PROTEIN KINASE INHIBITORS
Technical field
The present invention relates to therapeutically active compounds and pharma-
ceutically acceptable salts thereof which are useful e.g. in the treatment of cancer.
Background of the invention
Protein kinases are a class of proteins (enzymes) that regulate a variety of
cellular functions. This is accomplished by phosphorylation of specific amino acids on
protein substrates resulting in conformational alteration of the substrate protein. The
conformational change modulates the activity of the substrate or its ability to interact
with other binding partners. Tyrosine kinases are a subset of protein kinases that
catalyze the transfer of the terminal phosphate of adenosine triphosphate (ATP) to
tyrosine residues on protein substrates. The human genome contains around 90 tyrosine
kinases and 43 tyrosine kinase like genes, the products of which regulate cellular
proliferation, survival, differentiation, function and motility.
Tyrosine kinases are of two varieties, i.e. receptor and non-receptor tyrosine
kinases. Receptor tyrosine kinases (e.g., FGFR) are trans-membrane proteins with a
ligand-binding extracellular domain and a catalytic intracellular kinase domain, while
non-receptor tyrosine kinases (e.g., c-ABL) lack trans-membrane domains and are found
in the cytosol, nucleus and inner surface of cell membrane. Kinase domains of all
tyrosine kinases have bilobar architecture, with an N-terminal lobe that binds ATP and
magnesium, a C-terminal lobe containing an activation loop, and a cleft between the
lobes to which polypeptide substrates bind.
Receptor tyrosine kinases become activated when ligand binds to the
extracellular domain, resulting in receptor oligomerization and autophosphorylation of a
regulatory tyrosine within the activation loop of the kinase domain. These phenomena

reorient important amino acid residues, thereby enhancing catalytic activity of the
enzyme.
Fibroblast growth factor (FGF) has been recognized as an important mediator of
many physiological processes, such as cell migration, proliferation, survival and
differentiation during development and angiogenesis. There are currently over 25 known
members of the FGF family. The fibroblast growth factor receptor (FGFR) family
consists of four members with each composed of an extra cellular ligand binding
domain, a single trans-membrane domain and an intracellular cytoplasmic protein
tyrosine kinase domain. Upon stimulation with FGF, FGFRs undergo dimerisation and
transphosphorylation. Upon dimerization, FGFRs activate range of downstream
signaling pathways, such as MAPK and PKB/Akt pathways (Zhou, W. et. al. Chemistry
& Biology, 2010, 17, 285). Abnormal FGFR signaling has been reported in many tumor
types including multiple myeloma, gastric, endometrial, prostate and breast (Squires M.
et. al. Mol. Cancer Ther., September 2011, 10:1542-1552). FGFs also have role in
tumor angiogenesis and mediate resistance to vascular endothelial growth factor
receptor 2 (VEGFR2) inhibitors (Casanovas, O. et. al., Cancer Cell, 2005, 8, 299).
Consequently, FGF and FGFRs have the potential to initiate and/or promote
tumorigenesis. Due to this, the FGF signaling system happens to be an attractive
therapeutic target, mainly because therapies targeting FGFRs and/or FGF signaling may
affect both the tumor cells and also tumor angiogenesis (Foote, K. M. et. al., WO
2009/019518 Al). Consequently, FGF and FGFRs have the potential to initiate and/or
promote tumorigenesis.
Summary of the invention
It has been found that compounds of formula (I) inhibit or modulate the activity
of certain protein kinases, more specifically protein tyrosine kinases. In particular, it has
been found that the compounds of formula (I) are potent and selective inhibitors of
FGFR kinases. The compounds of the invention have antiproliferative activity and are
particularly useful in the treatment of cancer.

The compounds of the present invention have a structure represented by
formula (I)

wherein
Z1 is N and Z2 is CH, or
Z1 is CH and Z2 is N, or
Z1 and Z2 is N;
Z is CH or N;
A is a phenyl ring or a 5 -12 membered heterocyclic ring;
R1 is H, C1-7 alkyl, C3-7 cycloalkyl, C3.7 cycloalkyl C1-7 alkyl, C1-7 alkoxy, C1-7
alkyl carbonyl, amino, hydroxy, hydroxy C1-7 alkyl, halo C1-7 alkyl, C1-7 alkylamino C1-7
alkyl, -R16-C(O)-R17 or -E-R6;
R2 is H, halogen or C1-7 alkyl;
B is a 5-12 membered carbocyclic or heterocyclic ring;
R3 is H, halogen, C1-7 alkyl, C1-7 alkoxy, halo C1-7 alkyl or halo C1-7 alkoxy;
R4 is H, halogen, C1-7 alkyl or oxo;
R5 is H, -C(O)R7, -SO2R8 or an optionally substituted 5-6 membered
heterocyclic ring;
R6 is an optionally substituted 5-6 membered heterocyclic ring;
R7 is C1-7 alkyl, C2-7 alkenyl, C1-7 alkoxy, C1-7 alkoxy C1-7 alkyl, carboxy C1-7
alkyl, C1-7 alkoxy carbonyl C1-7 alkyl, C1-7 alkylamino C1-7 alkyl, -NH-R10 or -NH-X1-
R11;
R8 is C1-7 alkyl, C2-7 alkenyl, C3-7 cycloalkyl, hydroxy C1-7 alkyl, -NR13R14, -NH-
X2-R15, phenyl or an optionally substituted 5-6 membered heterocyclic ring;
R10 is C1-7 alkyl or C3-7 cycloalkyl;
R11 is phenyl or an optionally substituted 5-6 membered heterocyclic ring;

R12 is Hor C1-7ulkyl;
R13 and R14 are, independently, H, C1-7 alkyl or C3-7 cycloalkyl;
R15 is phenyl or an optionally substituted 5-6 membered heterocyclic ring;
R16 is a bond or a C1-7 alkyl;
R17 is C1-7 alkyl, C1-7 alkoxy, C1-7 alkylamino, amino or hydroxy;
E is a bond or a C1-7 alkyl;
X1 and X2 are, independently, a bond or C1-7 alkyl:
and pharmaceutically acceptable salts thereof.
In one class of compounds are compounds of formula (I), wherein Z is CH. In
another class of compounds are compounds of formula (I), wherein Z1 is N and Z2 is
CH. In another class of compounds are compounds of formula (I), wherein Z1 is CH and
Z2 is N. In another class of compounds are compounds of formula (I), wherein Z1 and Z2
isN.
In a subclass class of any of the above classes are compounds of formula (I),
wherein ring A is any one of the following groups or tautomers thereof:

and R1 and R2, as defined above, are attached to the above A-rings.

In a subclass class of any of the above classes are compounds of formula (I),
wherein ring B is any one of the following groups or tautomers thereof:

and R3 and R4, as defined above, are attached to the above B-rings.
Another subclass of the above classes are compounds wherein
A is a ring of formula (1'), (2'), (3'), (4'), (5'), (7'), (14'), (16') or (20');
R1 is H, C1-7 alkyl, C1-7 alkoxy, hydroxy C1-7 alkyl, C1-7 alkylamino C1-7 alkyl or
-E-R6;
R2 is H;
Z is CH;
B is a ring of formula (1"), (2"), (3"), (4") or (6");
E is a bond or C1-7 alkyl;
R6 is any of the following groups

R3 is H, halogen, C1-7 alkyl, C1-7 alkoxy;
R4 is H or halogen;
R5 is -C(O)R7 or -SO2R8 or any one of the following groups

R7 is C1-7 alkyl, C2-7 alkenyl or -NH-R10;
R8 is C1-7 alkyl, C1-7 alkenyl, C3-7 cycloalkyl, hydroxy C1-7 alkyl or -NR13R14; and
R10 is C1-7 alkyl or C3-7 cycloalkyl.

In one class of compounds are compounds of formula (I), wherein R5 is -C(O)R.7
or -SO2R8 or any one of the following groups

In one class of compounds are compounds of formula (I), wherein R5 is -SO2R.8.
In one class of compounds are compounds of formula (I), wherein R6 is any of
the following groups

The present invention also provides a pharmaceutical composition comprising a
compound of formula (I) or a pharmaceutically acceptable salt thereof together with a
pharmaceutically acceptable carrier.
The present invention provides further a use of a compound of formula (I) or a
pharmaceutically acceptable salt thereof in the manufacture of a medicament for the
treatment of a condition, where FGFR kinase inhibition is desired.
The present invention provides further a use of a compound of formula (I) or a
pharmaceutically acceptable salt thereof in the manufacture of a medicament for the
treatment of cancer.
The present invention provides a compound of formula (I) or a pharmaceutically
acceptable salt thereof for use in the treatment of a condition, where FGFR kinase
inhibition is desired.
The present invention provides a compound of formula (I) or a pharmaceutically
acceptable salt thereof for use in the treatment of cancer.

The present invention provides further a method for the treatment of a condition,
where FGFR kinase inhibition is desired comprising administering to a subject in need
thereof a therapeutically effective amount of a compound of formula (I).
The present invention provides further a method for the treatment of cancer
comprising administering to a subject in need thereof a therapeutically effective amount
of a compound of formula (I).
Detailed description of the invention
The compounds of the invention can be prepared by a variety of synthetic routes
analogously to the methods known in the literature using suitable starting materials. The
compounds according to formula (I) can be prepared e.g. analogously or according to
the following reaction Schemes. Some compounds included in the formula (I) can be
obtained by converting the functional groups of the other compounds of formula (I)
obtained in accordance with the following Schemes, by well known reaction steps such
as oxidation, reduction, hydrolysis, acylation, alkylation, amidation, amination,
sulfonation and others. It should be noted that any appropriate leaving groups, e.g. N-
protecting groups, such as a t-butoxycarbonyl (t-BOC) group or a phenylsulfonyl group,
can be used in well known manner during the syntheses in order to improve the
selectivity of the reaction steps
Compounds of formula (I), wherein R5 is -C(O)CH3 can be prepared, for
example, according to Scheme 1, wherein R1; R2, R3, R4, ring A, ring B and Z, Z1 and Z2
are as defined above, and R is hydrogen or alkyl. In the method of Scheme 1, the N-(3-
bromo-5-nitrophenyl)acetamide [1] is coupled in a suitable solvent such as 1,2-
dimethoxyethane with a boronic acid derivative [2] or a suitable ester thereof in the
presence of Pd(dppf)Cl2 and aqueous sodium carbonate at elevated temperature. The
nitro group of the obtained compound [3] is reduced, e.g. with hydrogen and Pd/C
catalyst, iron powder and aqueous calcium chloride or zinc and aqueous ammonium
chloride, and the resulting amine [4] is reacted with compound [5] in a suitable solvent
such as DMF in the presence of potassium fluoride at elevated temperature to obtain

compound [6]. In case Z is CH in the compound [5], X" is suitably fluoro, and when Z
is N, X" is suitably chloro. The nitro group in compound [6] is reduced, e.g. by using
zinc and aqueous ammonium chloride or iron powder and aqueous calcium chloride,
and the resulting amine [7] is heated with formic acid to produce compound [8] in a ring
closure reaction. Finally, compound [10] is obtained by the Suzuki coupling between
compound [8] and a boronic acid derivative [9] or a suitable ester thereof in a suitable
solvent such as 1,2-dimethoxyethane in the presence of Pd(dppf)Cl2 and aqueous
sodium carbonate at elevated temperature.


Alternatively, the compound of formula [3] can be prepared according to Scheme
2, wherein R3, R4, Z1 and Z2, ring B and R are as defined above, using the boronic acid
derivative [11] or a suitable ester thereof in the presence of Pd(dppf)Cl2 and aqueous
sodium carbonate. Compound [11] can be prepared, e.g. by treating iV-(3-bromo-5-
nitrophenyl)acetamide with bis(pinacolato)diboron in the presence of Pd(dppf)Cl2and
potassium acetate.


In case the B-ring in the compound [3] is a heterocycle linked to phenyl via a
nitrogen heteroatom, the compound [3] can be also prepared using a copper-catalyzed
Buchwald amination in the presence of a base such cesium carbonate or potassium
carbonate according to Scheme 3, wherein Z); Z2, R3 and R4 are as defined above.

In case the B-ring in the compound [3] is pyrrole ring linked to phenyl via a
nitrogen atom, the compound [3] can be also prepared from 3,5-dinitroaniline [15] and
2,5-dimethoxytetrahydrofuran according to Scheme 4, wherein Z1 and Z2 are as defined
above. The pyrrole derivative [16] formed is reduced using ammonium sulphide to
obtain compound [17], which is subsequently reacted with acetic anhydride to afford
compound [18].


In case where ring A in the compound [10] is an oxazol-5-yl ring, the compound
[10] can be also prepared according to Scheme 5, wherein ring B, R3, R4, Z1 and Z2 are
as defined above. In this method the compound [4] is treated with 4-fluoro-3-nitro-
benzaldehyde and the resulting compound [20] is thereafter reacted with toluene-
sulfonylmethyl isocyanide to produce the oxazol-5-yl compound [21] in a ring closure
reaction. The nitro group of compound [21] can be further reduced, e.g. by
hydrogenation, to produce the corresponding amine, which can be then treated with
formic acid according to Scheme 1 to afford the end product in the ring closure reaction.

In case where ring A in the compound [10] is a hetcrocycle linked to the carbon
atom of the bicyclic ring via a nitrogen heteroatom, the compound [10] can be also

prepared using Buchwald coupling according to Scheme 6, wherein X', ring B, R1, R2,
R3, R4, Z1 and Z2 are as defined above.
SCHEME 6.

In case where ring A in the compound [10] is an 1H-l,2,3-triazol-4-yl ring and
R2 is hydrogen, the compound [10] can be also prepared according to Scheme 7,
wherein X', Z, R1, R3, R4, Z1, Z2 and ring B, are as defined above. The starting
compound [8] is silylated by reacting with ethynyltrimethylsilane in the presence of
tetrakis(triphenylphosphine)palladium(O) (Pd(PPh3)4) and Cu(I)iodide to produce
compound [32]. Treatment with TBAF affords the ethynyl compound [33] which can be
reacted with azido compound R1-N3 in a suitable solvent, such as DMSO:THF:water
(1:1:1) or DMSO:DCM:water (1:1:1) to afford compound [34].


In case where ring A in the compound [10] is a 1-methyl-1H-pyrazol-3-yl ring,
the compound [10] can be also prepared according to Scheme 8, wherein R3, R4, Z1, Z2
and ring B, are as defined above. In this method the compound [4] is treated with l-(4-
fluoro-3-nitrophenyl)ethanone and the resulting compound [36] is thereafter reacted
with DMF dimethylacetal to produce the oxazol-5-yl compound [37]. Subsequent
treatment with methyl hydrazine produces compound [38] in a ring closure reaction. The
nitro group of compound [38] can be further reduced, e.g. by aqueous ammonium and
zinc, to produce the corresponding amine, which can be then treated with formic acid
according to Scheme 1 to afford the end product in the ring closure reaction.


In case where ring A in the compound [10] is a 1H-imidazol-2-yl ring, the
compound [10] can be also prepared according to Scheme 9, wherein R3, R4, Z1, Z2 and
ring B, are as defined above. In this method the compound [20] of Scheme 5 is treated
with ethylene diamine and N-bromosuccinimide affording compound [39] in a ring
closure reaction. The nitro group of compound [39] can be further reduced, e.g. by
aqueous ammonium and zinc, to produce the corresponding amine, which can be then
treated with formic acid according to Scheme 1 to afford the end product in the ring
closure reaction.


Various compounds of formula (I), wherein R5 is other than -C(O)CH3, can be
prepared, for example, according to Scheme 10, wherein R1, R2, R3, R4, R7, R%, Z, Z1, Z2,
ring A and ring B are as defined above. The acetamide compound [10] can be converted
to its corresponding amine [24], for example, by heating in ethanol in the presence of a
base, such as aqueous sodium hydroxide or potassium hydroxide, or an acid such as
aqueous HC1. The obtained amine [24] can be used as a starting material for subsequent
reaction steps. The compounds of formula (I), wherein R5 is -SO2R8 can be prepared, for
example, by treating the amine [24] with Cl-SO2R8 in suitable solvent such as DCM in
the presence of pyridine. Compounds of formula (I), wherein R5 is -C(O)R7 and R7is
C1-7 alkyl or C1-7 alkylamino C1-7 alkyl, can be prepared, for example, by reacting the
amine [24] with HOOC-R7 in suitable solvent such as DMF in the presence of 2-(1H-7-
azabenzotriazol-l-yl)-l,l,3,3-tetramethyluroniumhexafluorophosphate
methanaminium (HATU) and DIPEA.


Compounds of formula (I), wherein R7 is -NH-R10 or -NH-X-Rn, can be
prepared, for example, according to Scheme 11 by reacting the amine [24] in a suitable
solvent such n-butanol with isocyanato derivatives O=C=N-R10 or O=C=N-X-R11 in the
presence of suitable base such as triethylamine (TEA). Alternatively, compounds
wherein R7 is -NH-X-Rn can be prepared by treating amine [24] in suitable solvent such
as DCM with phosgene and then with H2N-X-R11, see Scheme 11.

Compounds wherein R5 is -C(O)R7, -SO2R8 or an optionally substituted 5-6
membered heterocyclic ring can also be prepared according to Scheme 12 starting from
compound [40] wherein X is a halogen such as Br or Cl, and R1, R2, R3, R4, Z, Z1, Z2
and ring B are as defined above, using palladium (e.g. Pd2(dba)3) catalyzed C-N
coupling in the presence of a metal chelating ligand such as Xantphos.


Compounds of formula (I) can be also prepared according to Scheme 13 by
reacting compound [42] with compound [43] to produce compound [44] wherein X is a
halogen such as Cl or Br, and R1, R2, R3, R4, Z, Z1, Z2 and ring B are as defined above,
followed by the bicyclic ring closure as in Scheme 1 and addition of the -NHR5 group
according to Scheme 12.

Compounds of formula (I) can be also prepared according to Scheme 14 by
reacting compound [45] with compound [46] wherein X is a halogen such as Cl or Br,
and R1, R2, R3, R4, R5, Z, Z1, Z2 and rings A and B are as defined above.


Compounds of formula (I) can be also prepared according to Scheme 15 by
reacting compound [48] with compound [49] wherein X is a halogen such as Cl or Br,
and R1, R2, R5, Z, Z1, Z2 and rings A and B are as defined above. The formed compound
[50] can be subjected to bicyclic ring closure and addition of B-ring by Suzuki coupling
as described in Scheme 1 to obtaing compounds of formula (I).

Pharmaceutically acceptable salts are well known in the field of pharmaceuticals.
Non-limiting examples of suitable salts include metal salts, ammonium salt, salts with
organic base, salts with inorganic acid, salts with organic acid, and salts with basic or
acidic amino acid. Non-limiting examples of metal salts include alkali metal salts such
as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, and
magnesium salt. Non-limiting examples of salts with inorganic or organic acids include
chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates,
maleates, citrates, benzoates, salicylates and ascorbates. Pharmaceutically acceptable
esters, when applicable, may be prepared by known methods using pharmaceutically
acceptable acids that are conventional in the field of pharmaceuticals and that retain the

pharmacological properties of the free form. Non-limiting examples of these esters
include esters of aliphatic or aromatic alcohols, e.g. methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec-butyl, tert-butyl esters. Phosphate esters and carbonate esters, are
also within the scope of the invention.
The terms employed herein have the following meanings:
The term "halo" or "halogen", as employed herein as such or as part of another
group, refers to chlorine, bromine, fluorine or iodine.
The term "C1-7 alkyl", as employed herein as such or as part of another group,
refers to a straight or branched chain saturated hydrocarbon group having 1, 2, 3, 4, 5, 6
or 7 carbon atom(s). Representative examples of C1-7 alkyl include, but are not limited
to, methyl, ethyl, n-propyl, iso-propyl, rc-butyl, wo-butyl, sec-butyl, tert-butyl, n-pentyl,
iso-pentyl and n-hexyl. The term "C1-3 alkyl" refers to an preferred embodiment of "C1-7
alkyl" having 1, 2 or 3 carbon atoms.
The term "C3-7 cycloalkyl", as employed herein as such or as part of another
group, refers to a saturated cyclic hydrocarbon group containing 3, 4, 5, 6 or 7 carbon
atoms. Representative examples of cycloalkyl include, but are not limited to, cyclo-
propyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term "C3-7 cycloalkyl C1-7 alkyl", as employed herein refers to a C3-7 cyclo-
alkyl group, as defined herein, appended to the parent molecular moiety through a C1-7
alkyl group, as defined herein.
The term "C2-7 alkenyl", as employed herein as such or as part of another group,
refers to an aliphatic hydrocarbon group having 2 to 7 carbon atoms and containing one
or several double bonds. Representative examples include, but are not limited to,
ethenyl, propenyl and cyclohexenyl.

The term "hydroxy", as employed herein as such or as part of another group,
refers to an -OH group. The term "cyano", as employed herein as such or as part of
another group, refers to a -CN group. The term "carboxy", as employed herein as such
or as part of another group, refers to -COOH group. The term "carbonyl", as employed
herein as such or as part of another group, refers to a carbon atom double-bonded to an
oxygen atom (C=O). The term "oxo", as employed herein as such or as part of another
group, refers to oxygen atom linked to another atom by a double bond (=O).
The term "C1-7 alkoxy", as employed herein as such or as part of another group,
refers to C1-7 alkyl, as defined herein, appended to the parent molecular moiety through
an oxygen atom. Representative examples of C1-7 alkoxy include, but are not limited to
methoxy, ethoxy, propoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.
The term "hydroxyl C1-7 alkyl", as employed herein, refers to at least one
hydroxy group, as defined herein, appended to the parent molecular moiety through a
C1-7 alkyl group, as defined herein. Representative examples of hydroxyl C1-7 alkyl
include, but are not limited to, hydroxymethyl, 2,2-dihydroxyethyl, 1-hydroxyethyl, 3-
hydroxypropyl, 1-hydroxypropyl, 1-methyl-1-hydroxyethyl and 1-methyl-1-hydroxy-
propyl.
The term "halo C1-7 alkyl", as employed herein, refers to at least one halogen, as
defined herein, appended to the parent molecular moiety through a C1-7 alkyl group, as
defined herein. Representative examples of halo C1-7 alkyl include, but are not limited
to, fluoromethyl, difluoromethyl, trifluoromefhyl, 2-chloroethyl and 3-bromopropyl.
The term "cyano C1-7 alkyl", as employed herein, refers to a cyano group, as
defined herein, appended to the parent molecular moiety through a C1-7 alkyl group, as
defined herein. Representative examples of cyano C1-7 alkyl include, but are not limited
to, cyanomethyl, 1-cyanoethyl, 1-cyanopropyl and 2-cyanopropyl.

