HK1200451B

HK1200451B - Protein kinase inhibitors

Info

Publication number: HK1200451B
Application number: HK15100949.5A
Authority: HK
Inventors: Tero Linnanen; Gerd Wohlfahrt; Srinivas Nanduri; Ravi UJJINAMATADA; Srinivasan Rajagopalan; Subhendu MUKHERJEE
Original assignee: 奥瑞基尼肿瘤有限公司
Priority date: 2011-10-10
Filing date: 2012-10-09
Publication date: 2017-02-03

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. Once stimulated with FGF, FGFRs undergo dimerization and transphosphorylation. 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 (squiresm et al, mol. cancer. September2011,10: 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, WO2009/019518a 1). Thus, FGFs and FGFRs 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

Z is CH or N;

g is cyano, -C (O) NR₁₅R₁₆、-C(O)OR₁₇、-C(O)R₂₁、-C(CH₃)=NOR₂₂Or a group of the formula

Wherein A is a benzene ring or a 5-12 membered heterocyclic ring, and

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 radical, C_1-7Alkylamino radical C_1-7Alkyl, phenyl C_1-7Alkoxy, -NHC (O) -R₂₁、-R₁₂-C(O)-R₁₃、-SO₂-R₁₄or-E-R₆And is and

R₂is H, halogen, C_1-7Alkyl or oxo;

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

R₃is H, halogen, C_1-7Alkyl radical, C_1-7Alkoxy, cyano or an optionally substituted 5-6 membered heterocyclic ring;

R₄is H, halogen, C_1-7Alkyl or oxo;

m is hydroxy, C_1-7Alkyl or-NHR₅;

R₅Is H, -C (O) R₇、-SO₂R₈、-C(O)-D-R₉Or 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_3-7Cycloalkyl 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, -NR₁₈R₁₉、-NH-X₂-R₂₀Phenyl or an optionally substituted 5-6 membered heterocyclic ring;

R₉is phenyl or an optionally substituted 5-6 membered heterocyclic ring;

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

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

R₁₂and R₂₁Is C_1-7An alkyl group;

R₁₃is C_1-7Alkoxy, amino or hydroxy;

R₁₄is C_1-7Alkyl or C_3-7A cycloalkyl group;

R₁₅、R₁₆、R₁₇、R₁₈and R₁₉Independently is H, C_1-7Alkyl or C_3-7A cycloalkyl group;

R₂₀is phenyl or an optionally substituted 5-6 membered heterocyclic ring;

R₂₁is an optionally substituted 5-6 membered heterocyclic ring;

R₂₂is H or C_1-7An alkyl group;

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

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

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

and pharmaceutically acceptable salts thereof.

One preferred class of compounds is that of formula (I) wherein ring a is any one of the following groups or tautomers thereof:

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

Another preferred class of compounds are those of formula (I) wherein ring B is any one of the following groups or tautomers thereof:

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

Another preferred class of compounds are compounds of formula (I) wherein Z is CH. Another preferred class of compounds are compounds of formula (I) wherein Z is N.

A subclass of the above preferred classes are compounds wherein G is a group of the formula:

wherein A is a ring of formula (1 '), (2 '), (3 '), (4 '), (5 '), (7 '), (10 '), (12 '), (14 '), (16 ') or (20 ');

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

R₂Is H;

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;

m is-NHR₅;

R₅is-C (O) R₇、-SO₂R₈or-C (O) -D-R₉Or any one of the following groups

R₇Is C_1-7Alkyl radical, C_2-7Alkenyl, -NH-R₁₀or-NH-X₁-R₁₁;

R₈Is C_1-7Alkyl radical, C_2-7Alkenyl radical, C_3-7Cycloalkyl, hydroxy C_1-7Alkyl, -NR₁₈R₁₉、-NH-X₂-R₂₀Phenyl or a group

R₉Is phenyl or any one of the following groups

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

R₁₁is phenyl, 4-fluorophenyl or any one of the following groups

R₁₈And R₁₉Independently is H, C_1-7Alkyl or C_3-7A cycloalkyl group;

R₂₀is a group

X₁And X₂Independently is a bond or C_1-7Alkyl radical, and

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

One class of compounds is compounds of formula (I) wherein M is-NHC (O) R₇Wherein R is₇Is C_1-7Alkyl radical, C_2-7Alkenyl radical, C_3-7Cycloalkyl, -NH-R₁₀or-NH-X₁-R₁₁Wherein R is ₁₀Is C_1-7Alkyl or C_3-7Cycloalkyl radical, X₁Is a bond or C_1-7Alkyl and R₁₁Is optionally substituted by one or two C_1-7An alkyl-substituted 5-6 membered heterocyclic ring.

Another class of compounds are those of formula (I) wherein M is-NHSO₂R₈Wherein R is₈Is C_1-7Alkyl radical, C_2-7Alkenyl radical, C_3-7Cycloalkyl, phenyl or NR₁₈R₁₉Wherein R is₁₈And R₁₉Independently is H, C_1-7Alkyl or C_3-7A cycloalkyl group.

Another class of compounds are those of formula (I), wherein M is-NHC (O) -D-R₉Wherein D is a bond or C_1-7Alkyl and R₉Is optionally substituted by one or two C_1-7An alkyl-substituted 5-6 membered heterocyclic ring.

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 where 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 a compound 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 condition in which inhibition of an 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 G is an optionally substituted A-ring and R₅is-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 are as 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 in the presence of an aqueous solution of sodium carbonate at elevated temperature. The obtained compound [3 ]]E.g. with hydrogen and a Pd/C catalyst, iron powder and aqueous calcium chloride solution or aqueous zinc and ammonium chloride solution, and then reducing the amine [4 ] formed]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]Where Z in (e) is CH, X "is suitably fluorine, and when Z is N, X" is suitably chlorine. Reacting the compound [6 ]]The nitro group in (1) is reduced, for example, by using an aqueous solution of zinc and ammonium chloride or an aqueous solution of iron powder and calcium chloride, and the amine formed is then [7 ]]Heating with formic acid to produce compound [8 ] in a ring closure reaction]. Finally, compound [10]Through 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.

Scheme 1

Or, formula [3]Can also be according to scheme 2 (wherein R is ₃、R₄Ring B and R are as defined above) with a boronic acid derivative [11]Or suitable esters thereof in Pd (dppf) Cl₂And in the presence of an aqueous solution of sodium carbonate. Compound [11]Can be prepared, for example, 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 R is₃And R₄As defined above.

Scheme 3

In the case where the B-ring in the compound [3] is a pyrrole ring bonded to the phenyl group through a nitrogen atom, the compound [3] can also be prepared from 3, 5-dinitroaniline [15] and 2, 5-dimethoxytetrahydrofuran according to scheme 4. The pyrrole derivative [16] thus formed is reduced with ammonium sulfide to obtain a compound [17], which is then reacted with acetic anhydride to obtain a 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, R₃And R₄As 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 prepare in a ring closure reactionAzol-5-yl compound [21]. Reacting a compound [21 ]]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 in a ring closure reaction.

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、R₃And R₄As 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、R₄And ring B is as defined above. Starting compound [8 ]]By reaction with ethynyl trimethylsilaneIn tetrakis (triphenylphosphine) palladium (0) (Pd (PPh)₃)₄) And copper (I) iodide in the presence of a catalyst to produce a compound [32 ]]. Treatment with TBAF to give the ethynyl compound [33]Reacting it with an azido compound R₁-N₃Reaction in a suitable solvent, e.g., DMSO: THF: water (1:1:1) or DMSO: DCM: water (1:1:1) affords compound [34 ]。

Scheme 7

In the compound [10]In the case where ring A in (A) is a 1-methyl-1H-pyrazol-3-yl ring, the compound [10]Can also be prepared according to scheme 8, wherein R₃、R₄And 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]With DMF dimethyl acetal to obtainAzol-5-yl compound [37 ]]. Subsequent treatment with methylhydrazine in a ring closure reaction affords the compound [38 ]]. A compound [38 ]]The nitro group of (b) is further reduced, for example by 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、R₄And 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 (A) is further reduced, for example, by aqueous ammonium and zinc to give the corresponding amine, which is then reacted withThis was 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) CH ₃Can be prepared, for example, according to scheme 10, wherein R₁、R₂、R₃、R₄、R₇、R₈、R₉Z, D, Ring 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 2- (1H-7-azabenzotriazol-1-yl) -1,1,3, 3-tetramethyluronium hexafluorophosphate methylammonium salt (HATU) and DIPEA. Wherein R is₅is-C (O) -D-R₉The compounds of formula (I) can be prepared, for example, by reacting amines [24 ]]With HOOC-D-R₉In a suitable solvent such as DMF in the presence of EDC, HOBt and DIPEA. Wherein R is₅is-C (O) -D-R₉D is a bond and R₉Compounds of formula (I) which are heterocycles linked to the carbonyl carbon atom through the nitrogen heteroatom may be prepared by reacting an amine [24 ] ]With phosgene and then with the compound [29 ]]Reacted as shown in scheme 10.

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 isocyanate derivatives O = C = N-R in a suitable solvent, e.g. 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

Compounds wherein G is not optionally substituted ring a can be prepared similarly using the procedure of scheme 1, wherein X' is replaced by G. Wherein G is-C (O) NH₂The compound of formula (I) can also be prepared by heating a compound [8 ] wherein X' is cyano in an aqueous potassium hydroxide solution]To prepare the compound.

The compound wherein M is hydroxy may suitably be selected from the formula [42]Followed by bicyclic ring closure as depicted in scheme 1 and B-ring addition by, for example, Suzuki coupling as depicted in scheme 1. Can be prepared, for example, by reacting thiourea/AlCl₃Heating the alkoxy compound in the presence of the pair of reagents converts the alkoxy group of the resulting compound into a hydroxyl group.

Finally, where R is₅Compounds which are optionally substituted 5-6 membered heterocyclic rings can be used according to scheme 12 or 13Compound [40]Or [42 ]]As starting material (wherein R₃、R₄Z, Ring B and G are as defined above) with palladium (e.g. Pd₂(dba)₃) The catalyzed C-N coupling is prepared in the presence of a metal chelating ligand such as Xantphos.

Scheme 12

Scheme 13

Pharmaceutically acceptable salts, such as acid addition salts with inorganic and organic acids, are known in the pharmaceutical art. Non-limiting examples of such salts include chloride, bromide, sulfate, nitrate, phosphate, sulfonate, formate, tartrate, maleate, citrate, benzoate, salicylate, and ascorbate. 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 "halogen" as used herein by itself or as part of another group refers to chlorine, bromine, fluorine or iodine. Fluorine is the preferred halogen.

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

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 "amino" as used herein by itself or as part of another group refers to-NH₂A 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) that is bonded to an oxygen atom by a double bond. The term "oxo" as used herein by itself or as part of another group refers to an oxygen atom connected to another atom through a double bond (= O).

The term "C" as used herein_1-7Alkoxy "by itself or as part of another group means a C, as defined herein, appended to the parent molecular moiety through an oxygen atom_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_1-7An alkoxy group is appended to at least one phenyl group on the parent molecular moiety.

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 used herein, by itself or as part of another group, means an amino group, as defined herein, 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, as defined herein, 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 as defined herein_1-7An alkyl group. C_1-7Alkyl ammoniaRepresentative examples of radicals include, but are not limited to, methylamino, ethylamino, propylamino, butylamino, dimethylamino, diethylamino, and N-ethyl-N-methylamino.

The 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. In one group of substituents, preferred substituents are one or two C_1-7Alkyl substituents, especially one or two C_1-3Alkyl substituents, in particular from methyl and ethyl substituents.

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 atoms, wherein 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, without limitation, 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 stereoisomers of the compound, including geometric isomers, such as Z and E isomers (cis and trans isomers) and optical isomers, such as diastereomers and enantiomers, as well as all prodrug esters, such as phosphate esters and carbonates, and isotopes. Furthermore, the present invention also includes within its scope individual isomers and any mixtures thereof, such as racemic mixtures. The individual isomers may be obtained using the isomeric forms of the corresponding starting materials or they may be separated after preparation of the final compound by conventional separation methods. For the separation of optical isomers, e.g. enantiomers, from mixtures thereof, conventional resolution methods, e.g. fractional crystallisation, may be used.

The compounds of the present invention may be administered to a patient in a therapeutically effective amount, which is generally from about 0.1 to about 2000 mg/day, depending on age, weight, race, condition of the patient, condition to be treated, route of administration and 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 are 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 and other kinases

Method of producing a composite material

FGFR1 assay

Compounds were screened in the TR-FRET assay with FGFR1 kinase. 5ngFGFR1[ Upstate, USA)]The kinase was used in the assay. Compounds were incubated with kinase for 30 minutes at room temperature. After incubation, substrate mix [40nM ultra light poly GT (PerkinElmer, USA) and 13 μ MATP (Sigma)]. After 30 minutes of kinase reaction, the reaction was stopped by adding 40mM EDTA. Eu-labeled anti-phospho-tyrosine antibody [ PerkinElmer, 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 100 nFGFR 1 was made>Compound inhibited by 50%. The final DMSO concentration in the assay was 1%. For IC ₅₀Determination of (2) from a 20mM MSMSO stock solution, 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 PerkinElmer Wallac1420multilabelCounterVictor 3. IC (integrated circuit)₅₀Determined by fitting the dose response data with a sigmoidal curve fitting equation using GraphPadPrism software V5.

c-Met assay

Compounds were screened in a TR-FRET assay with c-Met kinase. 0.1ngc-Met [ internally expressed ]]The kinase was used in the assay. Compounds were incubated with kinase for 60 minutes at room temperature. After incubation, substrate mix [40nM ultra light poly GT (PerkinElmer, USA) and 10 μ MATP (Sigma)]. After 30 minutes of kinase reaction, the reaction was stopped by adding 40mM EDTA. Eu-labeled anti-phospho-tyrosine antibody [ PerkinElmer, 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 100nMc-Met was made>50% inhibitionThe compound is prepared. The final DMSO concentration in the assay was 1%. For IC₅₀Determination of (2) from a 20mM MSMSO stock solution, 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 PerkinElmer Wallac1420multilabelCounterVictor 3. IC (integrated circuit)₅₀Determined by fitting the dose response data with a sigmoidal curve fitting equation using GraphPadPrism software V5.

Results

The enzyme activities and selectivities of selected compounds of the invention against different kinases are shown in table 1. It can be seen that the compounds of the present invention are potent and selective FGFR kinase inhibitors.

TABLE 1 inhibition of FGFR1 and c-Met kinase

nd = undetermined

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

N, N-dimethyl-2- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) ethylamine

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

To a solution of 4-bromo-1H-pyrazole (5g,34mmol) in DMF was added K₂CO₃(11.75g,85.03mmol,2.5eq.) and 2-chloro-N, N-dimethylethylamine HCl (7.35g,51mmol,1.5 eq.) and the mixture was stirred at room temperature for 12 h. The mixture was quenched with water and extracted with DCM (3X 150 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, 1% methanol in DCM) to give the product in 86% yield (6.4 g). ¹HNMR(300MHz,DMSO-d₆) 7.95(s,1H),7.25(s,1H),4.18(t,2H),2.61(t,2H),2.15(s,6H), LC-MS (ESI) calculated mass 218.09, measured mass 219.8[ M + H [, M + H ] ]]⁺(retention time: 0.439 minutes).

b) N, N-dimethyl-2- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) ethylamine

To degassing (N)₂Bubbling) intermediate to a solution of the compound of example 1(a) (10g,45.85mmol) in 1, 4-dioxane (50ml) was added 4,4,4',4',5,5,5',5' -octamethyl-2, 2' -bis (1,3, 2-dioxolane) (17.47g,68.78mmol,1.5eq.), Pd (dppf) Cl₂(1.87g,2.29mmol,0.05eq.) and potassium acetate (11.23g,114.6mmol,2.5 eq.). The mixture was heated in a sealed tube at 100 ℃ for 12 hours. The mixture was diluted with ethyl acetate and filtered through a pad of celite. The solvent was distilled off to leave the product (7.0 g). LC-MS (ESI) for calculating mass 265.16 and measured mass 266.2M + H]⁺(retention time: 0.09 minutes).

Intermediate example 2

4- (2- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) ethyl) morpholine

This compound was synthesized using the method described in example 1. LC-MS (ESI) calculated mass 307.2, measured mass 308.1[ M + H ]]⁺(retention time: 0.11 minutes).

