ HN
HN toluene )-="N
N
t---N 0 rt [00720] 4-Fluoro-2-bromopyridine (308.4 mg, 1.753 mmol, 10 equiv) was treated with isopropyl magnesiumbromide (2M, THF, 0.789 mL, 1.58 mmol, 9 equiv) in toluene (3 mL) at room temperature for 1 h. To the reation mixture was added 643,5-dimethylisoxazol-4-y1)-2-methy1-1H-benzo[d]imidazole-4-carboxylate (50.0 mg, 0.175 mmol) at room temperature. After 2 h stirring, the reaction mixture was worked-up. The crude mixture was purified by a prep-HPLC to give (6-(3,5-dimethylisoxazol-4-y1)-2-methy1-1H-benzokl]imida7o1-4-y1)bis(5-fluoropyridin-2-yOmethanol.
[00721] C24H19F2N502. MS. 448.1 (M+1). 1H NMR (Me0H-d4) 6 8.42 (d, J= 2.9 Hz, 1H), 7.72 (dd, J= 8.5, 5.8 Hz, 1H), 7.65 (dd, J= 8.5, 2.9 Hz, 1H), 7.61 (d, J= 1.6 Hz, 1H), 7.25 (d, J= 1.5 Hz, 1H), 2.84 (s, 2H), 2.36 (s, 2H), 2.18 (s, 2H).
Example 219 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)bis(5-methylthiazol-2-yemethanol (1020-219) O-N O-N
0 $ OH
Boc-N HN \
<r-N 0 N
S N N
[00722] To a solution of 5-methylthiazole (170 mg, 2.0 mmol) in THF (5 mL) was added butyllithium (96 mg, 1.5 mmol) and the solution was stirred at -78 C
for lh. To the solution of 1-tert-butyl 4-ethyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazole-1,4-dicarboxylate (212 mg, 0.50 mmol) in THF (5 mL) was added a 9hQ

solution of the lithiate prepared above at room temperature and the solution was stirred at room temperature for 4h. Water (2 mL) was added and the solution was stirred at room temperature for lh. Et0Ac (100 mL) was added and the organic solution was washed with brine and dried over Na2SO4. Solvent was removed and the residue was purified by silica gel column chromatography (0-50% Me0H/CH2C12) to give (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yObis(5-methylthiazol-2-yl)methanol.
[00723] C24H23N502S2. MS m/z 478.1 (M+1). NMR (Methanol-d4) 7.41 (d, J
= 24.1 Hz, 3H), 7.12 (s, 1H), 2.49¨ 2.40 (m, 6H), 2.34 (s, 3H), 2.26 (d, J=
15.4 Hz, 1H), 2.18 (s, 3H), 1.18 ¨ 1.07 (m, 4H).
Example 220 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyridin-y1)(thiazol-2-yOmethanol (1020-220) aOH/
NH S-N
p -N
[00724] (2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyridin-2-y1)(thiazol-2-y1)methanol was synthesized in a similar fashion as Example , 219.
[00725] C22Hi9N50252. 449.9 (M+1). 1H NMR (400MHz, CD30D) 6 8.47 (d, J =
1.6 Hz, 2H), 7.60 (d, J= 1.2 Hz, 1H), 7.35 (d, J= 1.6 Hz, 2H), 7.10 (d, J= 1.2 Hz, 1H), 2.68-2.64 (m, 1H), 2.33 (s, 3H), 2.18 (s, 3H), 1.57-1.51 (m, 2H), 1.44-1.39 (m, 2H).
Example 221 (2-cyclopronyl-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)bis(2-methylpyridin-3-yl)methanol (1020-221) 7'7n HN
/
[00726] (2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)bis(2-methylpyridin-3-y1)methanol was synthesized in a similar fashion as Example 219.
[00727] C28H27N502. 466.2 (M+1). 1H NMR (400MHz, CD30D) 6 8.48 (d, J =
4.4 Hz, 2H), 7.42 (s, 2H), 7.36 (bs, 3H), 6.38 (s, 1H), 2.44 (s, 6H), 2.23 (s, 3H), 2.18-2.11 (m, 1H), 2.03 (s, 3H), 1.17-1.13 (m, 2H), 1.08-1.05 (m, 2H).
Example 222 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzokliimidazol-4-y1)bis(2,6-dimethylpyridin-3-y1)methanol (1020-222) O-N
HN
HO
N¨

[00728] (2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)bis(2,6-dimethylpyridin-3-yl)methanol was synthesized in a similar fashion as Example 219.
[00729] C301-131N502. 494.3 (M+1). 1H NMR (400MHz, CD30D) 6 7.87-7.85 (m, 2H), 7.60 (s, 1H), 7.58 (s, 1H), 7.55 (d, J= 1.2 Hz, 1H), 6.72 (d, J= 1.2 Hz, 1H), 2.75 (s, 6H), 2.64 (s, 6H), 2.33 (s, 3H), 2.22-2.18 (m, 1H), 2.14 (s, 3H), 1.25-1.21 (m, 2H), 1.10-1.09 (m, 2H).
Example 223 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yObis(5-fluoropyridin-3-yl)methanol (1020-223) O-N

HN
F
N¨

[00730] (2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)bis(5-fluoropyridin-3-yl)methanol was synthesized in a similar fashion as Example 219.
[00731] C26H21F2N502. 474.0 (M+1). 1H NMR (400MHz, CD30D) 6 8.42 (d, J=
2.8 Hz, 2H), 8.32 (t, J= 1.6 Hz, 2H), 7.61-7.58 (m, 2H), 7.46 (d, J= 1.6 Hz, 1H), 6.79 (d, J= 1.2 Hz, 1H), 2.48-2.42 (m, 1H), 2.44 (s, 3H), 2.04 (s, 3H), 1.39-1.38 (m, 2H), 1.27-1.24 (m, 2H).
Example 224 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-7-fluoro-1H-benzo[d]imidazol-4-yl)di(pyridin-2-yemethanol (1020-224) Step 1: Methyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-7-fluoro-1H-benzoldlimidazole-4-carboxylate 1. >¨%
F TEA, CH2Cl2 JO
H N o 2. 150 C, AcOH HN 0 [00732] To a flask containing methy1-2,3-diamino-5-(3,5-dimethylisoxazol-4-y1)-4-fluorobenzoate (500 mg, 1.95mmol, 1 equiv.) is added 1,2 DCE (20 ml, 0.1M) and DIPEA (1.0 mL, 5.87 mmol, 3 equiv.). At 0 C, cyclopropanecarbonyl chloride (198 77?

L, 3.4 mmol, 1.1 equiv.) was added. After an hour, the reaction was complete.
The reaction was extracted with Et0Ac and washed with water and saturated NH4C1.
After drying with MgSO4, it was filtered and concentrated to dryness and used in the next reaction as crude methyl 2-amino-3-(cyclopropanecarboxamido)-5-(3,5-dimethylisoxazol-4-y1)-4-fluorobenzoate.
[00733] Into a microwave vial was placed methyl 2-amino-3-(cyclopropanecarboxamido)-5-(3,5-dimethylisoxazol-4-y1)-4-fluorobenzoate and to it added acetic acid (10 mL) and heated in the microwave for 150 C for 30 minutes. The reaction was concentrated down and extracted with Et0Ac and washed with water (3x), saturated NaHCO3 and brine. After drying with MgSO4, it was filtered and concentrated to dryness. Silica gel chromatography was carried out with Hexanes-Et0Ac to furnish methyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-7-fluoro-1H-benzo[d]imidazole-4-carboxylate (535 mg, 85%) as a light brown powder.
[00734] LCMS (m/z+1) 330.04 Step 2: (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-7-fluoro-1H-benzo[d]imidazol-4-y1)di(pyridin-2-y1)methanol BrN
F F
N
0 ___________________________________ HN n-BuLi HN OH

N
[00735] A flask containing 2-bromopridine (135 ,L, 1.37 mmol, 7 equiv.) and THF (3 mL) is cooled to -78 C before BuLi (0.86 mL, 1.37 mmol, 7 equiv.) is added.
After 30 min, methyl 6-(3,5-dimethylisoxazol-4-y1)-7-fluoro-2-oxo-2,3-dihydro-benzo[d]imidazole-4-carboxylate (60 mg, 0.197 mmol, 1 equiv.) dissolved in THF
(2 mL) is added to the reaction mixture. After completion, the reaction was quenched and extracted with Et0Ac and washed with water, saturated NH4C1. After drying with Mg504, it was filtered and concentrated to dryness. Purification was carried out by reverse phase HPLC to furnish (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-7-fluoro-rn 1H-benzo[d]imidazol-4-yl)di(pyridin-2-yOmethanol.
1007361 LCMS (m/z+1) 455.48. IFI NMR (400 MHz, Methanol-d4) 6 8.62 (ddd, J
= 5.1, 1.8, 0.9 Hz, 1H), 8.09 (ddd, J = 9.5, 6.5, 1.8 Hz, 1H), 7.88 (dq, J =
8.0, 1.5, 1.0 Hz, 1H), 7.58 (ddd, J = 7.4, 5.0, 1.3 Hz, 1H), 6.97 ¨6.67 (m, OH), 2.37 (td, J
= 8.9, 8.4, 4.2 Hz, 1H), 2.27 (s, 1H), 2.09 (s, 2H), 1.46¨ 1.14 (m, 2H). 19F NMR (377 MHz, Methanol-d4) 8 -77.94, -132.51.
Example 225 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-5-fluoro-1H-benzo[d]imidazol-4-yDdi(pyridin-2-yl)methanol (1020-225) Br Br _...).-0B-is,o1 /
N
* F si F 0 7 OH 0,, CH2Cl2 ' PEPPSI-!Pr F0 NH2 0 Me0H NH2 0 Cs2003 =HCI DMF, H20 NH2 0 step 1 step 2 N-0 N-0 1. >--io / /
/ /

BF4-N102+ SnCl2 TEA, CH2Cl2 Of F
_____ 1... . F ___________________________________ 1.
TFA Et0H F 2. 15000 AcOH 0,.

step 3 02N -, step4 H2N step 5-6 <--=-N

Step 1: Methyl 6-amino-3-bromo-2-fluorobenzoate 100737] Into a flask 6-amino-3-bromo-2-fluorobenzoic acid. HC1. salt, (6000 mg, 22 mmol, 1 equiv.), DCM (75 mL) and Me0H (20 mL) is added Trimethylsilyldiazomethane (22 mL, 44 mmol, 2 equiv.) slowly over 5 min. After an hour the reaction is quenched with 1N HCL (3 mL) and concentrated in vacuo.
DCM is added and the reaction is washed with a solution of sodium bicarbonate and water and NH4C1 solution. After drying with MgSO4, it was filtered and concentrated to dryness.
The material is used as is without further purification to methyl 6-amino-3-bromo-2-fluorobenzoate.

[00738] 1H NMR (400 MHz, Chloroform-d) 6 7.20 (dd, J = 8.9, 7.1 Hz, 1H), 6.37 -6.18 (m, 1H), 3.77 (s, 3H). 19F NMR (377 MHz, Chloroform-d) 8 -99.18 (d, J =
7.0 Hz).
Step 2: Methyl 6-amino-3-(3,5-dimethylisoxazol-4-y1)-2-fluorobenzoate [00739] Methyl 6-amino-3-bromo-2-fluorobenzoate (5100 mg, 20.56mol, 1 equiv.), 3,5-dimethylisoxazole-4-boronic acid, pinacol ester (6880 mg, 30.84 mmol, 1.5 equiv.), Pd(PH3)4 (1155 mg, 1.03 mmol, 0.05 equiv.), cesium carbonate (20098 mg, 61.68 mmol, 3 equiv.) in 150mL DME:H20 (2:1) were stirred and heated to 13 C
in a pressure tube. The reaction was then cooled and partitioned between water and ethyl acetate. The organic layer was washed with water then brine and dried over sodium sulfate. Purification on silica gel (Hex/Et0Ac) afforded methyl 6-amino-3-(3,5-dimethylisoxazol-4-y1)-2-fluorobenzoate.
[00740] LCMS (m/z+1) 265.30. 1H NMR (400 MHz, Chloroform-d) 7.03 (dd, = 8.6, 7.6 Hz, 1H), 6.54 (dd, J = 8.5, 1.1 Hz, 1H), 3.92 (s, 3H), 2.31 (d, J =
0.9 Hz, 3H), 2.18 (d, J = 0.9 Hz, 3H). 19F NMR (377 MHz, Chlorofonn-d) 6 -106.99 (d, J =
7.5 Hz).
Step 3 and 4: Methyl 2,3-diamino-5-(3,5-dimethylisoxazol-4-y1)-6-fluorobenzoate [00741] Methyl 6-amino-3-(3,5-dimethylisoxazol-4-y1)-2-fluorobenzoate (1400 mg, 5.29 mmol) was dissolved in TFA (20 mL) and cooled to 0 C under argon. To this was slowly added Nitronium tetrafluoroborate (13.7 mL, 6.89 mmol, 1.3 equiv., 0.5M
sulfolane) slowly over 20 minutes. The reaction was stirred at 0 C, then after 1 hour was allowed to warm and react overnight. Reaction solvents were removed under reduced pressure and the residue taken up Et0Ac and washed with aq. NaHCO3, then water, brine and dried over sodium sulfate before removing solvents under reduced pressure to yield a dark red oil/liquid. This material was taken up in 20 mL ethanol and stannous (II) chloride (2.50 g, 13.25 mmol, 2.5 equiv.) and heated to 110 C in a pressure tube.
After 2 hr. the reaction was allowed to cool and to it added NaOH (10 mL, 1 N) and stirred for an additional 10 min and the solvents removed under reduced pressure. The residue was taken up Et0Ac and washed with aq. NaHCO3, then water, brine and dried over sodium sulfate before removing solvents under reduced pressure. Crude residue was purified by silica gel chromatography (Hex/Et0Ac as the eluent) to afford methyl-2,3-diamino-5-(3,5-dimethylisoxazol-4-y1)-6-fluorobenzoate (1.63 g 41% yield) as a light coloured oil.
[00742] LCMS (m/z+1) 280.2 Step 5 and 6: tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-formy1-benzo[d]imidazole-1-carboxylate [00743] To a flask containing Methyl 2,3-diamino-5-(3,5-dimethylisoxazol-4-y1)-6-fluorobenzoate] (150 mg, 0.53 mmol, 1 equiv.) is added 1,2 DCE (10 ml, 0.1M) and DIPEA (0.44mL, 1.53 mmol, 3 equiv.). At 0 C, cyclopropanecarbonyl chloride (38 uL, 0.58 mmol, 1.1 equiv.) was added. After an hour, the reaction was complete.
The reaction was extracted with Et0Ac and washed with water and saturated NH4C1.
After drying with MgSO4, it was filtered and concentrated to dryness and used in the next reaction as methyl 3-amino-2-(cyclopropanecarboxamido)-5-(3,5-dimethylisoxazol-y1)-6-fluorobenzoate.
[00744] Into a microwave vial was placed methyl 3-amino-2-(cyclopropanecarboxamido)-5-(3,5-dimethylisoxazol-4-y1)-6-fluorobenzoate and to it added acetic acid (10 mL) and heated in the microwave for 150 C for 30 minutes. The reaction was concentrated down and extracted with Et0Ac and washed with water (3x), saturated NaHCO3 and brine. After drying with MgSO4, it was filtered and concentrated to dryness. Silica gel chromatography was carried out with Hexanes-Et0Ac to furnish methyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-7-fluoro-1H-benzo[d]imidazole-4-carboxylate (97 mg, 55%) as a light brown powder.
[00745] LCMS (m/z+1) 330.04 Step 7:

401 F BuLi, 2-Bromopyridine N
I

HN -78 C, THF HN
N H O
N
I
'1'7A

[00746] A flask containing 2-bromopridine (60 uL, 0.61 mmol, 8 equiv) and THF
(3 mL) is cooled to -78 C before BuLi (0.38 mL, 0.61 mmol, 8 equiv.) is added.
After 30 min, methyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-5-fluoro-1H-benzo[d]imidazole-4-earboxylate (25 mg, 0.076 mmol, 1 equiv.) dissolved in THF
(2 mL) is added to the reaction mixture. After completion, the reaction was quenched and extracted with Et0Ac and washed with water followed by saturated NH4C1. After drying with MgSO4, it was filtered and concentrated to dryness. Purification was carried out by reverse phase HPLC to furnish (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-5-fluoro-1H-benzo[d]imidazol-4-yl)di(pyridin-2-yl)methanol.
[00747] LCMS (m/z+1) 455.48. 11-1 NMR (400 MHz, Methanol-d4) 6 8.63 (ddd, J
= 5.1, 1.9, 0.9 Hz, 1H), 8.02 (td, J = 8.1, 2.0 Hz, 1H), 7.64 (dd, J = 8.1, 1.2 Hz, 1H), 7.60 ¨7.42 (m, 1H), 2.58 (d, 3= 4.7 Hz, OH), 2.27 (s, 2H), 2.07 (s, 1H), 1.49 (dd, J = 8.3, 3.0 Hz, 1H), 1.34 (dd, J = 4.9, 2.7 Hz, 1H). 19F NMR (376 MHz, Methanol-d4) 6 -77.91.
Example 226 (2-cyclopropy1-5-(3,5-dimethylisoxazol-4-y1)-1-methyl-1H-benzo[d]imidazol-7-yl)di(pyridin-2-y1)methanol (1020-226) Br N
MeNH2 B r2 K2C 03 1101 AcOH 0 02N le C) CH2Cl2 02N

PEPPSI-IPr NH 0 Cs2CO3 110 C, 1h SnCl2 H2N (") 50 C N\N 0 0 , NH 0 Step 1:

