HK1217198B - Protein kinase inhibitors - Google Patents

Description

Protein kinase inhibitors

Technical Field

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

Background

Protein kinases are a class of proteins (enzymes) that regulate a variety of cellular functions. This can be achieved by phosphorylation of specific amino acids on the protein substrate which results in a conformational change in the substrate protein. Conformational changes modulate 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 of protein substrates. The human genome contains about 90 tyrosine kinases and 43 tyrosine kinase-like genes, the products of which regulate cell proliferation, survival, differentiation, function and viability.

Tyrosine kinases have two variants, receptor-type and non-receptor-type tyrosine kinases. Receptor-type tyrosine kinases (e.g., FGFRs) are transmembrane proteins with an extracellular domain that binds to a ligand and a catalytic intracellular kinase domain, while non-receptor-type tyrosine kinases (e.g., c-ABL) lack a transmembrane domain and are present on the inside surfaces of the cytoplasm, nucleus, and cell membrane. The kinase domain of all tyrosine kinases has a two-leaf structure including an N-terminal leaf that binds ATP and magnesium, a C-terminal leaf that contains an activation loop, and a cleft between the two leaves to which the polypeptide substrate binds.

When the ligand binds to the extracellular domain, the receptor-type tyrosine kinase is activated, resulting in receptor oligomerization and autophosphorylation of the regulatory tyrosine within the activation loop of the kinase domain. These phenomena reorient important amino acid residues, thereby increasing the catalytic activity of the enzyme.

Fibroblast Growth Factor (FGF) has been recognized as an important regulator of cell migration, proliferation, survival and differentiation in many physiological processes, such as development and angiogenesis. The current FGF family has more than 25 known members. The Fibroblast Growth Factor Receptor (FGFR) family is composed of four members, each consisting of an extracellular ligand-binding domain, a single transmembrane domain, and an intracellular cytoplasmic protein tyrosine kinase domain. Upon stimulation with FGF, FGFR will dimerize and transphosphorylate. Once dimerized, FGFR activates a series of downstream signaling channels such as MAPK and PKB/Akt channels (Zhou, w. et al, Chemistry & Biology,2010,17, 285). Abnormal FGFR signals have been found in many tumor types, including multiple myeloma, gastric, endometrial, prostate, and breast tumors (Squires m. et al, mol. cancer ther., September 2011,10: 1542-. FGF also has effects on tumor angiogenesis and mediates resistance to inhibitors of vascular endothelial growth factor receptor 2(VEGFR2) (Casanovas, o. et al, Cancer Cell,2005,8, 299). Thus, FGF and FGFR have the potential to initiate and/or promote tumorigenesis. Therefore, FGF signaling systems have become an attractive therapeutic target, mainly because therapies targeting FGFR and/or FGF signaling can affect both tumor cells as well as tumor angiogenesis (Foote, k.m. et al, WO 2009/019518 a 1). Thus, FGF and FGFR have the potential to initiate and/or promote tumorigenesis.

Summary of The Invention

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

The compounds of the invention have the structure shown in formula (I)

Wherein

Z₁Is N and Z₂Is CH, or

Z₁Is CH and Z₂Is N, or

Z₁And Z₂Is N;

z is CH or N;

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

R₁is H, C_1-7Alkyl radical, C_3-7Cycloalkyl radical, C_3-7Cycloalkyl radical C_1-7Alkyl radical, C_1-7Alkoxy radical, C_1-7Alkylcarbonyl, amino, hydroxy C_1-7Alkyl, halo C_1-7Alkyl radical, C_1-7Alkylamino radical C_1-7Alkyl, -R₁₆-C(O)-R₁₇or-E-R₆；

R₂Is H, halogen or C_1-7An alkyl group;

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

R₃is H, halogen, C_1-7Alkyl radical, C_1-7Alkoxy, halo C_1-7Alkyl or halo C_1-7An alkoxy group;

R₄is H, halogen, C_1-7Alkyl or oxo;

R₅is H, -C (O) R₇、-SO₂R₈Or an optionally substituted 5-6 membered heterocyclic ring;

R₆is an optionally substituted 5-6 membered heterocyclic ring;

R₇is C_1-7Alkyl radical, C_2-7Alkenyl radical, C_1-7Alkoxy radical, C_1-7Alkoxy radical C_1-7Alkyl, carboxyl C_1-7Alkyl radical, C_1-7Alkoxycarbonyl radical C_1-7Alkyl radical, C_1-7Alkylamino radical C_1-7Alkyl, -NH-R₁₀or-NH-X₁-R₁₁；

R₈Is C_1-7Alkyl radical, C_2-7Alkenyl radical, C_3-7Cycloalkyl, hydroxy C_1-7Alkyl, -NR₁₃R₁₄、-NH-X₂-R₁₅Phenyl or optionally substituted 5-to 6-memberedA heterocycle;

R₁₀is C_1-7Alkyl or C_3-7A cycloalkyl group;

R₁₁is phenyl or an optionally substituted 5-6 membered heterocyclic ring;

R₁₂is H or C_1-7An alkyl group;

R₁₃and R₁₄Independently of one another is H, C_1-7Alkyl or C_3-7A cycloalkyl group;

R₁₅is phenyl or an optionally substituted 5-6 membered heterocyclic ring;

R₁₆is a bond or C_1-7An alkyl group;

R₁₇is C_1-7Alkyl radical, C_1-7Alkoxy radical, C_1-7Alkylamino, amino or hydroxy;

e is a bond or C_1-7An alkyl group;

X₁and X₂Independently of one another is a bond or C_1-7An alkyl group;

and pharmaceutically acceptable salts thereof.

In one class of compounds, the compounds are of formula (I) wherein Z is CH. In another class of compounds, the compounds are of formula (I), wherein Z₁Is N and Z₂Is CH. In another class of compounds, the compounds are of formula (I), wherein Z₁Is CH and Z₂Is N. In another class of compounds, the compounds are of formula (I), wherein Z₁And Z₂Is N.

In a subclass of any of the above classes of compounds, the compound is of formula (I), wherein ring a is any one of the following groups or a tautomer thereof:

and R is as defined above₁And R₂Attached to the above A ring.

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

and R is as defined above₃And R₄Attached to the above B ring.

Another subclass of the above classes are those compounds wherein

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

R₁is H, C_1-7Alkyl radical, C_1-7Alkoxy, hydroxy C_1-7Alkyl radical, C_1-7Alkylamino radical C_1-7Alkyl or-E-R₆；

R₂Is H;

z is CH;

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

e is a bond or C_1-7An alkyl group;

R₆is any one of the following groups

R₃Is H, halogen, C_1-7Alkyl radical, C_1-7An alkoxy group;

R₄is H or halogen;

R₅is-C (O) R₇or-SO₂R₈Or any one of the following groups

R₇Is C_1-7Alkyl radical, C_2-7Alkenyl or-NH-R₁₀；

R₈Is C_1-7Alkyl radical, C_2-7Alkenyl radical, C_3-7Cycloalkyl, hydroxy C_1-7Alkyl or-NR₁₃R₁₄(ii) a And is

R₁₀Is C_1-7Alkyl or C_3-7A cycloalkyl group.

In one class of compounds, the compounds are of formula (I), wherein R₅is-C (O) R₇or-SO₂R₈Or any one of the following groups

In one class of compounds, the compounds are of formula (I), wherein R₅is-SO₂R₈。

In one class of compounds, the compounds are of formula (I), wherein R₆Is any one of the following groups

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

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

The invention further provides the 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 compounds of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a condition where inhibition of FGFR kinase is required.

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

The invention further provides a method of treating a disorder in which inhibition of FGFR kinase is desired, which method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I).

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

Detailed Description

The compounds of the invention can be prepared by various synthetic routes analogous to those known in the literature, using appropriate starting materials. The compounds of the formula (I) can be prepared, for example, analogously to or according to the following reaction scheme. Certain compounds included within formula (I) may be obtained by conversion of functional groups of other compounds of formula (I) obtained according to the following schemes, by known reaction steps such as oxidation, reduction, hydrolysis, acylation, alkylation, amidation, amination, sulfonation, and other reaction steps. It should be noted that any suitable leaving group such as an N-protecting group, e.g. a tert-butoxycarbonyl (t-BOC) group or a phenylsulfonyl group may be used in a known manner during the synthesis to enhance the selectivity of the reaction step.

Wherein R is₅is-C (O) CH₃The compounds of formula (I) can be prepared, for example, according to scheme 1, wherein R₁、R₂、R₃、R₄Ring A, ring B and Z, Z₁And Z₂As defined above, and R is hydrogen or alkyl. In the process of scheme 1, N- (3-bromo-5-nitrophenyl) acetamide [1 ]]With boric acid derivatives [2 ] in a suitable solvent, e.g. 1, 2-dimethoxyethane]Or suitable esters thereof in Pd (dppf) Cl₂And coupling at elevated temperature in the presence of an aqueous solution of sodium carbonate. The obtained compound [3 ]]Is reduced with, for example, hydrogen and Pd/C catalysts, iron powder and aqueous calcium chloride solution or aqueous zinc and ammonium chloride solution, and the amine formed is [4 ]]With compound [5 ]]Reaction in a suitable solvent such as DMF in the presence of potassium fluoride at elevated temperature to give compound [6]. In the compound [5]In the case where Z in (A) is CH, X "is preferably fluorine, and when Z is N, X" is preferably chlorine. Reacting the compound [6 ]]The nitro group in (A) is reduced with, for example, aqueous zinc and ammonium chloride solutions or aqueous iron and calcium chloride solutions and the amine formed [7 ]]Heating with formic acid to produce compound [8 ] by ring closure reaction]. Finally, by the compound [8 ]]And boric acid derivative [9]Or a suitable ester thereof in a suitable solvent, e.g. 1, 2-dimethoxyethane, in Pd (dppf) Cl₂And Suzuki coupling in the presence of aqueous sodium carbonate solution at elevated temperature to give the compound [10]。

Scheme 1

Or, formula [3]The compound of (1) can be prepared by using a boronic acid derivative [11 ] according to scheme 2]Or suitable esters thereof in Pd (dppf) Cl₂And aqueous sodium carbonate solution, wherein R₃、R₄、Z₁And Z₂Ring B and R are as defined above. Compound [11]Can be prepared by reacting N- (3-bromo-5-nitrophenyl) acetamide with bis (pinacolato) diboron in Pd (dppf) Cl₂And potassium acetate in the presence of a solvent.

Scheme 2

In the compound [3]In which the B-ring is a heterocyclic ring linked to the phenyl group through a nitrogen heteroatom [3 ]]It can also be prepared according to scheme 3 using copper catalyzed Buchwald amination in the presence of a base such as cesium carbonate or potassium carbonate, where Z₁、Z₂、R₃And R₄As defined above.

Scheme 3

In the compound [3]In the case where the B-ring in (A) is a pyrrole ring linked to the phenyl group through a nitrogen atom, the compound [3]Can also be selected from 3, 5-dinitroaniline [15 ]]And 2, 5-Dimethoxytetrahydrofuran are prepared according to scheme 4, wherein Z₁And Z₂As defined above. Pyrrole derivative to be formed [16]Reduction with ammonium sulfide to give compound [17]Which is subsequently reacted with acetic anhydride to give the compound [18 ]]。

Scheme 4

In the compound [10]In which ring A isIn the case of an oxazol-5-yl ring, the compound [10 ]]Can also be prepared according to scheme 5, wherein ring B, R₃、R₄、Z₁And Z₂As defined above. In this method, the compound [4 ]]Treatment with 4-fluoro-3-nitrobenzaldehyde and subsequent reaction of the resulting compound [20 ]]With tosylmethylisonitrile to give by ring closureAzol-5-yl compound [21]. Can convert compound [2 ]1]The nitro group of (a) is further reduced, for example by hydrogenation, to give the corresponding amine, which is then treated with formic acid according to scheme 1 to give the final product by ring closure.

Scheme 5

In the compound [10]In the case where ring A in (a) is a heterocyclic ring bonded to a carbon atom of the bicyclic ring through a nitrogen heteroatom, the compound [10]It can also be prepared using Buchwald coupling as in scheme 6, where X', ring B, R₁、R₂、R₃、R₄、Z₁And Z₂As defined above.

Scheme 6

In the compound [10]Ring A in (1) is a 1H-1,2, 3-triazol-4-yl ring and R₂In the case of hydrogen, the compound [10]Can also be prepared according to scheme 7, wherein X', Z, R₁、R₃、R₄、Z₁、Z₂And ring B is as defined above. Starting compound [8 ]]By reaction with ethynyltrimethylsilane in tetrakis (triphenylphosphine) palladium (0) (Pd (PPh)₃)₄) And copper (I) iodide to obtain a compound [32 ]]. Treatment with TBAF to give the ethynyl compound [33]Reacting it with an azido compound R₁-N₃Reaction in a suitable solvent such as DMSO: THF: water (1:1:1) or DMSO: DCM: water (1:1:1) gives compound [34]。

Scheme 7

In the compound [10]In (1)In the case where ring A is a 1-methyl-1H-pyrazol-3-yl ring, the compound [10]Can also be prepared according to scheme 8, wherein R₃、R₄、Z₁、Z₂And ring B is as defined above. In this method, the compound [4 ]]Treatment with 1- (4-fluoro-3-nitrophenyl) ethanone and subsequent reaction of the resulting compound [36]Reaction with DMF dimethyl acetal to formAzol-5-yl compound [37 ]]. Subsequent treatment with methylhydrazine in a ring closure reaction affords the compound [38 ]]. Can convert compound [38 ]]The nitro group of (b) is further reduced by, for example, aqueous ammonium and zinc to give the corresponding amine, which is then treated with formic acid in a ring closure reaction according to scheme 1 to give the final product.

In the compound [10]In the case where ring A in (A) is a 1H-imidazol-2-yl ring, the compound [10]Can also be prepared according to scheme 9, wherein R₃、R₄、Z₁、Z₂And ring B is as defined above. In this method, the compound [20 ] of scheme 5]Treatment with ethylenediamine and N-bromosuccinimide in a ring closure reaction to give the compound [39 ]]. Reacting a compound [39 ]]The nitro group of (b) is further reduced, for example by aqueous ammonium and zinc, to form the corresponding amine, which is then treated with formic acid in a ring closure reaction according to scheme 1 to give the final product.

Scheme 9

Wherein R is₅Is not-C (O) CH₃Can be prepared, for example, according to scheme 10, wherein R₁、R₂、R₃、R₄、R₇、R₈、Z、Z₁、Z₂Ring A and ring B are as defined above. Can convert acetamide Compound [10 ]]Conversion to its corresponding amine [24 ]]The conversion is carried out, 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. Obtained amine [24 ]]Can be used as starting material for the subsequent reaction steps. Wherein R is₅is-SO₂R₈The compounds of formula (I) can be prepared, for example, by reacting amines [24 ]]With Cl-SO₂R₈In the presence of pyridine in a suitable solvent such as DCM. Wherein R is₅is-C (O) R₇And R is₇Is C_1-7Alkyl or C_1-7Alkylamino radical C_1-7Alkyl compounds of formula (I) can be prepared, for example, by reacting amines [24 ]]With HOOC-R₇In a suitable solvent such as DMF in the presence of methylammonium 2- (1H-7-azabenzotriazol-1-yl) -1,1,3, 3-tetramethyluronium Hexafluorophosphate (HATU) and DIPEA.

Scheme 10

Wherein R is₇is-NH-R₁₀or-NH-X-R₁₁The compounds of formula (I) can be prepared, for example, by reacting an amine [24 ] according to scheme 11]With the isocyanate derivative O-C-N-R in a suitable solvent such as N-butanol₁₀Or O ═ C ═ N-X-R₁₁In the presence of a suitable base such as Triethylamine (TEA). Or, wherein R₇is-NH-X-R₁₁Can also be prepared by reacting an amine [24 ]]Treatment with phosgene and then H in a suitable solvent such as DCM₂N-X-R₁₁Processed to obtain, see scheme 11.

Scheme 11

Wherein R is₅is-C (O) R₇、-SO₂R₈Or is optionally substitutedThe 5-6 membered heterocyclic compound of (1) can be further treated with a compound [40 ] according to scheme 12]As the raw material, palladium (e.g., Pd) is used₂(dba)₃) The catalyzed C-N coupling is prepared in the presence of a metal chelating ligand such as Xantphos, where X is a halogen such as Br or Cl, R₁、R₂、R₃、R₄、Z、Z₁、Z₂And ring B is as defined above.

Scheme 12

Compounds of formula (I) can also be prepared according to scheme 13 by reacting compounds [42]And compound [43]Reaction to produce a compound [44](wherein X is a halogen such as Cl or Br, and R₁、R₂、R₃、R₄、Z、 Z₁、Z₂And ring B as defined above), followed by bicyclic closure as described in scheme 1 and-NHR as described in scheme 12₅Addition of groups.

Scheme 13

Compounds of formula (I) can also be prepared according to scheme 14 by reacting compounds [45]And compound [46]By reaction, wherein X is a halogen such as Cl or Br, and R₁、R₂、R₃、R₄、R₅、Z、Z₁、Z₂Ring a and ring B are as defined above.

Scheme 14

Compounds of formula (I) can also be prepared according to scheme 15 by reacting compounds [48]And are combined withThing [49 ]]By reaction, wherein X is a halogen such as Cl or Br, and R₁、R₂、R₅、Z、Z₁、Z₂Rings a and B are as defined above. The resulting compound [50]Bicyclic ring closure and addition of the B ring by Suzuki coupling can be performed as described in scheme 1 to give compounds of formula (I).

Scheme 15

Pharmaceutically acceptable salts are well known in the pharmaceutical art. Non-limiting examples of suitable salts include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids. Non-limiting examples of metal salts include alkali metal salts such as sodium and potassium salts; alkaline earth metal salts such as calcium and magnesium salts. 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 can be prepared, where appropriate, by known methods using pharmaceutically acceptable acids which are customary in the pharmaceutical field and retain the pharmacological properties in free form. Non-limiting examples of such esters include esters of aliphatic or aromatic alcohols, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl esters. Phosphates and carbonates are also within the scope of the present invention.

The terms used herein have the following meanings:

the term "halo" or "halogen" as used herein by itself or as part of another group refers to chloro, bromo, fluoro or iodo.

The term "C" as used herein_1-7Alkyl "by itself or as part of another group means a straight or branched chain saturated hydrocarbon radical having 1,2,3, 4,5,6 or 7 carbon atoms。C_1-7Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, and n-hexyl. The term "C_1-3Alkyl "means" C "having 1,2 or 3 carbon atoms_1-7Alkyl "is a preferred embodiment.

The term "C" as used herein_3-7Cycloalkyl "by itself or as part of another group means a saturated cyclic hydrocarbon group containing 3, 4,5,6 or 7 carbon atoms. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The term "C" as used herein_3-7Cycloalkyl radical C_1-7Alkyl "refers to C as defined herein_1-7C as defined herein with the alkyl group pendant to the parent molecular moiety_3-7A cycloalkyl group.

The term "C" as used herein_2-7Alkenyl "by itself or as part of another group refers to an aliphatic hydrocarbon group having 2 to 7 carbon atoms and containing one or several double bonds. Representative examples include, but are not limited to, ethenyl, propenyl, and cyclohexenyl.

The term "hydroxy" as used herein by itself or as part of another group refers to an-OH group. The term "cyano" as used herein by itself or as part of another group refers to a-CN group. The term "carboxy" as used herein by itself or as part of another group refers to a-COOH group. The term "carbonyl" as used herein by itself or as part of another group refers to a carbon atom (C ═ O) bonded to an oxygen atom through a double bond. The term "oxo" as used herein by itself or as part of another group refers to an oxygen atom (═ O) connected to another atom by a double bond.