Intermediate example 3

1-fluoro-4-iodo-2-nitrobenzene

To a solution of 1-fluoro-2-nitrobenzene (5g,35.43mmol) in trifluoromethanesulfonic acid (15.6ml,177.15mmol,5eq.) was added dropwise N-iodosuccinimide (9.57g,42.5mmol,1.2eq.) at 0 ℃ and the mixture was stirred at room temperature for 1 hour. The mixture was quenched by addition of water and extracted with diethyl ether (3X 150 ml). The combined organic layers were washed with water, aqueous sodium thiosulfate, brine and dried over sodium sulfate. The solvent was evaporated and the crude residue was purified by column chromatography (60-120 silica gel, 5% ethyl acetate in hexane) to give the title compound in 66% yield (6.2 g).¹HNMR(300MHz,DMSO-d₆):8.42(dd,1H),8.18-8.13(m,1H),7.46-7.39(m,1H)。

Intermediate example 4

4-fluoro-3-nitrobenzaldehyde

The nitrated mixture (40 ml of sulphuric acid + 5.5ml of nitric acid) was added dropwise to 4-fluorobenzaldehyde (10g,80.57mmol) at 0 ℃ and the mixture was stirred for 20 minutes at 5 ℃ and then for 1 hour at room temperature. The mixture was quenched by the addition of crushed ice. The precipitate formed was filtered and washed repeatedly with water to give a white solid. The solid was dried in vacuo to give the product in 77% yield (10.5 g).¹HNMR(300MHz,CDCl₃):10.04(s,1H),8.58(dd,1H),8.22-8.18(m,1H),7.5(t,1H)。

Intermediate example 5

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

a) 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester

To piperidin-4-ol (3.5g,34.6mmol) in CH ₂Cl₂(50ml) solution Boc was added at 0 deg.C₂O (11.3g,51.9mmol,1.5eq) and Et₃N (7.2ml,51.9mmol,1.5 eq). The mixture was stirred at room temperature for 1 hour, quenched and extracted as described for intermediate example 1 (a). Evaporating off the solventThe crude product (7.0g) was obtained.

b)4- (methylsulfonyloxy) piperidine-1-carboxylic acid tert-butyl ester

The compound of intermediate example 5(a) (7g,34.7mmol) was dissolved in CH₂Cl₂(70ml) and Et was added at 0 ℃₃N (10ml,69.4mmol,2eq.) and methanesulfonyl chloride (2.7ml,34.7mmol,1 eq.). The mixture was stirred at room temperature for 3 hours, the reaction was terminated and extracted as described in the previous example. The solvent was distilled off to leave a crude product (6.7 g).

c)4- (4-bromo-1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester

To a cooled solution of the compound from example 5(b) (6.7g,23.9mmol) in DMF (50ml) were added NaH (2.8g,119mmol,5eq.) and 4-bromo-1H-pyrazole (2.8g,19.1mmol,0.8eq.) and stirred at 80 ℃ for 12H. The mixture was quenched and extracted with ethyl acetate (3X 100 ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. The solvent was distilled off to leave a crude product (8.0 g).

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

Using the procedure described in intermediate example 1(b), to (N)₂Bubbling) intermediate to a solution of the compound of example 5(c) (8g,24.2mmol) in 1, 4-dioxane (100ml) was added 4,4,4',4', -5,5,5',5' -octamethyl-2, 2' -bis (1,3, 2-dioxolane) (7.36g,29mmol,1.2eq.), Pd (dppf) Cl₂(2g,2.42mmol,0.1eq.) and potassium acetate (8g,82.4mmol,3.4 eq.). The solvent was evaporated and the residue was purified by column chromatography (60-120 silica gel, 10% ethyl acetate in hexane) to give the product in 59% yield (5.4 g). LC-MS (ESI) calculated mass 377.29 and measured mass 378.3[ (M + H)]⁺(retention time: 1.83 minutes).

Intermediate example 6

4-azido-2-methylbutan-2-ol

a) 4-bromo-2-methylbutan-2-ol

To a cooled solution of ethyl 3-bromopropionate (0.5g,2.8mmol) in diethyl ether (50ml) was added methyl magnesium bromide (0.98g,8.3mmol,3eq.) dropwise over 5 minutes at 0 ℃ and the mixture was stirred until TLC showed complete disappearance of starting material. The mixture was quenched and extracted as described for intermediate example 5 (c). The solvent was distilled off to leave a crude product (0.4 g).

b) 4-azido-2-methylbutan-2-ol

To CH of 4-bromo-2-methylbutan-2-ol (0.4g,2.4mmol) and triethylamine (1ml,7mmol,3eq.) was added₂Cl₂(15ml) to the mixture was added sodium azide (0.47g,7mmol,3eq.) in H ₂O (5ml) solution and the mixture was stirred overnight. The mixture was quenched with water and CH₂Cl₂Extraction (3X 50 ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. Evaporation of the solvent gave the product in 65% yield (0.2 g).¹HNMR(300MHz,DMSO-d₆):4.39(brs,1H),3.40-3.32(m,2H),1.15(t,2H),1.23-1.04(m,6H)。

Intermediate example 7

Azidocyclopentane

To a solution of iodocyclopentane (0.5g,2.55mmol) in DMF (2ml) was added aqueous sodium azide (0.33g,5.1 mmol). The mixture was stirred at room temperature for 10 minutes and then at 80 ℃ overnight. The mixture was extracted with diethyl ether (3 × 50ml) and the combined organic layers were washed with water, brine and dried over sodium sulfate. The solvent was distilled off to give the product in 64% yield (0.18g), which was used directly in the next step. FTIR (pure sample): v 3448,2471,2100,1671,1498,1438,1383,1256,1094,865cm^-1。

Intermediate example 8

(azidomethyl) cyclobutane

To a solution of (bromomethyl) cyclobutane (0.5g,3.35mmol) in DMF (2ml) was added aqueous sodium azide (0.43g,6.7 mmol). The mixture was stirred at room temperature for 10 minutes and then at 80 ℃ overnight. Mixing the mixture according toThe method described in the previous example. Evaporation of the solvent gave the product in 54% yield (0.2 g).¹HNMR(300MHz,DMSO-d₆):3.66-3.53(m,2H),2.66-2.21(m,1H),2.06-2.00(m,2H),1.84-1.66(m,4H)。

Intermediate example 9

1- (cyclopropylmethyl) -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole

a) 4-bromo-1- (cyclopropylmethyl) -1H-pyrazole

To a solution of 4-bromo-1H-pyrazole (0.1g,0.68mmol) in DMF (20ml) was added K₂CO₃(0.19g,1.36mmol,2eq.) and (bromomethyl) cyclopropane (92mg,0.68mmol,1 eq.). The mixture was stirred at room temperature for 4 hours. The mixture was quenched and extracted as described for intermediate example 5 (c). The solvent was distilled off to leave a crude product (0.15 g).

b)1- (cyclopropylmethyl) -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole

Using the procedure of intermediate example 1(b), degassing (N)₂Bubbling) intermediate to a solution of the compound of example 9(a) (0.15g,0.75mmol) in 1, 4-dioxane (10ml) was added 4,4,4',4',5,5,5',5' -octamethyl-2, 2' -bis (1,3, 2-dioxolane) (0.23g,0.9mmol,1.2eq.), Pd (dppf) Cl₂(0.12g,0.15mmol,0.2eq.) and potassium acetate (0.25g,2.55mmol,3.4 eq.). Evaporation of the solvent gave a crude residue which was purified by column chromatography (60-120 silica gel, 30% ethyl acetate in hexane) to give the product in 81% yield (0.15 g). LC-MS (ESI) calculated mass 248.13 and actual measured mass 249.2[ (M + H)]⁺(retention time: 1.58 minutes).

Intermediate example 10

2- (morpholin-4-yl) acetic acid

a)2- (Morpholin-4-yl) acetic acid ethyl ester

To a solution of ethyl 2-chloroacetate (0.5g,5.74mmol) in DMF (70ml) at 10 ℃ K was added ₂CO₃(1.98g,14.34mmol,2.5eq.) and 1-methylpiperazine (1.05g,8.6mmol,1.5eq.) and the mixture was stirred at room temperature for 2 hours. The mixture was quenched and extracted as described for intermediate example 5 (c). The solvent was evaporated and the crude residue was purified by column chromatography (60-120 silica gel, 40% ethyl acetate in hexane) to give the product in 74% yield (0.74 g). LC-MS (ESI) calculated mass 173.2, measured mass 174.0[ M + H [)]⁺(retention time: 0.20 minutes).

b)2- (morpholin-4-yl) acetic acid

A solution of ethyl 2- (morpholin-4-yl) acetate (1.8g,11.44mmol) in 8N HCl (5ml) was heated at 90 ℃ for 12 h. The mixture was concentrated to give the product in 64% yield (0.9 g). LC-MS (ESI) calculated mass 145.16 and measured mass 146.3[ M + H ]]⁺(retention time: 0.21 minutes). Intermediate example 11

4-azido-1-methylpiperidine

a) 1-methylpiperidin-4-yl methanesulfonate

1-Methylpiperidin-4-ol (4g,34.7mmol) was dissolved in CH at 0 deg.C₂Cl₂(70ml) then Et was added₃N (10ml,69.4mmol,2eq.) and methanesulfonyl chloride (2.7ml,34.7mmol,1 eq.). The mixture was stirred at room temperature for 3 hours, quenched and extracted as described for intermediate example 5 (a). The solvent was distilled off to leave a crude product (6.7 g).

b) 4-azido-1-methylpiperidine

To a solution of the compound from intermediate example 11(a) (2.1g,10.9mmol) in DMF (30ml) was added sodium azide (1g,16.32mmol,1.5 eq.). The mixture was stirred at 60 ℃ for 12 hours. The mixture was then quenched with water and extracted with diethyl ether (3X 100 ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. The solvent was distilled off to leave the product (1.3 g).¹HNMR(300MHz,CDCl₃) 3.49-3.37(M,1H),2.71-2.67(M,2H)2.24(s,3H)2.18-2.09(M,2H)1.93-1.85(M,2H)1.72-1.60(M,2H), LC-MS (ESI), calculated mass 140.1, measured mass 141.1[ M + H [, ]]⁺(retention time: 0.13 minutes).

Intermediate example 12

1-isopropyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole

a) 4-bromo-1-isopropyl-1H-pyrazoles

To a solution of 4-bromo-1H-pyrazole (5g,34mmol) in DMF (70ml) was added K₂CO₃(11.83g,85.6mmol,2.5eq.) and 2-bromopropane (6.3g,51.36mmol,1.5eq.) and the mixture was stirred at room temperature for 12 hours. The mixture was quenched and extracted as described for intermediate example 5 (a). 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 product in 89% yield (5.8 g).¹HNMR(300MHz,DMSO-d₆):8.01(s,1H),7.50(s,1H),4.49-4.43(m,1H),1.38(d,6H)。

b) 1-isopropyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole

Using the procedure of intermediate example 1(b), degassing (N)₂Bubbling) intermediate of example 12(a) A solution of 4-bromo-1-isopropyl-1H-pyrazole (1.5g,7.9mmol) in 1, 4-dioxane (30ml) was added 4,4,4',4',5,5,5',5' -octamethyl-2, 2' -bis (1,3, 2-dioxaborolane) (3g,11.84mmol,1.5eq.), Pd (dppf) Cl₂(0.64g,0.79mmol,0.1eq.) and potassium acetate (1.93g,19.74mmol,2.5 eq.). Evaporation of the solvent gave the product in 67% yield (1.2 g). LC-MS (ESI) calculated mass 236.12 and measured mass 237.1[ M + H]⁺(retention time: 1.41 minutes).

Intermediate example 13

1-ethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole

a) 4-bromo-1-ethyl-1H-pyrazoles

To a solution of 4-bromo-1H-pyrazole (5g,34mmol) in DMF was added K₂CO₃(11.75g,85.03mmol,2.5eq.) and iodoethane (8g,51mmol,1.5eq.) and the mixture was stirred at room temperature for 12 hours. According to intermediate example 5(c)The method terminates the reaction of the mixture and extracts the mixture. The solvent was evaporated and the crude residue was purified by column chromatography (60-120 silica gel, 40% ethyl acetate in hexane) to give the product in 84% yield (5 g).¹HNMR(300MHz,DMSO-d₆) 8.02(s,1H),7.55(s,1H),4.15(q,2H),1.37(t,3H), LC-MS (ESI) calculated mass 175.03, measured mass 177.0[ M + H [ ], mass ]⁺(retention time: 0.56 minutes).

b) 1-ethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole

Using the procedure of intermediate example 1(b), degassing (N)₂Bubbling) 4-bromo-1-ethyl-1H-pyrazole (2g,11.42mmol) in 1, 4-dioxane (30ml) was added 4,4,4',4',5,5,5',5' -octamethyl-2, 2' -bis (1,3, 2-dioxaborolane) (4.35g,17.14mmol,1.5eq.), Pd (dppf) Cl₂(0.93g,1.14mmol,0.1eq.) and potassium acetate (2.79g,28.55mmol,2.5 eq.). Evaporation of the solvent gave the product in 88% yield (2.2 g). LC-MS (ESI) for calculating mass 222.09 and measured mass 223.3M + H]⁺(retention time: 0.83 minutes).

Intermediate example 14

2-chloro-5-iodo-3-nitropyridine

a) 5-iodo-3-nitropyridin-2-amines

To a solution of 3-nitropyridin-2-amine (1.2g,8.63mmol) in acetic acid (5ml), water (1ml) and sulfuric acid (0.2ml) was added periodic acid (0.4g,1.72mmol,0.2eq.) and the mixture was stirred at 90 ℃ for 15 min. Iodine (0.87g,3.45mmol,0.4eq.) was added portionwise and the mixture was heated at 90 ℃ for 1 hour. The mixture was quenched by addition of water and extracted with ethyl acetate (3X 150 ml). The combined organic layers were washed with water, aqueous sodium thiosulfate, brine and dried over sodium sulfate. Evaporation of the solvent gave the product in 57% yield (1.3 g). ¹HNMR(300MHz,DMSO-d₆) 8.58(d,1H),8.54(d,1H)8.04(brs,2H), LC-MS (ESI), calculated mass 265.01, measured mass 265.9[ M + H ]]⁺(retention time: 1.36 minutes).

b) 2-chloro-5-iodo-3-nitropyridine

To a concentrated HCl solution of 5-iodo-3-nitropyridin-2-amine (1.3g,4.9mmol) was added sodium nitrite (6.73g,97.13mmol,20eq.) in portions at 0 ℃ followed by copper (I) chloride (0.5g,4.9mmol,1eq.) and the mixture was stirred at room temperature for 12 hours. The mixture was then poured into a mixture of ammonium hydroxide and water (1:1) and extracted with ethyl acetate (3X 150 ml). The combined organic layers were washed with water, aqueous sodium thiosulfate, brine and dried over sodium sulfate. Evaporation of the solvent gave the product in 43% yield (0.6 g).

Intermediate example 15

2- (4-ethylpiperazin-1-yl) acetic acid

a)2- (4-methylpiperazin-1-yl) acetic acid ethyl ester

To a solution of 1-methylpiperazine (1g,8.771mmol,1.0eq) in DMF was added K₂CO₃(265mg,21.927mmol,2.5eq) and ethyl 2-bromoacetate (167mg,13.15mmol,1.5 eq). The mixture was stirred at room temperature for 16 hours, quenched and extracted as described for intermediate example 5 (a). Evaporation of the solvent gave the product in 76.4% yield (1.3 g).

b)2- (4-ethylpiperazin-1-yl) acetic acid

A solution of methyl 2- (4-ethylpiperazin-1-yl) acetate (1.3g,6.50mmol,1.0eq) in 8N HCl was stirred at 95 ℃ for 16 h and concentrated in vacuo. The mixture was quenched with sodium bicarbonate solution 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 product in 54.5% yield (0.6 g). LC-MS (ESI) calculated mass 158.0 and measured mass 159.1[ M + H ] ]⁺(retention time: 0.102 min).

Intermediate example 16

N-cyclopropyl-2-oxoOxazolidine-3-sulfonamides

To bromine ethylA solution of chlorosulfonyl isocyanate (1.13g,8.06mmol) in DCM was added to a solution of alcohol (1g,8.06mmol) in DCM and the solution was added dropwise over 2 minutes to a solution of cyclopropylamine (0.552g,0.009mmol) and triethylamine (1ml,0.007mmol) in DCM and stirred at room temperature for 1 hour. The mixture was quenched with 0.2M HCl solution and extracted with DCM (3X 150 ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. Evaporation of the solvent gave the product in 48% yield (0.8 g).¹HNMR(400MHz,DMSO-d₆):8.15-8.14(d,1H),4.42(t,2H),3.70(t,2H),2.35(m,1H),0.58-0.53(m,4H)。

Intermediate example 17

N- (1H-pyrazol-4-yl) acetamide

Acetic anhydride (0.7ml,8.433mmol.) was added dropwise to 1H-pyrazol-4-amine (0.7g,8.433mmol) at 0 ℃. The mixture was stirred at room temperature for 30 minutes and the reaction was stopped by adding crushed ice. The mixture was extracted with ethyl acetate and the combined organic layers were washed with water, brine and dried over sodium sulfate. Evaporation of the solvent gave the product in 54% yield (0.6 g). LC-MS (ESI) calculated mass 125.0 and measured mass 126.0[ M + H ]]⁺(retention time: 0.115 minutes).