[00748] To a stirred solution of methyl 2-f1uoro-3-nitrobenzoate (1 g, 5 mmol) in DCM (10 mL), potassium carbonate (1.38 g, 10 mmol) was added at room temperature.
To the reaction was then added methylamine in THF (20 mL, 40 mmol, 2M). The progress of reaction was monitored by LCMS which shows complete conversion of methyl 2-fluoro-3-nitrobenzoate, Reaction was diluted with water (50mL) then extracted with DCM (50 mL). Organic was condensed to give methyl 2-(methylamino)-3-nitrobenzoate (1 g, 95%) Step 2:
[00749] To a stirred solution of methyl 2-(methylamino)-3-nitrobenzoate (2 g, 10 mmol) in acetic acid (14 mL) bromine (0.49 mL, 10 mmol) in acetic acid (2 mL) was added. Reaction was stirred at rt for 30 min. The reaction was complete by LCMS and then was poured on ice (-100 g). The resulting solid was filtered and dried on high vac to give methyl 5-bromo-2-(methylamino)-3-nitrobenzoate (2.6 g, 94%) as a orange solid.
Step 3:
[00750] To a stirred solution of methyl 5-bromo-2-(methylamino)-3-nitrobenzoate (1.5 g, 5.2 mmol) in 1,2-deimethoxyethane (15 mL) and water (3 mL), 3,5-dimethy1-4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-yl)isoxazole (2.1 g, 9.3 mmol) was added, followed by cesium carbonate (2.8 g, 8.6 mmol). After addition was completed, resulting reaction mixture was stirred at rt for 30 mm. followed by degas with argon for 15 min.
TM
Then PEPPSI-IPr catalyst (0.2 g, 0.2 mmol) was added and again reaction mixture was degas with argon for another 15 mm, Then resulting reaction mixture was heated to stir at 110 C for 1 h under argon atmosphere. Reaction monitored by LCMS till completion.
Reaction was cooled to rt then diluted with Et0Ac (25 mL) and water (15 mL).
Et0Ac (25 mL) was used twice to extract product. Organic layers were combined and dried with magnesium sulfate and condensed. The resulting mixture was purified via noimal phase 0-25% (Et0Ac/Hexanes) to give methyl 5-(3,5-dimethylisoxazol-4-y1)-2-(methylamino)-3-nitrobenzoate (1.5 g, 38%) Step 4:
[00751] To a stirred solution of methyl 5-(3,5-dimethylisoxazol-4-y1)-2-(methylamino)-3-nitrobenzoate (0.6 g, 2 mmol) in Et0H (15 mL) stannous chloride (1.87 g, 10 mmol) was added at room temperature. Then resulting reaction mixture was heated to stir at 60 C for 1 h under argon atmosphere reaction was monitored by LCMS
to be complete. Material was condensed to a dark solid, then slurried in Et0Ac. This was then filtered thru celite and condensed down to give methyl 3-amino-5-(3,5-dimethylisoxazol-4-y1)-2-(methylamino)benzoate (0.5 g 99%).
Step 5:
[00752] To a stirred solution of methyl 3-amino-5-(3,5-dimethylisoxazol-4-y1)-2-(methylamino)benzoate (6.5 g, 24.0 mmol) in Me0H (125 mL), ethyl cyclopropanecarbimidate hydrochloride (4.2 g, 30 mmol) was added. The reaction was then heated to 50C overnight. The reaction was then condensed down and coevaporated with Toluene (100 mL) to give methyl 2-cyclopropy1-5-(3,5-dimethylisoxazol-4-y1)-1-methyl-1H-benzo[d]imidazole-7-carboxylate (7.5 g, 98%) Step 6: (2-cyclopropy1-5-(3,5-dimethylisoxazol-4-y1)-1-methyl-1H-benzo[d]imidazol-7-yl)di(pyridin-2-yOmethanol BrN
le Or C). n-BuLi N
I
[00753] 2-bromopyridine (0.18 mL, 1.84 mmol) was dissolved in THF (22 mL) and cooled to -78 C. n-BuLi (1.28 mL, 2.02 mmol, 1.6 M) was added dropwise and the reaction was allowed to stir for 30 minutes at -78 C methyl 2-cYclopropy1-5-(3,5-dimethylisoxazol-4-y1)-1-methyl-1H-benzo[d]imidazole-7-carboxylate (150 mg, 0.46 mmol) in THF (3 mL) was added. The reaction was allowed to stir at rt for 1 hour. The reaction was monitored by LCMS and when complete it was quenched with water (50 mL) and Et0Ac (50 mL) the organic layer was extracted and condensed to an light oil.
The oil was purified by RPHPLC 0-50% (Acetonitrile/water) to give (2-cyclopropy1-5-(3 ,5-dimethylisoxazol-4-y1)-1-methy1-1H-benzo [d]imidazol-7-yl)di(pyridin-2-yl)methanol (110 mg, 54%) [00754] C27H25N502 MS = 452.21 (M + H+). NMR (400 MHz, Methanol-d4) 6 8.58 (ddd, J = 5.0, 1.8, 0.9 Hz, 2H), 7.95 -7.86 (m, 2H), 7.62- 7.51 (m, 3H), 7.44 (ddd, J = 7.6, 4.9, 1.1 Hz, 2H), 6.50 (d, J = 1.6 Hz, 1H), 3.67 (d, J = 13.5 Hz, 3H), 2.42-2.34 (m, 1H), 2.25 (s, 3H), 2.07 (s, 3H), 1.46- 1.39 (m, 2H), 1.32- 1.23 (m, 2H).
Example 227 (2-cyclopropy1-5-(3,5-dimethylisoxazol-4-y1)-1-methyl-1H-benzo[d]imidazol-7-y1)(pyridin-2-y1)(pyrimidin-2-yl)methanol (1020-227) 0,N
NaOH
Me0H
=HCI

OH
0=-. la %1 HATU'' Br N
n-BuLi N 0 THF
Step 1:
[00755] To a stirred solution of methyl 2-cyclopropy1-5-(3,5-dimethylisoxazol-4-y1)-1-methy1-1H-benzo[d]imidazole-7-carboxylate (4.5 g, 14 mmol) in Me0H (100 mL) was added sodium hydroxide (1.2 g, 30 mmol). The reaction was heated to 40C
overnight under an atmosphere of argon. The reaction was monitored by LCMS and was complete. The reaction was then condensed down to a solid to give 2-cyclopropy1-5-(3,5-dimethylisoxazol-4-y1)-1-methyl-1H-benzo[d]imidazole-7-carboxylic acid (4.1 g, 95%) Step 2:
[00756] 2-cyclopropy1-5-(3,5-dimethylisoxazol-4-y1)-1-methyl-1H-12n benzo[d]imidazole-7-carboxylic acid (1.2 g, 3.9 mmol) in DMF (15 mL) with HATU

(1.76 g, 4.6 mmol) for 15mins, then added N,0-dilmethylhydroxylamine HC1 salt (0.56 g, 5.8 mmol) and DIPEA (3.1 mL, 22 mmol), stirred at RT overnight. Diluted with Et0Ac, washed with brine, backextracted with Et0Ac 4 times, evaporated organic solvent, purified with normal phase 0-100% (Et0Ac/Hexanes) to give 2-cyclopropy1-5-(3 ,5-dimethylisoxazol-4-y1)-N-methoxy-N,1 -dimethy1-1H-b enzo [d]imidazole-7-carboxamide (1 g, 73%) Step 3:
[00757] 2-bromopyridine (0.80 mL, 8.4 mmol) was dissolved in THF (35 mL) and cooled to -78 C. n-BuLi (6.2 mL, 10.0 mmol, 1.6 M) was added dropwise and the reaction was allowed to stir for 1 hour at -78 C. 2-cyclopropy1-5-(3,5-dimethylisoxazol-4-y1)-N-methoxy-N,1-dimethyl-1H-benzo[d]imidazole-7-carboxamide (0.5 g, 1.4mmol) in THF (5 mL) was added and the reaction was allowed to come to 0 C and stir for 15 minutes before being quenched with water. Reaction was diluted with Et0Ac, washed twice with brine, concentrated, and purified by silica gel chromatography to give (2-cyclopropy1-5 -(3 ,5-dimethylisoxazol-4-y1)-1-methy1-1H-benzo [d]imidazol-7-yl)(pyridin-2-yl)methanone (0.46 g, 88%) Step 4: (2-cyclopropy1-5-(3,5-dimethylisoxazol-47y1)-1-methyl-1H-benzo[d]imidazol-7-y1)(pyridin-2-y1)(pyrimidin-2-yOmethanol 11101 Br N, N _________________________________________________ 7. I
.(2--N 0 n-BuLi THF N N

[00758] (2-cyclopropy1-5-(3,5-dimethylisoxazol-4-y1)-1-methy1-1H-benzo[d]imidazol-7-y1)(pyridin-2-y1)(pyrimidin-2-y1)methanol was synthesized using 2-bromopyrimidine and (2-cyclopropy1-5-(3,5-dimethylisoxazol-4-y1)-1-methyl-1H-benzo[d]imidazol-7-y1)(pyridin-2-yl)methanone in a similar fashion as Example No. 1 [00759] C26H24N602 MS = 453.23 (M + H+). 1H NMR (400 MHz, Methanol-d4) 6 9.21 (dd, J= 4.9, 1.6 Hz, 1H), 8.63 ¨ 8.60 (m, 1H), 8.06¨ 7.96 (m, 2H), 7.92 (td, 7.8, 1.8 Hz, 1H), 7.87 ¨ 7.78 (m, 2H), 7.62 (d, J= 1.6 Hz, 1H), 7.51 (dt, J=
8.0, 1.0 Hz, 1H), 7.46 (ddd, J= 7.6, 4.9, 1.1 Hz, 1H), 6.53 (d, J= 1.6 Hz, 1H), 3.92 (s, 1H), 3.67 (d, J
= 11.2 Hz, 3H), 2.47 ¨ 2.33 (m, 3H), 2.26 (s, 3H), 2.08 (s, 3H), 1.49¨ 1.36 (m, 3H), 1.28 (dt, J= 6.5, 3.4 Hz, 3H).
Example 228 (2-cyclopropy1-5-(3,5-dim ethylisoxazol-4-y1)-1-m ethy1-1H-benzo [d] imidazol-yl)(pyridazin-3-y1)(pyridin-2-yl)methanol (1020-228) N
NN- N la OH I
N
____________________________________ ' LiTMP
n-BuLi THF
= N
[00760] 2,2,6,6-Tetramethylpiperidine(0.15 mL, 0.88 mmol) in THF (4 mL) was cooled to -78C, n-BuLi (0.50 mL, 0.80 mmol) was added and the reaction was allowed to stir at OC for 1 hr. The reaction was cooled to -78C and pyridazine (0.06 mL, 0,80 mmol) was added. The reaction was stirred for 5 minutes and to this was added (2-cyclopropy1-5-(3,5-dimethylisoxazol-4-y1)-1-methyl-1H-benzo[d]imidazol-7-yl)(pyridin-2-yl)methanone (100 mg, 0.27 mmol) in THF (1 mL). The reaction was allowed to warm to rt then quenched with 1M HC1 (5 mL) the reaction was tehn concentrated and TFA (2 mL) was added and concentrated again to a light yellow oil.
The reaction was then purified vial RPHPLC 0-60% (Acetonitrile/water) to give (2-cyclopropy1-5-(3,5-dimethylisoxazol-4-y1)-1-methyl-1H-benzo[d]imidazol-7-yl)(pyridazin-3-y1)(pyridin-2-yl)methanol.
[00761] C26H24N602 MS = 453.32 (M + H+). 1H NMR (400 MHz, Methanol-d4) 6 8.85 (d, J = 4.9 Hz, 2H), 7.94 (ddd, J = 8.0, 7.6, 1.8 Hz, 1H), 7.70 (dt, J =
8.0, 1.0 Hz, 1H), 7.61 (d, J = 1.6 Hz, 1H), 7.50 (t, J = 4.9 Hz, 1H), 7.44 (ddd, J = 7.5, 4.9, 1.1 Hz, 1H), 6.48 (d, J = 1.6 Hz, 1H), 3.71 (s, 3H), 2.40 (tt, J = 8.5, 5.2 Hz, 1H), 2.26 (s, 3H), 2.08 (s, 3H), 1.50 ¨ 1.39 (m, 3H), 1.30 (ddt, J = 5.8, 4.8, 1.9 Hz, 3H).
2.9 Example 229 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)di(thiophen-2-yl)methanol (1020-229) Brs, 1) nBuLi, -780 Boc,N 1.1 0 2) TFA le OH s HN \
V S
[00762] (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)di(thiophen-2-yl)methanol was synthesized using 1-tert-butyl 4-methyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazole-1,4-dicarboxylate and 2-bromothiophene in a similar fashion to Example 206.
[00763] C24H21N302S2 MS 447.80 (M + Fr). 1H NMR (400 MHz, Methanol-d4) 6 7.48 (d, J= 1.4 Hz, 1H), 7.44 (dd, J= 5.0, 1.3 Hz, 1H), 7.04 ¨ 6.94 (m, 3H), 6.90 (s, 1H), 3.75 (s, 1H), 3.65 (s, 1H), 2.32 (s, 2H), 2.14 (s, 3H), 1.45 (s, 2H), 1.34 (d, J=
7.6 Hz, 3H).
Example 230 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(furan-2-y1)(pyridin-2-yl)methanol (1020-230) [00764] The title compound was synthesized in a similar fashion as that of Example 106, step 2.

)---0 n-BuLi OH
THF HNI.

[00765] C25H22N403. MS. 427.1 (M+1). 1H NMR (Me0H-d4) 6 8.00 (td, J= 8.0, 1.9 Hz, 1H), 7.78 (d, J= 8.0 Hz, 1H), 7.60 (dd, J= 4.8, 1.0 Hz, 1H), 7.54 (d, J= 1.9 Hz, 1H), 7.49 (ddd, J= 8.0, 4.8, 1.0 Hz, 1H), 7.08 (d, J= 1.9 Hz, 1H), 6.47 (dd, J= 4.8, 1.6 Hz, 1H), 6.19 (dd, J= 4.8, 1.0 Hz, 1H), 2.65-2.56 (m, 1H), 2.36 (s, 3H),2.18 (s, 3H), 1.60-1.34 (m, 4H).
Example 231 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyridin-y1)(5-(trifluoromethyl)thiophen-2-yl)methanol (1020-231) [00766] The title compound was synthesized in a similar fashion as that of Example 106, step 2.

/ F
n-BuLi el OH
THF _____________________________________ r-HN

-N 0 -78 C <r-N
S
F F
[00767] C26H21F3N402S. MS. 511.1 (M+1). 1H NMR (Me0H-d4) 6 8.64 (td, J=
4.8 Hz, 1H), 7.92 (td, J= 8.0, 1.6 Hz, 1H), 7.81 (d, J= 8.0 Hz, 1H), 7.53 (d, J= 1.6 Hz, 1H), 7.46-7.40 (m, 2H), 7.22 (d, J= 1.6 Hz, 1H), 7.03 (d, J= 4.8 Hz, 1H), 2.68-2.60 (m, 1H), 2.34 (s, 3H), 2.16 (s, 3H), 1.60-1.48 (m, 2H), 1.44-1.34 (m, 2H).
Example 232 (5-chlorothiophen-2-y1)(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyridin-2-yl)methanol (1020-232) [00768] The title compound was synthesized in a similar fashion as that of Example 106, step 2.

BrçSCl n-BuLi el OH
HN
j--:"-N 0 Me-THF
-78 C Z Sc, [00769] C25H21 C1N402S. MS. 477.1 (M+1). 1H NMR (Me0H-d4) 6 8.62 (d, J=
4.8 Hz, 1H), 7.91 (td, J= 8.0, 1.6 Hz, 1H), 7.78 (d, J= 8.0 Hz, 1H), 7.52 (d, J= 1.6 Hz, 1H), 7.41 (dd, J= 6.7, 4.8 Hz, 1H), 7.21 (d, J= 1.6 Hz, 1H), 6.88 (d, J= 3.2 Hz, 1H), 6.73 (d, J= 3.2 Hz, 1H), 2.67-2.58 (m, 1H), 2.36 (s, 3H), 2.18 (s, 3H), 1.60-1.48 (m, 2H), 1.44-1.34 (m, 2H).
Example 233 Benzofuran-2-y1(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanol (1020-233) [00770] The title compound was synthesized in a similar fashion as that of Example 106, step 2.

Br 0 \ AL
n-BuLi el OH
O HN
Me-THF
<r-N

[00771] C29H24N403. MS. 477.2 (M+1). 1H NMR (Me0H-d4) 6 8.60 (d, J= 4.8 Hz, 1H), 7.96 (td, J= 6.4, 1.6 Hz, 1H), 7.84 (d, J= 6.4 Hz, 1H), 7.57 (d, J=
6.4 Hz, 1H), 7.54 (d, J= 1.6 Hz, 1H), 7.46 (dd, J= 6.4, 4.8 Hz, 1H), 7.42 (d, J= 6.4 Hz, 1H), 7.30 (d, J= 6.4 Hz, 1H), 7.24 (d, J= 6.4 Hz, 1H), 7.18 (d, J= 1.6 Hz, 1H), 6.60 (s, 1H), 1.60-1.30 (m, 4H).
Example 234 (2-Cyclopropyl-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyridin-y1)(quinolin-7-yOmethanol (1020-234) [00772] The title compound was synthesized in a similar fashion as that of Example 106, step 2.
N-0 Br N-0 n-BuLi el OH
HN
ON
0 Me-THF *

[00773] C30H25N502. MS. 488.2 (M+1). 1H NMR (Me0H-d4) 8 8.75 (dd, J= 4.3, 1.7 Hz, 1H), 8.71 (d, J= 8.7 Hz, 1H),.8.66 (d, J= 4.6 Hz, 1H), 8.02 (d, J= 8.5 Hz, 1H), 7.81 (td, J= 7.9, 1.8 Hz, 1H), 7.57 (dd, J= 8.5, 7.3 Hz, 1H), 7.47 ¨7.34 (m, 3H), 7.28 (dd, J= 8.8, 4.3 Hz, 1H), 6.84 (dd, J= 7.4, 1.1 Hz, 1H), 6.31 (d, J= 1.5 Hz, 1H), 2.24 ¨
2.14 (m, 1H), 2.05 (s, 3H), 1.84 (s, 3H), 1.17 ¨ 1.06 (m, 4H).
Example 235 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyridin-y1)(m-tolypmethanol (1020-235) Br 3 eq.
tert-butyllithium (6 eq.) 140 41) THF HN
0 C, 45 min 0 .(r-N HO N /
[00774] In a 2-neck, 50-mL round bottom flask, a solution of 3-bromotoluene (30 L, 0.25 mmol) stirring in tetrahydrofuran (2 mL) was cooled to -78 C in a dry ice/acetone bath. A 1.47 M tert-butyllithium solution in pentane (330 iLtL, 0.48 mmol) was added dropwise and the reaction mixture was stirred at -78 C for 15 minutes. In a solution of 1 mL of tetrahydrofuran, tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-picolinoy1-1H-benzo[d]imidazole-1-carboxylate (36.8mg, 0.0803 mmol) was added dropwise and the reaction mixture was waimed to room temperature. The reaction was complete after fifteen minutes and quenched with brine and diluted with ethyl acetate. The organic layer was separated and saved and the aqueous layer was back-extracted three times with ethyl acetate. The organic layers were combined, dried over sodium sulfate, decanted and concentrated. The crude reaction mixture was isolated by preparatory TLC to yield the title compound (19.4, 54%).
[00775] C28H26N402. 451.2 (M+1). Rf= 0.15 (1:1 Ethyl Acetate:Hexane). 1H
NMR (400 MHz, Chlorofoim-d) 6 8.81 (d, J= 5.5 Hz, 1H), 8.25 (t, J= 8.0 Hz, 1H), 7.84 (dd, J= 7.4, 5.5 Hz, 1H), 7.65 (d,./ = 1.4 Hz, 1H), 7.48 (d, J= 7.9 Hz, 1H), 7.29¨ 7.26 (m, 2H), 7.00 (d, J= 1.9 Hz, 1H), 6.91 (dd, J= 5.8, 2.4 Hz, 1H), 6.76 (d, J=
1.4 Hz, 1H), 2.43 (td, J= 8.5, 4.4 Hz, 1H), 2.30 (s, 3H), 2.27 (s, 3H), 2.07 (s, 3H), 1.60¨ 1.47 (m, 2H), 1.41 (dd, J= 8.5, 4.5 Hz, 2H).
Example 236 cyclopenty1(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanol (1020-236) Boc-N
HN

'N
101 'N
<r-N HO 40 [00776] tert-Butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-picolinoy1-1H-benzo[d]imidazole-1-carboxylate (35 mg, 0.076 mmol) was dissolved in 5m1 THF, to the reaction flask was added cyclopropylmagnesium bromide at RT. The reaction mixture was stirred at RT overnight. Then it was quenched with water. To the work-up mixture was added lml of TFA, heated to 70 C for lh. Then the solvent was evaporated, the residue was purified with Prep HPLC to afford cyclopenty1(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyridin-2-yOmethanol.