The term "carboxy C1-7 alkyl", as employed herein as such or as part of another
group, refers to a carboxy group, as defined herein, appended to the parent molecular
moiety through a C1-7 alkyl group, as defined herein.
The term "halo C1-7 alkoxy", as employed herein, refers to at least one halogen,
as defined herein, appended to the parent molecular moiety through a C1-7 alkoxy group,
as defined herein.
The term "phenyl C1-7 alkoxy", as employed herein, refers to at least one phenyl
group appended to the parent molecular moiety through a C1-7 alkoxy group, as defined
herein.
The term "C1-7 alkylcarbonyl", as employed herein as such or as part of another
group, refers to a C1-7 alkyl group, as defined herein, appended to the parent molecular
moiety through a carbonyl group, as defined herein.
The term "C1-7 alkoxycarbonyl", as employed herein as such or as part of another
group, refers to a C1-7 alkoxy group, as defined herein, appended to the parent molecular
moiety through a carbonyl group, as defined herein.
The term "C1-7 alkoxycarbonyl C1-7 alkyl", as employed herein as such or as part
of another group, refers to a C1-7 alkoxycarbonyl group, as defined herein, appended to
the parent molecular moiety through a C1-7 alkyl group, as defined herein.
The term "aminocarbonyl", as employed herein as such or as part of another
group, refers to an amino group appended to the parent molecular moiety through a
carbonyl group, as defined herein.
The term "amino C1-7 alkyl", as employed herein, refers to at least one amino
group appended to the parent molecular moiety through a C1-7 alkyl group, as defined
herein. Representative examples of amino C1-7 alkyl include, but are not limited to,

aminomethyl, 2-aminoethyl, 1-aminoethyl, 2,2-diaminoethyl, 3-aminopropyl, 2-
aminopropyl, 4-aminobutyl and 1-methyl-1-aminoethyl.
The term "C1-7 alkylamino", as employed herein as such or as part of another
group, refers to at least one C1-7 alkyl group, as defined herein, appended to the parent
molecular moiety through an amino group. Representative examples of C1-7 alkylamino
include, but are not limited to methylamino, ethylamino, propylamino, butylamino,
dimethylamino, diethylamino and N-ethyl-N-methylamino.
The term "C1-7 alkylamino C1-7 alkyl", as employed herein as such or as part of
another group, refers to at least one C1-7 alkylamino group, as defined herein, appended
to the parent molecular moiety through an C1-7 alkyl group, as defined herein.
The term "carboxy C1-7 alkylamino", as employed herein as such or as part of
another group, refers to at least one carboxy group, as defined herein, appended to the
parent molecular moiety through an C1-7 alkylamino group, as defined herein
The term "C1-7 alkoxy C1-7 alkyl", as employed herein, refers to at least one C1-7
alkoxy group, as defined herein, appended to the parent molecular moiety through an
C1-7 alkyl group, as defined herein.
The term "C1-7 alkoxycarbonyl C1-7 alkyl", as employed herein, refers to at least
one C1-7 alkoxycarbonyl group, as defined herein, appended to the parent molecular
moiety through an C1-7 alkyl group, as defined herein.
The term "substituted" as used herein in connection with various residues refers
to halogen substituents, such as fluorine, chlorine, bromine, iodine, or C1-7 alkyl, C3-7
cycloalkyl, halo C1-7 alkyl, hydroxy, amino, C1-7 alkoxy, C1-7 acyl C1-7 alkylamino, amino
C1-7 alkyl, nitro, cyano, thiol or methylsulfonyl substituents. Preferred are halogen, C1-7
alkyl, halo C1-7 alkyl, hydroxy, amino, C1-7 alkoxy and methylsulfonyl substituents.
Particularly preferred are 1 to 3 of C1-3 alkyl substituents.

The "substituted" groups may contain 1 to 3, preferably 1 or 2, of the above
mentioned substituents.
The term "5 - 6 membered heterocyclic ring" as employed herein, refers to a
saturated, partially saturated or aromatic ring with 5 or 6 ring atoms, of which 1-4 atoms
are heteroatoms selected from a group consisting of N, O and S. Representative
examples of 5-6-membered heterocyclic ring include, but are not limited to, pyrazolyl,
1,2,4-triazol-l-yl, 1,2,3-triazol-l-yl, pyrimidinyl, pyridinyl, tetrazolyl, piperazinyl,
furanyl, morpholinyl, piperidinyl, pyrrolidinyl, thiazolyl, isoxazolyl, pyrazinyl
tetrahydropyranyl, 1,2,4-oxadiazolyl, oxazolyl, imidazolyl, indolyl and 4,5-
dihydroimidazolyl rings.
The term "5 - 12 membered heterocyclic ring" as employed herein, refers to a
monocyclic or bicyclic saturated, partially saturated or aromatic ring with 5 to 12 ring
atoms, of which 1-5 atoms are heteroatoms selected from a group consisting of N, O and
S. Representative examples of 5 - 12 membered heterocyclic ring include the examples
given above and additionally, but not limited to, indazolyl, pyrazolo[l,5-a]pyrimidinyl,
benzo[d]imidazolyl, imidazo[4,5-b]pyridinyl, 4,5,6,7-tetrahydrobenzo[d]imidazolyl and
benzofuranyl rings.
The term "5-12 membered carbocyclic ring" as employed herein, refers to a
saturated, partially saturated or aromatic ring with 5 to 12 ring atoms consisting of
carbon atoms only. Representative examples of 5 - 12 membered carbocyclic ring
include, but are not limited to, phenyl, naphtyl and cyclohexyl rings.
The definition of formula (I) above is inclusive of all the possible isotopes and
isomers, such as stereoisomers, of the compounds, including geometric isomers, for
example Z and E isomers (cis and trans isomers), and optical isomers, such as
diastereomers and enantiomers, and prodrug esters, e.g. phosphate esters and carbonate
esters.

It will be appreciated by those skilled in the art that the present compounds may
contain at least one chiral center. Accordingly, the compounds may exist in optically
active or racemic forms. It is to be understood that the formula (I) includes any racemic
or optically active form, or mixtures thereof. In one embodiment, the compounds are the
pure (R)-isomers. In another embodiment, the compounds are the pure (S)-isomers. In
another embodiment, the compounds are a mixture of the (R) and the (S) isomers. In
another embodiment, the compounds are a racemic mixture comprising an equal amount
of the (R) and the (S) isomers. The compounds may contain two chiral centers. In such
case, according to one embodiment, the compounds of the invention are pure
diasteromers. According to other embodiment, the compounds are a mixture of several
diasteromers. The individual isomers may be obtained using the corresponding isomeric
forms of the starting material or they may be separated after the preparation of the end
compound according to conventional separation methods. For the separation of optical
isomers, e.g. enantiomers or diastereomers, from the mixture thereof the conventional
resolution methods, e.g. fractional crystallisation, may be used.
The present compounds may also exist as tautomers or equilibrium mixtures
thereof wherein a proton of a compound shifts from one atom to another. Examples of
tautomers include, but are not limited to, keto-enol, phenol-keto, oxime-nitroso, nitro-
aci, imine-enamine and the like. Tautomeric forms are intended to be encompassed by
compounds of formula (I), even though only one tautomeric form may be depicted.
Examples of preferred compounds of formula (I) include
4-(2,4-Difluorophenyl)-N-(l-methyl-1H-pyrazol-3-yl)-6-(5-(l-methyl-1H-
pyrazol-4-yl)-1H-benzo [d]imidazol-1 -yl) pyridin-2-amine;
N-(4-(2,4-difluorophenyl)-6-(5-( 1 -methyl-1 H-pyrazol-4-yl)-1 H-benzo [d] -
imidazol-1-yl)pyridin-2-yl)cyclopropanesulfonamide;
N-(4-(2,4-difluorophenyl)-6-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]-
imidazol-1-yl)pyridin-2-yl)methanesulfonamide;
N-(4-(2,4-difluorophenyl)-6-(5-( 1 -methyl-1H-pyrazol-4-yl)-1 H-benzo [d] -
imidazol-1-yl)pyridin-2-yl)ethanesulfonamide;

N-(4-(2,4-difluorophenyl)-6-(5-(l-methyl-1H-pyrazol-4-yl)-1H-benzo[d]-
imidazol-1 -yl)pyridin-2-yl)propane-2-sulfonamide;
N-(4-(2-fluorophenyl)-6-(5-( 1 -methyl-1 H-pyrazol-4-yl)-1 H-benzo [d]imidazol-1 -
yl)pyridin-2-yl)cyclopropanesulfonamide;
N-(4-(2-fluorophenyl)-6-(5-( 1 -methyl-1 H-pyrazol-4-yl)-1 H-benzo [d]imidazol-1 -
yl)pyridin-2-yl)methanesulfonamide;
N-(4-(2-fluorophenyl)-6-(5-( 1 -methyl- 1H-pyrazol-4-yl)-1 H-benzo [d]imidazol-1 -
yl)pyridin-2-yl)ethanesulfonamide;
N-(4-(4-fluorophenyl)-6-(5-(l-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-l-
yl)pyridin-2-yl)cyclopropanesulfonamide;
N-(4-(4-fluorophenyl)-6-(5-( 1 -methyl-1 H-pyrazol-4-yl)-1 H-benzo [d]imidazol-1 -
yl)pyridin-2-yl)methanesulfonamide;
N-(4-(4-fluorophenyl)-6-(5-( 1 -methyl- 1H-pyrazol-4-yl)-1 H-benzo [d]imidazol-1 -
yl)pyridin-2-yl)propane-2-sulfonamide;
N-(3-fluoro-6'-(5-(l-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-l-yl)-[2,4'-
bipyridin]-2'-yl)cyclopropanesulfonamide;
N-(3-fluoro-6'-(5-(l-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-l-yl)-[2,4'-
bipyridin] -2'-yl) acetamide;
N-(4-(2,4-difluorophenyl)-6-(5-(l-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-
1 H-benzo [d] imidazol-1 -yl)pyridin-2-yl)cyclopropanesulfonamide;
N-(4-(2-fluorophenyl)-6-(5-( 1 -methyl-1 H-pyrazol-4-yl)-1 H-benzo [d]imidazol-1 -
yl)pyrimidin-2-yl)cyclopropanesulfonamide;
N-(6-(5-( 1 H-pyrazol-1 -yl)-1 H-benzo [d]imidazol-1 -yl)-4-(2,4-difluorophenyl)-
pyridin-2-yl)cyclopropanesulfonamide;
N-(3,5-difluoro-6'-(5-(l-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-l-yl)-
[2,4'-bipyridin]-2'-yl)cyclopropanesulfonamide;
N-(3,5-difluoro-6'-(5-(l-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-l-yl)-
[2,4'-bipyridin]-2'-yl)acetamide;
N-(4-(2-chlorophenyl)-6-(5-(l-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-l-
yl)pyridin-2-yl)cyclopropanesulfonamide;
N-(3-chloro-6'-(5-(l-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-l-yl)-[2,4'-
bipyridin]-2'-yl)cyclopropanesulfonamide;

N-(5-fluoro-6'-(5-( 1 -methyl- 1H-pyrazol-4-yl)-1 H-benzo[d]imidazol-1 -yl)-[2,4'-
bipyridin]-2'-yl)cyclopropanesulfonamide;
N-(6-(5-(1H-imidazol-l-yl)-1H-benzo[d]imidazol-l-yl)-4-(2,4-difluorophenyl)-
pyridin-2-yl)cyclopropanesulfonamide;
N-(4-(2,4-difluorophenyl)-6-(5-(l-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-
benzo [d] imidazol-1 -yl)pyridin-2-yl)cyclopropanesulfonamide;
N-(4-(2,4-difluorophenyl)-6-(5-(l-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)-1H-
benzo[d]imidazol-1 -yl)pyridin-2-yl)cyclopropanesulfonamide;
N-(4-(2,4-difluorophenyl)-6-(5-(l-ethyl-1H-l,2,3-triazol-4-yl)-1H-benzo[d]-
imidazol-1 -yl)pyridin-2-yl)cyclopropanesulfonamide;
N-(4-(2,4-difluorophenyl)-6-(5-(l-methyl- 1H-1,2,3-triazol-4-yl)- 1H-benzo[d]-
imidazol-1 -yl)pyridin-2-yl)cyclopropanesulfonamide;
N-(4-(2,4-difluorophenyl)-6-(5-( 1 -methyl-1 H-imidazol-4-yl)- 1H-benzo [d] -
imidazol-1 -yl)pyridin-2-yl)cyclopropanesulfonamide;
or a pharmaceutically acceptable salt or tautomer thereof.
Compounds of the invention may be administered to a patient in therapeutically
effective amounts which range usually from about 0.1 to about 1000 mg per day
depending on the age, weight, ethnic group, condition of the patient, condition to be
treated, administration route and the active ingredient used. The compounds of the
invention can be formulated into dosage forms using the principles known in the art.
The compound can be given to a patient as such or in combination with suitable
pharmaceutical excipients in the form of tablets, granules, capsules, suppositories,
emulsions, suspensions or solutions. Choosing suitable ingredients for the composition
is a routine for those of ordinary skill in the art. Suitable carriers, solvents, gel forming
ingredients, dispersion forming ingredients, antioxidants, colours, sweeteners, wetting
compounds and other ingredients normally used in this field of technology may be also
used. The compositions containing the active compound can be given enterally or
parenterally, the oral route being the preferred way. The contents of the active
compound in the composition is from about 0.5 to 100 %, preferably from about 0.5 to
about 20 %, per weight of the total composition.

The compounds of the invention can be given to the subject as the sole active
ingredient or in combination with one of more other active ingredients for treatment of a
particular disease, for example cancer.
The present invention will be explained in more detail by the following
experiments and examples. The experiments and examples are meant only for
illustrating purposes and do not limit the scope of the invention defined in claims.
EXPERIMENTS
1. Inhibition of FGFR1 kinase
FGFR1 assay
Compounds were screened in the TR-FRET assay with FGFR1 kinase. 5 ng of
FGFR1 [Upstate, USA] kinase was used for assay. The compound was incubated with
the kinase for 30 minutes at room temperature. After the incubation, substrate mix [40
nM Ultra light poly GT (Perkin Elmer, USA) and 13 uJM ATP (Sigma)] was added. The
above reaction was stopped by the addition of 40mM EDTA after the 30 min kinase
reaction. The Eu-labelled antiphospho-tyrosine antibody [Perkin Elmer, USA] was
added at 0.5 nM and the fluorescence emission at 615 nm/665 nm [excitation at 340 nm]
was measured. The compounds were initially screened at 100 nM and 1 uM
concentrations. The compounds with >50 % inhibition at 100 nM of FGFR1 were taken
for the full dose response studies. The final DMSO concentration in the assay was 1 %.
For IC50 determination, l/3rd serial dilution was made from the 20 mM DMSO stock
solution. 2 ul of these were transferred to the test wells containing 20 ul of the reaction
mixture [total reaction volume 20 u.1]. The fluorescence was measured in Perkin Elmer
Wallac 1420 Multilabel Counter Victor 3. The IC50 was determined by fitting the dose
response data to sigmoidal curve fitting equation using GraphPad Prism software V5.
Results

Enzymatic activity and selectivity of selected compounds of the invention on
different kinases is presented in Table 1. The compounds of the invention were found to
be potent and selective FGFR kinase inhibitors.


The preparation of the compounds of the invention is illustrated by the following
Examples.
EXAMPLES.
LCMS data has been recorded in +ve mode unless otherwise mentioned.
Intermediate Example 1.
4-( 1 -Methyl-1 H-pyrazol-4-yl)-2-nitroaniline
A solution of 4-bromo-2-nitroaniline (6 g, 27.6 mmol) in 1, 2-dimethoxyethane
(15 ml) was degassed by N2 bubbling for 5 min. l-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-1H-pyrazole (6.90 g, 33.1 mmol, 1.2 eq) was added and the
mixture was degassed for another 5 min. Pd(dppf)Cl2 (2.25 g, 27.6 mmol, 0.1 eq) and
aqueous sodium carbonate (8.79 g, 82.9 mmol, 3.0 eq) were added sequentially and the
mixture was further degassed for 5 min and then heated at 90 °C for 2 h. The reaction
mixture was quenched with water and extracted with ethyl acetate (3 x 50 ml). The
combined organic layer was washed with water, brine and dried over sodium sulphate.
The solvent was distilled off under reduced pressure to afford the crude residue which
was purified by column chromatography (60-120 silica gel, 40 % ethyl acetate in
hexane) to afford the title product in 75 % yield (4.5 g). LC-MS (ESI): Calculated mass:
218.21; Observed mass: 218.9 [M+H]+ (rt: 0.390 min).
Intermediate Example 2.
tert-Butyl 3-(4-(1H-benzo[d]imidazol-5-yl)-1H-pyrazol-l-yl)pyrrolidine-l-
carboxylate
a) tert-Butyl 3-(methylsulfonyl) pyrrolidine-1-carboxylate
To a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (0.5 g, 2.67 mmol,
1.0 eq) in DCM (10 ml) was added TEA (0.8 ml, 5.35 mmol, 2.0 eq). The mixture was
stirred at RT for 15 min. Then methanesulfonyl chloride (0.23 ml, 2.94 mmol 1.1 eq)
was added and the mixture was stirred for 3 h. The mixture was then quenched with

water and extracted with CH2C12 (3 x 50 ml). The solvent was distilled off to afford the
title product in 86 % yield (0.6 g).
b) tert-butyl 3-(4-(4,4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-1H-pyrazol-l-
yl) pyrrolidine-1-carboxylate
To a solution of 4 4-(4,4,5,5-tetramemyl-l,3,2-dioxaborolan-2-yl)-1H-pyrazole
(0.6 g, 2.26 mmol) in DMF were added sodium hydride at 0 °C (0.108 g, 4.53 mmol, 2
eq) and the compound of Intermediate Example 2(a) (0.44 g, 2.26 mmol, 1.0 eq.). The
mixture was stirred at RT for 1 h and heated at 90 °C for 4 h and quenched with ice and
extracted as in Intermediate Example 1. The solvent was distilled off to afford the crude
residue in 50 % yield (0.4 g).
c) tert-Butyl 3-(4-(1H-benzo[d]imidazol-5-yl)-1H-pyrazol-1 -yl)pyrrolidine-1 -
carboxylate
To a degassed (N2 bubbling) solution of 5-bromo-1H-benzo[d]imidazole (0.050
g, 0.15 mmol) in 1,4-dioxane (10 ml) were added the compound of Intermediate
Example 2(b) (0.052 g, 0.15 mmol, 1 eq), Pd(PPh3)4 (16 mg, 0.015 mmol, 0.1 eq) and
cesium carbonate (0.118 g, 0.36 mmol, 2.5 eq) using the procedure of Intermediate
Example 1. The mixture was heated at 90 °C for 16 h. The reaction mixture was
quenched and extracted as in Intermediate Example 1. The solvent was distilled off to
afford the product in 40 % yield (20 mg). LC-MS (ESI): Calculated mass: 353.2;
Observed mass: 354.4 [M+H]+ (rt: 0.11 min).
Intermediate Example 3.
4-( 1 -(2-(Dimethylamino)ethyl)-1 H-pyrazol-4-yl)-2-nitroaniline
a) 2-(4-iodo- 1H-pyrazol-1 -yl)-N,N-dimethylethanamine
To a solution of 4-iodo-1H-pyrazole (2.8 g, 10 mmol) in acetonitrile (50 ml)
were added cesium carbonate (5.04 g, 15 mmol, 1.5 eq) and 2-chloro-JV,JV-dimethyl-
ethanamine hydrochloride (2.96 g, 20 mmol, 2 eq) and the mixture was stirred at RT for

8 h. The mixture was quenched with water and extracted with EtOAc (3 x 150 ml). The
combined organic layer was washed with water, brine and dried over sodium sulphate.
The solvent was distilled off to afford the crude product in 38 % yield (1 g).
b) 4-( 1 -(2-(dimethylamino)ethyl)- 1H-pyrazol-4-yl)-2-nitroaniline
A solution of the compound of Example 3(a) (0.5 g, 1.9 mmol) in 1, 2-di-
methoxyethane (15 ml) was degassed by N2 bubbling for 5 min. 2-Nitro-4-(4,4,5,5-
tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (0.74 g, 2.8 mmol, 1.5 eq) was added and
the mixture was degassed for another 5 min. Pd(dppf)Ci2 (0.16 g, 0.2 mmol, 0.1 eq) and
aqueous sodium carbonate (0.5 g, 4.7 mmol, 2.5 eq) were added sequentially using the
procedure of Intermediate Example 1 and the mixture was heated at 90 °C for 16 h. The
reaction mixture was quenched and extracted as in Intermediate Example 1. The solvent
was distilled off to afford the crude residue which was purified by column
chromatography (60-120 silica gel, 70 % ethyl acetate in hexane) to afford the title
product in 65 % yield (0.3 g). LC-MS (ESI): Calculated mass: 275.14; Observed mass:
276.15 [M+H]+ (it: 0.18 min).
Intermediate Example 4.
5-( 1 H-Pyrazol-1 -yl)-1 H-benzo [d] imidazole
a) 2-nitro-4-( 1 H-pyrazol-1 -yl)aniline
To a solution of 4-bromo-2-nitroaniline (3 g, 13.8 mmol) in DMF (12 ml) were
added pyrazole (1.12 g, 16.4 mmol, 1.2 eq.), copper(I) oxide (0.1 g, 0.69 mmol, 0.05
eq.) and cesium carbonate (8 g, 24.6 mmol, 1.8 eq.) and the mixture was heated at 100
°C overnight. The mixture was quenched and extracted as in Intermediate Example 1.
The solvent was distilled off and the crude residue was purified by column
chromatography (60-120 silica gel, 20 % ethyl acetate in hexane) to afford the title
product in 53.5 % yield (1.5 g).
b) 5-( 1 H-pyrazol-1 -yl)-1 H-benzo[d]imidazole

