PROTEIN KINASE INHIBITORS

Technical field

The present invention relates to therapeutically active compounds and pharmaceutically acceptable salts thereof which are useful e.g. in the treatment of cancer.

Background of the invention

Protein kinases are a class of proteins (enzymes) that regulate a variety of cellular functions. This is accomplished by phosphorylation of specific amino acids on protein substrates resulting in conformational alteration of the substrate protein. The conformational change modulates the activity of the substrate or its ability to interact with other binding partners. Tyrosine kinases are a subset of protein kinases that catalyze the transfer of the terminal phosphate of adenosine triphosphate (ATP) to tyrosine residues on protein substrates. The human genome contains around 90 tyrosine kinases and 43 tyrosine kinase like genes, the products of which regulate cellular proliferation, survival; differentiation, function and motility.

Tyrosine kinases are of two varieties, i.e. receptor and non-receptor tyrosine kinases. Receptor tyrosine kinases (e.g., FGFR) are trans-membrane proteins with a ligand-binding extracellular domain and a catalytic intracellular kinase domain, while non-receptor tyrosine kinases (e.g., c-ABL) lack trans-membrane domains and are found in the cytosol, nucleus and inner surface of cell membrane. Kinase domains of all tyrosine kinases have bilobar architecture, with an N-terminal lobe that binds ATP and magnesium, a C-terminal lobe containing an activation loop, and a cleft between the lobes to which polypeptide substrates bind.

Receptor tyrosine kinases become activated when ligand binds to the

extracellular domain, resulting in receptor oligomerization and autophosphorylation of a regulatory tyrosine within the activation loop of the kinase domain. These phenomena reorient important amino acid residues, thereby enhancing catalytic activity of the enzyme.

Fibroblast growth factor (FGF) has been recognized as an important mediator of many physiological processes, such as cell migration, proliferation, survival and differentiation during development and angiogenesis. There are currently over 25 known members of the FGF family. The fibroblast growth factor receptor (FGFR) family consists of four members with each composed of an extra cellular ligand binding domain, a single trans-membrane domain and an intracellular cytoplasmic protein tyrosine kinase domain. Upon stimulation with FGF, FGFRs undergo dimerisation and transphosphorylation. Upon dimerization, FGFRs activate range of downstream signaling pathways, such as MAPK and P B/Akt pathways (Zhou, W. et. al. Chemistry & Biology, 2010, 17; 285). Abnormal FGFR signaling has been reported in many tumor types including multiple myeloma,' gastric, endometrial, prostate and breast (Squires M. et. al. Mol. Cancer then September 2011, 10: 1542-1552). FGFs also have role in tumor angiogenesis and mediate resistance to vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors (Casanovas, O. et. al., Cancer Cell, 2005, 8, 299). Consequently, FGF and FGFRs have the potential to initiate and/or promote

tumorigenesis. Due to this, the FGF signaling system happens to be an attractive therapeutic target, mainly because therapies targeting FGFRs arid/or FGF signaling may affect both the tumor cells and also tumor angiogenesis (Foote, K M. et. al., WO n ■ ' 2009/019518 Al). Consequently, FGF arid FGFRs have the potential to initiate and/or promote tumorigenesis.

Summary of the invention

It has been found that compounds of formula (I) inhibit or modulate the activity of certain protein kinases, more' specifically prdtein tyrosine kinases. In particular, it has been found that the compounds of formula (I) are potent and selective inhibitors of FGFR kinases. The compounds of the invention have antiproliferative activity and are particularly useful in the treatment of cancer.

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

(I)

wherein

Zi is N and Z2 is CH, or

Zi is CH and Z2 is N, or

Z| and Z2 is N;

Z is CH or N;

A is a phenyl ring or a 5 - 12 membered heterocyclic ring;

Ri is H, C1-7 alkyl, C3.7 cycloalkyl, C3-7 cycloalkyl C1-7 alkyl, C1-7 alkoxy, Ci-7 alkyl carbonyl, amino, hydroxy, hydroxy C1-7 alkyl, halo C1-7 alkyl, C1-7 alkylamino C1-7 alkyl, -R16-C(0)-R17 or -E-R6;

R2 is H, halogen or C1- alkyl;

B is a 5-12 membered carbocyclic or heterocyclic ring;

R3 is H, halogen, C1-7 alkyl, C)-7 alkoxy, halo C1-7 alkyl or halo C1-7 alkoxy;

R4 is Hi halogen, C1-7 alkyl or oxo;

R5 is H, -C(0)R7, -SO2R8 or an optionally substituted 5-6 membered heterocyclic ring; - R6 is an optionally substituted 5-6 membered heterocyclic ring;