[00777] C26H28N402. 429.1 (M+1). 1H NMR (400 MHz, CD30D) 8.49-8.48 (m, 1H), 7.78-7.76 (m, 2H), 7.57 (s, 1H), 7.31 (s, 1H), 7.27-7.24 (m, 1H), 3.40-3.36 (m, 1H), 2.55-2.52 (m, 1H), 2.30 (s, 3H), 2.13 (s, 3H), 1.58-1.50 (m, 6H), 1.44-1.42 (m, 2H), 1.18-1.08 (m, 4H).
Example 237 Cyclopropy1(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyridin-2-y1)methanol (1020-237) N 1>¨MgBr THF
la OH
HN HN
NO
[00778] Cyclopropylmagnesium bromide (0.9 mL, 0.45 mmol) was added to a solution of (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyridin-2-yl)methanone (40 mg, 0.11 mmol) in THF (1.2 mL) at room temperature and allowed to stir for 30 minutes before being quenched with water, concentrated, and purified by reverse-phase HPLC to afford cyclopropy1(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyridin-2-yOmethanol [00779] C24E1241\1402 401.4 (M+1). NMR (400 MHz, DMSO-d6) 8 8.53 (dt, J
= 4.8, 1.3 Hz, 1H), 7.95 -7.87 (m, 2H), 7.61 (d, J= 1.5 Hz, 1H), 7.49 (s, 1H), 7.36 (ddd, J= 7.1, 5.0, 2.3 Hz, 111), 2.61 (d, J= 5.0 Hz, 111), 2.42 (s, 311), 2.23 (s, 3H), 2.17 (s, 1H), 1.42 - 1.24 (m, 4H), 0.70 -0.40 (m, 4H).
Example 238 and 239 (R) and (S)-(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyridin-2-y1)(pyrimidin-2-yl)methanol ?RR

fa OH -N\
HN
<r-N
N
[00780] The enantiomers described by compound 1020-108 were separated by a chiral column (DAICEL, ChiralPak AD-H, Heptane/IPA 70:30) to afford the following enantiomers.
First eluting compound is 1020-238; the second eluting compound is 1020-239.
Example 240 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(1H-imidazol-2-y1)(pyridin-2-yl)methanol (1020-240) Step 1: Preparation of (1-(tert-butyldimethylsily1)-1H-imidazol-2-y1)(2-cyclopropyl-6-(3 ,5-dim ethylisoxazol-4-y1)-1H-benzo [d]imidazol-4-y1)(pyridin-2-y1)methanol O-N O-N
\Z-Boc-N N HN \
<r-N 0 <rN
NN
[00781] To a solution of N-TBS imidazole (16 mg, 0.087 mmol) in THF (5 mL) was added LiBu (0.044 mmol) and the solution was stirred at -78 C for lh. To the solution was added tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-picolinoy1-1H-benzo[d]imidazole-l-carboxylate (20 mg, 0.044 mmol) in THF (3 mL). The reaction solution was stirred at room temperature for lh. Et0Ac (100 mL) was added and the organic solution was washed with brine and dried over Na2SO4. Solvent was removed and the residue was purified by silica gel column chromatography (0-50%
Me0H/CH2C12) to give fraction containing (1-(tert-butyldimethylsily1)-1H-imidazol-2-yl)(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyridin-2-yOmethanol identified by LCMS, which was used for the next deprotection without further purification.
Step 2: (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(1H-imidazol-2-y1)(pyridin-2-y1)methanol 1101 OH r\i 1110 OH H
N
HN \ HN
NN
NN
<r-N
N
[00782] To a solution of crude (1-(tert-butyldimethylsily1)-1H-imidazol-2-y1)(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyridin-2-yOmethanol in THF (5 mL) was added TBAF (0.029 g, 0.11 mmol) and the solution was stirred at room temperature for 20h. Solvent was removed and the residue was purified by HPLC to give (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[djimidazol-4-y1)(1H-imidazol-2-y1)(pyridin-2-y1)methanol.
1007831 C24H22N602. MS m/z 427.1 (M+1). IFI NMR (Methanol-d4) 6 8.76 (dd, J
= 2.4, 0.8 Hz, 1H), 8.71 (dd, J=5.1, 1.5 Hz, 1H), 8.15 (ddd, J= 8.2, 2.4, 1.5 Hz, 1H), 7.69 (ddd, J= 8.2, 5.1, 0.8 Hz, 1H), 7.65 - 7.50 (m, 3H), 7.12 (d, J= 1.4 Hz, 1H), 2.45 (tt, J= 8.4, 5.0 Hz, 111), 2.36 (s, 314), 2.18 (s, 3H), 1.41 (dd, J= 8.4, 1.7 Hz, 2H), 1.28 (ddd, J= 7.8, 3.6, 1.8 Hz, 3H).
Example 241 and 242 1-(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)-2,2-dimethylpropan-1-one (1020-241) and 3-(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)-2,2,4,4-tetramethylpentan-3-ol (1020-242) ?AO

la t-BuMgCI

THF la 0 OH
HN HN HN
O
[007841 In a flame dried flask containing methyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazole-4-earboxylate (50 mg, 0.16 mmo1) in THF was added tert-Butyl Magnesium Chloride (1.6 mL, 1.6 mmol) in THF. The reaction was allowed to run for 24 hours. Once complete, the solution was quenched with DI H20 and extracted three times with Et0Ac. The combined organic layers were washed with saturated NaC1, dried over sodium sulfate, filtered and concentrated in vacua Purification was carried out by reverse phase HPLC to afford 1-(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)-2,2-dimethylpropan-1-one. In some cases, the ketone, secondary, and tertiary alcohol were isolated and characterized.
[00785] Compound 1020-241: C20H23N302. MS. m/z 338.5 (M+1). 1H NMR (400 MHz, cd3od) 6 7.73 (s, 1H), 7.59 (s, 1H), 2.43 (s, 3H), 2.27 (s, 3H), 1.28 (dd, J= 30.6, 6.8 Hz, 1H), 1.17 (d, J = 7.0 Hz, 4H).
[00786] Compound 1020-242: C24H33N302. MS. m/z 396.3 (M+1)11-1 NMR (400 MHz, cd3od) 6 7.29 (d, J= 6.7 Hz, 1H), 7.20 (s, 1H), 2.40 (s, 1H), 2.24 (s, 3H), 2.20 (d, J= 7.2 Hz, 3H), 1.36- 1.26 (m, 1H), 1.13 (d, J= 9.0 Hz, 23H).
Example 243 Preparation of (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(6-methylpyridin-2-ypmethanone (1020-243) N

[00787] (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(6-methylpyridin-2-yemethanone was synthesized in a similar fashion as that of Example 241, substituting tert-Butyl Magnesium Chloride for (6-methylpyridin-2-yl)magnesium bromide.
[00788] C22H20N402. MS. m/z 373.2 (M+1).11.1 NMR (400 MHz, cd3od) 6 7.92 (t, J= 7.7 Hz, 3H), 7.83 (d, J= 7.6 Hz, 1H), 7.72 (s, 1H), 7.51 (d, J= 7.6 Hz, 1H), 2.61 (s, 3H), 2.44 (s, 3H), 2.35 (t, J= 6.5 Hz, 1H), 2.28 (s, 2H), 1.25 ¨ 1.18 (m, 4H).
Example 244 1-(2-cyclopropy1-5-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-7-y1)-1-(pyridin-2-yl)prop-2-yn-1-ol (1020-244) THF
Mg-Br -78 C to rt NH
0 .<--NH HO 1,1 [00789] (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyridin-2-yl)methanol (100 mg, 0.28 mmol) was dissolved in THF (10 ml) and cooled to -78 C under argon. To this was added 0.5M ethynylmagnesium bromide (5.6 ml, 2.8 mmol) and reaction wamied to room temperature and allowed to react for hours. Reaction was diluted in EtAc and aqueous ammonium chloride, extracted 3x with EtAc then washed with ammonium chloride, water, brine before drying the organics over sodium sulfate. Material was filtered and solvents removed under reduced pressure afford crude material which was purified by silica gel chromatography using Hex / EtAc as the eluent to afford 1-(2-cyclopropy1-5-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-7-y1)-1-(pyridin-2-yl)prop-2-yn-1-ol.
[00790] .LCMS (m/z +1) 385.1. 1H NMR (400 MHz, DMSO-d6) 6 8.46 (dt, J =
4.7, 1.3 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.86 (td, J = 7.7, 1.8 Hz, 1H), 7.73 (s, 1H), 7.55 (s, 1H), 7.48 (d, J = 1.5 Hz, 1H), 7.29 (ddd, J = 7.5, 4.8, 1.2 Hz, 1H), 3.89 (s, 1H), 2.61 (s, 1H), 2.39 (s, 3H), 2.21 (s, 3H), 1.33¨ 1.22 (m, 4H).

Example 245 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyridin-y1)(1H-1,2,3-triazol-4-ypmethanol (1020-245) N-0 0¨ N-0 ,N
" 'NH
" TFA
____________________________________________ HN
HN HO N"
N \
HO i \
[007911 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(1-(4-methoxybenzy1)-1H-1,2,3-triazol-4-y1)(pyridin-2-yOmethanol (25 mg, 0.05 mmol) from ag-2238 was dissolved in 5mL TFA and heated to 65 C for 4 hours.
Solvents were removed under reduced pressure and crude material was pufiried by reverse phase HPLC to afford (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyridin-2-y1)(1H-1,2,3-triazol-4-yl)methanol as a TFA
salt.
[00792] .LCMS (m/z +1) 428.1. 1H NMR (400 MHz, Methanol-d4) 6 8.58 (ddd, J = 5.0, 1.8, 0.9 Hz, 1H), 7.93 ¨7.81 (m, 2H), 7.76 (s, 1H), 7.48 (d, J = 1.5 Hz, 1H), 7.38 (ddd, J = 7.3, 4.8, 1.3 Hz, 1H), 7.28 ¨7.22 (m, 1H), 2.65 ¨2.56 (m, 1H), 2.34 (s, 3H), 2.17 (s, 3H), 1.56¨ 1.47 (m, 2H), 1.41 ¨ 1.35 (m, 2H).
Example 246 (6-bromo-3-fluoro-2-methylpyridin-4-y1)(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyridin-2-yl)methanol (1020-246) F

/(N
o 40Br nBuLi, -78C , BOON HN /N
<r-N
N IN Br [00793] (6-Bromo-3-fluoro-2-methylpyridin-4-y1)(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyridin-2-yl)methanol was synthesized using 6-bromo-3-fluoro-2-methylpyridine and tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-picolinoy1-1H-benzo[d]imidazole-1-carboxylate in a similar fashion as Example No. 5 [00794] C271123BrFN502 MS = 548.50 (M + H ). 1H NMR (400 MHz, Chloroform-d) 6 8.61 ¨ 8.52 (m, 1H), 7.72 (td, J= 7.8, 1.7 Hz, 1H), 7.39 (d, J= 16.1 Hz, 2H), 7.28 (ddd, J= 7.3, 4.9, 1.0 Hz, 1H), 7.05 (d, J= 4.8 Hz, 1H), 6.63 (s, 1H), 2.37 (d, J
= 3.2 Hz, 3H), 2.23 (s, 3H), 2.13 ¨ 1.96 (m, 4H), 1.24¨ 1.12 (m, 2H), 1.07 (dt, J= 8.6, 3.4 Hz, 2H).
Example 247 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(3-fluoro-2-methylpyridin-4-y1)(pyridin-2-yOmethanol (1020-247) I l OH Pd/C, H2 411 OH
Et0H
HN /N ____________ HN /N
N Br N
[00795] (2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(3-fluoro-2-methylpyridin-4-y1)(pyridin-2-ypmethanol (40 mg, 0.07 mmol) was dissolved in Et0H (5mL) and to the reaction was added Pd/C (20 mg). The reaction was then degassed and put under a atmosphere of Hydrogen via balloon. After 2h the reaction was stopped and filtered through celite. Et0H was condensed down and purified via RPHPLC 0-40% (Acetonitrile/water w/ 0.1% TFA).
[00796] C27f123BrFN502 MS = 470.25 (M + H ). 1H NMR (400 MHz, Chloroform-d) 6 8.58 ¨ 8.47 (m, 1H), 8.31 (d, J= 5.5 Hz, 1H), 7.79 (td, J=
7.8, 1.7 Hz, 1H), 7.59 (d, J= 1.4 Hz, 1H), 7.43 (d, J= 8.0 Hz, 1H), 7.38 ¨ 7.33 (m, 1H), 7.30 (t, J=
5.8 Hz, 1H), 6.79 (t, J= 1.3 Hz, 1H), 2.57 ¨ 2.43 (m, 4H), 2.23 (s, 3H), 2.06 (s, 3H), 1.29 (dq, J= 7.9, 4.6 Hz, 2H).

Example 248 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(thiazol-yl)methanol (1020-248) O-N O-N

Boc-N mir"HN
0 <rN OH
[007971 tert-Butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(thiazole-carbony1)-1H-benzo[d]imidazole-1-carboxylate in was dissolved in 2m1Me0H, the reaction flask was then put in ice bath, to the solution was added NaBH4 (10mg, 0.26 mmol), slowly raised T to RT, stirred overnight. Then the reaction was quenched with NH4C1, extracted with Et0Ac to afford 170mg crude product. Dissolved 60mg crude product in Et0Ac, added 0.5ml TFA, heated overnight at 60 C, then evaporated solvent, the residue was purified with Prep HPLC to afford 25mg (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(thiazol-2-yl)methanol.
[007981 C19H18N402S. 367.0 (M+1). 1H NMR (400 MHz, CD30D) 6 7.64 (d, J =
3.2 Hz, 1H), 7.49 (d, J = 3.2 Hz, 1H), 7.42 (d, J = 0.9 Hz, 1H), 7.39 (s, 1H), 6.43 (s, 1H), 2.51-2.47 (m, 1H), 2.30 (s, 3H), 2.15 (s, 3H), 1.48-1.45 (m, 2H), 1.36-1.33 (m, 2H).
Example 249 4-(4-(cyclopropoxy(pyridin-2-yl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-249) Step 1:

O-N O-N
I
Boc-N N Boc-N

.<(----=N OH
[00799] tert-Butyl 2-cyclopropy1-6-(3 ,5 -dim ethylisoxazol-4-y1)-4-pi colino y1-1H-benzo [d] imidazole-1-carboxyl ate (170mg, 0.37 mmol) was dissolved in 5m1 Me0H, lowered T to 0 degree, added NaBH4(21mg, 0.56 mmol) to the solution, slowly raised T
to RT, stirred overnight. Then the reaction was quenched with NE14C1, extracted with Et0Ac, evaporated organic solvent to afford 170mg crude 4-(4-(cyclopropoxy(pyridin-2-y1)methy1)-2-cyclopropy1-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole.
[00800] C26H28N404. 461.5 (M+1).
Step 2:
O
O-N -N
Boc-N N HN
<r-N OH
[00801] 4-(4-(Cyclopropoxy(pyridin-2-yl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (32mg, 0.09 mmol) was dissolved in 5m1 DCM, to the solution was added SOC12(42mg, 0.36 mmol), stirred at RT for 10mins.
Then to the reaction mixture was added cyclopropanol (41mg, 0.7 mmol) at RT.
Reaction completed instantly and was quenched with aq. NaHCO3, evaporated organic solvent, the residue was purified with Prep HPLC to afford 4-(4-(cyclopropoxy(pyridin-2-yl)methyl)-2-cyclopropyl-1H-b enz o (1] imi dazol-6-y1)-3 ,5-dim ethylisoxazol e.
[00802] C24H24N402. 401.1 (M+1). 1H NMR (400 MHz, CD30D) 6 8.82-8.81 (m, 1H), 7.90-7.88 (m, 1H), 7.86 (d, J = 1.6 Hz, 1H), 7.66-7.64 (m, 1H), 7.50-7.47 (m, 2H), 6.66 (s, 1H), 3.98-3.87 (m, 1H), 2.40-2.38 (m, 1H), 2.32 (s, 3H), 2.15 (s, 3H), 2.16-2.10 (m, 2H), 1.35-1.24 (m, 8H).