Intermediate example 18

2- (1H-1,2, 4-triazol-1-yl) acetic acid

a)2- (1H-1,2, 4-triazol-1-yl) acetic acid ethyl ester

To a solution of 1H-1,2, 4-triazole (2g,29.9mmol,1.0eq) in DMF was added K₂CO₃(12.3g,88.9mmol,3eq.) and ethyl 2-bromoacetate (4.8g,29.9mmol,1 eq). The mixture was stirred at room temperature for 16 hours. The mixture was quenched and extracted as described for intermediate example 5 (a). Evaporation of the solvent gave the product in 65% yield (3 g). LC-MS (ESI) with calculated mass of 155.0 and measured mass of 156.1[ M + H ]]⁺(retention time: 0.113 min).

b)2- (1H-1,2, 4-triazol-1-yl) acetic acid

Intermediate example 18(a) Compound(3g,19.35mmol,1.0eq) of an 8N HCl solution was stirred at 95 ℃ for 16 h and concentrated in vacuo. The mixture was quenched and extracted as described for intermediate example 15 (b). Evaporation of the solvent gave the desired product in 62% yield (1.5 g). LC-MS (ESI) with calculated mass of 127.0 and measured mass of 128.0[ M + H ]]⁺(retention time: 0.24 minutes).

Intermediate example 19

a)2- (pyrrolidin-1-yl) acetic acid ethyl ester

To a solution of pyrrolidine (1.2g,16.3mmol,1.0eq) in DMF was added K₂CO₃(5.63g,40.7mmol,2.5eq.) and ethyl 2-bromoacetate (1.73g,24.4mmol,1.5 eq.). The mixture was stirred at room temperature for 16 hours, quenched and extracted as described for intermediate example 5 (a). Evaporation of the solvent gave the product in 80% yield (2 g). LC-MS (ESI) calculated mass 157.2, measured mass 158.1[ M + H ] ]⁺(retention time: 0.2 minutes).

b)2- (pyrrolidin-1-yl) acetic acid

A solution of ethyl 2- (pyrrolidin-1-yl) acetate (2g,12.7mmol,1.0eq) in 8N HCl was stirred at 95 ℃ for 16 h. The mixture was concentrated, quenched and extracted as described for intermediate example 15 (b). Evaporation of the solvent gave the product in 91% yield (1.5 g). LC-MS (ESI) mass 129.1, measured mass 130.1[ M + H ]]⁺(retention time: 0.26 min).

Intermediate example 20

2- (morpholin-4-yl) acetic acid

a)2- (Morpholin-4-yl) acetic acid ethyl ester

To a solution of morpholine (1.4g,16.3mmol,1.0eq) in DMF was added K₂CO₃(5.63g,40.7mmol,2.5eq.) and ethyl 2-bromoacetate (4.07g,24.4mmol,1.5 eq.). The mixture was stirred at room temperature for 16 hours, quenched and extracted as described for intermediate example 5 (a). Evaporation of the solvent gave the product in 71.4% yield (2 g). LC-MS (ESI) calculated mass 173.2, measured mass 174.0[ M + H [)]⁺(retention time: 0.20 minutes).

b)2- (morpholin-4-yl) acetic acid

A solution of ethyl 2- (morpholin-4-yl) acetate (1g,57.8mmol,1.0eq) in 8N HCl was stirred at 95 ℃ for 16 h. The mixture was concentrated, quenched and extracted as described for intermediate example 15 (b). Evaporation of the solvent gave the product in 96.3% yield (0.8 g). LC-MS (ESI) calculated mass 145.16 and measured mass 146.3[ M + H ] ]⁺(retention time: 0.21 minutes).

Intermediate example 21

2- (piperidin-1-yl) acetic acid

a)2- (piperidin-1-yl) acetic acid ethyl ester

To a solution of piperidine (3.4g,40.7mmol,1.0eq) in DMF was added K₂CO₃(14g,101.0mmol,2.5eq.) and ethyl 2-chloroacetate (4.83ml,48.9mmol,1.2 eq). The mixture was stirred at room temperature for 16 hours. The mixture was quenched and extracted as described for intermediate example 5 (a). Evaporation of the solvent gave the product in 72% yield (5 g). LC-MS (ESI) calculated mass 171.1 and measured mass 172.3[ M + H ]]⁺(retention time: 0.1 min).

b)2- (piperidin-1-yl) acetic acid

A solution of ethyl 2- (piperidin-1-yl) acetate (1g,5.84mmol,1.0eq) in 8N HCl was stirred at 95 ℃ for 16 hours. The mixture was concentrated, quenched and extracted as described for intermediate example 15 (b). Evaporation of the solvent gave the product in 95% yield (0.8 g). LC-MS (ESI) mass 143.1, mass 144.4[ M + H [ ]]⁺(retention time: 0.21 minutes).

Intermediate example 22

2- (3, 5-dimethylpiperazin-1-yl) acetic acid

a)2- (3, 5-dimethylpiperazin-1-yl) acetic acid ethyl ester

To a solution of 2, 6-dimethylpiperazine (500mg,4.378mmol,1.0eq) in THF was addedK₂CO₃(1.2g,8.75mmol,2.2eq.) and ethyl 2-bromoacetate (731mg,4.378mmol,1 eq). The mixture was stirred at room temperature for 4 hours, then quenched and extracted as described for intermediate example 5 (a). Evaporation of the solvent gave the product in 34% yield (0.3 g). LC-MS (ESI) with calculated mass of 200.0 and measured mass of 201.0M + H ]⁺(retention time: 0.102 min).

b)2- (3, 5-dimethylpiperazin-1-yl) acetic acid

A solution of the compound from intermediate example 22(a) (300mg,1.5mmol,1.0eq) in 8N HCl was stirred at 95 ℃ for 16 h. The mixture was concentrated, quenched and extracted as described for intermediate example 15 (b). Evaporation of the solvent gave the product in 96% yield (250 mg). LC-MS (ESI) with calculated mass of 172.0 and measured mass of 173.1[ M + H ]]⁺(retention time: 0.094 minutes). Intermediate example 23

2- (4- (tert-butoxycarbonyl) piperazin-1-yl) acetic acid

a)4- (2-ethoxy-2-oxoethyl) piperazine-1-carboxylic acid tert-butyl ester

To a solution of piperazine-1-carboxylic acid tert-butyl ester (2.9g,10.7mmol,1.0eq) in THF was added potassium carbonate (2.96g,21.0mmol,2eq) and ethyl 2-bromoacetate (1.58g,10.7mmol,1 eq). The mixture was stirred at room temperature for 16 hours. The mixture was quenched and extracted as described for intermediate example 5 (a). Evaporation of the solvent gave the product in 51% yield (1.5 g).

b)2- (4- (tert-butoxycarbonyl) piperazin-1-yl) acetic acid

To a solution of the compound (1.5g,5.51mmol) of intermediate example 23(a) in methanol (10ml) was added aqueous NaOH (0.8g,22.0mmol,4 eq). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated and extracted as described for intermediate example 5 (c). Evaporation of the solvent gave the product in 76% yield (1 g). LC-MS (ESI) calculated mass 244.29, measured mass 145.1[ M-Boc + H ]⁺(retention time: 0.102 min).

Intermediate example 24

a)2- (4-ethylpiperazin-1-yl) acetic acid ethyl ester

To a solution of 1-ethylpiperazine (1g,8.771mmol,1.0eq) in DMF was added K₂CO₃(3g,21.927mmol,2.5eq.) and ethyl 2-bromoacetate (2.19g,13.156mmol,1.5 eq.). The mixture was stirred at room temperature for 16 hours. The mixture was quenched and extracted as described for intermediate example 5 (a). Evaporation of the solvent gave the product in 76.4% yield (1.3 g).

b)2- (4-ethylpiperazin-1-yl) acetic acid

A solution of ethyl 2- (4-ethylpiperazin-1-yl) acetate (1.3g,6.50mmol,1.0eq) in 8N HCl was stirred at 95 ℃ for 16 h. The mixture was concentrated in vacuo, the reaction was terminated and extracted as described for intermediate example 15 (b). Evaporation of the solvent gave the product in 54.5% yield (0.6 g).

Intermediate example 25

1-isopropyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole

a) 4-bromo-1-isopropyl-1H-pyrazoles

To a solution of 4-bromo-1H-pyrazole (5g,34.24mmol,1.0eq) in DMF was added K₂CO₃(11.83g,85.60mmol,2.5eq.) and 2-bromopropane (6.31g,51.36mmol,1.5eq.) the mixture was stirred at room temperature for 12 hours. The mixture was quenched and extracted as described for intermediate example 5 (a). Evaporation of the solvent gave the product in 76.9% yield (5.0 g).

b) 1-isopropyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole

Using the procedure of intermediate example 1(b) to (N)₂Bubbling) 4-bromo-1-isopropyl-1H-pyrazole (1.5g,7.894mmol) in 1, 4-dioxane (15ml) was added 4,4,4',4',5,5,5',5' -octamethyl-2, 2' -bis (1,3, 2-dioxolane) (3.0g,11.84mmol,1.5eq.), Pd (dppf) Cl₂(0.644g,0.784mmol,0.1eq.) and potassium acetate (1.93g,19.73mmol,2.5 eq.). Evaporating off the solventAnd the residue was purified by column chromatography (60-120 silica gel, 15% ethyl acetate in hexane) to give the product in 66.6% yield (1.2 g). LC-MS (ESI) calculated mass 236.17 and measured mass 237.1[ M + H]⁺(retention time: 1.4 minutes).

Intermediate example 26

2- (piperidin-1-yl) acetic acid

a)2- (piperidin-1-yl) acetic acid ethyl ester

To a solution of piperidine (1.5g,17.61mmol,1.0eq) in DMF was added K₂CO₃(6.08g,44.02mmol,2.5eq.) and ethyl 2-chloroacetate (3.23g,26.42mmol,1.5 eq.). The mixture was stirred at room temperature for 12 hours, quenched and extracted as described for intermediate example 5 (a). Evaporation of the solvent gave the product in 80% yield (2.4 g). LC-MS (ESI) calculated mass 171.1 and measured mass 172.3[ M + H ]]⁺(retention time: 0.1-0.2 min).

b)2- (piperidin-1-yl) acetic acid

A solution of ethyl 2- (piperidin-1-yl) acetate (2.4g,14.0mmol,1.0eq) in 8N HCl was stirred at 95 ℃ for 16 hours. The mixture was concentrated in vacuo, the reaction was terminated and extracted as described for intermediate example 15 (b). Evaporation of the solvent gave the product in 60% yield (1.2 g). LC-MS (ESI) mass 143.1, mass 144.4[ M + H [ ]]⁺(retention time: 0.21 minutes).

Intermediate example 27

2- (morpholin-4-yl) acetic acid

a)2- (Morpholin-4-yl) acetic acid ethyl ester

To a solution of morpholine (0.5g,5.739mmol,1.0eq) in DMF was added K₂CO₃(1.98g,14.34mmol,2.5eq.) and ethyl 2-chloroacetate (1.05g,8.60mmol,1.5 eq.). The mixture was stirred at room temperature for 12 hours. The mixture was quenched and extracted as described for intermediate example 5 (a). Evaporation of the solvent gave the product in 73.9% yield (0.735 g). LC-MS (ESI) calculated mass 173.21, measured mass 174.0[ M + H [)]⁺(retention time: 0.1-0.4 min).

b)2- (morpholin-4-yl) acetic acid

A solution of ethyl 2- (morpholin-4-yl) acetate (0.73g,4.24mmol,1.0eq) in 8N HCl was stirred at 95 ℃ for 16 h. The mixture was concentrated on a vacuum pump, quenched and extracted as described for intermediate example 15 (b). Evaporation of the solvent gave the product in 60% yield (0.37 g). LC-MS (ESI) with calculated mass of 145.1 and measured mass of 146.3[ M + H ] ]⁺(retention time: 0.28 minutes).

Intermediate example 28

2- (pyrrolidin-1-yl) acetic acid

a)2- (pyrrolidin-1-yl) acetic acid ethyl ester

To a solution of pyrrolidine (0.9g,12.65mmol,1.0eq) in DMF was added K₂CO₃(4.37g,31.62mmol,2.5eq.) and ethyl 2-chloroacetate (2.32g,18.98mmol,1.5 eq.). The mixture was stirred at room temperature for 12 hours. The mixture was quenched and extracted as described for intermediate example 5 (a). Evaporation of the solvent gave the product in 94.7% yield (1.8 g). LC-MS (ESI) calculated mass 157.2, measured mass 158.1[ M + H ]]⁺(retention time: 0.2-0.3 min).

b)2- (pyrrolidin-1-yl) acetic acid

A solution of ethyl 2- (pyrrolidin-1-yl) acetate (1.8g,11.95mmol,1.0eq) in 8N HCl was stirred at 95 ℃ for 16 h. The mixture was concentrated in vacuo, the reaction was terminated and extracted as described for intermediate example 15 (b). Evaporation of the solvent gave the product in 54% yield (1.4 g). LC-MS (ESI) mass 129.1, measured mass 130.1[ M + H ]]⁺(retention time: 0.26 min).

Intermediate example 29

2-methyl-4- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) butan-2-ol

a) 4-bromo-2-methylbutan-2-ol

To a solution of methyl 3-bromopropionate (5.0g,29.94mmol, and 1.0eq) in dry THF was added methylmagnesium bromide at 0 deg.C. The mixture was stirred at room temperature for 16 hours, quenched and extracted as described for intermediate example 5 (c). The solvent was evaporated to give a crude residue which was purified by column chromatography (60-120 silica gel, 50% ethyl acetate in hexane). Yield 48.9% (2.4 g). LC-MS (ESI) calculated mass 167.0, measured mass 167.1[ M + H ] ]⁺(retention time: 0.8-1.0 min).

b)4- (4-bromo-1H-pyrazol-1-yl) -2-methylbutan-2-ol

To a solution of 4-bromo-1H-pyrazole (1g,6.84mmol,1.0eq) in DMF was added K₂CO₃(2.3g,17.1mmol,2.5eq.) and 4-bromo-2-methylbutan-2-ol (1.7g,10.27mmol,1.5 eq.). The mixture was stirred at room temperature for 16 hours. The mixture was quenched and extracted as described for intermediate example 5 (a). Evaporation of the solvent gave the product in 60% yield (0.9 g). LC-MS (ESI) mass 233.0 calculated mass 235.0 measured mass [ M + H ]]⁺(retention time: 0.64 min).

c) 2-methyl-4- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) butan-2-ol

Using the procedure of intermediate example 1(b), degassing (N)₂Bubbling) intermediate to a solution of the compound (0.5g,2.16mmol) of example 29(b) in 1, 4-dioxane (5ml) was added 4,4,4',4',5,5,5',5' -octamethyl-2, 2' -bis (1,3, 2-dioxolane) (0.824g,3.24mmol,1.5eq.), Pd (dppf) Cl₂(0.1766g,0.216mmol,0.1eq.) and potassium acetate (0.529g,5.40mmol,2.5 eq.). The solvent was evaporated and purified by column chromatography (60-120 silica gel, 15% ethyl acetate in hexane) to give the product in 49.6% yield (0.3 g). LC-MS (ESI) for calculating mass 280.1 and measured mass 281.2M + H ]⁺(retention time: 0.8 minutes).

Intermediate example 30

3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-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 tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1.0g,5.34mmol,1.0eq) in DCM (10ml) was added TEA (1.08g,10.68mmol,2.0eq) and DMAP (65mg,0.53 mmol). The mixture was stirred at room temperature for 15 minutes. Methanesulfonyl chloride (0.730g 6.41mmole 1.2eq) was then added and the mixture was stirred overnight. The mixture was quenched and extracted as described for intermediate example 5 (a). Evaporation of the solvent gave the product in 71.4% yield (1.0 g).

b)3- (4-bromo-1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of 4-bromo-1H-pyrazole (0.65g,4.42mmol) in DMF was added sodium hydride (0.159g,6.6mmol,1.5eq.) and the compound of intermediate example 30(a) (1.1g,4.42mmol,1.0eq.) at 0 ℃. The mixture was stirred at room temperature for 16 hours, quenched and extracted as described for intermediate example 5 (a). Evaporation of the solvent gave a crude residue which was purified by column chromatography (60-120 silica gel, 1% methanol in DCM) to give the product in 61.5% yield (0.85 g).

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

Using the procedure of intermediate example 1(b), degassing (N)₂Bubbling) intermediate to a solution of the compound of example 30(b) (0.850g,2.68mmol) in 1, 4-dioxane (10ml) was added 4,4,4',4', -5,5,5',5' -octamethyl-2, 2' -bis (1,3, 2-dioxolane) (0.819g,3.22mmol,1.2eq.), Pd (dppf) Cl₂(0.218g,0.268mmol,0.1eq.) and potassium acetate (0.788g,8.04mmol,3.0 eq.). Evaporation of the solvent gave the product in 84.5% yield (0.82 g). LC-MS (ESI) calculated mass 363.2 and measured mass 364.2[ M + H]⁺(retention time: 1.73 minutes).