R7 is C1-7 alkyl, C2.7 alkenyl, C1-7 alkoxy, C1-7 alkoxy C1-7 alkyl, carboxy Ci.7 alkyl, C1-7 alkoxy carbonyl C1-7 alkyl, C1-7 alkylamino C1-7 alkyl, -NH-R10 or -NH-Xr

Rg is C1-7 alkyl, C2-7 alkenyl, C3-7 cycloalkyl, hydroxy C1-7 alkyl, -NR13R14, -NH-X2-R15, phenyl or an optibiially substituted 5-6 membered heterocyclic ring;

R10 is Ci-7 alkyl or C3-7 cycloalkyl;

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

R12 is H or C1-7 alkyl;

R13 and R14 are, independently, H, C1-7 alkyl or C3-7 cycloalkyl;

R15 is phenyl or an optionally substituted 5-6 membered heterocycl

R16 is a bond or a C1-7 alkyl;

R17 is C1-7 alkyl, C1-7 alkoxy, C1-7 alkylamino, amino or hydroxy;

E is a bond or a C1-7 alkyl;

X} and X2 are, independently, a bond or C1-7 alkyl;

and pharmaceutically acceptable salts thereof.

In one class of compounds are compounds of formula (I), wherein Z is CH. In another class of compounds are compounds of formula (I), wherein ¾ is N and Z2 is CH. In another class of compounds are compounds of formula (I), wherein Ζγ is CH and Z2 is NJ In another class of compounds are compounds of formula (I), wherein Zi and Z2 is N. ■ ■ r ,< :. . -. ·, < ' ■ ■<■■■>■. - . ■ ■:< . -,■■■:

In a subclass class of any of the above classes are compounds of formula (I), wherein ring A is anyone of the following1 groups or tautomers thereof:

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

and R3 and R4, as defined above, are attached to the above B-rihgs.

Another subclass of the above classes are compounds wherein

A is a ring of formula (Ι '), (2'), (3'), (4'), (5'), (7'), (14*), (16') or (20');

Ri is Η, C1-7 alkyl, C1-7 alkoxy, hydroxy C1-7 alkyl, C1-7 alkylamino C1-7 alkyl or -E-R6;

R2 is H; ■■

z is CH;

B is a ring of formula ( Γ '), (2"), (3"), (4") or (6");

E is a bond or d-7 alkyl;

R6 is any of the following groups

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

R7 is C1.7 alkyl, C2-7 alkenyl or -NH-R10;

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

In one class of compounds are compounds of formula (I), wherein R5 is -C(0)R7 or -S02R8 or any one of the following groups

In one class of compounds are compounds of formula (I), wherein R5 is -S02R8.

, In one class of compounds are compounds of formula (I), wherein R6 is any of the following groups

The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier. ^

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

The present invention provides further a use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cancer.

';.■■>■?■ ■■■

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a condition, where FGFR kinase inhibition is desired.

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of cancer.

The present invention provides further a method for the treatment of a condition, where FGFR kinase inhibition is desired comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I).

The present invention provides further a method for the treatment of cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I).

Detailed description of the invention ■ ■■■

The compounds of the invention can be prepared by a variety of synthetic routes analogously to the methods known in the literature using suitable starting materials. The compounds according to formula (I) can be prepared e.g. analogously or according to the following reaction Schemes. Some compounds included in the formula (I) can be obtained by converting the functional groups of the other compounds of formula (I) obtained in accordance with the following Schemes, by well known reaction steps such as oxidation, reduction, hydrolysis, acylation, alkylation, amidation, amination, sulfonation and others. It should be noted that any appropriate leaving groups, e.g. N-protecting groups, such as a t-butoxycarbonyl (t-BOC) group or a phenylsulfonyl group, can be used in well known manner during the syntheses in order to improve the selectivity of the reaction steps ;

Compounds of formula (I), wherein R5 is -C(0)CH3 can be prepared, for example, according to Scheme 1, wherein R1; R2, R3, R4, ring A, ring B and Z, Zi and Z2 are as defined above, and R is hydrogen or alkyl. In the method of Scheme 1, the N-(3-bromo-5-nitrophenyl)acetamide [1] is coupled in a suitable solvent such as 1,2-dimethoxyethane with a boronic acid derivative [2] or a suitable ester thereof in the presence of Pd(dppf)Cl2 and aqueous sodium carbonate at elevated temperature. The nitro group of the obtained compound [3] is reduced, e.g. with hydrogen and Pd/C catalyst, iron powder and aqueous calcium chloride or zinc and aqueous ammonium chloride, and the resulting amine [4] is reacted with compound1 [5] in a suitable solvent such as DMF in the presence of potassium fluoride at elevated temperature to obtain compound [6]. In case Z is CH in the compound [5], X" is suitably fluoro, and when Z is N, X" is suitably chloro. The nitro group in compound [6] is reduced, e.g. by using zinc and aqueous ammonium chloride or iron powder and aqueous calcium chloride, and the resulting amine [7] is heated with formic acid to produce compound [8] in a ring closure reaction. Finally, compound [10] is obtained by the Suzuki coupling between ( compound [8] and a boronic acid derivative [9] or a suitable ester thereof in a suitable solvent such as 1,2-dimethoxyethane in the presence of Pd(dppf)Cl2 and aqueous sodium carbonate at elevated temperature.