Example 250 4-(4-((1H-imidazol-1-y1)(pyridin-2-yl)methyl)-2-eyelopropyl-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-250) O-N
HN
N (\
[00803] 4-(4-((1H-imidazol-1-y1)(pyridin-2-yl)methyl)-2-eyelopropyl-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole was synthesized in a similar fashion to Example 249.
[00804] C24H22N60. 411.0 (M+1). 1H NMR (400 MHz, CD30D) 5 9.01-9.00 (m, 1H), 8.66-8.65 (m, 1H), 7.94-7.89 (m, 1H), 7.71-7.70 (m, 1H), 7.58 (d, J = 2.0 Hz, 2H), 7.54 (d, J = 0.8 Hz, 2H), 7.52-7.46 (m, 1H), 7.01 (s, 1H), 2.35-2.32 (m, 1H), 2.31 (s, 3H), 2.14 (s, 3H), 1.34-1.24 (m, 4H).
Example 251 eyelopenty1(2-eyelopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyrimidin-2-yl)methanol (1020-251) Step 1: tert-butyl 2-eyelopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(pyrimidine-2-earbony1)-1H-benzordiimidazole-1-carboxylate N-o N-0 I
Boc /0 n-BuLi, THF, -78C . 0 , ,N
Boc-N
N
<r-N
N N
[00805] To a dry, argon purged round-bottom flask was added tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-iodo-1H-benzo[d]imidazole-1-carboxylate (2.00g 0.004 mol) in THF (75 mL), flask was placed in a -78C bath. To the reaction was added n-Butyllithium (3.39 mL, 0.01mol) over a period of 2 minutes. N-methoxy-N-methylpyrimidine-2-carboxamide (1.74g 0.01mol) in 25mL THF was added quickly and the reaction was allowed to stir for 10minutes. To the reaction was added Sat.
Ammonium Chloride (50 mL) followed by Et0Ac (250 mL). Organic layer was washed with Sat. Brine (50 mL) then dried over Magnesium Sulfate and condensed to a dark brown oil. Material was then purified via normal phase chromatography 0-50%
Et0Ac/Hexanes to give tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(pyrimidine-2-carbony1)-1H-benzo[d]imidazole-1-carboxylate which was used for the next examples.
Step 2: cyclopenty1(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyrimidin-2-yl)methanol Iv Iv 1)cyclopentylmagnesium bromide o THF, -780 2) TFA, DCM
40 OF.
Boc-N HN
N N
<r-N
N N
[00806] tert-Butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(pyrimidine-2-carbony1)-1H-benzo[d]imidazole-1-carboxylate (100mg, 0.21 mmol) was dissolved in THF (5 mL), reaction was cooled to OC. Cyclopentylmagnesium bromide (2.0M) (0.43 mL, 0.87 mmol) was added. The reaction was stirred for 30 minutes, to the reaction was added Sat. Ammonium Chloride (15 mL) followed by Et0Ac (20 mL). Organic layer was washed with Sat. Brine (15 mL) then dried over Magnesium Sulfate and condensed to an yellow oil. The material was then run through a small silica plug and condensed down. This oil was then dissolved in DCM (5 mL) and TFA (1 mL) was added. The reaction was stirred for 30 mins then condensed down to a yellow oil. The residue was purified by RPHPLC (5-50% Acetonitrile/Water), affording cyclopenty1(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyrimidin-2-y1)methanol.

C25H27N502 MS = 430.23 (M + H+). 1H NMR (400 MHz, Chloroform-d) 6 10.83 (s, 1H), 8.77 (d, J = 4.9 Hz, 2H), 7.65 (d, J = 1.5 Hz, 1H), 7.42 (d, J = 1.5 Hz, 1H), 5.98 (s, 1H), 3.31 (t, J = 8.4 Hz, 1H), 2.40 (s, 3H), 2.27 (s, 3H), 2.11 (d, J = 3.8 Hz, 2H), 1.70 -1.43 (m, 6H), 1.37 (s, 1H), 1.34- 1.13 (m, 7H).
Example 252 (2-eyelopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(5-fluoropyridin-2-y1)(pyrimidin-2-yOmethanol (1020-252) 0 Fr HN
N N
[00807] (2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(5-fluoropyridin-2-y1)(pyrimidin-2-yl)methanol was synthesized using 2-magnesiumbromide-5-fluoropyridine and tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(pyrimidine-2-carbony1)-1H-benzo[d]imidazole-1-carboxylate in a similar fashion as Example 248 step 2.
[00808] C25H21FN602 MS = 457.27 (M + H+). 1H NMR (400 MHz, Chloroform-d) 6 8.79 (d, J = 4.8 Hz, 2H), 8.35 (d, J = 2.7 Hz, 1H), 7.65 -7.52 (m, 2H), 7.39 (td, J =
8.4, 2.8 Hz, 1H), 7.32 (t, J = 4.9 Hz, 1H), 2.39 (s, OH), 2.35 (s, 3H), 2.27 (d, J = 10.5 Hz, OH), 2.18 (s, 2H), 1.36- 1.28 (m, 2H), 1.28 - 1.16 (m, 2H).
Example 253 (5-chloropyridin-2-y1)(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyrimidin-2-yl)methanol (1020-253) Iv lel OH N
HN / CI
N N
[00809] (5-Chloropyridin-2-y1)(2-eyelopropyl-6-(3,5-dimethylisoxazol-4-y1)-benzo[d]imidazol-4-y1)(pyrimidin-2-yOmethanol was synthesized using 2-magnesiumbromide-5-chloropyridine tert-butyl 2-eyelopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(pyrimidine-2-carbony1)-1H-benzo[d]imidazole-1-earboxylate in a similar fashion as Example 248, step 2.
[00810] C25H21C1N602 MS = 473.36 (M + H+). 11-1NMR (400 MHz, Chlorofoim-d) 6 8.79 (d, J = 4.9 Hz, 2H), 8.46 (d, J = 2.3 Hz, 1H), 7.66 (dd, J = 8.6, 2.4 Hz, 1H), 7.63 ¨7.49 (m, 3H), 7.33 (d, J = 4.9 Hz, 1H), 2.36 (s, 4H), 2.21 (s, 3H), 1.49¨ 1.18 (m, 7H), 0.92 ¨ 0.83 (m, 1H).
Example 254 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(phenyl)(pyrimidin-2-yemethanol (1020-254) Iv OH
11101 A rk HN
I IF
N N
1008111 (2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(phenyl)(pyrimidin-2-yOmethanol was synthesized using phenylmagnesium bromide and tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(pyrimidine-2-earbony1)-1H-benzo[d]imidazole-1-carboxylate in a similar fashion as Example 248, step 2.
[00812] C26H23N502 MS = 438.28 (M + Hi). 1H NMR (400 MHz, Chloroform-d) 6 8.82 (d, J = 4.7 Hz, 2H), 7.57 (d, J = 1.6 Hz, 1H), 7.51 (d, J = 1.4 Hz, 1H), 7.37 (t, J =
4.6 Hz, 1H), 7.30 (d, J = 3.0 Hz, 3H), 7.22 (dd, J = 6.4, 2.9 Hz, 2H), 3.02 (s, 1H), 2.93 (s, 1H), 2.41 (d, J = 11.9 Hz, 1H), 2.33 (s, 3H), 1.42 (d, J = 5.1 Hz, 2H), 1.38 -1.29 (m, 2H), 1.27 (d, J = 8.7 Hz, 1H).
Example 255 (6-Bromo-3-fluoro-2-methylpyridin-4-y1)(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyrimidin-2-yl)methanol (1020-255) O-N O-N
Boc-N IS 0 HN = OHF
/N
1\1' N
N N Br [00813] To a solution of 2-bromo-5-fluoro-6-methylpyridine (165 mg, 0.87 mmol) in THF (5 mL) was added BuLi (56 mg, 0.87 mmol, 1.6 M in hexanes) and the solution was stirred at -78 C for lh. To the solution was added a solution of tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(pyrimidine-2-carbony1)-1H-benzo[d]imidazole-1-carboxylate (100 mg, 0.22 mmol) in THF (2 mL) and the solution was stirred at -78 C for lh. Aq NH4C1 was added and the solution was extracted with Et0Ac (200 mL). The organic solution was washed with brine and dried over Na20S4.
Solvent was removed and the residue was purified by silica gel column chromatography (0-10% Me0H in CH2C12) to give N-Boc protected intermediate which was dissolved in THF (2 mL), TFA (2 mL) and water (0.1 mL). The solution was heated at 50 C
for 3h and concentrated to dryness under reduced pressure. The residue was purified by HPLC
to give (6-bromo-3-fluoro-2-methylpyridin-4-y1)(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyrimidin-2-yOmethanol.
[00814] C26HnBrFN602. MS. tniz 549.5 (M+1). 11-1 NMR (Methanol-c14) 6 8.86 (d, J= 4.9 Hz, 2H), 7.64 - 7.55 (m, 2H), 7.50 (t, J= 4.9 Hz, 1H), 7.13 (t, J= 1.7 Hz, 1H), 2.61 (tt, J = 8.4, 5.0 Hz, 1H), 2.41 -2.29 (m, 6H), 2.16 (s, 3H), 1.60- 1.51 (m,2H), 1.51 -1.38 (m, 2H).

Example 256 and 257 (2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(2,6-difluorophenyl)(pyrimidin-2-y1)methanol (1020-256) and (2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(2,4-difluorophenyl)(pyrimidin-2-y1)methanol (1020-257) N-0 Br N-0 N-0 F
01-1\n Boc,N F
HN HN
n-BuLi, THF
N
HO
---=-.<?N F
N
[00815] 1-Bromo-2,4-difluorobenzene (520 mg, 2,70 mmol) was dissolved in THF (5 mL) and cooled to -78 C. n-BuLi (1.68 mL, 2.70 mmol, 1.6 M) was added dropwise and the reaction was allowed to stir for 30 minutes at -78 C. To the reaction was added Compound A. The reaction was allowed to stir for 30 minutes to the reaction was added Sat. Ammonium Chloride (15 mL) followed by Et0Ac (20 mL). Organic layer was washed with Sat. Brine (15 mL) then dried over Magnesium Sulfate and condensed to an oil. The material was then run through a small silica plug and condensed down. This oil was then dissolved in DCM (5 mL) and TFA (1 mL) was added. The reaction was stirred for 30 minutess then condensed down to an oil. The residue was purified by normal phase chromatography (0-10%) Me0H/DCM.
[00816] (2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(2,6-difluorophenyl)(pyrimidin-2-y1)methanol: C26H21F2N502 MS = 474.22 (M +

H+). IHNMR (400 MHz, Methanol-d4) 6 8.83 (dd, J = 10.2, 4.9 Hz, 2H), 7.53 (dd, J
1.5 Hz, 1H), 7.47 ¨7.39 (m, 3H), 6.98 ¨6.89 (m, 2H), 2.60 (tt, J = 8.4, 5.0 Hz, 1H), 2.34 (d, J = 5.8 Hz, 3H), 2.16 (d, J = 5.7 Hz, 3H), 1.59¨ 1.48 (m, 2H), 1.48¨ 1.34 (m, 2H) [00817] (2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(2,4-difluorophenyl)(pyrimidin-2-yOmethanol: C26H21F2N502 MS = 474.28 (M +
H+).

1H NMR (400 MHz, Methanol-d4) 6 8.85 (d, J = 4.9 Hz, 2H), 7.54 (d, J = 1.5 Hz, 1H), 7.47 (t, J = 4.9 Hz, 1H), 7.29 ¨7.23 (m, 1H), 7.22 (q, J = 1.5 Hz, 1H), 6.99 ¨
6.91 (m, 2H), 2.99 (s, OH), 2.86 (d, J = 0.8 Hz, OH), 2.59 (tt, J = 8.4, 5.0 Hz, 1H), 2.34 (s, 3H), 2.15 (s, 3H), 1.57¨ 1.49 (m, 2H), 1.43 ¨ 1.37 (m, 2H).
Example 258 1-(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)-1-(pyridin-3-ypethanol (1020-258) Step 1:
O-N O-N
SI
HNHN
j---N 0 <rN
[00818] 2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-N-methoxy-N-methyl-1H-benzo[d]imidazole-4-carboxamide (116mg, 0.34 mmol) was dissolved in THF (2 ml), the reaction flask was put in ice bath. To the solution was added methylmagnesium bromide (0.45 mL, 3M in THF) and stirred at 0 C for 4h. The reaction mixture was diluted with Et0Ac, washed with brine, back-extracted with Et0Ac, evaporated organic solvent to afford 116mg of 1-(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-ypethanone.
[00819] C17H17N302. 296.2 (M+1).
Step 2:
O-N O-N
HN HN

[00820] 1-(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-yl)ethanone (30mg, 0.1 mmol) was dissolved in THF (1 ml), the reaction flask was put in ice bath. To the solution was added 2-pyridylmagnesium bromide (2.4 mL, 0.25M in THF) and stirred RT overnight. The reaction mixture was diluted with Et0Ac, washed with brine, back-extracted with Et0Ac, evaporated organic solvent and then purified with Prep HPLC to afford 1-(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)-1-(pyridin-3-yl)ethanol.
[008211 C22H22N402. 373.3 (M-1). 1H NMR (400 MHz, CD30D) 8.91 (d, J = 1.6 Hz, 1H), 8.54 (dd, J = 1.2, 5.2 Hz, 1H), 8.34 (tt, J = 1.6, 8.0 Hz, 1H), 7.67 (dd, J = 1.2, 8.0 Hz, 1H), 7.41 (d, 3= 1.2 Hz, 1H), 7.31 (d, J = 1.6 Hz, 1H), 2.54-2.50 (m, 1H), 2.31 (s, 311), 2.14 (s, 311), 2.07 (s, 3H), 1.45-1.39 (m, 2H), 1.31-1.25 (m, 2H).
Example 259 4-(2-cyclopropy1-4-(1-(pyridin-3-yl)viny1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-259) O-N O-N
HN HN
HO
[00822] 1-(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-y1)-1-(pyridin-3-yeethanol (10mg, 0.27 mmol) was dissolved in 2m1 of TFA, heated to 160 C in microwave reactor for 6h. Solvent was evaporated and the residue was purified with Prep HPLC for to afford 4-(2-cyclopropy1-4-(1-(pyridin-3-yOviny1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole.
[00823] C22H20N40. 357.3 (M+1). 1H NMR (400 MHz, CD30D) 8.75 (s, 111), 8.69 (d, J = 4.8 Hz, 111), 8.25-8.22 (m, 1H), 7.78-7.63 (m, 1H), 7.41 (d, J =
1.2 Hz, 1H), 7.63 (d, J = 1.2 Hz, 1H), 7.30 (d, J = 1.6 Hz, 1H), 6.36 (s, 1H), 5.94 (s, 1H), 2.47-2.43 (m, 1H), 2.41 (s, 3H), 2.24 (s, 3H), 1.54-1.49 (m, 2H), 1.41-1.39 (m, 2H).
Example 260 4-(2-cyclopropy1-4-(1-(pyridin-3-ypethyl)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (1020-260) O-N O-N
HN HN
[00824] 4-(2-cyclopropy1-4-(1-(pyridin-3-ypviny1)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole (5mg, 0.014 mmol) was dissolved in Et0Ac (2 ml). The reaction flask was degassed and to the solution as added palladium (5mg, 10% on activated carbon). The flask as degassed again and a hydrogen balloon was put on the top of reaction flask. The reaction mixture was stirred at RT for lh. Then the reaction mixture was filtered, solvent was evaporated, and the residue was purified with Prep HPLC to afford 5mg of 4-(2-cyclopropy1-4-(1-(pyridin-3-ypethyl)-1H-benzo[d]imidazol-6-y1)-3,5-dimethylisoxazole.
[00825] C22H22N40. 359.3 (M+1). 1H NMR (400 MHz, CD30D) 8.63 (s, 1H), 8.52 (d, J = 5.2 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 5.2, 8.0 Hz, 1H), 7.39 (d, J = 1.6Hz, 1H), 7.18 (d, J = 1.2 Hz, 1H), 4.85 (q, J = 6.8 Hz, 1H), 2.39-2.28 (m, 1H), 2.28 (s, 3H), 2.11 (s, 3H), 1.78 (d, J = 6.8 Hz, 1H), 1.43-1.40 (m, 2H), 1.31-1.28 (m, 2H).
Examples 261 and 262 34(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(hydroxy)(pyridin-2-yl)methyl)bicyclo[2.2.1]heptan-2-one (1020-261) and (1020-262) = + 0 \ 0 LDA, THF
1111*
1114 _______________________________________ HO N" \
[00826] Norcamphor (494.84 mg, 4.49 mmol) was taken up in THF (40 ml) in a dry argon purged flask. Solution was cooled to -78 C under argon. To this was added 2M lithium diisopropylamide (2.34 ml) slowly and reaction allowed to mature for 30 minutes. At this point a solution of (2-cyclopropy1-5-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-7-y1)(pyridin-2-yOmethanone (230 mg, 0.64 mmol) in 20 mL THF
was added rapidly and reaction allowed to stir at -78 C for 10 minutes.
Reaction was removed from ice bath and allowed to warm for 30 minutes. Reaction was quenched into stirring EtAc, aqueous ammonium chloride and was extracted 3x with EtAc, washed with water then brine and dried over sodium sulfate before removing solvents under reduced pressure. A portion of this material was purified by reverse phase HPLC
to afford 2 diastereomers of 34(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(hydroxy)(pyridin-2-yl)methyebicyclo[2.2.1]heptan-2-one.
[00827] LCMS (m/z +1) 469.2 [00828] 1020-261 ¨ Diastereomer "A"
[00829] 1H NMR (400 MHz, DMSO-d6) 6 9.21 (s, 1H), 8.71 (d, J = 30.1 Hz, 2H), 8.34 (s, 1H), 8.11 (s, 1H), 7.54 (d, J = 42.0 Hz, 2H), 6.77 (s, 1H), 2.89 (s, 2H), 2.39 ¨
1.81 (m, 6H), 1.53 (dd, J = 31.5, 18.4 Hz, 2H), 1.36¨ 1.06 (m, 5H), 0.89 (d, 3 = 50.4 Hz, 3H).
[00830] 1020-262 ¨ Diastereomer "B"
[00831] 1H NMR (400 MHz, DMSO-d6) 6 11.44 (s, 1H), 9.33 (d, J = 6.1 Hz, 1H), 8.50 (t, J = 7.8 Hz, 1H), 8.15 (t, J = 6.9 Hz, 1H), 7.75 (d, J.= 8.1 Hz, 1H), 7.64 (s, 1H), 7.43 (d, J = 1.5 Hz, 1H), 7.21 (s, 1H), 3.00 (d, J = 3.0 Hz, 1H), 2.81 (s, 1H), 2.75 (s, 1H), 2.46 (s, 3H), 2.27 (s, 3H), 2.05 (td, J = 8.0, 3.2 Hz, 2H), 1.68 (dp, J = 7.3, 4.1, 3.6 Hz, 2H), 1.43¨ 1.30 (m, 2H), 1.11 (qd, 3= 6.2, 3.2 Hz, 3H), 0.95 (dd, J = 9.6, 4.5 Hz, 1H), 0.75 (d, J = 9.0 Hz, 1H).
Example 263 34(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(hydroxy)(pyridin-2-yl)methyl)bicyclo[2.2.1]heptan-2-ol (1020-263) 100 0 44, NaBH4 10 HO 11,.
HN Me0H, 0 C HN
HO 14/ HO 14/ \
[00832] Crude 3-02-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(hydroxy)(pyridin-2-yl)methyl)bicyclo[2.2.1]heptan-2-one (300 mg, 0.64 mmol) 25mL methanol and cooled to 0 C under nitrogen. To this was added sodium borohydride (145 mg, 3.84 mmol) and reaction allowed to stir at 0 C.
After 2 hours reaction was quenched into stirring EtAc, aqueous ammonium chloride and was extracted 3x with EtAC, washed with water then brine and dried over sodium sulfate before removing solvents under reduced pressure. Material was purified by silica gel chromatography using Hex / EtAc as the eluent. Material was then farther purified by reverse phase HPLC to afford 34(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(hydroxy)(pyridin-2-34)methyl)bicyclo[2.2.1]heptan-2-ol as a racemic mixture as the TFA salt.
[00833] LCMS (m/z +1) 471.2. IFI NMR (400 MHz, Methanol-d4) 6 8.62 (ddd, J = 5.1, 1.7, 0.9 Hz, 1H), 7.96 ¨ 7.88 (m, 1H), 7.85 (dt, J = 8.1, 1.1 Hz, 1H), 7.51 (d, J =
1.4 Hz, 1H), 7.45 ¨ 7.32 (m, 2H), 4.23 ¨4.13 (m, 1H), 2.68 (tt, J = 8.5, 5.0 Hz, 1H), 2.52 (dd, J = 5.4, 1.8 Hz, 1H), 2.35 (s, 3H), 2.17 (s, 4H), 1.96 ¨ 1.81 (m, 3H), 1.55 ¨ 1.28 (m, 10H).
Example 264 and 265 242-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(hydroxy)(pyridin-2-yl)methyl)cyclopentanol (1020-264) and (1020-265) 40 +
LDA, THF e NaBH4 1 11' Me0H, 0 C

