AU2014246961A1 - Protein kinase inhibitors - Google Patents

Abstract

A compound of formula (I), wherein R

Description

WO 2014/162039 PCT/F12014/000003 1 PROTEIN KINASE INHIBITORS Technical field 5 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 10 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 i interact 15 With other binding partners. Tyrosine kinases are a subset of protein kihases 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. 20 Tyrosine kinases "are of tWo varieties, i.e. receptor and non-recoptor tyrosine kinases Receptor tyrosie kinases(e.g., FGFR) are trans-membrane proteins With a ligandbinding extracellular domain and a catalytic intracellular kinase domain, while non-receptor tyrosine kinases (e.g., c-ABL) lack trans-membrane domains and are found 25 in the cytosol, nucleus and innet 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 t which polpeptide substrates bind. 30 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 WO 2014/162039 PCT/F12014/000003 2 reorient important amino acid residues, thereby enhancing catalytic activity of the enzyme. Fibroblast growth factor (FGF) has been recognized as an important mediator of 5 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 10 tyrosine kinase domain. Upon stimulation with FGF, FGFRs undergo dimerisation and transphosphorylation. Upon dimerization, FGFRs activate range of downstream signalig 'pathways,'such as;MAPKarid PKB/Akt gathways (Zhou, W. et. al. Cheiistr & Biolgy, 2010, 17, 285). Abnorrhal FGFR signaling has been reported in many tumor types including multiple myeloma, gastric, endometrial, prostate and breast (Squires M. 15 et. al. Mol. Cancer Ther, September 2011, 10:1542-1552). FGFs also haverole in tumor angiogenesis and mediate resistance to vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors (Casanovas, 0. 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 20 therapeutic target, mainly because therapies targeting FGFRs and/or FGF signaling may affet both the tunor cells and also turor angiogenesis (Foote, K. M. et.al., WO 2009/019518 Al). Consequently, FGF and FGFRs have the potential to initiate and/or promote tumnorigenesis. 25 Summary of the invention It has been found that compounds of formula (1) inhibit or modulate the activity of certain protein kinases, more specifically protein tyrosirie kinases. Ii particular, it has been found that the compounds of formula (I) are potent and selective inhibitors of 30 FGFR kinases. The compounds of the invention have antiproliferative activity and are part cularly useful in the treatment of cancer.

WO 2014/162039 PCT/F12014/000003 3 The compounds of the present invention have a structure represented by formula (I) A N R2Z N Z1 R3 Z2NHRs R4 B (I) 5 wherein

Z

1 is N and Z 2 is CH, or

Z

1 is CH and Z 2 is N, or

Z

1 and Z 2 is N; Z is CH orN; 10 A is a phenyl ring or a 5 -12 membered heterocyclic ring;

R

1 is H, C 1 7 alkyl, C 3

.

7 cycloalkyl, C 3

-

7 cycloalkyl C1.

7 alkyl, C 1

.

7 alkoxy, C 1

.

7 alkyl carbonyl, amino, hydroxy, hydroxy C 1

.

7 alkyl, halo C 1

.

7 alkyl, C 1

.

7 alkylamino C 1

.

7 alkyl, -R 1 6

-C(O)-R

1 7 or -E-R 6 ;

R

2 is H, halogen or C 1

.

7 alkyl; 15 B is a 5-12 meibered carbocyclic or heterocyclic ring;

R

3 is H, halogen, Cr.

7 alkyl, C1.7 alkoxy, halo C 1 7 alkyl or halo C 1 .7 alkoxy;

R

4 is H, halogen, C 1

.

7 alkyl or oxo;

R

5 is HI -C(O)R 7 , -S0 2

R

8 or an optionally substituted 5-6 membered heterocyclic ring; 20 R 6 is an optionally substituted 5-6 membered heterocyclic ring;

R

7 is C 1

.

7 alkyl, C 2 - alkenyl, Cp 7 alkoxy, C 1

.

7 alkoxy C1.7 alkyl, carboxy C 1

.

7 alkyl, C 1

.

7 alkoxy carbonyl C 1 7 alkyl, C 1 7 alkylamino C 1

.

7 alkyl, -NH-Rio or -NH-X 1 R 8 is C 17 alkyl, C 2 - alkenyl, C 3

-

7 cycloalkyli hydroxy C1.

7 alkyl, -NR 1 3

R

14 , -NH 25 X 2

-R

15 , phenyl or an optionally substituted 5-6 membered heterocyclic ring; Rio is C 1 7 alkyl or C 3

-

7 cycloalkyl; Ra is phenyl or an optionally substituted 5-6 membered heterocyclic ring; WO 2014/162039 PCT/F12014/000003 4 R12 is H or C 1 7 alkyl;

R

13 and R 14 are, independently, H, C 1

_

7 alkyl or C3-7 cycloalkyl;

R

15 is phenyl or an optionally substituted 5-6 membered heterocyclic ring;

R

16 is a bond or a C 1 7 alkyl; 5 R 17 is Cy- 7 alkyl, C 1 7 alkoxy, C 1 7 alkylamino, amino or hydroxy; E is a bond or a C 1 7 alkyl;

X

1 and X 2 are, independently, a bond or C 1 7 alkyl; and pharmaceutically acceptable salts thereof. 10 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 Z 1 is N and Z 2 is CH. In another class of compounds are compounds of formula (I), wherein Z is CH and

Z

2 is N.In another class of compounds are compounds of formula (I), wherein Z 1 and Z 2 is N. 15 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: N ,N NN N NN NN ON N N 3) 4) ((1) (1) 86) N NN S NN NN 20 (19 (20') (21) (22') and R, and R 2 , as defined above, are attached to the above e A-rings.

WO 2014/162039 PCT/F12014/000003 5 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: N N NN NN (6") (7") (8") (9"1) (10") 5 and R 3 and R 4 , 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 (), (2'), (3'), (4'), (5'), (T), (14'), (16') or (20');

R

1 is H, C 1

.

7 'alkyl, C1.

7 alkoxy, hydroxy C 1

.

7 alkyl, C .

7 alkylamino C 1

.

7 alkyl or 10 E-R 6 ; R2'is H; Z is CH; B is a ring of formula (1"), (2"), (3"), (4") or (6"); E is a bond orCi 7 alkyl; 15 R 6 is any of the following groups N -- N (a) (b) (c) (d) (e)

R

3 is H, halogen, C 1 .7 alkyl, C 1

.-

7 alkoxy;. R4 is H or halogen; 20 R 5 is -C(O)R 7 or -S0 2

R

8 or any one of the following groups NN N N (a)(b")(")")e) (f"

R

7 is C 1

.

7 alkyl, C2- 7 alkenyl or -NH-Rio;

R

8 is C 1

.

7 alkyl, C 2 -7 alkenyl, C 3

-

7 cycloalkyl, hydroxy CI.7 alkyl or -NR 1 3

R

1 4 ; and Rio is C 17 alkyl or C3.7 cycloalkyl.

WO 2014/162039 PCT/F12014/000003 6 In one class of compounds are compounds of formula (I), wherein R 5 is -C(O)R 7 or -S0 2

R

8 or any one of the following groups N -- N N - NN N :N 5 (a") (b") (c") (d") (e") (f") In one class of compounds are compounds of formula (I), wherein R 5 is -S0 2

R

8 . In one class of compounds are compounds of formula (I), wherein R 6 is any of 10 the following groups 6 N -NN (a) (b) (c) (d) (e) The present invention also provides a pharmaceutical composition comprising a 15 compound of formula (I) or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable cartier. 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 20 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. 25 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. 30 The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of cancer.

WO 2014/162039 PCT/F12014/000003 7 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). 5 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). 10 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 15 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, hydr6lysis, acylation, alkylation, amidation, amination, sulfonation and others. It should be noted that any appropriate leaving groups, e.g. N 20 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 (1), wherein R 5 is -C(O)CH 3 can be prepared, for 25 example, according to Scheme 1, wherein R 1 , R 2 , R 3 , R 4 , ring A, ring B and Z, Z and Z 2 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)C1 2 and aqueous sodium carbonate at elevated temperature. The 30 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 WO 2014/162039 PCT/F12014/000003 8 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 5 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)Cl 2 and aqueous sodium carbonate at elevated temperature. 10 WO 2014/162039 PCT/F12014/000003 9 SCHEME 1. 02N Br B(O R) 2 B2N R4 Z1 -- Z2 R3[]Z, Z2 R3 T [2] 2 NH Suzuki coupling rNH Pd/C, H 2 o Pd(dppf)C1 2 / Na 2

CO

3 0 [1][3

H

2 N 4 Z X Z NH Z 1 1 Z 2

R

3 [5] Z KF / D 1F I , NH Zn/NH 4 CI X=Brorl Z L 2 0 X"=ForC B H O4]

R

3

R

4 [6] X' NH 2 X R1 B(OR) 2 Z NH Z N 9 [9] Z1 Z0 Suzuki coupling

Z

2 N O Z N O Pd(dppf)C 2 / Na 2

CO

3 B H B H

R'R

4

[]R

3

R

4 [8 ZN B H

R

4 [10] Alternatively, the cornpound of formula [3] can be prepared according to Scheme 2, wherein R 3 , 1 4 , Z 1 and Z 2 , ring B and R are as defined above, using the boronic acid 5 derivative [11] or a suitable ester thereof in the presence of Pd(dppf)Cl 2 and aqueous sodium carbonate. Compound [11] can be prepared, e.g. by treating N-(3-bromo-5 nitrophenyl)acetamide with bis(pinacolato)diboron in the presence of Pd(dppf)Cl 2 and potassium acetate.

WO 2014/162039 PCT/F12014/000003 10 SCHEME 2. Br 0 2 N N B (O R ) 2 4B r O2N R

Z

1

-Z

2 R 2 NWH uzki[12] z 1 3- R4 SuzukicouplingH Pd(dppf)C 2 / Na 2

CO

3 [11]0 [3] In case the B-ring in the compound [3] is a heterocycle linked to phenyl via a 5 nitrogen heteroatom, the compound [3] can be also prepared using a copper-catalyzed Buchwald amination iftthe presence 'of a base such cesium carbonate or potassium carbonate according to Scheme 3, wherein Z 1 , Z 2 , R 3 and R 4 are as defined above. SCHEME 3. B N-H 2R 2 N N B [13] : IR NH Buchwald amination Cu 2 0 Is 2

CO

3 [1] [14]. 10 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 Z 1 and Z 2 are as defined above. The pyrrole derivative [16] formed is reduced using ammonium sulphide to 15 obtain compound [17], which is subsequently reacted with acetic anhydride to afford compound [18].

WO 2014/162039 PCT/F12014/000003 11 SCHEME 4. 02N NH AcOH 0 2 NN 02N 2,5-dimethoxy- Z 1 Z2 Z1Z2 NH

NO

2 tetrahydrofuran NNf AC20 NO2 NH12 O [15] [16] (17] [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, R 3 , R 4 , Zi and Z 2 are 5 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 10 formic acid according to Scheme 1 to afford the end product in the ring closure reaction. SCHEME 5. ONO RNF NToluenesulfonyl 1 Z] R3 Z methyl isocyanid "NH Z 2 N 0 KC0 NH KF/DMF B H K2CO3 0 [4] 4R 3 R4 [20] N NH

Z

2 N O B H 3

R

4 [21] - In case where ring A in the compound [10] is a heterocycle linked to the carbon 15 atom of the bicyclic ring via a nitrogen heteroatom, the compound [10] can be also WO 2014/162039 PCT/F12014/000003 12 prepared using Buchwald coupling according to Scheme 6, wherein X', ring B, R 1 , R 2 ,

R

3 , R 4 , Z 1 and Z 2 are as defined above. SCHEME 6. XN NN-ANH R2 A XR1 z N N [22] Z N Buchwald amination Z N 0 H Cu 2 Q / Cs 2

CO

3 B H

R

3

R

4 [8] R 3 R 23] 5 In case where ring A in the compound [10] is an 1H-1,2,3-triazol-4-yl ring and

R

2 is hydrogen, the compound [10] can be also prepared according to Scheme 7, wherein X', Z, R 1 , R 3 , R 4 , Z 1 , Z 2 and ring B, are as defined above. The starting compound [8] is silylated by reacting with ethynyltrimethylsilane in the presence of 10 tetrakis(triphenylphosphine)paladium(O) (Pd(PPh 3

)

4 ) and Cu(I)iodide to produce compound [32]. Treatment with TBAF affords the ethynyl compound [33] which can be reacted with azido compound R 1

-N

3 in a suitable solvent, such as DMSO:THF:water (1:1:1) or DMSO:DCM:water (1:1:1) to afford compound [34].

WO 2014/162039 PCT/F12014/000003 13 SCHEME 7. X,~ N -SI. ~N z N Ethynyltrimethylsilane Z Z1 Z1 TBAFI/THF Z N O Pd(PPh3)4 Cu(I) iodide Z N O

Z

2 N 0 Z 2 N 0L B H B H

R

4 [8 R 3

R

4 [32] R N4 *.N NzN ZR-N3 Z N

Z

2 N O Sodium ascorbate B H CuSO 4 5H 2 0

Z

2 N O

R

3

R

4 [33] B H

R

3

R

4 [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 R 3 , R 4 , Z 1 , Z 2 5 and ring B, are as defined above. In this method the compound [4] is treated with 1-(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 10 zinc, to produce the corresponding amine, which can be then treated with formic acid according to Scheme 1 to afford the end product inthe ring closure reaction.