SCHEME 1.

SCHEME 2.

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

SCHEME 3.

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 ¾ and Z2 are as defined above. The pyrrole derivative [16] formed is reduced using ammonium sulphide to obtain compound [17], which is subsequently reacted with acetic anhydride to afford compound [18].

SCHEME 4.

In case where ring A in the compound [10] is an oxazol-5-yl ring, the compound [10] can be also prepared according to Scheme 5, wherein ring B, R3, R4, Ί,χ and Z2 are as defined above. In this method the compound [4] is treated with 4-fluoro-3-nitr0- benzaldehyde and the resulting compound [20] is thereafter reacted with toluene- sulfonylmethyl isocyanide to produce the oxazol-5-yl compound [21] in a ring closure reaction. The nitro group of compound [21] can be further reduced, e.g. by

hydrogenation, to produce the corresponding amine, which can be then treated with formic acid according to Scheme 1 to afford the end product in the ring closure reaction.

:

prepared using Buchwald coupling according to Scheme 6, wherein X', ring B, R], R2, R3, R4, Z\ and Z2 are as defined above.

SCHEME 6.

In case where ring A in the compound [10] is an lH-l,2,3-triazol-4-yl ring and R2 is hydrogen, the compound [10] can be also prepared according to Scheme 7, wherein X', Z, Ri, R3, R4, Z1? Z2 and ring B, are as defined above. The starting compound [8] is silylated by reacting with ethynyltrimethylsilane in the presence of tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4) and Cu(I)iodide to produce compound [32]. Treatment with TBAF affords the ethynyl compound [33] which can be reacted with azido compound RrN3 in a suitable solvent, such as DMSO:THF: water (1:1:1) or DMSO:DCM:water (1: 1: 1) to afford compound [34].

SCHEME 7.

In case where ring A in the compound [10] is a l-methyl-lH-pyrazol-3-yl ring, the compound [10] can be also prepared according to Scheme 8, wherein R3, R , Zl5 Z2 and ring B, are as defined above. In this method the compound [4] is treated with l-(4-fluoro-3-nitrophenyl)ethanone and the resulting compound [36] is thereafter reacted with D F dimethylacetal to produce the oxazol-5-yl compound [37]. Subsequent treatment with methyl hydrazine produces compound [38] in a ring closure reaction. The nitro group of compound [38] can be further reduced, e.g. by aqueous ammonium and zinc, to produce the corresponding amine, which can be then treated with formic acid according to Scheme 1 to afford the end product in the ring closure reaction.

In case where ring A in the compound [10] is a lH-imidazol-2-yl ring, the compound [10] can be also prepared according to Scheme 9, wherein R3, R4, Z1; ¾ and ring B, are as defined above. In this method the compound [20] of Scheme 5 is treated with ethylene diamine and N-bromosuccinimide affording compound [39] in a ring closure reaction. The nitro group of compound [39] can be further reduced, e.g. by aqueous ammonium and zinc, to produce the corresponding amine, which can be then treated with formic acid according to Scheme 1 to afford the end product in the ring closure reaction.

Various compounds of formula (I), wherein R5 is other than -C(0)CH3, can be prepared, for example, according to Scheme 10, wherein Rl5 R2, R3, R4, R7, R8, Z, Zj, Z2, ring A and ring B are as defined above. The acetamide compound [10] can be converted to its corresponding amine [24], for example, by heating in ethanol in the presence of a base, such as aqueous sodium hydroxide or potassium hydroxide, or an acid such as aqueous HCl. The obtained amine [24] can be used as a starting material for subsequent reaction steps. The compounds of formula (I), wherein R5 is -S02R8 can be prepared, for example, by treating the amine [24] with C1-S02R8 in suitable solvent such as DCM in the presence of pyridine. Compounds of formula (Γ , wherein R5 is -C(0)R7 and R7 is Ci-7 alkyl or Ci-7 alkylamino Q.? alkyl, can be prepared, for example, by reacting the " amine [24] with HOOC-R7 in suitable solvent such as DMF in the presence of 2-( l H-7-azabenzotriazol- 1 -yl)- 1 , 1 ,3,3-tetramethyl uronium hexafluorophosphate : - ' ! i ; methanaminium (HATU) and D1PEA.