HN HN
<i---NH 0 HO N" \<)=N

HO N/ \
Step 1: Preparation of 242-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(hydroxy)(pyridin-2-yl)methypcyclopentanone [00834] Cyclopentanone (0.13 ml, 1.46 mmol) was taken up in THF (5 ml) in a dry nitrogen purged flask. Solution was cooled to -78 C under argon. To this was added 2M lithium diisopropylamide (0.73 ml) slowly and reaction allowed to mature for 30 minutes. At this point a solution of (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyridin-2-yOmethanol (75 mg, 0.21 mmol) in 1 mL THF was added slowly and reaction allowed to stir at -78 C for 10 minutes. Reaction was quenched into stirring EtAc, aqueous ammonium chloride, was extracted 3x with EtAc, washed with water, brine, dried over sodium sulfate. Solvents were then removed under reduced pressure (92 mg, 100%).
[00835] LCMS (m/z +1) 443.1 Step 2: Preparation of 24(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(hydroxy)(pyridin-2-yl)methyl)cyclopentanol [00836] Crude 24(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(hydroxy)(pyridin-2-yl)methyl)cyclopentanone (92 mg, 0.21 mmol) was taken up in 5 ml methanol, cooled to 0 C under nitrogen and to it added sodium borohydride (23.75 mg, 0.63 mmol). Reaction was allowed to stir for 2 hours at 0 C. Solvents were removed under reduced pressure and reaction was diluted in EtAc and aq. ammonium chloride. Reaction was then extracted 3x with EtAc, washed with water, brine, dried over sodium sulfate. Solvents were then removed under reduced pressure and the residue was purified by reverse phase HPLC to afford 24(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)(hydroxy)(pyridin-2-yl)methypeyclopentanol as two diastereomers.

[00837] LCMS (m/z +1) 445.2 [00838] 1020-264 ¨ Diastereomer "A"
[00839] 1H NMR (400 MHz, DMSO-d6) 8 8.53 ¨ 8.39 (m, 1H), 7.92 (dt, J =
8.1, 1.1 Hz, 1H), 7.79 (td, J = 7.7, 1.8 Hz, 1H), 7.71 (s, 1H), 7.41 (d, J = 1.5 Hz, 1H), 7.24 ¨
7.12 (m, 1H), 6.98 (s, 1H), 3.93 (dt, J = 6.1, 4.3 Hz, 1H), 2.68 (s, 1H), 2.41 (s, 3H), 2.23 (s, 3H), 1.83 ¨ 1.07 (m, 11H).
[00840] 1020-265 ¨ Diastereomer "B"
[00841] 1H NMR (400 MHz, DMSO-d6) 6 8.65 ¨ 8.53 (m, 1H), 8.00 (dt, J =
8.1, 1.1 Hz, 1H), 7.83 (td, J = 7.8, 1.8 Hz, 1H), 7.53 (d, J = 1.5 Hz, 1H), 7.40 (d, J = 1.4 Hz, 1H), 7.27 (ddd, J = 7.5, 4.8, 1.2 Hz, 1H), 6.97 (s, 1H), 3.42 (ddd, J = 12.0, 8.5, 3.9 Hz, 1H), 2.73 (ddd, J = 13.1, 8.3, 5.0 Hz, 1H), 2.34 (s, 3H), 2.15 (s, 3H), 2.01 ¨
1.87 (m, 1H), 1.83 ¨ 1.67 (m, 2H), 1.63 ¨ 1.50 (m, 2H), 1.46¨ 1.27 (m, 6H).
Example 266 N-(4-(dicyclopentyl(hydroxy)methyl)-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-2-yl)methanesulfonamide (1020-266) O-N O-N
N

HN
HN
0 OH =
HN
HN
-\ /
S=0 -\S=0 /

[00842] To a mixture containing methyl 6-(3,5-dimethylisoxazol-4-y1)-2-(methylsulfonamido)-1H-benzo[d]imidazole-4-carboxylate (40 mg, 0.11 mmol, 1 equiv.) and THF (3 mL) is added cylopentylmagnesium chloride (0.38 mL, 0.77 mmol, 7 equiv.) at 0 C for 30 mm. After completion, the reaction was quenched and extracted with Et0Ac and washed with water, saturated NH4C1. After drying with MgSO4, it was filtered and concentrated to dryness. Purification was carried out by reverse phase HPLC
IAQ

to furnish N-(4-(dicyclopentyl(hydroxy)methyl)-6-(3,5-dimethylisoxazol-4-y1)-benzo[d]imidazol-2-yl)methanesulfonamide.
[00843] LCMS (m/z+1) 472.3. 1H NMR (400 MHz, DMSO-d6) 8 7.33 (s, 1H), 7.09 (s, 1H), 6.5 (s, 1H), 5.20 (bs, 1H), 2.90 (s, 3H), 2.48 (s, 3H), 2.15 (s, 3H), 1.80 ¨
1.72 (m, 2H), 1.43 -1.15 (m, 16H.
Example 267 (6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)di(pyridin-2-yOmethanol (1020-267) Step 1:

la-N

[00844] Butyllithium (1.6 M in hexanes, 21 mL, 34 mmol) was added dropwise to a solution of 2-bromopyridine (3.0 mL, 31 mmol) in MeTHF (100 mL) at -78 C.
The reaction mixture was stirred for 1 hour and methyl 2,3-diamino-5-(3,5-dimethylisoxazol-4-yl)benzoate (2g, 7.7 mmol) in MeTHF (10 mL) was added. The reaction mixture was wamied to room temperature, and quenched with 1M HCI, neutralized with sodium bicarbonate solution, extracted with ethyl acetate and purified silica-gel chromatography (Et0Ac/Me0H/NH4OH) to give (2,3-diamino-5-(3,5-dimethylisoxazol-4-yl)phenyl)di(pyridin-2-yl)methanol.
[00845] 1H NMR (400 MHz, DMSO-d6) 6 8.53 (dd, J= 5.1, 1.5 Hz, 2H), 7.95 (t, J
= 8.0 Hz, 2H), 7.64 (d, J= 8.1 Hz, 2H), 7.42 (t, J= 6.1 Hz, 2H), 6.94 (s, 1H), 6.08 (s, 1H), 2.21 (s, 3H), 2.01 (s, 3H).
Step 2:
n HN \
N
[00846] (2,3-diamino-5-(3,5-dimethylisoxazol-4-yl)phenyl)di(pyridin-2-yl)methanol (75 mg, 0.19 mmol) was dissolved in formic acid (1 mL) and heated to 120 C for 3 hours. The reaction mixture was purified by reverse-phase HPLC to give the desired product.
[00847] C23Hi9N502 398.1 (M+1). 1H NMR (400 MHz, DMSO-d6) 6 9.22 (s, 1H), 8.51 (ddd, J= 5.0, 1.7, 0.9 Hz, 2H), 7.89 (td, J= 7.8, 1.8 Hz, 2H), 7.71 (d, J= 1.5 Hz, 1H), 7.65 (dt, J= 8.0, 1.0 Hz, 2H), 7.37 (ddd, J= 7.6, 4.9, 1.1 Hz, 2H), 7.19 (d, J= 1.5 Hz, 1H), 2.33 (s, 3H), 2.13 (s, 3H).
Example 268 (6-(3,5-dimethylisoxazol-4-y1)-2-methy1-1H-benzo[d]imidazol-4-yl)di(pyridin-2-yl)methanol (1020-268) OH N
HN \
tN/N
[00848] A solution of (2,3-diamino-5-(3,5-dimethylisoxazol-4-yl)phenyl)di(pyridin-2-yl)methanol (100 mg, 0.26 mmol) and ethyl acetimidate hydrochloride (52 mg, 0.52 mmol) was heated at 50 C for 24 hours. The reaction mixture was concentrated and purified by reverse-phase HPLC to give the desired product.
[00849] C24H21N502 412.1 (M+1). 1H NMR (400 MHz, DMSO-d6) 6 8.61 - 8.43 (m, 2H), 7.88 (td, J= 7.7, 1.8 Hz, 2H), 7.74 - 7.58 (m, 3H), 7.44- 7.29 (m, 2H), 7.12 (d, J= 1.6 Hz, 1H), 2.77 (s, 3H), 2.32 (s, 3H), 2.12 (s, 3H).
Example 269 (6-(3,5-dimethylisoxazol-4-y1)-2-isopropy1-1H-benzo[d]imidazol-4-yDdi(pyridin-y1)methanol (1020-269) OH N
HN \
(N N
[00850] The title compound was made in a similar fashion as that of Example 268, using isopropyl acetimidate hydrochloride.
[00851] 1H NMR (400 MHz, DMSO-d6) 6 8.63 ¨ 8.44 (m, 2H), 7.88 (td, J= 7.7, 1.8 Hz, 2H), 7.71 ¨7.54 (m, 3H), 7.37 (ddd, J= 7.6, 4.9, 1.2 Hz, 2H), 7.13 (d, J= 1.6 Hz, 1H), 3.58 (p, J= 7.0 Hz, 1H), 2.31 (s, 3H), 2.10 (s, 3H), 1.38 (d, J= 7.0 Hz, 6H).
Example 270 (2-(difluoromethyl)-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)di(pyridin-2-yl)methanol (1020-270) O-N O-N

Fy11.0)ty F
F F
, N
tel OH iPr2EtN 10 OH I

CH2Cl2 HN
0 C to reflux N
F
[00852] (2,3-Diamino-5-(3,5-dimethylisoxazol-4-yl)phenyl)di(pyridin-2-yl)methanol (30.0 mg, 0.049 mmol) was treated with difluoroactic anhydride (8.5 mg, 0.049 mmol) in the presence of iPr2EtN (0.1 mL) in CH2C12 (3 mL) at 0 C for 15 min.
'117 The reaction mixture was heated under a reflux conditions for 15 h. After removing the solvent under a reduced pressure, the mixture was purified by prep-HPLC to give (2-(difluoromethyl)-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yDdi(pyridin-2-yl)methanol.
[00853] C24Hi9F2N502. MS. 448.1 (M+1). IFI NMR (Me0H-d4) 6 8.66 (d, J= 4.8 Hz, 2H), 8.23 (td, J= 8.0, 1.6 Hz, 1H), 8.11 (d, J= 8.0 Hz, 2H), 7.70 (ddd, J=
8.0, 4.8, 1.6 Hz, 2H), 7.63 (d, J= 1.6 Hz, 1H), 6.92 (d, J= 1.6 Hz, 1H), 6.84 (t, J=
51.2 Hz, 1H), 2.35 (s, 3H), 2.18 (s, 3H).
Example 271 (2-cyclobuty1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)di(pyridin-2-yOmethanol (1020-271) r N
NH-CIH
OH NJ_ I
0 n-BuLi, THF, -780 H2N H2N \ Me0H, 500 HN

Step 1:
[00854] 2-bromopyridine (1.83 mL, 19 mmol) dissolved in THF (75 mL) and then cooled to -78C. N-BuLi (12 mL, 19 mmol, 1.6M) was then added. The reaction was allowed to stir 2 minutes then (methyl 2,3-diamino-5-(3,5-dimethylisoxazol-4-yl)benzoate (1.0 g, 3.8 mmol) was added in THF (25 mL) the reaction was allowed to stir for 30 minutes. To the reaction was added Sat. Ammonium Chloride (50 mL) followed by Et0Ac (100 mL). Organic layer was washed with Sat. Brine (50 mL) then dried over Magnesium Sulfate and condensed to a dark oil.
Step 2:
[00855] The material was then run through a small silica plug and condensed down to get 350 mg of (2,3-diamino-5-(3,5-dimethylisoxazol-4-yl)phenyl)di(pyridin-2-yl)methanol. (2,3-diamino-5-(3,5-dimethylisoxazol-4-yl)phenyl)di(pyridin-2-yOmethanol (100 mg, 0.26 mmol) was taken and dissolved in Me0H (10 mL) and to this was added ethyl cyclobutanecarbimidate hydrochloride (64 mg, 0.39 mmol). The reaction was then heated at 50C for 2h. The reaction was then condensed down and purified via RPHPLC 0-50% (Acetonitrile/Water) [00856] C271125N502 MS = 452.25 (M + H ). 1HNMR (400 MHz, Chloroform-d) 6 8.56 (dt, J = 4.8, 1.4 Hz, 2H), 7.78 ¨ 7.70 (m, 3H), 7.63 (s, 1H), 7.32 ¨
7.19 (m, 3H), 7.10 (s, 1H), 3.83 (dd, 3 = 16.9, 8.0 Hz, 1H), 2.49 (q, J = 9.7 Hz, 4H), 2.33 (s, 3H), 2.18 (s, 4H), 1.25 (s, 1H).
Example 272 N-(6-(3,5-dimethylisoxazol-4-y1)-4-(hydroxydi(pyridin-2-yOmethyl)-1H-benzo[d]imidazol-2-yl)methanesulfonamide (1020-272) I V
Z
( ___________________________ la OH N-- + N Ca2 9S N -+ _________ *
\ / 8 IPA, AcOH, NCI
HN . OH N\---- /

NH2 / N 2 80 C )=---N / N
1 FIN \
0=S=0 I
[008571 Preparation of N-(6-(3,5-dimethylisoxazol-4-y1)-4-(hydroxydi(pyridin-2-yOmethyl)-1H-benzo[d]imidazol-2-yOmethanesulfonamide from (2,3-diamino-5-(3,5-dimethylisoxazol-4-yl)phenyl)di(pyridin-2-yl)methanol was accomplished in a similar fashion to N-(6-(3,5-dimethylisoxazol-4-y1)-4-iodo-1H-benzo[d]imidazol-2-yl)methanesulfonamide. Isolated solids were then purified by reverse phase HPLC to furnish N-(6-(3,5-dimethylisoxazol-4-y1)-4-(hydroxydi(pyridin-2-yl)methyl)-1H-benzo[d]imidazol-2-y1)methanesulfonamide as a TFA salt.
[00858] LCMS (m/z +1) 491.2 1H NMR (400 MHz, DMSO-d6)45 11.96 (s, 1H), 11.31 (s, 1H), 8.50 (ddd, J = 4.8, 1.7, 0.8 Hz, 2H), 7.87 (td, J = 7.8, 1.9 Hz, 2H), 7.60 (d, J = 8.1 Hz, 2H), 7.35 (dd, J = 7.4, 5.0 Hz, 2H), 7.17 (d, J = 1.5 Hz, 1H), 7.07 (s, 1H), 2.83 (s, 3H), 2.33 (s, 3H), 2.13 (s, 3H).
q 14 Example 273 (2-cycl opropy1-6-(3 ,5 -dimethyli soxazol-4-y1)-1H-b enzo [d] imidazol-4-y1) (5-methylpip eridin-3-yl)methanol (1020-273) O-N O-N O-N