The term "C" as used herein_1-7Alkoxy "by itself or as part of another group, as used herein, means a group appended to the parent molecular moiety through an oxygen atomDefined C_1-7An alkyl group. C_1-7Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

The term "hydroxy C" as used herein_1-7Alkyl "refers to C as defined herein_1-7The alkyl group is appended to at least one hydroxyl group, as defined herein, on the parent molecular moiety. Hydroxy radical C_1-7Representative examples of alkyl groups include, but are not limited to, hydroxymethyl, 2-dihydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 1-methyl-1-hydroxyethyl, and 1-methyl-1-hydroxypropyl.

The term "halo C" as used herein_1-7Alkyl "refers to C as defined herein_1-7At least one halogen, as defined herein, appended to the parent molecular moiety is an alkyl group. Halogen substituted C_1-7Representative examples of alkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-chloroethyl, and 3-bromopropyl.

The term "cyano C" as used herein_1-7Alkyl "refers to C as defined herein_1-7An alkyl group, as defined herein, appended to the parent molecular moiety through a cyano group. Cyano group C_1-7Representative examples of alkyl groups include, but are not limited to, cyanomethyl, 1-cyanoethyl, 1-cyanopropyl, and 2-cyanopropyl.

The term "carboxy C" as used herein_1-7Alkyl "by itself or as part of another group means through C as defined herein_1-7An alkyl group is appended to the carboxyl group, as defined herein, on the parent molecular moiety.

The term "halo C" as used herein_1-7Alkoxy "refers to C as defined herein_1-7At least one halogen, as defined herein, appended to the parent molecular moiety through an alkoxy group.

The term "phenyl C" as used herein_1-7Alkoxy "refers to C as defined herein_1-7Alkoxy groups pendant to the parent moietyAt least one phenyl group on a subpart.

The term "C" as used herein_1-7Alkylcarbonyl "by itself or as part of another group means C, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein_1-7An alkyl group.

The term "C" as used herein_1-7Alkoxycarbonyl "by itself or as part of another group means a C, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein_1-7An alkoxy group.

The term "C" as used herein_1-7Alkoxycarbonyl radical C_1-7Alkyl "by itself or as part of another group means through C as defined herein_1-7C as defined herein with the alkyl group pendant to the parent molecular moiety_1-7An alkoxycarbonyl group.

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

The term "amino C" as used herein_1-7Alkyl "refers to C as defined herein_1-7An alkyl group is appended to at least one amino group on the parent molecular moiety. Amino group C_1-7Representative examples of alkyl groups include, but are not limited to, aminomethyl, 2-aminoethyl, 1-aminoethyl, 2-diaminoethyl, 3-aminopropyl, 2-aminopropyl, 4-aminobutyl, and 1-methyl-1-aminoethyl.

The term "C" as used herein_1-7Alkylamino "by itself or as part of another group means at least one C as defined herein appended to the parent molecular moiety through an amino group_1-7An alkyl group. C_1-7Representative examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, propylamino, butylamino, dimethylamino, diethylamino, and N-ethyl-N-methylamino.

Such as bookThe term "C" as used herein_1-7Alkylamino radical C_1-7Alkyl "by itself or as part of another group means through C as defined herein_1-7At least one C, as defined herein, having an alkyl group pendant to the parent molecular moiety_1-7An alkylamino group.

The term "carboxy C" as used herein_1-7Alkylamino "by itself or as part of another group means through C as defined herein_1-7An alkylamino group is appended to at least one carboxyl group, as defined herein, on the parent molecular moiety.

The term "C" as used herein_1-7Alkoxy radical C_1-7Alkyl "refers to C as defined herein_1-7At least one C, as defined herein, having an alkyl group pendant to the parent molecular moiety_1-7An alkoxy group.

The term "C" as used herein_1-7Alkoxycarbonyl radical C_1-7Alkyl "refers to C as defined herein_1-7At least one C, as defined herein, having an alkyl group pendant to the parent molecular moiety_1-7An alkoxycarbonyl group.

The term "substituted" as used herein in connection with various residues refers to halogen substituents, such as fluorine, chlorine, bromine, iodine, or C_1-7Alkyl radical, C_3-7Cycloalkyl, halo C_1-7Alkyl, hydroxy, amino, C_1-7Alkoxy radical, C_1-7Acyl radical C_1-7Alkylamino radical, amino radical C_1-7Alkyl, nitro, cyano, thiol or methylsulfonyl substituents. Preferred are halogen, C_1-7Alkyl, halo C_1-7Alkyl, hydroxy, amino, C_1-7Alkoxy and methylsulfonyl substituents. Particularly preferably 1 to 3C_1-3An alkyl substituent.

A "substituted" group may contain 1 to 3, preferably 1 or 2, of the above substituents.

The term "5-6 membered heterocyclic ring" as used herein refers to a saturated, partially saturated or aromatic ring having 5 or 6 ring atomsWherein 1-4 atoms are heteroatoms selected from N, O and S. Representative examples of 5-6 membered heterocycles include, but are not limited to, pyrazolyl, 1,2, 4-triazol-1-yl, 1,2, 3-triazol-1-yl, pyrimidinyl, pyridyl, tetrazolyl, piperazinyl, furyl, morpholinyl, piperidinyl, pyrrolidinyl, thiazolyl, isoxazolylAzolyl, pyrazinyl, tetrahydropyranyl, 1,2,4-A diazolyl group,Oxazolyl, imidazolyl, indolyl and 4, 5-dihydroimidazolyl rings.

The term "5-12 membered heterocyclic ring" as used herein refers to a monocyclic or bicyclic saturated, partially saturated or aromatic ring having 5 to 12 ring atoms, wherein 1-5 atoms are heteroatoms selected from N, O and S. Representative examples of 5-12 membered heterocycles include the examples given above, and additionally include, but are not limited to, indazolyl, pyrazolo [1,5-a ] pyrimidinyl, benzo [ d ] imidazolyl, imidazo [4,5-b ] pyridinyl, 4,5,6, 7-tetrahydrobenzo [ d ] imidazolyl, and benzofuranyl rings.

The term "5-12 membered carbocyclic ring" as used herein refers to a saturated, partially saturated or aromatic ring having 5 to 12 ring atoms consisting of carbon atoms only. Representative examples of 5-12 membered carbocycles include, but are not limited to, phenyl, naphthyl, and cyclohexyl rings.

The definition of formula (I) above includes all possible isotopes and isomers of the compound, such as stereoisomers, including geometric isomers, such as Z and E isomers (cis and trans isomers) and optical isomers, such as diastereomers and enantiomers, and prodrug esters, such as phosphate esters and carbonate esters.

One skilled in the art will appreciate that the compounds of the present invention may contain at least one chiral center. Thus, the compounds of the present invention may exist in optically active or racemic forms. It is to be understood that formula (I) includes any racemic or optically active form or mixtures thereof. In one embodiment, the compound is the pure (R) -isomer. In another embodiment, the compound is the pure (S) -isomer. In another embodiment, the compound is a mixture of the (R) and (S) isomers. In another embodiment, the compound is a racemic mixture comprising equal amounts of the (R) and (S) isomers. The compound may contain 2 chiral centers. In this case, according to one embodiment, the compounds of the invention are pure diastereomers. According to another embodiment, the compound is a mixture of several diastereomers. The individual isomers can be obtained from the corresponding isomeric forms of the starting materials or, after the preparation of the final compound, they can be separated by customary separation methods. To separate optical isomers, such as enantiomers or diastereomers, from mixtures thereof, conventional resolution methods, such as fractional crystallization, can be used.

The compounds of the present invention may also exist as tautomers or equilibrium mixtures thereof wherein a proton of a compound moves from one atom to another. Examples of tautomers include, but are not limited to, amide-imide, keto-enol, phenol-keto, oxime-nitroso, nitro-acid, imine-enamine, and the like. The compounds of formula (I) include tautomeric forms of the compounds of formula (I), even though only one tautomeric form may be depicted. For example, compounds of the formula (Ib

Wherein R is₁、R₂、R₃、R₄、R₅、Z、Z₂And A and B are as defined above, are imide tautomers of amide compounds of formula (Ib), and are therefore within the scope of formula (I) as defined herein.

Examples of preferred compounds of formula (I) include:

4- (2, 4-difluorophenyl) -N- (1-methyl-1H-pyrazol-3-yl) -6- (5- (1-methyl-1H-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 [ d ] imidazol-1-yl) pyridin-2-yl) cyclopropanesulfonamide;

the sodium salt of the imide 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;

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

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

the sodium salt of the imide 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;

an imide form of 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;

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

the sodium salt of the imide form of N- (4- (2-fluorophenyl) -6- (5- (1-methyl-1H-pyrazol-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- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) pyridin-2-yl) ethanesulfonamide;

the sodium salt of N- (4- (2-fluorophenyl) -6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) pyridin-2-yl) ethanesulfonamide in imide form;

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

the sodium salt of the imide 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;

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-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) pyridin-2-yl) methanesulfonamide;

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

the sodium salt of the imide form of N- (4- (4-fluorophenyl) -6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) pyridin-2-yl) propane-2-sulfonamide;

n- (3-fluoro-6 ' - (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [2,4' -bipyridinyl ] -2' -yl) cyclopropanesulfonamide;

n- (3-fluoro-6 ' - (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [2,4' -bipyridinyl ] -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-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) pyrimidin-2-yl) cyclopropanesulfonamide;

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

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

n- (3, 5-difluoro-6 ' - (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [2,4' -bipyridinyl ] -2' -yl) acetamide;

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

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

n- (5-fluoro-6 ' - (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [2,4' -bipyridinyl ] -2' -yl) cyclopropanesulfonamide;

n- (6- (5- (1H-imidazol-1-yl) -1H-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;

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;

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

n- (4- (2, 4-difluorophenyl) -6- (5- (1-methyl-1H-1, 2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) pyridin-2-yl) cyclopropanesulfonamide;

n- (4- (2, 4-difluorophenyl) -6- (5- (1-methyl-1H-imidazol-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) pyrimidin-2-yl) acetamide;

1- (1- (6- (cyclopropanesulfonylamino) -4- (2, 4-difluorophenyl) pyridin-2-yl) -1H-benzo [ d ] imidazol-5-yl) -1H-1,2, 3-triazole-4-carboxylic acid ethyl ester;

n- (4- (2- (difluoromethoxy) -4-fluorophenyl) -6- (5- (1-methyl-1H-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) 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.

The compounds of the invention may be administered to a patient in a therapeutically effective amount, which is generally from about 0.1 to about 5000 mg/day, preferably from about 1 to about 2000 mg/day, depending on the age, weight, race, condition of the patient, the condition to be treated, the route of administration and the active ingredient used. The compounds of the present invention may be formulated into dosage forms using principles known in the art. The compounds are administered to the patient as such or in combination with suitable pharmaceutical excipients in the form of tablets, granules, capsules, suppositories, emulsions, suspensions or solutions. Selection of the appropriate ingredients for the composition is routine skill of one of ordinary skill in the art. Suitable carriers, solvents, gel-forming ingredients, dispersion-forming ingredients, antioxidants, colorants, sweeteners, wetting compounds and other ingredients commonly used in the art may also be used. Compositions containing the active compounds may be administered enterally or parenterally, the oral route being the preferred mode. The active compound is present in the composition in an amount of about 0.5 to 100%, preferably about 0.5 to about 20%, by weight of the total composition.

The compounds of the present invention may be administered to an individual as the active ingredient alone or in combination with one or more other active ingredients useful for the treatment of a particular disease, such as cancer.

The present invention is explained in more detail by the following experiments and examples. The experiments and examples are for illustrative purposes only and do not limit the scope of the invention as defined by the claims.

Experiment of

Inhibition of FGFR1 kinase

FGFR1 assay

Compounds were screened in the TR-FRET assay with FGFR1 kinase. 5ng FGFR1[ Upstate, USA)]The kinase was used in the assay. Compounds were incubated with kinase for 30 minutes at room temperature. After incubation, the substrate mixture [40nM ultra light poly GT (Perkin Elmer, USA) and 13 μ M ATP (Sigma) were added]. After 30 minutes of kinase reaction, the reaction was stopped by adding 40mM EDTA. Eu-labeled anti-phospho-tyrosine antibody [ Perkin Elmer, USA ] was added at 0.5nM]Then, the fluorescence emission at 615nm/665nm [ excitation at 340nm ] was measured]. Compounds were initially screened at 100nM and 1 μ M concentrations. For a complete dose response study, a selection with 100nM FGFR1>Compound inhibited by 50%. The final DMSO concentration in the assay was 1%. For IC₅₀Determination of (8) was performed from a 20mM DMSO stock solution at 1/3^rdAnd (4) carrying out serial dilution. Mu.l of this was transferred to a reaction mixture containing 20. mu.l of the reaction mixture [ total reaction volume 20. mu.l]In the test well. Fluorescence was measured in a Perkin Elmer Wallac 1420Multilabel Counter Victor 3. IC was determined by fitting the dose response data with a sigmoidal curve fitting equation using GraphPad Prism software V5₅₀。

Results

The enzyme activities and selectivities of selected compounds of the invention against different kinases are shown in table 1. The compounds of the invention were found to be potent and selective FGFR kinase inhibitors.

TABLE 1 inhibition of FGFR1 kinase

The preparation of the compounds of the invention is illustrated by the following examples.

Examples

LCMS data were recorded in + ve mode unless otherwise indicated.

Intermediate example 1

4- (1-methyl-1H-pyrazol-4-yl) -2-nitroaniline

A solution of 4-bromo-2-nitroaniline (6g,27.6mmol) in 1, 2-dimethoxyethane (15ml) was degassed for 5 minutes by bubbling nitrogen through it. 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (6.90g,33.1mmol,1.2eq) was added and the mixture was degassed for a further 5 minutes. Pd (dppf) Cl was added in succession₂(2.25g,27.6mmol,0.1eq) and sodium carbonate (8.79g,82.9mmol,3.0eq) in water and the mixture was degassed for an additional 5 minutes and then heated at 90 ℃ for 2 hours the reaction mixture was quenched with water and extracted with ethyl acetate (3 × 50ml), the combined organic layers were washed with water, brine and dried over sodium sulfate, the solvent was evaporated under reduced pressure to give a crude residue which was purified by column chromatography (60-120 silica gel, 40% ethyl acetate in hexane) to give the title product in 75% yield (4.5g), LC-MS ESI (mass calculated: 218.21; mass found: 218.9[ M + H ESI ] (mass calculated: 218.21)]⁺(rt:0.390min)。

Intermediate example 2

3- (4- (1H-benzo [ d ] imidazol-5-yl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester

a)3- (methylsulfonyl) pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of 3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (0.5g,2.67mmol,1.0eq) in DCM (10ml) was added TEA (0.8ml,5.35mmol,2.0 eq). The mixture was stirred at room temperature for 15 minutes. Methanesulfonyl chloride (0.23ml,2.94mmol 1.1eq) was then added and the mixture stirred for 3 hours. The mixture was quenched with water and CH₂Cl₂Extraction (3 × 50ml) Evaporation of the solvent gave the title product in 86% yield (0.6 g).

b)3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of 44- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (0.6g,2.26mmol) in DMF was added sodium hydride (0.108g,4.53mmol,2eq) and then the compound of intermediate example 2(a) (0.44g,2.26mmol,1.0eq.) at 0 ℃. The mixture was stirred at room temperature for 1 hour and heated at 90 ℃ for 4 hours, then quenched with ice and extracted as described for intermediate example 1. Evaporation of the solvent gave a crude residue in 50% yield (0.4 g).

c)3- (4- (1H-benzo [ d ] imidazol-5-yl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester

By following the procedure of example 1, the intermediate was degassed (N-N)₂Air bubble) 5-bromo-1H-benzo [ d]To a solution of imidazole (0.050g,0.15mmol) in 1, 4-dioxane (10ml) were added the compound (0.052g,0.15mmol,1eq) of intermediate example 2(b), Pd (PPh)₃)₄(16mg,0.015mmol,0.1eq) and cesium carbonate (0.118g,0.36mmol,2.5 eq). The mixture was heated at 90 ℃ for 16 hours. The reaction mixture was quenched and extracted as in intermediate example 1. Evaporation of the solvent gave the product in 40% yield (20 mg). LC-MS (ESI) mass calculated value of 353.2; measured value of mass 354.4[ M + H]⁺(rt:0.11min)。

Intermediate example 3

4- (1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl) -2-nitroaniline

a)2- (4-iodo-1H-pyrazol-1-yl) -N, N-dimethylethylamine

To a solution of 4-iodo-1H-pyrazole (2.8g,10mmol) in acetonitrile (50ml) were added cesium carbonate (5.04g,15mmol,1.5eq) and 2-chloro-N, N-dimethylethylamine hydrochloride (2.96g,20mmol,2eq) and the mixture was stirred at room temperature for 8 hours. The mixture was quenched with water and extracted with ethyl acetate (3X 150 ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. Evaporation of the solvent gave the crude product in 38% yield (1 g).

b)4- (1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl) -2-nitroaniline

A solution of the compound from example 3(a) (0.5g,1.9mmol) in 1, 2-dimethoxyethane (15ml) was degassed by bubbling nitrogen through it for 5 minutes. 2-Nitro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (0.74g,2.8mmol,1.5eq) was added and the mixture was degassed for a further 5 minutes. Pd (dppf) Cl was added in succession following the procedure of intermediate example 1₂(0.16g,0.2mmol,0.1eq) and sodium carbonate (0.5g,4.7mmol,2.5eq) in water and the mixture heated at 90 ℃ for 16 h. The reaction mixture was quenched and extracted as in intermediate example 1. The solvent was evaporated to give a crude residue which was purified by column chromatography (60-120 silica gel, 70% ethyl acetate in hexane) to give the title product in 65% yield (0.3 g). LC-MS (ESI) mass calculated value 275.14; measured value of mass 276.15[ M + H]⁺(rt:0.18min)。

Intermediate example 4

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 (3g,13.8mmol) in DMF (12ml) were added pyrazole (1.12g,16.4mmol,1.2eq.), copper (I) oxide (0.1g,0.69mmol,0.05eq.) and cesium carbonate (8g,24.6mmol,1.8eq.) and the mixture was heated at 100 ℃ overnight. The mixture was quenched and extracted as in intermediate example 1. The solvent was evaporated and the crude residue was purified by column chromatography (60-120 silica gel, 20% ethyl acetate in hexane) to give the title product in 53.5% yield (1.5 g).

b)5- (1H-pyrazol-1-yl) -1H-benzo [ d ] imidazole

A mixture of the compound from example 4(a) (0.5g,2.5mmol) and iron powder (1.39g,25mmol,10eq) was refluxed in formic acid (20ml) overnight. The formic acid was evaporated 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 sulfate. Evaporation of the solvent gave the title product in 87% yield (0.4 g). LC-MS (ESI) mass calculated value 184.07; measured value of mass 185.3[ M + H ]]⁺(rt:0.097min)。

Intermediate example 5

N- (6-chloro-4- (2, 4-difluorophenyl) pyridin-2-yl) cyclopropanesulfonamide

a)2, 6-dichloro-4- (2, 4-difluorophenyl) pyridine

A solution of 2, 6-dichloro-4-iodopyridine (1.5g,5.49mmol) in 1, 2-dimethoxyethane (15ml) was degassed by bubbling nitrogen through it for 5 minutes. 2, 4-difluorophenylboronic acid (0.86g,5.49mmol,1eq) was added and the mixture was degassed for an additional 5 minutes. Pd (dppf) Cl was added in succession following the procedure of intermediate example 1₂(0.358g,0.43mmol,0.08eq) and sodium carbonate (1.45g,13.7mmol,2.5eq) in water and the mixture heated at 90 ℃ for 16 h. The reaction mixture was quenched and extracted as in intermediate example 1. Evaporation of the solvent gave a crude residue which was purified by column chromatography (60-120 silica gel, 3% ethyl acetate in hexane) to give the title product in 98.5% yield (1.4 g).