A mixture of the compound of Example 4(a) (0.5 g, 2.5 rnmol) and iron powder
(1.39 g, 25 rnmol, 10 eq) were refluxed in formic acid (20 ml) overnight. The formic
acid was distilled off and the crude product was dissolved in ethyl acetate and filtered.
The ethyl acetate layer was washed with water, brine and dried over sodium sulphate.
The solvent was distilled off to afford the title product in 87 % yield (0.4 g). LC-MS
(ESI): Calculated mass: 184.07; Observed mass: 185.3 [M+H]+ (rt: 0.097 min).
Intermediate Example 5.
N-(6-chloro-4-(2,4-difluorophenyl)pyridin-2-yl)cyclopropanesulfonamide
a) 2,6-dichloro-4-(2,4-difluorophenyl)pyridine
A solution of 2,6-dichloro-4-iodopyridine (1.5 g, 5.49 rnmol) in 1,2-dimethoxy-
ethane (15 ml) was degassed by N2 bubbling for 5 min. 2,4-Difluorophenylboronic acid
(0.86 g, 5.49 rnmol, 1 eq) was added and the mixture was degassed for another 5 min.
Pd(dppf)Cl2 (0.358 g, 0.43 rnmol, 0.08 eq) and aqueous sodium carbonate (1.45 g, 13.7
rnmol, 2.5 eq) were added sequentially using the procedure of Intermediate Example 1
and the mixture was heated at 90 °C for 16 h. The reaction mixture was quenched and
extracted as in Intermediate Example 1. The solvent was distilled off to afford the crude
residue which was purified by column chromatography (60-120 silica gel, 3 % ethyl
acetate in hexane) to yield the title product in 98.5 % yield (1.4 g).
b) N-(6-chloro-4-(2,4-difluorophenyl)pyridin-2-yl)cyclopropanesulfonamide
A solution of the compound of Intermediate Example 5(a) (0.9 g, 3.46 mmol) in
dioxane (20 ml) was degassed by N2 bubbling for 5 min. Cyclopropane sulfonamide
(0.36 g, 2.94 mmol, 1 eq) was added and the mixture was degassed for another 5 min.
Palladium acetate (39 mg, 0.173 mmol, 0.05 eq) and xantphos (200 mg, 0.35 mmol, 0.1
eq) and CS2CO3 (3.37 g, 10.4 mmol, 3.0 eq) were added and the mixture was further
degassed for 5 min and then heated at 100 °C for 16 h. The mixture was filtered through
celite and extracted with ethyl acetate (3 x 50 ml). The combined organic layer was
washed with water, brine and dried over sodium sulphate. The solvent was distilled off
to afford the crude residue which was purified by column chromatography (60-120 silica

gel, 30 % ethyl acetate in hexane) to afford the title product in 50 % yield (0.6 g). 1H
NMR (300 MHz, DMSO-d6): δ 11.05 (s, 1H), 7.76-7.68 (m, 1H), 7.51-7.43 (m, 1H),
7.35 (s, 1H), 7.30-7.24 (m, 1H), 7.16 (s, 1H), 3.09-3.01 (m, 1H), 1.22-1.09 (m, 2H),
1.08-1.03 (m, 2H).
Intermediate Example 6.
5-( 1 -Methyl-1 H-pyrazol-4-yl)-1 H-benzo [d]imidazole
A mixture of the compound of Intermediate Example 1 (3 g, 13.7 mmol) and iron
powder (7.68 g, 137 mmol, 10 eq) were refluxed in formic acid (50 ml) overnight. The
formic acid was distilled off and the crude product was dissolved in ethyl acetate and
filtered. The ethyl acetate layer was washed with water, brine and dried over sodium
sulphate. The solvent was distilled off to afford the title product in 55.5 % yield (1.5 g).
LC-MS (ESI): Calculated mass: 198.09; Observed mass: 199.2 [M+H]+ (rt: 0.097 min).
Intermediate Example 7.
5 -(1 -Methyl-1 H-pyrazol-4-yl)-3 -nitropyridin-2-amine
A solution of 5-bromo-3-nitropyridin-2-amine (5 g, 23 mmol) in 1, 2-dimethoxy-
ethane (50 ml) was degassed by N2 bubbling for 5 min. l-Methyl-4-(4,4,5,5-tetramethyl-
l,3,2-dioxaborolan-2-yl)-1H-pyrazole(7.2 g, 37 mmol, 1.5 eq) was added and the
mixture was degassed for another 5 min. Pd(dppf)Ci2 (1.88 g, 2.3 mmol, 0.1 eq) and
aqueous sodium carbonate (6.1 g, 52 mmol, 2.5 eq) were added sequentially using the
procedure of Intermediate Example 1 and the mixture was heated at 90 °C for 16 h. The
reaction mixture was quenched and extracted as in Intermediate Example 1. The solvent
was distilled off to afford the crude residue which was purified by column
chromatography (60-120 silica gel, 70 % ethyl acetate in hexane) to afford the title
product in 50 % yield (2.5 g). LC-MS (ESI): Calculated mass: 219.08; Observed mass:
220.1 [M+H]+ (rt: 0.22 min).
Intermediate Example 8.
4-(l-(2-Morpholinoethyl)-1H-pyrazol-4-yl)-2-nitroaniline

a) 4-(2-(4-bromo-1 H-pyrazol-1 -yl)ethyl)morpholine
To a solution of 4-(2-chloroethyl)morpholine (2.55 g, 13.6 mmol) and 4-bromo-
1H-pyrazole (2 g, 13.6 mmol, 1 eq) in DMF (50 ml) was added K2C03 (0.16 g, 6.72
mmol, 1.5 eq) and the mixture was stirred at RT for 24 h. The mixture was then
quenched with water and extracted with ethyl acetate (3 x 100 ml). The combined
organic layer was washed with water, brine and dried over sodium sulphate. The solvent
was distilled off to afford the crude product in 57 % yield (2 g).
b) 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H-pyrazol-1 -yl)ethyl)-
morpholine
A solution of the compound of Intermediate Example 8(a) (1 g, 3.8 mmol) in
DME (15 ml) was degassed by N2 bubbling for 5 min. Bispinacolato diborane (1.46 g,
5.7 mmol, 1.5 eq) was added and the mixture was degassed for another 5 min.
Pd(dppf)Cl2 (0.313 g, 0.38 mmol, 0.1 eq) and potassium acetate (1.32 g, 13.4 mmol, 3.5
eq) were added sequentially using the procedure of Intermediate Example 1 and the
mixture was then heated at 100 °C for 4 h. The reaction mixture was then quenched and
extracted as in Intermediate Example 1. The solvent was distilled off to afford the crude
residue which was purified by column chromatography (60-120 silica gel, 50 % ethyl
acetate in hexane) to afford the title product in 87 % yield (1 g). LC-MS (ESI):
Calculated mass: 307.2; Observed mass: 308.5 [M+H]+ (rt: 0.10 min).
c) 4-( 1 -(2-morpholinoethyl)-1 H-pyrazol-4-yl)-2-nitroaniline
A solution of the compound of Intermediate Example 8(b) (1 g, 4.6 mmol) in
1,2-dimethoxyethane (15 ml) was degassed by N2 bubbling for 5 min. 4-Bromo-2-
nitroaniline (1.41 g, 4.6 mmol, 1 eq) was added and the mixture was degassed for
another 5 min. Pd(dppf)Cl2 (0.38 g, 0.46 mmol, 0.1 eq) and aqueous sodium carbonate
(1.41 g, 13.8 mmol, 3 eq) were added sequentially using the procedure of Intermediate
Example 1 and the mixture was then heated at 100 °C for 4 h. The reaction mixture was
then quenched and extracted as in Intermediate Example 1. The solvent was distilled off
to afford the crude residue which was purified by column chromatography (60-120 silica

gel, 50 % ethyl acetate in hexane) to afford the title product in 42 % yield (0.6 g). LC-
MS (ESI): Calculated mass: 317.15; Observed mass: 318.05 [M+H]+ (it: 0.20 min).
Intermediate Example 9.
4-( 1 H-Imidazol-1 -yl)-2-nitroaniline
To a solution of 4-bromo-2-nitroaniline (3 g, 13.8 mmol) in DMF (12 ml) were
added imidazole (2.71 g, 27.6 mmol, 2 eq), copper(I) oxide (0.1 g, 0.69 mmol, 0.05 eq.
and cesium carbonate (13.4 g, 41.4 mmol, 3 eq) and the mixture was heated at 100 °C
overnight. The mixture was quenched and extracted as in Intermediate Example 1. The
solvent was distilled off and the crude residue was purified by column chromatography
(60-120 silica gel, 50 % ethyl acetate in hexane) to afford the title product in 40 % yield
(1.1 g). lH NMR (300 MHz, DMSO-d6): δ 8.17 (br s, 1H), 8.12 (d, 1H), 7.73-7.68 (m,
2H), 7.59 (s, 2H), 7.15 (d, 1H), 7.08 (s, 1H).
Intermediate Example 10.
5-( 1 -Ethyl- 1H-1,2,3-triazol-4-yl)- 1H-benzo[d] imidazole
a) 2-Nitro-4-((trimethylsilyl)ethynyl)aniline
A solution of the compound of 4-iodo-2-nitroaniline (1 g, 3.8 mmol) in DMF-
Et3N (1:1; 20 ml) was degassed by N2 bubbling for 15 min. Pd(PPh3)4 (0.22 g, 0.19
mmol, 0.05 eq.), copper(I) iodide (0.073g, 0.386 mmol, 0.1 eq.) and ethynyltri-
methylsilane (0.45 ml, 4.63 mmol, 1.2 eq.) were added sequentially and the mixture was
stirred for 12 h at RT. The mixture was quenched and extracted as in Intermediate
Example 1. The solvent was distilled off and the crude residue was purified by column
chromatography (60-120 silica gel, 10 % ethyl acetate in hexane) to afford the title
product in 67 % yield (0.6 g).
b) 4-Ethynyl-2-nitroaniline
To a solution of the compound of Intermediate Example 10(a) (0.5 g, 2.15 mmol)
in THF (10 ml) at 0°C was added TBAF (0.5 g, 2.17 mmol, 1.2 eq.) and the mixture

was stirred for 0.5 h. The mixture was filtered over a pad of silica and distilled to afford
the title product in 86 % yield (0.3 g).
c) 4-( 1 -Ethyl- 1H-1,2,3-triazol-4-yl)-2-nitroaniline
A mixture of the compound of Intermediate Example 10(b) (0.3 g, 1.85 mmol),
sodium azide (0.24 g, 3.7 mmol, 1.0 eq.), methyl iodide (0.23 g, 1.85 mmol, 1.0 eq.),
sodium ascorbate (0.36 g, 1.85 mmol, 1.0 eq.) and copper sulfate pentahydrate (0.23 g,
0.92 mmol, 0.5 eq.) in DMSO, THF and water (1:1:0.5, 5 ml) was stirred for 12 h at RT.
The mixture was quenched with water and the precipitate formed was filtered and dried.
The crude product was purified by by column chromatography (60-120 silica gel, 30 %
ethyl acetate in hexane) to afford the title product in 25 % yield (100 mg).
d) 5-( 1 -Ethyl- 1H-1,2,3-triazol-4-yl)- 1H-benzo[d]imidazole
A solution of the compound of Intermediate Example 10(c) (0.1 g, 0.42 mmol) in
formic acid (2 ml), iron (0.23 g, 4.2 mmol) was added and heated at 100 °C for 16 h.
The formic acid was distilled off under reduced pressure and the crude product was
dissolved in ethyl acetate. The ethyl acetate layer was washed with water, brine and
dried over sodium sulphate. The solvent was distilled off to afford the title product in 33
% yield (30 mg). LC-MS (ESI): Calculated mass: 213.1; Observed mass: 214.1 [M+H]+
(rt:0.14min).
Intermediate Example 11.
5 -(1 -Methyl-1 H-imidazol-4-yl)-1 H-benzo [d] imidazole
a) 4-( 1 -Methyl-1 H-imidazol-4-yl)-2-nitroaniline
A solution of 2-nitro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline
(1.45 g, 5.55 mmol, 1.1 eq) in 1,2-dimethoxyethane (15 ml) was degassed by N2
bubbling for 5 min. 4-Bromo-l-methyl-1H-imidazole (0.81 g, 5 mmol, 1 eq) was added
and the mixture was degassed for another 5 min. Pd(dppf)Cl2 (0.4 g, 0.5 mmol, 0.1 eq)
and aqueous sodium carbonate (1.59 g, 15 mmol, 3 eq) were added sequentially using

the procedure of Intermediate Example 1 and then heated at 100 °C for 4 h. The reaction
mixture was then quenched and extracted as in Intermediate Example 1. The solvent
was distilled off to afford the crude residue which was purified by column
chromatography (60-120 silica gel, 50 % ethyl acetate in hexane) to afford the title
product in 60 % yield (0.6 g). LC-MS (ESI): Calculated mass: 218.08; Observed mass:
219.2 [M+H]+ (rt: 0.09 min).
b) 5-( 1 -methyl-1 H-imidazol-4-yl)-1 H-benzo[d]imidazole
To a solution of the compound of Intermediate Example 11(a) (0.3 g, 1.376
mmol) in formic acid (5 ml), iron (0.77 g, 13.76 mmol) was added and the mixture was
heated at 90 °C for 12 h. The formic acid was distilled off and the crude product was
dissolved in ethyl acetate. The ethyl acetate layer was washed with water, brine and
dried over sodium sulphate. The solvent was distilled off to afford the title product in 26
% yield (0.07 g). LC-MS (ESI): Calculated mass: 198.09; Observed mass: 199.2
[M+H]+(rt: 0.10 min).
Intermediate Example 12.
5-((Trimethylsilyl)ethynyl)-1H-benzo[d]imidazole
a) 5-Iodo-1H-benzo[d]imidazole
To a solution 4-iodo-2-nitroaniline (1 g, 3.7 mmol) in formic acid (10 ml), iron
(2.1 g, 37 mmol) was added and heated at 90 °C for 12 h. The formic acid was distilled
off and the crude was dissolved in ethyl acetate. The ethyl acetate layer was washed with
water, brine and dried over sodium sulphate. The solvent was distilled off to afford the
title product in 68 % yield (0.85 g). LC-MS (ESI): Calculated mass: 243.95; Observed
mass: 244.8 [M+H]+ (rt: 0.173 min).
b) 5-((Trimethylsilyl)ethynyl)-1 H-benzo[d]imidazole
A solution of of the compound of Intermediate Example 12(a) (0.7 g, 2.56 mmol)
in DMF-Et3N (1:1; 10 ml) was degassed by N2 bubbling for 15 min. Pd(dppf)Cl2 (0.11

g, 0.14 mmol, 0.05 eq), copper(I) iodide (0.054g, 0.25 mmol, 0.1 eq) and ethynyltri-
methylsilane (0.3 g, 3.15 mmol, 1.1 eq) were added sequentially and the mixture was
stirred for 12 h at RT. The mixture was quenched and extracted as in Intermediate
Example 1. The solvent was distilled off and the crude residue was recrystallized from
hexane to afford the title product in 57 % yield (0.35 g). LC-MS (ESI): Calculated mass:
214.09; Observed mass: 215.5 [M+H]+ (it: 0.22 min).
Intermediate Example 13.
4-(l-Methyl-1H-pyrazol-4-yl) benzene-1, 2-diamine
To a solution of the compound Intermediate Example 1 (1 g, 4.58 mmol) in THF
(10 ml) were added a solution of ammonium chloride (1.486 g, 27.5 mmol, 6 eq) in
water (5ml) and zinc (1.78 g, 27.5 mmol, 6 eq). The reaction mixture was stirred at RT
for 6 h and filtered. The filtrate was diluted with water and extracted with ethyl acetate
(3 x 100 ml). The combined organic layer was washed with water, brine and dried over
sodium sulphate. The solvent was distilled off to afford the crude residue which was
purified by column chromatography (60-120 silica gel, 3 % methanol in DCM) to afford
the title product in 58 % yield (0.5 g). LC-MS (ESI): Calculated mass: 188.11; Observed
mass: 189.0 [M+H]+ (rt: 0.113 min).
Intermediate Example 14.
Ethyl 1 -(1H-benzo[d]imidazol-5-yl)-1H-1,2,3-triazole-4-carboxylate
a) 1H-benzo[d]imidazol-5-amine
To a solution of 5-nitro-1H-benzo[d]imidazole (5 g, 44.2 mmol) in methanol
(100 ml) was added Pd/C and the reaction mixture was stirred at RT for 16 h and
filtered. The filtrate was diluted with water and extracted with ethyl acetate (3 x 100
ml). The combined organic layer was washed with water, brine and dried over sodium
sulphate. The solvent was distilled off to afford the crude residue which was purified by
washing with diethyl ether to afford the title product in 85 % yield (2.5 g). LC-MS
(ESI): Calculated mass: 133.06; Observed mass: 134.2 [M+H]+ (rt: 0.175 min).

b) 5-Azido-1H-benzo[d]imidazole
To a solution of the compound of Intermediate Example 14(a) (2 g, 15 mmol) in
concentrated HC1 (8 ml) at 0 °C was added aqueous solution of NaN02 (1.3 g, 18.7
mmol, 1.25 eq) dropwise and the mixture was stirred at 0 °C for 30 min. Then NaN3
(1.13 g, 18.7 mmol, 1.25 eq) was added at 0 °C and the mixture was stirred for 15 min.
The mixture was quenched and extracted as in Intermediate Example 1(a). The solvent
was distilled off to afford the product in 75 % yield (1.8 g). LC-MS (ESI): Calculated
mass: 159.05; Observed mass: 160.0 [M+H]+ (rt: 0.136 min).
c) Ethyl l-(1H-benzo[d]imidazol-5-yl)-1H-l,2,3-triazole-4-carboxylate
A mixture of the compound of Intermediate Example 14(b) (1.75 g, 10.99
mmol), ethyl propiolate (1.08 g, 10.99 mmol, 1.0 eq), sodium ascorbate (0.22 g, 1.09
mmol, 0.1 eq) and copper sulfate pentahydrate (30 mg, 0.1 mmol, 0.01 eq) in f-butanol
and water (1:0.5, 20 ml) was stirred for 48 h at RT. The volatiles were evaporated and
the reaction mixture was extracted with 10 % methanol in CH2CI2 (3 x 100 ml). The
combined organic layer was washed with water, brine and dried over sodium sulphate
and concentrated. The light brown solid obtained (1.6 g, 56.6 % yield) was directly
taken for the next step without further purification. LC-MS (ESI): Calculated mass:
257.09; Observed mass: 258.05 [M+H]+ (rt: 0.193 min).
Intermediate Example 15.
N-(6-chloro-4-(2-(difluoromethoxy)-4-fluorophenyl)pyridin-2-yl)cyclopropane-
sulfonamide
a) 1 -Bromo-2-(difluoromethoxy)-4-fluorobenzene
To a solution of 2-bromo-5-fluorophenol (3 g, 15.7 mmol) in DMF (5 ml) was
added cesium carbonate (7.7 g, 23.56 mmol, 1.5 eq) and sodium chlorodifluoroacetate
(6 g, 39.26 mmol, 2.5 eq) and the reaction mixture was heated at 100 °C for 15 h. The
reaction mixture was then extracted with water and ethyl acetate (3 x 50 ml). The

combined organic layer was washed with water, brine and dried over sodium sulphate.
The solvent was distilled off to afford the crude residue which was purified by column
chromatography (60-120 silica gel, 10 % ethyl acetate in hexane) in 58 % yield (2.2 g).
b) 2,6-Dichloro-4-(2-(difluoromethoxy)-4-fluorophenyl)pyridine
A solution of the compound of Intermediate Example 15(a) (2.2 g, 9.13 mmol)
in 1,2-dimethoxyethane (50 ml) was degassed by N2 bubbling for 5 min. 2,6-Dichloro-4-
(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (2.75 g, 10.04 mmol, 1.1 eq) was
added and the mixture was degassed for another 5 min. Pd(dppf)Cl2 (0.74 g, 0.9 mmol,
0.1 eq) and aqueous sodium carbonate (2.9 g, 27.3 mmol, 2.5 eq) were added
sequentially using the procedure of Intermediate Example 1 and then heated at 110 °C
for 4 h. The reaction mixture was then quenched and extracted as in Intermediate
Example 1. The solvent was distilled off to afford the crude residue which was purified
by column chromatography (60-120 silica gel, 10 % ethyl acetate in hexane) to afford
the title product in 43 % yield (1.2 g). LC-MS (ESI): Calculated mass: 306.98; Observed
mass: 307.85 [M+H]+ (rt: 2.0 min).
c) N-(6-chloro-4-(2-(difluoromethoxy)-4-fluorophenyl)pyridin-2-yl)cyclo-
propanesulfonamide
A solution of the compound of Intermediate Example 15(b) (0.5 g, 1.62 mmol) in
dioxane (10 ml) was degassed by N2 bubbling for 5 min. Cyclopropane sulfonamide
(0.19 g, 1.62 mmol, 1 eq) was added and the mixture was degassed for another 5 min.
Palladium acetate (18 mg, 0.08 mmol, 0.05 eq) and xantphos (46 mg, 0.08 mmol, 0.05
eq) and cesium carbonate (1.56 g, 4.8 mmol, 3.0 eq) were added sequentially and the
reaction mixture was further degassed for 5 min and then heated at 100 °C for 5 h. The
reaction mixture was filtered through celite pad and extracted with ethyl acetate (3 x 50
ml). The combined organic layer was washed with water, brine and dried over sodium
sulphate. The solvent was distilled off to afford the crude residue which was purified by
column chromatography (60-120 silica gel, 30 % ethyl acetate in hexane) in 47 % yield

(0.3 g). LC-MS (ESI): Calculated mass: 392.02; Observed mass: 392.85 [M+H]+ (it:
1.82 min).
Intermediate Example 16.
N-(6-chloro-4-(2,4-difluorophenyl)pyridin-2-yl)acetamide
A solution of the compound of Intermediate Example 5(a) (0.5 g, 1.92 mmol) in
dioxane (20 ml) was degassed by N2 bubbling for 5 min. Acetamide (0.11 g, 1.92 mmol,
1 eq) was added and the mixture was degassed for another 5 min. Palladium acetate (43
mg, 0.19 mmol, 0.1 eq) and xantphos (222 mg, 0.38 mmol, 0.2 eq) and Cs2C03 (1.88 g,
5.76 mmol, 3.0 eq) were added and the reaction mixture was further degassed for 5 min
and then heated at 100 °C for 16 h. The reaction mixture was filtered through celite and
extracted with ethyl acetate (3 x 50 ml). The combined organic layer was washed with
water, brine and dried over sodium sulphate. The solvent was distilled off to afford the
crude residue which was purified by column chromatography (60-120 silica gel, 30 %
ethyl acetate in hexane) to afford the title product in 64.5 % yield (0.35 g). LC-MS
(ESI): Calculated mass: 282.04; Observed mass: 283.0 [M+H]+ (rt: 1.60 min).
Example 1.
4-(2,4-Difluorophenyl)-N-(l-methyl-1H-pyrazol-3-yl)-6-(5-(l-methyl-1H-
pyrazol-4-yl)- 1H-benzo[d]imidazol- 1-yl) pyridin-2-amine
a) 6-Chloro-4-(2, 4-difluorophenyl)-N-(4-(l-methyl-1H-pyrazol-4-yl)-2-nitro-
phenyl) pyridin-2-amine
A solution of the compound of Intermediate Example 5(a) (0.8 g, 3.07 mmol) in
toluene (5 ml) was degassed by N2 bubbling for 5 min. The compound of Intermediate
Example 1 (0.8 g, 3.69 mmol, 1.2 eq) was added and the mixture was degassed for
another 5 min. Palladium acetate (0.027 g, 0.123 mmol, 0.04 eq) and BINAP (0.076 g,
0.123 mmol, 0.04 eq) and potassium fert-butoxide (0.69 g, 6.15 mmol, 2.0 eq) were
added sequentially and the mixture was further degassed for 5 min and then heated at
100 °C for 5 h. The mixture was filtered through celite pad and extracted with ethyl
acetate (3 x 50 ml). The combined organic layer was washed with water, brine and dried

over sodium sulphate. The solvent was distilled off to afford the crude residue which
was purified by column chromatography (60-120 silica gel, 30 % ethyl acetate in
hexane) in 29.5 % yield (0.4 g). LC-MS (ESI): Calculated mass: 441.2; Observed mass:
442.0 [M+H]+ (rt: 1.84 min).
b) l-(6-Chloro-4-(2, 4-difluorophenyl) pyridin-2-yl)-5-( 1 -methyl- 1H-pyrazol-4-
yl)- 1H-benzo[d]imidazole
To a solution of the compound of Example 1(a) (0.4 g, 0.907 mmol) in formic
acid (5 ml), iron (0.5 g,9.07 mmol) was added and the mixture was heated at 100°C for
16 h. The formic acid was distilled off and the crude product was dissolved in ethyl
acetate. The ethyl acetate layer was washed with water, brine and dried over sodium
sulphate. The solvent was distilled off to afford the title product in 47 % yield (0.18 g).
LC-MS (ESI): Calculated mass: 421.2; Observed mass: 422.5 [M+H]+ (rt: 1.83 min).
c)4-(2,4-Difluorophenyl)-N-(l-methyl-1H-pyrazol-3-yl)-6-(5-(l-methyl-1H-
pyrazol-4-yl)-1 H-benzo [d]imidazol-1 -yl) pyridin-2-amine
A solution of the compound of Example 1(b) (0.07 g, 0.166 mmol) in toluene (5
ml) was degassed by N2 bubbling for 5 min. 1-Methyl-1H-pyrazol-3-amine (0.024 g,
0.199 mmol, 1.2 eq) was added and the mixture was degassed for another 5 min.
Pd2(dba)3 (0.007 g, 0.0083 mmol, 0.05 eq) and xantphos (0.005g, 0.0083mmol, 0.05eq)
and CS2CO3 (0.162 g, 0.4988 mmol, 3.0 eq) were added sequentially using the
procedure of Example 1(a) and the mixture was heated at 100 °C for 16 h. The mixture
was filtered and extracted using the procedure of Example 1(a). The solvent was
distilled off to afford the crude residue which was purified by preparative HPLC to
afford the title product in 15 % yield (12 mg). !H NMR (400 MHz, CD3OD): δ 8.83 (s,
1H), 8.24-8.22 (d, 1H), 8.03 (s, 1H), 7.90-7.89 (d, 2H), 7.77-7.71 (m, 1H), 7.62-7.60 (m,
1H), 7.51 (d, 1H), 7.30-7.25 (d, 2H), 7.20-7.13 (m, 2H), 6.43-6.42 (d, 1H), 3.97 (s, 3H),
3.86 (s, 3H); LC-MS (ESI): Calculated mass: 482.18; Observed mass: 483.55 [M+H]+
(rt: 1.57 min).
Example 2.