0 110 _________________________ 1.1 HN OH ______ )10- Y OH O-INI
HN

100859] To a solution of the iodide (0.070 g) and the ketone (0.047 g) at -78C in THF (4 ml) was added drop wise BuLi (2.5 M, hexanes, 0.1 ml) and the solution wanned to RT (step 1). After adding Me0H (1 ml), volatiles were removed, the residue dissolved in TFA, volatiles removed, and the residue purified by reverse phase HPLC (5-95%
MeCN in water, 0.1% TFA) to afford (2-eyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(5-methylpiperidin-3-y1)methanol (step 2).
Step 1: LCMS (m/z +1) 467.1 Step 2: LCMS (m/z +1) 367.1. 11-1 NMR (400 MHz, Methanol-d4) 6 7.43 (d, J =
1.3 Hz, 1H), 7.26 (d, J = 1.4 Hz, 1H), 3.54 (dtd, J = 18.3, 7.6, 6.9, 4.4 Hz, 2H), 3.38 (p, J = 1.6 Hz, OH), 3.11 (ddd, J = 13.2, 7.7, 3.8 Hz, 1H), 3.03 (p, J = 1.6 Hz, OH), 2.61 ¨2.40 (m, 2H), 2.34 (s, 2H), 2.17 (s, 3H), 2.09 ¨ 1.99 (m, 1H), 1.56 ¨ 1.38 (m, 3H), 1.31 (dt, J
7.8, 4.8 Hz, 1H).
Example 274 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(quinuelidin-3-yl)methanol (1020-274) I -300.- HN
[00860] (2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(quinuclidin-3-yl)methanol was synthesized in a similar fashion to Example 273 using quinuclidine-3-one.
[00861] LCMS (m/z +1) 379.3 Example 275 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(1,3-dioxolan-2-yl)methanol (1020-275) Step 1: Preparation of tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-formy1-1H-benzojdlimidazole-1-carboxylate 110LiAIH4 Boc-N '0 THF, 0 C Boo - N H
0 .1-N 0 [00862] To a flame dried, nitrogen purged flask was added tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(methoxy(methypcarbamoy1)-1H-benzo[d]imidazole-1-carboxylate (5 g, 11.35 mmol) and 20 mL THF. Reaction was stirred and cooled to -78 C under nitrogen. To this was slowly added 1M
lithium aluminum hydride in diethyl ether (18 ml, 18 mmol). Reaction was queched into large stirring flask of EtAc, dilute ammonium chloride that was pre-cooled to 0 C.
Crude suspension was filtered thru celite extracted with EtAc (3x) and organics washed with water and then brine. Organics were dried over sodium sulfate before removing solvents under reduced pressure and purifying by silica gel chromatography to afford of tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-formy1-1H-benzo[d]imidazole-1-carboxylate 3.57 g (82.5%) as a yellow powder.
[00863] LCMS (m/z +1) = 381.8 Step 2: Preparation of tert-butyl 44(1,3-dioxolan-2-y1)(hydroxy)methyl)-2-cyclopropyl-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[djimidazole-1-carboxylate r-O\ tert-butyl hydroperoxide H
Boc -N 0-1 triethylborane Boc-N 0 [00864] tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-formy1-1H-benzo[d]imidazole-1-carboxylate (500 mg, 1.31 mmol) in 1,3-dioxolane (5 ml) was cooled to 0 C under nitrogen. To this was added 1M triethylborane (7.87 ml) followed by 5.5M tert-butyl hydroperoxide in decane (2.38 ml) . Reaction was allowed to warm and react for 3 days. To the reaction was then added NH4OH solution (5 mL) and after stirring for 5 minutes was added FeSO4-1-12SO4.H20 solution (5 mL). Solution was extracted with EtAc 3x, washed with water, added FeS040H2S0401-120 solution, water, brine then dried over sodium sulfate. Solvents were removed under reduced pressure to afford tert-butyl 4-((1,3-dioxolan-2-y1)(hydroxy)methyl)-2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazole-1-carboxylate as a yellow film.
(212 mg, 32%) [00865] LCMS (m/z +1) 455.9 Step 3: (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(1,3-dioxolan-2-yl)methanol 11110 TFA, DCM =
yo. 0 Boc N
HN
<?---L---N OH = OH
[00866] Crude tert-butyl 4-((1,3-dioxolan-2-y1)(hydroxy)methyl)-2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazole-1-carboxylate (53 mg, 0.116 mmol) was taken up in 5 mL DCM and to this was added lmL TFA and reaction stirred at rt for 3 hours. Solvents were removed under reduced pressure and crude material was purified by reverse phase HPLC to afford (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(1,3-dioxolan-2-y1)methanol.
[00867] LCMS (m/z +1) 356.1. 1H NMR (400 MHz, DMSO-d6) 6 7.46 (s, 1H), 7.34 (s, 1H), 6.24 -5.93 (m, 1H), 5.08 (d, J = 4.0 Hz, 1H), 5.01 (d, J = 3.9 Hz, 1H), 3.87 (q, J = 7.6, 7.1 Hz, 1H), 3.83 -3.69 (m, 4H), 2.40 (s, 3H), 2.21 (s, 3H), 1.43 - 1.22 (m, 4H).
Example 276 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(1,3-dioxolan-2-y1)(2-methylpyridin-3-yl)methanol (1020-276) Step 1: Preparation of tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-441,3-dioxolane-2-carbony1)-1H-benzo[d]imidazole-1-carboxylate Dess-martin periodinane 40 0 1 DCM
Boc-N 0 Boc-N 0 1-N OH j--=N 0 [00868] tert-butyl 441,3-dioxolan-2-y1)(hydroxy)methyl)-2-cyclopropyl-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazole-1-carboxylate (600 mg, 1.32 mmol) was taken up in 100 ml DCM and to this was added Dess-Martin periodinane (594.56 mg, 1.58 mmol) and reaction allowed to stir at room temperature under nitrogen.
After 1 hour reaction was quenched with aqueous sodium thiosulfate and stirred for 15 minutes.
Reaction was then extracted 3x with EtAc, washed with sodium thiosulfate, water, brine and finally dried over sodium sulfate. Solvents were removed under reduced pressure and residue was flashed on silica gel chromatography using Hex / EtAc as the eluent to afford tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(1,3-dioxolane-earbony1)-1H-benzo[d]imidazole-1-carboxylate (160 mg, 27%).
[00869] LCMS (m/z +1) 453.8 Step 2: Preparation of tert-butyl 44(1.3-dioxolan-2-y1)(hydroxy)(2-methylpyridin-3-yl)methyl)-2-cyclopropyl-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazole-1-carboxylate ioTHF 4N HCI iii dioxanes r I
MgBr -78 O Boc-N 0 N 0 HN
<I--N HO \ <(----N HO \
[00870] tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(1,3-dioxolane-2-carbony1)-1H-benzo[d]imidazole-1-carboxylate (50 mg, 0.11 mmol) was taken up in THF (5 ml) and cooled to -78 C under nitrogen. To this was added 0.25M (6-methylpyridin-2-yl)magnesium bromide (1.31 ml) over 5 minutes. Reaction was allowed to stir at -78 C for 30 minutes. Reaction was then quenched into stirring EtAc /
ammonium chloride extracted 3x with EtAc, organics were washed with ammonium chloride, water, brine then dried over sodium sulfate. Solvents were removed under reduced pressure and crude residue purified by silica gel chromatography using Hex / EtAc as the eluent to afford tert-butyl 44(1,3-dioxolan-2-y1)(hydroxy)(2-methylpyridin-3-yemethyl)-2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[cl]imidazole-1-carboxylate (20 mg, 34%).
[00871] LCMS (m/z +1) 546.3 Step 3: Preparation of (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzoldlimidazol-4-y1)(1,3-dioxolan-2-y1)(2-methylpyridin-3-ypmethanol [00872] tert-butyl 4-((1,3-dioxolan-2-y1)(hydroxy)(2-methylpyridin-3-yl)methyl)-2-cyclopropyl-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazole-1-carboxylate (20 mg, 0,037 mmol) was then dissolved in 2 ml 4N HC1 in dioxanes and 2 ml ethanol and heated to 75 C for 1 hour. Solvents were removed under reduced pressure and material was purified by reverse phase HPLC to afford (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(1,3-dioxolan-2-y1)(2-methylpyridin-3-yOmethanol as a mixture of diastereomers.
[00873] LCMS (m/z +1) 447.1. 1H NMR (400 MHz, DMSO-d6) 6 8.67 (d, J =
5.7 Hz, 2H), 7.86 (td, J = 14.4, 13.8, 5.4 Hz, 1H), 7.52 (s, 1H), 7.13 (s, 1H), 6.71 (s, 1H), 5.82 (s, 1H), 3.87 (dt, J = 15.4, 6.2 Hz, 4H), 2.81 (s, 1H), 2.43 -2.29 (m, 3H), 2.24 (s, 3H), 2.02 (s, 3H), 1.61 - 1.26 (m, 4H).
Example 277 and 278 34(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(hydroxy)methyl)bicyclo[2.2.1]heptan-2-one (1020-277) and (Z)-34(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)methylene)bicyclo[2.2.1]heptan-2-one (1020-278) Step 1: Preparation of tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-(hydroxy(-3-oxobicyclo(2.2.1]heptan-2-yl)methyl)-1H-benzo[d]imidazole-1-carboxylate Boc N H 0 LDA, THF Aki 0 - /1* ______________ Boc-N

[00874] 2-norbornanone (173.28 mg, 1.57 mmol) was taken up in THF (5 ml) and cooled to -78 C under nitrogen. To this was slowly added 2M lithium diisopropylamide 1N) in THF (0.92 ml) over 5 minutes and the resulting solution was allowed to stir for 30 minutes. At this time a solution of tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-formy1-1H-benzo[d]imidazole-l-carboxylate (100 mg, 0.26 mmol) in 2 mL
THF
was slowly added. Reaction was allowed to stir atr -78 C for 10 minutes before being allowed to warm up. when solution was at approximately 0 C material was quenched into stirring aqueous ammonium chloride / EtAc, extracted 3 with EtAc, then organics were washed with water, brine and dried over sodium sulfate before removing solvents under reduced pressure to afford crude tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazo1-4-y1)-4-(hydroxy(-3-oxobicyclo[2.2.1]heptan-2-yl)methyl)-1H-benzo[d]imidazole-carboxylate as a mixture of isomers (50 mg, 39%).
[00875] LCMS (m/z +1) 492.1 Step 2: Preparation of 34(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(hydroxy)methyl)bicyclo[2.2.1]heptan-2-one and (Z)-3-42-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzord]imidazol-4-yl)methylene)bicyclo[2.2.1]heptan-2-one =o in dioxanes le 0 )11, Boc-N =

ethanol HN HN
OH OH
[00876] 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(hydroxy(-3-oxobicyclo[2.2.1]heptan-2-yl)methyl)-1H-benzo[d]imidazole-1-carboxylate (50 mg, 0.1 mmol) was dissolved in 2 ml 4N HC1 in dioxanes and 2 ml ethanol and heated to for 1 hour. Solvents were removed under reduced pressure and material was purified via reverse phase HPLC to afford both 34(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(hydroxy)methyl)bicyclo[2.2.1]heptan-2-one and (Z)-34(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)methylene)bicyclo[2.2.1]heptan-2-one both as a mixture of isomers.
[00877] 34(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-yl)(hydroxy)methyl)bicyclo[2.2.1]heptan-2-one: LCMS (m/z +1) 392.2. 1H NMR
(400 MHz, DMSO-d6) 6 7.51 ¨ 7.38 (m, 1H), 7.23 (s, 1H), 5.91 (s, 1H), 5.22 (d, J =
5.7 Hz, 1H), 2.51 (m, 2H), 2.40 (s, 4H), 2.32 (dd, J = 5.8, 2.9 Hz, 1H), 2.21 (d, J =
2.2 Hz, 3H), 1.84 (d, J = 10.2 Hz, 1H), 1.76¨ 1.64 (m, 2H), 1.33 (td, J = 10.9, 10.1, 4.4 Hz, 7H).
[00878] (Z)-34(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)methylene)bieyelo[2.2.1]heptan-2-one: LCMS (m/z +1) 374.2.
1H NMR (400 MHz, DMSO-d6) 6 8.37 (d, J = 7.3 Hz, 2H), 8.15 (s, 1H), 3.61 ¨
3.53 (m, 1H), 3.28 (s, 3H), 3.10 (s, 4H), 3.00 ¨ 2.73 (m, 3H), 2.40 ¨ 2.26 (m, 2H), 2.18 (d, J =
3.7 Hz, 2H), 2.07 (d, J = 7.7 Hz, 8H).
Example 279 34(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(hydroxy)methyl)bicyclo[2.2.1]heptan-2-ol (1020-279) le 0 NaBH4 HOHN
11111. Me0H, 0 C* IW r HN

[00879] 342-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-y1)(hydroxy)methyl)bicyclo[2.2.1]heptan-2-one (15 mg, 0.04 mmol) was dissolved in lm Me0H and cooled to 0 C under argon. To this was added sodium borohydride (4.35 mg, 0.11 mmol) and reaction allowed to warm to room temperature for 2 hours. Solvents were removed under reduced pressure and residue' was diluted in EtAc /
aqueous ammonium chloride, extracted 3x with EtAc, washed with water then brine then dried over sodium sulfate before removing solvents under reduced pressure.
Crude residue was purified by reverse phase HPLC to afford 34(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(hydroxy)methyl)bicyclo[2.2.1]heptan-2-ol as a mixture of isomers.
lr) [00880] LCMS (m/z +1) 394.3. 1H NMR (400 MHz, DMSO-d6) 6 7.42 (s, 1H), 7.26 (s, 1H), 4.80 (d, J = 8.0 Hz, 1H), 2.40 (s, 3H), 2.21 (s, 3H), 2.15 ¨2.08 (m, 1H), 1.86¨ 1.75 (m, 1H), 1.72 (d, J = 4.0 Hz, 1H), 1.57 (d, J = 9.9 Hz, 1H), 1.43 (d, J = 8.7 Hz, 1H), 1.48 ¨ 0.91 (m, 9H).
Example 280 24(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)(hydroxy)methyl)cyclopentanol (1020-280) 0 *=
H + 1. LDA, THF,-78C Boc_ 40 HO _______________ = HO 4N HCI
in dioxanes Boc-N 2. NaBH4, Me0H, 0 N C ethanol HN
0 <ir-.="-N OH OH
<1--z--"N
Step 1: Preparation of tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-(hydroxy(2-hydroxycyclopentyl)methyl)-1H-benzo[d]imidazole-1-carboxylate [00881] Cyclopentanone (0.14 ml, 1.57 mmol) was taken up in THF (5 ml) and cooled to -78 C under argon. To this was slowly added 2M lithium diisopropylamide in THF (0.92 ml) over 5 minutes and the resulting solution was allowed to stir for 30 minutes. At this time a solution of tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-fonnyl-1H-benzo[djimidazole-l-carboxylate (100 mg, 0.26 mmol) in 2 mL
THF
was slowly added. Reaction was allowed to stir atr -78 C for 10 minutes quenched into stirring aqueous ammonium chloride / EtAc, extracted 3x with EtAc, washed with water then brine then dried over sodium sulfate before removing solvents under reduced pressure. Material was immediately taken up in 5 mL methanol, cooled to 0 C
and had sodium borohydrode (19.83 mg, 0.52 mmol) added to it. Reaction was allowed to warm to room temperature and react for 2 hours. Solvents were removed under reduced pressure. Residue was dissolved in EtAc / aqueous ammonium chloride, extracted 3x with EtAc, washed with water then brine then dried over sodium sulfate before removing solvents under reduced pressure to provide crude tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(hydroxy(2-hydroxycyclopentyl)methyl)-1H-benzo[d]imidazole-1-carboxylate as racemic mixture of 2 diastereomers.

[00882] LCMS (m/z +1) 468.2 Step 2: Preparation of 24(2-cycloprop_y1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(hydroxy)methyl)cyclopentanol [00883] tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(hydroxy(2-hydroxycyclopentypmethyl)-1H-benzo[d]imidazole-1-carboxylate (122 mg, 0.26 mmol) was taken up in ethanol (5 ml) and 2.5 mL HC1 in dioxane. Mixture was then heated to 65 C for 40 minutes. Solvents were removed under reduced pressure and residue purified by reverse phase HPLC to afford the TFA salt of 24(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(hydroxy)methypcyclopentanol as a racemic mixture of 4 diastereomers.
[00884] LCMS (m/z +1) 368.2. 1H NMR (400 MHz, DMSO-d6) 6 7.46 (dq, J =
4.5, 1.4 Hz, 1H), 7.40- 7.26 (m, 1H), 5.10 (d, J = 9.1 Hz, 0.3H), 5.01 (d, J =
9.1 Hz, 0.3H), 4.92 (d, J = 9.1 Hz, 0.3H), 4.87 (d, J = 9.1 Hz, 0.5H), 4.34 (t, J =
3.5 Hz, 0.3H), 4.10 (dt, J = 6.2, 4.3 Hz, 0.3H), 3.85 (q, J = 5.3 Hz, 0.5H), 3.61 (dd, J =
7.9, 4.3 Hz, 0.3H), 2.58 -2.49 (m, 1H), 2.39 (d, J = 1.7 Hz, 3H), 2.21 (d, J = 1.5 Hz, 4H), 1.88 - 1.26 (m, 10H).
Example 281 and 282 (S)-(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(6-methylpyridin-2-y1)((R)-tetrahydrofuran-2-yOmethanol (1020-281) and (R)-(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(6-methylpyridin-2-y1)((S)-tetrahydrofuran-2-yl)methanol (1020-282) Iv Iv Iv 401 0 __________________ = 9 o HN HN HN =
HO / N\ NHO /

[00885] From Example 114, the mixture was separated to provide the two enantiomers using HPLC chiral column.
LCMS (m/z +1) 445.23 Example 283 and 284 (R)-(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)((S)-tetrahydrofuran-2-yOmethanol (1020-283) and (R)-(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)((R)-tetrahydrofuran-2-yOmethanol (1020-284) 01 0 __________________________________ 0 BoeN
OH OH OH
[00886] To tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(hydroxy(tetrahydrofuran-2-yl)methyl)-1H-benzo[d]imidazole-1-carboxylate (36 mg, 0.079 mmol, 1 equiv.) 1 is added TFA (5 mL) and allowed to stir for 30 min.
After the reaction was complete, it was concentrated in vacuo. Purification was carried out by reverse phase HPLC to furnish a mixture of isomers. It was then separated to provide the two isomers using HPLC chiral separation to furnish (R)-(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)((S)-tetrahydrofuran-2-yemethanol and (R)-(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)((R)-tetrahydrofuran-2-yl)methanol.
[00887] Compound 1020-283: LCMS (m/z +1) 352.46. IHNMR (400 MHz, Methanol-d4) 6 7.33 (s, 1H), 7.19 (s, 1H), 5.05 (d, J = 6.0 Hz, 1H), 4.27 -4.18 (m, 1 H), 3.89-3.80 (m, 1 H), 3.78 -3 .60 (m, 1 H), 2.41 (s, 3H), 2.27 (s, 1H), 2.28 (m, 1 H), 1.49 (dd, J = 8.3, 3.0 Hz, 4H), 1.34 (dd, J = 4.9, 2.7 Hz, 4H). 19F NMR (376 MHz, Methanol-d4) 6 -77.91.