b) N- (6-chloro-4- (2, 4-difluorophenyl) pyridin-2-yl) cyclopropanesulfonamide

A solution of the compound from intermediate example 5(a) (0.9g,3.46mmol) in dioxane (20ml) was degassed by bubbling nitrogen through it for 5 minutes. Adding cyclopropane sulfonamide0.36g,2.94mmol,1eq) and the mixture is degassed for a further 5 minutes. Palladium acetate (39mg,0.173mmol,0.05eq), Xantphos (200mg,0.35mmol,0.1eq) and Cs were added₂CO₃(3.37g,10.4mmol,3.0eq) and the mixture was degassed for an additional 5 minutes then heated at 100 ℃ for 16 hours the mixture was filtered through celite and extracted with ethyl acetate (3 × 50 ml.) the combined organic layers were washed with water, brine and dried over sodium sulphate evaporating off the solvent to give a crude residue which was purified by column chromatography (60-120 silica gel, 30% ethyl acetate in hexane) to give the title product in 50% yield (0.6 g).¹H NMR (300MHz,DMSO-d₆):11.05(s,1H),7.76-7.68(m,1H),7.51-7.43(m,1H),7.35(s,1H),7.30-7.24(m,1H),7.16(s,1H),3.09-3.01(m,1H),1.22-1.09(m,2H),1.08-1.03(m,2H)。

Intermediate example 6

5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazole

A mixture of the compound from intermediate example 1 (3g,13.7mmol) and iron powder (7.68g,137mmol,10eq) was refluxed in formic acid (50ml) overnight. The formic acid was evaporated 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 sulfate. Evaporation of the solvent gave the title product in 55.5% yield (1.5 g). LC-MS (ESI) mass calculated value 198.09; measured value of mass 199.2[ M + H ]]⁺(rt:0.097min)。

Intermediate example 7

5- (1-methyl-1H-pyrazol-4-yl) -3-nitropyridin-2-amine

A solution of 5-bromo-3-nitropyridin-2-amine (5g,23mmol) in 1, 2-dimethoxyethane (50ml) was degassed for 5 minutes by bubbling nitrogen through it. 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (7.2g,37mmol,1.5eq) was added and the mixture was degassed for a further 5 minutes. Pd (dppf) Cl was added in succession following the procedure of intermediate example 1₂(1.88g,2.3mmol,0.1eq) and sodium carbonate (6.1g,52mmol,2.5eq) in water and the mixture was heated at 90 ℃ for 16 h. The reaction mixture was quenched according to the procedure of intermediate example 1And extracted. Evaporation of the solvent gave a crude residue which was purified by column chromatography (60-120 silica gel, 70% ethyl acetate in hexane) to give the title product in 50% yield (2.5 g). LC-MS (ESI) mass calculated value 219.08; measured value of mass 220.1[ M + H ]]⁺(rt:0.22min)。

Intermediate example 8

4- (1- (2-morpholinoethyl) -1H-pyrazol-4-yl) -2-nitroaniline

a)4- (2- (4-bromo-1H-pyrazol-1-yl) ethyl) morpholine

To a solution of 4- (2-chloroethyl) morpholine (2.55g,13.6mmol) and 4-bromo-1H-pyrazole (2g,13.6mmol,1eq) in DMF (50ml) was added K₂CO₃(0.16g,6.72mmol,1.5eq) and the mixture was stirred at room temperature for 24 h the mixture was quenched with water and extracted with ethyl acetate (3 × 100ml), the combined organic layers were washed with water, brine and dried over sodium sulfate, the solvent was evaporated to give 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

A solution of the compound from intermediate example 8(a) (1g,3.8mmol) in DME (15ml) was degassed by bubbling nitrogen through it for 5 minutes. Bis (pinacolato) diboron (1.46g,5.7mmol,1.5eq) was added and the mixture was degassed for an additional 5 minutes. Pd (dppf) Cl was added in succession following the procedure of intermediate example 1₂(0.313g,0.38mmol,0.1eq) and potassium acetate (1.32g,13.4mmol,3.5eq) and the mixture was then heated at 100 ℃ for 4 hours. The reaction mixture was quenched and extracted as in intermediate example 1. Evaporation of the solvent gave a crude residue which was purified by column chromatography (60-120 silica gel, 50% ethyl acetate in hexane) to give the title product in 87% yield (1 g). LC-MS (ESI) mass calculated value 307.2; measured value of mass 308.5[ M + H ]]⁺(rt:0.10min)。

c)4- (1- (2-morpholinoethyl) -1H-pyrazol-4-yl) -2-nitroaniline

Intermediate example 8(b) A solution of the compound (1g,4.6mmol) in 1, 2-dimethoxyethane (15ml) was degassed by bubbling nitrogen gas through it for 5 minutes. 4-bromo-2-nitroaniline (1.41g,4.6mmol,1eq) was added and the mixture was degassed for an additional 5 minutes. Pd (dppf) Cl was added in succession following the procedure of intermediate example 1₂(0.38g,0.46mmol,0.1eq) and aqueous sodium carbonate (1.41g,13.8mmol,3eq), and the mixture was then heated at 100 ℃ for 4 hours. The reaction mixture was quenched and extracted as in intermediate example 1. The solvent was evaporated to give a crude residue which was purified by column chromatography (60-120 silica gel, 50% ethyl acetate in hexane) to give the title product in 42% yield (0.6 g). LC-MS (ESI) mass calculated value 317.15; measured value of mass 318.05[ M + H]⁺(rt:0.20min)。

Intermediate example 9

4- (1H-imidazol-1-yl) -2-nitroaniline

To a solution of 4-bromo-2-nitroaniline (3g,13.8mmol) in DMF (12ml) were added imidazole (2.71g,27.6mmol,2eq), copper (I) oxide (0.1g,0.69mmol,0.05eq.) and cesium carbonate (13.4g,41.4mmol,3eq) and the mixture was heated at 100 ℃ overnight. The mixture was quenched and extracted as in intermediate example 1. The solvent was evaporated and the crude residue was purified by column chromatography (60-120 silica gel, 50% ethyl acetate in hexane) to give the title product in 40% yield (1.1 g).¹H NMR(300MHz,DMSO-d₆):8.17(br s,1H),8.12(d,1H),7.73-7.68(m,2H),7.59(s,2H),7.15(d,1H),7.08(s,1H)。

Intermediate example 10

5- (1-ethyl-1H-1, 2, 3-triazol-4-yl) -1H-benzo [ d ] imidazole

a) 2-nitro-4- ((trimethylsilyl) ethynyl) aniline

4-iodo-2-nitroaniline (1g,3.8mmol) in DMF-Et₃The N (1: 1; 20ml) solution was degassed for 15 minutes by bubbling nitrogen through it. Sequentially adding Pd (PPh)₃)₄(0.22g,0.19mmol,0.05eq.), copper (I) iodide (0.073g,0.386mmol,0.1eq.) and ethynyltrimethylsilane (0.45ml,4.63 eq.)mmol,1.2eq.) and the mixture was stirred at room temperature for 12 hours. The mixture was quenched and extracted as in intermediate example 1. The solvent was evaporated and the crude residue was purified by column chromatography (60-120 silica gel, 10% ethyl acetate in hexane) to give the title product in 67% yield (0.6 g).

b) 4-ethynyl-2-nitroaniline

To a solution of the compound from intermediate example 10(a) (0.5g,2.15mmol) in THF (10ml) at 0 ℃ was added TBAF (0.5g,2.17mmol,1.2eq.) and the mixture was stirred for 0.5 h. The mixture was filtered through a pad of silica gel and distilled to give the title product in 86% yield (0.3 g).

c)4- (1-ethyl-1H-1, 2, 3-triazol-4-yl) -2-nitroaniline

A mixture of the compound of intermediate example 10(b) (0.3g,1.85mmol), sodium azide (0.24g,3.7mmol,1.0eq.), methyl iodide (0.23g,1.85mmol,1.0eq.), sodium ascorbate (0.36g,1.85mmol,1.0eq.), and copper sulfate pentahydrate (0.23g,0.92mmol,0.5eq.) in DMSO, THF and water (1:1:0.5,5ml) was stirred at room temperature for 12 hours. The mixture is quenched with water, and the precipitate formed is filtered off and dried. The crude product was purified by column chromatography (60-120 silica gel, 30% ethyl acetate in hexanes) to give the title product in 25% yield (100 mg).

d)5- (1-ethyl-1H-1, 2, 3-triazol-4-yl) -1H-benzo [ d ] imidazole

To a solution of the compound from intermediate example 10(c) (0.1g,0.42mmol) in formic acid (2ml) was added iron (0.23g,4.2mmol) and heated at 100 ℃ for 16 hours. 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 sulfate. Evaporation of the solvent gave the title product in 33% yield (30 mg). LC-MS (ESI) mass calculated value 213.1; measured value of mass 214.1[ M + H ]]⁺(rt:0.14min)。

Intermediate example 11

5- (1-methyl-1H-imidazol-4-yl) -1H-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 (1.45g,5.55mmol,1.1eq) in 1, 2-dimethoxyethane (15ml) was degassed by bubbling nitrogen through it for 5 minutes. 4-bromo-1-methyl-1H-imidazole (0.81g,5mmol,1eq) was added and the mixture was degassed for an additional 5 minutes. Pd (dppf) Cl was added in succession following the procedure of intermediate example 1₂(0.4g,0.5mmol,0.1eq) and sodium carbonate (1.59g,15mmol,3eq) in water and heated at 100 ℃ for 4 hours. The reaction mixture was then quenched and extracted as in intermediate example 1. Evaporation of the solvent gave a crude residue which was purified by column chromatography (60-120 silica gel, 50% ethyl acetate in hexane) to give the title product in 60% yield (0.6 g). LC-MS (ESI) mass calculated value 218.08; measured value of mass 219.2[ M + H ]]⁺(rt:0.09min)。

b)5- (1-methyl-1H-imidazol-4-yl) -1H-benzo [ d ] imidazole

To a solution of the compound from intermediate example 11(a) (0.3g,1.376mmol) in formic acid (5ml) was added iron (0.77g,13.76mmol) and the mixture was heated at 90 ℃ for 12 hours. The formic acid was evaporated off and the crude product was dissolved in ethyl acetate. The ethyl acetate layer was washed with water, brine and dried over sodium sulfate. Evaporation of the solvent gave the title product in 26% yield (0.07 g). LC-MS (ESI) mass calculated value 198.09; measured value of mass 199.2[ M + H ]]⁺(rt:0.10min)。

Intermediate example 12

5- ((trimethylsilyl) ethynyl) -1H-benzo [ d ] imidazole

a) 5-iodo-1H-benzo [ d ] imidazoles

To a solution of 4-iodo-2-nitroaniline (1g,3.7mmol) in formic acid (10ml) was added iron (2.1g,37mmol) and heated at 90 ℃ for 12 hours. The formic acid was evaporated off and the crude product was dissolved in ethyl acetate. The ethyl acetate layer was washed with water, brine and dried over sodium sulfate. Evaporation of the solvent gave the title product in 68% yield (0.85 g). LC-MS (ESI) mass calculated value 243.95; actual measurement of massValue of 244.8[ M + H]⁺(rt:0.173min)。

b)5- ((trimethylsilyl) ethynyl) -1H-benzo [ d ] imidazole

The compound of intermediate example 12(a) (0.7g,2.56mmol) in DMF-Et₃The N (1: 1; 10ml) solution was degassed for 15 minutes by bubbling nitrogen through it. Pd (dppf) Cl was added in succession₂(0.11g,0.14mmol,0.05eq), copper (I) iodide (0.054g,0.25mmol,0.1eq) and ethynyltrimethylsilane (0.3g,3.15mmol,1.1eq) and the mixture was stirred at room temperature for 12 hours. The mixture was quenched and extracted as in intermediate example 1. The solvent was evaporated and the crude residue was recrystallized from hexane to give the title product in 57% yield (0.35 g). LC-MS (ESI) mass calculated value 214.09; found value of mass 215.5[ M + H ]]⁺(rt:0.22min)。

Intermediate example 13

4- (1-methyl-1H-pyrazol-4-yl) benzene-1, 2-diamine

To a solution of the compound of intermediate example 1 (1g,4.58mmol) in THF (10ml) was added a solution of ammonium chloride (1.486g,27.5mmol,6eq) in water (5ml) and zinc (1.78g,27.5mmol,6 eq.) the reaction mixture was stirred at room temperature for 6 hours and filtered, the filtrate was diluted with water and extracted with ethyl acetate (3 × 100ml), the combined organic layers were washed with water, brine and dried over sodium sulfate, the solvent was evaporated to give a crude residue which was purified by column chromatography (60-120 silica gel, 3% methanol/DCM) to give the title product in 58% yield (0.5 g.) LC-MS (ESI) mass calculated value: 188.11; mass found: 189.0[ M + H ] (ESI)]⁺(rt:0.113min)。

Intermediate example 14

1- (1H-benzo [ d ] imidazol-5-yl) -1H-1,2, 3-triazole-4-carboxylic acid ethyl ester

a) 1H-benzo [ d ] imidazol-5-amine

To 5-nitro-1H-benzo [ d ]]Pd/C was added to a solution of imidazole (5g,44.2mmol) in methanol (100ml) and the reaction mixture was stirred at room temperature for 16 h and filtered. Adding water to the filtrateDiluted and extracted with ethyl acetate (3 × 100 ml). the combined organic layers were washed with water, brine and dried over sodium sulfate, the solvent was evaporated to give a crude residue which was purified by washing with diethyl ether to give the title product in 85% yield (2.5 g). LC-MS (ESI) mass calculated value: 133.06; mass calculated value: 134.2[ M + H ], (ESI)]⁺(rt:0.175min)。

b) 5-azido-1H-benzo [ d ] imidazoles

To a solution of the compound of intermediate example 14(a) (2g,15mmol) in concentrated hydrochloric acid (8ml) was added NaNO dropwise at 0 deg.C₂(1.3g,18.7mmol,1.25eq) and the mixture was stirred at 0 ℃ for 30 min. Then adding NaN at 0 deg.C₃(1.13g,18.7mmol,1.25eq) and the mixture was stirred for 15 min. The mixture was quenched and extracted as in intermediate example 1 (a). Evaporation of the solvent gave the product in 75% yield (1.8 g). LC-MS (ESI) mass calculated value 159.05; measured value of mass 160.0[ M + H ]]⁺(rt:0.136min)。

c)1- (1H-benzo [ d ] imidazol-5-yl) -1H-1,2, 3-triazole-4-carboxylic acid ethyl ester

A mixture of the compound (1.75g,10.99mmol) of intermediate example 14(b), ethyl propiolate (1.08g,10.99mmol,1.0eq), sodium ascorbate (0.22g,1.09mmol,0.1eq) and copper sulfate pentahydrate (30mg,0.1mmol,0.01eq) in t-butanol and water (1:0.5,20ml) was stirred at room temperature for 48 hours. The volatile material was distilled off and the reaction mixture was taken up in 10% methanol/CH₂Cl₂(3 × 100ml) the combined organic layers were washed with water, brine and dried over sodium sulfate and concentrated the resulting light brown solid (1.6g, 56.6% yield) was used in the next step without further purification LC-MS (ESI) LC-MS mass calculated value: 257.09; mass found value: 258.05[ M + H ]]⁺(rt:0.193min)。

Intermediate example 15

N- (6-chloro-4- (2- (difluoromethoxy) -4-fluorophenyl) pyridin-2-yl) cyclopropanesulfonamide

a) 1-bromo-2- (difluoromethoxy) -4-fluorobenzene

To a solution of 2-bromo-5-fluorophenol (3g,15.7mmol) in DMF (5ml) was added cesium carbonate (7.7g,23.56mmol,1.5eq) and sodium chlorodifluoroacetate (6g,39.26mmol,2.5eq) and the reaction mixture was heated at 100 ℃ for 15 h. The reaction mixture was extracted with water and ethyl acetate (3X 50 ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. Evaporation of the solvent gave a crude residue which was purified by column chromatography (60-120 silica gel, 10% ethyl acetate in hexane) in 58% yield (2.2 g).

b)2, 6-dichloro-4- (2- (difluoromethoxy) -4-fluorophenyl) pyridine

A solution of the compound from intermediate example 15(a) (2.2g,9.13mmol) in 1, 2-dimethoxyethane (50ml) was degassed by bubbling nitrogen through it for 5 minutes. 2, 6-dichloro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (2.75g,10.04mmol,1.1eq) was added and the mixture was degassed for an additional 5 minutes. Pd (dppf) Cl was added in succession following the procedure of intermediate example 1₂(0.74g,0.9mmol,0.1eq) and sodium carbonate (2.9g,27.3mmol,2.5eq) in water, followed by heating at 110 ℃ for 4 hours. The reaction mixture was quenched and extracted as in intermediate example 1. The solvent was evaporated to give a crude residue which was purified by column chromatography (60-120 silica gel, 10% ethyl acetate in hexane) to give the title product in 43% yield (1.2 g). LC-MS (ESI) mass calculated value 306.98; measured value of mass 307.85[ M + H]⁺(rt:2.0min)。

c) N- (6-chloro-4- (2- (difluoromethoxy) -4-fluorophenyl) pyridin-2-yl) cyclopropanesulfonamide

A solution of the compound from intermediate example 15(b) (0.5g,1.62mmol) in dioxane (10ml) was degassed by bubbling nitrogen for 5 minutes, cyclopropanesulfonamide (0.19g,1.62mmol,1eq) was added and the mixture was degassed further for 5 minutes, palladium acetate (18mg,0.08mmol,0.05eq), Xantphos (46mg,0.08mmol,0.05eq) and cesium carbonate (1.56g,4.8mmol,3.0eq) were added in that order and the reaction mixture was degassed further for 5 minutes and then heated at 100 ℃ for 5 hours, the reaction mixture was filtered through a pad of celite and extracted with ethyl acetate (3 × 50 ml). The reaction mixture was filteredThe combined organic layers were washed with water, brine and dried over sodium sulfate. Evaporation of the solvent gave a crude residue which was purified by column chromatography (60-120 silica gel, 30% ethyl acetate in hexane) in 47% yield (0.3 g). LC-MS (ESI) mass calculated value 392.02; measured value of mass 392.85[ M + H]⁺(rt:1.82min)。

Intermediate example 16

N- (6-chloro-4- (2, 4-difluorophenyl) pyridin-2-yl) acetamide

A solution of the compound from intermediate example 5(a) (0.5g,1.92mmol) in dioxane (20ml) was degassed by bubbling nitrogen through it for 5 minutes. Acetamide (0.11g,1.92mmol,1eq) was added and the mixture was degassed for a further 5 minutes. Palladium acetate (43mg,0.19mmol,0.1eq), Xantphos (222mg,0.38mmol,0.2eq) and Cs were added sequentially₂CO₃(1.88g,5.76mmol,3.0eq) and the reaction mixture was degassed for a further 5 minutes and then heated at 100 ℃ for 16 hours the reaction mixture was filtered through celite and extracted with ethyl acetate (3 × 50 ml.) the combined organic layers were washed with water, brine and dried over sodium sulphate and the solvent evaporated to give a crude residue which was purified by column chromatography (60-120 silica gel, 30% ethyl acetate in hexane) to give the title product in 64.5% yield (0.35 g.) LC-MS (ESI): mass calculated value: 282.04; mass found: 283.0[ M + H ] mass calculated value]⁺(rt:1.60min)。

Example 1

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

a) 6-chloro-4- (2, 4-difluorophenyl) -N- (4- (1-methyl-1H-pyrazol-4-yl) -2-nitrophenyl) pyridin-2-amine

A solution of the compound from intermediate example 5(a) (0.8g,3.07mmol) in toluene (5ml) was degassed by bubbling nitrogen through it for 5 minutes. The compound of intermediate example 1 (0.8g,3.69mmol,1.2eq) was added and the mixture was degassed for an additional 5 minutes. Palladium acetate (0.027g, 0) was added sequentially123mmol,0.04eq), BINAP (0.076g,0.123mmol,0.04eq) and potassium tert-butoxide (0.69g,6.15 mmol,2.0eq) and the mixture is degassed for a further 5 minutes and then heated at 100 ℃ for 5 hours, the mixture is filtered over a pad of celite and extracted with ethyl acetate (3 × 50ml), the combined organic layers are washed with water, brine and dried over sodium sulfate, the solvent is evaporated off to give a crude residue which is purified by column chromatography (60-120 silica gel, 30% ethyl acetate in hexane), 29.5% yield (0.4g), LC-MS (ESI) mass calculated value 441.2, mass found 442.0[ M + H)]⁺(rt:1.84min)。

b)1- (6-chloro-4- (2, 4-difluorophenyl) pyridin-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazole

To a solution of the compound from example 1(a) (0.4g,0.907mmol) in formic acid (5ml) was added iron (0.5g,9.07mmol) and the mixture was heated at 100 ℃ for 16 h. The formic acid was evaporated off and the crude product was dissolved in ethyl acetate. The ethyl acetate layer was washed with water, brine and dried over sodium sulfate. Evaporation of the solvent gave the title product in 47% yield (0.18 g). LC-MS (ESI) mass calculated value 421.2; measured value of mass 422.5[ M + H]⁺(rt:1.83min)。

c)4- (2, 4-difluorophenyl) -N- (1-methyl-1H-pyrazol-3-yl) -6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) pyridin-2-amine

A solution of the compound from example 1(b) (0.07g,0.166mmol) in toluene (5ml) was degassed by bubbling nitrogen through it for 5 minutes. 1-methyl-1H-pyrazol-3-amine (0.024g,0.199mmol,1.2eq) was added and the mixture was degassed for a further 5 minutes. Pd was added in succession in accordance with the procedure of example 1(a)₂(dba)₃(0.007g,0.0083mmol,0.05eq), Xantphos (0.005g,0.0083mmol,0.05eq) and Cs₂CO₃(0.162g,0.4988mmol,3.0eq) and the mixture was heated at 100 ℃ for 16 h. The mixture was filtered and extracted according to the procedure of example 1 (a). Evaporation of the solvent gave a crude residue which was purified by preparative HPLC to give the title product in 15% yield (12 mg).¹H NMR(400MHz,CD₃OD):8.83(s,1H),8.24-8.22(d,1H),8.03(s,1H),7.90-7.89(d,2H),7.77-7.71(m,1H),7.62-760(m,1H),7.51(d,1H),7.30-7.25(d,2H),7.20-7.13(m,2H),6.43-6.42(d,1H),3.97(s,3H),3.86(s, 3H); LC-MS (ESI) mass calculated value 482.18; measured value of mass 483.55[ M + H]⁺(rt:1.57min)。

Example 2

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

A solution of the compound (42mg,0.1mmol) obtained in example 1(b) in dioxane (1ml) was degassed by bubbling nitrogen gas through the solution for 5 minutes. Cyclopropanesulfonamide (0.11g,0.1mmol,1eq) was added and the mixture was degassed for an additional 5 minutes. Palladium acetate (2mg,0.008mmol,0.08eq), Xantphos (5mg,0.008mmol,0.08eq) and Cs were added₂CO₃(100mg,0.3mmol,3.0eq) and the mixture was degassed for an additional 5 minutes then heated at 100 ℃ for 16 hours the mixture was filtered through celite and extracted with ethyl acetate (3 × 50ml), the combined organic layers were washed with water, brine and dried over sodium sulphate, the solvent was evaporated to give a crude residue which was purified by preparative HPLC to give the title product in 20% yield (10 mg).¹H NMR(300MHz,CD₃OD) 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) mass calculated value 506.1; measured value of mass 507.1[ M + H]⁺(rt:1.52min)。

Example 2 (imide)

Sodium salt of imide 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

This compound (34mg) was prepared from the title compound of example 2 using the method described for example 17 (imide). The desired compound was crystallized from ethanol.¹H NMR(300MHz,DMSO-d₆):8.83(s,1H),8.818.78(d,1H),8.19(s,1H),7.93(s,1H),7.88(d,1H),7.76-7.68(m,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) mass calculated value 506.1; measured value of mass 506.8[ M + H]⁺(rt:1.54min)。

Example 3

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

This compound was prepared from the compound of example 1(b) using the method of example 2.¹H NMR(400MHz,DMSO-d₆) 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) mass calculated value 444.15; measured value of mass 445.3[ M + H]⁺(rt:1.43min)。

Example 4

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

This compound was prepared from the compound of example 1(b) using the method of example 2.¹H NMR(400MHz,DMSO-d₆) 11.2(s,1H),9.03(s,1H),8.60(d,1H),8.21(s,1H),7.95(s,2H),7.89-7.82(m,1H),7.74(s,1H),7.59-7.48(m,2H),7.34-7.31(m,1H),7.05(s,1H),3.87(s,3H),3.38(s, 3H); LC-MS (ESI) mass calculated value 480.12; measured value of mass 481.05[ M + H]⁺(rt:1.39min)。

Example 5

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

This compound was prepared from the compound of example 1(b) using the method of example 2.¹H NMR(400MHz,DMSO-d₆) 11.1(s,1H),9.02(s,1H),8.61(d,1H),8.22(s,1H),7.95-7.94(m,2H),7.89-7.83(m,1H),7.74(s,1H),7.60-7.56(m,1H),7.54-7.48(m,1H),7.36-7.31(m,1H),7.06(s,1H),3.87(s,3H),3.54 (quartet, 2H),1.26(t, 3H); LC-MS (ESI) mass calculated value 494.13; measured value of mass 494.8[ M + H]⁺(rt:1.5min)。

Example 5 (imide).

Sodium salt of imide 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

This compound (30mg) was prepared from the title compound of example 5 using the method described for example 17 (imide). The desired compound was washed with diethyl ether and dried.¹H NMR(300MHz,DMSO-d₆)8.83 (s,1H),8.8-8.7(d,1H),8.19(s,1H),7.93(s,1H),7.88(s,1H),7.73-7.69(m,1H),7.52-7.49(dd,1H),7.27-7.21(t,1H),6.94(s,1H),6.48(s,1H),3.87(s,3H),3.11-3.04(q,2H),1.14-1.07(t, 3H); LC-MS (ESI) mass calculated value 494.13; measured value of mass 495.1[ M + H]⁺(rt:1.42min)。

Example 6

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

This compound was prepared from the compound of example 1(b) using the method of example 2.¹H NMR(400MHz,DMSO-d₆) 11.1(s,1H),9.04(s,1H),8.67(d,1H),8.22(s,1H),7.96-7.94(m,2H),7.87-7.85(m,1H),7.73(s,1H),7.61-7.52(m,2H),7.34(m,1H),7.06(s,1H),3.95(m,1H),3.87(s,3H),1.33(d, 6H); LC-MS (ESI) mass calculated value 508.15; measured value of mass 509.05[ M + H]⁺(rt:1.65min)。

Example 6 (imide)

Imide forms of 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

A slurry of the crude residue of the compound from example 6 (12g) was stirred with THF (166ml) at 65 ℃ and filtered hot. The solid material was dried in vacuo to give 3.5g of the title compound.¹H NMR(400MHz,DMSO-d₆)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,1H),3.87(s,3H),3.75-3.65(sep,1H),1.16-1.14(d, 6H); LC-MS (ESI) mass calculated 508.15 (free base); measured value of mass 508.8[ M + H ]]⁺(free base) (rt:1.51 min).

Example 7

N- (4- (2, 4-difluorophenyl) -6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) pyridin-2-yl) pyridazin-3-amine

This compound was prepared from the compound of example 1(b) using the method of example 2.¹H NMR(400MHz,DMSO-d₆) 10.29(s,1H),8.93(s,1H),8.90-8.87(m,1H),8.43-8.42(m,1H),8.24-8.18(m,2H),8.15-8.10(m,2H),7.99(s,1H),7.96(s,1H),7.65-7.62(m,2H),7.5-7.44(m,1H),7.36-7.28(m,2H),3.87(s, 3H); LC-MS (ESI) mass calculated value 480.16; found value of quality 481.1[ M + H ]]⁺(rt:1.39min)。

Example 8

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

a)2, 6-dichloro-4- (2-fluorophenyl) pyridine

2,6A solution of dichloro-4-iodopyridine (1.09g,4mmol) in 1, 2-dimethoxyethane (15ml) was degassed by bubbling nitrogen through it for 5 minutes. 2-Fluorophenylboronic acid (0.67g,4.8mmol,1.2eq) was added and the mixture was degassed for an additional 5 minutes. Pd (dppf) Cl was added in succession following the procedure of intermediate example 1₂(0.33g,0.4mmol,0.1eq) and sodium carbonate (1.27g,12mmol,3eq) in water and the mixture heated at 90 ℃ for 2 hours. The reaction mixture was quenched and extracted as in intermediate example 1. Evaporation of the solvent gave a crude residue which was purified by column chromatography (60-120 silica gel, 1% ethyl acetate in hexane) to give the title product in 100% yield (0.97 g).

b) 6-chloro-4- (2-fluorophenyl) -N- (4- (1-methyl-1H-pyrazol-4-yl) -2-nitrophenyl) pyridin-2-amine

A solution of the compound from example 8(a) (0.97g,4mmol) in toluene (5ml) was degassed for 5 minutes by bubbling nitrogen through it. The compound of intermediate example 1 (0.96g,4.4mmol,1.1eq) was added and the mixture was degassed for an additional 5 minutes. Palladium acetate (36mg,0.16mmol,0.04eq), BINAP (99mg,0.16mmol,0.04eq) and potassium tert-butoxide (0.67g,6mmol,1.5eq) were added in this order as in 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) mass calculated value 423.09; measured value of mass 424.05[ M + H]⁺(rt:2.04min)。

c)1- (6-chloro-4- (2-fluorophenyl) pyridin-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazole

To a solution of the compound from example 8(b) (0.59g,1.4mmol) in formic acid (5ml) was added iron (0.78g,14mmol) and heated at 100 ℃ for 16 h. The formic acid was evaporated off and the crude product was dissolved in ethyl acetate. The ethyl acetate layer was washed with water, brine and dried over sodium sulfate. Evaporation of the solvent gave the title product in 53% yield (0.3 g). LC-MS (ESI) mass calculated value 403.1; measured value of mass 404.1[ M + H]⁺(rt:1.66min)。

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

A solution of the compound from example 8(c) (0.1g,0.25mmol) in dioxane (1ml) was degassed by bubbling nitrogen through it for 5 minutes. Cyclopropanesulfonamide (30mg,0.25mmol,1eq) was added and the mixture was degassed for an additional 5 minutes. Palladium acetate (5mg,0.02mmol,0.08eq), Xantphos (12mg,0.02mmol,0.08eq) and Cs were added₂CO₃(0.24g,0.75mmol,3.0eq) and the mixture was degassed for a further 5 minutes and then heated at 100 ℃ for 16 hours. The mixture was filtered through celite and extracted as described in example 1. The solvent was evaporated to give a crude residue which was purified by preparative HPLC to give the title product in 8% yield (10 mg).¹H NMR(400MHz,CD₃OD) 8.91(s,1H),8.62(d,1H),8.05(s,1H),7.91(m,2H),7.73-7.67(m,3H),7.58-7.52(m,1H),7.41-7.33(m,2H),7.21(s,1H),3.97(s,3H),3.17-3.15(m,1H),1.30-1.26(m,2H),1.06-1.04(m, 2H); LC-MS (ESI) mass calculated value 488.14; measured value of mass 489.2[ M + H]⁺(rt:1.46min)。

Example 8 (imide)

Sodium salt of imide form of N- (4- (2-fluorophenyl) -6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) pyridin-2-yl) cyclopropanesulfonamide

This compound (45mg) was prepared from the title compound of example 8 using the method described for example 17 (imide).¹H NMR(300MHz,DMSO-d₆) 8.82(s,1H),8.79-8.76(d,1H),8.18(s,1H),7.91(s,1H),7.87(d,1H),7.67-7.62(m,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(m,1H),0.82-0.79(m,2H),0.61-0.57(m, 2H); LC-MS (ESI) mass calculated value 488.14; measured value of quality 489.4[ M + H ]]⁺(rt:1.49min)。

Example 9

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

This compound was prepared from the compound of example 8(c) using the procedure of example 8.¹H NMR(300MHz,CD₃OD) 8.88(s,1H),8.37-8.35(m,2H),8.01(s,1H),7.87(m,2H),7.69-7.61(m,3H),7.59-7.49(m,1H),7.36-7.34(m,2H),3.95(s,3H),2.26(m, 3H); LC-MS (ESI) mass calculated value 426.16; measured value of mass 427.25[ M + H]⁺(rt:1.4min)。

Example 10

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

This compound was prepared from the compound of example 8(c) using the procedure of example 8.¹H NMR(300MHz,DMSO-d₆) 11.2(s,1H),9.02(s,1H),8.60(d,1H),8.20(s,1H),7.94(s,2H),7.74(m,2H),7.56(m,2H),7.41(m,2H),7.07(s,1H),3.86(s,3H),3.38(s, 3H); LC-MS (ESI) mass calculated value 462.13; found value of mass 463.1[ M + H]⁺(rt:1.31min)。

Example 11

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

This compound was prepared from the compound of example 8(c) using the method of example 8 (d).¹H NMR(400MHz,DMSO-d₆) 11.1(s,1H),9.03(s,1H),8.61(d,1H),8.22(s, 1H),7.95-7.94(m,2H),7.79-7.76(m,2H),7.60-7.57(m,2H),7.46-7.40(m,2H),7.09(s,1H),3.87(s,3H),3.55 (quartet, 2H),1.26(t, 3H); LC-MS (ESI) mass calculated value 476.14; measured value of mass 477.0[ M + H ]]⁺(rt:1.41min)。

Example 11 (imide).

Sodium salt of N- (4- (2-fluorophenyl) -6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) pyridin-2-yl) ethanesulfonamide in imide form

This compound (34mg) was prepared from the title compound of example 11 using the method described for example 17 (imide). The desired compound was washed with diethyl ether and dried.¹H NMR(400MHz,DMSO-d₆)8.83 (s,1H),8.8-8.78(d,1H),8.2(s,1H),7.93(s,1H),7.89-7.88(d,1H),7.68-7.65(dt,1H),7.52-7.46(m,1H),7.38-7.33(m,2H),6.96(s,1H),6.51(s,1H),3.22(s,3H),3.11-3.06(q,2H),1.14-1.08(t, 3H); LC-MS (ESI) mass calculated value 476.14; measured value of mass 477.0[ M + H ]]⁺(rt:1.41 min). Measured value of mass 476.8[ M + H ]]⁺(rt:1.37min)。

Example 12

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

This compound was prepared from the compound of example 8(c) using the procedure of example 8.¹H NMR(300MHz,DMSO-d₆) 11.03(s,1H),9.03(s,1H),8.67(d,1H),8.22(s,1H),7.96-7.94(m,2H),7.79-7.73(m,2H),7.61-7.55(m,2H),7.42-7.39(m,2H),7.08(s,1H),3.96-3.93(m,1H),3.87(s,3H),1.33(d, 6H); LC-MS (ESI) mass calculated value 490.16; measured value of mass 491.1[ M + H]⁺(rt:1.48min)。

Example 12 (imide)

Sodium salt of imide 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

The title compound (24mg) was prepared from the title compound of example 12 using the method described for example 17 (imide).¹H NMR(400MHz,DMSO-d₆):8.83-8.81(m,2H),8.19(s,1H),7.92(s,1H),7.87(d,1H),7.67-7.63(dt,1H),7.51-7.46(m,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, 6H); LC-MS (ESI) mass calculated value 490.16; measured value of mass 491.4[ M + H]⁺(rt:1.5min)。

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

This compound was prepared from the compound of example 8(c) using the procedure of example 8.¹H NMR(400MHz,DMSO-d₆) 10.49(s,1H),9.01(s,1H),8.85-8.83(m,1H),8.32-8.29(m,1H),8.20(s,1H),8.05(s,1H),7.99-7.94(m,3H),7.79-7.78(m,1H),7.63-7.58(m,4H),7.47-7.41(m,2H),3.87(s, 3H); LC-MS (ESI) mass calculated value 462.17; found mass of 463.2[ M + H ]]⁺(rt:0.95min)。

Example 14

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

a)2, 6-dichloro-4- (4-fluorophenyl) pyridine

A solution of 2, 6-dichloro-4-iodopyridine (2.18g,8mmol) in 1, 2-dimethoxyethane (15ml) was degassed by bubbling nitrogen through it for 5 minutes. 4-Fluorophenylboronic acid (1.34g,9.6mmol,1.2eq) was added and the mixture was degassed for an additional 5 minutes. Pd (dppf) Cl was added in succession following the procedure of intermediate example 1₂(1.3g,1.6mmol,0.2eq) and sodium carbonate (2.54g,24mmol,3eq) in water and the mixture heated at 90 ℃ for 2 hours. The reaction mixture was quenched and extracted as in intermediate example 1. Evaporation of the solvent gave a crude residue which was purified by column chromatography (60-120 silica gel, 1% ethyl acetate in hexane) to give the title product in 77% yield (1.5 g). LC-MS (ESI) mass calculated value 240.99; measured value of mass 242.0[ M + H]⁺(rt:1.95min)。

b) 6-chloro-4- (4-fluorophenyl) -N- (4- (1-methyl-1H-pyrazol-4-yl) -2-nitrophenyl) pyridin-2-amine

A solution of the compound from example 14(a) (0.97g,4mmol) in toluene (5ml) was degassed for 5 minutes by bubbling nitrogen through it. The compound of intermediate example 1 (0.96g,4.4mmol,1.1eq) was added and the mixture was degassed for an additional 5 minutes. Palladium acetate (36mg,0.16mmol,0.04eq), BINAP (99mg,0.16mmol,0.04eq) and potassium tert-butoxide (0.67g,6mmol,1.5eq) were added in this order as in example 1 (a). The crude residue of the product was purified by column chromatography (60-120 silica gel, 50% ethyl acetate in hexane) in 15% yield (0.25 g).

c) N1- (6-chloro-4- (4-fluorophenyl) pyridin-2-yl) -4- (1-methyl-1H-pyrazol-4-yl) benzene-1, 2-diamine

To a solution of the compound from example 14(b) (0.25g,0.6mmol) in THF (10ml) was added a solution of ammonium chloride (0.26g,4.8mmol,8eq) in water (2ml) and zinc (0.31g,4.8mmol,8 eq). The mixture was stirred at room temperature for 6 hours and filtered. The filtrate was diluted with water and extracted as described in intermediate example 1. Evaporation of the solvent gave the title product in 100% yield (0.24 g). LC-MS (ESI) mass calculated value 393.12; measured value of mass 394.5[ M + H ]]⁺(rt:1.59min)。

d)1- (6-chloro-4- (4-fluorophenyl) pyridin-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazole

A solution of the compound from example 14(c) (0.24g,0.6mmol) and formic acid (5ml) was heated at 100 ℃ for 16 hours. The formic acid was distilled off and the crude product was extracted as described in example 8 (c). Evaporation of the solvent gave the title product in 38% yield (90 mg). LC-MS (ESI) mass calculated value 403.1; measured value of quality 404.2[ M + H ]]⁺(rt:1.68min)。

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

A solution of the compound (40mg,01mmol) obtained in example 14(d) in dioxane (1ml) was degassed by bubbling nitrogen gas through it for 5 minutes. Cyclopropanesulfonamide (12mg,0.1mmol,1eq) was addedAnd the mixture was degassed for an additional 5 minutes. Palladium acetate (2mg,0.008mmol,0.08eq), Xantphos (5mg,0.008mmol,0.08eq) and Cs were added₂CO₃(0.1g,0.3mmol,3.0eq) and the mixture was degassed for a further 5 minutes and then heated at 100 ℃ for 16 hours. The mixture was filtered through celite and extracted as described in example 1. The solvent was evaporated to give a crude residue which was purified by preparative HPLC to give the title product in 20% yield (10 mg).¹H NMR(400MHz,CD₃OD) 8.97(s,1H),8.68(d,1H),8.06(s,1H),7.92-7.89(m,4H),7.73(m,1H),7.69-7.67(m,1H),7.34-7.29(m,2H),7.21(m,1H),3.97(s,3H),3.16-3.09(m,1H),1.30-1.26(m,2H),1.05-1.03(m, 2H); LC-MS (ESI) mass calculated value 488.14; measured value of mass 489.1[ M + H]⁺(rt:1.5min)。