Intermediate example 31

4- (4-fluoro-3-nitrophenyl) -1-methyl-1H-pyrazole

4-bromo-1-fluoro-2-nitrobenzene (2g, 9.09)5mmol) of 1, 4-dioxane (20ml) was passed through N₂Bubbling and degassing for 5 minutes. 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (2.27g,10.91mmol,1.2eq.) and aqueous sodium carbonate (2.89g,27.27mmol,3.0eq.) were added and the mixture was degassed for a further 15 minutes. Followed by the addition of Pd (PPh)₃)₂Cl₂(0.638g,0.909mmol,0.1eq.) and the mixture was further degassed for 15 minutes and then heated at 90 ℃ for 2 hours. The mixture was quenched and extracted as described for intermediate example 5 (c). Evaporation of the solvent gave a crude residue which was purified by column chromatography (60-120 silica gel, 40-50% ethyl acetate in hexane) to give the product in 79% yield (1.6 g). ¹HNMR(300MHz,DMSO-d₆):8.32-8.26(m,2H),8.0-7.97(m,2H),7.62-7.55(m,1H)。

Intermediate example 32

1-cyclopentyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole

a) 1-cyclopentyl-4-iodo-1H-pyrazoles

To a solution of 4-iodo-1H-pyrazole (5g,25.78mmol,1.0eq.) in DMF (25ml) was added K₂CO₃(8.908g,64.45mmol,2.5eq.) and bromocyclopentane (4.96g,33.51mmol,1.3 eq.). The mixture was stirred at room temperature for 12 hours. The mixture was quenched and extracted as described for intermediate example 5 (a). The solvent was evaporated to give the product in 89.5% yield¹HNMR(300MHz,CDCl₃) 7.49(s,1H),7.45(s,1H),4.66-4.62(m,1H),2.17-2.02(m,1H),2.00-1.96(m,2H),1.93-1.78(m,2H),1.73-1.67(m, 2H). LC-MS (ESI) calculated mass 262, measured mass 263[ M + H ]]⁺(retention time: 1.57 minutes).

b) 1-cyclopentyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole

Using the procedure of intermediate example 1(b), degassing (N)₂Bubbling) of 1-cyclopentyl-4-iodo-1H-pyrazole (6.0g,22.90mmol) in DMSO (60ml) was added 4,4,4',4',5,5,5',5' -octamethyl-2, 2' -bis (1,3, 2-dioxolane) (8.312g,34.35mmol,1.5eq.), (ii) as a diluent,Pd(dppf)Cl₂(0.529g,0.45mmol,0.02eq.) and potassium acetate (4.494g,45.80mmol,2.0 eq.). The solvent was evaporated and purified by column chromatography (60-120 silica gel, 15% ethyl acetate in hexane) to give the product in 48% yield (2.89 g). ¹HNMR(300MHz,CDCl₃) 7.77(s,1H),7.72(s,1H),4.65(m,1H),2.17-2.02(m,1H),2.00-1.96(m,2H),1.93-1.78(m,2H),1.73-1.67(m,2H),1.30-1.24(m, 12H). LC-MS (ESI) for calculating mass 262 and actually measured mass 262.92M + H]⁺(retention time: 1.54 minutes).

Intermediate example 33

(5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) carbamic acid tert-butyl ester

To 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-amine (0.33g,1.5mmol) in CH₂Cl₂(5ml) solution Boc was added at 0 deg.C₂O (0.33g,1.5mmol,1eq.) and Et₃N (0.62ml,4.5mmol,3 eq.). The mixture was stirred at room temperature for 1 hour, then quenched and extracted as described for intermediate example 5 (a). The solvent was distilled off to leave a crude product (0.48 g).

Example 1

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

a) 1-bromo-3, 5-dinitrobenzene

1, 3-dibromo-5, 5-dimethylhydantoin (31.75g,0.111mol,0.75eq) was added dropwise to a solution of 1, 3-dinitrobenzene (25g,0.149mol) in concentrated sulfuric acid (100ml) at 0 ℃ over 30 minutes. The mixture was stirred at room temperature for 12 hours and the reaction was terminated by adding crushed ice. The precipitate formed was filtered and washed repeatedly with water to give a white solid. The solid was dried in vacuo to give the product in 87% yield (32 g).

b) 3-bromo-5-nitroaniline

To a solution of 1-bromo-3, 5-dinitrobenzene (20g,80.97mmol) in acetic acid (120ml) iron powder (11.3g,202.4mmol,2.5eq) was added slowly in portions over 30 minutes at 90 ℃ (note: highly exothermic reaction). After the addition was complete, the mixture was quenched by the addition of crushed ice. The precipitate formed was filtered and washed with cold water to give an orange solid. The solid was dried in vacuo to give the product in 80% yield (14 g).¹HNMR(300MHz,CDCl₃):10.55(brs,2H),8.46(s,1H),8.19(s,1H),8.02(s,1H)。

c) N- (3-bromo-5-nitrophenyl) acetamide

Acetic anhydride (14ml) was added dropwise to 3-bromo-5-nitroaniline (14g,64.5mmol) at 0 ℃. The mixture was stirred at room temperature for 30 minutes, and then the reaction was terminated by adding crushed ice. The precipitate formed was filtered and washed with cold water to give an off-white solid. The solid was dried in vacuo to give the product in 78% yield (13 g).¹HNMR(300MHz,DMSO-d₆):10.54(brs,1H),8.45(s,1H),8.2(s,1H),8.03(s,1H),2.11(s,3H)。

d) N- (2',4' -difluoro-5-nitrobiphenyl-3-yl) acetamide

A solution of N- (3-bromo-5-nitrophenyl) acetamide (1g,3.86mmol) in 1, 2-dimethoxyethane (15ml) was passed through N₂Bubbling and degassing for 5 minutes. 2, 4-difluorophenylboronic acid (0.727g,4.63mmol,1.2eq.) was added and the mixture was degassed for an additional 5 minutes. Pd (dppf) Cl was added in succession₂(0.627g,0.769mmol,0.2eq.) and aqueous sodium carbonate (1.22g,11.5mmol,3.0eq.) and the mixture was further degassed for 5 minutes and then heated at 90 ℃ for 2 hours. 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. The solvent was evaporated under reduced pressure and the crude residue was purified by column chromatography (60-120 silica gel, 30% ethyl acetate in hexane) to give the product in 80% yield (0.9 g). ¹HNMR(300MHz,DMSO-d₆):10.63(s,1H),8.7-8.69(m,1H),8.16(d,1H),8.04(s,1H),7.8-7.67(m,1H),7.53(m,1H),7.34(m,1H),2.19(s,3H)。

e) N- (5-amino-2 ',4' -difluorobiphenyl-3-yl) acetamide

To a solution of N- (2',4' -difluoro-5-nitrobiphenyl-3-yl) acetamide (4g,13.7mmol) in methanol (30ml) and ethyl acetate (15ml) was added 10% Pd/C (400mg,0.1eq.) and the reaction vessel purged with nitrogen for 5 minutes. Then the mixture is taken up with H₂Hydrogenation in balloon for 12 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to give the compound in 89% yield (3.2 g).¹HNMR(300MHz,DMSO-d₆):9.77(brs,1H),7.46-7.42(m,1H),7.35-7.28(m,1H),7.2-7.15(m,1H),6.99(brs,1H),8.86(d,1H),6.39(d,1H),5.45(brs,2H),2.02(s,3H)。

f) N- (5- (4-bromo-2-nitrophenylamino) -2',4' -difluorobiphenyl-3-yl) acetamide

A solution of N- (5-amino-2 ',4' -difluorobiphenyl-3-yl) acetamide (3.0g,11.44mmol), 4-bromo-1-fluoro-2-nitrobenzene (2.52g,11.44mmol,1.0eq.) and potassium fluoride (0.663g,11.44mmol,1.0eq.) in DMF was heated at 130 ℃ for 5 hours. The mixture was quenched and extracted as described in example 1 (d). The solvent was evaporated under reduced pressure and the crude residue was purified by column chromatography (60-120 silica gel, 40% ethyl acetate in hexane) to give the product in 45% yield (2.4 g).

g) N- (5- (2-amino-4-bromophenylamino) -2',4' -difluorobiphenyl-3-yl) acetamide

To a solution of N- (5- (4-bromo-2-nitrophenylamino) -2',4' -difluorobiphenyl-3-yl) acetamide (3.2g,6.92mmol) in THF (30ml) was added a solution of ammonium chloride (3.7g,69.22mmol,10eq.) in water (15ml) and zinc (4.53g,69.22mmol,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 example 1 (d). The solvent was evaporated under reduced pressure to give the product in 87% yield (2.6 g).

h) N- (5- (5-bromo-1H-benzo [ d ] imidazol-1-yl) -2',4' -difluorobiphenyl-3-yl) acetamide

A mixture of the compound from example 1(g) (2.6g,6.01mmol) and formic acid (10ml) was heated at 100 ℃ for 30 minutes. 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. Reduced pressureEvaporation of the solvent gave the product in 60% yield (1.6 g).¹HNMR(300MHz,DMSO-d₆):10.41(s,1H),8.72(s,1H),8.02(d,2H),7.82(s,1H),7.75-7.66(m,2H),7.53-7.41(m,3H),7.27(m,1H),2.11(s,3H)。

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

A solution of the compound from example 1(h) (1.5g,3.39mmol) in 1, 2-dimethoxyethane (15ml) was passed over N₂Bubbling and degassing for 5 minutes. 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (0.847g,4.07mmol,1.2eq.) was added and the mixture was degassed for an additional 5 minutes. Pd (dppf) Cl was added as described in example 1(d)₂(0.553g,0.678mmol,0.2eq.) and aqueous sodium carbonate (1.08g,10.18mmol,3.0 eq.). The crude residue of the product was purified by column chromatography (60-120 silica gel, 80% ethyl acetate in hexane) to afford the product in 67% yield (1.0 g).¹HNMR(300MHz,DMSO-d₆) 10.4(s,1H),8.64(s,1H),8.2(1H, s),8.07(s,1H),7.99(s,1H),7.94(s,1H),7.8-7.68(M,2H),7.6-7.45(M,4H),7.27(t,1H),3.88(s,3H),2.12(s,3H), LC-MS (ESI): calculated mass: 443.45; measured mass: 444.1[ M + H ESI ] ]⁺(retention time: 1.2 minutes).

Example 2

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

a)2',4' -difluoro-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-amine

To N- (2',4' -difluoro-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] of example 1]Imidazol-1-yl) biphenyl-3-yl) acetamide (1.0g,2.26mmol) in ethanol (10ml) aqueous sodium hydroxide (800mg,20mmol,8.9eq.) was added and the mixture was heated at 85 ℃ for 5 hours. The mixture was quenched and extracted as described in example 1 (d). The solvent was evaporated under reduced pressure to give the product in 66% yield (0.6 g). LC-MS (ESI) meterCalculated mass 401.41, measured mass 402.1[ M + H]⁺(retention time: 1.198 min).

b) N- (2',4' -difluoro-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) methanesulfonamide

To a solution of the compound from example 2(a) (50mg,0.125mmol) in DCM was added pyridine (20mg,0.249mmol,2.0eq.) followed by methanesulfonyl chloride (17mg,0.15mmol,1.2 eq.). The mixture was stirred for 1 hour, quenched with water and extracted with DCM (3X 50 ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the crude residue was purified by preparative HPLC to give the product in 33% yield (20 mg). ¹HNMR(300MHz,DMSO-d₆) 10.26(s,1H),8.66(s,1H),8.2(s,1H),7.98(s,1H),7.94(s,1H),7.75-7.67(M,2H),7.57(t,3H),7.45-7.43(M,2H),7.29-7.25(M,1H),3.87(s,3H),3.17(s,3H), LC-MS (ESI) calculating mass 479.5, measured mass 480.2[ M + H ] 480.2]⁺(retention time: 1.34 minutes).

Example 3

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

This compound was prepared from the compound of example 1 using the procedure of example 2.¹HNMR(300MHz,DMSO-d₆) 10.29(s,1H),8.84(s,1H),8.22(s,1H),7.99(s,1H),7.96(s,1H),7.78-7.62(M,3H),7.57(brs,2H),7.48-7.43(M,2H),7.29-7.25(M,1H),3.88(s,3H),3.29 (quartet, 2H),1.25(t,3H), LC-MS (ESI), calculated mass: 493.53, measured mass: 494.2[ M + H ], (M,1H), calculated mass: 493.53]⁺(retention time: 1.41 minutes).

Example 4

N- (2',4' -difluoro-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) propane-2-sulfonamide

The compound is prepared fromThe compound of example 1 was prepared using the procedure of example 2.¹HNMR(300MHz,DMSO-d₆) 10.29(s,1H),8.81(s,1H),8.22(s,1H),7.99(s,1H),7.95(s,1H),7.75-7.56(M,5H),7.48-7.43(M,2H),7.27(M,1H),3.88(s,3H),3.48-3.44(M,1H),1.3(d,6H), LC-MS (ESI) calculating mass 507.55, measured mass 508.2[ M + H ] 508 ]⁺(retention time: 1.47 minutes).

Example 5

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

This compound was prepared from the compound of example 1 using the procedure of example 2 and cyclopropanesulfonyl chloride.¹HNMR(300MHz,DMSO-d₆) 10.29(s,1H),8.88(s,1H),8.23(s,1H),8.0(s,1H),7.96(s,1H),7.76-7.64(M,3H),7.6(s,2H),7.5-7.46(M,2H),7.3-7.25(M,1H),3.88(s,3H),2.88-2.85(M,1H),1.02-1.0(M,4H), LC-MS (ESI) calculating mass 505.54, and measured mass 506.1[ M + H ] to obtain mass]⁺(retention time: 1.517 minutes).

Example 6

N- (2',4' -difluoro-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) cyclopentane sulfonamide

This compound was prepared from the compound of example 1 using the procedure of example 2.¹HNMR(300MHz,DMSO-d₆) 10.25(s,1H),8.96(s,1H),8.24(s,1H),8.0(s,1H),7.97(s,1H),7.77-7.66(M,3H),7.6-7.59(M,2H),7.49(M,1H),7.46-7.43(M,1H),7.3-7.25(M,1H),3.88(s,3H),3.83-3.78(M,1H),1.99-1.93(M,4H),1.69-1.64(M,2H),1.63-1.52(M,2H), LC-MS (ESI) calculating mass 533.59, measured mass 534.3[ M + H ] calculated mass 533.59]⁺(retention time: 1.57 minutes).

Example 7

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

This compound was prepared from the compound of example 1 using the procedure of example 2.¹HNMR(300MHz,DMSO-d₆) 8.57(s,1H),8.21(s,1H),7.96-7.95(M,2H),7.88-7.86(M,2H),7.72-7.61(M,4H),7.57-7.55(M,2H),7.5(brs,1H),7.45-7.32(M,4H),7.26-7.22(M,1H),3.88(s,3H), LC-MS (ESI), calculated mass 541.57, measured mass 542.1[ M + H ], (S,3H)]⁺(retention time: 1.642 min).

Example 8

N- (5- (5- (1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluorobiphenyl-3-yl) acetamide

A solution of the compound from example 1(h) (7g,15.83mmol) in 1, 2-dimethoxyethane (200ml) was passed over N₂Bubbling and degassing for 5 minutes. N, N-dimethyl-2- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) ethylamine (6.3g,23.74mmol,1.5eq.) of intermediate example 1 was added and the mixture was degassed for an additional 5 minutes. Pd (PPh) was added in the same manner as in example 1(d)₃)₄(1.83g,1.583mmol,0.1eq.) and aqueous sodium carbonate (5.03g,47.5mmol,3.0 eq.). The crude residue of the product was purified by column chromatography (neutral alumina, 80% ethyl acetate in hexane) to afford the product in 19% yield (1.5 g).¹HNMR(300MHz,DMSO-d₆) 10.45(s,1H),8.8(s,1H),8.35(s,1H),8.15(s,2H),8.05(s,1H),7.6-7.7(M,4H),7.4-7.55(M,2H),7.2-7.3(M,1H),4.56(t,2H),3.65-3.63(M,2H),2.85(s,6H),2.12(s,3H), LC-MS (ESI), calculated mass 500.54, and measured mass 501.2[ M + H + M, 501H ] ]⁺(retention time: 0.277 min).