[00888] Compound 1020-284: LCMS (m/z +1) 352.42. 1H NMR (400 MHz, Methanol-d4) 6 7.33 (s, 1H), 7.19 (s, 1H), 5.04 (d, J= 6.1 Hz, 1H), 4.31 ¨4.15 (m, 1H), 3.96 ¨ 3.82 (m, 1H), 3.79 (q, J= 7.3, 6.9 Hz, 1H), 2.41 (s, 4H), 2.25 (s, 5H), 1.95¨ 1.68 (m, 5H), 1.21 (ddt, J= 10.3, 7.5, 2.6 Hz, 5H).
Example 285 Cyclopenty1(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yl)methanone (1020-285) HN
*
100889] Into a flask containing cyclopenty1(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)methanol (25 mg, 0.07 mmol, 1 equiv.) in DCM (3 mL) is added Dess-Martin periodinane (150 mg, 0.36 mmol, 5 equiv.). The reaction was extracted with DCM and washed with water, saturated NH4C1.
After drying with MgSO4, it was filtered and concentrated to dryness.
Purification was carried out by reverse phase HPLC to furnish cyclopenty1(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-yOmethanone.
[00890] LCMS (m/z+1) 350.28. 1H NMR (400 MHz, Methanol-d4) 6 7.77 (s, 1H), 7.64 (s, 1H), 4.00 -3.90 (m, 1 H), 2.42 (s, 3H), 2.27 (s, 3H), 2.32-2.25 (m, 1 H), 2.05-1.90 (m, 4H), 1.75-1.60 (m, 4H), 1.20-1.10 (m, 4H). 1.9F NMR (376 MHz, Methanol-d4) 6 -77.91.
Example 286 (2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyrimidin-2-y1)(tetrahydrofuran-2-yOmethanol (1020-286) Br -*)-0 =1) -78 C, n-BuLi, DCM
+ NNIS OH

2) TFA HN

¨N <1--N

[00891] In a flame dried flask containing 2-bromopyrimidine (111 mg, 0.70 mmol) in DCM was added n-BuLi (0.39 mL, 0.62 mmol) at -78 C. The solution was allowed to stir for 30 minutes, followed by the addition of tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(tetrahydrofuran-2-carbony1)-1H-benzo[d]imidazole-1-carboxylate (70 mg, 0.16 mmol). The solution was allowed to warm to room temperature. Once complete, the solution was quenched with DI H2O and extracted three times with Et0Ac. The combined organic layers were washed with saturated NaC1, dried over sodium sulfate, filtered and concentrated in vacuo. To the crude product was added mL of TFA and was allowed to stir for 30 minutes. The solution was concentrated in vacuo and was purified via reverse phase HPLC to afford (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyrimidin-2-y1)(tetrahydrofuran-2-yOmethanol.
[00892] C24H25N503. MS. m/z 432.5 (M+1). 1H NMR (400 MHz, ed3od) 6 8.86 (d, J = 4.9 Hz, 2H), 7.94 (d, J= 1.4 Hz, 1H), 7.48 (d, J= 1.4 Hz, 1H), 7.41 (t, J= 4.9 Hz, 1H), 5.24 (t, Jr 6.8 Hz, 1H), 3.92 (dt, J = 13.8, 7.0 Hz, 2H), 3.76 (dd, J=
12.4, 7.4 Hz, 2H), 2.43 (s, 3H), 2.26 (s, 3H).
Example 287 642-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(hydroxy)(tetrahydrofuran-2-ypmethyl)-1-methylpyridin-2(1H)-one (1020-287) HN
.(1-N

[00893] 6-42-cyclopropyl-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-y1)(hydroxy)(tetrahydrofuran-2-y1)methyl)-1-methylpyridin-2(1H)-one was synthesized in a similar fashion to Example 286, substituting 2-bromopyrimidine for 6-bromo-1-methylpyridin-2(1H)-one (128 mg, 0.68 mmol), and DCM for THF as the solvent.
[00894] C26H28N404. MS. m/z 641.5 (M+1). 1H NMR (400 MHz, cd3od) 6 7.61 (dd, J= 9.0, 7.4 Hz, 1H), 7.52 (d, J= 1.3 Hz, 1H), 7.17 (d, J= 6.5 Hz, 1H), 6.80 (d, J=
1.1 Hz, 1H), 6.61 (d, J= 8.2 Hz, 1H), 3.28 (s, 3H), 2.27 (s, 3H), 2.06 (s, 3H), 1.95- 1.79 (m, 3H), 1.59 (td, J= 7.8, 5.0 Hz, 2H), 1.49- 1.43 (m, 2H), 1.43- 1.34 (m, 1H).
Example 288 (2-Cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyridin-y1)(tetrahydrofuran-2-yOmethanol (1020-288) Iv la OH
HN
N
[00895] (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyridin-2-y1)(tetrahydrofuran-2-yl)methanol was synthesized in a similar fashion to Example 286, substituting 6-bromo-1-methylpyridin-2(1H)-one for 2-bromopyridine.
[00896] C25H26N403. MS. m/z 431.5 (M+1). 1H NMR (400 MHz, cd3od) 6 8.74 (d, J= 4.7 Hz, 1H), 8.25 (td, J= 7.9, 1.6 Hz, 1H), 8.12 (d, J= 8.1 Hz, 1H), 7.73 -7.69 (m, 1H), 7.59 (d, J= 1.3 Hz, 1H), 7.53 (d, J= 1.2 Hz, 1H), 5.19 (t, J= 6.8 Hz, 1H), 3.99 '1')S2 ¨ 3.90 (m, 1H), 3.85 (dd, J= 14.2, 6.6 Hz, 1H), 2.67 (ddd, J= 13.5, 8.5, 5.0 Hz, 1H), 2.38 (s, 3H), 2.21 (s, 3H), 1.96¨ 1.86 (m, 4H), 1.57¨ 1.51 (m, 2H), 1.45 ¨
1.38 (m, 2H).
Example 289 and 290 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyridazin-3-y1)(tetrahydrofuran-2-yOmethanol enantiomer 1 (1020-289) and (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyridazin-3-y1)(tetrahydrofuran-2-yl)methanol enantiomer 2 (1020-290) el OH 0 HN
j="-N N
I AI
[00897] Enantiomers were resolved using a Chiralpak AD-H column (Heptane:IPA, 70:30) to afford the two title compounds.
Example 291 tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(hydroxy(2-(methylthio)phenyl)(tetrahydrofuran-2-yemethyl)-1H-benzo[d]imidazole-1-carboxylate (1020-291) O¨N O¨N

_________________________________________ HN

[00898] The ketone (0.1g) was dissolved in 2-Me-THE (4 ml), cooled to -20 C, and the Grignard reagent (0.1 ml, 0.5 M in THF) added drop wise, After stirring for 20 mm, Me0H (1 ml) was added, volatiles were removed and the residue purified by reverse phase HPLC (5-95% MeCN in water, 0.1% TFA) to afford tert-butyl 2-cyclopropy1-6-(3 ,5-dim ethyli soxazol-4-y1)-4-(hydroxy(2 -(methylthio)phenyl)(tetrahydro furan-2-yl)methyl)-1H-benzo [d] imidazol e-l-carboxylate.
[00899] LCMS (m/z +1) 440.1. 1H NMR (400 MHz, Acetonitrile-d3) 8 12.05 (s, 1H), 7.81 -7.70 (m, 1H), 7.45 (d, J = 1.5 Hz, 1H), 7.40 (d, J = 1.4 Hz, OH), 7.27 - 7.17 (m, 2H), 7.14 (ddd, J = 7.7, 6.2, 2.6 Hz, 1H), 7.07 (d, J = 1.4 Hz, OH), 7.00 (d, J = 4.4 Hz, 1H), 6.46 (d, J = 1.5 Hz, 1H), 4.73 (dd, J = 7.6, 6.2 Hz, 1H), 4.34 (d, J
= 13.0 Hz, 1H), 3.96 - 3.79 (m, 2H), 3.77 - 3.58 (m, 1H), 2.52 (tt, J = 8.5, 5.1 Hz, 2H), 2.24 (s, 1H), 1.92 (s, 2H), 1.83 - 1.48 (m, 7H), 1.45 - 1.33 (m, 2H), 1.34- 1.24 (m, 1H), 1.19 (s, 1H).
Example 292 1-(2-cyclopropy1-6-(3 ,5-dim ethyli soxazol-4-y1)-1H-b enz o [d]imidazol-4-y1)-2-methy1-1-(tetrahydrofuran-2-yl)propan-1-01 (1020-292) la 0 si OH
Boc-N
HN
<r-N 0 <r-N

[00900] To a solution of tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(tetrahydrofuran-2-carbony1)-1H-benzo[d]imidazole-1-carboxylate (100 mg, 0.22 mmol) in toluene (4 mL) was added iPrMgC1 (273 mg, 2.66 mmol) and the solution was stirred at room temperature overnight. Et0Ac (100 mL) was added and the solution was washed with aq NH4C1, brine and dried over Na2SO4. Solvent was removed and the residue was purified by silica gel column (0-15% Me0H in CH2C12), then (0-60% Et0Ac in hexane) to give product as N-Boc intermediate which was dissolved in a mixture of MeTHF (2 mL), TFA (2 mL) and H20 (0.2 mL). The solution was heated at 50 C for lh. The solution was concentrated to dryness and the residue was purified by HPLC to give 1-(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)-2-methyl-1-(tetrahydrofuran-2-yl)propan-1-01.
[00901] C23H29N303. MS. m/z 396.2 (M+1). 11-1NMR (Methanol-d4) 8 7.45 (d, J

= 1.4 Hz, 1H), 7.19 (d, J= 1.5 Hz, 1H), 4.64 (t, J= 7.4 Hz, 1H), 3.91 - 3.76 (m, 2H), 2.66 (tt, J= 8.5, 5.1 Hz, 1H), 2.54 -2.38 (m, 4H), 2.25 (s, 3H), 1.88 - 1.73 (m, 2H), 1.70 - 1.60 (m, 2H), 1.58- 1.49 (m, 2H), 1.46- 1.33 (m, 2H), 0.94 (dd, J= 13.2, 6.8 Hz, 6H).
Example 293 (6-bromo-3-fluoro-2-methylpyridin-4-y1)(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(tetrahydrofuran-2-yemethanol (1020-293) O-N O-N O-N

B H
Boc-N Boc-N /N 110 O0 HN N
<r-N 0 0 r <r-N
Br [00902] To a solution of 2-bromo-5-fluoro-6-methyl-2-pyridine (337 mg, 1.77 mmol) in THF (10 mL) was added BuLi (0.113 mg, 1.77 mmol) and the solution was stirred at -78 C for lh. To the solution was added a solution of tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(tetrahydrofuran-2-carbony1)-1H-benzo[d]imidazole-1-carboxylate (200 mg, 0.443 mmol) in THF (2 mL) and the solution was stirred at for lh. Aq NH4C1 was added and the solution was extracted with Et0Ac (200 mL).
The organic solution was washed with brine and dried over Na20S4. Solvent was removed and the residue was purified by silica gel column chromatography (0-10% Me0H
in CH2C12) to give tert-butyl 446-bromo-3-fluoro-2-methylpyridin-4-y1)(hydroxy)(tetrahydrofuran-2-yl)methyl)-2-cyclopropyl-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazole-1-carboxylate and (6-bromo-3-fluoro-2-methylpyridin-4-y1)(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(tetrahydrofuran-2-yl)methanol.
[00903] tert-Butyl 4-((6-bromo-3-fluoro-2-methylpyridin-4-y1)(hydroxy)(tetrahydrofuran-2-yOmethyl)-2-cyclopropyl-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazole-1-carboxylate: C311-134BrFN405. MS. m/z 640.6 (M+1). 11-1 NMR
(Chloroform-d) 6 7.88 (d, J= 5.1 Hz, 1H), 7.72 (d, J= 1.4 Hz, 1H), 7.32 (dd, J= 2.4, 1.5 Hz, 1H), 5.25 (t, J= 6.6 Hz, 1H), 4.05 -3.95 (m, 1H), 3.88 (td, J= 7.5, 5.2 Hz, 1H), 2.91 -2.74 (m, 1H), 2.43 (s, 3H), 2.34 (d, J= 3.4 Hz, 3H), 2.29 (s, 3H), 2.02-1.76 (m, 4H), 1.68 (s, 9H), 1.18 (ddt,J= 10.8, 5.3, 2.6 Hz, 4H).
[00904] (6-Bromo-3-fluoro-2-methylpyridin-4-y1)(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(tetrahydrofuran-2-yl)methanol:
C26H26BrFN403. MS. m/z 541.5 (M+1). 1H NMR (Methanol-d4). 1H NMR (Methanol-d4) 8 8.07 (d, J= 5.0 Hz, 1H), 7.47 (d, J= 1.4 Hz, 1H), 7.31 - 7.21 (m, 1H), 5.07 (t, J-6.5 Hz, 1H), 4.01 (q, J= 7.1 Hz, 1H), 3.95 - 3.81 (m, 1H), 2.77 -2.63 (m, 1H), 2.37 -2.29 (m, 6H), 2.17 (s, 3H), 2.01 - 1.86 (m, 3H), 1.76 (d, J= 6.0 Hz, 1H), 1.56 (dd, 1=
8.5, 2.8 Hz, 2H), 1.47 - 1.33 (m, 2H).
Example 294 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(3-fluoro-2-methylpyridin-4-y1)(tetrahydrofuran-2-yl)methanol (1020-294) O-N O-N

HN N HN z N
0 Br [00905] A mixture of (6-bromo-3-fluoro-2-methylpyridin-4-y1)(2-cyclopropy1-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(tetrahydrofuran-2-yOmethanol (25 mg, 0.046 mmol) and Pd/C (10 % 10 mg) in Me0H (5 mL) was stirred under H2 balloon for 3h. Reaction mixture was filtered and the filtrate was concentrated to dryness to give (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(3-fluoro-2-methylpyridin-4-y1)(tetrahydrofuran-2-ypmethanol.
[00906] C26H27FN403. MS. m/z 463.2 (M+1). IFINMR (Methanol-d4) 6 8.38 (d, J
= 5.5 Hz, 1H),8.10 (t, J= 5.8 Hz, 1H),7.50 (d, J= 1.4 Hz, 1H), '7.22 (t, J=
1.3 Hz, 1H), 5.11 (t, J= 7.0 Hz, 1H), 4.09 - 3.96 (m, 1H), 3.89 (ddd, J= 7.9, 6.4, 4.4 Hz, 1H), 2.73 (tt,J= 8.4, 5.0 Hz, 1H), 2.44 (d, J= 3.2 Hz, 3H), 2.34 (s, 3H), 2.16 (s, 3H), 2.04- 1.90 (m, 3H), 1.78 (qd, J= 7.1, 4.8 Hz, 1H), 1.62- 1.50 (m, 2H), 1.43 (tt, J= 5.1, 3.8 Hz, 2H).
Example 295 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-111-benzo[d]imidazol-4-y1)(3-fluoro-2-methy1-6-(methylthio)pyridin-4-y1)(tetrahydrofuran-2-yl)methanol (1020-295) la OH F op OH
HN / N HN N
<r-N
0 Br [00907] To a solution of (6-bromo-3-fluoro-2-methylpyridin-4-y1)(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(tetrahydrofuran-2-yOmethanol (20 mg, 0.037 mmol) in DMF (5 mL) was added NaSMe (0.1 g, excess) and the mixture was heated a 120 C for lh. Solvent was removed and the residue was purified by HPLC
to give (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(3-fluoro-2-methyl-6-(methylthio)pyridin-4-y1)(tetrahydrofuran-2-y1)methanol.
[009081 C27H29FN403S. MS m/z 509.3 (M+1). 1H NMR (Methanol-d4) 6 7.74 -7.68 (m, 1H), 7.45 (d, J- 1.4 Hz, 1H), 7.22 (t, J= 1.4 Hz, 1H), 5.06 (d, J=
6.8 Hz, 1H), 4.05 -3.96 (m, 1H), 3.89 (t, J= 6.9 Hz, 1H), 2.68 (dq, J= 9.2, 5.3, 4.6 Hz, 1H), 2.54 (s, 3H), 2.37 - 2.28 (m, 6H), 2.16 (s, 3H), 1.92 (s, 3H), 1.74 (d, J= 7.3 Hz, 1H), 1.55 (dd, J
= 8.5, 2.8 Hz, 2H), 1.45 - 1.35 (m, 2H).
Example 296 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(5,5-dimethyltetrahydrofuran-2-y1)(pyridin-2-ypmethanol (1020-296) Step 1: Tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-445,5-dimethyltetrahydrofuran-2-y1)(hydroxy)methyl)-1H-benzo[d]imidazole-1-carboxylate qqq triethylborane, 2,2-D1MeTHF
H t-butylhydroperoxide 0 BocN BocN
<r-N 0 <r-N OH
0 C tort [00909] Into a flask containing tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-formy1-1H-benzo[d]imidazole-l-carboxylate (600 mg, 1.57 mmol, 1 equiv.) was added 2,2-dimethyltetrahydrofuran (20 mL) and cooled to 0 C before adding triethylborane (2.2 mL, 14.16 mmol, 9 equiv.). Tert-butylhydroperoxide (1.7 mL, 9.43 mmol, 6 equiv., 6 M decanes) was added slowly to the reaction mixture and the reaction allowed to waini up slowly to room temperature. After completion, the reaction was quenched with NH4OH solution (5 mL) and extracted with Et0Ac and washed with water (spiked with a solution of FeSO4.H2SO4.H20 (2 mL)) and then with saturated NH4C1. After drying with MgSO4, it was filtered and concentrated to dryness.
Purification was carried out by flash column chromatography to tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-44(5,5-dimethyltetrahydrofuran-2-ye(hydroxy)methyl)-1H-benzo[d]imidazole-1-carboxylate (505 mg, y. 41%, dr 3:2).
[00910] LCMS (m/z +1) 481.14 Step 2: tert-buty1-2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(5,5-dimethyltetrahydrofuran-2-carbony1)-1H-benzo[d]imidazole-1-carboxylate =o = 0 BocN BocN
<?---2"--N OH ,irN 0 [00911] Into a flask containing to tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-44(5,5-dimethyltetrahydrofuran-2-y1)(hydroxy)methyl)-1H-benzo[d]imidazole-1-carboxylate (505 mg, 0.73 mmol, 1 equiv.) was added DCM
(100 mL) and Dess-Martin periodinane (467 mg, 1.10 mmol, 1.5 equiv.). After completion, the reaction was quenched with sodium thiosulfate solution and allowed to stir for several minutes. It was extracted with DCM and washed with water and saturated NH4C1. After drying with MgSO4, it was filtered and concentrated to dryness.
Purification was carried out by flash column chromatography to furnish tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(5,5-dimethyltetrahydrofuran-2-carbony1)-1H-benzo[d]imidazole-1-carboxylate (202 mg, y.57%).
[00912] LCMS (m/z +1) 480.51 Step 3: (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(5,5-dimethyltetrahydrofuran-2-y1)(pyridin-2-yl)methanol FIN
BocN HO 0 [00913] In a flame dried flask containing 2-bromopyrimidine (99 pL, 1.04 mmol, equiv.) in THF was added n-BuLi (0.71 mL, 1.14 mmol, 11 equiv.) at -78 C. The solution was allowed to stir for 30 minutes, followed by the addition furnish tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(5,5-dimethyltetrahydrofuran-2-carbonye-1H-benzo[d]imidazole-1-carboxylate (50 mg, 0.10 mmol, 1 equiv.). The solution was allowed to walln to room temperature. Once complete, the solution was quenched with water and extracted three times with Et0Ac. The combined organic layers were washed with saturated NaC1, dried over sodium sulfate, filtered and concentrated in vacuo. To the crude product was added 5 mL of TFA and was allowed to stir for 30 minutes. The solution was concentrated in vacuo and was purified via reverse phase HPLC to afford (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(5,5-dimethyltetrahydrofuran-2-y1)(pyridin-2-yOmethanol.
11c [00914] 1H NMR (400 MHz, Methanol-d4) 6 8.76 ¨ 8.59 (m, 1H), 7.96 (t, J =
7.6 Hz, 1H), 7.89 ¨ 7.80 (m, 1H), 7.71 (d, J = 1.5 Hz, 1H), 7.55 ¨7.39 (m, 1H), 5.24 (t, J
7.3 Hz, 1H), 2.61 (ddd, J = 8.5, 5.0, 3.5 Hz, 1H), 2.41 (s, 3H), 2.24 (s, 3H), 2.05¨ 1.69 (m, 4H), 1.68 ¨ 1.44 (m, 2H), 1.44¨ 1.30 (m, 1H), 1.25 (s, 3H), 1.17 (s, 3H), 1.00 (t, J =
7.4 Hz, 1H). 19F NMR (377 MHz, Methanol-d4) 6 -77.90.
Example 297 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[djimidazol-4-y1)(5,5-dimethyltetrahydrofuran-2-y1)(6-methylpyridin-2-y1)methanol (1020-297) 1. \MgBr THF 40 0 BooN
2. TFA HO
[00915] Into a flask containing tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(5,5-dimethyltetrahydrofuran-2-carbony1)-1H-benzo[d]imidazole-1-carboxylate (50mg, 0.10 mmol, 1 equiv.) is added THF (5 mL) and to it is added (6-methylpyridin-2-yl)magnesium bromide (2.5 mL, 0.63 mmol, 6 equiv., 0.25 M THF, Rieke Metals).
After completion, the reaction was quenched and extracted with Et0Ac and washed with water, saturated NH4C1. After drying with MgSO4, it was filtered and concentrated to dryness. To the crude material is added TFA (5 mL) and allowed to stir for 30 min. After the reaction was complete, it was concentrated in yam). Purification was carried out by reverse phase HPLC to furnish (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(5,5-dimethyltetrahydrofuran-2-y1)(6-methylpyridin-2-yl)methanol (as a racemic single diastereomer).
[00916] 1H NMR (400 MHz, Methanol-d4) 6 7.99 ¨ 7.80 (m, 1H), 7.70 (q, J =
3.5 Hz, 3H), 7.50 ¨ 7.46 (m, 1H), 7.37 (s, 1H), 5.21 (t, J = 7.3 Hz, 1H), 2.67 (s, 4H), 2.64 ¨
2.53 (m, 1H), 2.41 (s, 4H), 2.24 (s, 4H), 2.05 ¨ 1.81 (m, 2H), 1.83 ¨ 1.70 (m, 1H), 1.64 ¨
1.55 (m, 1H), 1.54¨ 1.47 (m, 2H), 1.36 (dd, J = 6.1, 2.6 Hz, 2H), 1.25 (s, 4H), 1.17 (s, 4H). 19F NMR (377 MHz, Methanol-d4) -77.87.