WO 2014/162039 PCT/F12014/000003 14 SCHEME 8. O NO 2 0B NO2 NH R4 F Z N,N-dimethylformamide Z 1 Z 2

R

3 (35] , Z dimethylacetal

Z

2 N _0 NH KF / DMF B H DMF/ethanol S [4] R3 R4 [36] O N-N NNO2

NO

2 NH Methyl hydrazine NH Z EtOH Z1

Z

2 N 0 Z , N 0 B H B *H

R

3

R

4 [371 R4 38] 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 R 3 , R 4 , Z 1 , Z 2 and 5 ring B, are as defined above. In this method the compound [20] of Scheme 5 is treated with ethylene diamind and N-bromosuccinimide affording compound [391 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 10 closure reaction. SCHEME 9. NNH Ethylene diamine / NH N-bromosuccinimide

'Z

2 N 0 0CM Z 2 N 0 M. H 320]

R

3

R

4 [39] WO 2014/162039 PCT/F12014/000003 15 Various compounds of formula (I), wherein R 5 is other than -C(O)CH 3 , can be prepared, for example, according to Scheme 10, wherein R 1 , R 2 , R 3 , R4, R 7 , R 8 , Z, Z 1 , Z 2 , 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 5 base, such as aqueous sodium hydroxide or potassium hydroxide, or an acid such as aqueous HCl. The obtained amine [24] can be used as a starting material for subsequent reaction steps. The compounds of formula (I), wherein R 5 is -S0 2

R

8 can be prepared, for example, by treating the amine [24] with Cl-S0 2

R

8 in suitable solvent such as DCM in the presence of pyridine. Compounds of formula (I), wherein R 5 is -C(O)R 7 and R 7 is 10 C 1 alkyl or C 1 7 alkylamino Cj'y alkyl,'can be prepared, for example, by reacting the anine [24] with HOOC-R in suitable solvent such as DMF in the presence of 2-(1I4-7L azabenzotriazol- 1eyl)- 1, 1,3 3-tetramethyl uronium hexafluorophosphate methanaminium (HATU) and DIPEA. SCHEME 10. A R ~N A RZZ ~ N c Zac z N .'z, 0 B H N s

Z

2 N it~ B H O

R

4 (10] C'-S0 2

-R

8

R

3 [25] Pyridine / CH 2

CI

2 NaOH / H 2 0-EtOH A A \> NzzN z~ N HOOC-Ry Z N 7Z1 O HATU/ DIPEA Z B, Z 2 N R 7 B H

Z

2

NH

2 R4 B R3 [26] 15

R

3 , RR [24] WO 2014/162039 PCT/F12014/000003 16 Compounds of formula (I), wherein R 7 is -NH-Rio or -NH-X-R 1 , 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-Rio or O=C=N-X-Ru 1 in the presence of suitable base such as triethylamine (TEA). Alternatively, compounds 5 wherein R 7 is -NH-X-R 11 can be prepared by treating amine [24] in suitable solvent such as DCM with phosgene and then with H 2

N-X-R

1 , see Scheme 11. SCHEME 11. RR A Z N O=C=N-R 10 Z N TEA

Z

1 0

Z

2

NH

2

Z

2 N N B H H R3 R 4 [24]

R

3 R4 [30]

O=C=N-X-R

11 TEA A i)Phosgene R N 2 2) H2N-X-R1 \ N A N Z, 0 ZRO2 Z N N N R1 1 B H H ZR 0 R[31] B H H

R

3 [31] 10 Compounds wherein R 5 is -C(O)R 7 , -S0 2

R

8 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 R 1 , R 2 , R 3 , R 4 , , Z 1 , Z 2 and ring B are as defined above, using palladium (e.g. Pd 2 (dba) 3 ) catalyzed C-N coupling in the presence of a metal chelating ligand such as Xantphos. 15 WO 2014/162039 PCT/F12014/000003 17 SCHEME 12. RH A , A O TX N H 2

N-R

5 N Pd2(dba)3 Z1 xantphos Z1 B Z X B Z 2

NHR

5

R

4 [40]

R

4 [41] 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 5 halogen such as Cl or Br, and R 1 , R 2 , R 3 , R 4 , Z, ZI, Z 2 and ring B are as defined above, followed by the bicyclic ring closure as in Scheme 1 and addition of the -NHR 5 group according to Scheme 12. SCHEME 13. X Z 2NH 2 A

NO

2 XA ~ z R Z NH [431 B Z X Pd(OAc)2 Z 2 X

R

4 [42] BINAP B R3

R

3

R

4 [44] 10 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 RI, R 2 , R 3 , R 4 , R 5 , Z, Z 1 , Z 2 and rings A and B are as defined above.

WO 2014/162039 PCT/F12014/000003 18 SCHEME 14. X R A R, AN Z1ZN Z NHR 5 [46] Z N B Z1 NH 5 R3 R4 [451 NaH /DMF B Z2 NHR5

R

3

R

4 [471 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 R 1 , R 2 , R 5 , Z, Z 1 , Z 2 and rings A and B are as defined above. The formed compound 5 [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). SCHEME 15. NH2R

NH

2 R A

NH

2 NH 2 R1, R2 A I X X Z NH SR2 [49] Z Z 2 Zi

NH-R

5 NsHCO3/EtOH X Z 2

NH-R

5 [48] [50] 10 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 15 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 WO 2014/162039 PCT/F12014/000003 19 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. 5 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. 10 The term "C 1 alkyll", as employed herein as such or as part of another group, refers t6 a straight or branched chain saturated hydrocarbon group having 1, 2, 3, 4, 5, 6 or 7 carbon atom(s). Representative examples of C 1

.

7 alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopIropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, 15 iso-pentyl and n-hexyl. The term "C 1 3 alkyl" refers to an preferred embodiment of "C 1

.

7 alkyl" having 1, 2 or 3 carbon atoms. The term "C 3

-

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 20 atoms. Representative examples of cycloalkyl include, but are not limited to, cyclo propyl, cyclobutyl, Icyclopentyl and cyclohexyl. The term "C 3 7 cycloalkyl C- 7 alkyl", as employed herein refers to a C 3 7 cyclo alkyi group, as defined herein, appended to the parent molecular moiety through a C 1 7 25 alkyl group, as defined herein. The term "C 2

-

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, 30 ethenyl, propenyl and cyclohexenyl.

WO 2014/162039 PCT/F12014/000003 20 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 5 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 (=0). The term "C1-, alkoxy", as employed herein as such or as part of another group, 10 refers to C 1 7 alkyl, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of C 1 7 alkoxy include, but are not limited to niethoxy, ethoxy, propoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy. The term "hydroxyl C 1

.

7 alkyl", as employed herein, refers to at least one 15 hydroxy group, as defined herein, appended to the parent molecular moiety through a

C

1 -7 alkyl group, as defined herein. Representative examples of hydroxyl C- 7 alkyl include; but are not limited to, hydroxymethyl, 2,2-dihydroxyethyl, i-hydroxyethyl, 3 hydroxypropyl, 1 -hydro xypropyl, 1-nethyl-I -hydroxyethyl and 1-methyl-i -hydroxy propyL 20 The term "halo C 1 7 alkyl", as employed herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through a C 1 7 alkyl group, as defined herein. Representative examples of halo C 1 7 alkyl include, but are not limited to, fluoromethyl, difludromethyl, trifluoromethyl, 2-chloroethyl and 3-bromopropyl. 25 The term "cyano C.-, alkyl", as employed herein, refers to a cyano group, as defined herein, appended to the parent molecular moiety through a C 1 7 alkyl group, as defined herein. Representative examples of cyano C 1 .7 alkyl include, but are not limited to, cyanomethyl, 1-cyanoethyl, 1-cyanopropyl and 2-cyanopropyl. 30 WO 2014/162039 PCT/F12014/000003 21 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 C 1

.

7 alkyl group, as defined herein. 5 The term "halo CI-7 alkoxy", as employed herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through a C 1

.

7 alkoxy group, as defined herein. The term "phenyl C 1

.

7 alkoxy", as employed herein, refers to at least one phenyl 10 group appended to the parent molecular moiety through a C 1

_

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 C 1 7 alkyl group, as defined herein, appended to the parent molecular 15 moiety through a carbonyl group, as defined herein. The term "C 1 7 alkoxycarbonyl", as employed herein as such or as part of another group, refers to a C 1 7 alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. 20 The term "C 1 7 alkoxycarbonyl C 1 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 C 1

.

7 alkyl group, as defined herein. 25 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 C 1 7 alkyl", as employed herein, refers to at least one amino 30 group appended to the parent molecular moiety through a C 1 7 alkyl group, as defined herein. Representative examples of amino C 1

.

7 alkyl include, but are not limited to, WO 2014/162039 PCT/F12014/000003 22 aminomethyl, 2-aminoethyl, 1-aminoethyl, 2,2-diaminoethyl, 3-aminopropyl, 2 aminopropyl, 4-aminobutyl and 1-methyl-i -aminoethyl. The term "CI.

7 alkylamino", as employed herein as such or as part of another 5 group, refers to at least one C 7 alkyl group, as defined herein, appended to the parent molecular moiety through an amino group. Representative examples of C 1 7 alkylamino include, but are not limited to methylamino, ethylamino, propylamino, butylamino, dimethylamino, diethylamino and N-ethyl-N-methylamino. 10 The term "C 1 7 alkylamino C 1 7 alkyl", as employed herein as such or as part of another group, refers to at least one C 1

.

7 alkylamino group, as defined herein, appended to the parent molecular moiety through an C 1

-

7 alkyl group, as defined herein. The term "carboxy C 1 7 alkylamino", as employed herein as such or as part of 15 another group, refers to at least one carboxy group, as defined herein, appended to the parent molecular moiety through an C 1

.

7 alkylamino group, as defined herein The term "C7 alkoxy C 1 7 alkyl"; as employed hereinrefers to at least oneC 1 7 alkoxy group, as defined herein, appended to the parent molecular moiety through an 20 CIy alkyl group, as defined herein. The term "C 1

.

7 alkoxycarbonyl C 1 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 C 1 7 alkyl group, as defined herein. 25 The term "substituted" as used herein in connection with various residues refers to halogen substituents, such as fluorine, chlorine, bromine, iodine, or C 1 7 alkyl, C 3 7 cycloalkyl, halo C 1 7 alkyl, hydioxy, amino, C 1 7 alkoxy, C 1 7 acyl C 1 7 alkylamino, amino

C

1 7 alkyl, nitro, cyano, thiol or methylsulfonyl substituents. Preferred are halogen, C 1

.

7 30 alkyl, halo C 1 7 alkyl, hydroxy, amino, C 1

.

7 alkoxy and methylsulfonyl substituents. Particularly preferred are 1 to 3 of C 1 3 alkyl substituents.

WO 2014/162039 PCT/F12014/000003 23 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 5 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, 0 and S. Representative examples of 5-6-membered heterocyclic ring include, but are not limited to, pyrazolyl, 1,2,4-triazol-1-yl, 1,2,3-triazol-1-yl, pyrimidinyl, pyridinyl, tetrazolyl, piperazinyl, furanyl, morpholinyl, piperidinyl, pyrrolidinyl, thiazolyl, isoxazolyl, pyrazinyl 10 tetrahydiopyranyl, 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 15 atoms, of which 1-5 atoms are heteroatoms selected from a group consisting of N, 0 and S. Representative exam ples of 5 - 12 membered heterocycli& ring include the examples given above and additionally, but not limited to, indazolyl, pyrazolo[1,5-a]pyrimidinyl, benzo[dlimidazolyl, imidazo[4,5-b]pyridinyl, 4,5,6,7-tetrahydrobenzo[d]imidazolyl and benzofuranyl rings. 20 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. 25 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 30 esters.

WO 2014/162039 PCT/F12014/000003 24 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 (1) includes any racemic or optically active form, or mixtures thereof. In one embodiment, the compounds are the 5 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 orie embodiment, the compounds of the invention are pure 10 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 abdording to conventional separation methods. For the separation of optical isomers, e.g. enantiomers or diastereomers, from the mixture thereof the conventional 15 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, amido-imido, keto-enol, phenol-keto, oxime 20 nitroso, nitro-aci, imine-enamine and the like. Tautomeric forms of compounds of formula (I)'are intended to be encompassed by compounds formula (I) even though only one tautomeric form may be depicted. For example, compounds of formula (Ib') A A R ZR 2 ZI N N 2> R Z~ NN

Z

2

NHR

5

Z

2

NR

5

R

4 B B (Ib) (Ib) WO 2014/162039 PCT/F12014/000003 25 wherein R 1 , R 2 , R 3 , R 4 , R 5 , Z, Z 2 and rings A and B are as defined above, are imido tautomers of amido compounds of formula (Ib) and are, therefore, within the scope of formula (I) as defined herein. 5 Examples of preferred compounds of formula (I) include 4-(2, 4-Difluorophenyl)-N-(1-methyl-iH-pyrazol-3-yl)-6-(5-(1-methyl-iH pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl) pyridin-2-amine; N-(4-(2,4-difluorophenyl)-6-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[dl imidazol- 1-yi)pyridin-2-yl)cyclopropanesulfonamide; 10 Sodiui salt of irido form of N-(4-(2,4-difluorophenyl)-6-(5-(l1-methyl-iH pyrazol-4-yl)-1H-benzo[d]iinidazol-1-yl)pyridin-2-yl)cyclopropanesulfonamide; N-(4-(2,4-difluorophenyl)-6-(5-(1-methyl-iH-pyrazol-4-yl)-1H-benzo[d] imidazol- lyl)pyridin-2-yl)nethanesulfonamide; N-(4-(2'4-difluorophenyl)-6-(5'(1-methyl-iH-pyrazol-4-yl)-IH-benzo[d] 15 imidazol-1-yl)pyridin-2-yl)ethanesulfonamide; Sodium salt of imido form of N-(4-(2,4-difluorophenyl)-6-(5-(1-methyI-1H pyrazol-4-yl); lH-benzo[djimidazoll-yl)pyridin-2-yl)ethanesulfonamide; N-(4-(2,4-difluorophenyl)-6-(5-(1-methyl-iH-pyrazol-4-yl)-1H-benzo[d] imidazol- 1-yl)pyridin-2-yl)propane-2-silfonamide; 20 Imido form of N-(4-(2,4-difluorophenyl)-6-(5-(1-methyl-iH-pyrazol-4-yl)-1H benzo [d]imidazol- 1 -yl)pyridin-'2-yl)propane-2-sulfonamide; N-(4-(2-fluorophenyl)-6-(5-(i -methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1 yl)pyridin-2-yl)cyclopropanesulfonamide; Sodium salt of imido form of N-(4-(2-fluorophenyl)-6-(5-(1-methyl-1 H-pyrazol 25 4-yl)-1H-benzo[d]imidazol- 1 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-(i-methyl-iH-pyrazol-4-yl)-1H-benzo[d]imidazol-1 yl)pyridin-2-yl)ethanesulfonamide 30 Sodium salt of imido form of N-(4-(2-fluorophenyl)-6-(5-(I-methyl-1H-pyrazol 4-yl)-1H-benzo[d]imidazol-1-yl)pyridin-2-yl)ethanesulfonamide; WO 2014/162039 PCT/F12014/000003 26 N-(4-(2-fluorophenyl)-6-(5-(1-methyl-i H-pyrazol-4-yl)- 1H-benzo[d]imidazol- 1 yl)pyridin-2-yl)propane-2-sulfonamide; Sodium salt of imido form of N-(4-(2-fluorophenyl)-6-(5-(1-methyl-1H-pyrazol 4-yl)-1H-benzo[d]imidazol-1-yl)pyridin-2-yl)propane-2-sulfonamide; 5 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-(1-methyl-iH-pyrazol-4-yl)-1H-benzo[d]imidazol-1 yl)pyridin-2-yl)methanesulfonamide; N-(4-(4-fluorophenyl)-6-(5-(1-methyl-iH-pyrazol-4-yl)-1H-benzo[d]imidazol-1 10 yl)pyridin-2-yl)propane-2-sulfonamide; Sodium salt of imido form of N-(4-(4-fluorophenyl)-6-(5-(i-inethyl-1H-pyrazol 44l)-1H-benio[d] imidazol-i-yl)pyridin-2-yl)propane-2-sulfonainide; N-(3-fluoro-6'-(5-(1-methyl-iH-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[2,4' bipyridin]-2'-yl)cyclopropanesulfonamide; 15 N-(3-fluoro-6'-(5-(I-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazoil-1-yl)-[2,4' biIyridin] -2'-yl)acetamide; N-(4-(2,4-difluorophenyl)-6-(5-(1-(2-(dimethylamino)ethyl)- 1H-pyrazol-4-yl) 1H-benzo[d]imidazol-1-yl)pyridin-2-yl)cyclopropanesulfonamide; N-(4-(2-fluorophenyl)-6-(5-(1-methyl-iH-pyrazol-4-yl)-1H-benzo[d]imidazol- 1 20 yl)pyrimidin-2-yl)cyclopropanesulfonamide; N-(6-(5-(1H-pyrazol1 -yl)-1H-benzo[d]imidazol-1-yl)-4-(2,4-difluorophenyl) pyridin-2-yl)cyclopropanesulfonamide; N-(3,5-difluoro-6'-(5-(1-methyl-iH-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yi) [2,4'-bipyridin]-2'-yl)cyclopropanesulfonamide; 25 N-(3,5-difluoroa6'-(5-(1i-methyl-iH-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl) [2,4'-bipyridin]-2'-yl)acetamide; N-(4-(2-chlorophenyl)-6-(5-(1-methyl-iH-pyrazol-4-yl)-1H-benzo[d]imidazol-1 yl)pyridin-2-yl)cyclopropanesulfonamide; N-(3-chloro-6'-(5-(1-methyl-iH-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[ 2