SCHEME 10.

Compounds of formula (I), wherein R7 is -NH-R10 or -NH-X-Rn, can be prepared, for example, according to Scheme 11 by reacting the amine [24] in a suitable solvent such n-butanol with isocyanato derivatives O=C=N-R10 or 0=C=N-X-R1 1 in the presence of suitable base such as triethylamine (TEA). Alternatively, compounds wherein R7 is -NH-X-Ri i can be prepared by treating amine [24] in suitable solvent such as DCM with phosgene and then with H2N-X-Ri i, see Scheme 11.

Compounds wherein R5 is -C(0)R7, -S02R8 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 CI, and R1? R2, R3, R4, Z, Z1 ; Z2 and ring B are as defined above, using palladium (e.g. Pd2(dba)3) catalyzed C-N coupling in the presence of a metal chelating ligand such as Xantphos.

SCHEME 12.

Compounds of formula (I) can be also prepared according to Scheme 13 by reacting compound [42] with compound [43] to produce compound [44] wherein X is a halogen such as CI or Br, and Rl5 R2, R3, R4, Z, Zj, Z2 and ring B are as defined above, followed by the bicyclic ring closure as in Scheme 1 and addition of the -NHR5 group according to Scheme 12.

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

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

Pharmaceutically acceptable salts are well known in the field of pharmaceuticals. Non-limiting examples of suitable sajts include mbtal salts, ammonium salt, salts with organic base, salts with inorganic acid, salts with organic acid, and salts with basic or acidic amino acid. Non-limiting examples of metal salts include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, and magnesium salt. Non-limiting examples of salts with inorganic or organic acids include chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, citrates, benzoates, salicylates and ascorbates. Pharmaceutically acceptable esters, when applicable, may be prepared by known methods using pharmaceutically acceptable acids that are conventional in the field of pharmaceuticals and that retain the pharmacological properties of the free form. Non-limiting examples of these esters include esters of aliphatic or aromatic alcohols, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl esters. Phosphate esters and carbonate esters, are also within the scope of the invention.

The terms employed herein have the following meanings:

The term "halo" or "halogen", as employed herein as such or as part of another group, refers to chlorine, bromine, fluorine or iodine. i

The term "C - alkyl'', as employed herein as such or as part of another group, refers to a straight or branched chain saturated hydrocarbon group having 1 , 2, 3, 4, 5, 6 or 7 carbon atom(s). Representative examples of C1-7 alkyl include, but are not limited to, methyl, ethyl, M-propyl, ¾o-propyl, n-butyl, wo-butyl, sec-butyl, teri-butyl, n-pentyl, isopentyl and n-hexyl. The term "C1-3 alkyl" refers to an preferred embodiment of "C1-7 alkyl" having 1 , 2 or 3 carbon atoms.

The term "C3- cycloalkyl", as employed herein as such or as part of another group, refers to a saturated cyclic hydrocarbon group containing 3, 4, 5, 6 or 7 carbon atoms. Representative examples of cycloalkyl include, but are riot limited to, cyclo-propyl, eyclobutyl, cyclopentyl and cyclohexyl.

The term "C3-7 cycloalkyl Q-7 alkyl", as employed herein refers to a C3-7 cycloalkyl group, as defined herein, appended to the parent molecular moiety through a C1-7 alkyl group, as defined herein.

The term "C2-7 alkeriyl", 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, etheriyl, propenyl and cyclohexenyl.

The term "hydroxy", as employed herein as such or as part of another group, refers to an -OH group. The term "cyano", as employed herein as such or as part of another group, refers to a -CN group; The term "carboxy", as employed herein as such or as part of another group, refers to -COOH group. The term "carbonyl", as employed herein as such or as part of another group, refers to a carbon atom double-bonded to an oxygen atom (C=0). 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 "C1-7 alkoxy", as employed herein as such or as part of another group, refers to C1-7 alkyl, as defined herein; appended to the parent molecular moiety through an oxygen atom. Representative examples of C1-7 alkoxy include, but are not limited to mefhoxy, ethoxy, propoxy, butoxy, isobuidxy, .ver.-butoxy and tert-butoxy.