N-(4-(2,4-difluorophenyl)-6-(5-(l-methyl-1H-pyrazol-4-yl)-1H-benzo[d]-
imidazol-1 -yl)pyridin-2-yl)cyclopropanesulfonamide
A solution of the compound of Example 1(b) (42 mg, 0.1 mmol) in dioxane (1
ml) was degassed by N2 bubbling for 5 min. Cyclopropane sulfonamide (0.11 g, 0.1
mmol, 1 eq) was added and the mixture was degassed for another 5 min. Palladium
acetate (2 mg, 0.008 mmol, 0.08 eq) and xantphos (5 mg, 0.008 mmol, 0.08 eq) and
CS2CO3 (100 mg, 0.3 mmol, 3.0 eq) were added and the mixture was further degassed
for 5 min and then heated at 100 °C for 16 h. The mixture was filtered through celite and
extracted with ethyl acetate (3 x 50 ml). The combined organic layer was washed with
water, brine and dried over sodium sulphate. The solvent was distilled off to afford the
crude residue which was purified by preparative HPLC to yield the title product in 20 %
yield (10 mg). !H NMR (300 MHz, CD3OD): δ 9.33 (s, 1H), 8.68 (d, 1H), 8.08 (s, 1H),
7.94-7.92 (m, 2H), 7.81-7.73 (m, 2H), 7.70 (s, 1H), 7.24-7.16 (m, 3H), 3.96 (s, 3H),
3.16-3.09 (m, 1H), 1.28-1.24 (m, 2H), 1.05-1.01 (m, 2H); LC-MS (ESI): Calculated
mass: 506.1; Observed mass: 507.1 [M+H]+ (rt: 1.52 min).
Example 3.
N-(4-(2,4-difluorophenyl)-6-(5-(l-methyl-1H-pyrazol-4-yl)-1H-benzo[d]-
imidazol-1 -yl)pyridin-2-yl)acetamide
The compound was prepared from the compound of Example 1(b) using the
procedure of Example 2. 1H NMR (400 MHz, DMSO-d6): δ 10.81 (s, 1H), 9.07 (s, 1H),
8.58 (d, 1H), 8.32-8.22 (m, 2H), 7.96-7.95 (m, 2H), 7.85-7.81 (m, 2H), 7.59 (d, 1H),
7.61-7.49 (m, 1H), 7.36-7.31 (m, 1H), 3.89 (s, 3H), 2.21 (s, 3H); LC-MS (ESI):
Calculated mass: 444.15; Observed mass: 445.3 [M+H]+ (rt: 1.43 min).
Example 4.
N-(4-(2,4-difluorophenyl)-6-(5-(l-methyl-1H-pyrazol-4-yl)-1H-benzo[d]-
imidazol-1 -yl)pyridin-2-yl)methanesulfonamide
The compound was prepared from the compound of Example 1(b) using the
procedure of Example 2. !H NMR (400 MHz, DMSO-J6): δ 11.2 (s, 1H), 9.03 (s, 1H),

8.60 (d, 1H), 8.21 (s, 1H), 7.95 (s, 2H), 7.89-7.82 (m, 1H), 7.74 (s, 1H), 7.59-7.48 (m,
2H), 7.34-7.31 (m, 1H), 7.05 (s, 1H), 3.87 (s, 3H), 3.38 (s, 3H); LC-MS (ESI):
Calculated mass: 480.12; Observed mass: 481.05 [M+H]+ (rt: 1.39 min).
Example 5.
N-(4-(2,4-difluorophenyl)-6-(5-( 1 -methyl- 1H-pyrazol-4-yl)-1 H-benzo [d] -
imidazol-1 -yl)pyridin-2-yl)ethanesulfonamide
The compound was prepared from the compound of Example 1(b) using the
procedure of Example 2. 1H NMR (400 MHz, DMSO-J6): δ 11.1 (s, 1H), 9.02 (s, 1H),
8.61 (d, 1H), 8.22 (s, 1H), 7.95-7.94 (m, 2H), 7.89-7.83 (m, 1H), 7.74 (s, 1H), 7.60-7.56
(m, 1H), 7.54-7.48 (m, 1H), 7.36-7.31 (m, 1H), 7.06 (s, 1H), 3.87 (s, 3H), 3.54 (quartet,
2H), 1.26 (t, 3H); LC-MS (ESI): Calculated mass: 494.13; Observed mass: 494.8
[M+H]+(rt: 1.5 min).
Example 6.
N-(4-(2,4-difluorophenyl)-6-(5-(l-methyl-1H-pyrazol-4-yl)-l H-benzo [d]-
imidazol-1 -yl)pyridin-2-yl)propane-2-sulfonamide
The compound was prepared from the compound of Example 1(b) using the
procedure of Example 2. !H NMR (400 MHz, DMSO-J6): δ 11.1 (s, 1H), 9.04 (s, 1H),
8.67 (d, 1H), 8.22 (s, 1H), 7.96-7.94 (m, 2H), 7.87-7.85 (m, 1H), 7.73 (s, 1H), 7.61-7.52
(m, 2H), 7.34 (m, 1H), 7.06 (s, 1H), 3.95 (m, 1H), 3.87 (s, 3H), 1.33 (d, 6H); LC-MS
(ESI): Calculated mass: 508.15; Observed mass: 509.05 [M+H]+ (rt: 1.65 min).
Example 7.
N-(4-(2,4-difluorophenyl)-6-(5-(l-methyl-1H-pyrazol-4-yl)-1H-benzo[d]-
imidazol-1 -yl)pyridin-2-yl)pyridazin-3-amine
The compound was prepared from the compound of Example 1(b) using the
procedure of Example 2. 1H NMR (400 MHz, DMSO-d6): δ 10.29 (s, 1H), 8.93 (s, 1H),
8.90-8.87 (m, 1H), 8.43-8.42 (m, 1H), 8.24-8.18 (m, 2H), 8.15-8.10 (m, 2H), 7.99 (s,

1H), 7.96 (s, 1H), 7.65-7.62 (m, 2H), 7.5-7.44 (m, 1H), 7.36-7.28 (m, 2H), 3.87 (s, 3H);
LC-MS (ESI): Calculated mass: 480.16; Observed mass: 481.1 [M+H]+ (rt: 1.39 min).
Example 8.
N-(4-(2-fluorophenyl)-6-(5-( 1 -methyl-1 H-pyrazol-4-yl)- 1H-benzo [d]imidazol-1 -
yl)pyridin-2-yl)cyclopropanesulfonamide
a)2,6-Dichloro-4-(2-fluorophenyl)pyridine
A solution of 2,6-dichloro-4-iodopyridine (1.09 g, 4 mmol) in 1,2-dimethoxy-
ethane (15 ml) was degassed by N2 bubbling for 5 min. 2-Fluorophenylboronic acid
(0.67 g, 4.8 mmol, 1.2 eq) was added and the mixture was degassed for another 5 min.
Pd(dppf)Cl2 (0.33 g, 0.4 mmol, 0.1 eq) and aqueous sodium carbonate (1.27 g, 12
mmol, 3 eq) were added sequentially using the procedure of Intermediate Example 1 and
the mixture was then heated at 90 °C for 2 h. The reaction mixture was then quenched
and extracted as in Intermediate Example 1. The solvent was distilled off to afford the
crude residue which was purified by column chromatography (60-120 silica gel, 1 %
ethyl acetate in hexane) to yield the title product in 100 % yield (0.97 g).
b) 6-Chloro-4-(2-fluorophenyl)-N-(4-(l-methyl-1H-pyrazol-4-yl)-2-nitrophenyl)
pyridin-2-amine
A solution of the compound of Example 8(a) (0.97 g, 4 mmol) in toluene (5 ml)
was degassed by N2 bubbling for 5 min. The compound of Intermediate Example 1
(0.96 g, 4.4 mmol, 1.1 eq) was added and the mixture was degassed for another 5 min.
Palladium acetate (36 mg, 0.16 mmol, 0.04 eq) and BINAP (99 mg, 0.16 mmol, 0.04
eq) and potassium terf-butoxide (0.67 g, 6 mmol, 1.5 eq) were added sequentially
following the procedure of Example 1(a). The crude residue of the product was purified
by column chromatography (60-120 silica gel, 50 % ethyl acetate in hexane) in 36 %
yield (0.6 g). LC-MS (ESI): Calculated mass: 423.09; Observed mass: 424.05 [M+H]+
(rt: 2.04 min).

c) 1 -(6-chloro-4-(2-fluorophenyl) pyridin-2-yl)-5-( 1 -methyl-1 H-pyrazol-4-yl)-
1 H-benzo [d] imidazole
To a solution the compound of Example 8(b) (0.59 g, 1.4 mmol) in formic acid
(5 ml), iron (0.78 g, 14 mmol) was added and heated at 100 °C for 16 h. The formic
acid was distilled off and the crude product was dissolved in ethyl acetate. The ethyl
acetate layer was washed with water, brine and dried over sodium sulphate. The solvent
was distilled off to afford the title product in 53 % yield (0.3 g). LC-MS (ESI):
Calculated mass: 403.1; Observed mass: 404.1 [M+H]+ (rt: 1.66 min).
d) N-(4-(2-fluorophenyl)-6-(5-( 1-methyl-1 H-pyrazol-4-yl)-1 H-benzo[d]imidazol-
l-yl)pyridin-2-yl)cyclopropanesulfonamide
A solution of the compound of Example 8(c) (0.1 g, 0.25 mmol) in dioxane (1
ml) was degassed by N2 bubbling for 5 min. Cyclopropane sulfonamide (30 mg, 0.25
mmol, 1 eq) was added and the mixture was degassed for another 5 min. Palladium
acetate (5 mg, 0.02 mmol, 0.08 eq) and xantphos (12 mg, 0.02 mmol, 0.08 eq) and
CS2CO3 (0.24 g, 0.75 mmol, 3.0 eq) were added and the mixture was further degassed
for 5 min and then heated at 100 °C for 16 h. The mixture was filtered through celite and
extracted as in Example 1. The solvent was distilled off to afford the crude residue
which was purified by preparative HPLC to afford the title product in 8 % yield (10 mg).
!H NMR (400 MHz, CD3OD): δ 8.91 (s, 1H), 8.62 (d, 1H), 8.05 (s, 1H), 7.91 (m, 2H),
7.73-7.67 (m, 3H), 7.58-7.52 (m, 1H), 7.41-7.33 (m, 2H), 7.21 (s, 1H), 3.97 (s, 3H),
3.17-3.15 (m, 1H), 1.30-1.26 (m, 2H), 1.06-1.04 (m, 2H); LC-MS (ESI): Calculated
mass: 488.14; Observed mass: 489.2 [M+H]+ (rt: 1.46 min).
Example 9.
N-(4-(2-fluorophenyl)-6-(5-( 1 -methyl-1 H-pyrazol-4-yl)-1 H-benzo [d]imidazol-1 -
yl)pyridin-2-yl)acetamide
The compound was prepared from the compound of Example 8(c) using the
procedure of Example 8. !H NMR (300 MHz, CD3OD): δ 8.88 (s, 1H), 8.37-8.35 (m,
2H), 8.01 (s, 1H), 7.87 (m, 2H), 7.69-7.61 (m, 3H), 7.59-7.49 (m, 1H), 7.36-7.34 (m,

2H), 3.95 (s, 3H), 2.26 (m, 3H); LC-MS (ESI): Calculated mass: 426.16; Observed
mass: 427.25 [M+H]+ (rt: 1.4 min).
Example 10.
N-(4-(2-fluorophenyl)-6-(5-( 1 -methyl-1 H-pyrazol-4-yl)-1 H-benzo [djimidazol-1 -
yl)pyridin-2-yl)methanesulfonamide
The compound was prepared from the compound of Example 8(c) using the
procedure of Example 8. lH NMR (300 MHz, DMSO-d6): δ 11.2 (s, 1H), 9.02 (s, 1H),
8.60 (d, 1H), 8.20 (s, 1H), 7.94 (s, 2H), 7.74 (m, 2H), 7.56 (m, 2H), 7.41 (m, 2H), 7.07
(s, 1H), 3.86 (s, 3H), 3.38 (s, 3H); LC-MS (ESI): Calculated mass: 462.13; Observed
mass: 463.1 [M+H]+ (rt: 1.31 min).
Example 11.
N-(4-(2-fluorophenyl)-6-(5-(l-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-l-
yl)pyridin-2-yl)ethanesulfonamide
The compound was prepared from the compound of Example 8(c) using the
procedure of Example 8(d). ]H NMR (400 MHz, DMSO-J6): δ 11.1 (s, 1H), 9.03 (s,
1H), 8.61 (d, 1H), 8.22 (s, 1H), 7.95-7.94 (m, 2H), 7.79-7.76 (m, 2H), 7.60-7.57 (m,
2H), 7.46-7.40 (m, 2H), 7.09 (s, 1H), 3.87 (s, 3H), 3.55 (quartet, 2H), 1.26 (t, 3H); LC-
MS (ESI): Calculated mass: 476.14; Observed mass: 477.0 [M+H]+ (rt: 1.41 min).
Example 12.
N-(4-(2-fluorophenyl)-6-(5-( 1 -methyl- 1H-pyrazol-4-yl)-1 H-benzo [djimidazol-1 -
yl)pyridin-2-yl)propane-2-sulfonamide
The compound was prepared from the compound of Example 8(c) using the
procedure of Example 8. !H NMR (300 MHz, DMSO-J6): 6 11.03 (s, 1H), 9.03 (s, 1H),
8.67 (d, 1H), 8.22 (s, 1H), 7.96-7.94 (m, 2H), 7.79-7.73 (m, 2H), 7.61-7.55 (m, 2H),
7.42-7.39 (m, 2H), 7.08 (s, 1H), 3.96-3.93 (m, 1H), 3.87 (s, 3H), 1.33 (d, 6H); LC-MS
(ESI): Calculated mass: 490.16; Observed mass: 491.1 [M+H]+ (rt: 1.48 min).

Example 13.
N-(4-(2-fluorophenyl)-6-(5-( 1 -methyl-1 H-pyrazol-4-yl)-1 H-benzo[d]imidazol-1 -
yl)pyridin-2-yl)pyridazin-3 -amine
The compound was prepared from the compound of Example 8(c) using the
procedure of Example 8. 1H NMR (400 MHz, DMSO-J6): δ 10.49 (s, 1H), 9.01 (s, 1H),
8.85-8.83 (m, 1H), 8.32-8.29 (m, 1H), 8.20 (s, 1H), 8.05 (s, 1H), 7.99-7.94 (m, 3H),
7.79-7.78 (m, 1H), 7.63-7.58 (m, 4H), 7.47-7.41 (m, 2H), 3.87 (s, 3H); LC-MS (ESI):
Calculated mass: 462.17; Observed mass: 463.2 [M+H]+ (rt: 0.95 min).
Example 14.
N-(4-(4-fluorophenyl)-6-(5-( 1-methyl-1 H-pyrazol-4-yl)-1H-benzo [d]imidazol-1-
yl)pyridin-2-yl)cyclopropanesulfonamide
a) 2,6-Dichloro-4-(4-fluorophenyl)pyridine
A solution of 2,6-dichloro-4-iodopyridine (2.18 g, 8 mmol) in 1,2-dimethoxy-
ethane (15 ml) was degassed by N2 bubbling for 5 min. 4-Fluorophenylboronic acid
(1.34 g, 9.6 mmol, 1.2 eq) was added and the mixture was degassed for another 5 min.
Pd(dppf)Cl2 (1.3 g, 1.6 mmol, 0.2 eq) and aqueous sodium carbonate (2.54 g, 24 mmol,
3 eq) were added sequentially using the procedure of Intermediate Example 1 and the
mixture was then heated at 90 °C for 2 h. The reaction mixture was quenched and
extracted as in Intermediate Example 1. The solvent was distilled off to afford the crude
residue which was purified by column chromatography (60-120 silica gel, 1 % ethyl
acetate in hexane) to yield the title product in 77 % yield (1.5 g). LC-MS (ESI):
Calculated mass: 240.99; Observed mass: 242.0 [M+H]+ (rt: 1.95 min).
b) 6-Chloro-4-(4-fluorophenyl)-N-(4-( 1 -methyl-1 H-pyrazol-4-yl)-2-nitrophenyl)
pyridin-2-amine
A solution of the compound of Example 14(a) (0.97 g, 4 mmol) in toluene (5 ml)
was degassed by N2 bubbling for 5 min. The compound of Intermediate Example 1
(0.96 g, 4.4 mmol, 1.1 eq) was added and the mixture was degassed for another 5 min.

Palladium acetate (36 mg, 0.16 mmol, 0.04 eq) and BINAP (99 mg, 0.16 mmol, 0.04
eq) and potassium te/t-butoxide (0.67 g, 6 mmol, 1.5 eq) were added sequentially
following the procedure of Example 1(a). The crude residue of the product was purified
by column chromatography (60-120 silica gel, 50 % ethyl acetate in hexane) in 15 %
yield (0.25 g).
c) N1 -(6-chloro-4-(4-fluorophenyl)pyridin-2-yl)-4-( 1 -methyl- 1H-pyrazol-4-yl)-
benzene-1,2-diamine
To a solution of the compound of Example 14(b) (0.25 g, 0.6 mmol) in THF (10
ml) were added a solution of ammonium chloride (0.26 g, 4.8 mmol, 8 eq) in water (2
ml) and zinc (0.31 g, 4.8 mmol, 8 eq). The mixture was stirred at RT for 6 h and filtered.
The filtrate was diluted with water and extracted as in Intermediate Example 1. The
solvent was distilled off to afford the title product in 100 % yield (0.24 g). LC-MS
(ESI): Calculated mass: 393.12; Observed mass: 394.5 [M+H]+ (rt: 1.59 min).
d) l-(6-chloro-4-(4-fluorophenyl)pyridin-2-yl)-5-(l-methyl-1H-pyrazol-4-yl)-
1 H-benzo [d] imidazole
A solution of the compound of Example 14(c) (0.24 g, 0.6 mmol) and formic
acid (5 ml) was heated at 100 °C for 16 h. The formic acid was distilled off and the
crude product was extracted as in Example 8(c). The solvent was distilled off to afford
the title product in 38 % yield (90 mg). LC-MS (ESI): Calculated mass: 403.1;
Observed mass: 404.2 [M+H]+ (rt: 1.68 min).
e)N-(4-(4-fluorophenyl)-6-(5-(l-mefhyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-
l-yl)pyridin-2-yl)cyclopropanesulfonamide
A solution the compound of Example 14(d) (40 mg, 01 mmol) in dioxane (1 ml)
was degassed by N2 bubbling for 5 min. Cyclopropane sulfonamide (12 mg, 0.1 mmol, 1
eq) was added and the mixture was degassed for another 5 min. Palladium acetate (2 mg,
0.008 mmol, 0.08 eq) and xantphos (5 mg, 0.008 mmol, 0.08 eq) and Cs2C03 (0.1 g, 0.3
mmol, 3.0 eq) were added and the mixture was further degassed for 5 min and then

heated at 100 °C for 16 h. The mixture was filtered through celite and extracted as in
Example 1. The solvent was distilled off to afford the crude residue which was purified
by preparative HPLC to afford the title product in 20 % yield (10 mg). 1H NMR (400
MHz, CD3OD): δ 8.97 (s, 1H), 8.68 (d, 1H), 8.06 (s, 1H), 7.92-7.89 (m, 4H), 7.73 (m,
1H), 7.69-7.67 (m, 1H), 7.34-7.29 (m, 2H), 7.21 (m, 1H), 3.97 (s, 3H), 3.16-3.09 (m,
1H), 1.30-1.26 (m, 2H), 1.05-1.03 (m, 2H); LC-MS (ESI): Calculated mass: 488.14;
Observed mass: 489.1 [M+H]+ (rt: 1.5 min).
Example 15.
N-(4-(4-fluorophenyl)-6-(5-( 1 -methyl-1 H-pyrazol-4-yl)-1 H-benzo [d]imidazol-1 -
yl)pyridin-2-yl)acetamide
The compound was prepared from the compound of Example 14(d) using the
procedure of Example 14. ]H NMR (400 MHz, DMSO-d6): δ 10.75 (s, 1H), 9.13 (s,
1H), 8.59 (d, 1H), 8.29 (d, 1H), 7.93-7.89 (m, 5H), 7.56 (d, 2H), 7.43-7.4 (m, 2H), 3.86
(s, 3H), 2.19 (m, 3H); LC-MS (ESI): Calculated mass: 426.16; Observed mass: 427.5
[M+H]+(rt: 1.47 min).
Example 16.
N-(4-(4-fluorophenyl)-6-(5-(l-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-l-
yl)pyridin-2-yl)methanesulfonamide
The compound was prepared from the compound of Example 14(d) using the
procedure of Example 14. 1H NMR (400 MHz, DMSO-d6): δ 11.2 (s, 1H), 9.12 (s, 1H),
8.63 (d, 1H), 8.22 (s, 1H), 7.96-7.92 (m, 4H), 7.86 (s, 1H), 7.59-7.57 (m, 1H), 7.46-7.42
(m, 2H), 7.11 (s, 1H), 3.88 (s, 3H), 3.38 (s, 3H); LC-MS (ESI): Calculated mass:
462.13; Observed mass: 462.8 [M+H]+ (rt: 1.43 min).
Example 17.
N-(4-(4-fluorophenyl)-6-(5-( 1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-
yl)pyridin-2-yl)propane-2-sulfonamide