,

4

'

30 bipyridin]-2'-yl)cyclopropanesulfonamide; N-(5-fluoro-6'-(5-(1-methyl-iH-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yi)-[2,4' bipyridin]-2'-yl)cyclopropanesulfonamide; WO 2014/162039 PCT/F12014/000003 27 N-(6-(5-(1H-imidazol- I-yl)-1 H-benzo[d]imidazol- 1 -yl)-4-(2,4-difluorophenyl) pyridin-2-yl)cyclopropanesulfonamide; N-(4-(2,4-difluorophenyl)-6-(5-(1-(2-morpholinoethyl)- 1H-pyrazol-4-yl)- 1H benzo[d]imidazol- 1 -yl)pyridin-2-yl)cyclopropanesulfonamide; 5 N-(4-(2,4-difluorophenyl)-6-(5-(1 -(pyrrolidin-3-yl)- 1H-pyrazol-4-yl)- iH benzo[d]imidazol- 1 -yl)pyridin-2-yl)cyclopropanesulfonamide; N-(4-(2,4-difluorophenyl)-6-(5-(1-ethyl-i H-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-i H-1,2,3-triazol-4-yl)- 1 H-benzo[d] 10 imidazol- 1 -yl)pyridini2-yl)cyclopropanesulfonamide; N-(4-(2,4-difluorophenyl)-6-(5-(i-methyl-iH-imidazol-4-yl)-1H-benzo[d] imidazol- 1 yl)pyridin-2-yl)cyclopropanesulfonamide; N-(4-(2, 4-difluorophenyl)-6-(5-(1 -methyl-i H-pyrazol-4-yl)- 1 H-benzo[d] imidazol-1-yl) pyrimidin-2-yl) acetamide; 15 Ethyl 1-(1-(6-(cyclopropanesulfonamido)-4-(2,4-difluorophenyl)pyridin-2-yl) 1H-benzo[d]imidazol-5-yl)-1H-1,2,3-triazole-4-carboxylate; N-(4-(2-(difluoromethoxy)-4-fluorophenyl)-6-(5-(1-methyl-iH-pyrazol-4-yl) 1H-benzo[d]imidazol-1-yl)pyridin-2-yl)cyclopropanesulfonamide; N-(4-(2,4-difluorophenyl)-6-(5-(i-methyl-iH-pyrazol-4-yl)-1H-benzo[d] 20 imidazol-1-yl)pyrimidin-2-yl)cyclopropanesulfonamide; N-(6-(2, 4-difluorophenyl)-4-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d] imidazol-1-yl) pyridin-2-yl) cyclopropanesulfonamide; or a pharmaceutically acceptable salt or tautomer thereof. 25 Compounds of the invention may be administered to a patient in therapeutically effective amounts which range usually from about 0.1 to about 5000 mg, preferably from about 1 to about 2000 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 30 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 WO 2014/162039 PCT/F12014/000003 28 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 5 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 10 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 15 illustrating purposes and do not limit the scope of the invention defined in claims. EXPERIMENTS 20 1. Inhibition of FGFR I kinase FGFR1 assay Compounds were screened in the TR-FRET assay with FGFR1 kinase. 5 ng of 25 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 [tM 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 30 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 I [M concentrations. The compounds with >50 % inhibition at 100 nM of FGFR1 were taken WO 2014/162039 PCT/F12014/000003 29 for the full dose response studies. The final DMSO concentration in the assay was 1 %. For IC 50 determination, 1

/

3 rd serial dilution was made from the 20 mM DMSO stock solution. 2 pd of these were transferred to the test wells containing 20 ptl of the reaction mixture [total reaction volume 20 pl]. The fluorescence was measured in Perkin Elmer 5 Wallac 1420 Multilabel Counter Victor 3. The IC 50 was determined by fitting the dose response data to sigmoidal curve fitting equation using GraphPad Prism software V5. Results 0 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. TABLE 1. Inhibition of FGFR1 kinase Inhibition (%) of

IC

50 of FGFR1 Compound FGFR1 at 1000 inhibition (nM) nM Example 1 97 16.5 Example 2 99 3.9 Example 2 (imido) 97 3.3 Example 4 98 4.3 Example 5 99 1.1 Example 5 (imido) 98 4.4 Example 6 99 1.7 Example 6 (imido) 98 1.7 Example 8 99 5.42 Example 8 (imido) 97 3.3 Example 10 97 5.8 Example 11 98 2.8 Example 11 (imido) 98 3.2 Example 12 97 1.5 Example 12 (imido) 99 5.2 Example 14 98 14.4 Example 16 97 3.4 Example 17 96 4.6 Example 17 (imido) 97 5.2 WO 2014/162039 PCT/F12014/000003 30 Example 18 97 5 Example 19 96 28.5 Example 21 99 3.7 Example 22 97 9.2 Example 23 97 10 Example 25 97 3.1 Example 26 94 21.9 Example 28 97 7.2 Example 29 97 9.7 Example 30 96 24 Example 32 99 21.7 Example 33 99 2 Example 34 99 1.6 Example 35 99 2 Example 36 99 4.7 Example 37 99 1.3 Example 38 87 12 Example 39 81 294.2 Example 40 76 293.5 Example 41 93 32.7 Example 43 94 43.4 The preparation of the compounds of the invention is illustrated by the following Examples. 5 EXAMPLES. LCMS data has been recorded in +ve mode unless otherwise mentioned. Intermediate Example 1. 10 4-(1-Methyl-iH-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 N 2 bubbling for 5 min. 1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yI)-1H-pyrazole (6.90 g, 33.1 mmol, 1.2 eq) was added and the 15 mixture was degassed for another 5 min. Pd(dppf)Cl 2 (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 WO 2014/162039 PCT/F12014/000003 31 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 5 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. 10 tert-Butyl 3-(4-(1iH-benzo[d]imidazol-5-yl)-IH-pyrazol-1-yl)pyrrolidine-1 carboxylate a) tert-Butyl 3-(methylsulfonyl) pyrrolidine-1-carboxylate 15 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 mn. 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 CH 2

C

2 (3 x 50 ml). The solvent was distilled off to afford the 20 title product in 86 % yield (0.6 g). b) tert-butyl 3-(4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)-1H-pyrazol-1 yl) pyrrolidine-1-carboxylate 25 To a solution of 4 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.6 g, 2.26 mmol) in DMF were added sodium hydride at 0 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 30 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 WO 2014/162039 PCT/F12014/000003 32 To a degassed (N 2 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(PPh 3

)

4 (16 mg, 0.015 mmol, 0.1 eq) and 5 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). 10 Intermediate Example 3. 4-( 1:(2-Dimethylamirio)ethyl)- 1Hepyrazol-4-yl)-2 nitroaniline a) 2-(4-iodo-1H-pyrazol-1-yl)-N,N-dimethylethanamine 15 To a solution of 4-iodo1IH-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-NN-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 20 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 25 A solution of the compound of Example 3(a) (0.5 g, 1.9 nimol) in 1, 2-di methoxyethane (15 ml) was degassed by N 2 bubbling for 5 min. 2-Nitro-4-(4,4,5,5 tetramethyl-1,3,2-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)C1 2 (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 30 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 WO 2014/162039 PCT/F12014/000003 33 product in 65 % yield (0.3 g). LC-MS (ESI): Calculated mass: 275.14; Observed mass: 276.15 [M+H]* (rt: 0.18 min). Intermediate Example 4. 5 5-(1H-Pyrazol-1-yl)-1H-benzo[d]imidazole a) 2-nitro-4-(1H-pyrazol-1-yl)aniline To a solution of 4-bromo-2-nitroaniline (3 g, 13.8 mmol) in DMF (12 ml),were 10 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 overnightThe 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 15 product in 53.5% yield (1.5 g). b) 5-(1H-pyrazol- 1 yl)d-1 H-benzo[d]imidazole A mixture of the compound of Example 4(a) (0.5 g, 2.5 mmol) and iron:powder 20 (1.39 g, 25 mmol, 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+HJ (rt: 0.097 min). 25 hitermediate Example 5. N-(6-chloro-4-(2,4-difluorophenyl)pyridin-2-yl)cyclopropanesulfonamide a) 2,6-dichloro-4-(2,4-difluorophenyl)pyridine 30 A solution of 2,6-dichloro-4-iodopyridine (1.5 g, 5.49 mmol) in 1,2-dimethoxy ethane (15 ml) was degassed by N 2 bubbling for 5 min. 2,4-Difluorophenylboronic acid (0.86 g, 5.49 mmol, 1 eq) was added and the mixture was degassed for another 5 min.

WO 2014/162039 PCT/F12014/000003 34 Pd(dppf)C1 2 (0.358 g, 0.43 mmol, 0.08 eq) and aqueous sodium carbonate (1.45 g, 13.7 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 5 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 10 A solution of the compound of Intermediate Example 5(a) (0.9 g, 3.46 mmol) in dioxane (20 ml) was degassed by N 2 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 Cs 2

CO

3 (3.37 g, 10.4 mmol, 3.0 eq) were added and the mixture was further 15 degassed for 5 min and then heated at 100 0 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). H 20 NMR (300 MHz, DMSO-d 6 ): 8 11.05 (s, 1H), 7.76-7.68 (m, 1H), 7.51-7.43 (m, 1H), 735 (s, 1H), 7.30-7.24 (m, 1R), 7.16 (s, 1H), 3.09-3.01 (m, 1H), 1.22-1.09 (m, 2R), 1.08"1.03 (in, 2H). Intermediate Example 6. 5-( 1-Methyl-i1H-pyrazol-4-yl)- 1H-benzo[dlimidazole 25 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 30 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.

WO 2014/162039 PCT/F12014/000003 35 5-(1 -Methyl.-1H-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 N 2 bubbling for 5 min. 1-Methyl-4-(4,4,5,5-tetramethyl 5 1,3,2-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)C1 2 (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 10 was distilled off to afford the crude residue which was purified by column chromatography (60-120 silica gel, 70 % ethyl acetate in hexarie) 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). 15 Intermediate Example 8. 4-(1 -(2-Motpholinoethyl)-1H-pyrazol-4-yl)-2-nitroaniline a) 4-(2-(4-bromo-1H-pyrazol- 1-yl)ethyl)morpholine, 20 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 K 2

CO

3 (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 25 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)-1H-pyrazol-1-yl)ethyl) morpholine 30 A solution of the compound of Intermediate Example 8(a) (1 g, 3.8 mmol) in DME (15 ml) was degassed by N 2 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)C1 2 (0.313 g, 0.38 mmol, 0.1 eq) and potassium acetate (1.32 g, 13.4 mmol, 3.5 WO 2014/162039 PCT/F12014/000003 36 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 5 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)-1H-pyrazol-4-yl)-2-nitroaniline 10 A solution of the compound of Intermediate Example 8(b) (1 g, 4.6 mmol) in 1,2-dimethoxyethane (15 ml) was degassed by N 2 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)C1 2 (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 15 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 [IM+HI+ (rt: 0.20 min). 20 Intermediate Example 9. 4-(1H-Imidazol- 1 -yl)-2-nitroaniline To a solution of 4-bromo-2-nitroaniline (3 g, 13.8 mmol) in DMF (12 ml) were 25 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 30 (1.1 g). H NMR (300 MHz, DMSO-d 6 ):, 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.

WO 2014/162039 PCT/F12014/000003 37 5-(1-Ethyl-i H-1,2,3-triazol-4-yl)- 1 H-benzo[d]imidazole a) 2-Nitro-4-((trimethylsilyl)ethynyl)aniline 5 A solution of the compound of 4-iodo-2-nitroaniline (1 g, 3.8 mmol) in DMF Et 3 N (1:1; 20 ml) was degassed by N 2 bubbling for 15 min. Pd(PPh 3

)

4 (0.22 g, 0.19 mmol, 0.05 eq.), copper(I) iodide (0.073g, 0.386 mmol, 0.1 eq.) and ethynyltrimethyl silane (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. 10 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 15 To a solution of the compound:of Intermediate Example 10(a) (0.5 g, 2.15 mmol) in THF (10 ml) at 0C 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). 20 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.), 25 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). 30 d) 5-(1-Ethyl-1H-l;2,3-triazol-4-yl)-1H-benzo[d]imidazole WO 2014/162039 PCT/F12014/000003 38 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 5 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: 0.14 min). Intermediate Example 11. 10 5-(1-Methyl-iH-imidazol-4-yl)-i1H-benzo[d]imidazole a) 4-(1-Methyl-1H-imidazol-4-yl)-2-nitroaniline A solution of 2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline 15 (1.45 g, 5.55 mmol, 1.1 eq) in 1,2-dimethoxyethane (15 ml) was degassed by N 2 bubbling for 5 min. 4-Bromo-1-methyl-1H-imidazole (0.81 g, 5 mmol, 1 eq) was added and the mixture was degassed for another 5 min. Pd(dppf)Cl 2 (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 20 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). 25 b) 5-(1-methyl-1H-imidazol-4-yl)-1H-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 30 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 WO 2014/162039 PCT/F12014/000003 39 % 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 5-((Trimethylsilyl)ethynyl)-1H-benzo[d]imidazole a) 5-Iodo-1H-benzo[d]imidazole To a solution 4-iodlo-2-nitroaniline (1 g, 3.7 mmol), in formic acid (10 ml), iron 10 (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). 15 b) 5-((Trimethylsilyl)ethynyl)-1H-benzo[d]imidazole A solution of of the compound of Intermediate Example 12(a) (0.7 g, 2.56 mmol) in DMF-Et 3 N (1:1; 10 ml) was degassed by N 2 bubbling for 15 min. Pd(dppf)C1 2 (0.11 20 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 wasa 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: 25 214.09; Observed mass: 215.5 [M+H] + (rt: 0.22 min). Intermediate Example 13. 4-(1-Methyl-1H-pyrazol-4-yl) benzene-1, 2-diamine 30 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 (5 ml) 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 WO 2014/162039 PCT/F12014/000003 40 (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 5 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 10 a) lH-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 15 ml). Thecombined 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). 20 b) 5-Azido-1H-benzo[d]imidazole To a solution of the compound of Intermediate Example 14(a) (2 g, 15 mmol) in concentrated HCl (8 ml) at 0 0 C was added aqueous solution of NaNO 2 (1.3 g, 18.7 mmol, 1.25 eq) dropwise and the mixture was stirred at 0 'C for 30 min. Then NaN 3 25 (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). 30 c) Ethyl 1-(1H-benzo[d]imidazol-5-yl)-1H-1,2,3-triazole-4-carboxylate WO 2014/162039 PCT/F12014/000003 41 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 t-butanol and water (1:0.5, 20 ml) was stirred for 48 h at RT. The volatiles were evaporated and 5 the reaction mixture was extracted with 10 % methanol in CH 2 Cl 2 (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). 10 Intermediate Example 15. N-(6-chioro-4-(2-(difluoromethoxy)-4-fluorophenyl)pyrdin2-yl)cyclopropatfe sulfonamide 15 a) 1 Bromo-2-(difluoromethoxy4)--fluorobenzene To a solution of 2-brorno-5-flu6rophenol (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 mnniol, 2.5 eq) and the reaction mixture was heated at 100 OC for 15 h. The 20 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). 25 b) 2,6-Dichloro-4-(2-(difluoromethoxy)-4-fluorophenyl)pyridine 'A solution of the conpo nd of Intermediate Example 15(a) (2.2 g, 9.1 mmol) in 1,2-dimethoxyethane (50 ml) was degassed by N 2 bubbling for 5 mil. 2,6-Dichloro-4 (4,4,5,5-tetramethyll,3,2-dioxaborolan-2-yl)pyridine (2.75 g, 10.04 mmol, 1.1 q)was 30 added and the mixturewasdegassed for another 5 min. Pd(dppf)C 2 (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 WO 2014/162039 PCT/F12014/000003 42 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 5 mass: 307.85 [M+H]* (rt: 2.0 min). c) N-(6-chloro-4-(2-(difluoromethoxy)-4-fluorophenyl)pyridin-2-yl)cyclo propanesulfonamide 10 A solution of the compound of Intermediate Example 15(b) (0.5 g, 1.62 mnol) in dioxane (10 ml) was degassed by N 2 'bubbling for 5 min. Cyclopropane sulfonamide (0.19 , 1.62 mmol, 1 eq) was added and the mixture was degassed for another 5 min. Palladium acetate (18 nig, 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 15 reaction mixture was furtherdegassed for 5 min and then heated at 100 0 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 20 (0.3 g). LC-MS (ESI): Calculated mass: 392.02; Observed mass: 392.85 [M+H]* (rt: 1.82 mm). Intermediate Example 16. N-(6-chloro-4-(2,4-difluorophenyl)pyridin-2-yl)acetamide 25 A solution of the compound of Intermediate Example 5(a) (0.5 g, 1.92 mmol) in dioxane (20 ml) was degassed by N 2 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 Cs 2