The term "hydrOxyl C1-7 alkyl", as employed herein, refers to at least one hydroxy group, as defined herein, appended to the parent molecular moiety through a Cj-7 alkyl group, as defined herein. Representative examples of hydroxyl Ci-7 alkyl include, but are not limited to, hydroxymethyl, 2,2-dihydroxyethyl, l-hydroxyethyl, 3-hydroxypropyl, 1-hydroxypropyl, 1 -methyl- 1 -hydroxyethyl arid 1 -methyl- 1 -hydroxy-propyl. ":

'

The term "halo C1-7 alkyl", as employed herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through a C1-7 alkyl group, as defined herein. Representative examples of halo C1-7 alkyl include, but are not limited to, flUoromethyl, difluoromethyl, trifluorbmethyl, 2-chloroethyl and 3-brom0propyl.

The term "cyano C].7 alkyl", as employed herein, refers to a cyano group, as defined herein, appended to the parent molecular moiety through a C1-7 alkyl group, as defined herein. Representative examples of cyano C1-7 alkyl include, but are not limited to, cyanomethyl, 1-cyanoethyl, 1-cyanopropyl and 2-cyanopropyl.

The term "carboxy C1-7 alkyl", as employed herein as such or as part of another group, refers to a carboxy group, as defined herein, appended to the parent molecular moiety through a C1-7 alkyl group, as defined herein.

The term "halo Ci-7 alkoxy", as employed herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through a C1-7 alkoxy group, as defined herein.

The term "phenyl C1-7 alkoxy", as employed herein, refers to at least one phenyl group appended to the parent molecular moiety through a Ci_7 alkoxy group, as defined herein. !

The term "C1-7 alkylcarbonyl", as employed herein as such or as part of another group, refers to a C1-7 alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.

The term "C1-7 alkoxycarbonyl", as employed herein as such or as part of another group, refers to a C1-7 alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.

The term "C1-7 alkoxycarbonyl C1-7 alkyl", as employed herein as such or as part of another group, refers to a C1-7 alkoxycarbonyl group, as defined herein, appended to the parent molecular moiety through a C1-7 alkyl group, as defined herein.

The term "aminocarbonyl", as employed herein as such or as part of another group, refers to an amino group appended to the parent molecular moiety through a carbonyl group, as defined herein.

The term "amino C1-7 alkyl", as employed herein, refers to at least one amino group appended to the parent molecular moiety through a C1-7 alkyl group, as defined herein. Representative examples of amino C1-7 alkyl include, but are not limited to, aminomethyl, 2-aminoethyl, 1-aminoethyl, 2,2-diaminoethyl, 3-aminopropyl, 2- aminopropyl, 4-aminobutyl and 1 -methyl- 1-aminoethyl.

The term "C1-7 alkylamino", as employed herein as such or as part of another group, refers to at least one C^ alkyl group, as defined herein, appended to the parent molecular moiety through an amino group. Representative examples of C1-7 alkylamino include, but are not limited to methylamino, ethylamino, propylamino, butylamino, dimethylamino, diethylamino and N-ethyl-N-methylamino.

The term "C1-7 alkylamino C1-7 alkyl", as employed herein as such or as part of another group, refers to at least one C1-7 alkylamino group, as defined herein, appended to the parent molecular moiety through an C1-7 alkyl group, as defined herein.

The term "carboxy C1 7 alkylamino", as employed herein as such or as part of another group, refers to at least one carboxy group, as defined herein, appended to the parent molecular moiety through an C1-7 alkylamino group, as defined herein

The term "C1- alkoxy C1-7 alkyl", as employed herein, refers to ait least one C1-7 alkoxy group, as defined herein, appended to the parent molecular moiety through an Ci-7 alkyl group, as defined herein.

The term "C1-7 alkoxycarbonyl C1-7 alkyl", as employed herein, refers to at least one C1-7 alkoxycarbonyl group, as defined herein, appended to the parent molecular moiety through an C1-7 alkyl group, as defined herein.

The term "substituted" as used herein in connection with various residues refers to halogen substituerits, such as fluorine, chlorine, bromine, iodine, or C1-7 alkyl, C3-7 cycloalkyl, halo C1-7 alkyl, hydroxy, amino, C1-7 alkoxy, C1-7 acyl C1-7 alkylamino, amino Ci-7 alkyl, nitro, cyano, thiol or methylsulfonyl substituents. Preferred are halogen, C1-7 alkyl, halo C1-7 alkyl, hydroxy, amino, C1-7 alkoxy and methylsulfonyl substituents. Particularly preferred are 1 to 3 of C1-3 alkyl substituents.

The "substituted" groups may contain 1 to 3, preferably 1 or 2, of the above mentioned substituents.