The compound was prepared from the compound of Example 14(d) using the
procedure of Example 14(e). 1H NMR (300 MHz, DMSO-d6): δ 11.0 (s, 1H), 9.13 (s,
1H), 8.68 (d, 1H), 8.22 (s, 1H), 7.96-7.87 (m, 5H), 7.62-7.58 (m, 1H), 7.47-7.41 (m,
2H), 7.12 (s, 1H), 3.99-3.93 (m, 1H), 3.87 (s, 3H), 1.34 (d, 6H); LC-MS (ESI):
Calculated mass: 490.16; Observed mass: 491.05 [M+H]+ (rt: 1.58 min).
Example 18.
N-(3-fluoro-6'-(5-(l-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-l-yl)-[2,4'-
bipyridin]-2'-yl)cyclopropanesulfonamide
a) 2,6-Dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
A solution of 2,6-dichloro-4-iodopyridine (15 g, 54.9 mmol) in DMF (150 ml)
was degassed by N2 bubbling for 5 min. Bispinacolato diborane (17.63 g, 82.4 mmol,
1.5 eq) was added and the mixture was degassed for another 5 min. Pd(dppf)Cl2 (2.24 g,
2.7 mmol, 0.05 eq) and potassium acetate (8.07 g, 82.4 mmol, 1.5 eq) were added
sequentially using the procedure of Intermediate Example 1 and the mixture was then
heated at 90 °C for 3 h. The reaction mixture was then quenched and extracted as in
Intermediate Example 1. The solvent was distilled off to afford the crude residue which
was purified by column chromatography (60-120 silica gel, 50 % ethyl acetate in
hexane) to afford the title product in 67 % yield (10 g). !H NMR (300 MHz, CDC13): δ
7.59 (s, 2H), 1.35 (s, 6H), 1.26 (s, 6H).
b) 2',6'-Dichloro-3 -fluoro-2,4'-bipyridine
A solution of 2-bromo-3-fluoropyridine (3 g, 17 mmol) in 1,2-dimethoxyethane
(30 mL) was degassed by N2 bubbling for 5 min. The compound of Example 18(a) (9.3
g, 34 mmol, 2 eq) was added and the mixture was degassed for another 5 min.
Pd(dppf)Ci2 (1.39 g, 1.7 mmol, 0.1 eq) and aqueous sodium carbonate (4.5 g, 42 mmol,
2.5 eq) were added sequentially using the procedure of Intermediate Example 1 and the
mixture was then heated at 110 °C for 4 h. The reaction mixture was then quenched and
extracted as in Intermediate Example 1. The solvent was distilled off to afford the crude
residue which was purified by column chromatography (60-120 silica gel, 10 % ethyl

acetate in hexane) to afford the title product in 30 % yield (1.2 g). !H NMR (300 MHz,
CDC13): 6 7.61-7.55 (m, 2H), 7.42-7.31 (m, 3H).
c) 6'-chloro-3-fluoro-N-(4-(l-methyl-1H-pyrazol-4-yl)-2-nitrophenyl)-[2,4'-bi-
pyridin] -2'-amine
A solution of the compound of Example 18(b) (1.2 g, 5 mmol) in dioxane (12
ml) was degassed by N2 bubbling for 5 min. The compound of Intermediate Example 1
(1.29 g, 6 mmol, 1.2 eq) was added and the mixture was degassed for another 5 min.
Palladium acetate (110 mg, 0.5 mmol, 0.1 eq) and BINAP (610 mg, 1 mmol, 0.2 eq)
and cesium carbonate (4.07 g, 12.4 mmol, 2.5 eq) were added sequentially following the
procedure of Example 1(a). The crude residue of the product was purified by column
chromatography (60-120 silica gel, 70 % ethyl acetate in hexane) to yield the title
product in 38 % yield (0.8 g).
d)Nl-(6'-chloro-3-fluoro-[2,4'-bipyridin]-2'-yl)-4-(l-methyl-1H-pyrazol-4-yl)-
benzene-1,2-diamine
To a solution of the compound of Example 18(c) (0.8 g, 1.9 mmol) in THF (15
ml) were added a solution of ammonium chloride (0.8 g, 15.1 mmol, 8 eq) in water (5
ml) and zinc (0.97 g, 15.1 mmol, 8 eq). The mixture was stirred at RT for 6 h and
filtered. The filtrate was diluted with water and extracted as in Intermediate Example 1.
The solvent was distilled off to afford the title product in 100 % yield (0.8 g). LC-MS
(ESI): Calculated mass: 394.11; Observed mass: 395.0 [M+H]+ (rt: 1.34 min).
e) l-(6'-chloro-3-fluoro-[2,4'-bipyridin]-2'-yl)-5-(l-methyl-1H-pyrazol-4-yl)-1H-
benzo [d]imidazole
A solution of the compound of Example 18(d) (0.4 g, 1 mmol) and formic acid
(5 ml) was heated at 110 °C for 12 h. The formic acid was distilled off and the crude was
extracted as in Example 8(c). The solvent was distilled off to afford the title product in
100 % yield (0.4 g). !H NMR (300 MHz, CD3OD): δ 8.95 (s, 1H), 8.64 (m, 1H), 8.38 (s,

1H), 8.29-8.27 (m, 2H), 8.03-8.02 (m, 2H), 7.92-7.81 (m, 2H), 7.69-7.64 (m, 2H), 3.95
(s, 3H).
f) N-(3-fluoro-6'-(5-( 1 -methyl-1 H-pyrazol-4-yl)-1 H-benzo[d]imidazol-1 -yl)-
[2,4'-bipyridin]-2'-yl)cyclopropanesulfonamide
A solution of the compound of Example 18(e) (40 mg, 0.1 mmol) in dioxane (1
ml) was degassed by N2 bubbling for 5 min. Cyclopropane sulfonamide (12 mg, 0.1
mmol, 1 eq) was added and the mixture was degassed for another 5 min. Pd2(dba)3 (9
mg, 0.01 mmol, 0.1 eq) and xantphos (6 mg, 0.01 mmol, 0.1 eq) and CS2CO3 (80 mg,
0.25 mmol, 2.5 eq) were added and the mixture was further degassed for 5 min and then
heated atl 10 °C for 16 h. The mixture was filtered through celite and extracted as in
Example 1. The solvent was distilled off to afford the crude residue which was purified
by column chromatography (60-120 silica gel, 10 % methanol in CHCI3) to afford the
title product in 50 % yield (15 mg). JH NMR (300 MHz, DMSO-d6): δ 11.22 (s, 1H),
9.0 (s, 1H), 8.69-8.63 (m, 2H), 8.24 (s, 1H), 8.04-7.98 (m, 4H), 7.71-7.6 (m, 2H), 7.49
(s, 1H), 3.88 (s, 3H), 3.17-3.15 (m, 1H), 1.13-1.12 (m, 2H), 1.05-1.02 (m, 2H); LC-MS
(ESI): Calculated mass: 489.14; Observed mass: 490.01 [M+H]+ (it: 0.57 min).
Example 19.
N-(3-fluoro-6'-(5-(l-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-l-yl)-[2,4'-
bipyridin]-2'-yl)acetamide
The compound was prepared from the compound of Example 18(e) using the
procedure of Example 18. 1H NMR (300 MHz, DMSO-J6): δ 11.1 (s, 1H), 9.34 (s, 1H),
8.84 (s, 1H), 8.62 (d, 1H), 8.45 (d, 1H), 8.12 (s, 1H), 8.07 (s, 1H), 7.94-7.92 (m, 2H),
7.86-7.74 (m, 2H), 7.63-7.57 (m, 1H), 3.89 (s, 3H), 2.22 (m, 3H); LC-MS (ESI):
Calculated mass: 427.16; Observed mass: 428.3 [M+H]+ (rt: 0.7 min).
Example 20.
N-(3-fluoro-6'-(6-(l-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-
[2,4'-bipyridin]-2'-yl)cyclopropanesulfonamide

a)6'-Chloro-3-fluoro-N-(5-(l-methyl-1H-pyrazol-4-yl)-3-nitropyridin-2-yl)-[2,4'-
bipyridin] -2'-amine
A solution of 2',6'-dichloro-3-fluoro-2,4'-bipyridine (0.5 g, 2.1 mmol) in dioxane
(12 ml) was degassed by N2 bubbling for 5 min. The compound of Intermediate
Example 7 (0.55 g, 2.5 mmol, 1.2 eq) was added and the mixture was degassed for
another 5 min. Pd2(dba)3 (0.19 g, 0.21 mmol, 0.1 eq) and xantphos (0.24 g, 0.42 mmol,
0.2 eq) and cesium carbonate (1.68 g, 5.2 mmol, 2.5 eq) were added sequentially
following the procedure of Example 1(a). The crude residue of the product was purified
by column chromatography (60-120 silica gel, 70 % ethyl acetate in hexane) to yield the
title product in 32 % yield (0.28 g). LC-MS (ESI): Calculated mass: 425.08; Observed
mass: 426.3 [M+H]+ (rt: 1.72 min).
b)N2-(6'-chloro-3-fluoro-[2,4'-bipyridin]-2'-yl)-5-(l-methyl-1H-pyrazol-4-
yl)pyridine-2,3-diamine
To a solution of the compound of Example 20(a) (0.28 g, 0.7 mmol) in THF (10
ml) were added a solution of ammonium chloride (0.28 g, 5.6 mmol, 8 eq) in water (5
ml) and zinc (0.33 g, 5.6 mmol, 8 eq). The mixture was stirred at RT for 2 h and filtered.
The filtrate was diluted with water and extracted as in Intermediate Example 1. The
solvent was distilled off to afford the title product in 72 % yield (0.2 g).
c)3-(6'-Chloro-3-fluoro-[2,4'-bipyridin]-2'-yl)-6-(l-methyl-1H-pyrazol-4-yl)-3H-
imidazo[4,5-b]pyridine
A solution the compound of Example 20(b) (0.2 g, 0.5 mmol) and formic acid (5
ml) was heated at 100 °C for 16 h. The formic acid was distilled off and the crude was
extracted as in Example 8(c). The solvent was distilled off to afford the title product in
75% yield (0.15 g).
d)N-(3-fluoro-6'-(6-(l-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-
[2,4'-bipyridin]-2'-yl)cyclopropanesulfonamide

A solution of the compound of Example 20(c) (40 mg, 0.1 mmol) in dioxane (1
ml) was degassed by N2 bubbling for 5 min. Cyclopropane sulfonamide (14 mg, 0.12
mmol, 1.2 eq) was added and the mixture was degassed for another 5 min. Pd2(dba)3 (9
mg, 0.01 mmol, 0.1 eq) and xantphos (6 mg, 0.01 mmol, 0.1 eq) and CS2CO3 (80 mg,
0.25 mmol, 2.5 eq) were added and the mixture was further degassed for 5 min and then
heated atl 10 °C for 16 h. The mixture was filtered through celite and extracted as in
Example 1. The solvent was distilled off to afford the crude residue which was purified
by column chromatography (60-120 silica gel, 10 % methanol in CHCI3) to afford the
title product in 8 % yield (5 mg). 1H NMR (300 MHz, CDC13): δ 9.24 (s, 1H), 9.16 (s,
1H), 8.69 (s, 1H), 8.64 (m, 1H), 8.3 (s, 1H), 7.98 (s, 1H), 7.85 (s, 1H), 7.73 (s, 1H),
7.61-7.58 (m, 2H), 7.48-7.44 (m, 1H), 4.0 (s, 3H), 2.88 (m, 1H), 1.40-1.31 (m, 2H),
1.08-1.1 (m, 2H); LC-MS (ESI): Calculated mass: 490.13; Observed mass: 491.0
[M+H]+(rt: 1.16 min).
Example 21.
N-(4-(2,4-difluorophenyl)-6-(5-( 1 -(2-(dimethylamino)ethyl)-1 H-pyrazol-4-yl)-
1 H-benzo [d] imidazol-1 -yl)pyridin-2-yl)cyclopropanesulfonamide
a)6-Chloro-4-(2,4-difluorophenyl)-N-(4-(l-(2-(dimethylamino)ethyl)-1H-
pyrazol-4-yl)-2-nitrophenyl)pyridin-2-amine
A solution of the compound of Intermediate Example 5(a) (0.2 g, 0.8 mmol) in
dioxane (15 ml) was degassed by N2 bubbling for 5 min. The compound Intermediate
Example 3 (0.23 g, 0.9 mmol, 1.1 eq) was added and the mixture was degassed for
another 5 min. Palladium acetate (0.017 g, 0.08 mmol, 0.1 eq) and BINAP (0.1 g, 0.16
mmol, 0.2 eq) and cesium carbonate (0.65 g, 2 mmol, 2.0 eq) were added sequentially
and the mixture was further degassed for 5 min and then heated at 110 °C for 12 h. The
mixture was filtered through celite and extracted as in Example 1. The solvent was
distilled off to afford the crude residue which was purified by column chromatography
(60-120 silica gel, 10 % methanol in CH2C12) to afford the title product in 55 % yield
(0.1 g). LC-MS (ESI): Calculated mass: 498.14; Observed mass: 499.7 [M+H]+ (rt: 1.41
min).

b) N1 -(6-chloro-4-(2,4-difluorophenyl)pyridin-2-yl)-4-( 1 -(2-(dimethylamino)-
ethyl)- 1H-pyrazol-4-yl)benzene-1,2-diamine
To a solution of the compound of Example 21(a) (0.1 g, 0.2 mmol) in THF (10
ml) were added a solution of ammonium chloride (85 mg, 1.6 mmol, 8 eq) in water (2
ml) and zinc (0.1 g, 1.6 mmol, 8 eq). The mixture was stirred at RT for 12 h and filtered.
The filtrate was diluted with water and extracted as in Intermediate Example 1. The
solvent was distilled off to afford the title product in 100 % yield (93 mg).
c) 2-(4-(l-(6-chloro-4-(2,4-difluorophenyl)pyridin-2-yl)-1H-benzo[d]imidazol-5-
yl)-1 H-pyrazol-1 -yl)-N,N-dimethylethanamine
A solution the compound of Example 21(b) (93 mg, 0.2 mmol) and formic acid
(5 ml) was heated at 100 °C for 12 h. The formic acid was distilled off and the crude was
extracted as in Example 8(c). The solvent was distilled off to afford desired title product
in 83 % yield (80 mg). LC-MS (ESI): Calculated mass: 478.15; Observed mass: 479.45
[M+H]+(rt: 1.36 min).
d)N-(4-(2,4-difluorophenyl)-6-(5-(l-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-
1 H-benzo [d] imidazol-1 -yl)pyridin-2-yl)cyclopropanesulfonamide
A solution of the compound of Example 21(c) (80 mg", 0.2 mmol) in dioxane (5
ml) was degassed by N2 bubbling for 5 min. Cyclopropane sulfonamide (29 mg, 0.24
mmol, 1.2 eq) was added and the mixture was degassed for another 5 min. Pd(OAc)2 (5
mg, 0.02 mmol, 0.1 eq) and xantphos (23 mg, 0.04 mmol, 0.2 eq) and CS2CO3 (162 mg,
0.5 mmol, 2.5 eq) were added and the mixture was further degassed for 5 min and then
heated atl 10 °C for 12 h. The mixture was filtered through celite and extracted as in
Example 1. The solvent was distilled off to afford the crude residue which was purified
by column chromatography (60-120 silica gel, 10 % methanol in CH2CI2) to afford the
desired title product in 35 % yield (20 mg). !H NMR (400 MHz, CDC13): δ 8.7 (s, 1H),
8.04 (m, 2H), 7.82 (d, 2H), 7.56 (m, 2H), 7.41 (m, 2H), 7.07-7.02 (m, 2H), 4.29 (m,
2H), 2.89-2.84 (m, 3H), 2.33 (s, 6H), 1.39 (m, 2H), 1.08 (m, 2H); LC-MS (ESI):
Calculated mass: 563.19; Observed mass: 564.25 [M+H]+ (rt: 0.59 min).

Example 22.
N-(4-(2-fluorophenyl)-6-(5-( 1 -methyl- 1H-pyrazol-4-yl)- 1H-benzo[d]imidazol-1 -
yl)pyrimidin-2-yl)cyclopropanesulfonamide
a)4-Chloro-6-(2-fluorophenyl)pyrimidin-2-amine
A solution of 4,6-dichloropyrimidin-2-amine (5 g, 30.6 mmol) in 1,2-di-
methoxyethane (50 ml) was degassed by N2 bubbling for 5 min. 2-Fluorophenylboronic
acid (4.27 g, 30.6 mmol, 1.2 eq) was added and the mixture was degassed for another 5
min. Pd(dppf)Cl2 (1.25 g, 1.53 mmol, 0.05 eq) and aqueous sodium carbonate (8.12 g,
76.6 mmol, 2.5 eq) were added sequentially using the procedure of Intermediate
Example 1 and then heated at 90 °C for 3 h. The reaction mixture was then quenched
and extracted as in Intermediate Example 1. The solvent was distilled off to afford the
crude residue which was purified by column chromatography (60-120 silica gel, 30 %
ethyl acetate in hexane) to afford the title product in 15 % yield (1 g). LC-MS (ESI):
Calculated mass: 223.03; Observed mass: 224.0 [M+H]+ (rt: 1.53 min).
b)N-(4-chloro-6-(2-fluorophenyl)pyrimidin-2-yl)cyclopropanesulfonamide
To an icecold solution of the compound of Example 22(a) (1 g, 4.48 mmol) in
DMF (50 ml) was added NaH (0.16 g, 6.72 mmol, 1.5 eq). The mixture was stirred for
10 min and cyclopropylsulfonyl chloride (0.76 g, 5.38 mmol, 1.2 eq) was added and the
mixture was stirred at RT for 24 h. The mixture was then quenched with water and
extracted with ethyl acetate (3 x 100 ml). The combined organic layer was washed with
water, brine and dried over sodium sulphate. The solvent was distilled off to afford the
crude product which was purified by column chromatography (60-120 silica gel, 5 %
ethyl acetate in hexane) to afford the title product in 34 % yield (0.5 g). LC-MS (ESI):
Calculated mass: 327.02; Observed mass: 327.8 [M+H]+ (rt: 1.61 min).
c) N-(4-(2-fluorophenyl)-6-(5-( 1 -methyl-1 H-pyrazol-4-yl)-1 H-benzo [d] imidazol-
l-yl)pyrimidin-2-yl)cyclopropanesulfonamide

To an icecold solution of the compound of Example 22(b) (0.2 g, 0.61 mmol) in
DMF (50 ml) in a sealed tube was added NaH (22 mg, 0.9 mmol, 1.5 eq). The mixture
was stirred for 10 min and the compound of Intermediate Example 6 (0.12 g, 0.61
mmol, 1 eq) was added. The mixture was stirred at RT for 24 h and then quenched and
extracted with ethyl acetate (3 x 100 ml). The combined organic layer was washed with
water, brine and dried over sodium sulphate. The solvent was distilled off to afford a
crude product mixture from which the title compound was isolated by preparative TLC
in 0.01% yield (3 mg). JH NMR (400 MHz, CDC13): δ 8.75 (s, 1H), 8.36 (d, 1H), 8.24-
8.21 (m, 2H), 7.99 (s, 1H), 7.85-7.81 (m, 2H), 7.69 (s, 1H), 7.63-7.55 (m, 3H), 7.39-
7.37 (m, 1H), 3.99 (s, 3H), 3.3 (m, 1H), 1.12-1.10 (m, 2H), 0.88-0.84 (m, 2H); LC-MS
(ESI): Calculated mass: 489.14; Observed mass: 490.4 [M+H]+ (rt: 1.43 min).
Example 23.
N-(6-(5-(1H-pyrazol-l-yl)-1H-benzo[d]imidazol-l-yl)-4-(2,4-difluorophenyl)-
pyridin-2-yl)cyclopropanesulfonamide
A solution of the title compound of Intermediate Example 5 (50 mg, 0.144
mmol) in dioxane (5 ml) was degassed by N2 bubbling for 5 min. The compound of
Intermediate Example 4 (26 mg, 0.144 mmol, 1 eq) was added and the mixture was
degassed for another 5 min. Cul(1.3 mg, 0.0072 mmol, 0.05 eq), N,N-dimethyl glycine
(1.4 mg, 0.0144 mmol, 0.1 eq) and Cs2C03 (141 mg, 0.434 mmol, 3.0 eq) were added
and the reaction mixture was further degassed for 5 min and then heated at 100 °C for
24 h. The reaction mixture was filtered through celite and washed with ethyl acetate.
The solvent was distilled off to afford a crude product mixture from which the title
compound was isolated by preparative HPLC to afford the title compound in 14 % yield
(10 mg). !H NMR (400 MHz, DMSO-d6): 6 11.2 (s, 1H), 9.18 (d, 1H), 8.86 (d, 1H),
8.66 (d, 1H), 8.23 (d, lH),7.96-7.86 (m, 2H), 7.83-7.78 (m, 2H), 7.59-7.51 (m,lH),
7.39-7.34 (m, 1H), 7.16 (s, 1H), 6.59 (s, 1H), 3.19-3.14 (m, 1H), 1.24-1.12 (m, 2H),
1.06-1.03 (m, 2H); LC-MS (ESI): Calculated mass: 492.12; Observed mass: 493.4
[M+H]+(rt: 1.71 min).
Example 24.