CO

3 (1.88 g, 30 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 WO 2014/162039 PCT/F12014/000003 43 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). 5 Example 1. 4-(2, 4-Difluorophenyl)-N-(1-methyl-i H-pyrazol-3-yl)-6-(5-(1-methyl-iH pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl) pyridin-2-anine a)'6-Chloto-4-(2, 4-difluorophenyl)-N-(4-( 1-methyl-i H p-2nitio6 10 phenyl) pyridin'2 amiine A solution of the compound of Intermediate Example 5(a) (0.8 g, 3.07 mmol) in toluene (5 mi) was degassed by N 2 bubbling for 5 min. The compound of Intermediate 15 Example 1 (0. 8 g, 3.69 mmoI, 1.2 eq) was added and the mixture was degassed' for an6ihr 5 min. Palladiu acetate (0.027 g 0.123 mmol,0.04 eq) and BINAP (0.076 g, 0.123 mmol, 0.04 eq) and potassium tert-butoxide (0.69 g, 6.15 mmol, 2.0 eq) were added sequentially and the mixture' wasfurther degassed for 5 min and then heated at 100 "C for 5 h. The mixture was filtered through celite pad and extracted with ethyl 20 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 chroatography (60-12O silica gel, 30 % ethyl acetate in hexane) in 29.5 % yield (0.4 g). LC-MS (ESI): Calculated mass 41.2 Obsered mass: 442.0 [MliH] (t: 1.84 min). 25 b) l (6-Chloro-4-(2, 4-difluorophenyl) pyridin-2-yl)-5-(1-methyl-iH- 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 30 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 WO 2014/162039 PCT/F12014/000003 44 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-(1-methyl-iH-pyrazol-3-yl)-6-(5-(1-methyl-iH 5 pyrazol-4-yl)- 1H-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 N 2 bubbling for 5 min. 1-Methyl-1H-pyrazol-3-amine (0.024 g, 0.199 mmol, 1.2eq) was added and the mixture was degassed for another 5, min. x 10 Pd 2 (dba) 3 (0.007 g, 0.0083 mmol; 0.05 eq) and xantphos (0.005g, 0.0083 mmol, 0,05 eq) and Cs 2

CO

3 (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 i. 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 15 afford the title product in 15 % Yield (12mg). IH NMR (400 MHz, CD 3 OD): 8 8.83 (s, IH);-8.24-8.22 (d, 1H), 8.03:(s, 1Ii), 7.90-7.89 (d, 2H), 7.77-7.71 (m, 1H), 7'62-7.60 (m, 1N), 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, 311); LC-MS(U): Calculated mass: 482.18; Observed mass: 483.55 [M+H]* (rt 1.57min). 20 Exapl 2. N-(4-(2,4-difluorophenyl)-6-(5-( 1-methyl- 1 H-pyrazol-4-yl)- 1H-benzo[d] imidazol- 1 -yl)pyridin-2-yl)cyclopropanesulfonamide 25 A solution of the compound of Example 1(b) (42 mg, 0.1 mmol) in dioxane (1 ml) was degassed by N 2 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 inmol, 0.08 eq) and Cs 2

CO

3 (100 mg, 0.3 mmol, 3.0 eq) were added and the mixture was further degassed 30 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 % WO 2014/162039 PCT/F12014/000003 45 yield (10 mg). 1H NMR (300 MHz, CD 3 OD): 6 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). 5 Example 2 (imido). Sodium salt of imido form of N-(4-(2,4-difluorophenyl)-6-(5-(1-methyl-1H pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)pyridin-2-yl)cyclopropanesulfonamide The compound (34,mg) was prepared using the procedure described in Example 17 10 (imido) starting fr om the title compound of Example 2. The desired compound was crystallized from ethanol. 'H NMR (300,M11z, DMSOd 6 ) § 8.83 (s, 1H), 8.81-8.78 (d, lH),8.19 (s, 1H), 7,93 (s, 1H), 7.88 (d, 1H), 7.76-7.68 (i, 1H), 7.53-7.5 (d, 1H), 7.45 7.37 (dt, 1H), 7.27-7.20 (dt, 1H), 6.93 (s, 1H), 6.5 (s, 1H), 3.87 (s, 3H), 2.9 (m, 1H), 0.81-0.8 (m, 2H), 0.6-0.58 (m, 2H); LC-MS (ESI): Calculated mass: 506.1; Observed 15 mass: 506.8 [M+Hl+ (rt: 1.54 min). Example 3. N-(4-(2,4-difluorophenyl)-6-(5-(1 -methyl-1 IH-pyrazol-4-yl)- 1 H-benzo [d] inidazol- 1 yl)pyridin-2-yl)acetaimide 20 The compound was prepared from the compound of Example 1(b) using the procedure of Example 2. 'H NMR (400 MHz, DMSO-d 6 ): 6 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): 25 Calculated mass: 444.15; Observed mass: 445.3 [M+H]* (rt: 1.43 min). Example 4. N-(4-(2,4-difluorophenyl)-6-(5-( 1-methyl-iH-pyrazol-4-yl)-1H-benzo[d] inidazol- 1 -yl)pyridin-2-yl)methanesulfonamide 30 The compound was prepared from the compound of Example 1(b) using the procedure of Example 2. 'H NMR (400 MHz, DMSO-d 6 ): 6 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, WO 2014/162039 PCT/F12014/000003 46 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-iH-pyrazol-4-yl)-1H-benzo[d] 5 imidazol-1-yl)pyridin-2-yl)ethanesulfonamide The compound was prepared from the compound of Example 1(b) using the procedure of Example 2. 'H NMR (400 MHz, DMSO-d 6 ): 6 11.1 (s, 1H), 9.02 (s, 1H), &61 (d, 1H), 8.22 (s, 1H), 7.95,-7.94 (m, 2H), 7.89-7.83 (m, 1H); 7.74:(slH),:7.60-7.56 10 (m, 1H), 7.54-7.48 (in, 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]

4 (rt 1.5 min). Example 5 (imido). Sodium salt of imido form of N-(4-(2,4-difluorophenyl)-6-(5-(1-methyl-1H 15 pyrazol-49I)- IH-benzofd]iridazol-1 -yl)pyridin-2-yl)ethanesulfohaiide The compound (30 mg)was prepared using the procedure described in Example 17 (iido) starting fromnthetlile compound of Example 5. The desired compound was washed with diethylether and dried. H NMR (300 MHz, DMSO-d 6 ): 6 8.83 (s, 1H), 20 8.8-8.7 (d, 1H), 8.19 (s, 1H); 7.93 (s, 1H), 7.88 (s, 1H), 7.73-7.69 (mi 1H), 7.52-7.49 (dd, 1H),727721(, 1H) 6.94 (s, IH), 6.48 (s, 1H), 3.87 (s, 3H), 3.11-3.04 (q, 2H), 1.14-1.07 (t, 3H); LC-MS (ESI) Calculafed mass: 494.13; Observed mass: 495.1 [M4H] (rt: 1.42 min). 25 Example 6. N-(4-(2,4-difluorophenyl)-6-(5-(1-methyl- H-pyrazol-4-yl)-LH-benzo[d] imidazol- 1 -yl)pyridin-2-yl)propane-2-sulfonamide The compound was prepared from the compound of Example 1(b) using the 30 procedure of Example 2. H NMR (400 MHz, DMSO-d): 8 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 (i, 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).

WO 2014/162039 PCT/F12014/000003 47 Example 6 (imido). Imido form of N-(4-(2,4-difluorophenyl)-6-(5-(1-methyl-1H-pyrazol-4-yl)-1H benzo[dlimidazol-1-yl)pyridin-2-yl)propane-2-sulfonamide 5 A slurry of the crude residue of the compound of Example 6 (12 g) was stirred at 65 "C with THF (166 ml) and filtered in hot condition. The solid material was dried under vacuum to afford 3.5 g of the title compound. 1H NMR(400MHz, DMSO-d 6 ) 6 8.83 8.81 (m, 2H), 8.18 (s, 1H), 7.92 (s, 1H), 7.87 (s, 1H), 7.73-7.69 (m, 1H), 7.5-7.48 (d, 1H), 7.43-7.37 (dt, 1H), 7.25-7.21(dt, 1H), 6.93 (s, 1H), 6.49 (s, 111), 3.87 (s, 3H), 3.75 10 3.65 (sep, lH), 1.16-1. 14 (d, 6H), LC-MS (ESI): Calculated mass: 508.15 (free base); Observed mass: 508.8 [M+H]* (free base) (rt: 1.51 min). Example 7. N-(4-(2,4-difluorophenyl )6-(5-(1-methyl-iH-pyrazol-4-yl)-1H-benzo[d] 15 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. H NMR (400 MHz, DMSO-d 6 ): 6 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, 20 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, 311); 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-1H-pyrazol-4-yl)-1H-benzo[d]iiidazol-1 yl)pyridin-2-yl)cyclopropanesulfonamide 25 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 N 2 bubbling for 5 min. 2-Fluorophenylboronic acid 30 (0.67 g, 4.8 mmol, 1.2 eq) was added and the mixture was degassed for another 5 min. Pd(dppf)C1 2 (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 WO 2014/162039 PCT/F12014/000003 48 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). 5 b) 6-Chloro-4-(2-fluorophenyl)-N-(4-(1-methyl-1IH-pyrazol-4-yl)-2-nitrophenyl) pyridin-2-amine 10 A solution of the compound of Example 8(a) (0.97 g, 4 minol) in toluene (5 ml) was degassed by N 2 bubbling for 5 min.: The compound of Intermediate Example 1 (0.96 g, 4.4' nmol, 1.1 eq) was added and the mixture was degassed for another 5 min. Palladium acetate (36 rg, 0.1 mol, 0.04 eq) and BI3NAP (99 ig, 0.16 mmol, 0.04 eq) and potassium tert-butoxide (0.67 g, 6 mmol, 1.5 eq) were added sequentially 15 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 mii). 20 c) 1-(6-chloro-4-(2-fluorophenyl) pyridin-2-yl)-5-( 1-methyl-i H-pyrazol-4-yl) 1H-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 100C for .16 h.. The formic 25 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). 30 d) N-(4-(2-fluorophenyl)-6-(5-(1-methyl-iH-pyrazol-4-yl)-1H-benzo[d]imidazol 1-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 N 2 bubbling for 5 min. Cyclopropane sulfonamide (30 mg, 0.25 WO 2014/162039 PCT/F12014/000003 49 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 Cs 2