The term "5 - 6 membered heterocyclic ring" as employed herein, refers to a saturated, partially saturated or aromatic ring with 5 or 6 ring atoms, of which 1-4 atoms are heteroatoms selected from a group consisting of N, O and S. Representative examples of 5-6-membered heterocyclic ring include, but are not limited to, pyrazolyl, 1,2,4-triazol-l-yl, 1,2,3-triazol-l-yl, pyrimidinyl, pyridinyl, tetrazolyl, piperazinyl, furanyl, morpholinyl, piperidiriyl, pyrrolidinyl, thiazolyl, isoxazolyl, pyrazinyl tetrahydropyranyl,T,2,4-oxadiazolyl, oxazolyl, imidazolyl, indolyl and 4,5- dihydroimidazolyl rings.

Claims

1. A compound of formula (I)

wherein ' · ,"'

Zi is N and Z2 is CH, or

Z\ is CH and Z2 is N, or

Z] and Z2 is N;

Z is CH or N;

A is a phenyl ring or a 5 -12 membered heterocyclic ring;

is H, C1-7 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1- alkyl, Ci-7 alkoxy, Ci-7 alkyl carbonyl, amino, hydroxy, hydroxy C1-7 alkyl, halo Ci-7 alkyl, C1-7 alkylamino Q alkyl, -R16-C(0)-R17 or -E-R6;

R2 is H, halogen or C1-7 alkyl;

B is a 5-12 membered carbocyclic or heterocyclic ring;

R3 is H, halogen, Ci-7 alkyl, C1-7 alkoxy, halo C1-7 alkyl or halo C1-7 alkoxy;

R4 is H, halogen, Ci-7 alkyl or oxo;

R5 is H, -C(0)R , -S02R8 or an optionally substituted 5-6 membered heterocyclic ring;

R6 is an optionally substituted 5-6 membered heterocyclic ring;

R7 is Ci-7 alkyl, C2-7 alkenyl, Ci-7 alkoxy, Ci-7 alkoxy Cj.7 alkyl, carboxy C1-7 alkyl, C1-7 alkoxy carbonyl d÷7 alkyl, C1-7 alkylamino C1-7 alkyl, -NH-Rio or -NH-Xj- R.8 is C]-7 alkyl, C2-7 alkenyl, C3-7 cycloalkyl, hydroxy C1-7 alkyl, -NR13R14, -NH-X2-Ri5, phenyl or an optionally substituted 5-6 membered heterocyclic ring;

R10 is C1-7 alkyl or C3.7 cycloalkyl;

Rn is phenyl or an optionally substituted 5-6 membered heterocyclic ring; R12 is H or C1-7 alkyl;

Ri3 and R14 are, independently, H, C1-7 alkyl or C3,7 cycloalkyl;

R15 is phenyl or an optionally substituted 5-6 membered heterocyclic ring;

R16 is a bond or a C1-7 alkyl;

Rn is C1-7 alkyl, C1-7 alkoxy, C1-7 alkylamino, amino or hydroxy;

E is a bond or a C1-7 alkyl;

Xi and X2 are, independently, a bond or C1-7 alkyl;

and pharmaceutically acceptable salts thereof.

2. A compound according to claim 1, wherein Z is CH.

3. A compound according to clai 1 Or 2, wherein ϊ\ is N and Z2 is CH.

4. A compound according to to claim 1 or 2, wherein Zi is CH and Z2 is N.

5. A compound according to to claim 1 or 2, wherein Z and Z2 is N.

6. A compound according to any of claims 1 to 5, wherein ring A is any one of

(7) (8') (9') (10') (Ι Ι') (12')

is any one of

8. A compound according to any of claims 1 to 7, wherein

A is a ring of formula (1'), (2'), (3'), (4'), (5'), (7'), (14'), (16') or (20');

Rj is Η, C1-7 alkyl, C1-7 alkoxy, hydroxy C1-7 alkyl, C1-7 alkylamino C1-7 alkyl or

R2 is H;

Z is CH; ■

B is a ring of formula (1"), (2"), (3"), (4") or (6");

E is a bond or C1-7 alkyl;

(a) (b) (c) (d) (e)

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

R4 is H or halogen;

-C(0)R7 or -S02R8 or any one of the following groups

R7 is C1-7 alkyl, C2-7 alkenyl or -NH-R10;

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

9. A compound according to any of claims 1 to 8, wherein B is a ring of formula (l"), (3") or (6").

10. A compound according to any of claims 1 to 9, wherein A is a ring of formula ( ), (2'), (4'), (5') or (20").

11. A compound according to any of claims 1 to 10, wherein Rs is -S02R8.

12. A compound according to any of claims 1 to 11, wherein Z is CH, Z is N and Z2 is CH, A is a ring of formula (Γ), B is a ring of formula ( 1"), R[ is C1-7 alkyl, R2 is H, R3 is halogen, R4 is H or halogen, R5 is -S02R8 and R8 is C1-7 alkyl or

C3-7 cycloalkyl.