Example 9

N- (5- (5- (1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluorobiphenyl-3-yl) methanesulfonamide

a)5- (5- (1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluorobiphenyl-3-amine

To a solution of the compound from example 8 (1.5g,3.0mmol) in ethanol (30ml) was added aqueous sodium hydroxide (1.5g,37.5mmol,12.5eq.) and the mixture was heated at 100 ℃ for 4 hours. The mixture was quenched and extracted as described in example 1 (d). Evaporation of the solvent gave the product in 58% yield (0.8 g).

b) N- (5- (5- (1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluorobiphenyl-3-yl) methanesulfonamide

To a solution of the compound from example 9(a) (200mg,0.436mmol) in DCM was added pyridine (69mg,0.872mmol,2.0eq.) followed by methanesulfonyl chloride (75mg,0.654mmol,1.5 eq.). The mixture was stirred for 1 hour, the reaction was terminated and extracted as described in example 2 (b). The solvent was evaporated and the crude residue was purified by preparative HPLC to give the product in 13% yield (30 mg).¹HNMR(300MHz,DMSO-d₆) 8.66(s,1H),8.26(s,1H),7.99(d,1H),7.96(s,1H),7.81-7.7(M,2H),7.68(s,1H),7.62-7.57(M,3H),7.5-7.44(M,2H),7.3-7.25(M,1H),4.23(t,2H),3.18(s,3H),2.75-2.73(M,2H),2.12(s,6H), LC-MS (ESI), calculated mass 536.6, measured mass 537.3[ M + H ESI ] ]⁺(retention time: 0.26 min).

Example 10

N- (5- (5- (1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluorobiphenyl-3-yl) ethanesulfonamide

This compound was prepared from the compound of example 8 using the procedure of example 9.¹HNMR(300MHz,DMSO-d₆) 10.35(s,1H),9.2-9.4(brs,1H),8.8(s,1H),8.4(s,1H),8.15(s,1H),8.0(s,1H),7.6-7.8(m,2H),7.6(s,2H),7.4-7.5(m,2H),7.2-7.3(m,1H),4.55(t,2H),3.65-3.63(m,2H),3.3 (quartet, 2H),2.85(s,6H),1.26(t,3H), LC-MS (ESI) mass 550.62, mass measured mass 550.62Amount 551.2[ M + H]⁺(retention time: 0.365 min).

Example 11

N- (5- (5- (1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluorobiphenyl-3-yl) propane-2-sulfonamide

This compound was prepared from the compound of example 8 using the procedure of example 9.¹HNMR(300MHz,CD₃OD is 8.5(s,1H),8.1(s,1H),7.9-7.95(d,2H),7.55-7.7(M,5H),7.45-7.5(M,2H),7.05-7.1(M,2H),4.32(t,2H),3.44-3.39(M,1H),2.85(t,2H),2.3(s,6H),1.4(d,6H), LC-MS ESI (ESI) (calculated mass: 564.65; measured mass: 565.2[ M + H ], (M, 1H))]⁺(retention time: 0.507 minutes).

Example 12

N- (2',4' -difluoro-5- (5- (1- (2- (morpholin-4-yl) ethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) acetamide

This compound was prepared using the procedure of example 8 using the compound of intermediate example 2.¹HNMR(300MHz,DMSO-d₆) 10.43(s,1H),8.82(s,1H),8.35(s,1H),8.13(s,2H),8.05(s,1H),7.79-7.73(M,3H),7.67-7.63(M,1H),7.51-7.44(M,2H),7.31-7.27(M,1H),4.6(t,2H),3.93-3.88(M,4H),3.67-3.63(M,4H),3.82-3.78(M,2H),2.1(s,3H), LC-MS (ESI): 542.58, 543.2[ M + H ], (M + H)]⁺(retention time: 0.24 minutes).

Example 13

N- (2',4' -difluoro-5- (5- (1- (2- (morpholin-4-yl) ethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) methanesulfonamide

This compound was prepared from the compound of example 12 using the procedure of example 9.¹HNMR(300MHz,DMSO-d₆):10.3(s,1H),8.8(s,1H),8.35(s,1H),8.15(s,1H),8.05(s,1H),7.7-7.8(M,2H),7.6-7.7(M,1H),7.55-7.6(M,2H),7.4-7.5(M,2H),7.25-7.35(M,1H),4.59(t,2H),4.0(M,4H),3.82-3.78(M,2H),3.5(M,4H),3.18(s,3H), LC-MS (ESI): calculated mass: 578.63; measured mass: 579.2[ M + H ], (M, 4H): measured mass: 579.2]⁺(retention time: 0.383 min).

Example 14

N- (2',4' -difluoro-5- (5- (1- (2- (morpholin-4-yl) ethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) ethanesulfonamide

This compound was prepared from the compound of example 12 using the procedure of example 9.¹HNMR(300MHz,DMSO-d₆) 10.35(s,1H),8.85(s,1H),8.35(s,1H),8.15(s,1H),8.05(s,1H),7.77-7.68(M,3H),7.58(s,2H),7.48-7.45(M,2H),7.31-7.27(M,1H),4.59(t,2H),4.0-3.92(M,4H),3.82-3.78(M,2H),3.5-3.41(M,4H),3.29 (quartet, 2H),1.25(t,3H), LC-MS (ESI), calculating mass 592.66, and measuring mass 593.2[ M + H + 592.66 ]]⁺(retention time: 0.419 minutes).

Example 15

N- (2',4' -difluoro-5- (5- (1- (2- (morpholin-4-yl) ethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) propane-2-sulfonamide

This compound was prepared from the compound of example 12 using the procedure of example 9.¹HNMR(300MHz,CD₃OD is 8.5(s,1H),8.1(s,1H),7.93(s,1H),7.9(s,1H),7.6-7.7(M,4H),7.5(s,2H),7.1-7.15(M,2H),4.33(t,2H),3.67(t,4H),3.46-3.39(M,1H),2.85(t,2H),2.52(t,4H),1.4(d,6H), LC-MS (ESI), calculated mass 606.69, measured mass 607.3[ M + H (M,4H) ]]⁺(retention time: 0.62 minutes).

Example 16

N- (2',4' -difluoro-5- (5- (1- (2- (morpholin-4-yl) ethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) cyclopropanesulfonamide

This compound was prepared from the compound of example 12 using the procedure of example 9 and cyclopropanesulfonyl chloride.¹HNMR(300MHz,DMSO-d₆) 8.6(s,1H),8.25(s,1H),7.98(s,1H),7.95(s,1H),7.74-7.65(M,2H),7.59-7.55(M,1H),7.45-7.38(M,2H),7.28-7.24(M,4H),4.24(t,2H),3.56(t,4H),2.75(t,2H),2.67-2.64(M,1H),2.42(t,4H),0.91-0.88(M,4H), LC-MS (ESI) calculating mass 604.67, measured mass 605.4[ M + H ] 605.4 ]⁺(retention time: 0.68 minutes).

Example 17

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

a) N- (2',4' -difluoro-5- (4-iodo-2-nitrophenylamino) biphenyl-3-yl) acetamide

A solution of the compound from example 1(e) (4.6g,17.54mmol), 1-fluoro-4-iodo-2-nitrobenzene from intermediate example 3 (4.683g,17.54mmol,1.0eq.) and potassium fluoride (1.22g,21.05mmol,1.2eq.) in DMF was heated at 130 ℃ for 5 hours. The mixture was quenched and extracted as described in example 1 (d). 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 product in 76% yield (6.8 g).¹HNMR(300MHz,DMSO-d₆):10.15(brs,1H),9.41(s,1H),8.35(d,1H),7.78(dd,1H),7.66-7.54(m,3H),7.39(m,1H),7.22(m,1H),7.14-7.11(m,2H),2.06(s,3H)。

b) N- (5- (2-amino-4-iodophenylamino) -2',4' -difluorobiphenyl-3-yl) acetamide

To a solution of the compound from example 17(a) (3.0g,5.89mmol) in THF (30ml) was added a solution of ammonium chloride (1.26g,23.56mmol,4eq.) in water (5ml) and zinc (1.54g,23.56mmol,4 eq.). The mixture was stirred at room temperature for 0.5 hour and filtered. The filtrate was diluted with water and extracted as described in example 1 (d). Evaporating off the solvent to obtainProduct, 77% yield (2.18 g).¹HNMR(300MHz,DMSO-d₆) 9.85(brs,1H),7.44 (quartet, 1H),7.36-7.31(m,2H),7.19-7.14(m,2H),7.07(s,1H),7.02(s,1H),6.82(s,2H),6.53(brs,1H),5.03(brs,2H),2.0(s, 3H).

c) N- (2',4' -difluoro-5- (5-iodo-1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) acetamide

A mixture of the compound from example 17(b) (2.18g,4.55mmol) and formic acid (10ml) was heated at 100 ℃ for 30 minutes. 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 product in 47% yield (1.05 g).

d) N- (2',4' -difluoro-5- (5- ((trimethylsilyl) ethynyl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) acetamide

The compound from example 17(c) (0.7g,1.43mmol) in DMF-Et₃The N (1:1;20ml) solution was passed through N₂Bubbling and degassing for 15 minutes. Sequentially adding Pd (PPh)₃)₄(0.165g,0.143mmol,0.1eq.), copper (I) iodide (0.027g,0.143mmol,0.1eq.) and ethynyltrimethylsilane (0.4ml,2.86mmol,2eq.) and the mixture was stirred at room temperature for 12 hours. The mixture was quenched and extracted as described in example 1 (d). The solvent was evaporated and the crude residue was purified by column chromatography (60-120 silica gel, 60% ethyl acetate in hexane) to give the product in 68% yield (0.45 g).¹HNMR(300MHz,DMSO-d₆):10.42(s,1H),8.79(brs,1H),8.03(s,1H),7.89-7.84(m,2H),7.78-7.7(m,2H),7.51-7.41(m,3H),7.29-7.24(m,1H),2.12(s,3H),0.23(s,9H)。

e) N- (5- (5-ethynyl-1H-benzo [ d ] imidazol-1-yl) -2',4' -difluorobiphenyl-3-yl) acetamide

To a solution of the compound from example 17(d) (0.41g,0.9mmol) in THF was added TBAF (1M in THF; 0.28ml,1.07mmol,1.2eq.) at 0 deg.C and the mixture was stirred for 0.5 h. The mixture was filtered through a pad of silica and distilled to give the product in 89% yield (0.31 g). ¹HNMR(300MHz,DMSO-d₆):10.3(brs,1H),8.79(s,1H),8.1(s,1H),7.96(s,1H),7.88(s,1H),7.82-7.73(m,2H),7.54-7.45(m,3H),7.34-7.27(m,1H),4.2(s,1H),2.16(s,3H)。

f) N- (2',4' -difluoro-5- (5- (1-methyl-1H-1, 2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) acetamide

A mixture of the compound (115mg,0.297mmol) from example 17(e), sodium azide (19mg,0.297mmol,1.0eq.), methyl iodide (42mg,0.297mmol,1.0eq.), sodium ascorbate (59mg,0.297mmol,1.0eq.), and copper sulfate pentahydrate (37mg,0.149mmol,0.5eq.) in DMSO, THF and water (1:1:1,3ml) was stirred at room temperature for 12 hours. The mixture was quenched with water and the precipitate formed was filtered and dried. The crude product was purified by preparative HPLC to give the product in 15% yield (20 mg).¹HNMR(300MHz,DMSO-d₆) 10.4(s,1H),8.7(s,1H),8.6(s,1H),8.25(s,1H),8.05(s,1H),7.7-7.95(M,4H),7.4-7.55(M,2H),7.2-7.3(M,1H),4.1(s,3H),2.1(s,3H), LC-MS (ESI) calculating mass 444.44, and 445.1[ M + H ] measured mass]⁺(retention time: 1.039 minutes).

Example 18

N- (2',4' -difluoro-5- (5- (1-methyl-1H-1, 2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) methanesulfonamide

a)2',4' -difluoro-5- (5- (1-methyl-1H-1, 2, 3-triazol-4-yl) -1H-benzo [ d]Imidazol-1-yl) biphenyl_-3_-Amines as pesticides

To a solution of the compound from example 17 (300mg,0.675mmol) in ethanol (10ml) was added aqueous sodium hydroxide (338mg,8.44mmol,12.5eq.) and the mixture was heated at 85 ℃ for 5 hours. The mixture was quenched and extracted as described in example 1 (d). Evaporation of the solvent gave the product in 44% yield (0.12 g). LC-MS (ESI) mass calculated 402.4 and measured mass 403.4M + H ]⁺(retention time: 1.03 minutes).

b) N- (2',4' -difluoro-5- (5- (2-methyl-2H-1, 2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) methanesulfonamide

To a solution of the compound from example 18(a) (90mg,0.224mmol) in DCM was added pyridine (35mg,0.447mmol,2.0eq.) followed by methanesulfonyl chloride (26mg,0.224mmol,1.0 eq.). The reaction was monitored by LCMS. After completion of the reaction, the solvent was removed and the crude product was purified by preparative HPLC to give the product in 13% yield (14 mg).¹HNMR(300MHz,DMSO-d₆) 10.31(s,1H),8.84(brs,1H),8.61(s,1H),8.25(s,1H),7.92(d,1H),7.8-7.74(M,2H),7.59(d,2H),7.49-7.43(M,2H),7.31-7.26(M,1H),4.11(s,3H),3.18(s,3H), LC-MS (ESI), calculated mass 480.49, measured mass 481.1[ M + H ] and measured mass 481.1]⁺(retention time: 1.357 minutes).

Example 19

N- (2',4' -difluoro-5- (5- (2-methyl-2H-1, 2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) benzenesulfonamide

This compound was prepared from the compound of example 17 using the procedure of example 18.¹HNMR(300MHz,DMSO-d₆) 10.9(s,1H),8.73(s,1H),8.62(s,1H),8.22(s,1H),7.9-7.87(M,3H),7.71-7.62(M,4H),7.55(s,1H),7.47-7.39(M,4H),7.28-7.24(M,1H),4.12(s,3H), LC-MS (ESI) calculating mass: 542.56, measured mass: 543.2[ M + H ESI ]]⁺(retention time: 1.52 minutes).

Example 20

N- (5- (5- (1- (2- (dimethylamino) ethyl) -1H-1,2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluorobiphenyl-3-yl) acetamide

A mixture of the compound (115mg,0.297mmol) from example 17(e), 2-azido-N, N-dimethylethylamine (34mg,0.297mmol,1.0eq.), sodium ascorbate (59mg,0.297mmol,1.0eq.), and copper sulfate pentahydrate (37mg,0.149mmol,0.5eq.) in DMSO, THF, and water (1:1:1,3ml) was stirred at room temperature for 12 hours. The mixture was quenched with water and the precipitate formed was filtered and dried. Will be coarseThe product was purified by preparative HPLC to give the product in 27% yield (40 mg).¹HNMR(300MHz,DMSO-d₆) 10.45(s,1H),8.71(s,2H),8.25(s,1H),8.1(s,1H),7.9(d,1H),7.81-7.72(M,3H),7.52(s,1H),7.48-7.42(M,1H),7.3-7.25(M,1H),4.82(brs,2H),3.59(brs,2H),2.78(brs,6H),2.1(s,3H), LC-MS (ESI) calculating mass 501.53, measured mass 502.2[ M + H ] (ESI)]⁺(retention time: 0.259 min).

Example 21

N- (2',4' -difluoro-5- (5- (1- (2- (morpholin-4-yl) ethyl) -1H-1,2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) acetamide

This compound was prepared from the compound of example 17(e) using the procedure of example 20.¹HNMR(300MHz,DMSO-d₆) 10.42(s,1H),8.79(s,1H),8.72(s,1H),8.27(s,1H),8.12(s,1H),7.94-7.92(M,1H),7.82-7.72(M,3H),7.54(s,1H),7.48-7.42(M,1H),7.3-7.25(M,1H),4.89(t,2H),4.09(M,4H),3.76(M,2H),2.54-2.46(M,4H),2.1(s,3H), LC-MS (ESI): 543.57, 544.2[ M + H ], (S,3H) measured mass: (LC-MS (ESI): 543.57) ]⁺(retention time: 0.277 min).