CO

3 (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 5 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, CD 3 0D): 6 8.91 (s, 1H), 8.62 (d, 1H), 8.05 (s, 1H), 7.91 (m; 2H), 7.73-7.67 (in, 3H), 7.58-7.52 (m, 1H), 7.41-7.33 (in, 2H), 7.21 (s, 1H), 3.97 (s, 3H), 3.17-3.15 (in, 1H), 130-1.26 (in, 2H), 1.06-1.04 (m, 2H); LC-MS (ESI): Calculated 10 mass! 488.14; Observed mass: 489.2 [M+H]* (rt: 1.46 min). Example 8 (imido). Sodium salt of imido form of N-(4-(2-fluorophenyl)-6-(5-(1-iethyl-Il-pyrazol 4-yl)-1H-beizo[d]imidazob 1 -yl)pyridin-2-yl)cyclopropanesulfonamide 15 The compound (mg) Wa prepared using the procedure described in Example 17 (imido) starting fromlthe title compound of Example 8. 'H NMR (300 MHz, DMSO d 6 ): 6 8.82 (s, 1i), 8.79-8.76 (d, 1H), 8.18 (s, 1H), 7.91 (s, 1H), 7.87 (d, 1H), 7.67-7.62 (ni, 1H), 7.52-7.42 (m, 2H), 7.37-7.31 (m, 2H), 6.93 (s, 1H), 6.53 (s, 1H), 3.86 (s, 3H), 2.89 (i, 1H), 0.82-0.79 (m, 2H), 0.61-0.57 (in, 2H); LC-MS (ESI): Calculated mass: 20 488.14; Observed mass: 489.4 [M+H] (rt: 1.49 min). Example 9. N-(4-(2-fluorophenyl)-6-(5-( 1-methyl-iH-pyrazol-4-yl)-lH-benzo[d]imidazol-1 yl)pyridin-2-yl)adetamide 25 The compound was prepared from the compound of Example 8(c) using the procedure of Example 8. 'H NMR (300 MHz, CD 3 0D): 6 8.88 (s, 1H), 8.37-8.35 (m, 2H),:8.01 (s, 1H), 7.87 (m, 2H), 7.697.61 (m, 3H), 7.59-7.49 (in, 1H), 7.36-7.34 (m, 2H), 3.95 (s, 3H), 2.26 (11, 3H); LC-MS (ESI): Calculated mass: 426.16; Observed 30 mass: 427.25 [M+H]* (rt: 1.4 min). Example 10. N-(4-(2-fluorophenyl)-6-(5-(1-methyl-iH-pyrazol-4-yi)-1H-benzo[d]imidazol-1 yl)pyridin-2-yl)methanesulfonamide WO 2014/162039 PCT/F12014/000003 50 The compound was prepared from the compound of Example 8(c) using the procedure of Example 8. 'H NMR (300 MHz, DMSO-d 6 ): 8 11.2 (s, 1H), 9.02 (s, 114), 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 5 (s, 11), 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-(1-methyl-iH-pyrazol-4-yl)-1H-benzo[d]imidazol-1 yl)pyridin-2-yl)ethanesulfonamide 10 The compound was prepared from the compound of Example 8(c) using the procedure of Example 8(d). 1H NMR (400 MHz, DMSO-d 6 ): 8 11.1 (s, 1H), 9.03 (s, 1IH), 8.61 (d, 1H), 8.22 (s, 1H), 7.95-7.94 (in, 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 15 MS (ESI): Calculated mass: 476.14; Observed mass: 477.0 [M+H]* (rt: 1.41 min). Example 11 (imido). Sodium salt of imido form of N-(4-(2-fluorophenyl)-6-(5-(1-methyl-1H-pyrazol 4-yl)-1H-benzo[d]imidazol- 1-yl)pyridin-2-yl)ethanesulfonamide 20 The compound (34 mg) was prepared using the procedure described in Example 17 (imido) starting from the title compound of Example 11. The desired compound was washed with diethyl ether and-dried. 1H NMR (400 MHz, DMSO-d 6 ): 6 8.83 (s, 1H), 8.8-8.78 (d, 1H), 8.2 (s, 1H), 7.93 (s, 114), 7.89-7.88 (d, 1H), 7.68-7.65 (dt, 1H), 7.52 7.46 (m, 114), 7.38-7.33 (m, 2H), 6.96 (s, 1H), 6.51 (s, 1H), 3.22 (s, 3H), 3.11-3.06 (q, 25 2H), 1.14-1.08 (t, 3H); LC-MS (ESI): Calculated mass: 476.14; Observed mass: 477.0 [M+H]* (rt: 1.41 min). Observed mass: 476.8 [M+H]* (rt: 1.37 min). Example 12. N-(4-(2-fluorophenyl)-6-(5-(1-methyl- 1 H-pyrazol-4-yl)- 1 H-benzo[d]imidazol- 1 30 yl)pyridin-2-yl)propane-2-sulfonamide The compound was prepared from the compound of Example 8(c) using the procedure of Example 8. 1H NMR (300 MHz, DMSO-d 6 ): 6 11.03 (s, 1H), 9.03 (s, 1H), WO 2014/162039 PCT/F12014/000003 51 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 12 (imido). 5 Sodium salt of imido form of N-(4-(2-fluorophenyl)-6-(5-(1-methyl-1H-pyrazol 4-yl)-lH-benzo[d]imidazol-1-yl)pyridin-2-yl)propane-2-sulfonamide The title compound (24 mg) was prepared using the procedure described in Example 17 (imido) starting from the title compound of Example 12:'H NMR (400 MHz, DMSO 10 d 6 ): 6 8.83-8.81 (m, 21i), 8.19 (s, 1H), 7.92 (s, 1H), 7.87 (d, 11-1), 7.67-7.63 (dt, 1H), 7.51-7.46 (in, 2H), 7.37-7.32 (m, 2H), 6.94 (s, 1H), 6.51 (s, 1H); 3.87 (s, 3H), 3.75-3.65 (m, 1H) 1.16-1.14 (d, 614); LC-MS (ESI): Calculated mass: 490.16; Observed mass: 491.4 [M+HIf (rt: 1.5 min). 15 Example 13. N-(4-(2 fluorophenyl)-6-(5( 1-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 8(c) using the 20 procedure of Example 8. 'H NMR (400 MHz, DMSO-d 6 ): 8 10.49 (s, 1H), 9.01 (s,. 1H), 8.85-8.83 (in, -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 (in, 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. 25 N-(4-(4-fluorophenyl)-6-(5-(1-methyl-1-pyrazol-4-yl)-1H-benzo[d]imidazol-1 yl)pyridin-2-yl)cyclopropanesulfonamide a) 2,6-Dichloro-4-(4-fluorophenyl)pyridine 30 A solution of 2,6-dichloro-4-iodopyridine (2.18 g, 8 mmol) in 1 ,2-dimethoxy ethane (15 ml) was degassed by N 2 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)C1 2 (1.3 g, 1.6 mimol, 0.2,eq) and aqueous sodium carbonate (2.54 g, 24 mmol, WO 2014/162039 PCT/F12014/000003 52 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 5 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 10 A solution of the compound of Example 14(a) (0.97 g, 4 nmmol) in toluene (5 ml) was degassed by N 2 bubbling for min. The compound of Intermediate Example I (0.96 g, 4.4 mmol, 1. 1 eq) was added and the mixture was degassed for another 5 min. 15 Palladium acetate (36 mg, 0.16 immol, 0.04 eq) and BINAP (99 mg, 0.16 mmol, 0.04 eq) and potassium tert-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). 20 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 25 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). 30 d) 1-(6-chloro-4-(4-fluorophenyl) pyridin-2-yl)-5-(1-methyl-iH-pyrazol-4-yl) 1 H-benzo[d]imidazole WO 2014/162039 PCT/F12014/000003 53 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; 5 Observed mass: 404.2 [M+H] + (rt: 1.68 min). e) N-(4-(4-fluorophenyl)-6-(5-(1-methyl-IH-pyrazol-4-yl)-1H-benzo[d]imidazol 1-yl)pyridin-2-yl)cyclopropanesulfonamide 10 A solution the compound of Example 14(d) (40 mg, 01 mmol) in dioxane (1 ml) was degassed by N 2 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 Cs 2

CO

3 (0.1 g, 0.3 mmol, 3.0 eq) were added and the mixture was further degassed for 5 min and then 15 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). 'H NMR (400 MHz, CD 3 0D): 8 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, 20 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-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1 yl)pyridin-2-yl)acetamide 25 The compound was prepared from the compound of Example 14(d) using the procedure of Example 14. 'H NMR (400 MHz, DMSO-d 6 ): 6 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 30 [M+H]* (rt: 1.47 min). Example 16. N-(4-(4-fluorophenyl)-6-(5-(1-methyl-iH-pyrazol-4-yl)-1H-benzo[d]imidazol-1 yl)pyridin-2-yl)methanesulfonamide WO 2014/162039 PCT/F12014/000003 54 The compound was prepared from the compound of Example 14(d) using the procedure of Example 14. 1H NMR (400 MHz, DMSO-d 6 ): 8 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 5 (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-iH-pyrazol-4-yl)-IH-benzo[d]imidazol-1 yl)pyridin-2-yl)propane-2-sulfonamide 10 The compound Was prepared from the compound of Example 14(d) using the procedure of Example 14(e).-'H NMR (300 MHz, DMSO-dQ): 8 11.0 (s, 1H), 9.13 (s, 1H),8168 (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): 15 Calculated mass: 490.16; Observed mass: 491.05 [M+H]* (rt: 1.58 min). Example 17 (imido). Sodium salt of imido form of N-(4-(4-fluorophenyl)-6-(5-(1-methyl-iH-pyrazol 4-yl)-1H- benzo[d]imidazol-1-yl)pyridin-2-yl)propane-2-sulfonamide 20 To the compound of Example 17 (37 mg) isopropyl alcohol (1 ml) and sodium tert butoxide (7 mg) were added and after refluxing overnight the mixture was evaporated to yield 32 mg of the title compound. 'H NMR (300 MHz, DMSO-d 6 ): 6 8.9 (s, 1H), 8.87 8.84 (d, 1H), 7.9 (s, 1H), 7.85-7.8 (m, 3H), 7.49-7.46 (d, 1H), 7.35-7.29 (t, 2H), 7.08 (s, 1H), 6.6 (s, 1H), 3.86;(s, 3H), 3.73-3.69 (m, 1H), 1.15-1.31 (d, 611): Calculated mass: 25 490.16; Observed inass: 491.45 [M+H]* (rt: 1.52m)in. Example 18. N-(3-fluoro-6'-(5-(1-methyl-iH-pyrazol-4-yl)-1 H-ben zo[djimidazol 1-yl) [2,4' bipyridin]-2'-yl)cyclopropanesulfonamide 30 a) 2,6-Dichloro-4-(4,45 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine WO 2014/162039 PCT/F12014/000003 55 A solution of 2,6-dichloro-4-iodopyridine (15 g, 54.9 mmol) in DMF (150 ml) was degassed by N 2 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)C1 2 (2.24 g, 2.7 mmol, 0.05 eq) and potassium acetate (8.07 g, 82.4 mmol, 1.5 eq) were added 5 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, CDCl 3 ): 6 10 7.59 (s, 2H), 1.35 (s, 61-1), 1.26 (s, 6H). b) 2!',6Dichloro-3fluor&2,4 bipyridine A solution of 2-bromo-3-fluoropyridine (3 g, 17 mmol) in 1,2-dimethoxyethane 15 (30 mL) was degassed by N 2 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)Cl 2 (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 20 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, CDCl 3 ): 8 7.61-7.55 (m, 2H), 7.42-7.31 (m, 3H). 25 c) 6'-chloro-3-fluoro-N-(4-(1-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 30 ml) was degassed by N 2 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 WO 2014/162039 PCT/F12014/000003 56 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). 5 d) N1-(6'-chloro-3-fluoro-[2,4'-bipyridin]-2'-yl)-4-(1-methyl-iH-pyrazol-4-y1) 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 10 nil) 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: 394A 1; Observed mass: 395.0 [M+H] t (rt: 1.34 min). 15 e) 1-(6'-chloro-3-fluoro-[2,4'-bipyridin]-2'-yl)-5-(1-methyl-iH-pyrazol-4-yl)-1H benzo[d]imidazole A solution of the compoundof Example 18(d) (0.4 g, I mmol) and formic acid (5 ml) was heated at 110 "C for 12 h. The formic acid was distilled off and the crude was 20 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, CD 3 0D): 6 8.95 (s, 1H), 8.64 (m, 1H), 8.38 (s, 1H),8.29-8.27 (m, 211), 8.03-8.02 (m, 2H), 7.92-7.81 (m, 2H), 7.69-7.64 (m, 2H), 3.95 (s, 3H). 25 f) N-(3-fluoro-6'-(5-(i-methyl-iH-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl) [2,4'-bipyridinl-2'-yl)cyclopropanesulfonamide A solution of the compound of Example 18(e) (40 mg, 0.1 mmol) in dioxane (1 ml) was degassed by N 2 bubbling for 5 min. Cyclopropane sulfonamide (12 mg, 0.1 30 mmol, 1 eq) was added and the mixture was degassed for another 5 min. Pd 2 (dba) 3 (9 mg, 0.01 mmol, 0.1 eq) and xantphos (6 mg, 0.01 mmol, 0.1 eq) and Cs 2

CO

3 (80 mg, 0.25 mmol, 2.5 eq) were added and the mixture was further degassed for 5 min and then heated at1 10 "C for 16 h. The mixture was filtered through elite and extracted as in WO 2014/162039 PCT/F12014/000003 57 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 CHCl 3 ) to afford the title product in 50 % yield (15 mg). 'H NMR (300 MHz, DMSO-d 6 ): 8 11.22 (s, 1H), 9.0 (s, 111), 8.69-8.63 (m, 2H), 8.24 (s, 11), 8.04-7.98 (m, 4H), 7.71-7.6 (m, 2H), 7.49 5 (s, 1H), 3.88 (s, 3H), 3.17-3.15 (m, 1H), 1.13-1.12 (m, 211), 1.05-1.02 (m, 2FH); LC-MS (ESI): Calculated mass: 489.14; Observed mass: 490.01 [M+H]* (rt: 0.57 min). Example 19. N-(3-fluoro-6'-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[2,4' bipyridin]-2'-yl)acetamide 10 The compound was prepared from the compound of Example 18(e) using the Procedure of Example 18. 1H NMR (300 MHz, DMSO-d 6 ): 6 11.1 (s, 1H), 9.34 (s, 111), 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): 15 Calculated mass: 427.16; Observed mass: 428.3 [M+H]* (rt: 0.7 min). Example 20. N-(3-flioro-6'-(6-(1-methyl-iH-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl) [2,4'-bipyridin]-2'-yl)cyclopropanesulfonamide 20 a) 6'-Chloro-3-fluoro-N-(5-(1-methyl-iH-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 25 (12 ml) was degassed by N 2 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. Pd 2 (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 immol, 2.5 eq) were added sequentially following the procedure of Example 1(a). The crude residue of the product was purified 30 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).

WO 2014/162039 PCT/F12014/000003 58 b) N2-(6'-chloro-3-fluoro-[2,4'-bipyridin]-2'-yl)-5-(1-methyl-iH-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 5 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). 10 c) 3-(6'-Chloro-3-fluoro- [2,4'-bipyridin]-2'-yl)-6-(1-methyl-iH-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 15 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-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl) [2,4'-bipyridin]-2'-yl)cyclopropanesulfonamide 20 A solution of the compound of Example 20(c) (40 mg, 0.1 mmol) in dioxane (1 ml) was degassed by N 2 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. Pd 2 (dba) 3 (9 mg, 0.01 mmol, 0.1 eq) and xantphos (6 mg, 0.01 mmol, 0.1 eq) and Cs 2

CO

3 (80 mg, 25 0.25 mmol, 2.5 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 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 CHCl 3 ) to afford the title product in 8 % yield (5 mg). 1H NMR (300 MHz, CDCl 3 ): 6 9.24 (s, 1H), 9.16 (s, 30 111), 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).

WO 2014/162039 PCT/F12014/000003 59 Example 21. N-(4-(2,4-difluorophenyl)-6-(5-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl) 1H-benzo[d]imidazol- 1-yl)pyridin-2-yl)cyclopropanesulfonamide 5 a) 6-Chloro-4-(2,4-difluorophenyl)-N-(4-(1-(2-(dimethylanino)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 10 dioxane (15 ml) was degassed by N 2 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 15 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 CI 2 Cl 2 ) 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 muin). 20 b) N1-(6-chloro-4-(2,4-difluorophenyl)pyridin-2-yl)-4-(1-(2-(dimethylamino) ethyl)- 1 H-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 25 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). 30 c) 2-(4-(I-(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 WO 2014/162039 PCT/F12014/000003 60 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). 5 d) N-(4-(2,4-difluorophenyl)-6-(5-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl) 1H-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 N 2 bubbling for 5 min. Cyclopropane sulfonamide (29 mg, 0.24 10 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 Cs 2

CO

3 (162 mg, 0.5 mmol, 2.5 eq) were added and the mixture was further degassed for 5 min and then heated at1 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 15 by column chromatography (60-120 silica gel, 10 % methanol in CH 2 Cl 2 ) to afford the desired title product in 35 % yield (20 mg). 'H NMR (400 MHz, CDCl 3 ): S 8.7 (s, H), 8.04 (m, 2H), 7.82 (d, 2H), 7.56 (m, 2H), 7.41 (in, 2H), 7.07-7.02 (m, 211), 4.29 (m, 2H), 2.8912.84 (m, 311), 2.33 (s, 6H), 1.39 (in, 2H), 1.08'(m, 2H); LCMS (ESI) Calculated mass: 563.19; Observed mass: 564.25 [M+H]* (rt: 0.59 min). 20 Example 22. N(4-(2-fluorophenyl)-6-(5-( 1-methyl-iH-pyrazol-4-yl)-1H-benzo[d]iidazol 1 yl)pyrihidin-2-yl)cyclopropanesulfonamide a) -Chloro(2-fluorophenyl)pyrimidin-2-amine 25 A solution of 4,.6dichloropyrimidin-2-amine (5 g, 30.6 mmol) in 1,2-di methoxyethane (50 ml) was degassed by N 2 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)Cl 2 (1.25 g, 1.53r mmol, 0.05 eq) and aqueous sodium carbonate (8.12 g, 30 76.6 mnol, 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 % WO 2014/162039 PCT/F12014/000003 61 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 5 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 10 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). 15 c) N-(4-(2-fluorophenyl)-6-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol 1-yl)pyrimidin-2-yl)cyclopropanesulfonamide To an icecold solution of the compound of Example 22(b) (0.2 g, 0.61 mmol) in 20 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 25 crude product mixture from which the title compound was isolated by preparative TLC in 0.0 1% yield (3 mg). 'H NMR (400 MHz, CDCl 3 ): 6 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+HJ] (rt: 1.43 min). 30 Example 23. N-(6-(5-(1H-pyrazol-il-yl)-1H-benzo[d]imidazol-1-yl)-4-(2,4-difluorophenyl) pyridin-2-yl)cyclopropanesulfonamide WO 2014/162039 PCT/F12014/000003 62 A solution of the title compound of Intermediate Example 5 (50 mg, 0.144 mmol) in dioxane (5 ml) was degassed by N 2 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. CuI (1.3 mg, 0.0072 mmol, 0.05 eq), N,N-dimethyl glycine 5 (1.4 mg, 0.0144 mmol, 0.1 eq) and Cs 2

CO

3 (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 (10 mg). I NMR (400 MHz, DMSO-d 6 ): 8 11.2 (s, 1H), 9.18 (d, 1H), 8.86 (d, 1H), 8.66 (d, 1H), 8.23 (d, 1H),7.96-7.86 (m, 211), 7.83-7.78 (m, 2H), 7.59-7.51 (m,1H), 7.39 7.34 (m, 1H), 7.16 (s, 1I), 6.59 (s, 1H), 3.19-3.14 (m, 1H), 1.24-1.12 (m, 211), 1.06-1.03 (m, 2H); LC-MS (ESI): Calculated mass: 492.12; Observed mass: 493.4 [M+H] (rt: 1.71 min). 15 Example 24. N-(4-(2,4-difluorophenyl)-6-(6-(1-methyl-i H-pyrazol-4-yl)-3H-imidazo [4,5 b]pyridin-3-yl)pyridin-2-yl)cyclopropanesulfonamide a) 6-Chloro-4-(2,4-difluorophenyl)-N-(5-(1-methyl-iH-pyrazol-4-yl)-3 20 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 N 2 bubbling for 5 min. The compound of Intermediate Example 25 7 (0.42 g, 1.92 mmol, 1 eq) was added and the mixture was degassed for another 5 min. Pd 2 '(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 30 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).