13. A compound according to any of claims 1 to 12, which is

4-(2, 4-Difluorophenyl)-N-( 1 -methyl- 1 H-pyrazol-3-yl)-6-(5-( 1 -methyl- 1 H-pyrazol-4-yl)- 1 H-benzo[d]irriidazol- 1 -yl) pyridin-2-amine;

N-(4-(2,4-difluorophenyl)-6-(5-( 1-methyl- lH-pyrazol-4-yl)- lH-benzo[d]-imidazol-l-yl)pyridin-2-yl)cyclopropanesulfonamide;

Sodium salt of imido form of N-(4-(2,4-difluorophenyl)-6-(5-(l-methyl-lH-pyrazol-4-yl)-lH-benzo[d]imidazol-l-yl)pyridin-2-yl)cyclopropanesulfonamide;

N-(4-(2,4-difluorophenyl)-6-(5-( 1 -methyl- 1 H-pyrazol-4-yl)- lH-benzo[d]-imidazol- 1 -yl)pyridin-2-yl)methanesulfonamide;

N-(4-(2,4-difluorophenyl)-6-(5-( 1 -methyl- 1 H-pyrazol-4-yl)- 1 H-benzo [d] -iriiidazol- 1 -yl)pyridin-2-yl)ethariesulfonamide;

Sodium salt of imido form of N-(4-(2,4-difluorophenyl)-6-(5-( 1 -methyl- 1H- pyrazol-4-yl)- 1 H-benzo [d]imidazol- 1 -yl)pyridin-2-yl)ethanesulfonamide;

N-(4-(2,4-difluorophenyl)-6-(5-( 1 -methyl- 1 H-pyrazol-4-yl)- 1 H-benzo[d] - imidazol- 1 -yl)pyridin-2-yl)propane-2-sulfonarnide;

Imido form of N-(4-(2,4-difluorophenyl)-6-(5-(l-methyl-lH-pyrazol-4-yl)-lH-benzo[d]imidazol-l-yl)pyridin-2-yl)propane-2-sulfonamide;

N-(4-(2-fluorophenyl)-6-(5-( 1 -methyl- 1 H-pyrazol-4-yl)- 1 H-benzo [d]imidazol- 1 yl)pyridin-2-yl)cyclopropanesulfonamide;

Sodium salt of imido form of N-(4-(2-fluorophenyl)-6-(5-(l -methyl- lH-pyrazol 4^yl)-lH-benzo[d]imidazol-l-yl)pyridin-2-yl)cyclopropanesulfonarnide;

N-(4-(2-fluorophenyl)-6-(5-(l-methyl-lH-pyrazol-4-yl)-lH-benzo[d]imidazol-l yl)pyridin-2-yl)methanesulfonamide;

N-(4-(2-fluorophenyl)-6-(5-( 1 -methyl- lH-pyrazol-4-yl)- 1 H-benzo [djimidazol- 1 yl)pyridin-2-yl)ethanesulfonamide;

Sodium salt of imido form of N-(4-(2-fluorophenyl)-6-(5-(l -methyl- lH-pyrazol 4-yl)-lH-benzo[d]in idazol-l-yl)pyridin-2-yl)ethanesulfonamide;

N-(4-(2-fluorophenyl)-6-(5-(l -methyl- lH-pyrazol-4-yl)-IH-benzo[d]imidazol-l yl)pyridin-2-yl)propane-2-sulfonamide;

Sodium salt of imido form of N-(4-(2-fluorophenyl)-6-(5-(l -methyl- lH-pyrazol-4-yl)-lH-benzo[d]irmdazol-l-yl)pyridin-2-yl)propane-2-sulfonan ide;

N-(4-(4-fluorophenyl)-6-(5-( 1 -methyl- lH-pyrazol-4-yl)- 1 H-benzo [djimidazol- 1 -yl)pyridin-2-yl)cyclopropanesulfonan ide;

N-(4-(4-fluorophenyl)-6-(5-(l-methyl-lH-pyrazol-4-yl)-lH-benzo[d]imidazol-l-yl)pyridin-2-yl)methatiesulfonamide;

N-(4-(4-fluorophenyl)-6-(5-( 1 -methyl- 1 H-pyrazol-4-yl)- 1 H-benzo [djimidazol- 1 -yl)pyridin-2-yl)propane-2-sulfonamide;

Sodium salt of imido form of N-(4-(4-fluorophenyl)-6-(5-(l-methyl-lH-pyrazol-4-yl)-lH-benzo[d]irrudazol-l-yl)pyridin-2-yl)propane-2-sulforiarnide;

N-(3-fluoro-6^(5-(l-methyl-lH-pyrazol-4-yl)-lH-benzo[d]imidazol-l-yl)-[2,4'-bipyridin]-2'-yl)cyclopropanesulfonamide;