N-(4-(2,4-difluorophenyl)-6-(6-(l-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-
b]pyridin-3-yl)pyridin-2-yl)cyclopropanesulfonamide
a)6-Chloro-4-(2,4-difluorophenyl)-N-(5-(l-methyl-1H-pyrazol-4-yl)-3-
nitropyridin-2-yl)pyridin-2-amine
A solution of the compound of Intermediate Example 5(a) (0.5 g, 1.92 mmol) in dioxane
(5 ml) was degassed by N2 bubbling for 5 min. The compound of Intermediate Example
7 (0.42 g, 1.92 mmol, 1 eq) was added and the mixture was degassed for another 5 min.
Pd2(dba)3 (0.087 g, 0.09 mmol, 0.05 eq) and xantphos (0.11 g, 0.192 mmol, 0.1 eq) and
cesium carbonate (1.56 g, 4.8 mmol, 2.5 eq) were added sequentially following the
procedure of Example 1(a) and the mixture was then heated at 110 °C for 16 h. The
mixture was filtered through celite and extracted as in Example 1. The solvent was
distilled off to afford the crude residue which was purified by column chromatography
(60-120 silica gel, 20 % ethyl acetate in hexane) to afford the title product in 46 % yield
(0.4 g).
b) N2-(6-chloro-4-(2,4-difluorophenyl)pyridin-2-yl)-5-( 1 -methyl-1 H-pyrazol-4-
yl)pyridine-2,3-diamine
To a solution of the compound of Example 24(a) (0.39 g, 0.88 mmol) in THF
(10 ml) were added a solution of ammonium chloride (0.37 g, 7 mmol, 8 eq) in water (2
ml) and zinc (0.46 g, 7 mmol, 8 eq). The mixture was stirred at RT for 6 h and filtered.
The filtrate was diluted with water and extracted as in Intermediate Example 1. The
solvent was distilled off to afford the title product in 88 % yield (0.32 g).
c)3-(6-Chloro-4-(2,4-difluorophenyl)pyridin-2-yl)-6-(l-methyl-1H-pyrazol-4-
yl)-3H-imidazo[4,5-b]pyridine
A solution the compound of Example 24(b) (0.32 g, 0.77 mmol) and formic acid
(10 ml) was heated at 100 °C for 16 h. The formic acid was distilled off and the crude
was extracted as in Example 8(c). The solvent was distilled off to afford the title product

in 70 % yield (0.23 g). LC-MS (ESI): Calculated mass: 422.09; Observed mass: 423.2
[M+H] + (rt: 1.74 min).
d)N-(4-(2,4-difluorophenyl)-6-(6-(l -methyl- 1H-pyrazol-4-yl)-3H-imidazo [4,5-
b]pyridin-3-yl)pyridin-2-yl)cyclopropanesulfonamide
A solution of the compound of Example 24(c) (150 mg, 0.35 mmol) in dioxane
(5 ml) was degassed by N2 bubbling for 5 min. Cyclopropane sulfonamide (55 mg, 0.46
mmol, 1.3 eq) was added and the mixture was degassed for another 5 min. Pd(OAc)2 (4
mg, 0.017 mmol, 0.05 eq) and xantphos (20 mg, 0.03 mmol, 0.1 eq) and Cs2C03 (288
mg, 0.88 mmol, 2.5 eq) were added and the mixture was further degassed for 5 min and
then heated atl 10 °C for 12 h. The mixture was filtered through celite and extracted as
in Example 1. The solvent was distilled off to afford the crude residue which was
purified by column chromatography (60-120 silica gel, 3 % methanol in CH2C12) to
afford the title product in 27 % yield (48 mg). !H NMR (300 MHz, DMSO-J6): δ 11.07
(s, 1H), 9.09 (s, 1H), 8.80 (d, 1H), 8.49-8.45 (m, 2H), 8.30 (s, 1H), 8.05 (d, 1H), 7.81-
7.73 (m, 1H), 7.57-7.49 (m, lH),7.38-7.32 (m, 1H), 7.1 l(s, 1H), 3.89 (s, 3H), 3.41-3.37
(m, 1H), 1.13-1.10 (m, 4H); LC-MS (ESI): Calculated mass: 507.13; Observed mass:
508.1 [M+H]+(rt: 1.54 min).
Example 25.
N-(3,5-difluoro-6'-(5-(l-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-l-yl)-
[2,4'-bipyridin]-2'-yl)cyclopropanesulfonamide
a)2',6'-Dichloro-3,5-difluoro-2,4'-bipyridine
A solution of 2-bromo-3,5-difluoropyridine (1.6 g, 5.84 mmol) in 1,2-di-
methoxyethane (30 ml) was degassed by N2 bubbling for 5 min. The compound of
Example 18(a) (1.36 g, 7 mmol, 2 eq) was added and the mixture was degassed for
another 5 min. Pd(dppf)Cl2 (0.47 g, 0.58 mmol, 0.1 eq) and aqueous sodium carbonate
(1.85 g, 17.5 mmol, 3 eq) were added sequentially using the procedure of Intermediate
Example 1 and the mixture was then heated at 90 °C for 2 h. The reaction mixture was
quenched and extracted as in Intermediate Example 1. The solvent was distilled off to

afford the crude residue which was purified by column chromatography (60-120 silica
gel, 5 % ethyl acetate in hexane) to afford the title product in 72 % yield (1.1 g).
b)6'-Chloro-3,5-difluoro-N-(4-(l-methyl-1H-pyrazol-4-yl)-2-nitrophenyl)-[2,4'-
bipyridin] -2'-amine
A solution of the compound of Example 25(a) (0.4 g, 1.5 mmol) in dioxane (12
ml) was degassed by N2 bubbling for 5 min. The compound of Intermediate Example 1
(0.4 g, 1.84 mmol, 1.2 eq) was added and the mixture was degassed for another 5 min.
Palladium acetate (17 mg, 0.08 mmol, 0.05 eq) and BINAP (47 mg, 0.08 mmol, 0.05
eq) and potassium terf-butoxide (0.26 g, 2.29 mmol, 1.5 eq) were added sequentially
following the procedure of Example 1(a) and the mixture was then heated at 110 °C for
72 h. The crude residue of the product was purified by column chromatography (60-120
silica gel, 50 % ethyl acetate in hexane) to afford the title product in 18 % yield (0.12 g).
LC-MS (ESI): Calculated mass: 442.08; Observed mass: 443.05 [M+H]+ (rt: 1.98 min).
c)Nl-(6'-chloro-3,5-difluoro-[2,4'-bipyridin]-2'-yl)-4-(l-methyl-1H-pyrazol-4-
yl)benzene-1,2-diamine
To a solution of the compound of Example 25(b) (0.12 g, 0.27 mmol) in THF
(15 ml) were added a solution of ammonium chloride (0.15 g, 2.7 mmol, 8 eq) in water
(2 ml) and zinc (0.18 g, 2.7 mmol, 8 eq). The mixture was stirred at RT for 6 h and
filtered. The filtrate was diluted with water and extracted as in Intermediate Example 1.
The solvent was distilled off to afford the title product in 90 % yield (0.1 g).
d) l-(6'-Chloro-3,5-difluoro-[2,4'-bipyridin]-2'-yl)-5-(l-methyl-1H-pyrazol-4-yl)-
1 H-benzo [d] imidazole
A solution the compound of Example 25(c) (0.1 g, 0.242 mmol) and formic acid
(10 ml) was heated at 100 °C for 16 h. The formic acid was distilled off and the crude
product was extracted as in Example 8(c). The solvent was distilled off to afford the title
product in 78 % yield (80 mg). LC-MS (ESI): Calculated mass: 422.09; Observed mass:
422.8 [M+H]+ (rt: 1.69 min).

e) N-(3,5-difluoro-6'-(5-( 1 -methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1 -yl)-
[2,4'-bipyridin]-2'-yl)cyclopropanesulfonamide
A solution of the compound of Example 25(d) (80 mg, 0.19 mmol) in dioxane
(5 ml) was degassed by N2 bubbling for 5 min. Cyclopropane sulfonamide (28 mg, 0.23
mmol, 1.2 eq) was added and the mixture was degassed for another 5 min. Pd(OAc)2
(4.2 mg, 0.019 mmol, 0.1 eq) and xantphos (22 mg, 0.04 mmol, 0.2 eq) and Cs2C03
(185 mg, 0.57 mmol, 3 eq) were added and the mixture was further degassed for 5 min
and then heated at 110 °C for 12 h. The mixture was filtered through celite and extracted
as in Example 1. The solvent was distilled off to afford the crude residue which was
purified by preparative TLC to afford the title product in 5 % yield (5 mg). 1H NMR
(300 MHz, DMSO-d6): δ 8.98 (s, 1H), 8.76 (d, 1H), 8.61 (d, 1H), 8.25-8.18 (m, 2H),
7.96 (m, 3H), 7.62-7.59 (m, 1H), 7.47 (s, 1H), 3.88 (s, 3H), 3.12 (m, 1H), 1.14-1.12 (m,
2H), 1.04-1.02 (m, 2H); LC-MS (ESI): Calculated mass: 507.13; Observed mass: 508.1
[M+H]+(rt: 1.27 min).
Example 26.
N-(3,5-difluoro-6'-(5-(l-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-l-yl)-
[2,4'-bipyridin]-2'-yl)acetamide
The compound was prepared from the compound of Example 25(d) using the
procedure of Example 28. !H NMR (400 MHz, DMSO-d6): δ 10.85 (s, 1H), 9.0 (s, 1H),
8.76 (d, 1H), 8.58 (s, 1H), 8.50 (d, 1H), 8.23-8.21 (m, 2H), 8.0 (s, 1H), 7.95 (m, 2H),
7.62-7.59 (m, 1H), 3.88 (s, 3H), 2.21 (s, 3H); LC-MS (ESI): Calculated mass: 445.15;
Observed mass: 446.1 [M+H]+ (rt: 1.08 min).
Example 27.
N-(6-(5-( 1 -methyl-1 H-pyrazol-4-yl)-1 H-benzo [djimidazol-1 -yl)-4-( 1 H-pyrrol-1 -
yl)pyridin-2-yl) acetamide
a) 2,6-Dichloro-4-(l H-pyrrol-l-yl)pyridine

A solution 2,6-dichloropyridin-4-amine (2 g, 12.3 mmol) and 2,5-dimethoxy-
furan (1.94 g, 14.7 mmol, 1.2 eq) in acetic acid (10 ml) was heated at 90 °C for 2 h. The
mixture was quenched with water and extracted with EtOAc (3 x 50 ml). The combined
organic layer was washed with water, brine and dried over sodium sulphate. The solvent
was distilled off to afford the title product in 80 % yield (2.1 g).
b) 6-Chloro-N-(4-( 1 -methyl-1 H-pyrazol-4-yl)-2-nitrophenyl)-4-( 1 H-pyrrol-1 -yl)-
pyridin-2-amine
To an icecold solution of the compound of Example 27(a) (1 g, 4.58 mmol) in
DMSO (20 ml) was added NaH (0.13 g, 5.5 mmol, 1.2 eq). The mixture was stirred for
10 min and the compound of Intermediate Example 1 (1.1 g, 5.5 mmol, 1.2 eq) was
added. The mixture was stirred at RT for 16 h and then quenched with water and
extracted with ethyl acetate (3 x 50 ml). The combined organic layer was washed with
water, brine and dried over sodium sulphate. The solvent was distilled off to afford the
crude product which was purified by column chromatography (60-120 silica gel, 50 %
ethyl acetate in hexane) to afford the title product in 25 % yield (0.45 g). LC-MS (ESI):
Calculated mass: 394.09; Observed mass: 394.8 [M+H]+ (rt: 1.87 min).
c) N1 -(6-chloro-4-( 1 H-pyrrol-1 -yl)pyridin-2-yl)-4-( 1 -methyl- 1H-pyrazol-4-
yl)benzene-1,2-diamine
To a solution of the compound of Example 27(b) (0.43 g, 1.1 mmol) in THF (30
ml) were added a solution of ammonium chloride (0.58 g, 10.9 mmol, 10 eq) in water (5
ml) and zinc (0.71 g, 10.9 mmol, 10 eq). The mixture was stirred at RT for 6 h and
filtered. The filtrate was diluted with water and extracted as in Intermediate Example 1.
The solvent was distilled off to afford the product in 90 % yield (0.36 g). LC-MS (ESI):
Calculated mass: 364.12; Observed mass: 365.0 [M+H]+ (rt: 1.47 min).
d) l-(6-Chloro-4-(1H-pyrrol-l-yl)pyridin-2-yl)-5-(l-methyl-1H-pyrazol-4-yl)-
1 H-benzo [d] imidazole

A solution of the compound of Example 27(c) (0.35 g, 0.96 mmol) and formic
acid (10 ml) was heated at 100 °C for 16 h. The formic acid was distilled off and the
crude was extracted as in Example 8(c). The solvent was distilled off to afford the title
product in 97 % yield (350 mg). LC-MS (ESI): Calculated mass: 374.10; Observed
mass: 375.1 [M+H] + (rt: 1.59 min).
e) N-(6-(5-( 1 -methyl-1 H-pyrazol-4-yl)-1 H-benzo[d]imidazol-1 -yl)-4-( 1 H-pyrrol-
1 -yl)pyridin-2-yl)acetamide
A solution of the compound of Example 27(d) (100 mg, 0.27 mmol) in dioxane
(5 ml) was degassed by N2 bubbling for 5 min. Acetamide (19 mg, 0.32 mmol, 1.2 eq)
was added and the mixture was degassed for another 5 min. Pd(OAc)2 (3 mg, 0.013
mmol, 0.05 eq) and xantphos (15 mg, 0.026 mmol, 0.1 eq) and CS2CO3 (261 mg, 0.8
mmol, 3 eq) were added and the mixture was further degassed for 5 min and then heated
at 110 °C for 12 h. The mixture was filtered through celite and extracted as in Example
1. The solvent was distilled off to afford the crude residue which was purified by
preparative HPLC to afford the title product in 75 % yield (80 mg). 1H NMR (400 MHz,
DMSO-d6): δ 10.79 (s, 1H), 9.13 (s, 1H), 8.63 (d, 1H), 8.21 (s, 2H), 7.95-7.93 (m, 2H),
7.84 (d, 1H), 7.60-7.57 (m, 3H), 6.41-6.40 (m, 2H), 3.88 (s, 3H), 2.21 (s, 3H); LC-MS
(ESI): Calculated mass: 397.17; Observed mass: 398.1 [M+H]+ (rt: 1.24 min).
Example 28.
N-(4-(2-chlorophenyl)-6-(5-( 1 -methyl-1 H-pyrazol-4-yl)-1H-benzo [d]imidazol-1 -
yl)pyridin-2-yl)cyclopropanesulfonamide
a) 2,6-Dichloro-4-(2-chlorophenyl)pyridine
A solution of 2,6-dichloro-4-iodopyridine (1 g, 3.65 mmol) in 1,2-dimethoxy-
ethane (15 ml) was degassed by N2 bubbling for 5 min. 2-Chlorophenylboronic acid
(0.68 g, 4.38 mmol, 1.2 eq) was added and the mixture was degassed for another 5 min.
Pd(dppf)Cl2 (0.3 g, 0.37 mmol, 0.1 eq) and aqueous sodium carbonate (1.16 g, 10.9
mmol, 3 eq) were added sequentially using the procedure of Intermediate Example 1 and
the mixture was heated at 90 °C for 2 h. The reaction mixture was then quenched and

extracted as in Intermediate Example 1. The solvent was distilled off to afford the crude
residue which was purified by column chromatography (60-120 silica gel, 5 % ethyl
acetate in hexane) to afford the title product in 74 % yield (0.7 g). !H NMR (300 MHz,
CDC13): δ 7.53-7.49 (m, 1H), 7.41-7.35 (m, 3H), 7.32-7.29 (m, 1H), 7.26 (m, 1H).
b) 6-Chloro-4-(2-chlorophenyl)-N-(4-( 1 -methyl-1 H-pyrazol-4-yl)-2-nitrophenyl)-
pyridin-2-amine
A solution of the compound of Example 28(a) (0.7 g, 2.7 mmol) in toluene (10
ml) was degassed by N2 bubbling for 5 min. The compound of Intermediate Example 1
(0.6 g, 2.7 mmol, 1 eq) was added and the mixture was degassed for another 5 min.
Palladium acetate (24 mg, 0.11 mmol, 0.04 eq) and BINAP (67 mg, 0.11 mmol, 0.04
eq) and potassium tert-butoxide (0.3 g, 2.7 mmol, 1 eq) were added sequentially
following the procedure of Example 1(a) and the mixture was heated at 100 °C
overnight. The crude residue of the product was purified by column chromatography
(60-120 silica gel, 30 % ethyl acetate in hexane) to afford the title product in 71 % yield
(0.5 g). LC-MS (ESI): Calculated mass: 439.06; Observed mass: 439.95 [M+H]+ (rt:
2.02 min).
c) l-(6-Chloro-4-(2-chlorophenyl)pyridin-2-yl)-5-(l-methyl-1H-pyrazol-4-yl)-
1H-benzo [d] imidazole
A solution of the compound of Example 28(b) (0.5 g, 1.13 mmol) in formic acid
(10 ml), iron (0.63 g, 11.4 mmol) was added and heated at 100 °C for 16 h. The formic
acid was distilled off and the crude was dissolved in ethyl acetate. The ethyl acetate
layer was washed with water, brine and dried over sodium sulphate. The solvent was
distilled off to afford the title product in 63 % yield (0.3 g). LC-MS (ESI): Calculated
mass: 419.07; Observed mass: 421.8 [M+H]+ (rt: 1.84 min).
d)N-(4-(2-chlorophenyl)-6-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo [d]-
imidazol-1 -yl)pyridin-2-yl)cyclopropanesulfonamide

A solution of the compound of Example 28(c) (200 mg, 0.47 mmol) in dioxane
(5 ml) was degassed by N2 bubbling for 5 min. Cyclopropanesulfonamide (63 mg, 0.52
mmol, 1.1 eq) was added and the mixture was degassed for another 5 min. Pd(OAc)2 (5
mg, 0.023 mmol, 0.05 eq) and xantphos (15 mg, 0.023 mmol, 0.05 eq) and Cs2CO3 (450
mg, 1.41 mmol, 3 eq) were added and the mixture was further degassed for 5 min and
then heated at 110 °C for 12 h. The mixture was filtered through celite and extracted as
in Example 1. The solvent was distilled off to afford the crude residue which was
purified by column chromatography (2 % methanol in CHCI3) to afford the title product
in 15 % yield (30 mg). 1H NMR (400 MHz, DMSO-J6): δ 11.17 (s, 1H), 9.0 (s, 1H),
8.71 (d, 1H), 8.23 (s, 1H), 7.96-7.94 (m, 2H), 7.67-7.65 (m, 2H), 7.62-7.59 (m, 2H),
7.54-7.52 (m, 2H), 6.98 (s, 1H), 3.87 (s, 3H), 3.16 (m, 1H), 1.12-1.11 (m, 2H), 1.04-
1.02 (m, 2H); LC-MS (ESI): Calculated mass: 504.11; Observed mass: 504.7 [M+H]+
(rt: 1.59 min).
Example 29.
N-(3-chloro-6'-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-l-yl)-[2,4'-
bipyridin]-2'-yl)cyclopropanesulfonamide
a)2',3,6'-Trichloro-2,4'-bipyridine
A solution of (2,6-dichloropyridin-4-yl)boronic acid (0.76 g, 4 mmol) in 1,2-
dimethoxyethane (15 ml) was degassed by N2 bubbling for 5 min. 2-Bromo-3-chloro-
pyridine (0.7 g, 3.63 mmol, 1.2 eq) was added and the mixture was degassed for another
5 min. Pd(dppf)Cl2 (0.3 g, 0.36 mmol, 0.1 eq) and aqueous sodium carbonate (1.15 g,
10.9 mmol, 3 eq) were added sequentially using the procedure of Intermediate Example
1 and then heated at 90 °C for 2 h. The reaction mixture was then quenched and
extracted as in Intermediate Example 1. The solvent was distilled off to afford the crude
residue which was purified by column chromatography (60-120 silica gel, 10 % ethyl
acetate in hexane) to afford the title product in 74 % yield (0.7 g). 1H NMR (300 MHz,
CDCl3): δ 8.63 (dd, 1H), 7.86 (m, 1H), 7.68 (s, 2H), 7.37 (dd, 1H).
b) 3,6'-Dichloro-N-(4-( 1-methyl-1H-pyrazol-4-yl)-2-nitrophenyl)-[2,4'-bi-
pyridin]-2'-amine

A solution of the compound of Example 29(a) (0.69 g, 3.17 mmol) in toluene (10
ml) was degassed by N2 bubbling for 5 min. The compound of Intermediate Example 1
(0.69 g, 3.17 mmol, 1.1 eq) was added and the mixture was degassed for another 5 min.
Palladium acetate(25 mg, 0.115 mmol, 0.04 eq) and BINAP (71 mg, 0.115 mmol, 0.04
eq) and potassium tert-butoxide (0.38 g, 3.46 mmol, 1.2 eq) were added sequentially
following the procedure of Example 1(a) and the mixture was heated at 100 °C
overnight. The crude residue of the product was purified by column chromatography
(60-120 silica gel, 30 % ethyl acetate in hexane) to afford the title product in 43 % yield
(0.3 g). !H NMR (300 MHz, CDC13): δ 10.25 (s, 1H), 8.77 (d, 1H), 8.65-8.63 (m, 1H),
8.30 (d, 1H), 7.88-7.85 (m, 1H), 7.79-7.73 (m, 2H), 7.67 (s, 1H), 7.37-7.33 (m, 2H),
7.22 (m, 1H), 3.97 (s, 3H).
c) l-(3,6'-Dichloro-[2,4'-bipyridin]-2'-yl)-5-(l-methyl-1H-pyrazol-4-yl)-1H-
benzo[d]imidazole
A solution of the compound of Example 29(b) (0.3 g, 0.68 mmol) in formic acid
(10 ml), iron (0.38 g, 6.8 mmol) was added and heated at 100 °C for 16 h. The formic
acid was distilled off and the crude was dissolved in ethyl acetate. The ethyl acetate
layer was washed with water, brine and dried over sodium sulphate. The solvent was
distilled off to afford the title product in 64 % yield (0.18 g). LC-MS (ESI): Calculated
mass: 420.07; Observed mass: 421.2 [M+H]+ (rt: 1.56 min).
d)N-(3-chloro-6'-(5-(l-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-l-yl)-
[2,4'-bipyridin]-2'-yl)cyclopropanesulfonamide
A solution of the compound of Example 29(c) (100 mg, 0.24 mmol) in dioxane
(5 ml) was degassed by N2 bubbling for 5 min. Cyclopropanesulfonamide (34 mg, 0.28
mmol, 1.2 eq) was added and the mixture was degassed for another 5 min. Pd(OAc)2 (3
mg, 0.011 mmol, 0.05 eq) and xantphos (6 mg, 0.011 mmol, 0.05 eq) and Cs2CO3 (230
mg, 0.71 mmol, 3 eq) were added and the mixture was further degassed for 5 min and
then heated at 110 °C for 12 h. The mixture was filtered through celite and extracted as
in Example 1. The solvent was distilled off to afford the crude residue which was

purified by column chromatography (2 % methanol in CHCI3) to afford the title product
in 15 % yield (17 mg). lH NMR (300 MHz, DMSO-J6): δ 11.22 (s, 1H), 8.98 (s, 1H),
8.74-8.67 (m, 2H), 8.23 (s, 1H), 8.19-8.16 (m, 1H), 7.97-7.95 (m, 2H), 7.85 (m, 1H),
7.62-7.58 (m, 2H), 7.19 (s, 1H), 3.87 (s, 3H), 3.16 (m, 1H), 1.13-1.12 (m, 2H), 1.06-
1.02 (m, 2H); LC-MS (ESI): Calculated mass: 505.11; Observed mass: 506.00 [M+H]+
(it: 1.52 min).
Example 30.
N-(5-fluoro-6'-(5-(l-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-l-yl)-[2,4'-
bipyridin]-2'-yl)cyclopropanesulfonamide
a)2',6'-Dichloro-5-fluoro-2,4'-bipyridine
A solution of 2-bromo-5-fluoropyridine (2 g, 11 mmol) in 1,2-dimethoxyethane
(30 ml) was degassed by N2 bubbling for 5 min. The compound of Example 18(a) (3.11
g, 11 mmol, 1 eq) was added and the mixture was degassed for another 5 min. Pd(PPhs)4
(1.31 g, 0.011 mmol, 0.1 eq) and aqueous sodium carbonate (9.28 g, 28.5 mmol, 2.5 eq)
were added sequentially using the procedure of Intermediate Example 1 and then heated
at 90 °C for 2 h. The reaction mixture was then quenched and extracted as in
Intermediate Example 1. The solvent was distilled off to afford the crude residue which
was purified by column chromatography (60-120 silica gel, 5 % ethyl acetate in hexane)
to afford the title product in 39 % yield (1 g).
b)6'-Chloro-5-fluoro-N-(4-(l-methyl-1H-pyrazol-4-yl)-2-nitrophenyl)-[2,4'-
bipyridin] -2'-amine
A solution of the compound of Example 30(a) (0.2 g, 0.82 mmol) in toluene (12
ml) was degassed by N2 bubbling for 5 min. The compound of Intermediate Example 1
(0.2 g, 0.9 mmol, 1.1 eq) was added and the mixture was degassed for another 5 min.
Palladium acetate (14.7 mg, .065 mmol, 0.08 eq) and BINAP (40 mg, 0.065 mmol, 0.08
eq) and potassium te/t-butoxide (0.23 g, 2.06 mmol, 2.5 eq) were added sequentially
following the procedure of Example 1(a) and then heated at 110 °C for 16 h. The crude

residue of the product was purified by column chromatography (60-120 silica gel, 50 %
ethyl acetate in hexane) to afford the title product in 29 % yield (0.1 g).
c) N1 -(6'-chloro-5-fluoro- [2,4'-bipyridin]-2'-yl)-4-( 1 -methyl-1 H-pyrazol-4-
yl)benzene-1,2-diamine
To a solution of the compound of Example 30(b) (0.28 g, 0.66 mmol) in THF
(10 ml) were added a solution of ammonium chloride (0.29 g, 5.28 mmol, 8 eq) in water
(2 ml) and zinc (0.34 g, 5.28 mmol, 8 eq). The mixture was stirred at RT for 1 h and
filtered. The filtrate was diluted with water and extracted as in Intermediate Example 1.
The solvent was distilled off to afford the title product in 96 % yield (0.25 g). LC-MS
(ESI): Calculated mass: 394.11; Observed mass: 395.1 [M+H]+ (rt: 1.42 min).
d)l-(6'-Chloro-5-fluoro-[2,4'-bipyridin]-2'-yl)-5-(l-methyl-1H-pyrazol-4-yl)-1H-
benzo [d] imidazole
A solution of the compound of Example 30(c) (0.25 g, 0.63 mmol) and formic
acid (10 ml) was heated at 100 °C for 4 h. The formic acid was distilled off and the
crude was extracted as in Example 8(c). The solvent was distilled off to afford the title
product in 55 % yield (150 mg). LC-MS (ESI): Calculated mass: 404.1; Observed mass:
404.8 [M+H]+ (rt: 1.7 min).
e) N-(5-fluoro-6'-(5-( 1 -methyl-1 H-pyrazol-4-yl)-1 H-benzo[d]imidazol-1 -yl)-
[2,4'-bipyridin]-2'-yl)cyclopropanesulfonamide
A solution of the compound of Example 30(d) (50 mg, 0.123 mmol) in dioxane
(5 ml) was degassed by N2 bubbling for 5 min. Cyclopropanesulfonamide (15 mg, 0.123
mmol, 1 eq) was added and the mixture was degassed for another 5 min. Pd(OAc)2 (2
mg, 0.009 mmol, 0.08 eq) and xantphos (5.7 mg, 0.008 mmol, 0.08 eq) and Cs2CO3
(120 mg, 0.37 mmol, 3 eq) were added and the mixture was further degassed for 5 min
and then heated at 100 °C for 24 h. The mixture was filtered through celite and extracted
as in Example 1. The solvent was distilled off to afford the crude residue which was
purified by preparative TLC to afford the title product in 25 % yield (15 mg). !H NMR