WO 2014/162039 PCT/F12014/000003 63 b) N2-(6-chloro-4-(2,4-difluorophenyl)pyridin-2-yl)-5-(1-methyl-iH-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 5 (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). 10 c) 3-(6-Chloro-4-(2,4-difluorophenyl)pyridin-2-yl)-6-(1-methyl-iH-pyrazol-4 yl)-3H-imidazo[4,5-blpyridine 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 15 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-(1-methyl-iH-pyrazol-4-yl)-3H-imidazo[4,5 20 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 N 2 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 25 mg, 0.017 mmol, 0.05 eq) and xantphos (20 mg, 0.03 mmol, 0.1 eq) and Cs 2

CO

3 (288 mg, 0.88 mmol, 2.5 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 (60-120 silica gel, 3 % methanol in CH 2 Cl 2 ) to 30 afford the title product in 27 % yield (48 mg). 1H NMR (300 MHz, DMSO-d 6 ): S 11.07 (s, 1H), 9.09 (s, 1H), 8.80 (d, 1H), 8.49-8.45 (in, 2H), 8.30 (s, 1H), 8.05 (d, 1H), 7.8 1 7.73 (m, 1H), 7.57-7.49 (m, 1H),7.38-7.32 (in, 1H), 7.1l(s, 1H), 3.89 (s, 3H), 3.41-3.37 WO 2014/162039 PCT/F12014/000003 64 (I, 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-(1-methyl-iH-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl) 5 [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 10 methoxyethane (30i ml) was degassed by N 2 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)C 2 (0.47 g, 0.58 mmol, 0.1 eq) and aqueous sodium carbonate (1.85 g,,17.5 nimol, 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 15 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-(1-methyl-iH-pyrazol-4-yl)-2-nitrophenyi)-[2,4' 20 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 N 2 bubbling for 5 min. The compound of Intermediate Example 1 25 (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 tert-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 30 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).

WO 2014/162039 PCT/F12014/000003 65 c) N1-(6'-chloro-3,5-difluoro-[2,4'-bipyridin]-2'-yl)-4-(1-methyl-iH-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 5 (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). 10 d) 1-(6'-Chloro-3,5-difluoro-[2,4'-bipyridin]-2'-yl)-5-(1-methyl-iH-pyrazol-4-yl) 1H-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 15 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-iH-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl) 20 [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 N 2 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 25 (4.2 mg, 0.019 mmol, 0.1 eq) and xantphos (22 mg, 0.04 mmol, 0.2 eq) and Cs 2

CO

3 (185 mg, 0.57 mmol, 3 eq) were added and the mixture was further degassed for 5 min and then heated at 110 .9C 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). 'H NMR 30 (300 MHz, DMSO-dd): & 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 (in, 1H), 7.47 (s, 1H), 3.88 (s, 3H), 3.12 (in, 1H), 1.14-1.12 (in, 2H), 1.04-1.02 (m, 2H); LC-MS (ESI): Calculated mass: 507.13; Observed mass: 508.1 [M+H]* (rt: 1.27 min).

WO 2014/162039 PCT/F12014/000003 66 Example 26. N-(3,5-difluoro-6'-(5-(1-methyl-iH-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl) [2,4'-bipyridin]-2'-yl)acetamide 5 The compound was prepared from the compound of Example 25(d) using the procedure of Example 28. 'H NMR (400 MHz, DMSO-d 6 ): 6 10.85 (s, 1H), 9.0 (s, 1H), 8.76 (d, 111), 8.58 (s, 1H), 8.50 (d, 1H), 8.23-8.21 (m, 2H), 8.0 (s, 1H), 7.95 (m, 211), 7.62-7.59 (m, 111), 3.88 (s, 3H), 2.21 (s, 3H); LC-MS (ESI): Calculated mass: 445.15; Observed mass:A446.1 [M+H]* (rt: 1.08 min). 10 Example'27. N-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-4-(1H-pyrrol-1 yl)pyridin-2-yl)acetamide a) 2,6-Dichloro-4-(1H-pyrrol-1 -yl)pyridine 15 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 20 was distilled .off to afford the title product in 80 % yield (2.1 g). b) 6-Chloro-N-(4-( 1-methyl-iH-pyrazol-4-yl)-2-nitrophenyl)-4-(1H-pyrrol-1-yl) pyridin-2-amine 25 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 30 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).

WO 2014/162039 PCT/F12014/000003 67 c) N1-(6-chloro-4-(1H-pyrrol-1-yl)pyridin-2-yl)-4-(1-methyl-iH-pyrazol-4 yl)benzene-1,2-diamine 5 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): 10 Calculated mass: 364.12; Observed mass: 365.0 [M+HJ* (rt: 1.47 min). d) 1-(6-Chloro-4-(1H-pyrrol-1-yl)pyridin-2-yl)-5-(1-methyl-iH-pyrazol-4-yl) 1H-benzo[d]imidazole 15 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). 20 e) N-(6-(5-(i-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-4-(1H-pyrrol 1-yl)pyridin-2-yl)acetamide A solution of the compound of Example 27(d) (100 mg, 0.27 mmol) in dioxane 25 (5 ml) was degassed by N 2 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 Cs 2

CO

3 (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 30 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). 'H NMR (400 MHz, DMSO-d 6 ): 6 10.79 (s, 1H), 9.13 (s, 1H), 8.63 (d, IH), 8.21 (s, 2H), 7.95-7.93 (m, 2H), WO 2014/162039 PCT/F12014/000003 68 7.84 (d, 1H), 7.60-7.57 (m, 314), 6.41-6.40 (m, 2H), 3.88 (s, 3H), 2.21 (s, 311); 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-i H-pyrazol-4-yl)- 1H-benzo[d]imidazol- 1 5 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 10 ethane (15 ml) was degassed by N 2 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)C1 2 (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 15 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, CDCl 3 ): 6 7.53-7.49 (m, 114), 7.41-7.35 (m, 3H), 7.32-7.29 (m, 1H), 7.26 (m, 1H). 20 b) 6-Chloro-4-(2-chlorophenyl)-N-(4-(1-methyl-iH-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 25 ml) was degassed by N 2 bubbling for 5 min. The compound of Intermediate Example 1 (0.6 g, 2.7 mmol, I 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 30 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).

WO 2014/162039 PCT/F12014/000003 69 c) 1-(6-Chloro-4-(2-chlorophenyl)pyridin-2-yl)-5-(1-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 5 (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). 10 d) N-(4-(2-chlorophenyl)-6-(5-(1-methyl-iH-pyrazol-4-yl)-1H-benzo[d] imidazoi- 1 -yl)pyridin-2-yl)cyclopropanesulfonamide A solution of the compound of Example 28(c) (200 mg, 0.47 mmol) in dioxane 15 (5 ml) was degassed by N 2 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 Cs 2

CO

3 (450 mg, 1.41 mmol;,3 eq) were added and the mixture was further degassed for 5 min and then heated at 1.10 "C for 12 h. The mixture was filtered through celite and extracted as 20 in Example 1. The solvent was distilled off to afford the crude residue which was purified by column chromatography (2 % methanol in CHC1 3 ) to afford the title product in 15 % yield (30 mg). 'H NMR (400 MHz, DMSO-d 6 ): 8 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 (in, 2H), 6.98 (s, 1I), 3.87 (s, 3H), 3.16 (m, 1H), 1.12-1.11 (m, 2H), 1.04 25 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-i H-pyrazol-4-yl)-1H-benzo[d]inidazol-l-yl)-[2,4' bipyridin]-2'-yl)cyclopropanesulfonamide 30 a) 2',3,6'-Trichloro-2,4'-bipyridine WO 2014/162039 PCT/F12014/000003 70 A solution of (2,6-dichloropyridin-4-yl)boronic acid (0.76 g, 4 mmol) in 1,2 dimethoxyethane (15 ml) was degassed by N 2 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)C 2 (0.3 g, 0.36 mmol, 0.1 eq) and aqueous sodium carbonate (1.15 g, 5 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). 'H NMR (300 MHz, 10 CDCl 3 ): 6 8.63 (dd; 1H)", 7.86 (m, 1H), 7.68 (s, 2H), 7.37 (dd, 1H). b) 3,6'-Dichloro-N-(4-(1-methyl-iH-pyrazol-4-yl)-2-nitrophenyl)-[2,4'-bi pyridin]-2'-amine 15 A solution of the compound of Example 29(a) (0.69 g, 3.17 mmol) in toluene (10 ml) was degassed by N 2 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(5 mg, 0. 115 mmol, 0.04 eq) and BINAP (71 mg, 0.115 mmol, 0.04 20 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, CDC 3 ): 6 10.25 (s, 1H), 8.77 (d, 1H), 8.65-8.63 (m, 1H), 25 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, 1IH), 3.97 (s, 3H). c) 1-(3,6'-Dichloro-[2,4'-bipyridin]-2'-yl)-5-(1-methyl-iH-pyrazol-4-yl)-1H benzo[d]imidazole 30 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 WO 2014/162039 PCT/F12014/000003 71 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). 5 d) N-(3-chloro-6'-(5-(1-methyl-iH-pyrazol-4-yl)-1H-benzo[dljimidazol-1-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 N 2 bubbling for 5 min. Cyclopropanesulfonamide (34 mg, 0.28 10 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 Cs 2

CO

3 (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 15 purified by column chromatography (2 % methanol in CHCl 3 ) to afford the title product in 15 % yield (17 mg). H NMR (300 MHz, DMSO-d 6 ): 6 11.22 (s, 1H), 8.98 (s, 111), 8.74-8.67 (m, 211), 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 (n, 2H), 1.06 1.02 (m, 2H); LC-MS (ESI): Calculated mass: 505.11; Observed mass: 506.00 [M+H]+ 20 (rt: 1.52 min). Example 30. N-(5-fluoro-6'-(5-(1-methyl-iH-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[2,4' bipyridin]-2'-yl)cyclopropanesulfonamide 25 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 N 2 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(PPh 3

)

4 30 (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 WO 2014/162039 PCT/F12014/000003 72 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-(1-methyl-iH-pyrazol-4-yl)-2-nitrophenyl)-[2,4' 5 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 N 2 bubbling for 5 min. The compound of Intermediate Example 1 10 (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 tert-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 % 15 ethyl acetate in hexane) to afford the title product in 29 % yield (0.1 g). c) Ni (5-fh ro {2,4'-bip idin]-2'-yl)-4-(1-methyl-iH-pyrazol-4 yl)benzene 1 ,2-di amine 20 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 25 (ESI): Calculated mass: 394.11; Observed mass: 395.1 [M+H]* (rt: 1.42 min). d) 1-(6'-Chloro-5-fluoro-[2,4'-bipyridin]-2'-yl)-5-(1-methyl-iH-pyrazol-4-yl)-1H benzo[d]imidazole 30 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).

WO 2014/162039 PCT/F12014/000003 73 e) N-(5-fluoro-6'-(5-(1-methyl-iH-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl) [2,4'-bipyridin]-2'-yl)cyclopropanesulfonamide 5 A solution of the compound of Example 30(d) (50 mg, 0.123 mmol) in dioxane (5 ml) was degassed by N 2 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 Cs 2

CO

3 (120 mg, 0.37 mmol, 3 eq) were added and the mixture was further degassed for 5 min 10 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-dQ): 8 11.16 (s, IH), 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 15 1H), 7.62-7.59 (m, 1H), 3.89 (s, 3H), 3.16-3.12 (in, IH), 1.13-1.10 (m, 211), 1.03-1.0 (m, 2H); LC-MS (hSI): Calculated mass: 489.14; Observed mass: 490 .4 [M+H]+ (rt: 1.23 min). Example 3. N-(5-fluoro-6'-(5 -(1-methyl-1H-pyrazol-4-yl)-1H-benzo[djimidazol- 1-yl)-[2,4' 20 bipyridin]-2'-yl)acetamide The compound was prepared from the compound of Example 30(d). 1H NMR (400 MHz, DMSO-d 6 ): 6 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 (n, 1H), 7.96 (s, 2H), 7.62-7.59 (m, 25 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-(52(1H-imidazol-1-yl)-1H-benzo[d]imidazol- 1 -yl)-4-(2,4-difluorophenyl) pyridin-2-yl)cyclopropanesulfonamide 30 a) N-(4-(1H-imidazol-1-yl)-2-nitrophenyl)-6-chloro-4-(2,4-difluorophenyl) pyridin-2-amine WO 2014/162039 PCT/F12014/000003 74 A solution of the compound of Intermediate Example 5(a) (0.6 g, 2.94 mmol) in toluene (5 ml) was degassed by N 2 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 5 another 5 min. Palladium acetate (32 mg, 0.147 mmol, 0.05 eq) and BINAP (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 10 chromatography (60-120 silica gel, 50 % ethyl acetate in hexane) to afford the title product in 12 % yield (150 mg). b) N1 (6-chlor6-4-(2,4-difliorophenyl)pyridin-2-yl)-4-(1H imidazol-lyl) benzene-1,2-diamine 15 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. 20 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 25 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). 30 d) N-(6-(5-(1H-imidazol1-yl)-1H-benzo[d]imidazol-1-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 N 2 bubbling for 5 min. Cyclopropanesulfonamide (15 mg, 0.122 WO 2014/162039 PCT/F12014/000003 75 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 Cs 2