Example 15

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

This compound was prepared from the compound of example 14(d) using the procedure of example 14.¹H NMR(400MHz,DMSO-d₆) 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) mass calculated value 426.16; measured value of mass 427.5[ M + H ]]⁺(rt:1.47min)。

Example 16

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

This compound was prepared from the compound of example 14(d) using the procedure of example 14.¹H NMR(400MHz,DMSO-d₆) 11.2(s,1H),9.12(s,1H),8.63(d,1H),8.22(s,1H),7.96-7.92(m,4H),7.86(s,1H),7.59-7.57(m,1H),7.46-7.42(m,2H),7.11(s,1H),3.88(s,3H),3.38(s, 3H); LC-MS (ESI) mass calculated value 462.13; measured value of quality:462.8[M+H]⁺(rt:1.43min)。

Example 17

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

This compound was prepared from the compound of example 14(d) using the procedure of example 14 (e).¹H NMR(300MHz,DMSO-d₆) 11.0(s,1H),9.13(s,1H),8.68(d,1H),8.22(s,1H),7.96-7.87(m,5H),7.62-7.58(m,1H),7.47-7.41(m,2H),7.12(s,1H), 3.99-3.93(m,1H),3.87(s,3H),1.34(d, 6H); LC-MS (ESI) mass calculated value 490.16; measured value of mass 491.05[ M + H]⁺(rt:1.58min)。

Example 17 (imide)

Sodium salt of imide form of N- (4- (4-fluorophenyl) -6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) pyridin-2-yl) propane-2-sulfonamide

To the compound (37mg) of example 17 were added isopropanol (1ml) and sodium tert-butoxide (7mg), and after refluxing overnight the mixture was evaporated to give 32mg of the title compound.¹H NMR(300MHz,DMSO-d₆) 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,6H) mass calculated value of 490.16; measured value of mass 491.45[ M + H]⁺(rt:1.52min)。

Example 18

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

a)2, 6-dichloro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine

A solution of 2, 6-dichloro-4-iodopyridine (15g,54.9mmol) in DMF (150ml) was degassed by bubbling nitrogen through it for 5 minutes. Bis (pinacolato) diboron (17.63g,82.4mmol,1.5eq) was added and the mixture was degassed for an additional 5 minutes. Pd (dppf) Cl was added in succession following the procedure of intermediate example 1₂(2.24g,2.7mmol,0.05eq) and potassium acetate (8.07g,82.4mmol,1.5eq) and the mixture was heated at 90 ℃ for 3 hours. The reaction mixture was then quenched and extracted as in intermediate example 1. Evaporation of the solvent gave a crude residue which was purified by column chromatography (60-120 silica gel, 50% ethyl acetate in hexane) to give the title product in 67% yield (10 g).¹H NMR(300MHz,CDCl₃):7.59(s,2H),1.35(s,6H),1.26(s,6H)。

b)2',6' -dichloro-3-fluoro-2, 4' -bipyridine

A solution of 2-bromo-3-fluoropyridine (3g,17mmol) in 1, 2-dimethoxyethane (30mL) was degassed for 5 minutes by bubbling nitrogen through it. The compound from example 18(a) (9.3g,34mmol,2eq) was added and degassing of the mixture was continued for 5 min. Pd (dppf) Cl was added in succession following the procedure of intermediate example 1₂(1.39g,1.7mmol,0.1eq) and sodium carbonate (4.5g,42mmol,2.5eq) in water and the mixture heated at 110 ℃ for 4 hours. The reaction mixture was quenched and extracted as in intermediate example 1. The solvent was evaporated to give a crude residue which was purified by column chromatography (60-120 silica gel, 10% ethyl acetate in hexane) to give the title product in 30% yield (1.2 g).¹H NMR(300MHz,CDCl₃):7.61-7.55(m,2H),7.42-7.31(m,3H)。

c)6' -chloro-3-fluoro-N- (4- (1-methyl-1H-pyrazol-4-yl) -2-nitrophenyl) - [2,4' -bipyridine ] -2' -amine

A solution of the compound from example 18(b) (1.2g,5mmol) in dioxane (12ml) was degassed by bubbling nitrogen through it for 5 minutes. The compound of intermediate example 1 (1.29g,6mmol,1.2eq) was added and the mixture was degassed for an additional 5 minutes. Palladium acetate (110mg,0.5mmol,0.1eq), BINAP (610mg,1mmol,0.2eq) and cesium carbonate (4.07g,12.4mmol,2.5eq) were added in this order as in example 1 (a). The crude residue of the product was purified by column chromatography (60-120 silica gel, 70% ethyl acetate in hexane) to give the title product in 38% yield (0.8 g).

d) N1- (6' -chloro-3-fluoro- [2,4' -bipyridine ] -2' -yl) -4- (1-methyl-1H-pyrazol-4-yl) benzene-1, 2-diamine

To a solution of the compound from example 18(c) (0.8g,1.9mmol) in THF (15ml) was added a solution of ammonium chloride (0.8g,15.1mmol,8eq) in water (5ml) and zinc (0.97g,15.1mmol,8 eq). The mixture was stirred at room temperature for 6 hours and filtered. The filtrate was diluted with water and extracted as described in intermediate example 1. Evaporation of the solvent gave the title product in 100% yield (0.8 g). LC-MS (ESI) mass calculated value 394.11; measured value of mass 395.0[ M + H ]]⁺(rt:1.34min)。

e)1- (6' -chloro-3-fluoro- [2,4' -bipyridine ] -2' -yl) -5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazole

A solution of the compound from example 18(d) (0.4g,1mmol) and formic acid (5ml) was heated at 110 ℃ for 12 hours. The formic acid was distilled off and the crude product was extracted as described in example 8 (c). Evaporation of the solvent gave the title product in 100% yield (0.4 g).¹H NMR(300MHz,CD₃OD):8.95 (s,1H),8.64(m,1H),8.38(s,1H),8.29-8.27(m,2H),8.03-8.02(m,2H),7.92-7.81(m,2H),7.69-7.64(m,2H),3.95(s,3H)。

f) N- (3-fluoro-6 ' - (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [2,4' -bipyridinyl ] -2' -yl) cyclopropanesulfonamide

A solution of the compound (40mg,0.1mmol) prepared in example 18(e) in dioxane (1ml) was degassed by bubbling nitrogen gas through it for 5 minutes. Cyclopropanesulfonamide (12mg,0.1mmol,1eq) was added and the mixture was degassed for an additional 5 minutes. Adding Pd₂(dba)₃(9mg,0.01mmol,0.1eq), Xantphos (6mg,0.01mmol,0.1eq) and Cs₂CO₃(80mg,0.25mmol,2.5eq) and the mixture was degassed for a further 5 minutes and then heated at 110 ℃ for 16 hours. The mixture was filtered through celite and extracted as described in example 1. The solvent was evaporated to give a crude residue which was purified by column chromatography (60-120 silica gel,10% methanol/CHCl₃) The title product was obtained in 50% yield (15 mg).¹H NMR(300MHz,DMSO-d₆) 11.22(s,1H),9.0(s,1H),8.69-8.63(m,2H),8.24(s,1H),8.04-7.98(m,4H),7.71-7.6(m,2H),7.49(s,1H),3.88(s,3H),3.17-3.15(m,1H),1.13-1.12(m,2H),1.05-1.02(m, 2H); LC-MS (ESI) mass calculated value 489.14; measured value of mass 490.01[ M + H]⁺(rt:0.57min)。

Example 19

N- (3-fluoro-6 ' - (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [2,4' -bipyridinyl ] -2' -yl) acetamide

This compound was prepared from the compound of example 18(e) using the procedure of example 18.¹H NMR(300MHz,DMSO-d₆) 11.1(s,1H),9.34(s,1H),8.84(s,1H),8.62(d,1H),8.45(d,1H),8.12(s,1H),8.07(s,1H),7.94-7.92(m,2H),7.86-7.74(m,2H),7.63-7.57(m,1H),3.89(s,3H),2.22(m, 3H); LC-MS (ESI) mass calculated value 427.16; measured value of mass 428.3[ M + H]⁺(rt:0.7min)。

Example 20

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

a)6' -chloro-3-fluoro-N- (5- (1-methyl-1H-pyrazol-4-yl) -3-nitropyridin-2-yl) - [2,4' -bipyridine ] -2' -amine

A solution of 2',6' -dichloro-3-fluoro-2, 4' -bipyridine (0.5g,2.1mmol) in dioxane (12ml) was degassed by bubbling nitrogen through it for 5 minutes. The compound of intermediate example 7 (0.55g,2.5mmol,1.2eq) was added and the mixture was degassed for an additional 5 minutes. Pd was added in succession in accordance with the procedure of example 1(a)₂(dba)₃(0.19g,0.21mmol,0.1eq), Xantphos (0.24g,0.42mmol,0.2eq) and cesium carbonate (1.68g,5.2mmol,2.5 eq). The crude residue of the product was purified by column chromatography (60-120 silica gel, 70% ethyl acetate in hexane)Liquid) gave the title product in 32% yield (0.28 g). LC-MS (ESI) mass calculated value 425.08; found value of mass 426.3[ M + H ]]⁺(rt:1.72min)。

b) N2- (6' -chloro-3-fluoro- [2,4' -bipyridine ] -2' -yl) -5- (1-methyl-1H-pyrazol-4-yl) pyridine-2, 3-diamine

To a solution of the compound from example 20(a) (0.28g,0.7mmol) in THF (10ml) was added a solution of ammonium chloride (0.28g,5.6mmol,8eq) in water (5ml) and zinc (0.33g,5.6mmol,8 eq). The mixture was stirred at room temperature for 2 hours and filtered. The filtrate was diluted with water and extracted as described in intermediate example 1. Evaporation of the solvent gave the title product in 72% yield (0.2 g).

c)3- (6' -chloro-3-fluoro- [2,4' -bipyridine ] -2' -yl) -6- (1-methyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridine

A solution of the compound from example 20(b) (0.2g,0.5mmol) and formic acid (5ml) was heated at 100 ℃ for 16 hours. The formic acid was distilled off and the crude product was extracted as described in example 8 (c). Evaporation of the solvent gave 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

A solution of the compound (40mg,0.1mmol) prepared in example 20(c) in dioxane (1ml) was degassed by bubbling nitrogen gas through it for 5 minutes. Cyclopropanesulfonamide (14mg,0.12mmol,1.2eq) was added and the mixture was degassed for an additional 5 minutes. Adding Pd₂(dba)₃(9mg,0.01mmol,0.1eq), Xantphos (6mg,0.01mmol,0.1eq) and Cs₂CO₃(80mg,0.25mmol,2.5eq) and the mixture was degassed for a further 5 minutes and then heated at 110 ℃ for 16 hours. The mixture was filtered through celite and extracted as described in example 1. Evaporation of the solvent gave a crude residue which was purified by column chromatography (60-120 silica gel, 10% methanol in CHCl)₃) The title product was obtained in 8% yield (5 mg).¹H NMR(300MHz,CDCl₃):9.24(s,1H),9.16(s,1H),8.69(s,1H),8.64(m,1H),8.3(s,1H),7.98(s,1H),7.85(s,1H)7.73(s,1H),7.61-7.58(m,2H),7.48-7.44(m,1H),4.0(s,3H),2.88(m,1H),1.40-1.31(m,2H),1.08-1.1(m, 2H); LC-MS (ESI) mass calculated value 490.13; measured value of mass 491.0[ M + H]⁺(rt:1.16min)。

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

a) 6-chloro-4- (2, 4-difluorophenyl) -N- (4- (1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl) -2-nitrophenyl) pyridin-2-amine

A solution of the compound from intermediate example 5(a) (0.2g,0.8mmol) in dioxane (15ml) was degassed by bubbling nitrogen through it for 5 minutes. The compound of intermediate example 3 (0.23g,0.9mmol,1.1eq) was added and the mixture was degassed for an additional 5 minutes. Palladium acetate (0.017g,0.08mmol,0.1eq), BINAP (0.1g,0.16mmol,0.2eq) and cesium carbonate (0.65g,2mmol,2.0eq) were added successively and the mixture was degassed for a further 5 minutes and then heated at 110 ℃ for 12 hours. The mixture was filtered through celite and extracted as described in example 1. Evaporation of the solvent gave a crude residue which was purified by column chromatography (60-120 silica gel, 10% methanol/CH)₂Cl₂) The title product was obtained in 55% yield (0.1 g). LC-MS (ESI) mass calculated value 498.14; measured value of quality 499.7[ M + H ]]⁺(rt:1.41min)。

b) N1- (6-chloro-4- (2, 4-difluorophenyl) pyridin-2-yl) -4- (1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl) benzene-1, 2-diamine

To a solution of the compound from example 21(a) (0.1g,0.2mmol) in THF (10ml) was added a solution of ammonium chloride (85mg,1.6mmol,8eq) in water (2ml) and zinc (0.1g,1.6mmol,8 eq). The mixture was stirred at room temperature for 12 hours and filtered. The filtrate was diluted with water and extracted as described in intermediate example 1. Evaporation of the solvent gave the title product in 100% yield (93 mg).

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

A solution of the compound from example 21(b) (93mg,0.2mmol) and formic acid (5ml) was heated at 100 ℃ for 12 hours. The formic acid was distilled off and the crude product was extracted as described in example 8 (c). Evaporation of the solvent gave the desired title product in 83% yield (80 mg). LC-MS (ESI) mass calculated value 478.15; measured value of mass 479.45[ M + H]⁺(rt:1.36min)。

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 (80mg,0.2mmol) prepared in example 21(c) in dioxane (5ml) was degassed by bubbling nitrogen gas through it for 5 minutes. Cyclopropanesulfonamide (29mg,0.24mmol,1.2eq) was added and the mixture was degassed for an additional 5 minutes. Addition of Pd (OAc)₂(5mg,0.02mmol,0.1eq), Xantphos (23mg,0.04mmol,0.2eq) and Cs₂CO₃(162mg,0.5mmol,2.5eq) and the mixture was degassed for a further 5 minutes and then heated at 110 ℃ for 12 hours. The mixture was filtered through celite and extracted as described in example 1. Evaporation of the solvent gave a crude residue which was purified by column chromatography (60-120 silica gel, 10% methanol/CH)₂Cl₂) The desired title product was obtained in 35% yield (20 mg).¹H NMR(400MHz,CDCl₃) 8.7(s,1H),8.04(m,2H),7.82(d,2H),7.56(m,2H),7.41(m,2H),7.07-7.02(m,2H),4.29(m,2H),2.89-2.84(m,3H),2.33(s,6H),1.39(m,2H),1.08(m, 2H); LC-MS (ESI) mass calculated value 563.19; measured value of mass 564.25[ M + H]⁺(rt:0.59min)。

Example 22

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

a) 4-chloro-6- (2-fluorophenyl) pyrimidin-2-amine

A solution of 4, 6-dichloropyrimidin-2-amine (5g,30.6mmol) in 1, 2-dimethoxyethane (50ml) was degassed by bubbling nitrogen through it for 5 minutes. 2-Fluorophenylboronic acid (4.27g,30.6mmol,1.2eq) was added and the mixture was degassed for an additional 5 minutes. Pd (dppf) Cl was added in succession following the procedure of intermediate example 1₂(1.25g,1.53mmol,0.05eq) and sodium carbonate (8.12g,76.6mmol,2.5eq) in water and heated at 90 ℃ for 3 hours. The reaction mixture was then quenched and extracted as in intermediate example 1. The solvent was evaporated to give a crude residue which was purified by column chromatography (60-120 silica gel, 30% ethyl acetate in hexane) to give the title product in 15% yield (1 g). LC-MS (ESI) mass calculated value 223.03; measured value of mass 224.0[ M + H]⁺(rt:1.53min)。

b) N- (4-chloro-6- (2-fluorophenyl) pyrimidin-2-yl) cyclopropanesulfonamides

To an ice-cold solution of the compound from example 22(a) (1g,4.48mmol) in DMF (50ml) was added NaH (0.16g,6.72mmol,1.5 eq.) the mixture was stirred for 10 min, then cyclopropylsulfonyl chloride (0.76g,5.38mmol,1.2eq) was added and the mixture was stirred at room temperature for 24H the mixture was quenched with water and extracted with ethyl acetate (3 × 100ml), the combined organic layers were washed with water, brine and dried over sodium sulfate, the solvent was evaporated to give a crude product which was purified by column chromatography (60-120 silica gel, 5% ethyl acetate in hexane) to give the title product in 34% yield (0.5g) LC-MS (ESI): mass calculated value 327.02; mass found 327.8[ M + H + E: (ESI): mass calculated value)]⁺(rt:1.61min)。

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 ice-cold solution of the compound from example 22(b) (0.2g,0.61mmol) in DMF (50ml) in a sealed tube was added NaH (22mg,0.9mmol,1.5 eq.) the mixture was stirred for 10 min then the compound from intermediate example 6 (0.12g,0.61mmol, 1eq.) was added the mixture was stirred for 24 h at room temperature then the reaction was terminated and extracted with ethyl acetate (3 × 100 ml). the combined organic layers were washed with water, brine and extracted with sulfuric acid (3g, 0.61mmol, 1eq.)And (4) drying sodium. The solvent was evaporated to give a crude product mixture from which the title compound was isolated by preparative TLC in 0.01% yield (3 mg).¹H NMR(400MHz,CDCl₃) 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) mass calculated value 489.14; measured value of quality 490.4[ M + H ]]⁺(rt:1.43min)。

Example 23

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

A solution of the title compound of intermediate example 5 (50mg,0.144mmol) in dioxane (5ml) was degassed by bubbling nitrogen through it for 5 minutes. The compound of intermediate example 4 (26mg,0.144mmol,1eq) was added and degassing of the mixture continued for 5 min. CuI (1.3mg,0.0072mmol,0.05eq), N-dimethylglycine (1.4mg,0.0144mmol,0.1eq) and Cs were added₂CO₃(141mg,0.434mmol,3.0eq) and the reaction mixture was degassed for a further 5 minutes and then heated at 100 ℃ for 24 hours. The reaction mixture was filtered through celite and washed with ethyl acetate. The solvent was distilled off to give a crude product mixture, from which the title compound was isolated by preparative HPLC to give the title compound (10mg) in 14% yield.¹H NMR(400MHz,DMSO-d₆) 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,2H),7.83-7.78(m,2H),7.59-7.51(m,1H),7.39-7.34(m,1H),7.16(s,1H),6.59(s,1H),3.19-3.14(m,1H),1.24-1.12(m,2H),1.06-1.03(m, 2H); LC-MS (ESI) mass calculated value 492.12; measured value of quality 493.4[ M + H]⁺(rt:1.71min)。

Example 24

N- (4- (2, 4-difluorophenyl) -6- (6- (1-methyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) pyridin-2-yl) cyclopropanesulfonamide

a) 6-chloro-4- (2, 4-difluorophenyl) -N- (5- (1-methyl-1H-pyrazol-4-yl) -3-nitropyridin-2-yl) pyridin-2-amine

A solution of the compound from intermediate example 5(a) (0.5g,1.92mmol) in dioxane (5ml) was degassed by bubbling nitrogen through it for 5 minutes. The compound of intermediate example 7 (0.42g,1.92mmol, 1eq) was added and degassing of the mixture was continued for 5 min. Pd was added in succession in accordance with the procedure of example 1(a)₂(dba)₃(0.087g,0.09mmol,0.05eq), Xantphos (0.11g,0.192mmol,0.1eq) and cesium carbonate (1.56g,4.8mmol,2.5eq) and the mixture was heated at 110 ℃ for 16 h. The mixture was filtered through celite and extracted as described in example 1. The solvent was evaporated to give a crude residue which was purified by column chromatography (60-120 silica gel, 20% ethyl acetate in hexane) to give the title product in 46% yield (0.4 g).

b) N2- (6-chloro-4- (2, 4-difluorophenyl) pyridin-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) pyridine-2, 3-diamine