Example 22

N- (2',4' -difluoro-5- (5-) (Oxazol-5-yl) -1H-benzo [ d]Imidazol-1-yl) biphenyl-3-yl) acetamide

a) N- (2',4' -difluoro-5- (4-formyl-2-nitrophenylamino) biphenyl-3-yl) acetamide

A solution of the compound from example 1(e) (4.3g,16.4mmol), 4-fluoro-3-nitrobenzaldehyde from intermediate example 4 (2.46g,16.4mmol,1.0eq.) and potassium fluoride (0.95g,16.4mmol,1.0eq.) in DMF was heated at 130 ℃ for 5 hours. The mixture was quenched and extracted as described in example 1 (d). The solvent was distilled off and the crude residue was taken up inPurification by column chromatography (60-120 silica gel, 50% ethyl acetate in hexanes) gave the product in 45% yield (3.0 g).¹HNMR(300MHz,DMSO-d₆):10.22(s,1H),9.85(s,1H),8.7(s,1H),7.93-7.9(m,1H),7.73-7.58(m,3H),7.43-7.2(m,5H),2.07(s,3H)。

b) N- (2',4' -difluoro-5- (2-nitro-4-) (Azol-5-yl) phenylamino) biphenyl-3-yl) acetamide

To a solution of the compound from example 22(a) (2.0g,4.86mmol) in methanol was added potassium carbonate (0.74g,5.35mmol,1,1eq.) and the mixture was stirred at room temperature for 10 minutes. Tosylmethylisonitrile (1.044g,5.35mmol,1,1eq.) was added and the mixture was refluxed for 4 hours. Methanol was distilled off and water was added to the crude product. The mixture was extracted as described in example 1 (d). The solvent was evaporated and the residue was purified by column chromatography (60-120 silica gel, 40% ethyl acetate in hexane) to give the product in 64% yield (1.4 g). ¹HNMR(300MHz,DMSO-d₆):10.17(s,1H),9.59(s,1H),8.45(s,1H),8.4(d,1H),7.91-7.87(m,1H),7.71(s,2H),7.61-7.56(m,2H),7.44-7.37(m,2H),7.23-7.17(m,2H),2.07(s,3H)。

c) N- (5- (2-amino-4-) (Azol-5-yl) phenylamino) -2',4' -difluorobiphenyl-3-yl) acetamide

To a solution of the compound from example 22(b) (1g,2.22mmol) in methanol (35ml) and ethyl acetate (15ml) was added 10% Pd/C (200mg,0.2eq.) and the reaction vessel purged with nitrogen for 5 minutes. Then the mixture is taken up with H₂Hydrogenation in balloon for 12 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated to give the compound in 86% yield (0.8 g).

d) N- (2',4' -difluoro-5- (5-) (Oxazol-5-yl) -1H-benzo [ d]Imidazol-1-yl) biphenyl-3-yl) acetamide

A mixture of the compound from example 22(c) (1.5g,3.57mmol) and formic acid (6ml) was heated at 100 ℃ for 30 minutes. 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 product in 52% yield (0.8 g).¹HNMR(300MHz,DMSO-d₆) 10.44(s,1H),8.74(s,1H),8.45(s,1H),8.15(s,1H),8.07(s,1H),7.82-7.73(M,5H),7.52(s,1H),7.5-7.2(M,1H),7.27-7.23(M,1H),2.11(s,3H), LC-MS (ESI) calculating mass 430.41, measured mass 431.2[ M + H ], (M + H) calculating mass]⁺(retention time: 1.42 minutes).

Example 23

N- (2',4' -difluoro-5- (5-) (Oxazol-5-yl) -1H-benzo [ d]Imidazol-1-yl) biphenyl-3-yl) methanesulfonamide

a)2',4' -difluoro-5- (5-, ( Oxazol-5-yl) -1H-benzo [ d]Imidazol-1-yl) biphenyl-3-amine

To a solution of the compound from example 22 (800mg,1.86mmol) in ethanol (10ml) was added aqueous sodium hydroxide (640mg,16mmol,8.6eq.) and the mixture was heated at 85 ℃ for 5 hours. The mixture was quenched and extracted as described in example 1 (d). Evaporation of the solvent gave the product in 69% yield (0.5 g). LC-MS (ESI) for calculating mass 388.37 and measured mass 389.1M + H]⁺(retention time: 1.517 minutes).

b) N- (2',4' -difluoro-5- (5-) (Oxazol-5-yl) -1H-benzo [ d]Imidazol-1-yl) biphenyl-3-yl) methylSulfonamides

To a solution of the compound from example 23(a) (100mg,0.258mmol) in DCM was added pyridine (40mg,0.515mmol,2.0eq.) followed by methanesulfonyl chloride (35mg,0.309mmol,1.2 eq.). The reaction solution was stirred for 1 hour, and the reaction was terminated and extracted as described in example 2 (b). The solvent was evaporated and the crude residue was purified by preparative HPLC to give the product in 10% yield (12 mg).¹HNMR(300MHz,DMSO-d₆) 10.3(s,1H),8.78(s,1H),8.46(s,1H),8.16(s,1H),7.8-7.76(M,4H),7.6-7.56(M,2H),7.46(M,2H),7.34-7.27(M,1H),3.18(s,3H), LC-MS (ESI) calculating mass 466.46, measured mass 467[ M + H + ESI]⁺(retention time: 1.553 minutes).

Example 24

N- (2',4' -difluoro-5- (5-) (Oxazol-5-yl) -1H-benzo [ d]Imidazol-1-yl) biphenyl-3-yl) ethanesulfonamide

This compound was prepared from the compound of example 22 using the procedure of example 23.¹HNMR(300MHz,DMSO-d₆) 10.33(s,1H),8.78(s,1H),8.46(s,1H),8.15(s,1H),7.8-7.73(M,4H),7.58-7.55(M,2H),7.48-7.43(M,2H),7.29-7.25(M,1H),3.29 (quartet, 2H),1.25(t,3H), LC-MS (ESI): calculated mass: 480.49, measured mass: 481.1[ M + H: (ESI) ]]⁺(retention time: 1.517 minutes).

Example 25

N- (2',4' -difluoro-5- (5-) (Oxazol-5-yl) -1H-benzo [ d]Imidazol-1-yl) biphenyl-3-yl) propane-2-sulfonamide

This compound was prepared from the compound of example 22 using the procedure of example 23.¹HNMR(300MHz,DMSO-d₆) 10.31(s,1H),8.8(s,1H),8.46(s,1H),8.16(s,1H),7.78(d,4H),7.58(M,2H),7.5-7.43(M,2H),7.3-7.25(M,1H),3.49-3.47(M,1H),1.3(d,6H), LC-MS (ESI) calculating mass 495.41, measured mass 496.1[ M + H ]]⁺(retention time: 1.66 minutes).

Example 26

N- (2',4' -difluoro-5- (5-) (Oxazol-5-yl) -1H-benzo [ d]Imidazol-1-yl) biphenyl-3-yl) benzenesulfonamides

This compound was prepared from the compound of example 22 using the procedure of example 23.¹HNMR(300MHz,DMSO-d₆) 10.9(s,1H),8.77(s,1H),8.47(s,1H),8.14(s,1H),7.88(d,2H),7.78-7.74(M,2H),7.72-7.61(M,4H),7.54(s,1H),7.49-7.45(M,1H),7.43-7.39(M,3H),7.27-7.22(M,1H), LC-MS ESI (calculated mass: 528.53), measured mass: 529.1[ M + H ] M ]⁺(retention time: 1.641 minutes).

Example 27

N- (5- (5- (3, 5-dimethyliso) methyl esterOxazol-4-yl) -1H-benzo [ d]Imidazol-1-yl) -2',4' -difluorobiphenyl-3-yl) acetamide

This compound was prepared from the compound of example 1(h) using the procedure of example 1.¹HNMR(300MHz,DMSO-d₆) 12.15(brs,1H),10.24(s,1H),8.67(s,1H),8.08(s,1H),7.82(s,1H),7.78-7.73(M,2H),7.65(s,1H),7.53(s,1H),7.48-7.43(M,1H),7.3-7.25(M,2H),2.23(s,6H),2.12(s,3H), LC-MS (ESI), calculated mass 457.47, measured mass 458[ M + H ], calculated mass]⁺(retention time: 0.75 minutes).

Example 28

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

To a solution of the compound from example 1(h) (5g,11.31mmol) in DMF (20ml) was added pyrazole (5g,73.49mmol,6.5eq.) copper (I) oxide (4.86g,33.92mmol,3.0eq.) and cesium carbonate (14.73g,45.22mmol,4.0eq.) and the mixture was heated at 90 ℃ for 48 h. The mixture was quenched and extracted as described in example 1 (d). The solvent was evaporated and the crude residue was purified by column chromatography (neutral alumina, 1% methanol in DCM) to give the product in 49% yield (2.4 g).¹HNMR(300MHz,DMSO-d₆) 10.43(s,1H),8.8(s,1H),8.6(d,1H),8.25(s,1H),8.1(s,1H),7.9-8.0(M,1H),7.7-7.9(M,4H),7.4-7.6(M,2H),7.2-7.3(M,1H),6.6(M,1H),2.1(s,3H), LC-MS (ESI), calculated mass 429.42, measured mass 430.4[ M + H ], calculated mass ]⁺(retention time: 1.46 minutes).

Example 29

N- (5- (5- (1H-pyrazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluorobiphenyl-3-yl) methanesulfonamide

a)5- (5- (1H-pyrazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluorobiphenyl-3-amine

To a solution of the compound from example 28 (2.4g,5.59mmol) in ethanol (40ml) was added aqueous sodium hydroxide (2.4g,60mmol,10.7eq.) and the mixture was heated at 85 ℃ for 5 hours. The mixture was quenched and extracted as described in example 1 (d). Evaporation of the solvent gave the product in 69% yield (1.5 g).

b) N- (5- (5- (1H-pyrazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluorobiphenyl-3-yl) methanesulfonamide

To a solution of the compound from example 29(a) (250mg,0.645mmol) in DCM was added pyridine (102mg,1.29mmol,2.0eq.) followed by methanesulfonyl chloride (100mg,0.877mmol,1.4 eq.). The mixture was stirred for 1 hour according toThe reaction was terminated and extracted as described in example 2 (b). The solvent was evaporated and the residue was purified by preparative HPLC to give the product in 33% yield (100 mg).¹HNMR(300MHz,DMSO-d₆) 10.31(s,1H),8.85(s,1H),8.62(d,1H),8.25(d,2H),7.95-7.92(M,1H),7.84-7.77(M,3H),7.62(s,1H),7.58(s,1H),7.51-7.44(M,2H),7.33-7.27(M,1H),3.19(s,3H), LC-MS (ESI), calculated mass 465.48, measured mass 466.1[ M + H + M,3H ] ]⁺(retention time: 1.606 minutes).

Example 30

N- (5- (5- (1H-pyrazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluorobiphenyl-3-yl) ethanesulfonamide

This compound was prepared from the compound of example 28 using the procedure of example 29.¹HNMR(300MHz,DMSO-d₆) 10.3-10.4(Brs,1H),8.75(s,1H),8.6(d,1H),8.25(d,1H),7.9-7.95(dd,1H),7.7-7.8(M,3H),7.55(M,2H),7.4-7.5(M,2H),7.3(M,1H),6.55(M,1H),4.1(q,2H),1.2-1.3(t,3H), LC-MS (ESI): calculated mass: 479.5 and measured mass: 480.1[ M + H ] (ESI) ]]⁺(retention time: 1.641 minutes).

Example 31

N- (5- (5- (1H-pyrazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluorobiphenyl-3-yl) propane-2-sulfonamide

This compound was prepared from the compound of example 28 using the procedure of example 29.¹HNMR(300MHz,DMSO-d₆) 10.3(s,1H),8.78(s,1H),8.61(d,1H),8.25(d,1H),7.94(dd,1H),7.78-7.75(M,3H),7.61-7.57(M,2H),7.5-7.48(M,1H),7.46-7.43(M,1H),7.29-7.25(M,1H),6.6(s,1H),3.5-3.46(M,1H),1.31(d,6H), LC-MS (ESI), calculated mass 493.53, measured mass 494.1[ M + H ] 493.53]⁺(retention time: 1.61 minutes).

Example 32

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

This compound was prepared from the compound of example 28 using the procedure of example 29 and cyclopropanesulfonyl chloride. ¹HNMR(300MHz,DMSO-d₆) 10.34(s,1H),9.0(s,1H),8.64(d,1H),8.27(d,1H),7.99(dd,1H),7.85-7.76(M,3H),7.65-7.62(M,2H),7.54-7.45(M,2H),7.33-7.27(M,1H),6.59-6.57(M,1H),2.95-2.93(M,1H),1.04-1.02(M,4H), LC-MS (ESI): calculated mass 491.51, and actually measured mass 492.1[ M + H ESI]⁺(retention time: 1.659 minutes).

Example 33

1- (5- (5- (1H-pyrazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluorobiphenyl-3-yl) -3- (furan-2-ylmethyl) urea

To a solution of the compound from example 29(a) (250mg,0.645mmol) in n-butanol was added TEA (200mg,1.98mmol,3.05eq.) followed by 2- (isocyanatomethyl) furan (160mg,1.3mmol,2.0 eq.). The mixture was stirred for 1 hour, and then quenched and extracted as described in example 1 (d). The solvent was evaporated and the residue was purified by preparative HPLC to give the product in 18% yield (60 mg).¹HNMR(300MHz,DMSO-d₆) 9.07(s,1H),8.84(s,1H),8.61(d,1H),8.24(d,1H),7.96-7.93(M,2H),7.84-7.71(M,3H),7.64-7.6(M,2H),7.46-7.41(M,2H),7.27-7.23(M,1H),6.82(t,1H),6.58-6.56(M,1H),6.41-6.4(M,1H),6.28-6.27(M,1H),4.32(d,2H), LC-MS (ESI): calculated mass 510.49; measured mass 511.1[ M + H ], (M + H): measured mass 511.1]⁺(retention time: 1.59 minutes).

Example 34

N- (5- (5- (1H-imidazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluorobiphenyl-3-yl) acetamide

This compound was prepared from the compound of example 1(h) using the method of example 28.¹HNMR(300MHz,DMSO-d₆) 10.44(s,1H),8.86(s,1H),8.29(s,2H),8.14(s,1H),7.92(d,2H),7.79-7.71(M,4H),7.55(s,1H),7.47-7.43(M,1H),7.29-7.26(M,1H),2.1(s,3H), LC-MS (ESI) calculating mass 429.42, measured mass 430.2[ M + H ]]⁺(retention time: 0.21 minutes).

Example 35

N- (2',4' -difluoro-5- (4,5,6, 7-tetrahydro-1 ' H-1,5' -dibenzo [ d ] imidazol-1 ' -yl) biphenyl-3-yl) acetamide

This compound was prepared from the compound of example 1(h) using the method of example 28.¹HNMR(300MHz,CD₃OD is 8.66(s,1H),8.15(t,1H),7.86-7.75(M,4H),7.69-7.62(M,1H),7.55(d,1H),7.43(dd,1H),7.18-7.1(M,2H),2.67-2.57(M,4H),2.2(s,3H),1.91-1.85(M,4H), LC-MS (ESI) calculating mass 483.51, measured mass 484.2[ M + H ], [ measured mass ]]⁺(retention time: 0.632 minutes).

Example 36

N- (5- (5- (1-cyclopentyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluorobiphenyl-3-yl) acetamide

A solution of the compound from example 17(c) (60mg,0.123mmol) in 1, 2-dimethoxyethane (10ml) was passed through N₂Bubbling and degassing for 5 minutes. 1-cyclopentyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (35mg,0.135mmol,1.1eq.) was added and the mixture was degassed for an additional 5 minutes. Adding Pd (dppf) Cl ₂(20mg,0.025mmol,0.2eq.) and aqueous sodium carbonate (39mg,0.369mmol,3.0eq.) followed by the procedure of example 1 (d). The crude residue of the product was purified by preparative HPLC to give the product in 25% yield (15 mg).¹HNMR(300MHz,DMSO-d₆) 10.4(s,1H),8.63(s,1H),8.30(s,1H),8.07(s,1H),8.02(s,1H),7.95(s,1H),7.8(s,1H),7.78-7.76(m,2H),7.63-7.61(m,1H),7.51(s,1H),7.45-7.40(m,1H), 7.27(dt,1H),4.73-4.69(m,1H),2.12-2.01(m,5H),2.01-1.96(m,2H),1.85-1.81(m,2H),1.69-1.66(m,2H), LC-MS (ESI)497.54 mass, 498.5 measured mass M + H]⁺(retention time: 1.59 minutes).

Example 37

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

a)4- (4- (1- (5-acetylamino-2 ',4' -difluorobiphenyl-3-yl) -1H-benzo [ d ] imidazol-5-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester

A solution of the compound from example 17(c) (150mg,0.306mmol) in 1, 2-dimethoxyethane (5ml) was passed through N₂Bubbling and degassing for 5 minutes. Tert-butyl 4- (4(4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate from intermediate example 5 (173mg,0.460mmol,1.5eq.) was added and the mixture was degassed for a further 5 minutes. Adding Pd (PPh) ₃)₄(50mg,0.0613mmol,0.2eq.) and aqueous sodium carbonate (97mg,0.92mmol,3.0eq.), followed by the procedure of example 1 (d). The product was obtained as a crude residue in 64% yield (120 mg).

b) N- (2',4' -difluoro-5- (5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) acetamide

To a solution of the compound (120mg,0.2mmol) obtained in example 37(a) in 1, 4-dioxane (8ml) was added a solution of HCl in dioxane at 0 ℃ and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated and the residue was purified by preparative HPLC to give the product in 24% yield (25 mg).¹HNMR(300MHz,DMSO-d₆) 10.42(s,1H),8.83(brs,1H),8.70-8.68(M,1H),8.45-8.43(M,1H)8.34(s,1H),8.14-8.13(M,1H),8.06(s,2H),7.78(M,1H),7.76-7.72(M,2H),7.68(dd,1H),7.53(s,1H),7.43-7.40(M,1H),7.27(dt,1H),4.55-4.45(M,1H),3.17-3.08(M,4H),2.28-2.17(M,4H),2.12(s,3H), LC-MS ESI (A), (512.55) calculated mass, 513.2[ M + H ], (513.2M + H)]⁺(retention time: 0.22 minutes).