N-(3-fluoro-6'-(5 1 -methyl- 1 H-pyrazol-4-yl)- 1 H-benzo [djimidazol- 1 -yl)-[2,4'-bipyridin]-2'-yl)acetamide;

N-(4-(2,4-difluorophenyl)-6-(5-(l-(2-(dimethylamino)ethyl)-lH-pyrazol-4-yl)- 1 H-benzo [d] imidazol- 1 -yl)pyridin-2-yl)cyclopropanesulf onamide ;

N-(4-(2-fluorophenyl)-6-(5-(l-methyl-lH-pyrazol-4-yl)-lH-benzo[d]imidazol-l yl)pyrimidin-2-yl)cyclopropanesulfonamide;

N-(6-(5-( 1 H-pyrazol- 1 -yl)- 1 H-benzo [d]imidazol- 1 -yl)-4-(2,4-difluorophenyl)-pyridin-2-yl)cyclopropanesulfonamide;

N-(3 ,5-difluoro-6'-(5-( 1 -methyl- 1 H-pyrazol -4-yl)- 1 H-benzo [d]imidazol- 1 -yl)-[2,4'-bipyridin]-2'-yl)cyclopropanesulfonamide;

N-(3,5-difluoro-6'-(5-( 1 -methyl- 1 H-pyrazol-4-yl)- 1 H-benzo [d] imidazol- 1 -yl)-l2^4'-bipyridin]-2'-yl)acetamide;

N-(4-(2-chlorophenyl)-6-(5-(l-methyl-lH-pyrazol-4-yl)-lH-benzo[d]imidazol-l yl)pyridin-2-yl)cyclopropanesulfonamide;

N-(3-chloro-6'-(5-( 1 -methyl- 1 H-pyrazol-4-yl)- 1 H-benzo [d]imidazol- 1 -yl)-[2,4'-bipyridin]-2'-yl)cyclopropanesulfonamide;

N-(5-fluoro-6'-(5-( 1 -methyl- lH-pyrazol-4-yl)- 1 H-benzo [d]imidazol- 1 -yl)-[2,4'-bipyridin]-2'-yl)cyclopfopanesulfonamide;

N-(6-(5-( 1 H-imidazol- 1-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-moφholinoethyl)- 1 H-pyrazol-4-yl)- 1H-benzo [d]imidazol- 1 -yl)pyridin-2-yl)cyclopropanesulf onamide ;

N-(4-(2,4-difluorophenyl)-6-(5-(l-(pyrrolidin-3-yl)-lH-pyrazol-4-yl)-lH-benzo [d]imidazol- 1 -yl)pyridin-2-yl)cyclopropanesulfonamide;

N-(4-(2,4-difluorophenyl)-6-(5-( 1 -ethyl- 1H- 1 ,2,3-triazol-4-yl)- 1 H-benzo[d]-imidazol- 1 -yl)pyridin-2-yl)cyclopropahesulfonamide;

N-(4-(2,4-difluorophenyl)-6-(5-( 1 -methyl- 1H- 1 ,2,3-triazol-4-yl)-l H-benzo[d]-imidazol- 1 -yl)pyridiii-2-yl)cycl0pr0panesulf onamide ;

N-(4-(2,4-difluorophenyl)-6-(5-( 1 -methyl- 1 H-imidazol-4-yl)- 1 H-benzo [d]-imidazol- 1 -yl)pyridiri-2-yl)eyclopropanesulfonamide;

N-(4-(2, 4-diflUor0phehyl)-6-(5-( 1-methyl- lH-pyrazol-4-ylj- lH-benzo[d]-imidazol-l-yl) pyrimidin-2-yl) acetamide;

Ethyl l-(l-(6-(cyclopropanesulfonamido)-4-(2,4-difluorophenyl)pyridin-2-yl)-lH-benzo[d]iriiidazol-5-yl)- 1H- 1 ,2,3-triazole-4-carboxylate;

N-(4-(2-(difluoromethoxy)-4-fluorophenyl)-6-(5-( 1 -methyl- 1 H-pyrazol-4-yl)- 1 H-benzo [d] imidazol- 1 -yl)pyridin-2-yl)cyclopropanesulf onamide ;

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;

-(6-(2, 4-difluorophenyl)-4-(5-( 1 -methyl- 1 H-pyrazol-4-yl)- 1 H-benzo [d]-imidazol-l-yl) pyridin-2-yl) cyclopropanesulfonamide;

or a pharmaceutically acceptable salt or tautomer thereof.

14. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier.

15. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a condition, where FGFR kinase inhibition is desired.

16. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cancer.