To a solution of the compound from example 24(a) (0.39g,0.88mmol) in THF (10ml) was added a solution of ammonium chloride (0.37g,7mmol,8eq) in water (2ml) and zinc (0.46g,7mmol,8 eq). The mixture was stirred at room temperature for 6 hours and filtered. The filtrate was diluted with water and extracted as described in intermediate example 1. Evaporation of the solvent gave the title product in 88% yield (0.32 g).

c)3- (6-chloro-4- (2, 4-difluorophenyl) pyridin-2-yl) -6- (1-methyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridine

A solution of the compound from example 24(b) (0.32g,0.77mmol) and formic acid (10ml) was heated at 100 ℃ for 16 hours. The formic acid was distilled off and the crude product was extracted as described in example 8 (c). Evaporation of the solvent gave the title product in 70% yield (0.23 g). LC-MS (ESI) mass calculated value 422.09; measured value of mass 423.2[ M + H]⁺(rt:1.74min)。

d) N- (4- (2, 4-difluorophenyl) -6- (6- (1-methyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) pyridin-2-yl) cyclopropanesulfonamide

A solution of the compound from example 24(c) (150mg,0.35mmol) in dioxane (5ml) was degassed by bubbling nitrogen gas through it for 5 minutes. Cyclopropanesulfonamide (55mg,0.46mmol,1.3eq) was added and the mixture was degassed for an additional 5 minutes. Addition of Pd (OAc)₂(4mg,0.017mmol,0.05eq), Xantphos (20mg,0.03mmol,0.1eq) and Cs₂CO₃(288mg,0.88mmol,2.5eq) and the mixture was degassed for a further 5 minutes and then heated at 110 ℃ for 12 hours. The mixture was filtered through celite and extracted as described in example 1. Evaporation of the solvent gave a crude residue which was purified by column chromatography (60-120 silica gel, 3% methanol/CH)₂Cl₂) The title product was obtained in 27% yield (48 mg).¹H NMR(300MHz,DMSO-d₆) 11.07(s,1H),9.09(s,1H),8.80(d,1H),8.49-8.45(m,2H),8.30(s,1H),8.05(d,1H),7.81-7.73(m,1H),7.57-7.49(m,1H),7.38-7.32(m,1H),7.11(s,1H),3.89(s,3H),3.41-3.37(m,1H),1.13-1.10(m, 4H); LC-MS (ESI) mass calculated value 507.13; measured value of mass 508.1[ M + H]⁺(rt:1.54min)。

Example 25

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

a)2',6' -dichloro-3, 5-difluoro-2, 4' -bipyridine

A solution of 2-bromo-3, 5-difluoropyridine (1.6g,5.84mmol) in 1, 2-dimethoxyethane (30ml) was degassed by bubbling nitrogen through it for 5 minutes. The compound from example 18(a) (1.36g,7mmol,2eq) was added and the mixture was degassed for a further 5 minutes. Pd (dppf) Cl was added in succession following the procedure of intermediate example 1₂(0.47g,0.58mmol,0.1eq) and aqueous sodium carbonate (1.85g,17.5mmol,3eq) and the mixture was heated at 90 ℃ for 2 hours. The reaction mixture was quenched and extracted as in intermediate example 1. Evaporation of the solvent gave a crude residue which was purified by column chromatography (60-120 silica gel, 5% ethyl acetate in hexane) to give the title product, 72%Yield (1.1 g).

b)6' -chloro-3, 5-difluoro-N- (4- (1-methyl-1H-pyrazol-4-yl) -2-nitrophenyl) - [2,4' -bipyridine ] -2' -amine

A solution of the compound from example 25(a) (0.4g,1.5mmol) in dioxane (12ml) was degassed by bubbling nitrogen through it for 5 minutes. The compound of intermediate example 1 (0.4g,1.84mmol,1.2eq) was added and the mixture was degassed for an additional 5 minutes. Palladium acetate (17mg,0.08mmol,0.05eq) BINAP (47mg,0.08mmol,0.05eq) and potassium tert-butoxide (0.26g,2.29mmol,1.5eq) were added successively as in example 1(a) and the mixture was heated at 110 ℃ for 72 hours. The crude residue of the product was purified by column chromatography (60-120 silica gel, 50% ethyl acetate in hexanes) to afford the title product in 18% yield (0.12 g). LC-MS (ESI) mass calculated value 442.08; measured value of mass 443.05[ M + H]⁺(rt:1.98min)。

c) N1- (6' -chloro-3, 5-difluoro- [2,4' -bipyridine ] -2' -yl) -4- (1-methyl-1H-pyrazol-4-yl) benzene-1, 2-diamine

To a solution of the compound from example 25(b) (0.12g,0.27mmol) in THF (15ml) was added a solution of ammonium chloride (0.15g,2.7mmol,8eq) in water (2ml) and zinc (0.18g,2.7mmol,8 eq). The mixture was stirred at room temperature for 6 hours and filtered. The filtrate was diluted with water and extracted as described in intermediate example 1. Evaporation of the solvent gave the title product in 90% yield (0.1 g).

d)1- (6' -chloro-3, 5-difluoro- [2,4' -bipyridine ] -2' -yl) -5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazole

A solution of the compound from example 25(c) (0.1g,0.242mmol) and formic acid (10ml) was heated at 100 ℃ for 16 hours. The formic acid was distilled off and the crude product was extracted as described in example 8 (c). Evaporation of the solvent gave the title product in 78% yield (80 mg). LC-MS (ESI) mass calculated value 422.09; measured value of mass 422.8[ M + H]⁺(rt:1.69min)。

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

A solution of the compound (80mg,0.19mmol) obtained in example 25(d) in dioxane (5ml) was degassed by bubbling nitrogen gas through the solution for 5 minutes. Cyclopropanesulfonamide (28mg,0.23mmol,1.2eq) was added and the mixture was degassed for an additional 5 minutes. Addition of Pd (OAc)₂(4.2mg,0.019mmol,0.1eq), Xantphos (22mg,0.04mmol,0.2eq) and Cs₂CO₃(185mg,0.57mmol,3eq) and the mixture was degassed for a further 5 minutes and then heated at 110 ℃ for 12 hours. The mixture was filtered through celite and extracted as described in example 1. Evaporation of the solvent gave a crude residue which was purified by preparative TLC to give the title product in 5% yield (5 mg).¹H NMR(300MHz,DMSO-d₆) 8.98(s,1H),8.76(d,1H),8.61(d,1H),8.25-8.18(m,2H),7.96(m,3H),7.62-7.59(m,1H),7.47(s,1H),3.88(s,3H),3.12(m, 1H),1.14-1.12(m,2H),1.04-1.02(m, 2H); LC-MS (ESI) mass calculated value 507.13; measured value of mass 508.1[ M + H]⁺(rt:1.27min)。

Example 26

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

This compound was prepared from the compound of example 25(d) using the procedure of example 28.¹H NMR(400MHz,DMSO-d₆) 10.85(s,1H),9.0(s,1H),8.76(d,1H),8.58(s,1H),8.50(d,1H),8.23-8.21(m,2H),8.0(s,1H),7.95(m,2H),7.62-7.59(m,1H),3.88(s,3H),2.21(s, 3H); LC-MS (ESI) mass calculated value 445.15; measured value of mass 446.1[ M + H ]]⁺(rt:1.08min)。

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

A solution of 2, 6-dichloropyridin-4-amine (2g,12.3mmol) and 2, 5-dimethoxyfuran (1.94g,14.7mmol,1.2eq) in acetic acid (10ml) was heated at 90 ℃ for 2 h. The mixture was quenched with water and extracted with ethyl acetate (3X 50 ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. Evaporation of the solvent gave the title product in 80% yield (2.1 g).

b) 6-chloro-N- (4- (1-methyl-1H-pyrazol-4-yl) -2-nitrophenyl) -4- (1H-pyrrol-1-yl) pyridin-2-amine

To an ice-cold DMSO (20ml) solution of the compound of example 27(a) (1g,4.58mmol) was added NaH (0.13g,5.5mmol,1.2 eq.) the mixture was stirred for 10 min then the compound of intermediate example 1 (1.1g,5.5mmol,1.2 eq.) the mixture was stirred for 16H at room temperature then quenched with water and extracted with ethyl acetate (3 × 50 ml). the combined organic layers were washed with water, brine and dried over sodium sulfate, the solvent was evaporated to give the crude product, which was purified by column chromatography (60-120 silica gel, 50% ethyl acetate in hexane) to give the title product in 25% yield (0.45 g). LC-MS (ESI): 394.09; found in mass: 394.8[ M + H ]: 394.8]⁺(rt:1.87min)。

c) N1- (6-chloro-4- (1H-pyrrol-1-yl) pyridin-2-yl) -4- (1-methyl-1H-pyrazol-4-yl) benzene-1, 2-diamine

To a solution of the compound from example 27(b) (0.43g,1.1mmol) in THF (30ml) was added a solution of ammonium chloride (0.58g,10.9mmol,10eq) in water (5ml) and zinc (0.71g,10.9mmol,10 eq). The mixture was stirred at room temperature for 6 hours and filtered. The filtrate was diluted with water and extracted as described in intermediate example 1. Evaporation of the solvent gave the product in 90% yield (0.36 g). LC-MS (ESI) mass calculated value 364.12; measured value of mass 365.0[ M + H]⁺(rt:1.47min)。

d)1- (6-chloro-4- (1H-pyrrol-1-yl) pyridin-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazole

A solution of the compound from example 27(c) (0.35g,0.96mmol) and formic acid (10ml) was heated at 100 ℃ for 16 hours. By distilling off formic acidThe crude product was extracted as described in example 8 (c). Evaporation of the solvent gave the title product in 97% yield (350 mg). LC-MS (ESI) mass calculated value 374.10; measured value of mass 375.1[ M + H ]]⁺(rt:1.59min)。

e) 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 solution of the compound (100mg,0.27mmol) prepared in example 27(d) in dioxane (5ml) was degassed by bubbling nitrogen gas through it for 5 minutes. Acetamide (19mg,0.32mmol,1.2eq) was added and the mixture was degassed for a further 5 minutes. Addition of Pd (OAc)₂(3mg,0.013mmol,0.05eq), Xantphos (15mg,0.026mmol,0.1eq) and Cs₂CO₃(261mg,0.8mmol,3eq) and the mixture was degassed for a further 5 minutes and then heated at 110 ℃ for 12 hours. The mixture was filtered through celite and extracted as described in example 1. Evaporation of the solvent gave a crude residue which was purified by preparative HPLC to give the title product in 75% yield (80 mg).¹H NMR(400MHz,DMSO-d₆) 10.79(s,1H),9.13(s,1H),8.63(d,1H),8.21(s,2H),7.95-7.93 (m,2H),7.84(d,1H),7.60-7.57(m,3H),6.41-6.40(m,2H),3.88(s,3H),2.21(s, 3H); LC-MS (ESI) mass calculated value 397.17; measured value of mass 398.1[ M + H ]]⁺(rt:1.24min)。

Example 28

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

a)2, 6-dichloro-4- (2-chlorophenyl) pyridine

A solution of 2, 6-dichloro-4-iodopyridine (1g,3.65mmol) in 1, 2-dimethoxyethane (15ml) was degassed by bubbling nitrogen through it for 5 minutes. 2-Chlorophenylboronic acid (0.68g,4.38mmol,1.2eq) was added and the mixture was degassed for an additional 5 minutes. Pd (dppf) Cl was added in succession following the procedure of intermediate example 1₂(0.3g,0.37mmol,0.1eq) and aqueous sodium carbonate (1.16g,10.9mmol,3eq) and the mixture was added at 90 deg.CThe heat was applied for 2 hours. The reaction mixture was quenched and extracted as in intermediate example 1. Evaporation of the solvent gave a crude residue which was purified by column chromatography (60-120 silica gel, 5% ethyl acetate in hexane) to give the title product in 74% yield (0.7 g).¹H NMR(300MHz,CDCl₃):7.53-7.49(m,1H),7.41-7.35(m,3H),7.32-7.29(m,1H),7.26(m,1H)。

b) 6-chloro-4- (2-chlorophenyl) -N- (4- (1-methyl-1H-pyrazol-4-yl) -2-nitrophenyl) pyridin-2-amine

A solution of the compound from example 28(a) (0.7g,2.7mmol) in toluene (10ml) was degassed by bubbling nitrogen through it for 5 minutes. The compound of intermediate example 1 (0.6g,2.7mmol,1eq) was added and the mixture was degassed for an additional 5 minutes. Palladium acetate (24mg,0.11mmol,0.04eq) BINAP (67mg,0.11mmol,0.04eq) and potassium tert-butoxide (0.3g,2.7mmol,1eq) were added successively as in example 1(a) and the mixture was heated at 100 ℃ overnight. The crude residue of the product was purified by column chromatography (60-120 silica gel, 30% ethyl acetate in hexane) to give the title product in 71% yield (0.5 g). LC-MS (ESI) mass calculated value 439.06; measured value of mass 439.95[ M + H]⁺(rt:2.02min)。

c)1- (6-chloro-4- (2-chlorophenyl) pyridin-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazole

To a solution of the compound from example 28(b) (0.5g,1.13mmol) in formic acid (10ml) was added iron (0.63g,11.4mmol) and heated at 100 ℃ for 16 hours. The formic acid was evaporated off and the crude product was dissolved in ethyl acetate. The ethyl acetate layer was washed with water, brine and dried over sodium sulfate. Evaporation of the solvent gave the title product in 63% yield (0.3 g). LC-MS (ESI) mass calculated value 419.07; measured value of mass 421.8[ M + H]⁺(rt:1.84min)。

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

A solution of the compound (200mg,0.47mmol) obtained in example 28(c) in dioxane (5ml) was degassed by bubbling nitrogen gas through the solution for 5 minutes. Adding cyclopropylAlkanesulfonamide (63mg,0.52mmol,1.1eq) and the mixture was degassed for a further 5 min. Addition of Pd (OAc)₂(5mg,0.023mmol,0.05eq), Xantphos (15mg,0.023mmol,0.05eq) and Cs₂CO₃(450mg,1.41mmol,3eq) and the mixture was degassed for a further 5 minutes and then heated at 110 ℃ for 12 hours. The mixture was filtered through celite and extracted as described in example 1. Evaporation of the solvent gave a crude residue which was purified by column chromatography (2% methanol/CHCl)₃) The title product was obtained in 15% yield (30 mg).¹H NMR(400MHz,DMSO-d₆) 11.17(s,1H),9.0(s,1H),8.71(d,1H),8.23(s,1H),7.96-7.94(m,2H),7.67-7.65(m,2H),7.62-7.59(m,2H),7.54-7.52(m,2H),6.98(s,1H),3.87(s,3H),3.16(m,1H),1.12-1.11(m,2H),1.04-1.02(m, 2H); LC-MS (ESI) mass calculated value 504.11; measured value of mass 504.7[ M + H]⁺(rt:1.59min)。

Example 29

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

a)2',3,6' -trichloro-2, 4' -bipyridine

A solution of (2, 6-dichloropyridin-4-yl) boronic acid (0.76g,4mmol) in 1, 2-dimethoxyethane (15ml) was degassed by bubbling nitrogen through it for 5 minutes. 2-bromo-3-chloropyridine (0.7g,3.63mmol,1.2 eq) was added and the mixture was degassed for an additional 5 minutes. Pd (dppf) Cl was added in succession following the procedure of intermediate example 1₂(0.3g,0.36mmol,0.1eq) and sodium carbonate (1.15g,10.9mmol,3eq) in water and heated at 90 ℃ for 2 hours. The reaction mixture was then quenched and extracted as in intermediate example 1. The solvent was evaporated to give a crude residue which was purified by column chromatography (60-120 silica gel, 10% ethyl acetate in hexane) to give the title product in 74% yield (0.7 g).¹H NMR(300MHz,CDCl₃):8.63(dd,1H),7.86(m,1H),7.68(s,2H),7.37(dd,1H)。

b)3,6' -dichloro-N- (4- (1-methyl-1H-pyrazol-4-yl) -2-nitrophenyl) - [2,4' -bipyridine ] -2' -amine

A solution of the compound from example 29(a) (0.69g,3.17mmol) in toluene (10ml) was degassed by bubbling nitrogen through it for 5 minutes. The compound of intermediate example 1 (0.69g,3.17mmol,1.1eq) was added and the mixture was degassed for an additional 5 minutes. Palladium acetate (25mg,0.115mmol,0.04eq) BINAP (71mg,0.115mmol,0.04eq) and potassium tert-butoxide (0.38g,3.46mmol,1.2eq) were added successively as in example 1(a) and the mixture was heated at 100 ℃ overnight. The crude residue of the product was purified by column chromatography (60-120 silica gel, 30% ethyl acetate in hexane) to give the title product in 43% yield (0.3 g).¹H NMR(300MHz,CDCl₃):10.25(s,1H),8.77(d,1H),8.65-8.63(m,1H),8.30(d,1H),7.88-7.85(m,1H),7.79-7.73(m,2H),7.67(s,1H),7.37-7.33(m,2H),7.22(m,1H),3.97(s,3H)。

c)1- (3,6' -dichloro- [2,4' -bipyridine ] -2' -yl) -5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazole

To a solution of the compound from example 29(b) (0.3g,0.68mmol) in formic acid (10ml) was added iron (0.38g,6.8mmol) and heated at 100 ℃ for 16 hours. The formic acid was evaporated off and the crude product was dissolved in ethyl acetate. The ethyl acetate layer was washed with water, brine and dried over sodium sulfate. Evaporation of the solvent gave the title product in 64% yield (0.18 g). LC-MS (ESI) mass calculated value 420.07; measured value of mass 421.2[ M + H]⁺(rt:1.56min)。

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

A solution of the compound (100mg,0.24mmol) prepared in example 29(c) in dioxane (5ml) was degassed by bubbling nitrogen gas through it for 5 minutes. Cyclopropanesulfonamide (34mg,0.28mmol,1.2eq) was added and the mixture was degassed for an additional 5 minutes. Addition of Pd (OAc)₂(3mg,0.011mmol,0.05eq), Xantphos (6mg,0.011mmol,0.05eq) and Cs₂CO₃(230mg,0.71mmol,3eq) and the mixture was degassed for a further 5 minutes and then heated at 110 ℃ for 12 hours. The mixture was filtered through celite and extracted as described in example 1. Evaporating off the solvent to obtainThe crude residue was purified by column chromatography (2% methanol/CHCl)₃) The title product was obtained in 15% yield (17 mg).¹H NMR(300MHz,DMSO-d₆) 11.22(s,1H),8.98(s,1H),8.74-8.67(m,2H),8.23(s,1H),8.19-8.16(m,1H),7.97-7.95(m,2H),7.85(m,1H),7.62-7.58(m,2H),7.19(s,1H),3.87(s,3H),3.16(m,1H),1.13-1.12(m,2H),1.06-1.02(m, 2H); LC-MS (ESI) mass calculated value 505.11; measured value of mass 506.00[ M + H]⁺(rt:1.52min)。

Example 30

N- (5-fluoro-6 ' - (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [2,4' -bipyridinyl ] -2' -yl) cyclopropanesulfonamide

a)2',6' -dichloro-5-fluoro-2, 4' -bipyridine

A solution of 2-bromo-5-fluoropyridine (2g,11mmol) in 1, 2-dimethoxyethane (30ml) was degassed for 5 minutes by bubbling nitrogen through it. The compound from example 18(a) (3.11g,11mmol,1eq) was added and degassing of the mixture was continued for 5 min. Pd (PPh) was added in succession following the procedure of intermediate example 1₃)₄(1.31g,0.011mmol,0.1eq) and sodium carbonate (9.28g,28.5mmol,2.5eq) in water and heated at 90 ℃ for 2 hours. The reaction mixture was then quenched and extracted as in intermediate example 1. Evaporation of the solvent gave a crude residue which was purified by column chromatography (60-120 silica gel, 5% ethyl acetate in hexane) to give the title product in 39% yield (1 g).