Example 38

1- (5- (5- (1H-pyrazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluorobiphenyl-3-yl) -3-cyclopentylurea

To a solution of the compound from example 29(a) (200mg,0.52mmol) in n-butanol (10ml) was added triethylamine (157mg,1.56mmol,3eq.) followed by isocyanatocyclopentane (115mg,1.3mmol,1.04 eq.). The mixture was stirred for 1 hour, and then quenched and extracted as described in example 1 (d). The solvent was evaporated and the residue was purified by preparative HPLC to give the product in 15% yield (39 mg). ¹HNMR(300MHz,DMSO-d₆) 8.83(s,1H),8.72(s,1H),8.60(d,1H),8.23(d,1H),7.90(dd,2H),7.82-7.70(M,3H),7.60(d,1H),7.45(dt,1H),7.34(brs,1H),7.25(dt,1H),6.57-6.56(M,1H),6.46(d,1H),4.0-3.93(M,1H),1.87-1.82(M,2H),1.65-1.54(M,4H),1.43-1.39(M,2H), LC-MS (ESI), calculated mass 498.53, measured mass 499.3[ M + H ] 499.3]⁺(retention time: 1.66 minutes).

Example 39

N- (5- (5- (1- (2- (dimethylamino) ethyl) -1H-1,2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluorobiphenyl-3-yl) methanesulfonamide

a)5- (5- (1- (2- (dimethylamino) ethyl) -1H-1,2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluorobiphenyl-3-amine

To a solution of the compound from example 20 (450mg,0.9mmol) in ethanol (10ml) was added aqueous sodium hydroxide (450mg,11.25mmol,12.5eq.) and the mixture was heated at 85 ℃ for 2 hours. The mixture was quenched and extracted as described in example 1 (d). Evaporation of the solvent gave the product in 77% yield (0.32 g).

b) N- (5- (5- (1- (2- (dimethylamino) ethyl) -1H-1,2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluorobiphenyl-3-yl) methanesulfonamide

To a solution of the compound from example 39(a) (80mg,0.174mmol) in DCM (10ml)To this was added pyridine (28mg,0.35mmol,2eq.) followed by methanesulfonyl chloride (22mg,0.19mmol,1.1 eq.). The mixture was stirred for 2 hours, the reaction was terminated and extracted as described in example 2 (b). The solvent was evaporated and the residue was purified by preparative HPLC to give the product in 11% yield (10 mg). ¹HNMR(300MHz,DMSO-d₆) 10.32(s,1H),8.79(s,1H),8.73(s,1H),8.27(s,1H),7.92(dd,1H),7.82-7.77(M,2H),7.60(d,2H),7.49-7.44(M,2H),7.30-7.27(M,1H),4.88(t,2H),3.73(M,2H),3.19(s,3H),2.89(s,6H), LC-MS (ESI): calculated mass 537.58, measured mass 538.2[ M + H ] (ESI): calculated mass 538.2]⁺(retention time: 0.243 minutes).

Example 40

N- (5- (5- (1- (2- (dimethylamino) ethyl) -1H-1,2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluorobiphenyl-3-yl) ethanesulfonamide

This compound was prepared from the compound of example 20 using the procedure of example 39.¹HNMR(300MHz,DMSO-d₆) 10.37(s,1H),8.85(s,1H),8.73(s,1H),8.28(s,1H),8.83(d,1H),7.82-7.76(M,2H),7.59(s,2H),7.48-7.47(M,2H),7.29(dt,1H),4.89-4.86(M,2H),3.73(M,2H),3.30 (quartet, 2H),2.90(s,6H),1.26(t,3H), LC-MS (ESI), calculated mass 551.61, measured mass 552.2[ M + H ] M,2H, 6H, 1.26(t,3H)]⁺(retention time: 0.282 minutes).

EXAMPLE 41

N- (5- (5- (1- (2- (dimethylamino) ethyl) -1H-1,2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluorobiphenyl-3-yl) propane-2-sulfonamide

This compound was prepared from the compound of example 20 using the procedure of example 39.¹HNMR(300MHz,DMSO-d₆) 10.32(s,1H),8.79(s,1H),8.73(s,1H),8.27(s,1H),7.93(d,1H),7.80-7.75(m,2H),7.59(d,2H),7.50-7.47(m,2H),7.29(dt,1H),4.88(t,2H),3.74(m,2H),3.50-3.46(m,1H),2.89(s,6H),1.31(d,6H), LC-MS (ESI) calculating mass 565.64, measured mass: 566.2[M+H]⁺(retention time: 0.402 min).

Example 42

N- (5- (5- (1- (2- (dimethylamino) ethyl) -1H-1,2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluorobiphenyl-3-yl) cyclopropanesulfonamide

This compound was prepared from the compound of example 20 using the procedure of example 39 and cyclopropanesulfonyl chloride.¹HNMR(400MHz,CD₃OD) 8.93(s,1H),8.53(s,1H),8.32(s,1H),7.80(d,1H),7.82(d,1H),7.68-7.58(M,4H),7.17-7.10(M,2H),4.95(t,2H),3.85(t,2H),3.02(s,6H),2.78-2.71(M,1H),1.16-1.09(M,2H),1.05-1.01(M,2H), LC-MS (ESI), calculated mass 563.62, measured mass 564.2[ M + H ESI]⁺(retention time: 0.412 min).

Example 43

N- (5- (5- (1- (2- (dimethylamino) ethyl) -1H-1,2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluorobiphenyl-3-yl) benzenesulfonamide

This compound was prepared from the compound of example 20 using the procedure of example 39.¹HNMR(300MHz,DMSO-d₆) 10.92(s,1H),8.73(d,2H),8.25(s,1H),7.90-7.88(M,3H),7.70-7.62(M,4H),7.55-7.38(M,5H),7.26-7.20(M,1H),4.90-4.87(M,2H),3.73(t,2H),2.89(s,6H), LC-MS (ESI) calculating mass 599.65, and measured mass 600.2[ M + H ] (S, ESI)]⁺(retention time: 0.75 minutes).

Example 44

N- (2',4' -difluoro-5- (5- (1- (3-hydroxy-3-methylbutyl) -1H-1,2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) acetamide

The compound of example 17(e), the 4-azido-2-methylbutan-2-ol of intermediate example 6 (0.16g,1.25mmol,1.0eq.) were reacted with,Sodium ascorbate (0.25g,1.25mmol,1.0eq.) and copper sulfate pentahydrate (0.155g,0.62mmol,0.5eq.) in CH₂Cl₂The mixture in (5ml), DMSO (2ml) and water (2ml) was stirred at room temperature for 12 hours. The mixture was quenched with water and the precipitate formed was filtered and dried. The crude product was purified by preparative HPLC to give the product in 62% yield (0.4 g).¹HNMR(300MHz,DMSO-d₆) 10.43(s,1H),8.86(s,1H),8.70(s,1H),8.25(s,1H),8.09(s,1H),7.93(d,1H),7.84-7.81(M,3H),7.55(s,1H),7.50-7.43(M,1H),7.30-7.25(M,1H),4.51-4.56(M,2H),2.13(s,3H),2.05-1.99(t,2H),1.18(s,6H), LC-MS (ESI), a calculated mass of 516.54, an actually measured mass of 517.2[ M + H ] (M,1H)]⁺(retention time: 1.226 minutes).

Example 45

N- (2',4' -difluoro-5- (5- (1- (3-hydroxy-3-methylbutyl) -1H-1,2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) methanesulfonamide

a)4- (4- (1- (5-amino-2 ',4' -difluorobiphenyl-3-yl) -1H-benzo [ d ] imidazol-5-yl) -1H-1,2, 3-triazol-1-yl) -2-methylbutan-2-ol

To a solution of the compound from example 44 (400mg,0.77mmol) in ethanol (20ml) was added aqueous sodium hydroxide (385mg,9.63mmol,12.5eq.) and the mixture was heated at 90 ℃ for 3 hours. The mixture was quenched and extracted as described in example 1 (d). Evaporation of the solvent gave the product in 38% yield (140 mg).

b) N- (2',4' -difluoro-5- (5- (1- (3-hydroxy-3-methylbutyl) -1H-1,2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) methanesulfonamide

To a solution of the compound from example 45(a) (70mg,0.15mmol) in DCM (10ml) was added pyridine (24mg,0.3mmol,2eq.) followed by methanesulfonyl chloride (19mg,0.165mmol,1.1 eq.). The mixture was stirred for 2 hours, the reaction was terminated and extracted as described in example 2 (b). The solvent was evaporated and the residue was purified by preparative HPLC to give the product in 1.2% yield (1 mg).¹HNMR(300MHz,DMSO-d₆) 10.30(s,1H),8.83(s,1H),8.30(s,1H),8.25(s,1H),7.92(d,1H),7.82-7.80(M,2H),7.60(d,2H),7.47(s,2H),7.29-7.21(M,1H),4.49(M,2H),3.19(s,3H),2.02(M,2H),1.18(s,6H), LC-MS (ESI), calculated mass: 552.60, measured mass: 553.1[ M + H + M,2H ] (calculated mass: 552.60)]⁺(retention time: 1.352 min).

Example 46

N- (2',4' -difluoro-5- (5- (1- (3-hydroxy-3-methylbutyl) -1H-1,2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) ethanesulfonamide

The compound was prepared from the compound of example 44 using the procedure of example 45.¹HNMR(300MHz,DMSO-d₆) 10.34(s,1H),8.87(s,1H),8.70(s,1H),8.25(s,1H),7.93(dd,1H),7.84-7.80(M,2H),7.59(s,2H),7.49-7.44(M,2H),7.29(dt,1H),4.51-4.47(M,2H),3.30 (quartet, 2H),2.04-2.00(M,2H),1.26(t,3H),1.16(s,6H), LC-MS (ESI): calculation of mass: 566.62; measured mass: 567.2[ M + H ] (M, 2H): measured mass: 566.62 ]⁺(retention time: 1.42 minutes).

Example 47

N- (2',4' -difluoro-5- (5- (1- (3-hydroxy-3-methylbutyl) -1H-1,2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) cyclopropanesulfonamide

This compound was prepared from the compound of example 44 using the procedure of example 45 and cyclopropanesulfonyl chloride.¹HNMR(400MHz,CD₃OD) 9.09(s,1H),8.47(s,1H),8.30(s,1H),8.0(d,1H),7.83(d,1H),7.69-7.60(M,4H),7.17-7.10(M,2H),4.62-4.58(M,2H),2.78-2.69(M,1H),2.17-2.13(M,2H),1.29-1.15(M,8H),1.10-1.02(M,2H), LC-MS (ESI) calculated mass 578.63, measured mass 579.2[ M + H ] calculated mass 579.2 (M + ESI)]⁺(retention time: 1.449 minutes).

Example 48

N- (2',4' -difluoro-5- (5- (1- (2- (morpholin-4-yl) ethyl) -1H-1,2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) methanesulfonamide

a)2',4' -difluoro-5- (5- (1- (2- (morpholin-4-yl) ethyl) -1H-1,2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-amine

To a solution of the compound from example 21 (1g,1.9mmol) in ethanol (15ml) was added aqueous sodium hydroxide (0.95g,23.8mmol,12.5eq.) and the mixture was heated at 90 ℃ for 4 hours. The mixture was quenched and extracted as described in example 1 (d). Evaporation of the solvent gave the product in 63% yield (600 mg).

b) N- (2',4' -difluoro-5- (5- (1- (2- (morpholin-4-yl) ethyl) -1H-1,2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) methanesulfonamide

To a solution of the compound from example 48(a) (80mg,0.159mmol) in DCM (10ml) was added pyridine (25mg,0.318mmol,2eq.) followed by methanesulfonyl chloride (21mg,0.191mmol,1.2 eq.). The mixture was stirred for 2 hours, the reaction was terminated and extracted as described in example 2 (b). The solvent was evaporated and the residue was purified by preparative HPLC to give the product in 13% yield (12 mg).¹HNMR(300MHz,DMSO-d₆) 10.32(s,1H),8.80(s,1H),8.73(s,1H),8.28(s,1H),7.94-7.92(d,1H),7.82-7.72(M,2H),7.60(d,2H),7.46-7.40(M,2H),7.27(dt,1H),4.89(M,2H),3.96-3.94(M,6H),3.77(M,4H),3.19(s,3H), LC-MS (ESI) calculating mass 579.62, measured mass 580.2[ M + H ] (s,3H) ]]⁺(retention time: 0.29 minutes).

Example 49

N- (2',4' -difluoro-5- (5- (1- (2- (morpholin-4-yl) ethyl) -1H-1,2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) ethanesulfonamide

The compound was prepared from the compound of example 21 using the procedure of example 48.¹HNMR(300MHz,DMSO-d₆):10.41(s,1H),8.83(s,1H),8.80(s,1H),8.32(s,1H),7.97(d,1H),7.85-7.80(m,2H),7.63(s,2H),7.52-7.50(M,2H),7.33(d,1H),4.93(M,2H),4.0(M,6H),3.70(M,4H),3.34 (quartet, 2H),1.30(t,3H); LC-MS (ESI): calculated mass: 593.65; measured mass: 594.2[ M + H ]; measured mass: 594.2 ]⁺(retention time: 0.36 minutes).

Example 50

N- (2',4' -difluoro-5- (5- (1- (2- (morpholin-4-yl) ethyl) -1H-1,2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) cyclopropanesulfonamide

This compound was prepared from the compound of example 21 using the procedure of example 48 and cyclopropanesulfonyl chloride.¹HNMR(300MHz,DMSO-d₆) 10.9(s,1H),8.73(s,1H),8.62(s,1H),8.22(s,1H),7.9-7.87(M,3H),7.71-7.62(M,4H),7.55(s,1H),7.47-7.39(M,4H),7.28-7.24(M,1H),4.12(s,3H), LC-MS (ESI) calculating mass: 605.6, measured mass: 606.2[ M + H ESI ]]⁺(retention time: 0.367 minutes).

Example 51

N- (5- (5- (1-cyclopentyl-1H-1, 2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluorobiphenyl-3-yl) acetamide

A solution of the compound from example 17(e) (100mg,0.258mmol) in dry DMF (10ml) in a sealed tube with N₂Purify for 20 min, then add intermediate example 7 azidocyclopentane (34mg,0.3mmol,1.2eq.) and cuprous iodide (5mg,0.0258mmol,0.1eq.) and stir at 90 ℃ for 12 h. The solvent was evaporated and the residue was purified by preparative HPLC to give the product in 14% yield (18 mg).¹HNMR(400MHz,CD₃OD: 8.55(s,1H),8.43(s,1H),8.36(s,1H),8.23(brs,1H),8.10(s,1H),7.92-7.88(M,1H),7.74(d,2H),7.68-7.61(M,1H),7.52(s,1H),7.15-7.09(M,1H),5.09-5.03(M,1H),2.35-2.30(M,2H),2.19-2.12(M,5H),1.96-1.90(M,4H), LC-MS (ESI): calculated mass: 498.53; measured mass: 499.2[ M + H ], (M, 1H): calculated mass: 498.53; measured mass: 499.2[ M + H ] ]⁺(retention time: 1.55 minutes).

Example 52

N- (5- (5- (1- (cyclobutylmethyl) -1H-1,2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluorobiphenyl-3-yl) acetamide

This compound was prepared from the compound of example 17(e) using the intermediate compound of example 8 and the procedure of example 51.¹HNMR(300MHz,DMSO-d₆) 10.34(s,1H),8.13(s,1H),8.61(s,1H),8.24(s,1H),8.07(s,1H),7.92-7.90(d,1H),7.82-7.71(M,3H),7.52(s,1H),7.42(M,1H),7.24-7.20(M,1H),4.42(d,2H),2.10(s,3H),2.05(M,3H),1.90-1.83(M,4H), LC-MS (ESI), calculated mass 498.53, measured mass 499.2[ M + H + 3H ], (ESI)]⁺(retention time: 1.55 minutes).