(400 MHz, DMSO-J6): δ 11.16 (s, 1H), 9.14 (s, 1H), 8.81 (d, 1H), 8.73 (d, 1H), 8.40-
8.37 (m, 1H), 8.23 (s, 1H), 8.15 (s, 1H), 8.05-8.0 (m, 1H), 7.97-7.95 (m, 2H), 7.66 (s,
1H), 7.62-7.59 (m, 1H), 3.89 (s, 3H), 3.16-3.12 (m, 1H), 1.13-1.10 (m, 2H), 1.03-1.0
(m, 2H); LC-MS (ESI): Calculated mass: 489.14; Observed mass: 490.4 [M+H]+ (rt:
1.23 min).
Example 31.
N-(5-fluoro-6'-(5-(l-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-l-yl)-[2,4'-
bipyridin] -2'-yl)acetamide
The compound was prepared from the compound of Example 30(d). !H NMR
(400 MHz, DMSO-d6): δ 10.78 (s, 1H), 9.16 (s, 1H), 8.82-8.78 (m, 2H), 8.62 (d, 1H),
8.39-8.37 (m, 1H), 8.22-8.20 (m, 2H), 8.04-7.99 (m, 1H), 7.96 (s, 2H), 7.62-7.59 (m,
1H), 3.89 (s, 3H), 2.23 (m, 3H); LC-MS (ESI): Calculated mass: 427.16; Observed
mass: 428.3 [M+H]+ (rt: 1.91 min).
Example 32.
N-(6-(5-( 1H-imidazol-1-yl)-1H-benzo[d]imidazol-1-yl)-4-(2,4-difluorophenyl)-
pyridin-2-yl)cyclopropanesulfonamide
a) N-(4-( 1 H-imidazol-1 -yl)-2-nitrophenyl)-6-chloro-4-(2,4-difluorophenyl)-
pyridin-2-amine
A solution of the compound of Intermediate Example 5(a) (0.6 g, 2.94 mmol) in
toluene (5 ml) was degassed by N2 bubbling for 5 min. The compound of Intermediate
Example 9 (0.76 g, 2.94 mmol, 1 eq) was added and the mixture was degassed for
another 5 min. Palladium acetate (32 mg, 0.147 mmol, 0.05 eq) and BESTAP (182 mg,
0.294 mmol, 0.1 eq) and potassium tert-butoxide (0.9 g, 7.35 mmol, 2.5 eq) were added
sequentially and the mixture was further degassed for 5 min and then heated at 100 °C
for 12 h. The mixture was filtered through celite and extracted as in Example 1. The
solvent was distilled off to afford the crude residue which was purified by column
chromatography (60-120 silica gel, 50 % ethyl acetate in hexane) to afford the title
product in 12 % yield (150 mg).

b) N1 -(6-chloro-4-(2,4-difluorophenyl)pyridin-2-yl)-4-(1H-imidazol-1 -yl)-
benzene-1,2-diamine
To a solution of the compound of Example 32(a) (0.15 g, 0.35 mmol) in THF (10
ml) were added a solution of ammonium chloride (0.15 g, 2.81 mmol, 8 eq) in water (2
ml) and zinc (0.18 g, 2.81 mmol, 8 eq). The mixture was stirred at RT for 1 h and
filtered. The filtrate was diluted with water and extracted as in Intermediate Example 1.
The solvent was distilled off to afford the title product in 72 % yield (0.1 g).
c) 1 -(6-Chloro-4-(2,4-difluorophenyl)pyridin-2-yl)-5-( 1 H-imidazol-1 -yl)-1H-
benzo [d] imidazole
A solution of the compound of Example 32(b) (0.1 g, 0.25 mmol) and formic
acid (2 ml) was heated at 90 °C for 4 h. The formic acid was distilled off and the crude
was extracted as in Example 8(c). The solvent was distilled off to afford the title product
in 50 % yield (50 mg).
d)N-(6-(5-(1H-imidazol-l-yl)-1H-benzo[d]imidazol-l-yl)-4-(2,4-difluoro-
phenyl)pyridin-2-yl)cyclopropanesulfonamide
A solution of the compound of Example 32(c) (50 mg, 0.122 mmol) in dioxane
(5 ml) was degassed by N2 bubbling for 5 min. Cyclopropanesulfonamide (15 mg, 0.122
mmol, 1 eq) was added and the mixture was degassed for another 5 min. Pd(OAc)2 (2
mg, 0.009 mmol, 0.08 eq) and xantphos (5.7 mg, 0.008 mmol, 0.08 eq) and Cs2CO3
(120 mg, 0.37 mmol, 3 eq) were added and the mixture was further degassed for 5 min
and then heated at 100 °C for 12 h. The mixture was filtered through celite and extracted
as in Example 1. The solvent was distilled off to afford the crude residue which was
purified by preparative TLC to afford the title product in 33 % yield (20 mg). !H NMR
(400 MHz, DMSO-d6): δ 11.22 (s, 1H), 9.12 (s, 1H), 8.67 (d, 1H), 8.38 (s, 1H), 8.08 (d,
1H), 7.91-7.85 (m, 2H), 7.79 (s, 1H), 7.71-7.69 (m, 1H), 7.56-7.51 (m, 1H), 7.38-7.33
(m, 1H), 7.13 (s, 2H), 3.16-3.11 (m, 1H), 1.12-1.08 (m, 2H), 1.03-1.01 (m, 2H); LC-MS
(ESI): Calculated mass: 492.12; Observed mass: 493.1 [M+H]+ (rt: 0.30 min).

Example 33.
N-(4-(2,4-difluorophenyl)-6-(5-( 1 -(2-morpholinoethyl)-1 H-pyrazol-4-yl)-1H-
benzo [d] imidazol-1 -yl)pyridin-2-yl)cyclopropanesulfonamide
a) 6-Chloro-4-(2,4-difluorophenyl)-N-(4-(l -(2-morpholinoethyl)- 1H-pyrazol-4-
yl)-2-nitrophenyl)pyridin-2-amine
A solution of the compound of Intermediate Example 5(a) (0.49 g, 1.89 mmol) in
dioxane (5 ml) was degassed by N2 bubbling for 5 min. The compound of Intermediate
Example 8 (0.6 g, 1.89 mmol, 1 eq) was added and the mixture was degassed for
another 5 min. Palladium acetate (34 mg, 0.15 mmol, 0.08 eq) and BINAP (94 mg, 0.15
mmol, 0.08 eq) and potassium fert-butoxide (0.53 g, 4.73 mmol, 2.5 eq) were added
sequentially and the mixture was further degassed for 5 min and then heated at 100 °C
for 12 h. The mixture was filtered through celite and extracted as in Example 1. The
solvent was distilled off to afford the crude residue which was purified by column
chromatography (60-120 silica gel, 50 % ethyl acetate in hexane) to afford the title
product in 20 % yield (200 mg).
b)Nl-(6-chloro-4-(2,4-difluorophenyl)pyridin-2-yl)-4-(l-(2-morpholinoethyl)-
1 H-pyrazol-4-yl)benzene-1,2-diamine
To a solution of the compound of Example 33(a) (0.2 g, 0.37 mmol) in THF (10
ml) were added a solution of ammonium chloride (0.16 g, 2.96 mmol, 8 eq) in water (2
ml) and zinc (0.19 g, 2.96 mmol, 8 eq). The mixture was stirred at RT for 1 h and
filtered. The filtrate was diluted with water and extracted as in Intermediate Example 1.
The solvent was distilled off to afford the title product in 79 % yield (0.15 g). LC-MS
(ESI): Calculated mass: 510.17; Observed mass: 511.1 [M+H]+ (rt: 0.66 min).
c) 4-(2-(4-( 1 -(6-Chloro-4-(2,4-difluorophenyl)pyridin-2-yl)-1 H-benzo [d] -
imidazol-5-yl)-1 H-pyrazol-1 -yl)ethyl)morpholine

A solution the compound of Example 33(b) (0.15 g, 0.29 mmol) and formic acid
(2 ml) was heated at 90 °C for 12 h. The formic acid was distilled off and the crude was
extracted as in Example 8(c). The solvent was distilled off to afford the title product in
50 % yield (75 mg). LC-MS (ESI): Calculated mass: 520.16; Observed mass: 521.2
[M+H] + (rt: 1.03 min).
d) N-(4-(2,4-difluorophenyl)-6-(5-( 1 -(2-morpholinoethyl)-1 H-pyrazol-4-yl)-1H-
benzo [d] imidazol-1 -yl)pyridin-2-yl)cyclopropanesulfonamide
A solution of the compound of Example 33(c) (75 mg, 0.144 mmol) in dioxane
(5 ml) was degassed by N2 bubbling for 5 min. Cyclopropanesulfonamide (17 mg, 0.144
mmol, 1 eq) was added and the mixture was degassed for another 5 min. Pd(OAc)2 (2.5
mg, 0.011 mmol, 0.08 eq) and xantphos (8.3 mg, 0.0144 mmol, 0.1 eq) and Cs2CO3
(117 mg, 0.36 mmol, 2.5 eq) were added and the mixture was further degassed for 5 min
and then heated at 100 °C for 12 h. The mixture was filtered through celite and extracted
as in Example 1. The solvent was distilled off to afford the crude residue which was
purified by preparative TLC to afford the title product in 29 % yield (25 mg). 1H NMR
(400 MHz, DMSO-J6): δ 11.16 (s, 1H), 9.05 (s, 1H), 8.69 (d, 1H), 8.29 (s, 1H), 7.98-
7.96 (m, 2H), 7.88-7.85 (m, 1H), 7.75 (s, 1H), 7.62-7.59 (m, 1H), 7.56-7.49 (m, 1H),
7.37-7.32 (m, 1H), 7.09 (s, 1H), 4.27-4.24 (m, 2H), 3.58-3.55 (m, 4H), 3.18-3.13 (m,
1H), 2.78-2.74 (m, 2H), 2.53-2.49 (m, 4H), 1.15-1.07 (m, 2H), 1.05-1.01 (m, 2H); LC-
MS (ESI): Calculated mass: 605.2; Observed mass: 605.8 [M+H]+ (rt: 0.44 min).
Example 34.
N-(4-(2,4-difluorophenyl)-6-(5-(l-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)-1H-
benzo [d] imidazol-1 -yl)pyridin-2-yl)cyclopropanesulfonamide
a) tert-TSutyl 3-(4-( 1 -(6-(cyclopropanesulfonamido)-4-(2,4-difluorophenyl)-
pyridin-2-yl)- 1H-benzo[d]imidazol-5-yl)- 1H-pyrazol-1 -yl)pyrrolidine-1 -carboxylate
A solution of the compound of Intermediate Example 5(113mg, 0.347 mmol) in
dioxane (5 ml) was degassed by N2 bubbling for 5 min. The compound of Intermediate
Example 2 (120 mg, 0.347 mmol, 1 eq) was added and the mixture was degassed for

another 5 min. Cul(3.3 mg, 0.0174 mmol, 0.05 eq), N,N-dimethyl glycine (1.7 mg,
0.0174 mmol, 0.05 eq) and Cs2CO3 (282 mg, 0.87 mmol, 2.5 eq) were added and the
mixture was further degassed for 5 min and then heated at 100 °C for 24 h. The mixture
was filtered through celite and washed with ethyl acetate. The solvent was distilled off
to afford the crude product mixture which was purified by preparative TLC to afford the
title product in 10 % yield (20 mg). LC-MS (ESI): Calculated mass: 661.23; Observed
mass: 662.6 [M+H]+ (rt: 1.71 min).
b)N-(4-(2,4-difluorophenyl)-6-(5-(l-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)-1H-
benzo[d]imidazol-1 -yl)pyridin-2-yl)cyclopropanesulfonamide
To a solution of the compound of Example 34(a) (15 mg, 0.028 mmol) in 1,4-
dioxane (5 ml) at 0 °C was added HC1 in dioxane and stirred at RT for 1 h. The solvent
was distilled off and the residue was washed several times with diethyl ether to give the
title product in 78 % yield (10 mg). 1H NMR (400 MHz, DMSO-J6): δ 11.23 (s, 1H),
9.38 (s, 1H), 9.28 (s, 1H), 9.22 (s, 1H), 8.76 (d, 1H), 8.49 (s, 1H), 8.16 (s, 1H), 8.03 (s,
1H), 7.91-7.85 (m, 1H), 7.79 (s, 1H), 7.71-7.69 (m, 1H), 7.57-7.52 (m, 1H), 7.37-7.34
(m, 1H), 7.14 (s, 1H), 5.20-5.18 (m, 1H), 3.62-3.37 (m, 3H), 3.19-3.15 (m, 2H), 2.43-
2.33 (m, 2H), 1.19-1.12 (m, 2H), 1.05-1.02 (m, 2H); LC-MS (ESI): Calculated mass:
561.18; Observed mass: 562.6 [M+H]+ (RT: 0.40 min).
Example 35.
N-(4-(2,4-difluorophenyl)-6-(5-(l-ethyl-1H-l,2,3-triazol-4-yl)-1H-benzo[d]-
imidazol-1 -yl)pyridin-2-yl)cyclopropanesulfonamide
A solution of the compound of Intermediate Example 5 (48 mg, 0.14 mmol) in
dioxane (5 ml) was degassed by N2 bubbling for 5 min. The compound of Intermediate
Example 10 (30 mg, 0.14 mmol, 1 eq) was added and the mixture was degassed for
another 5 min. Cul(2 mg, 0.014 mmol, 0.1 eq), N,N-dimethyl glycine (1 mg, 0.014
mmol, 0.1 eq) and CS2CO3 (130 mg, 0.42 mmol, 3.0 eq) were added and the mixture
was further degassed for 5 min and then heated at 100 °C for 24 h. The mixture was
filtered through celite and washed with ethyl acetate. The solvent was distilled off to
afford the crude product mixture which was purified by preparative TLC to afford the

title product in 33 % yield (24 mg). JH NMR (400 MHz, DMSO-d6): δ 11.18 (s, 1H),
9.11 (s, 1H), 8.79 (d, 1H), 8.71 (s, 1H), 8.22 (s, 1H), 7.92-7.85 (m, 2H), 7.79 (s, 1H),
7.56-7.50 (m, 1H), 7.38-7.33 (m, 1H), 7.13 (s, 1H), 4.44 (quartet, 2H), 3.18-3.13 (m,
1H), 1.51 (t, 3H), 1.14-1.09 (m, 2H), 1.07-1.02 (m, 2H); LC-MS (ESI): Calculated
mass: 521.14; Observed mass: 522.1 [M+H]+ (rt: 1.52 min).
Example 36.
N-(4-(2,4-difluorophenyl)-6-(5-(l-methyl-1H-l,2,3-triazol-4-yl)-1H-benzo[d]-
imidazol-1 -yl)pyridin-2-yl)cyclopropanesulfonamide
a)N-(4-(2,4-difluorophenyl)-6-(5-ethynyl-1H-benzo[d]imidazol-l-yl)pyridin-2-
yl)cyclopropanesulfonamide
A solution of the compound of Intermediate Example 5 (0.17 g, 0.51 mmol, 1.1
eq) in dioxane (5 ml) was degassed by N2 bubbling for 5 min. The compound of
Intermediate Example 12 (100 mg, 0.46 mmol) was added and the mixture was
degassed for another 5 min. Cul(8 mg, 0.04 mmol, 0.1 eq), N,N-dimethyl glycine (4
mg, 0.04 mmol, 0.1 eq) and CS2CO3 (450 mg, 1.4 mmol, 3.0 eq) were added and the
mixture was further degassed for 5 min and then heated at 100 °C for 24 h. The mixture
was filtered through celite and washed with 3 % methanol/chloroform to afford crude
product mixture which was recrystallized from diethyl ether to afford the product
mixture in 40 % yield (80 mg) which was directly taken for the next step. LC-MS (ESI):
Calculated mass: 450.1; Observed mass: 451.3 [M+H]+ (rt: 1.65 min).
b)N-(4-(2,4-difluorophenyl)-6-(5-(l-methyl-1H-l,2,3-triazol-4-yl)-1H-benzo[d]-
imidazol-1 -yl)pyridin-2-yl)cyclopropanesulfonamide
A mixture of Example 36(a) (0.1 g, 0.22 mmol), sodium azide (28 mg, 0.44
mmol, 2.0 eq), methyl iodide (31 mg, 0.22 mmol, 1.0 eq), sodium ascorbate (43 mg,
0.022 mmol, 0.1 eq) and copper sulfate pentahydrate (5 mg, 0.022 mmol, 0.1 eq) in
DMSO and water (1:0.5, 3 ml) was stirred for 12 h at RT. The mixture was quenched
with water and the precipitate formed was filtered and dried. The crude product mixture
was purified by by column chromatography (60-120 silica gel, 2 % methanol in CHCI3)

to give the title product in 6.3 % yield (7 mg). !H NMR (400 MHz, DMSO-d6): δ 11.18
(s, 1H), 9.11 (s, 1H), 8.79 (d, 1H), 8.62 (s, 1H), 8.21 (d, 1H), 7.90-7.85 (m, 2H), 7.79 (s,
1H), 7.56-7.50 (m, 1H), 7.38-7.33 (m, 1H), 7.13 (s, 1H), 4.12 (s, 3H), 3.34-3.13 (m,
1H), 1.16-1.12 (m, 2H), 1.06-0.94 (m, 2H); LC-MS (ESI): Calculated mass: 507.13;
Observed mass: 508.1 [M+H]+ (rt: 1.52 min).
Example 37.
N-(4-(2,4-difluorophenyl)-6-(5-(l-methyl-1H-imidazol-4-yl)-1H-benzo[d]-
imidazol-1 -yl)pyridin-2-yl)cyclopropanesulfonamide
A solution of the compound of Intermediate Example 5 (34 mg, 0.1 mmol) in
DMF (5 ml) was degassed by N2 bubbling for 5 min. The compound of Intermediate
Example 11 (20 mg, 0.1 mmol, 1 eq) was added and the mixture was degassed for
another 5 min. Cul(2 mg, 0.01 mmol, 0.1 eq), N,N-dimethyl glycine (0.52 mg, 0.005
mmol, 0.05 eq) and CS2CO3 (82 mg, 0.25 mmol, 2.5 eq) were added and the mixture
was further degassed for 5 min and then heated at 100 °C for 24 h. The mixture was
filtered through celite and washed with ethyl acetate. The solvent was distilled off to
afford the crude product mixture which was purified by preparative TLC to yield the
title compound in 10 % yield (5 mg). !H NMR (400 MHz, DMSO-d6): δ 11.11 (s, 1H),
9.02 (s, 1H), 8.66 (d, 1H), 8.09 (d, 1H), 7.89-7.84 (m, 1H), 7.81-7.75 (m, 2H), 7.68-7.64
(m, 2H), 7.54-7.48 (m, 1H), 7.37-7.32 (m, 1H), 7.13 (s, 1H), 3.71 (s, 3H), 3.18-3.14 (m,
1H), 1.15-1.12 (m, 2H), 1.06-1.02 (m, 2H); LC-MS (ESI): Calculated mass: 506.13;
Observed mass: 507.35 [M+H]+ (rt: 0.18 min).
Example 38.
N-(4-(2, 4-difluorophenyl)-6-(5-(l-methyl-1H-pyrazol-4-yl)-1H-benzo[d]-
imidazol-1-yl) pyrimidin-2-yl) acetamide
a) N-(4, 6-dichloropyrimidin-2-yl) acetamide
To a solution of 4, 6-dichloropyrimidin-2-amine (5 g, 30.48 mmol) in toluene
(50 ml) was added acetic anhydride (15 ml, 152.43 mmol) and the mixture was heated at
120 °C for 16 h. The solvent was evaporated and the crude product was taken in hexane
(50 ml) and dichloromethane (6 ml) and filtered to afford the title product in 80 % yield