b)6' -chloro-5-fluoro-N- (4- (1-methyl-1H-pyrazol-4-yl) -2-nitrophenyl) - [2,4' -bipyridine ] -2' -amine

A solution of the compound from example 30(a) (0.2g,0.82mmol) in toluene (12ml) was degassed for 5 minutes by bubbling nitrogen through it. The compound of intermediate example 1 (0.2g,0.9mmol,1.1eq) was added and the mixture was degassed for an additional 5 minutes. Palladium acetate (14.7mg,0.065mmol,0.08eq), BINAP (40mg,0.065mmol,0.08eq) and potassium tert-butoxide (0.23g,2.06mmol,2.5eq) were added successively and heated at 110 ℃ for 16 hours as in example 1 (a). The crude residue of the product was purified by column chromatography (60-120 silica gel, 50% ethyl acetate in hexane) to give the title product in 29% yield (0.1 g).

c) N1- (6' -chloro-5-fluoro- [2,4' -bipyridine ] -2' -yl) -4- (1-methyl-1H-pyrazol-4-yl) benzene-1, 2-diamine

To a solution of the compound from example 30(b) (0.28g,0.66mmol) in THF (10ml) was added a solution of ammonium chloride (0.29g,5.28mmol,8eq) in water (2ml) and zinc (0.34g,5.28mmol,8 eq). The mixture was stirred at room temperature for 1 hour and filtered. The filtrate was diluted with water and extracted as described in intermediate example 1. Evaporation of the solvent gave the title product in 96% yield (0.25 g). LC-MS (ESI) mass calculated value 394.11; measured value of mass 395.1[ M + H]⁺(rt:1.42min)。

d)1- (6' -chloro-5-fluoro- [2,4' -bipyridine ] -2' -yl) -5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazole

A solution of the compound from example 30(c) (0.25g,0.63mmol) and formic acid (10ml) was heated at 100 ℃ for 4 hours. The formic acid was distilled off and the crude product was extracted as described in example 8 (c). Evaporation of the solvent gave the title product in 55% yield (150 mg). LC-MS (ESI) mass calculated value 404.1; measured value of mass 404.8[ M + H]⁺(rt:1.7min)。

e) N- (5-fluoro-6 ' - (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [2,4' -bipyridinyl ] -2' -yl) cyclopropanesulfonamide

A solution of the compound (50mg,0.123mmol) obtained in example 30(d) in dioxane (5ml) was degassed by bubbling nitrogen gas through the solution for 5 minutes. Cyclopropanesulfonamide (15mg,0.123mmol,1eq) was added and the mixture was degassed for an additional 5 minutes. Addition of Pd (OAc)₂(2mg,0.009mmol,0.08eq), Xantphos (5.7mg,0.008mmol,0.08eq) and Cs₂CO₃(120mg,0.37mmol,3eq) and the mixture was degassed for a further 5 minutes and then heated at 100 ℃ for 24 hours. The mixture was filtered through celite and extracted as described in example 1. Evaporation of the solvent gave a crude residue which was purified by preparative TLC to give the title product in 25% yield (15 mg).¹H NMR(400MHz,DMSO-d₆) 11.16(s,1H),9.14(s,1H),8.81(d,1H),8.73(d,1H),8.40-8.37(m,1H),8.23(s,1H),8.15(s,1H),8.05-8.0(m,1H),7.97-7.95(m,2H),7.66(s,1H),7.62-7.59(m,1H),3.89(s,3H),3.16-3.12(m,1H),1.13-1.10(m,2H),1.03-1.0(m, 2H); LC-MS (ESI) mass calculated value 489.14; measured value of quality 490.4[ M + H ]]⁺(rt:1.23min)。

Example 31

N- (5-fluoro-6 ' - (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [2,4' -bipyridinyl ] -2' -yl) acetamide

This compound was prepared from the compound of example 30 (d).¹H NMR(400MHz,DMSO-d₆) 10.78(s,1H),9.16(s,1H),8.82-8.78(m,2H),8.62(d,1H),8.39-8.37(m,1H),8.22-8.20(m,2H),8.04-7.99(m,1H),7.96(s,2H),7.62-7.59(m,1H),3.89(s,3H),2.23(m, 3H); LC-MS (ESI) mass calculated value 427.16; measured value of mass 428.3[ M + H]⁺(rt:1.91min)。

Example 32

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

a) N- (4- (1H-imidazol-1-yl) -2-nitrophenyl) -6-chloro-4- (2, 4-difluorophenyl) pyridin-2-amine

A solution of the compound from intermediate example 5(a) (0.6g,2.94mmol) in toluene (5ml) was degassed by bubbling nitrogen through it for 5 minutes. The compound of intermediate example 9 (0.76g,2.94mmol,1eq) was added and degassing of the mixture was continued for 5 min. Palladium acetate (32mg,0.147mmol,0.05eq), BINAP (182mg,0.294mmol,0.1eq) and potassium tert-butoxide (0.9g,7.35mmol,2.5eq) were added successively and the mixture was degassed for a further 5 minutes and then heated at 100 ℃ for 12 hours. The mixture was filtered through celite and extracted as described in example 1. Evaporation of the solvent gave a crude residue which was purified by column chromatography (60-120 silica gel, 50% ethyl acetate in hexane) to give the title product in 12% yield (150 mg).

b) N1- (6-chloro-4- (2, 4-difluorophenyl) pyridin-2-yl) -4- (1H-imidazol-1-yl) benzene-1, 2-diamine

To a solution of the compound from example 32(a) (0.15g,0.35mmol) in THF (10ml) was added a solution of ammonium chloride (0.15g,2.81mmol,8eq) in water (2ml) and zinc (0.18g,2.81mmol,8 eq). The mixture was stirred at room temperature for 1 hour and filtered. The filtrate was diluted with water and extracted as described in intermediate example 1. Evaporation of the solvent gave the title product in 72% yield (0.1 g).

c)1- (6-chloro-4- (2, 4-difluorophenyl) pyridin-2-yl) -5- (1H-imidazol-1-yl) -1H-benzo [ d ] imidazole

A solution of the compound from example 32(b) (0.1g,0.25mmol) and formic acid (2ml) was heated at 90 ℃ for 4 hours. The formic acid was distilled off and the crude product was extracted as described in example 8 (c). Evaporation of the solvent gave the title product in 50% yield (50 mg).

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

A solution of the compound from example 32(c) (50mg,0.122mmol) in dioxane (5ml) was degassed by bubbling nitrogen gas through it for 5 minutes. Cyclopropanesulfonamide (15mg,0.122mmol,1eq) was added and the mixture was degassed for an additional 5 minutes. Addition of Pd (OAc)₂(2mg,0.009mmol,0.08eq), Xantphos (5.7mg,0.008mmol,0.08eq) and Cs₂CO₃(120mg,0.37mmol,3eq) and the mixture was degassed for a further 5 minutes and then heated at 100 ℃ for 12 hours. The mixture was filtered through celite and extracted as described in example 1. Evaporation of the solvent gave a crude residue which was purified by preparative TLC to give the title product in 33% yield (20 mg).¹H NMR(400MHz,DMSO-d₆) 11.22(s,1H),9.12(s,1H),8.67(d,1H),8.38(s,1H),8.08(d,1H),7.91-7.85(m,2H),7.79(s,1H),7.71-7.69(m,1H),7.56-7.51(m,1H),7.38-7.33(m,1H),7.13(s,2H),3.16-3.11(m,1H),1.12-1.08(m,2H),1.03-1.01(m, 2H); LC-MS (ESI) substance492.12 as an amount calculated; measured value of mass 493.1[ M + H]⁺(rt:0.30min)。

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

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 from intermediate example 5(a) (0.49g,1.89mmol) in dioxane (5ml) was degassed by bubbling nitrogen through it for 5 minutes. The compound of intermediate example 8 (0.6g,1.89mmol,1eq) was added and degassing of the mixture was continued for 5 min. Palladium acetate (34mg,0.15mmol,0.08eq), BINAP (94mg,0.15mmol,0.08eq) and potassium tert-butoxide (0.53g,4.73mmol,2.5eq) were added successively and the mixture was degassed for a further 5 minutes and then heated at 100 ℃ for 12 hours. The mixture was filtered through celite and extracted as described in example 1. Evaporation of the solvent gave a crude residue which was purified by column chromatography (60-120 silica gel, 50% ethyl acetate in hexane) to give the title product in 20% yield (200 mg).

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 from example 33(a) (0.2g,0.37mmol) in THF (10ml) was added a solution of ammonium chloride (0.16g,2.96mmol,8eq) in water (2ml) and zinc (0.19g,2.96mmol,8 eq). The mixture was stirred at room temperature for 1 hour and filtered. The filtrate was diluted with water and extracted as described in intermediate example 1. Evaporation of the solvent gave the title product in 79% yield (0.15 g). LC-MS (ESI) mass calculated value 510.17; measured value of mass 511.1[ M + H]⁺(rt:0.66min)。

c)4- (2- (4- (1- (6-chloro-4- (2, 4-difluorophenyl) pyridin-2-yl) -1H-benzo [ d ] imidazol-5-yl) -1H-pyrazol-1-yl) ethyl) morpholine

A solution of the compound from example 33(b) (0.15g,0.29mmol) and formic acid (2ml) was heated at 90 ℃ for 12 hours. The formic acid was distilled off and the crude product was extracted as described in example 8 (c). Evaporation of the solvent gave the title product in 50% yield (75 mg). LC-MS (ESI) mass calculated value 520.16; measured value of mass 521.2[ M + H ]]⁺(rt:1.03min)。

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

A solution of the compound from example 33(c) (75mg,0.144mmol) in dioxane (5ml) was degassed by bubbling nitrogen through it for 5 minutes. Cyclopropanesulfonamide (17mg,0.144mmol,1eq) was added and the mixture was degassed for an additional 5 minutes. Addition of Pd (OAc)₂(2.5mg,0.011mmol,0.08eq), Xantphos (8.3mg,0.0144mmol,0.1eq) and Cs₂CO₃(117mg,0.36mmol,2.5eq) and the mixture was degassed for a further 5 minutes and then heated at 100 ℃ for 12 hours. The mixture was filtered through celite and extracted as described in example 1. Evaporation of the solvent gave a crude residue which was purified by preparative TLC to give the title product in 29% yield (25 mg).¹H NMR(400MHz,DMSO-d₆) 11.16(s,1H),9.05(s,1H),8.69(d,1H),8.29(s,1H),7.98-7.96(m,2H),7.88-7.85(m,1H),7.75(s,1H),7.62-7.59(m,1H),7.56-7.49(m,1H),7.37-7.32(m,1H),7.09(s,1H),4.27-4.24(m,2H),3.58-3.55(m,4H),3.18-3.13(m,1H),2.78-2.74(m,2H),2.53-2.49(m,4H),1.15-1.07(m,2H),1.05-1.01(m, 2H); LC-MS (ESI) mass calculated value of 605.2; measured value of mass 605.8[ M + H]⁺(rt:0.44min)。

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

a)3- (4- (1- (6- (cyclopropanesulfonylamino) -4- (2, 4-difluorophenyl) pyridin-2-yl) -1H-benzo [ d ] imidazol-5-yl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester

A solution of the compound from intermediate example 5 (113mg,0.347mmol) in dioxane (5ml) was degassed by bubbling nitrogen through it for 5 minutes. The compound of intermediate example 2 (120mg,0.347mmol,1eq) was added and the mixture was degassed for an additional 5 minutes. CuI (3.3mg,0.0174mmol,0.05eq), N-dimethylglycine (1.7mg,0.0174mmol,0.05eq) and Cs were added₂CO₃(282mg,0.87mmol,2.5eq) and the mixture was degassed for a further 5 minutes and then heated at 100 ℃ for 24 hours. The mixture was filtered through celite and washed with ethyl acetate. The solvent was evaporated to give a crude product mixture which was purified by preparative TLC to give the title product in 10% yield (20 mg). LC-MS (ESI) mass calculated value 661.23; measured value of mass 662.6[ M + H]⁺(rt:1.71 min). b) N- (4- (2, 4-difluorophenyl) -6- (5- (1- (pyrrolidin-3-yl) -1H-pyrazol-4-yl) -1H-benzo [ d]Imidazol-1-yl) pyridin-2-yl) cyclopropanesulfonamides

To a solution of the compound (15mg,0.028mmol) obtained in example 34(a) in 1, 4-dioxane (5ml) was added a solution of HCl in dioxane at 0 ℃ and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated and the residue washed several times with diethyl ether to give the title product in 78% yield (10 mg).¹H NMR(400MHz,DMSO-d₆) 11.23(s,1H),9.38(s,1H),9.28(s,1H),9.22(s,1H),8.76(d,1H),8.49(s,1H),8.16(s,1H),8.03(s,1H),7.91-7.85(m,1H),7.79(s,1H),7.71-7.69(m,1H),7.57-7.52(m,1H),7.37-7.34(m,1H),7.14(s,1H),5.20-5.18(m,1H),3.62-3.37(m,3H),3.19-3.15(m,2H),2.43-2.33(m,2H),1.19-1.12(m,2H),1.05-1.02(m, 2H); LC-MS (ESI) mass calculated value 561.18; measured value of mass 562.6[ M + H]⁺(RT:0.40min)。

Example 35

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

A solution of the compound of intermediate example 5 (48mg,0.14mmol) in dioxane (5ml) was degassed by bubbling nitrogen gas through it for 5 minutes. The compound of intermediate example 10 (30mg,0.14mmol,1eq) was added and the mixture was degassed for an additional 5 minutes. CuI (2mg,0.014mmol,0.1eq), N-dimethylglycine (1mg,0.014mmol,0.1eq) and Cs were added₂CO₃(130mg,0.42mmol,3.0eq) and the mixture was degassed for a further 5 minutes and then heated at 100 ℃ for 24 hours. The mixture was filtered through celite and washed with ethyl acetate. Evaporation of the solvent gave a crude product mixture which was purified by preparative TLC to give the title product in 33% yield (24 mg).¹H NMR(400MHz,DMSO-d₆) 11.18(s,1H),9.11(s,1H),8.79(d,1H),8.71(s,1H),8.22(s,1H),7.92-7.85(m,2H),7.79(s,1H),7.56-7.50(m,1H),7.38-7.33(m,1H),7.13(s,1H),4.44 (quartet, 2H),3.18-3.13(m,1H),1.51(t,3H),1.14-1.09(m,2H),1.07-1.02(m, 2H); LC-MS (ESI) mass calculated value 521.14; measured value of mass 522.1[ M + H ]]⁺(rt:1.52min)。

Example 36

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

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

A solution of the compound from intermediate example 5 (0.17g,0.51mmol,1.1eq) in dioxane (5ml) was degassed by bubbling nitrogen through it for 5 minutes. The compound of intermediate example 12 (100mg,0.46mmol) was added and the mixture was degassed for an additional 5 minutes. CuI (8mg,0.04mmol,0.1eq), N-dimethylglycine (4mg,0.04mmol,0.1eq) and Cs were added₂CO₃(450mg,1.4mmol,3.0eq) and the mixture was degassed for a further 5 minutes and then heated at 100 ℃ for 24 hours. The mixture was filtered through celite and washed with 3% methanol/chloroform to give a crude product mixture, which was recrystallized from ether to give a mixture of products in 40% yield (80mg), which was used directly in the next step. LC-MS (ESI) mass calculated value 450.1; measured value of mass 451.3[ M + H ]]⁺(rt:1.65min)。

b) N- (4- (2, 4-difluorophenyl) -6- (5- (1-methyl-1H-1, 2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) pyridin-2-yl) cyclopropanesulfonamide

A mixture of example 36(a) (0.1g,0.22mmol), sodium azide (28mg,0.44mmol,2.0eq), methyl iodide (31mg,0.22mmol,1.0eq), sodium ascorbate (43mg,0.022mmol,0.1eq), and copper sulfate pentahydrate (5mg,0.022mmol,0.1eq) in DMSO and water (1:0.5,3ml) was stirred at room temperature for 12 hours. The mixture is quenched with water, and the precipitate formed is filtered off and dried. The crude product mixture was purified by column chromatography (60-120 silica gel, 2% methanol/CHCl)₃) The title product was obtained in 6.3% yield (7 mg).¹H NMR(400MHz,DMSO-d₆) 11.18(s,1H),9.11(s,1H),8.79(d,1H),8.62(s,1H),8.21(d,1H),7.90-7.85(m,2H),7.79(s,1H),7.56-7.50(m,1H),7.38-7.33(m,1H),7.13(s,1H),4.12(s,3H),3.34-3.13(m,1H),1.16-1.12(m,2H),1.06-0.94(m, 2H); LC-MS (ESI) mass calculated value 507.13; measured value of mass 508.1[ M + H]⁺(rt:1.52min)。

Example 37

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

A solution of the compound from intermediate example 5 (34mg,0.1mmol) in DMF (5ml) was degassed by bubbling nitrogen through it for 5 minutes. The compound of intermediate example 11 (20mg,0.1mmol,1eq) was added and the mixture was degassed for an additional 5 minutes. CuI (2mg,0.01mmol,0.1eq), N-dimethylglycine (0.52mg,0.005mmol,0.05eq) and Cs were added₂CO₃(82mg,0.25mmol,2.5eq) and the mixture was degassed for a further 5 minutes and then heated at 100 ℃ for 24 hours. The mixture was filtered through celite and washed with ethyl acetate. The solvent was evaporated to give a crude product mixture which was purified by preparative TLC to give the title compound in 10% yield (5 mg).¹H NMR(400MHz,DMSO-d₆):11.11(s,1H),9.02(s,1H),8.66(d,1H),8.09(d,1H),7.89-7.84(m,1H),7.81-7.75(m,2H),7.68-7.64(m,2H),7.54-7.48(m,1H),7.37-7.32(m,1H),7.13(s,1H),3.71(s,3H),3.18-3.14(m,1H),1.15-1.12(m,2H),1.06-1.02(m, 2H); LC-MS (ESI) mass calculated value 506.13; measured value of mass 507.35[ M + H]⁺(rt:0.18min)。

Example 38

N- (4- (2, 4-difluorophenyl) -6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) pyrimidin-2-yl) acetamide

a) N- (4, 6-dichloropyrimidin-2-yl) acetamide

To a solution of 4, 6-dichloropyrimidin-2-amine (5g,30.48mmol) in toluene (50ml) was added acetic anhydride (15ml,152.43mmol) and the mixture was heated at 120 ℃ for 16 hours. The solvent was distilled off, hexane (50ml) and dichloromethane (6ml) were added to the crude product and filtered to give the title product in 80% yield (5 g). LC-MS (ESI) mass calculated value 206.0; measured value of mass 208.0[ M + H ]]⁺(rt:0.245min)。

b) N- (4- ((2-amino-4- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) -6-chloropyrimidin-2-yl) acetamide

A solution of the compound of intermediate example 13 (1.4g,7.44mmol), the compound of example 38(a) (1.53g,7.44mmol) and sodium bicarbonate (1.56g,18.6mmol,2.5eq) in ethanol was heated at 80 ℃ for 16H, the mixture was quenched with water and extracted with ethyl acetate (3 × 100ml), the combined organic layers were washed with water, brine and dried over sodium sulfate, the solvent was evaporated to give a crude residue which was purified by column chromatography (60-120 silica, 3% methanol/DCM) to give the title product in 19.2% yield (0.5g), LC-MS (ESI) mass calculated value 357.11, mass calculated value 358.1[ M + H ], (ESI)]⁺(rt:0.123min)。

c) N- (4-chloro-6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) pyrimidin-2-yl) acetamide

A mixture of the compound from example 38(b) (0.15g,0.42mmol) and formic acid (2ml) was heated at 80 ℃ for 2 hours. The formic acid is distilled off and the crude product is dissolvedIn ethyl acetate. The ethyl acetate layer was washed with water, brine and dried over sodium sulfate. Evaporation of the solvent gave the title product in 97% yield (0.15 g). LC-MS (ESI) mass calculated value 367.07; measured value of mass 368.1[ M + H]⁺(rt:0.318min)。

d) N- (4- (2, 4-difluorophenyl) -6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) pyrimidin-2-yl) acetamide