CO

3 (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 5 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). 1 H NMR (400 MHz, DMSO-d 6 ): 8 11.22 (s, 1H), 9.12 (s, 1H), 8.67 (d, 1H), 8.38 (s, 1H), 8.08 (d, 111), 7.91-7.85 (m, 2H), 7.79 (s, 111), 7.71-7.69 (m, 1H), 7.56-7.51 (m, 1H), 7.38-7.33 (m, 1H), 7.13 (s, 211), 3.16-3.11 (m, 1H), 1.12-1.08 (m, 2H), 1.03-1.01 (m, 2H); LC-MS 10 (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)- 1H-pyrazol-4-yl)-1H benzo[d]imidazol-1-yl)pyridin-2-yl)cyclopropanesulfonamide 15 a) 6-Chloro-4-(2,4-difluorophenyl)-N-(4-(1-(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 20 dioxane -(5 ml) was degassed by N 2 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 tert-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 25 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). 30 b) N1-(6-chloro-4-(2,4-difluorophenyl)pyridin-2-yl)-4-(1-(2-morpholinoethyl) 1H-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 WO 2014/162039 PCT/F12014/000003 76 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). 5 c) 4-(2-(4-(1-(6-Chloro-4-(2,4-difluorophenyl)pyridin-2-yl)-1H-benzo[dl imidazol-5-yl)-1H-pyrazol-1-yl)ethyl)morpholine A solution the compound of Example 33(b) (0.15 g, 0.29 mmol) and formic acid 10 (2 ml) was heated at 90 0 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). 15 d) N-(4-(2,4-difluorophenyl)-6-(5-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-iH benzo[djimidazol-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 N 2 bubbling for 5 min. Cyclopropanesulfonamide (17 mg, 0.144 20 mmol, 1 eq) was added and the mixture was degassed for another 5 min. Pd(OAc) 2 (2.5 img, 0.011 mmol, 0.08 eq) and xantphos (8.3 mg, 0.0 144 mmol, 0.1 eq) and Cs 2

CO

3 (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 25 purified by preparative TLC to afford the title product in 29 % yield (25 mg). 'H NMR (400 MHz, DMSO-d 6 ): 6 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 (in, 2H); LC 30 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-(1-(pyrrolidin-3-yl)- 1H-pyrazol-4-yl)- 1H benzo[d]imidazol- 1 -yl)pyridin-2-yl)cyclopropanesulfonamide WO 2014/162039 PCT/F12014/000003 77 a) tert-Butyl 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 5 A solution of the compound of Intermediate Example 5 (113mg, 0.347 mmol) in dioxane (5 ml) was degassed by N 2 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, 0.0 174 mmol, 0.05 eq), N,N-dimethyl glycine (1.7 mg, 0.0174 mmol, 0.05 eq) and Cs 2

CO

3 (282 mg, 0.87 mmol, 2.5 eq) were added and the 10 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 nig). LC-MS (ESI): Calculated mass: 661.23; Observed mass: 662.6 [M+HI* (rt: 1.71 min). 15 b) N-(4-(2,4-difluorophenyl)-6-(5-(1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)-1H benZo[d]imidazol- 1-y1)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 HCl in dioxane and stirred at RT for 1 h. The solvent 20 was distilled off and the residue was washed several times with diethyl ether to give the title product in 78 % yield (10 mg). 'H NMR (400 MHz, DMSO-d 6 ): 6 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, lH), 7.71-7.69 (m, 1H), 7.57-7.52 (m, 1H), 7.37-7.34 (m, lH), 7.14 (s, 111), 5.20-5.18 (m, 1H), 3.62-3.37 (m, 3H), 3.19-3.15 (m, 2H), 2.43 25 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-(1-ethyl-i H-1,2,3-triazol-4-yl)- 1H-benzo[d] 30 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 N 2 bubbling for 5 min. The compound of Intermediate WO 2014/162039 PCT/F12014/000003 78 Example 10 (30 mg, 0.14 mmol, 1 eq) was added and the mixture was degassed for another 5 min. CuI(2 mg, 0.014 mmol, 0.1 eq), N,N-dimethyl glycine (1 mg, 0.014 mmol, 0.1 eq) and Cs 2

CO

3 (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 5 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). 'H NMR (400 MHz, DMSO-d 6 ): 5 11.18 (s, 1H), 9.11 (s, 1H), 8.79 (d, 1H), 8.71 (s, 1H), 8.22 (s, 1H), 7.92-7.85 (in, 2H), 7.79 (s, 1H), 7.56-7.50 (in, 1H), 7.38-7.33 (in, 1H), 7.13 (s, 1H), 4.44 (quartet, 2H), 3.18-3.13 (m, 10 1H), 1.51 (t, 3H), 1.14-1.09 (i, 2H), 1.07-1.02 (in, 2H); LC-MS (ESI): Calculated nass: 521.14; Observed mass: 522.1 [M+H]* (rt: 1.52 min). Example 36. N-(4-(2,4-difluorophenyl)-6-(5-(1-methyl-1H-1i ,2,3-triazol-4-yl)- 1H-benzo[d] imidazol- 1 -yl)pyridin-2-y1)cyclopropanesulfonamide 15 a) N-(4-(2,4-difluorophenyl)-6-(5-ethynyl-1H-benzo[dlimidazol-1-yl)pyridin-2 yl)cyclopropanesulfonamide A solution of the compound of Intermediate Example 5 (0.17 g, 0.51 mmol, 1.1 20 eq) in dioxane (5 ml) was degassed by N 2 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 Cs 2

CO

3 (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 25 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). 30 b) N-(4-(2,4-difluorophenyl)-6-(5-(1-methyl-iH-1,2,3-triazol-4-yl)-1H-benzo[d] imidazol- 1 -yl)pyridin-2-yl)cyclopropanesulfonamide WO 2014/162039 PCT/F12014/000003 79 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 5 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 CHCl 3 ) to give the title product in 6.3 % yield (7 mg). 'H NMR (400 MHz, DMSO-d 6 ): 6 11.18 (s, 1H), 9.11 (s, 1H), 8.79 (d, 1H), 8.62 (s, 111), 8.21 (d, 1H), 7.90-7.85 (m, 2H), 7.79 (s, 1H), 7.56-7.50 (in, 1H), 7.39-.33 (i, 111), 7.l3(s, 1H), 4.12 (s, 3H), 3.34-3.13 (m, 10 1H), 1.16-1.12 (m, 2H), 1.06-094 (in, 2H); LC-MS (ESI): Calculated mass: 507.13; Observed masK: 508.1 [M+H} (rt: 1.52 min). Exmple 37. N-(4-(2,4-difluotOphenyl)-6-(5-(I-:methyl- H-imidazol-4-yl)-1H-benzo [d] imidazol- 1 -yl)pyridin-2-yl)cyclopropanesulfonamide 15 A solution of the compound of Intermediate Example 5 (34 mg, 0. 1 mmol) in DMF (5 ml) was degassed by N 2 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 20 mmol, 0.05 eq) and Cs 2

CO

3 (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 nig). H NMR (400 MHz, DMSO-d 6 ): 6 11.11 (s, 1H), 25 9.02 (s, 1H), 8.66 (d, 1H), 8.09 (d 1), 7.89-7.84 (m, 1H), 7.81-7.75 (in, 2H), 7.68-7.64 (in, 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 (in, IH), 1.15-1.12 (m, 2H), 1.06-1.02 (m, 2H); LC-MS (ESI): Calculated mass: 506.13; Observed mass: 507.35 [M+I4]1 (rt: 0. 18 min). Example 38. 30 N-(4-(2, 4-difluorophenyl)-6-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d] inidazol-1 -yl) pyrimidin 2-yl) acetainide a) N"(4, 6-dichloropyrimidin-2-yl) acetamide WO 2014/162039 PCT/F12014/000003 80 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 5 (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-(1-methyl-iH-pyrazol-4-yl) phenyl) amino)-6-chloro 10 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 15 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). 20 c) N-4-chloro-6-(5-(1-methyl-iH-pyrazol-4-yl)-1H-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 25 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). 30 d) N-(4-(2, 4-difluorophenyl)-6-(5-(1-methyl-iH-pyrazol-4-yl)-1H-benzo[d] imidazol-1-yl) pyrimidin-2-yl) acetamide WO 2014/162039 PCT/F12014/000003 81 A solution of the compound of Example 38(c) (0.08 g, 0.217 mmol) in dioxane (5 ml) was degassed by N 2 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(PPh 3

)

4 (0.025 g, 0.021mmol, 0.1 eq) and aqueous cesium carbonate (0.106 g, 5 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 10.4 % yield (10 mg). H NMR (400 MHz, DMSO- d 6 ): 8 11. 1 (s, 1H), 9.25 (s, 1H), 9.12 (d, 1H), 8.23 (s, 1H), 8.11-8.07 (in, 1H), 8.03 (s, 1H), 7.96 (d, 2H), 7.63 (d, 1H), 7.54 (t, 1H), 7.36 (t, 1H), 3.88 (s, 311), 2.27 (s, 3H); LC-MS (ESI): Calculated mass: 445.15; Observed mass: 445.9 [M+H]* (rt: 1.33 min). 15 Example 39. Ethyl 1-(1-(6'(cyclopropanesulfonamido)-4-(2,4-difluorophenyl)pyridin-2-yl) 1H-benzo[dlimidazol-5-yl)-1H-1,2,3-triazole-4-carboxylate A solution of the compound of Intermediate Example 5 (200 mg, 0.58 mmol) in 20 DMF (5:ml) was degassed by N 2 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 (11 mg, 0.05 mmol, 0.1 eq), N,N-dimethyl glycine (8 mg, 0.05 mmol, 0.1 eq) and Cs 2

CO

3 (570 mg, 1.74 mmol, 3 eq) were added and the mixture was further degassed for 5 min and then heated at 100 0 C for 24 h. The mixture was filtered 25 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-d 6 ): 6 11.11 (s, 1H), 9.59 (d, 1A), 9.26 (s, 1H), 8.95 (d, 111), 8.38 (s, 111), 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, 111), 4.38 (quartet, 2H), 3.17-3.13 (m, 30 111), 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.

WO 2014/162039 PCT/F12014/000003 82 N-(4-(2-(difluoromethoxy)-4-fluorophenyl)-6-(5-(1-methyl-i H-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 5 DMF (10 ml) was degassed by N 2 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 Cs 2

CO

3 (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 10 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). 'H NMR (400 MHz, CD 3 0D): 6 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), 15 7.15 (s, 111), 6.97 (s, 0.5 H), 6.79 (s, 0.5 H), 3.94 (s, 3H), 3.15-3.05 (m, 111), 1.28-1.15 (in, 211), 1.00-0.87 (m, 211); LC-MS (ESI): Calculated mass: 554.13; Observed mass: 555.5 [M+H]V (rt: 1.66 min). Example 41. N-(4-(2,4-difluorophenyl)-6-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d] 20 imidazol-l-l)pyrimidin-2-yl)cyclopropanesulfonamide a) 4-Chloro-6-(2,4-difluorophenyl)pyrimidin-2-amine 25 A solution of 4,6-dichloropyrimidin-2-amine (5 g, 30 mmol) in 1,2-dimethoxy ethane (50 ml) was degassed by N 2 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)Cl 2 (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 30 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).

WO 2014/162039 PCT/F12014/000003 83 b) 6-(2,4-Difluorophenyl)-N4-(4-(1-methyl-1H-pyrazol-4-yl)-2-nitrophenyl) pyrimidine-2,4-diamine 5 A solution of the compound of Example 41(a) (0.5 g, 2.1 mmol) in dioxane (5 ml) was degassed by N 2 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. Pd 2 dba 3 (0.19 g, 0.2 mmol, 0.1 eq) and xantphos (0.24 g, 0.4 mmol, 0.2 eq) and cesium 10 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 15 (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-iH-pyrazol-4-yl)phenyl)-6-(2,4-difluorophenyl) pyrimidine-2,4-diamine 20 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 25 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] 30 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, WO 2014/162039 PCT/F12014/000003 84 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-(1-methyl-iH-pyrazol-4-yl)-1H-benzo[d] 5 imidazol-1-yl)pyrimidin-2-yl)cyclopropanesulfonamide To an icecold solution of the compound of Example 4 1(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 nin and cyclopropylsulfonyl chloride (26 mg, 0.2 mmol, 2 eq) was added and the 10 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, CDCl 3 ): 6 8.73 (s, 1H), 8.39 (d, 1H), 8.36-8.27 (m, 15 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 mim). Example 42. 20 Ethyl 1-(1-(6-acetamido-4-(2,4-difluorophenyl)pyridin-2-yl)-1H-benzo[d] iniidazol-5yl)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'N 2 bubbling for 5 min. The compound of Intermediate 25 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 Cs 2

CO

3 (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 30 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-d 6 ): 6 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 WO 2014/162039 PCT/F12014/000003 85 (in, iH), 7.47-7.33 (in, 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). Example 43. N-(6-(2, 4-difluorophenyl)-4-(5-(1-methyl-iH-pyrazol-4-yl)-1H-benzo[d] 5 imidazol-1-yl) pyridin-2-yl) cyclopropanesulfonamide a) 4-(1-methyl-1H-pyrazol-4-yl)-2-nitroaniline A solution of 4-bromo-2-nitroaniline (6 g, 27.6 mmol) in 1, 2-dimethoxyethane 10 (15 ml) was degassed by N 2 bubbling for 5 min. 1-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)C 2 (2.25 g, 27.6 mmol, 0.1 eq) and aqueous sodium carbonate (8.79 g, 82.9i 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 mixture 15 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 yield the title product in 75 % yield (4.5 g). LC-MS (ESI): Calculated 'mass: 218.21; Observed 20 mass: 218.9 [M+H]+ (rt: 0.390 min). 1 H NMR (400 MHz, DMSO- dQ): 8 8.10-8.08 (in, 2H), 781 (s, 1H), 7.66-7.63 (m, LH), 7.44(s, 2H), 7.05-7.03(d, 1H), 3.84 (s, 3H). b) 2, 6-dichloro-N-(4-( 1-methyl-iH-pyrazol-4-yl)-2-nitrophenyl) pyridin-4 amine 25 A solution of 2,6-dichloro-4-iodopyridine (1 g, 3.66 minmol) in toluene (15 ml) was degassed by N 2 bubbling for 5 min. The compound of Example 43(a) (0.958 g, 4.39 mmol, 1.2 eq.) was added and the mixture was degassed for another 5 min. Palladium acetate (0.032 g, 0.146 mmol, 0.04 eq) and BINAP (0.091 g, 0.146 mmol, 0.04 eq.) and 30 potassium tert-butoxide (0.616 g, 5.49 mmol, 1.5 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 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 WO 2014/162039 PCT/F12014/000003 86 was distilled off under reduced pressure to afford the crude residue which was purified by column chromatography (60-120 silica gel, 25 % ethyl acetate in hexane) in 42.3 % yield (550 mg). LC-MS (ESI): Calculated mass: 363.04; Observed mass: 364.0 [M+H]* (rt: 1.578 min). 5 c) 1-(2, 6-dichloropyridin-4-yl)-5-(1-methyl-iH-pyrazol-4-yl)-1H-benzo[d] imidazole A solution of the compound of Example.43(b) (0.55 g, 1.51 nimol) in formic 10 acid: (10 ml) and iron (0.843 g, 15.1 mmol) was 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 under reduced pressure to afford the title compound in 77 % yield (0.4 g). LC-MS (ESI): Calculated mass: 343.04; Observed 15 mass: 344.05 [M+H] + (rt: 1.169 min). d) N-(6-chloro-4-(5-(1inethyl-iH-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl) pyridin-2-yl) Cycloprdpanesulfonamide 20 A solution of the compound of Example 43(c) (0.54 g, 1.56 mmol) in dioxane (15 ml) was degassed by N 2 bubbling for 5 min. Cyclopropane sulfonainide (0.189g, 1.56 mmol, 1 eq) was added and the mixture was degassed for another 5 min. Palladium acetate (0.028 g, 0.125 mmol, 0.08 eq) and xantphos (0.072 g, 0.125 mmol, 0.08 eq) and Cs 2

CO

3 (1.53 g, 4.7 mmol, 3.0 eq) were added and the mixture was further degassed 25 for 5 min and then heated at100 "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 under reduced pressure to afford the crude residue which was purified by column chromatography (60 120 silica gel, 3 % methanol in hexane) to yield the title product in 37 % yield (250 30 mg). LC-MS (ESi): Calculated mass: 428.08; Observed mass: 429.2 [M+H] + (rt: 0.854 min).