(5 g). LC-MS (ESI): Calculated mass: 206.0; Observed mass: 208.0 [M+H]+ (rt: 0.245
min).
b) N-(4-((2-amino-4-(l -methyl- 1H-pyrazol-4-yl) phenyl) amino)-6-chloro-
pyrimidin-2-yl) acetamide
A solution of the compound of Intermediate Example 13 (1.4 g, 7.44 mmol), the
compound of Example 38(a) (1.53 g, 7.44 mmol,) and sodium bicarbonate (1.56 g, 18.6
mmol, 2.5 eq) in ethanol was heated at 80 °C for 16 h. The mixture was quenched with
water and extracted with ethyl acetate (3 x 100 ml). The combined organic layer was
washed with water, brine and dried over sodium sulphate. The solvent was distilled off
to afford the crude residue which was purified by column chromatography (60-120 silica
gel, 3 % methanol in DCM) to afford the the title product in 19.2 % yield (0.5 g). LC-
MS (ESI): Calculated mass: 357.11; Observed mass: 358.1 [M+H]+ (rt: 0.123 min).
c) N-(4-chloro-6-(5-( 1 -methyl-1 H-pyrazol-4-yl)-1 H-benzo [d] imidazol-1 -yl)
pyrimidin-2-yl) acetamide
A mixture of the compound of Example 38(b) (0.15 g, 0.42 mmol) and formic
acid (2 ml) was heated at 80 °C for 2 h. The formic acid was distilled off and the crude
was dissolved in ethyl acetate. The ethyl acetate layer was washed with water, brine and
dried over sodium sulphate. The solvent was distilled off to afford the title product in 97
% yield (0.15 g). LC-MS (ESI): Calculated mass: 367.07; Observed mass: 368.1 [M+H]
+ (rt: 0.318 min).
d) N-(4-(2, 4-difluorophenyl)-6-(5-( 1 -methyl-1 H-pyrazol-4-yl)-1 H-benzo [d] -
imidazol-1-yl) pyrimidin-2-yl) acetamide
A solution of the compound of Example 38(c) (0.08 g, 0.217 mmol) in dioxane
(5 ml) was degassed by N2 bubbling for 5 min. 2,4-Difluorophenylboronic acid (0.04 g,
0.261 mmol, 1.2 eq) was added and the mixture was degassed for another 5 min.
Pd(PPh3)4 (0.025 g, 0.021mmol, 0.1 eq) and aqueous cesium carbonate (0.106 g,
0.326mmol, 1.5 eq) were added sequentially and the mixture was further degassed for 5

min and then heated at 100 °C for 2 h. The reaction mixture was quenched with water
and extracted with ethyl acetate (3 x 30 ml). The combined organic layer was washed
with water, brine and dried over sodium sulphate. The solvent was distilled off to afford
the crude residue which was purified by preparative HPLC to afford the title product in
10.4 % yield (10 mg). 1H NMR (400 MHz, DMSO- d6): δ 11.1 (s, 1H), 9.25 (s, 1H),
9.12 (d, 1H), 8.23 (s, 1H), 8.11-8.07 (m, 1H), 8.03 (s, 1H), 7.96 (d, 2H), 7.63 (d, 1H),
7.54 (t, 1H), 7.36 (t, 1H), 3.88 (s, 3H), 2.27 (s, 3H); LC-MS (ESI): Calculated mass:
445.15; Observed mass: 445.9 [M+H]+ (rt: 1.33 min).
Example 39.
Ethyl l-(l-(6-(cyclopropanesulfonamido)-4-(2,4-difluorophenyl)pyridin-2-yl)-
1H-benzo[d]imidazol-5-yl)-1H-l,2,3-triazole-4-carboxylate
A solution of the compound of Intermediate Example 5 (200 mg, 0.58 mmol) in
DMF (5 ml) was degassed by N2 bubbling for 5 min. The compound of Intermediate
Example 14 (149 mg, 0.58 mmol, 1 eq) was added and the mixture was degassed for
another 5 min. Cul(ll mg, 0.05 mmol, 0.1 eq), N,N-dimethyl glycine (8 mg, 0.05
mmol, 0.1 eq) and CS2CO3 (570 mg, 1.74 mmol, 3 eq) were added and the mixture was
further degassed for 5 min and then heated at 100 °C for 24 h. The mixture was filtered
through celite and washed with ethyl acetate. The solvent was distilled off to afford the
crude product mixture which was purified by preparative HPLC to afford the title
product in 5 % yield (18 mg). !H NMR (400 MHz, DMSO-J6): δ 11.11 (s, 1H), 9.59 (d,
1H), 9.26 (s, 1H), 8.95 (d, 1H), 8.38 (s, 1H), 8.02-8.00 (m, 1H), 7.92-7.83 (m, 2H),
7.56-7.51 (m, 1H), 7.51-7.34 (m, 1H), 7.17 (s, 1H), 4.38 (quartet, 2H), 3.17-3.13 (m,
1H), 1.36 (t, 3H), 1.13-1.12 (m, 2H), 1.04-1.02 (m, 2H); LC-MS (ESI): Calculated
mass: 565.13; Observed mass: 566.2 [M+H]+ (rt: 1.63 min).
Example 40.
N-(4-(2-(difluoromethoxy)-4-fluorophenyl)-6-(5-(l-methyl-1H-pyrazol-4-yl)-
1 H-benzo [d] imidazol-1 -yl)pyridin-2-yl)cyclopropanesulfonamide
A solution of the compound of Intermediate Example 15 (300 mg, 0.75 mmol) in
DMF (10 ml) was degassed by N2 bubbling for 5 min. The compound of Intermediate

Example 6 (149 mg, 0.75 mmol, 1 eq) was added and the mixture was degassed for
another 5 min. Cul(14 mg, 0.075 mmol, 0.1 eq), N,N-dimethyl glycine (8 mg, 0.075
mmol, 0.1 eq) and CS2CO3 (730 mg, 2.25 mmol, 3 eq) were added and the reaction
mixture was further degassed for 5 min and then heated at 100 °C for 2 days. The
reaction mixture was filtered through celite and washed with ethyl acetate. The solvent
was distilled off to afford the crude product mixture which was purified by column
chromatography (60-120 silica gel, 2 % methanol in chloroform) to afford the title
product in 2 % yield (8 mg). 1H NMR (400 MHz, CD3OD): δ 8.83 (s, 1H), 8.56 (d, 1H),
8.02 (s, 1H), 7.89-7.87 (m, 2H), 7.69-7.63 (m, 2H), 7.57 (s, 1H), 7.22-7.15 (m, 2H),
7.15 (s, 1H), 6.97 (s, 0.5 H), 6.79 (s, 0.5 H), 3.94 (s, 3H), 3.15-3.05 (m, 1H), 1.28-1.15
(m, 2H), 1.00-0.87 (m, 2H); LC-MS (ESI): Calculated mass: 554.13; Observed mass:
555.5 [M+H]+ (rt: 1.66 min).
Example 41.
N-(4-(2,4-difluorophenyl)-6-(5-(l-methyl-1H-pyrazol-4-yl)-1H-benzo[d]-
imidazol-1 -yl)pyrimidin-2-yl)cyclopropanesulfonamide
a) 4-Chloro-6-(2,4-difluorophenyl)pyrimidin-2-amine
A solution of 4,6-dichloropyrimidin-2-amine (5 g, 30 mmol) in 1,2-dimethoxy-
ethane (50 ml) was degassed by N2 bubbling for 5 min. 2,4-Difluorophenylboronic acid
(4.38 g, 27 mmol, 0.9 eq) was added and the mixture was degassed for another 5 min.
Pd(dppf)Cl2 (1.38 g, 1.5 mmol, 0.05 eq) and aqueous sodium carbonate (4.9 g, 46
mmol, 1.5 eq) were added sequentially using the procedure of Intermediate Example 1
and heated at 90 °C for 6 h. The reaction mixture was quenched and extracted as in
Intermediate Example 1. The solvent was distilled off to afford the crude residue which
was purified by column chromatography (60-120 silica gel, 70 % ethyl acetate in
hexane) to afford the title product in 70 % yield (4 g). LC-MS (ESI): Calculated mass:
241.02; Observed mass: 242.05 [M+H]+ (rt: 1.58 min).
b) 6-(2,4-Difluorophenyl)-N4-(4-(1-methyl-1H-pyrazol-4-yl)-2-nitrophenyl)-
pyrimidine-2,4-diamine

A solution of the compound of Example 41(a) (0.5 g, 2.1 mmol) in dioxane (5
ml) was degassed by N2 bubbling for 5 min. The compound of Intermediate Example 1
(0.5 g, 2.3 mmol, 1.1 eq) was added and the mixture was degassed for another 5 min.
Pd2dba3 (0.19 g, 0.2 mmol, 0.1 eq) and xantphos (0.24 g, 0.4 mmol, 0.2 eq) and cesium
carbonate (1.68 g, 5.2 mmol, 2.5 eq) were added sequentially and the mixture was
further degassed for 5 min and then heated at 110 °C for 16 h. The mixture was filtered
through celite pad and extracted with ethyl acetate (3 x 50 ml). The combined organic
layer was washed with water, brine and dried over sodium sulphate. The solvent was
distilled off to afford the crude residue which was purified by column chromatography
(60-120 silica gel, 70 % ethyl acetate in hexane) in 22.5 % yield (0.2 g). LC-MS (ESI):
Calculated mass: 423.13; Observed mass: 423.9 [M+H]+ (rt: 0.26 min).
c) N4-(2-amino-4-( 1-methyl-1H-pyrazol-4-yl)phenyl)-6-(2,4-difluorophenyl)-
pyrimidine-2,4-diamine
To a solution of the compound of Example 41(b) (0.12 g, 0.3 mmol) in THF (15
ml) were added a solution of ammonium chloride (0.12 g, 2.3 mmol, 8 eq) in water (5
ml) and zinc (0.145 g, 2.3 mmol, 8 eq). The mixture was stirred at RT for 2 h and
filtered. The filtrate was diluted with water and extracted with ethyl acetate (3 x 100
ml). The combined organic layer was washed with water, brine and dried over sodium
sulphate. The solvent was distilled off to afford the crude product in 83 % yield (0.1 g).
LC-MS (ESI): Calculated mass: 393.15; Observed mass: 394.3 [M+H]+ (rt: 0.14 min).
d) 4-(2,4-difluorophenyl)-6-(5-( 1 -methyl-1H-pyrazol-4-yl)-1H-benzo[d]-
imidazol-1 -yl)pyrimidin-2-amine
A solution of the compound of Example 41(c) (0.1 g, 0.2 mmol) in formic acid
(5 ml) was heated at 100 °C for 16 h. The formic acid was distilled off and the crude
product was dissolved in ethyl acetate. The ethyl acetate layer was washed with water,
brine and dried over sodium sulphate. The solvent was distilled off to afford the title
product in 24 % yield (20 mg).

e)N-(4-(2,4-difluorophenyl)-6-(5-(l-methyl-1H-pyrazol-4-yl)-1H-benzo[d]-
imidazol-1 -yl)pyrimidin-2-yl)cyclopropanesulfonamide
To an icecold solution of the compound of Example 41(d) (50 mg, 0.1 mmol) in
DMF (50 ml) was added NaH (4 mg, 0.2 mmol, 2 eq). The mixture was stirred for 10
min and cyclopropylsulfonyl chloride (26 mg, 0.2 mmol, 2 eq) was added and the
mixture was stirred at RT for 12 h. The mixture was then quenched with water and
extracted with ethyl acetate (3 x 100 ml). The combined organic layer was washed with
water, brine and dried over sodium sulphate. The solvent was distilled off to afford the
crude product which was purified by preparative HPLC to afford the title product in 6 %
yield (3 mg). 1H NMR (400 MHz, CDC13): δ 8.73 (s, 1H), 8.39 (d, 1H), 8.36-8.27 (m,
1H), 8.09 (s, 1H), 7.99 (s, 1H), 7.93 (d, 1H), 7.87 (d, 1H), 7.74 (d, 1H), 7.67-7.64 (m,
1H), 7.20-7.01 (m, 2H), 3.83 (s, 3H), 3.30-3.26 (m, 1H), 1.51-1.42 (m, 2H), 1.16-1.12
(m, 2H); LC-MS (ESI): Calculated mass: 507.13; Observed mass: 508.2 [M+H]+ (rt:
1.48 min).
Example 42.
Ethyl 1 -(1 -(6-acetamido-4-(2,4-difluorophenyl)pyridin-2-yl)-1 H-benzo[d] -
imidazol-5-yl)- 1H-1,2,3-triazole-4-carboxylate
A solution of the compound of Intermediate Example 16 (150 mg, 0.53 mmol) in
DMF (5 ml) was degassed by N2 bubbling for 5 min. The compound of Intermediate
Example 6 (137 mg, 0.53 mmol, 1 eq) was added and the mixture was degassed for
another 5 min. Cul (10 mg, 0.05 mmol, 0.1 eq), N,N-dimethyl glycine (7 mg, 0.05
mmol, 0.1 eq) and CS2CO3 ( 0.52 g, 1.59 mmol, 3 eq) were added and the mixture was
further degassed for 5 min and then heated at 110 °C for 16 h. The mixture was filtered
through celite and washed with ethyl acetate. The solvent was distilled off to afford the
crude product mixture which was purified by preparative HPLC to yield the title product
in 4.5 % yield (16 mg). !H NMR (400 MHz, DMSO-d6): δ 10.95 (s, 1H), 9.58 (d, 1H),
9.22 (s, 1H), 8.98 (d, 1H), 8.39 (s, 1H), 8.03-7.96 (m, 2H), 7.89-7.83 (m, 2H), 7.55-7.49
(m, 1H), 7.47-7.33 (m, 1H), 4.39 (quartet, 2H), 2.22 (s, 1H), 1.36 (t, 3H); LC-MS (ESI):
Calculated mass: 503.15; Observed mass: 504.1 [M+H]+ (rt: 1.63 min).

Abbreviations:
RT - Room temperature
rt - Retention time
BINAP - 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl
DMF - N, N-dimethylformamide
THF - Tetrahydrofuran
TEA - Triethyl amine
TLC - Thin layer chromatography
DCM - Dichloromethane
DME - Dimethoxyethane
DMSO - Dimethylsulfoxide
EDC - l-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride
HATU - 2-(1H-7-azabenzotriazol-l-yl)-1,1,3,3-tetramethyl uronium hexafluoro-
phosphate methanaminium
HOBt - Hydroxybenzotriazole
DIPEA - N,N-diisopropylethylamine
TBAF - tetra-n-butylammonium fluoride
Pd(dppf)Cl2 -1,1 '-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride
Pd(PPh3)4 - Tetrakis(triphenylphosphine)palladium(O)
Pd2(dba)3 - Tris(dibenzylideneacetone)dipalladium(O)

Claims
1. A compound of formula (I)

wherein
Z1 is N and Z2 is CH, or
Z1 is CH and Z2 is N, or
Z1 and Z2 is N;
Z is CH or N;
A is a phenyl ring or a 5 -12 membered heterocyclic ring;
R1 is H, C1-7 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1-7 alkyl, C1-7 alkoxy, C1-7
alkyl carbonyl, amino, hydroxy, hydroxy C1-7 alkyl, halo C1-7 alkyl, C1-7 alkylamino C1-7
alkyl, -R16-C(O)-R17 or -E-R6;
R2 is H, halogen or C1-7 alkyl;
B is a 5-12 membered carbocyclic or heterocyclic ring;
R3 is H, halogen, C1-7 alkyl, C1-7 alkoxy, halo C1-7 alkyl or halo C1-7 alkoxy;
R4 is H, halogen, C1-7 alkyl or oxo;
R5 is H, -C(O)R7, -SO2R8 or an optionally substituted 5-6 membered
heterocyclic ring;
R6 is an optionally substituted 5-6 membered heterocyclic ring;
R7 is C1-7 alkyl, C2-7 alkenyl, C1-7 alkoxy, C1-7 alkoxy C1-7 alkyl, carboxy C1-7
alkyl, C1-7 alkoxy carbonyl C1-7 alkyl, C1-7 alkylamino C1-7 alkyl, -NH-R10 or -NH-Xr

R8 is C1-7 alkyl, C2-7 alkenyl, C3-7 cycloalkyl, hydroxy C1-7 alkyl, -NR13R14, -NH-
X2-R15, phenyl or an optionally substituted 5-6 membered heterocyclic ring;
R10 is C1-7 alkyl or C3-7 cycloalkyl;
R11 is phenyl or an optionally substituted 5-6 membered heterocyclic ring;
R12 is H or C1-7 alkyl;
RB and R14 are, independently, H, C1-7 alkyl or C3-7 cycloalkyl;
R15 is phenyl or an optionally substituted 5-6 membered heterocyclic ring;
R16 is a bond or a C1-7 alkyl;
Rn is C1-7 alkyl, C1-7 alkoxy, C1-7 alkylamino, amino or hydroxy;
E is a bond or a C1-7 alkyl;
X1 and X2 are, independently, a bond or C1-7 alkyl;
and pharmaceutically acceptable salts thereof.
2. A compound according to claim 1, wherein Z is CH.
3. A compound according to claim 1 or 2, wherein Z1 is N and Z2 is CH.
4. A compound according to to claim 1 or 2, wherein Z1 is CH and Z2 is N.
5. A compound according to to claim 1 or 2, wherein Z1 and Z2 is N.
6. A compound according to any of claims 1 to 5, wherein ring A is any one of
the following groups or tautomers thereof



7. A compound according to any of claims 1 to 6, wherein ring B is any one of
the following groups or tautomers thereof

8. A compound according to any of claims 1 to 7, wherein
A is a ring of formula (1'), (2'), (3'), (4'), (5'), (7'), (14'), (16') or (20');
R1 is H, C1-7 alkyl, C1-7 alkoxy, hydroxy C1-7 alkyl, C1-7 alkylamino C1-7 alkyl or
-E-R6;
R2 is H;
Z is CH;
B is a ring of formula (1"), (2"), (3"), (4") or (6");
E is a bond or C1-7 alkyl;
R6 is any of the following groups

R3 is H, halogen, C1-7 alkyl, C1-7 alkoxy;

R4 is H or halogen;
R5 is -C(O)R7 or -SO2R8 or any one of the following groups

R7 is C1-7 alkyl, C2-7 alkenyl or -NH-R10;
Rg is C1-7 alkyl, C2-7 alkenyl, C3-7 cycloalkyl, hydroxy C1-7 alkyl or -NR13R14; and
R10 is C1-7 alkyl or C3-7 cycloalkyl.
9. A compound according to any of claims 1 to 8, wherein B is a ring of formula
(l"),(3")or(6").
10. A compound according to any of claims 1 to 9, wherein A is a ring of
formula (1'), (2'), (4'), (5') or (20").
11. A compound according to any of claims 1 to 10, wherein R5 is -SO2R8.
12. A compound according to any of claims 1 to 11, wherein Z is CH, Z1 is N
andZ2is CH, A is a ring of formula (1'), B is a ring of formula (1"), R1 is C1-7 alkyl, R2
is H, R3 is halogen, R4 is H or halogen, R5 is -SO2R8 and Rg is C1-7 alkyl or
C3-7 cycloalkyl.
13. A compound according to any of claims 1 to 12, which is
4-(2,4-Difluorophenyl)-N-(l-methyl-1H-pyrazol-3-yl)-6-(5-(l-methyl-1H-
pyrazol-4-yl)- 1H-benzo[d]imidazol-1 -yl) pyridin-2-amine;
N-(4-(2,4-difluorophenyl)-6-(5-(l-methyl-1H-pyrazol-4-yl)-1H-benzo[d]-
imidazol-1 -yl)pyridin-2-yl)cyclopropanesulfonamide;
N-(4-(2,4-difluorophenyl)-6-(5-(l-methyl-1H-pyrazol-4-yl)-1H-benzo[d]-
imidazol-1 -yl)pyridin-2-yl)methanesulfonamide;
N-(4-(2,4-difluorophenyl)-6-(5-(l-methyl-1H-pyrazol-4-yl)-1H-benzo[d]-
imidazol-1 -yl)pyridin-2-yl)ethanesulfonamide;
N-(4-(2,4-difluorophenyl)-6-(5-(l-methyl-1H-pyrazol-4-yl)-1H-benzo[d]-
imidazol-1 -yl)pyridin-2-yl)propane-2-sulfonamide;
N-(4-(2-fluorophenyl)-6-(5-(l-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-l-
yl)pyridin-2-yl)cyclopropanesulfonamide;

N-(4-(2-fluorophenyl)-6-(5-( 1 -methyl-1H-pyrazol-4-yl)-1H-benzo [d]imidazol-1 -
yl)pyridin-2-yl)methanesulfonamide;
N-(4-(2-fluorophenyl)-6-(5-( 1-methyl- 1H-pyrazol-4-yl)-1H-benzo [djimidazol-1 -
yl)pyridin-2-yl)ethanesulfonamide;
N-(4-(4-fluorophenyl)-6-(5-( 1 -methyl-1H-pyrazol-4-yl)-1H-benzo [d] imidazol-1 -
yl)pyridin-2-yl)cyclopropanesulfonamide;
N-(4-(4-fluorophenyl)-6-(5-(l-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-l-
yl)pyridin-2-yl)methanesulfonamide;
N-(4-(4-fluorophenyl)-6-(5-(l-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-l-
yl)pyridin-2-yl)propane-2-sulfonamide;
N-(3-fluoro-6'-(5-( 1 -methyl-1H-pyrazol-4-yl)- 1H-benzo [d]imidazol-1 -yl)- [2,4'-
bipyridin]-2'-yl)cyclopropanesulfonamide;
N-(3-fluoro-6'-(5-(l-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-l-yl)-[2,4'-
bipyridin]-2'-yl)acetamide;
N-(4-(2,4-difluorophenyl)-6-(5-(l-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-
1H-benzo[d]imidazol-l-yl)pyridin-2-yl)cyclopropanesulfonamide;
N-(4-(2-fluorophenyl)-6-(5-(l-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-l-
yl)pyrimidin-2-yl)cyclopropanesulfonamide;
N-(6-(5-( 1H-pyrazol-1 -yl)-1H-benzo[d]imidazol-1 -yl)-4-(2,4-difluorophenyl)-
pyridin-2-yl)cyclopropanesulfonamide;
N-(3,5-difluoro-6'-(5-(l-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-l-yl)-
[2,4'-bipyridin]-2'-yl)cyclopropanesulfonamide;
N-(3,5-difluoro-6'-(5-( 1 -methyl-1H-pyrazol-4-yl)-1 H-benzo [djimidazol-1 -yl)-
[2,4'-bipyridin]-2'-yl)acetamide;
N-(4-(2-chlorophenyl)-6-(5-( 1 -methyl-1H-pyrazol-4-yl)-1H-benzo [d]imidazol-1 -
yl)pyridin-2-yl)cyclopropanesulfonamide;
N-(3-chloro-6'-(5-(l-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-l-yl)-[2,4'-
bipyridin] -2'-yl)cyclopropanesulfonamide;
N-(5-fluoro-6'-(5-(l-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-l-yl)-[2,4'-
bipyridin]-2'-yl)cyclopropanesulfonamide;
N-(6-(5-( 1H-imidazol-1 -yl)-1 H-benzo [djimidazol-1 -yl)-4-(2,4-difluorophenyl)-
pyridin-2-yl)cyclopropanesulfonamide;

N-(4-(2,4-difluorophenyl)-6-(5-(l-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-
benzo[d]imidazol-l-yl)pyridin-2-yl)cyclopropanesulfonamide;
N-(4-(2,4-difluorophenyl)-6-(5-(l-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)-1H-
benzo [d] imidazol-1 -yl)pyridin-2-yl)cyclopropanesulfonamide;
N-(4-(2,4-difluorophenyl)-6-(5-( 1 -ethyl- 1H-1,2,3-triazol-4-yl)- 1H-benzo[d]-
imidazol-1 -yl)pyridin-2-yl)cyclopropanesulfonamide;
N-(4-(2,4-difluorophenyl)-6-(5-(l-methyl-1H-l,2,3-triazol-4-yl)-1H-benzo[d]-
. imidazol-1 -yl)pyridin-2-yl)cyclopropanesulfonamide;
N-(4-(2,4-difluorophenyl)-6-(5-(l-methyl-1H-imidazol-4-yl)-1H-benzo[d]-
imidazol-1 -yl)pyridin-2-yl)cyclopropanesulfonamide;
or a pharmaceutically acceptable salt or tautomer thereof.
14. A pharmaceutical composition comprising a compound of formula (I) or a
pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable
carrier.
15. Use of a compound of formula (I) or a pharmaceutically acceptable salt
thereof in the manufacture of a medicament for the treatment of a condition, where
FGFR kinase inhibition is desired.
16. Use of a compound of formula (I) or a pharmaceutically acceptable salt
thereof in the manufacture of a medicament for the treatment of cancer.

ABSTRACT

A compound of formula (I)

wherein R1 to R5, A, B, Z, Z1 and Z2 are as defined in the claims, and
pharmaceutically acceptable salts thereof are disclosed. The compounds of formula (I)
possess utility as FGFR inhibitors and are useful in the treatment of a condition, where
FGFR kinase inhibition is desired, such as cancer.