A solution of the compound from example 38(c) (0.08g,0.217mmol) in dioxane (5ml) was degassed by bubbling nitrogen through it for 5 minutes. 2, 4-difluorophenylboronic acid (0.04g,0.261mmol,1.2eq) was added and the mixture was degassed for an additional 5 minutes. Sequentially adding Pd (PPh)₃)₄(0.025g,0.021mmol,0.1eq) and cesium carbonate (0.106g,0.326mmol,1.5eq) in water and the mixture was degassed for an additional 5 minutes then heated at 100 ℃ for 2 hours the reaction mixture was quenched with water and extracted with ethyl acetate (3 × 30ml), the combined organic layers were washed with water, brine and dried over sodium sulfate, the solvent was evaporated to give a crude residue which was purified by preparative HPLC to give the title product in 10.4% yield (10 mg).¹H NMR(400MHz,DMSO-d₆) 11.1(s,1H),9.25(s,1H),9.12(d,1H),8.23(s,1H),8.11-8.07(m,1H),8.03(s,1H),7.96(d,2H),7.63(d,1H),7.54(t,1H),7.36(t,1H),3.88(s,3H),2.27(s, 3H); LC-MS (ESI) mass calculated value 445.15; measured value of mass 445.9[ M + H]⁺(rt:1.33min)。

Example 39

1- (1- (6- (cyclopropanesulfonylamino) -4- (2, 4-difluorophenyl) pyridin-2-yl) -1H-benzo [ d ] imidazol-5-yl) -1H-1,2, 3-triazole-4-carboxylic acid ethyl ester

A solution of the compound from intermediate example 5 (200mg,0.58mmol) in DMF (5ml) was degassed by bubbling nitrogen through it for 5 minutes. The compound of intermediate example 14 (149mg,0.58mmol,1eq) was added and the mixture was degassed for an additional 5 minutes. CuI (11mg,0.05mmol,0.1eq), N-dimethylglycine (8mg,0.05mmol,0.1eq) and Cs were added₂CO₃(570mg,1.74mmol,3 eq.) andthe mixture was degassed for an additional 5 minutes and then heated at 100 ℃ for 24 hours. The mixture was filtered through celite and washed with ethyl acetate. Evaporation of the solvent gave a crude product mixture which was purified by preparative HPLC to give the title product in 5% yield (18 mg).¹H NMR(400MHz,DMSO-d₆) 11.11(s,1H),9.59(d,1H),9.26(s,1H),8.95(d,1H),8.38(s,1H),8.02-8.00(m,1H),7.92-7.83(m,2H),7.56-7.51(m,1H),7.51-7.34(m,1H),7.17(s,1H),4.38 (quartet, 2H),3.17-3.13(m,1H),1.36(t,3H),1.13-1.12(m,2H),1.04-1.02(m, 2H); LC-MS (ESI) mass calculated value 565.13; measured value of mass 566.2[ M + H]⁺(rt:1.63min)。

Example 40

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

A solution of the compound from intermediate example 15 (300mg,0.75mmol) in DMF (10ml) was degassed for 5 minutes by bubbling nitrogen through it. The compound of intermediate example 6 (149mg,0.75mmol,1eq) was added and the mixture was degassed for an additional 5 minutes. CuI (14mg,0.075mmol,0.1eq), N-dimethylglycine (8mg,0.075mmol,0.1eq) and Cs were added₂CO₃(730mg,2.25mmol,3eq) and the reaction mixture was degassed for a further 5 minutes and then heated at 100 ℃ for 2 days. The reaction mixture was filtered through celite and washed with ethyl acetate. The solvent was evaporated to give a crude product mixture which was purified by column chromatography (60-120 silica gel, 2% methanol/chloroform) to give the title product in 2% yield (8 mg).¹H NMR(400MHz,CD₃OD) 8.83(s,1H),8.56(d,1H),8.02(s,1H),7.89-7.87(m,2H),7.69-7.63(m,2H),7.57(s,1H),7.22-7.15(m,2H),7.15(s,1H),6.97(s,0.5H),6.79(s,0.5H),3.94(s,3H),3.15-3.05(m,1H),1.28-1.15 (m,2H),1.00-0.87(m, 2H); LC-MS (ESI) mass calculated value 554.13; measured value of mass 555.5[ M + H]⁺(rt:1.66min)。

EXAMPLE 41

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

a) 4-chloro-6- (2, 4-difluorophenyl) pyrimidin-2-amine

A solution of 4, 6-dichloropyrimidin-2-amine (5g,30mmol) in 1, 2-dimethoxyethane (50ml) was degassed by bubbling nitrogen through it for 5 minutes. 2, 4-difluorophenylboronic acid (4.38g,27mmol,0.9eq) was added and the mixture was degassed for an additional 5 minutes. Pd (dppf) Cl was added in succession following the procedure of intermediate example 1₂(1.38g,1.5mmol,0.05eq) and sodium carbonate (4.9g,46mmol,1.5eq) in water and heated at 90 ℃ for 6 hours. The reaction mixture was quenched and extracted as in intermediate example 1. The solvent was evaporated to give a crude residue which was purified by column chromatography (60-120 silica gel, 70% ethyl acetate in hexane) to give the title product in 70% yield (4 g). LC-MS (ESI) mass calculated value 241.02; measured value of mass 242.05[ M + H]⁺(rt:1.58min)。

b)6- (2, 4-difluorophenyl) -N4- (4- (1-methyl-1H-pyrazol-4-yl) -2-nitrophenyl) pyrimidine-2, 4-diamine

A solution of the compound from example 41(a) (0.5g,2.1mmol) in dioxane (5ml) was degassed by bubbling nitrogen through it for 5 minutes. The compound of intermediate example 1 (0.5g,2.3mmol,1.1eq) was added and the mixture was degassed for an additional 5 minutes. Sequentially adding Pd₂dba₃(0.19g,0.2mmol,0.1eq), Xantphos (0.24g,0.4mmol,0.2eq) and cesium carbonate (1.68g,5.2mmol,2.5eq) and the mixture was degassed for an additional 5 minutes and then heated at 110 ℃ for 16 hours the mixture was filtered through a pad of celite and extracted with ethyl acetate (3 × 50ml), the combined organic layers were washed with water, brine and dried over sodium sulfate, the solvent was evaporated to give a crude residue which was purified by column chromatography (60-120 silica gel, 70% ethyl acetate in hexane), 22.5% yield (0.2g), LC-MS (ESI) mass calculated value: 423.13; mass found: 423.9[ M + H ] mass calculated value]⁺(rt:0.26min)。

c) N4- (2-amino-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -6- (2, 4-difluorophenyl) pyrimidine-2, 4-diamine

To a solution of the compound from example 41(b) (0.12g,0.3mmol) in THF (15ml) was added a solution of ammonium chloride (0.12g,2.3mmol,8eq) in water (5ml) and zinc (0.145g,2.3mmol, 8eq.) the mixture was stirred at room temperature for 2 hours and filtered, the filtrate was diluted with water and extracted with ethyl acetate (3 × 100ml), the combined organic layers were washed with water, brine and dried over sodium sulfate, the solvent was distilled off to give the crude product, 83% yield (0.1g), LC-MS ESI, (mass calculated value: 393.15; mass found: 394.3[ M + H ESI ] (mass calculated value: 393.15)]⁺(rt:0.14min)。

d)4- (2, 4-difluorophenyl) -6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) pyrimidin-2-amine

A solution of the compound from example 41(c) (0.1g,0.2mmol) in formic acid (5ml) was heated at 100 ℃ for 16 hours. The formic acid was evaporated off and the crude product was dissolved in ethyl acetate. The ethyl acetate layer was washed with water, brine and dried over sodium sulfate. Evaporation of the solvent gave the title product in 24% yield (20 mg).

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

To an ice-cold solution of the compound from example 41(d) (50mg,0.1mmol) in DMF (50ml) was added NaH (4mg,0.2mmol, 2eq.) the mixture was stirred for 10 min, then cyclopropylsulfonyl chloride (26mg,0.2mmol,2eq) was added and the mixture was stirred at room temperature for 12 h the mixture was quenched with water and extracted with ethyl acetate (3 × 100 ml). the combined organic layers were washed with water, brine and dried over sodium sulfate the solvent was evaporated to give the crude product which was purified by preparative HPLC to give the title product in 6% yield (3 mg).¹H NMR(400MHz,CDCl₃) 8.73(s,1H),8.39(d,1H),8.36-8.27(m,1H),8.09(s,1H),7.99(s,1H),7.93(d,1H),7.87(d,1H),7.74(d,1H),7.67-7.64(m,1H),7.20-7.01(m,2H),3.83(s,3H),3.30-3.26(m,1H),1.51-1.42(m,2H),1.16-1.12(m, 2H); LC-MS (ESI) mass calculated value 507.13; measured value of mass 508.2[ M + H ]]⁺(rt:1.48min)。

Example 42

1- (1- (6-acetylamino-4- (2, 4-difluorophenyl) pyridin-2-yl) -1H-benzo [ d ] imidazol-5-yl) -1H-1,2, 3-triazole-4-carboxylic acid ethyl ester

A solution of the compound from intermediate example 16 (150mg,0.53mmol) in DMF (5ml) was degassed for 5 minutes by bubbling nitrogen through it. The compound of intermediate example 6 (137mg,0.53mmol,1eq) was added and degassing of the mixture was continued for 5 min. CuI (10mg,0.05mmol,0.1eq), N-dimethylglycine (7mg,0.05mmol,0.1eq) and Cs were added₂CO₃(0.52g,1.59mmol,3eq) and the mixture was degassed for a further 5 minutes and then heated at 110 ℃ for 16 hours. The mixture was filtered through celite and washed with ethyl acetate. Evaporation of the solvent gave a crude product mixture which was purified by preparative HPLC to give the title product in 4.5% yield (16 mg).¹H NMR(400MHz,DMSO-d₆) 10.95(s,1H),9.58(d,1H),9.22(s,1H),8.98(d,1H),8.39(s,1H),8.03-7.96(m,2H),7.89-7.83(m,2H),7.55-7.49(m,1H),7.47-7.33(m,1H),4.39 (quartet, 2H),2.22(s,1H),1.36(t, 3H); LC-MS (ESI) mass calculated value 503.15; measured value of quality 504.1[ M + H ]]⁺(rt:1.63min)。

Example 43

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

a)4- (1-methyl-1H-pyrazol-4-yl) -2-nitroaniline

A solution of 4-bromo-2-nitroaniline (6g,27.6mmol) in 1, 2-dimethoxyethane (15ml) was degassed for 5 minutes by bubbling nitrogen through it. 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (6.90g,33.1mmol,1.2eq.) was added and the mixture was degassed for an additional 5 minutes. Pd (dppf) Cl was added in succession₂(2.25g,27.6mmol,0.1 eq.) and aqueous sodium carbonate (8.79g,82.9mmol,3.0 eq.) and the mixture was degassed for an additional 5 minutes, then added at 90 deg.CHeat for 2 hours the mixture was quenched with water and extracted with ethyl acetate (3 × 50ml), the combined organic layers were washed with water, brine and dried over sodium sulfate, the solvent was evaporated under reduced pressure to give a crude residue which was purified by column chromatography (60-120 silica gel, 40% ethyl acetate in hexane) to give the title product in 75% yield (4.5g), LC-MS (ESI) calculated as mass 218.21; found as mass 218.9[ M + H ]]⁺(rt:0.390min)。¹H NMR(400MHz,DMSO-d₆):8.10-8.08(m,2H),7.81(s,1H),7.66-7.63(m,1H),7.44(s,2H),7.05-7.03(d,1H),3.84(s,3H)。

b)2, 6-dichloro-N- (4- (1-methyl-1H-pyrazol-4-yl) -2-nitrophenyl) pyridin-4-amine

A solution of 2, 6-dichloro-4-iodopyridine (1g,3.66mmol) in toluene (15ml) was degassed by bubbling nitrogen for 5 minutes A solution of the compound from example 43(a) (0.958g,4.39mmol,1.2eq.) was added and the mixture was degassed for a further 5 minutes, palladium acetate (0.032g,0.146mmol,0.04 eq.), BINAP (0.091g,0.146mmol,0.04eq.) and potassium tert-butoxide (0.616g,5.49mmol,1.5 eq.) were added in that order and the mixture was degassed for a further 5 minutes and then heated at 100 ℃ for 5 hours, the mixture was filtered through celite and extracted with ethyl acetate (3 × 100ml), the combined organic layers were washed with water, brine and the solvent was distilled off under reduced pressure with sodium sulfate to give a crude residue which was purified by column chromatography (60-120 silica gel, 25% ethyl acetate in hexane, yield 42.3% ESI), calculated as 0.38% yield: (38: 38 mg: (LC: 38M): 363.04M)]⁺(rt:1.578min)。

c)1- (2, 6-dichloropyridin-4-yl) -5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazole

A solution of the compound from example 43(b) (0.55g,1.51mmol) in a mixture of formic acid (10ml) and iron (0.843g,15.1mmol) was heated at 100 ℃ 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 sulfate. The solvent was distilled off under reduced pressure to give the title compound in 77% yield (0.4 g). LC-MS (ESI) mass calculated value 343.04; measured value of mass 344.05[ M + H]⁺(rt:1.169min)。

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

A solution of the compound from example 43(c) (0.54g,1.56mmol) in dioxane (15ml) was degassed by bubbling nitrogen through it for 5 minutes. Cyclopropanesulfonamide (0.189g,1.56mmol,1eq) was added and the mixture was degassed for an additional 5 minutes. Palladium acetate (0.028g,0.125mmol,0.08eq), Xantphos (0.072g,0.125mmol,0.08eq) and Cs were added₂CO₃(1.53g,4.7mmol,3.0eq) and the mixture was degassed for a further 5 minutes and then heated at 100 ℃ for 16 hours the mixture was filtered through celite and extracted with ethyl acetate (3 × 50 ml.) the combined organic layers were washed with water, brine and dried over sodium sulphate and the solvent was evaporated under reduced pressure to give a crude residue which was purified by column chromatography (60-120 silica gel, 3% methanol/hexane) to give the title product in 37% yield (250 mg). LC-MS (ESI) mass calculated value: 428.08; mass found: 429.2[ M + H ] 428.08]⁺(rt:0.854min)。

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

A solution of the compound from example 43(d) (0.15g,0.350mmol) in DME (4ml) was degassed for 5 minutes by bubbling nitrogen through it. 2, 4-difluorophenylboronic acid (0.06g,0.385mmol,1.1eq) was added and the mixture was degassed for an additional 5 minutes. Sequentially adding Pd (PPh)₃)₄(0.039g,0.035mmol,0.1eq) and cesium carbonate (0.341g,1.051mmol,3eq) in water and the mixture was degassed for an additional 5 minutes then heated at 100 ℃ for 16 hours the reaction mixture was quenched with water and extracted with ethyl acetate (3 × 30ml), the combined organic layers were washed with water, brine and dried over sodium sulfate, the solvent was evaporated under reduced pressure to give a crude residue which was purified by preparative TLC to give the title product in 11.2% yield (20 mg).¹H NMR(400MHz,DMSO-d₆):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,2H),7.65-7.63(d,1H),7.49-7.43(m,1H),7.35-7.29(m,2H),3.87(s,3H),3.23(m,1H),1.13-1.06(m,4H)。LC-MS(ESI) 506.13 as mass calculation value; measured value of mass 507.5[ M + H]⁺(rt:1.583min)。

Abbreviations:

RT-Room temperature

rt-Retention time

BINAP-2,2 '-bis (diphenylphosphino) -1,1' -binaphthyl

DMF-N, N-dimethylformamide

THF-tetrahydrofuran

TEA-Triethylamine

TLC-thin layer chromatography

DCM-dichloromethane

DME-dimethoxyethane

DMSO-dimethyl sulfoxide

EDC-1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride

HATU-2- (1H-7-azabenzotriazol-1-yl) -1,1,3, 3-tetramethyluronium hexafluorophosphate methylammonium salt

HOBt-hydroxybenzotriazole

DIPEA-N, N-diisopropylethylamine

TBAF-tetra-n-butylammonium fluoride

Pd(dppf)Cl₂-1,1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride

Pd(PPh₃)₄Tetrakis (triphenylphosphine) palladium (0)

Pd₂(dba)₃-tris (dibenzylideneacetone) dipalladium (0).

Claims (11)

1. A compound of formula (I) and pharmaceutically acceptable salts thereof

Wherein

Z₁Is N and Z₂Is CH, or

Z₁Is CH and Z₂Is N, or

Z₁And Z₂Is N;

z is CH or N;

a is any one of the following groups or a tautomer thereof

R₁Is H, C_1-7Alkyl radical, C_1-7Alkylamino radical C_1-7Alkyl, -R₁₆-C(O)-R₁₇or-E-R₆；

R₂Is H;

b is any one of the following groups or a tautomer thereof

R₃Is halogen or halogeno C_1-7An alkoxy group;

R₄is H or halogen;

R₆is any one of the following groups

R₈Is C_1-7Alkyl or C_3-7A cycloalkyl group;

R₁₆is a bond;

R₁₇is C_1-7An alkyl group;

e is a bond or C_1-7An alkyl group.

2. The compound of claim 1, wherein Z is CH.

3. The compound of claim 1 or 2, wherein Z₁Is N and Z₂Is CH.

4. The compound of claim 1 or 2, wherein Z₁Is CH and Z₂Is N.

5. The compound of claim 1 or 2, wherein Z₁And Z₂Is N.

6. The compound of claim 1, wherein

A is a ring of formula (1 '), (2'), (4 ') or (5');

R₁is H, C_1-7Alkyl or-E-R₆；

R₂Is H;

z is CH;

b is a ring of formula (1 '), (3 '), or (6 ');

R₃is halogen; and is

R₈Is C_1-7Alkyl or C_3-7A cycloalkyl group.

7. The compound of claim 1, wherein Z is CH, Z₁Is N and Z₂Is CH, A is a ring of formula (1 '), B is a ring of formula (1'), R₁Is C_1-7Alkyl radical, R₂Is H, R₃Is halogen, R₄Is H or halogen and R₈Is C_1-7Alkyl or C_3-7A cycloalkyl group.

8. A compound according to claim 1, which is:

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

the sodium salt of the imide 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;

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

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

the sodium salt of the imide 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;

an imide form of 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;

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

the sodium salt of the imide form of N- (4- (2-fluorophenyl) -6- (5- (1-methyl-1H-pyrazol-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- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) pyridin-2-yl) ethanesulfonamide;

the sodium salt of N- (4- (2-fluorophenyl) -6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) pyridin-2-yl) ethanesulfonamide in imide form;

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

the sodium salt of the imide 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;

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-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) pyridin-2-yl) methanesulfonamide;

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

the sodium salt of the imide form of N- (4- (4-fluorophenyl) -6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) pyridin-2-yl) propane-2-sulfonamide;

n- (3-fluoro-6 ' - (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [2,4' -bipyridinyl ] -2' -yl) cyclopropanesulfonamide;

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-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) pyrimidin-2-yl) cyclopropanesulfonamide;

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

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

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

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

n- (5-fluoro-6 ' - (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [2,4' -bipyridinyl ] -2' -yl) cyclopropanesulfonamide;

n- (6- (5- (1H-imidazol-1-yl) -1H-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;

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;

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

n- (4- (2, 4-difluorophenyl) -6- (5- (1-methyl-1H-1, 2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) pyridin-2-yl) cyclopropanesulfonamide;

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

1- (1- (6- (cyclopropanesulfonylamino) -4- (2, 4-difluorophenyl) pyridin-2-yl) -1H-benzo [ d ] imidazol-5-yl) -1H-1,2, 3-triazole-4-carboxylic acid ethyl ester;

n- (4- (2- (difluoromethoxy) -4-fluorophenyl) -6- (5- (1-methyl-1H-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) 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.

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

10. Use of a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a condition in which inhibition of a FGFR kinase is indicated.

11. Use of a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.