WO 2014/162039 PCT/F12014/000003 87 e) N-(6-(2, 4-difluorophenyl)-4-(5-(1-methyl-iH-pyrazol-4-yl)-1H-benzo[d] imidazol-1-yl) pyridin-2-yl) cyclopropanesulfonamide A solution of the compound of Example 43(d) (0.15 g, 0.350 mmol) in DME (4 5 ml) was degassed by N 2 bubbling for 5 min. 2,4-Difluorophenylboronic acid (0.06 g, 0.385 mmol, 1.1 eq) was added and the mixture was degassed for another 5 min. Pd(PPh 3

)

4 (0.039 g, 0.035mmol, 0.1 eq) and aqueous cesium carbonate (0.341 g, 1.051 mmol, 3 eq) were added sequentially and the mixture was further degassed for 5 min and then heated at 100 "C for 16 h. The reaction mixture was quenched with water and 10 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 under reduced pressure to afford the crude rsidue which was purified by preparative TLC to yield the title product in 11.2 % yield (20 mg). IH NMR (400 MHz, DMSO- dQ): 6 11.0 (s, 1H), 8.78 (s, 1H), 8.21 (s, 1H), 8.08-8.04 (m, 1H), 8.00 (s, 1H), 7.95 (s, 1H), 7.78-7.76 (d, 15 2H), 7.65-7.63 (d, 1H), 7.49-7.43 (m, 1H), 7.35-7.29 (in, 2H), 3.87 (s, 3H), 3.23 (m,1H), 1.13-1.06 (m,4H). LC-MS (ESI): Calculated mass: 506.13; Observed mass: 507.5 [M+H]* (rt: 1.583 min). 20 Abbieviations: RT - Room temperature rt - Retention time BINAP - 2,2'-bis(diphenylphosphino)- 1,1 '-binaphthyl DMF - NN-dimethylformamide 25 THF - Tetrahydrofuran TEA - Triethyl amine TLC - Thin layer chromatography DCM - Dichloromethane DME - Dimethoxyethane 30 DMSO - Dimethylsulfoxide EDC - 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride WO 2014/162039 PCT/F12014/000003 88 HATU - 2-(1 H-7-azabenzotriazol- l-yl)- 1,1,3,3-tetramethyl uronium hexafluoro phosphate methanaminium HOBt - Hydroxybenzotriazole DIPEA - NN-diisopropylethylamine 5 TBAF - tetra-n-butylammonium fluoride Pd(dppf)C1 2 - 1,1 '-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride Pd(PPh 3

)

4 -Tetrakis(triphenylphosphine)palladium(O) Pd 2 (dba) 3 - Tris(dibenzylideneacetone)dipalladium(O)

Claims (14)

1. 2.:A compound according to claim 1, wherein Z is CH. 15
2. 3. A compound according to claim 1 or 2, wherein Z 1 is N and Z 2 is CH.
3. 4. A compound according to to claim 1 or 2, wherein Z 1 is CH and Z 2 is N. 20 5. A compound according to to claim 1 or 2, wherein Z 1 and Z 2 is N.
4. 6. A compound according to any of claims 1 to 5, wherein ring A is any one of the following groups or tautomers thereof N N N N NN (') (2') () (') (6') N N. (7) (8') (9') (10') (1') (12') WO 2014/162039 PCT/F12014/000003 91 N NNNN (13') (14') (15') (16') (17') (18') (19') (20') (21') (22')
5. 7. A compound according to any of claims 1 to 6, wherein ring B is any one of the following groups or tautomers thereof 5 j -NX N C C N n 3") (4") (5") (6") (7") (8") (9") (10")
6. 8. A compound according to any of claims I to 7, wherein A is a ring of formula (1'), (2'), (3), (4'), (5'), (T), (14'), (16') or (20'); 10 RI is H, C 1 . 7 alkyl, C 1 . 7 alkoxy, hydroxy C 1 . 7 alkyl, C 1 -7 alkylamino C 1 . 7 alkyl or -E-R6; R2is H; Zis CH; B is a ring of formula (1''), (2''), (3''), (4") or (6'); 15 E is a bond or C 1 . 7 alkyl; R 6 is any of the following groups N N --- NO (a) (b) (c) (d) (e) R 3 is H, halogen, C 1 . 7 alkyl, C 1 7 alkoxy; WO 2014/162039 PCT/F12014/000003 92 R4 is H or halogen; R 5 is -C(O)R 7 or -S0 2 R 8 or any one of the following groups NI N N (a") (b") (c") (d") (e") (f") R 7 is C 1 . 7 alkyl, C 2 - 7 alkenyl or -NH-Rio; 5 R 8 is C 1 -7 alkyl, C 2 - 7 alkenyl, C 3 . 7 cycloalkyl, hydroxy C 1 . 7 alkyl or -NR 13 R 1 4 ; and RIO is C 1 . 7 alkyl or C 3 . 7 cycloalkyl.
7. 9. A compound according to any of claims 1 to 8, wherein B is a ring of formula (1"), (3'') or (6"). 10
8. 10. A compound according to any of claims 1 to 9, wherein A is a ring of formula (l'), (2'), (4'), (5') or (20").
9. 11. A compound according to any of claims 1 to 10, wherein R 5 is -S0 2 R 8 . 15
10. 12. A compound according to any of claims I to 11, wherein Z is CH, Z1 is N and Z 2 is CH, A is a ring of formula (1'), B is a ring of formula (1") R 1 is CI 7 alkyl, R 2 is H, R 3 is halogen, R 4 is H or halogen, R 5 is -S0 2 R 8 and R 8 is C 1 7 alkyl or C 3 - 7 cycloalkyl. 20
11. 13. A compound according to any of claims 1 to 12, which is 4-(2, 4-Difluorophenyl)-N-(1-methyl-1H-pyrazol-3-yl)-6-(5-(1-methyl-1H pyrazol-4-yl)-iH-benzo[d]imidazol-il-yl) pyridin-2-amine; N-(4-(2,4-difluorophenyl)-6-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d] 25 imidazol- 1 -yl)pyridin-2-yl)cyclopropanesulfonamide; Sodium salt of imido form of N-(4-(2,4-difluorophenyl)-6-(5-(i-methyl-IH pyrazol-4-yl)-1H-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; 30 N-(4-(2,4-difluorophenyl)-6-(5-(1-methyl- 1H-pyrazol-4-yl)-1H benzo [d] imidazol- 1 -yl)pyridin-2-yl)ethanesulfonamide; WO 2014/162039 PCT/F12014/000003 93 Sodium salt of imido form of N-(4-(2,4-difluorophenyl)-6-(5-(1-methyl-1H pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)pyridin-2-yl)ethanesulfonamide; N-(4-(2,4-difluorophenyl)-6-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d] imidazol- 1 -yl)pyridin-2-yl)propane-2-sulfonamide; 5 Imido form of N-(4-(2,4-difluorophenyl)-6-(5-(1-methyl-iH-pyrazol-4-yl)-1IH benzo[d]imidazol-1-yl)pyridin-2-yl)propane-2-sulfonamide; N-(4-(2-fluorophenyl)-6-(5-(1-methyl-iH-pyrazol-4-yl)-1H-benzo[d]imidazol-1 yl)pyridin-2-yl)cyclopropanesulfonamide; Sodium salt of imido form of N-(4-(2-fluorophenyl)-6-(5-(1-methyl-i H-pyrazol 10 4-yl)- IH-benzo[d]imidazolI- -yl)pyridin-2-yl)cyclopropanesulfonamide; N-(4-(2-fluorophenyl)-6-(5-(1-methyl-i H-pyrazol-4-yl)- 1H-benzo[d]imidazol- 1 yl)pyridin-2-yl)methanesulfonamide; N-(4-(2-fluotophenyl)-6-(5-( 1-nethyl- 1H-pyrazol-4-yl)- 1 H-benzo[dlimidazol- 1 y1)pyridin-2-yl)ethanesulfonamide; 15 Sodium salt of imido form of N-(4-(2-fluorophenyl)-6-(5-(1-methyl-1H-pyrazoi 4-yl)-1H-benzo[d]imidazol-1-yl)pyridin-2-yl)ethanesulfonamide; N-(4-(2-fluorophenyl)-6-(5-( 1-methyl- 1H-pyrazol-4-yl) 1H-benzo[dl]imidazol- 1 yl)pyridin-2-yl)propane-2-sulfonamide; Sodium salt of imido form of N-(4-(2-fluorophenyl)-6-(5-(1-methyl-1H-pyrazol 20 4-yl)- 1H-benzo[d]imidazol-l-yl)pyridin-2-yl)propane-2-sulfonamide; N-(4-(4-fluorophenyl)-6-(5 (1-methyl-1H-pyrazol-4-yl)-il-benzo[d]imidazol-1 yl)pyridin-2-yl)cyclopropanesulfonamide; N-(4-(4-fluorophenyl)-6-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1 yl)pyridin-2-yl)methanesulfonamide; 25 N-(4-(4-fluorophenyl)-6-(5-(1-methyl-iH-pyrazol-4-yl)-1H-benzo[d]imidazol-1 yl)pyridin-2-yl)propane-2-sulfonamide; Sodium salt of imido form of N-(4-(4-fluorophenyl)-6-(5-(1-methyl-iH-pyrazol 4-yl)-iH-benzo[d]imidazol-1-yl)pyridin-2-yl)propane-2-sulfonamide; N-(3-fluoro-6'-(5-(i-methyl-iH-pyrazol-4-y1)-1H-benzo[d]imidazol-1-yl)-[2,4' 30 bipyridin]-2'-yl)cyclopropanesulfonamide; N-(3-fluoro-6'-(5-(1-methyl-1H-pyrazol-4-yl)-l H-benzo[d]imidazol-1-yl)-[2,4' bipyridin]-2'-yl)acetamide; WO 2014/162039 PCT/F12014/000003 94 N-(4-(2,4-difluorophenyl)-6-(5-(1-(2-(dimethylamino)ethyl)- 1H-pyrazol-4-yl) 1H-benzo[d]imidazol-1-yl)pyridin-2-yl)cyclopropanesulfonamide; N-(4-(2-fluorophenyl)-6-(5-( 1-methyl-1 H-pyrazol-4-yl)- 1H-benzo[d]imidazol- 1 yl)pyrimidin-2-yl)cyclopropanesulfonamide; 5 N-(6-(5-(1H-pyrazol- 1-yl)-1 H-benzo[d]imidazol- 1 -yl)-4-(2,4-difluorophenyl) pyridin-2-yl)cyclopropanesulfonamide; N-(3,5-difluoro-6'-(5-(1-methyl-i H-pyrazol-4-yl)- 1H-benzo[d]imidazol- I-yl) [2,4'-bipyridin]-2'-yl)cyclopropanesulfonamide; N-(3,5-difluoro-6'-(5(1-methyl-i H-pyrazol-4-yl)- 1 H-benzo[d]imidazol- 1 -yl) 10 [2,4'-bipyridin]-2'-yl)acetamide; N-(4-(2-chlorophenyl)-6-(5-(1-methyl-1H-pyrazol-4-yl)- 1 H-benzo[d]imidazol-1 yl)pyridin-2-yl)cyclopropanesulfenamide; N-(3-chloro-6'-(5-(1-methyl-iH-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[2,4' bipyridin]-2'-yl)cyclopropanesulfonamide; 15 N-(5-fluoro-6'-(5-(1-methyl-iH-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[2,4' bipyridin]-2'-yl)cyclopropanesulfonamide; N-(6-(5-(1H-imidazol-l-yl)-1H-benzo[d]imidazol-1-yl)-4-(2,4-difluorophenyl) yridin-2-yl)ycioropaiesulfonamide; N-(4-(2,4-difluorophenyl)-6-(5-(1-(2-morpholinoethyl)- 1IH-pyrazol-4-yl)-1H 20 benzo[d]imidazol- 1 -yl)pyridin-2-yl)cyclopropanesulfonamide; N-(4-(2,4-difluorophenyl)-6-(5-(1-,(pyrrolidin-3-yl)-1H-pyrazol-4-yl)- 1 H benzo[d]imidazol- 1-yl)pyridin-2-yl)cyclopropanesulfonamide; N-(4-(2,4-difluorophenyl)-6-(5-(1 -ethyl-i H-1,2,3-triazol-4-yl)- 1 H-benzo[d] imidazol-1-yl)pyridin-2-yl)cyclopropanesulfonamide; 25 N-(4-(2,4-difluorophenyl)-6-(5-(i-methyl- 1H- 1,2,3-friazol-4-yl)-iH-benzo[d] imidazol- 1-yl)pyridin-2-yl)cyclopropanesulfonamide; N-(4-(2,4-difluorophenyl)-6-(5-(i-methyl-iH-imidazol-4-yl)- 1H-benzo[d] imidazol-1-yl)pyridin-2-yl)cyclopropanesulfonamide; N-(4-(2, 4-difluorophenyl)-6-(5-(i-methyl-i H-pyrazol-4-yl)-1H-benzo[d] 30 imidazol-1-yl) pyrimidin-2-yl) acetamide; Ethyl 1-(1-(6-(cyclopropanesulfonamido)-4-(2,4-difluorophenyl)pyridin-2-yl) 1H-benzo[d]imidazol-5-yl)-1H-1,2,3-triazole-4-carboxylate; WO 2014/162039 PCT/F12014/000003 95 N-(4-(2-(difluoromethoxy)-4-fluorophenyl)-6-(5-(1-methyl-i H-pyrazol-4-yl) 1H-benzo[d]imidazol-1-yl)pyridin-2-yl)cyclopropanesulfonamide; N-(4-(2,4-difluorophenyl)-6-(5-(1-methyl-1 H-pyrazol-4-yl)- 1 H-benzo [d] imidazol-1-yl)pyrimidin-2-yl)cyclopropanesulfonamide; 5 N-(6-(2, 4-difluorophenyl)-4-(5-(1-methyl-i H-pyrazol-4-yl)- 1 H-benzo [d] imidazol-1-yl) pyridin-2-yl) cyclopropanesulfonamide; or a pharmaceutically acceptable salt or tautomer thereof.
12. 14. A pharmaceutical composition comprising a compound of formula (I) or a 10 pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier.
13. 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 15 FGFR kinase inhibition is desired.
14. 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. 20