Example 298 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(5,5-dimethyltetrahydrofuran-2-y1)(pyridazin-3-y1)methanol (1020-298) * 0 \ HN N
BocN
HO
<p-N
[00917] Into a flask containing pyridazine (110 p,L, 1.15 mml, 8 equiv.) was added MeTHF (5 mL) and to it slowly added TMP.MgCl.LiC1 (1.46 mL, 1.46 mmol, equiv., 1M) at -78 C over 10 mm. After 45 minutes tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(5,5-dimethyltetrahydrofuran-2-carbony1)-1H-benzo[d]imidazole-1-carboxylate (70 mg, 0.14 inmol, 1 equiv.) dissolved in MeTHF (2 ML) is added slowly to the reaction. After completion, the reaction was quenched and extracted with Et0Ac and washed with water, saturated NH4C1. After drying with MgSO4, it was filtered and concentrated to dryness. To the crude material is added TFA
(5 mL) and allowed to stir for 30 min. After the reaction was complete, it was concentrated in vacuo. Purification was carried out by reverse phase HPLC (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(5,5-dimethyltetrahydrofuran-2-y1)(pyridazin-3-yemethanol (as a racemic single diastereomer).
[00918] LCMS (m/z +1) 460.23. 1H NMR (400 MHz, Methanol-d4) 6 9.33 (dd, J
= 2.3, 1.2 Hz, OH), 9.18 (dd, J = 5.5, 1.2 Hz, OH), 9.11 (dd, J = 4.9, 1.6 Hz, 1H), 8.12 (dd, J = 8.7, 1.6 Hz, 1H), 8.03 (dd, J = 5.5, 2.4 Hz, OH), 7.65 (d, J = 1.5 Hz, 1H), 7.53 (d, J = 1.5 Hz, OH), 7.48 (d, J = 1.5 Hz, 1H), 5.41 (t, J = 7.4 Hz, 1H), 2.65 (s, 3H), 2.43 (d, J
=4.8 Hz, 2H), 2.38 (s, 3H), 2.34 - 2.11 (m, 5H), 2.13 - 1.86 (m, 3H), 1.86-1.58 (m, 4H), 1.58 - 1.45 (m, 4H), 1.45 - 1.34 (m, 4H), 1.34 - 1.10 (m, 8H), 1.06 (s, 1H). 19F
NMR (377 MHz, Methanol-d4) 6 -77.96.
Example 299 1'17 Preparation of (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(oxetan-2-yl)methanol (1020-299) Step 1: Preparation of tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-(hydroxy(oxetan-2-y1)methyl)-1H-benzo[dlimidazole-1-carboxylate TEB, t-BHP 0 Oxetane 0 C to RT

¨N H KI-N1 HO
[00919] Into a flask containing tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-formy1-1H-benzo[d]imidazole-1-carboxylate (100 mg, 0.73 mmol) is added Oxetane (10 mL) and cooled to Ot before adding triethylborane (3.1 mL, 3.14, mmol, 1M in hexanes). Tert-butylhydroperoxide (0.27 mL, 1.6 mmol, 5.5M) is added slowly to the reaction mixture and the reaction was allowed to warm slowly to room temperature.
After completion, the reaction was quenched with NH4OH solution and extracted with Et0Ac and washed with water (spiked with a solution of FeSO4.H2SO4.H20 (2 mL)) and then with saturated NH4C1. After drying with MgSO4, it was filtered and concentrated to dryness. Purification was carried out by flash column chromatography to afford tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(hydroxy(oxetan-2-yl)methyl)-1H-benzo[d]imidazole-1-carboxylate.
[00920] C24H29N305. MS. M/Z 440.5 (M+1).
Step 2: Preparation of tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-(oxetane-2-carbony1)-1H-benzo[djimidazole-1-carboxylate Dess-Martin 0 la Periodinane OH

DCM

"42R

[00921] To a flame dried flask containing tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(hydroxy(oxetan-2-yl)methyl)-1H-benzo[d]imidazole-1-carboxylate (155 mg, 0.35 mmol) was added Dess-Martin Periodinane (0.194g, 0.46 mmol). The reaction was allowed to stir for 1 hour. Once complete, the solution was quenched with saturated sodium thiosulfate and allowed to stir for 20 minutes.
Once complete, the solution was quenched with DI H20 and extracted three times with Et0Ac.
The combined organic layers were washed with saturated NaC1, dried over sodium sulfate, filtered and concentrated in yam() and purified via flash column chromatography (97.7 mg, 63% yield).
Step 3: Preparation of (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(oxetan-2-yl)methanol -)¨.0 OH TFA
HN OH

[00922] To a flask containing 5 mL of TFS was added tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(hydroxy(oxetan-2-yOmethyl)-1H-benzo[d]imidazole-carboxylate (34 mg, 0.08 mmol). The reaction was allowed to stir for 30 minutes. Once complete, the solution was concentrated in vacuo where is was then purified via reverse phase HPLC to afford (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(oxetan-2-yl)methanol.
[00923] C19H21N303. MS. m/z 440.5 (M+1).
Example 300 Preparation of 1-(2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)-1-(6-methylpyridin-2-yl)butane-1,2,4-triol (1020-300) MgBr 1) THF
0 110 0 + )N _______________________________ = 110 OH
OH
2) TFA HN OH

N
[00924] In a flame dried flask containing tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(oxetane-2-carbony1)-1H-benzo[d]imidazole-1-carboxylate (50 mg, 0.1 mmol) was added (6-methylpyridin-2-yl)magnesium bromide (2.74 mL, 0.69 mmol, 0.25M) in THF. The reaction was allowed to stir for 1 hour. Once complete, the solution was quenched with DI H2O and extracted three times with Et0Ac. The combined organic layers were washed with saturated NaC1, dried over sodium sulfate, filtered and concentrated in vacua. To the crude product was added 5 mL of TFA
and was allowed to stir for 30 minutes. The solution was concentrated in vacua and was purified via reverse phase HPLC to afford 1-(2-eyelopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)-1-(6-methylpyridin-2-yl)butane-1,2,4-triol.
[00925] C25H28N404. MS. m/z 449.5 (M+1). 111 NMR (400 MHz, cd3od) 6 7.83 (t, J= 7.8 Hz, 1H), 7.74 (d, J= 8.1 Hz, 1H), 7.50 (d, J= 1.3 Hz, 1H), 7.42 (d, J=
1.3 Hz, 1H), 7.29 (d, J= 7.5 Hz, 1H), 5.04 (dd, J= 10.3, 2.0 Hz, 2H), 3.70 (dd, J=
7.2, 5.3 Hz, 2H), 2.64 (s, 3H), 2.37 (s, 3H), 2.20 (s, 3H), 1.85 ¨ 1.74 (m, 2H), 1.56¨ 1.49 (m, 4H).
Example 301 Preparation of (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyridin-2-y1)(tetrahydrofuran-3-yl)methanol (1020-301) Step 1: Preparation of tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-(tetrahydrofuran-3-carbony1)-1H-benzo[d]imidazole-1-carboxylate 1.d.n 0/, j-78 C, n-BuLi I
<(_¨N

[00926] In a flame dried flask containing tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-iodo-1H-benzo[d]imidazole-1-carboxylate (712 mg, 1 mmol) and N-methoxy-N-methyltetrahydrofuran-3-carboxamide (215 mg, 1 mmol) at -78 C
in THF was added n-BuLi (1.1 mL, 2 mmol, 1.6M). The solution was allowed to stir for 10 minutes, then was pulled from the cold bath to warm to room temperature. Once complete, the solution was quenched with DI H2O and extracted three times with Et0Ac.
The combined organic layers were washed with saturated NaCl, dried over sodium sulfate, filtered and concentrated in vacuo and purified via flash column chromatography to afford tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(tetrahydrofuran-3-carbony1)-1H-benzokilimidazole-1-carboxylate (0.56 mg, 46% yield).
[00927] C25H29N305. MS. m/z 452.5 (M+1).
Step 2: Preparation of (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(pyridin-2-y1)(tetrahydrofuran-3-yl)methanol OH
HN
N

[00928] Was synthesized in a similar fashion as that of Example 288, substituting tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(tetrahydrofuran-2-earbonyl)-1H-benzo[d]imidazole-1-carboxylate for tert-butyl 2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-4-(tetrahydrofuran-3-carbony1)-1H-benzo[d]imidazole-1-carboxylate (275 mg, 0.6 mmol).

[00929] C25H26N403. MS. m/z 431.5 (M+1). 1H NMR (400 MHz, cd3od) 6 8.60 (dd, J= 6.7, 5.6 Hz, 2H), 7.92¨ 7.81 (m, 5H), 7.64 (d, J= 1.3 Hz, 1H), 7.61 (d, J= 1.3 Hz, 1H), 7.47 (d, J= 1.1 Hz, 2H), 7.38 ¨7.33 (m, 2H), 4.39 ¨ 4.28 (m, 1H), 4.16 ¨ 4.04 (m, 2H), 4.00 ¨3.83 (m, 7H), 3.83 ¨ 3.71 (m, 6H), 3.65 (dt, J= 15.8, 8.7 Hz, 3H), 2.46 (s, 2H), 2.40 (s, 3H), 2.39 (s, 3H), 2.36 ¨ 2.28 (m, 4H), 2.23 (s, 3H), 2.21 (s, 3H), 2.09 ¨
1.96 (m, 2H), 1.95 ¨ 1.79 (m, 3H), 1.79¨ 1.67 (m, 2H).
Example 302 Preparation of (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(6-methylpyridin-2-y1)(tetrahydrofuran-3-yl)methanol (1020-302) OH
HN
<r-N
N
I
[00930] (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(6-methylpyridin-2-y1)(tetrahydrofuran-3-yl)methanol was synthesized in a similar fashion as that of Example 301 step 2, substituting pyridin-2-ylmagnesium bromide for (6-methylpyridin-2-yl)magnesium bromide (2.4 mL, 0.61 mmol, 0.25 M).
[00931] C26H28N403. MS. m/z 445.5 (M+1). 1H NMR (400 MHz, ed3od) 7.89 (ddd, J= 13.2, 12.1, 7.8 Hz, 3H), 7.75 ¨ 7.67 (m, 3H), 7.63 (dd, J= 8.3, 1.3 Hz, 2H), 7.49 (dd, J= 3.1, 1.3 Hz, 2H), 7.37 (d, J= 7.7 Hz, 1H), 7.33 (d, J= 7.7 Hz, 1H), 4.16 ¨
4.04 (m, 1H), 3.97 ¨ 3.85 (m, 5H), 3.83 ¨ 3.72 (m, 5H), 3.70 ¨ 3.61 (m, 3H), 2.71 ¨2.60 (m, 9H), 2.41 (s, 3H), 2.40 (s, 3H), 2.24 (s, 3H), 2.23 (s, 3H), 2.03 (ddd, J=
18.6, 11.8, 5.6 Hz, 2H), 1.97 ¨ 1.80 (m, 3H), 1.80¨ 1.68 (m, 2H).
Example 303 (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-4-y1)(6-methylpyridin-2-y1)(tetrahydro-2H-pyran-2-yl)methanol (1020-303) 14.7 DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.

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Claims (15)

We claim:

1. A compound of Formula (I) wherein R1a and R1b are each independently C1-6 alkyl optionally substituted with from 1 to 5 R20 groups;
R2a and R2b are each independently H or halo;
R3 is -C(O)OR a, -NHC(O)OR a, -NHS(O)2R a, or -S(O)2NR a R b; or selected from the group consisting of C1-10 alkyl, C1-10 alkoxy, amino, C5-10 aryl, C6-20 arylalkyl, C1-10 heteroalkyl, C5-10 heteroaryl, and C6-20 heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R20 groups;
one of R4a and R4b is selected from the group consisting of H and C1-6 alkyl optionally substituted with from 1 to 5 R20 groups, and the other is absent;
R5 is -C(O)OR a, -NHC(O)OR a, -NHS(O)2R a, or -S(O)2NR a R b; or selected from the group consisting of H, C1-10 alkyl, C1-10 haloalkyl, C1-10 alkoxy, amino, C5-10 aryl, C6-20 arylalkyl, C1-10 heteroalkyl, C5-10 heteroaryl, and heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R20 groups;

each R a and R b is independently selected from the group consisting of H, C1-10 alkyl, C5-10 aryl, C6-20 arylalkyl, C1-10 heteroalkyl, C5-10 heteroaryl, and C6-20 heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R20 groups; and each R20 is independently selected from the group consisting of acyl, C1-10 alkyl, C1-10 alkoxy, amino, amido, amidino, C5-10 aryl, C6-20 arylalkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, C1-10 haloalkyl, C1-10 heteroalkyl, C5-10 heteroaryl, C6-20 heteroarylalkyl, hydroxy, hydrazino, hydroxyl, imino, oxo, nitro, sulfinyl, sulfonic acid, sulfonyl, thiocyanate, thiol, and thione;
wherein the C1-10 alkyl, C5-10 aryl, C6-20 arylalkyl, C1-10 heteroalkyl, C5-10 heteroaryl, and C6-20 heteroarylalkyl groups are optionally substituted with from 1 to 3 substituents independently selected from C1-6 alkyl, C5-10 aryl, halo, C1-6 haloalkyl, cyano, hydroxyl, and C1-6 alkoxy;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, said compound of Formula (Id) or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1, said compound of Formula (Ie) or a pharmaceutically acceptable salt thereof.

4.The compound of any one of claims 1-3, wherein R3 C1-10 alkyl, C1-10 alkoxy, or C1-heteroalkyl, each of which may be optionally substituted with from 1 to 5 R20 groups, or a pharmaceutically acceptable salt thereof.

5.The compound of any one of claims 1-3, wherein R3 an, C5-10 aryl, C6-20 arylalkyl, C5-10 heteroaryl, or C6-20 heteroarylalkyl, each of which may be optionally substituted with from 1 to 5 R20 groups, or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1, said compound selected from the group consisting of or a pharmaceutically acceptable salt thereof.

7. A compound of the following formula or a pharmaceutically acceptable salt thereof.

8. A compound of the following formula or a pharmaceutically acceptable salt thereof.

9. A compound of the following formula or a pharmaceutically acceptable salt thereof.

10. A compound of the following formula or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising the compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

12. Use of the compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, or the composition of claim 11, for treating a disease or condition responsive to the inhibition of a bromodomain-containing protein, wherein the disease or condition is a neoplasm, cancer or tumor of the colon, rectum, prostate, lung, pancreas, liver, kidney, cervix, uterus, stomach, ovary, breast, skin, or the nervous system.

13. Use of the compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, or the composition of claim 11, in the manufacture of a medicament for treating a disease or condition responsive to the inhibition of a bromodomain-containing protein, wherein the disease or condition is a neoplasm, cancer or tumor of the colon, rectum, prostate, lung, pancreas, liver, kidney, cervix, uterus, stomach, ovary, breast, skin, or the nervous system.

14. The use of claim 12 or 13, wherein the bromodomain-containing protein is BRD4.

15. The use of any one of claims 12-14, wherein the disease or condition is diffuse large B-cell lymphoma or multiple myeloma.