Example 53

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

a) N- (4' -fluoro-5-nitrobiphenyl-3-yl) acetamide

This compound was prepared from the compound of example 1(c) (10.0g,38.6mmol) using the method of example 1(d) and 4-fluorophenylboronic acid (6.48g,46.3mmol,1.2eq.) to give the product in 86% yield (9.1 g).¹HNMR(300MHz,DMSO-d₆) 10.53(s,1H),8.57(t,1H),8.17(s,1H),8.09(t,1H),7.86-7.74(M,2H),7.41(t,2H),7.15(t,1H),2.13(s,3H), LC-MS (ESI), calculated mass 274.25, measured mass 274.8[ M + H ] 274.8]⁺(retention time: 1.52 minutes).

b) N- (5-amino-4' -fluorobiphenyl-3-yl) acetamide

The compound was prepared from the compound (11.0g,40.1mmol) in example 53(a) by the method of example 1(e) and was obtained in 92% yield (9.0 g).¹HNMR(300MHz,DMSO-d₆) 9.73(s,1H),8.11(s,1H),7.53-7.48(M,2H),7.26(t,1H),6.94-6.92(M,2H),6.47(s,1H),5.22(s,2H),2.02(s,3H), LC-MS (ESI) calculating mass 244.26, and measuring mass 245.1 (M + H)]⁺(guarantee)Retention time: 0.312 minutes).

c) N- (5- (4-bromo-2-nitrophenylamino) -4' -fluorobiphenyl-3-yl) acetamide

This compound was prepared from the compound of example 53(b) (9.0g,36.85mmol) using the method of example 1 (f). The reaction solution was quenched with water. The precipitate formed was filtered, washed with cold water and hexanes and dried under high vacuum to give the product as an orange solid in 92% yield (15.0 g).¹HNMR(300MHz,DMSO-d₆) 10.14(s,1H),9.45(s,1H),8.25(d,1H),7.69-7.62(M,5H),7.35-7.24(M,4H),2.07(s,3H), LC-MS (ESI) calculating mass 444.25, actual measuring mass 446.1[ M + H [ ]]⁺(retention time: 1.84 minutes).

d) N- (5- (2-amino-4-bromophenylamino) -4' -fluorobiphenyl-3-yl) acetamide

The compound was prepared from the compound of example 53(c) (15g,33.77mmol) using the method of example 1(g) to give the product in 93% yield (13.0 g). ¹HNMR(300MHz,DMSO-d₆) 9.84(1H, s),7.53-7.49(M,3H),7.31-7.25(M,4H),6.98-6.91(M,2H),6.88-6.62(M,2H),5.11(s,2H),2.01(s,3H), LC-MS (ESI), calculating mass 414.27, and measuring mass 416 (M + H)]⁺(retention time: 1.73 minutes).

e) N- (5- (5-bromo-1H-benzo [ d ] imidazol-1-yl) -4' -fluorobiphenyl-3-yl) acetamide

The compound was prepared from the compound of example 53(d) (13.0g,31.38mmol) using the procedure of example 1(h) to give the product in 68% yield (9.0 g).¹HNMR(300MHz,DMSO-d₆) 10.38(s,1H),8.77(s,1H),8.14(s,1H),8.02-7.97(M,1H),7.9(s,1H),7.82-7.77(M,2H),7.7-7.67(M,1H),7.63-7.62(M,1H),7.54-7.5(M,1H),7.36(t,2H),2.12(s,3H), LC-MS ESI (calculated mass: 424.27), measured mass: 425.1[ M + H ], (actual mass: 425.1[ M + H ESI: (g, 1H))]⁺(retention time: 1.925 minutes).

f) N- (4' -fluoro-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) acetamide

The compound was obtained by using the compound of example 1(i)Prepared from the compound of example 53(e) (1.3g,3.06mmol) and 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (0.765g,3.68mmol,1.2eq.) to give the product in 46% yield (0.6 g).¹HNMR(300MHz,DMSO-d₆) 10.4(s,1H),9.0(s,1H),8.25(s,1H),8.08(s,1H),8.0(d,2H),7.90(s,1H),7.8(M,3H),7.65(M,2H),7.4(t,2H),3.9(s,3H),2.1(s,3H), LC-MS (ESI) calculating mass 425.46, measured mass 425.9[ M + H ] mass ]⁺(retention time: 1.13 minutes).

Example 54

N- (4' -fluoro-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) methanesulfonamide

a)4' -fluoro-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-amine

To a solution of the compound from example 53 (0.6g,1.41mmol) in ethanol (20ml) was added aqueous sodium hydroxide (451mg,11.3mmol,8.0eq.) and the mixture was heated at 85 ℃ for 4 hours. The mixture was quenched and extracted as described in example 1 (d). Evaporation of the solvent gave the product in 44% yield (0.24 g). LC-MS (ESI) calculated mass 383.42 and measured mass 384.1[ M + H]⁺(retention time: 1.004 minutes).

b) N- (4' -fluoro-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) methanesulfonamide

To a solution of the compound from example 54(a) (50mg,0.125mmol) in DCM was added pyridine (20mg,0.249mmol,2.0eq.) followed by methanesulfonyl chloride (17mg,0.15mmol,1.2 eq.). The mixture was stirred for 1 hour, the reaction was terminated and extracted as described in example 2 (b). The solvent was evaporated and the residue was purified by preparative HPLC to give the product in 33% yield (20 mg).¹HNMR(300MHz,DMSO-d₆) 10.23(brs,1H),8.71(s,1H),7.97(d,2H),7.85-7.8(M,2H),7.69(M,2H),7.61-7.58(M,2H),7.52(d,2H),7.38(t,2H),3.89(s,3H),3.19(s,3H), LC-MS (ESI) calculating mass 461.51, measured mass 461.9[ M + H ] mass ]⁺(retention time: 1.3 minutes).

Example 55

N- (4' -fluoro-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) ethanesulfonamide

The compound was prepared from the compound of example 53 using the procedure of example 54.¹HNMR(300MHz,DMSO-d₆) 10.36(brs,1H),9.35(brs,1H),8.28(s,1H),8.02(d,2H),7.85-7.79(M,2H),7.76-7.7(M,3H),7.6-7.57(M,2H),7.39(t,2H),3.89(s,3H),3.31 (quartet, 2H),1.27(t,3H), LC-MS (ESI), calculated mass 475.54, measured mass 475.9 (M + H, 2H), calculated mass]⁺(retention time: 1.38 minutes).

Example 56

N- (4' -fluoro-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) propane-2-sulfonamide

The compound was prepared from the compound of example 53 using the procedure of example 54.¹HNMR(300MHz,DMSO-d₆) 10.28(brs,1H),8.92(brs,1H),8.24(s,1H),7.99(d,2H),7.83-7.78(M,2H),7.71-7.67(M,3H),7.56(d,2H),7.38(t,2H),3.88(s,3H),3.52-3.48(M,1H),1.31(d,6H), LC-MS (ESI), calculated mass 489.56, measured mass 490.2[ M + H ] (M + ESI)]⁺(retention time: 1.46 minutes).

Example 57

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

This compound was prepared from the compound of example 53 using the method of example 54 and cyclopropanesulfonyl chloride. ¹HNMR(300MHz,DMSO-d₆):10.28(s,1H),9.1(brs,1H),8.26(s,1H),8.01(d,2H),7.84-7.81(m,2H),7.74-7.71(m,3H),7.59(s,2H),7.39(t,2H),3.89(s,3H),2.91-2.89(M,1H),1.03(d,4H); LC-MS (ESI): calculated mass: 487.55; measured mass: 488.1[ M + H ])]⁺(retention time: 1.42 minutes).

Example 58

1-cyclopentyl-3- (4' -fluoro-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) urea

To a solution of the compound from example 54(a) (100mg,0.261mmol) in n-butanol was added triethylamine (79mg,0.783mmol,3.0eq.) followed by isocyanatocyclopentane (58mg,0.522mmol,2.0 eq.). The mixture was stirred for 1 hour, and then quenched and extracted as described in example 1 (d). The solvent was evaporated and the residue was purified by preparative HPLC to give the product in 31% yield (40 mg).¹HNMR(300MHz,DMSO-d₆) 8.84(brs,1H),8.71(s,1H),8.22(s,1H),7.99(d,2H),7.88(s,1H),7.82-7.78(M,2H),7.73(d,1H),7.68-7.63(M,2H),7.48(s,1H),7.36(t,2H),6.4(d,1H),4.1-3.8(M,1H),3.88(s,3H),1.89-1.83(M,2H),1.69-1.5(M,4H),1.45-1.38(M,2H), LC-MS (ESI) calculated mass 494.56, measured mass 494.8[ M + H ], [ 494.56]⁺(retention time: 1.51 minutes).

Example 59

1- (4' -fluoro-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) -3- (1-methylpiperidin-4-yl) urea

To a solution of the compound from example 54(a) (50mg,0.13mmol) in DCM was added phosgene (20% in toluene) (0.1ml,0.195mmol,1.5eq.) at 0 ℃ and the mixture was stirred at 0 ℃ for 15 min, then at room temperature for 30 min. 1-methylpiperidin-4-amine (18mg,0.156mmol,1.2eq.) was added and the mixture was stirred for 16 hours. The mixture was quenched by the addition of water and extracted with 8% methanol in DCM (3X 50 ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. The solvent was evaporated and the residue was purified by preparative HPLC to give the product in 44% yield (30 mg). ¹HNMR(300MHz,DMSO-d₆) 8.48(s,1H),7.98(s,1H),7.89-7.85(M,4H),7.72-7.55(M,6H),7.39(s,1H),7.2(t,2H),3.94(s,3H),3.89-3.84(M,1H),3.42-3.33(M,2H),3.05-3.0(M,2H),2.78(s,3H),2.17-2.13(M,2H),1.85-1.81(M,2H), LC-MS (ESI), 523.6, 524[ M + H ] which is the measured mass]⁺(retention time: 0.2 minutes).

Example 60

1- (4' -fluoro-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) -3- (furan-2-ylmethyl) urea

This compound was prepared from the compound of example 54(a) using the procedure of example 58.¹HNMR(300MHz,CD₃OD is 9.1(s,1H),8.1(s,1H),8.02(s,2H),7.93(s,1H),7.85-7.81(M,2H),7.74-7.67(M,3H),7.53(d,1H),7.44(d,1H),7.22(t,2H),6.37-6.34(M,1H),6.3-6.29(M,1H),4.42(s,2H),3.95(s,3H), LC-MS (ESI) calculating mass 506.53, measured mass 507.1[ M + H + M,4H)]⁺(retention time: 1.44 minutes).

Example 61

1- (4' -fluoro-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) -3- ((5-methylfuran-2-yl) methyl) urea

This compound was prepared from the compound of example 54(a) using the procedure of example 58.¹HNMR(300MHz,CD₃OD) 9.51(s,1H),8.1(s,1H),8.02(s,2H),7.93(s,1H),7.85-7.73(M,4H),7.65(M,1H),7.53(s,1H),7.22(t,2H),6.2-6.14(M,1H),5.9-5.81(M,1H),4.38(s,2H),3.95(s,3H),2.26(s,3H), LC-MS (ESI): calculated mass 520.56, measured mass 521.1[ M + H (ESI) ] ]⁺(retention time: 1.51 minutes).

Example 62

N- (5- (5- (1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -4' -fluorobiphenyl-3-yl) acetamide

This compound was prepared from the compound of example 53(e) using the procedure of example 53.¹HNMR(300MHz,DMSO-d₆) 10.42(s,1H),8.98(s,1H),8.37(s,1H),8.14-8.06(M,3H),7.85-7.75(M,4H),7.68-7.66(M,2H),7.38(t,2H),4.57(t,2H),3.65-3.63(M,2H),2.85(d,6H),2.13(s,3H), LC-MS (ESI), calculated mass 482.55, measured mass 483.1[ M + H ], calculated mass]⁺(retention time: 0.19 minutes).

Example 63

N- (5- (5- (1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -4' -fluorobiphenyl-3-yl) methanesulfonamide

This compound was prepared from the compound of example 62 using the procedure of example 54.¹HNMR(300MHz,DMSO-d₆) 10.27(s,1H),8.87(s,1H),8.37(s,1H),8.14(s,1H),8.06(s,1H),7.84-7.8(M,2H),7.76-7.64(M,3H),7.55-7.52(M,2H),7.38(t,2H),4.57(t,2H),3.65-3.62(M,2H),3.19(s,3H),2.86(d,6H), LC-MS (ESI) calculating mass 518.61, and 519[ M + H ] measured mass]⁺(retention time: 0.22 minutes).

Example 64

N- (5- (5- (1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -4' -fluorobiphenyl-3-yl) ethanesulfonamide

This compound was prepared from the compound of example 62 using the procedure of example 54.¹HNMR(300MHz,DMSO-d₆) 10.29(s,1H),8.77(s,1H),8.35(s,1H),8.13(s,1H),8.06(s,1H),7.83-7.78(M,2H),7.72-7.63(M,3H),7.54-7.51(M,2H),7.38(t,2H),4.57(t,2H),.65-3.62(M,2H),3.3 (quartet, 2H),2.86(d,6H),1.27(t,3H), LC-MS (ESI): calculated mass 532.63, measured mass 533[ M + H ] 533[ (M + H, 2H) ], measured mass]⁺(retention time: 0.25 minutes).

Example 65

N- (5- (5- (1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -4' -fluorobiphenyl-3-yl) propane-2-sulfonamide

This compound was prepared from the compound of example 62 using the procedure of example 54.¹HNMR(300MHz,DMSO-d₆) 10.27(s,1H),8.82(s1H),8.36(s,1H),8.14(s,1H),8.06(s,1H),7.83-7.79(M,2H),7.71-7.65(M,3H),7.56-7.53(M,2H),7.38(t,2H),4.57(t,2H),3.67-3.64(M,2H),3.52-3.49(M,1H),2.85(d,6H),1.32(d,6H), LC-MS (ESI) calculating mass 546.66, and actually measuring mass 547.2[ M + H ] M]⁺(retention time: 0.507 minutes).

Example 66

N- (5- (5- (1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -4' -fluorobiphenyl-3-yl) cyclopropanesulfonamide

This compound was prepared from the compound of example 62 using the procedure of example 54 and cyclopropanesulfonyl chloride. ¹HNMR(300MHz,DMSO-d₆) 10.26(s,1H),8.84(s,1H),8.36(s,1H),8.14(s,1H),8.06(s,1H),7.82-7.79(M,2H),7.73-7.67(M,3H),7.56(d,2H),7.39(t,2H),4.57(t,2H),3.65-3.62(M,2H),2.9-2.87(M,1H),2.86(d,6H),1.02(d,4H), LC-MS (ESI), calculated mass 544.64, measured mass 546.2[ M + H ] 546.546]⁺(retention time: 0.401 min).

Example 67

N- (5- (5- (1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -4' -fluorobiphenyl-3-yl) benzenesulfonamide

This compound was prepared from the compound of example 62 using the procedure of example 54.¹HNMR(300MHz,DMSO-d₆):10.9(s,1H),8.78(s,1H),8.37(s,1H),8.14(s,1H),8.03(s,1H),7.89(d,2H),7.72-7.68(m,3H),7.66-7.61(m,4H),7.41-7.33(m,5H) 4.57(t,2H),3.66-3.63(M,2H),2.85(d,6H), LC-MS (ESI) calculated mass 580.68, measured mass 581.1[ M + H ]]⁺(retention time: 0.781 minutes).

Example 68

1-cyclopentyl-3- (5- (5- (1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -4' -fluorobiphenyl-3-yl) urea

This compound was prepared from the compound of example 62 using the procedure of example 58.¹HNMR(300MHz,DMSO-d₆) 9.33(brs,1H),8.87(s,1H),8.76(s,1H),8.36(s,1H),8.14(s,1H),8.05(s,1H),7.39(M,1H),7.82-7.75(M,3H),7.68-7.6(M,2H),7.48(M,1H),7.36(t,2H),4.57(t,2H),3.99-3.97(M,1H),3.65-3.62(M,2H),2.86(d,6H),1.89-1.82(M,2H),1.7-1.53(M,4H),1.45-1.37(M,2H); LC-MS (ESI calculated mass: 551.66; measured mass: 552.2[ M + H ]; 8932 ]⁺(retention time: 0.61 min).

Example 69

N- (4' -fluoro-5- (5- (6-methoxypyridin-3-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) acetamide

This compound was prepared using the procedure of example 53.¹HNMR(300MHz,DMSO-d₆) 10.41(s,1H),8.96(s,1H),8.58(d,1H),8.15-8.07(M,3H),7.91-7.89(M,1H),7.85-7.79(M,3H),7.74-7.67(M,2H),7.38(t,2H),6.95(d,1H),3.92(s,3H),2.14(s,3H), LC-MS (ESI), calculated mass 452.48, measured mass 453.1[ M + H ], calculated mass]⁺(retention time: 1.571 minutes).

Example 70

N- (5- (5- (1H-pyrazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -4' -fluorobiphenyl-3-yl) acetamide

To a solution of the compound from example 53(e) (1.0g,2.36mmol) in DMF (5ml) was added pyrazole (1.0mg,14.87mmol,6.3eq.), copper (I) oxide (1.0g,7.08mmol,3.0eq.) and cesium carbonate (3.0g,9.204mmol,3.9eq.) and the mixture was heated at 90 ℃ for 48 hours. The mixture was quenched and extracted as described in example 1 (d). The solvent was evaporated and the residue was purified by preparative HPLC to give the product in 62% yield (0.6 g).¹HNMR(300MHz,DMSO-d₆) 10.39(s,1H),8.8(s,1H),8.6(d,1H),8.24(d,1H),8.02(s,1H),7.93-7.9(M,2H),7.82-7.56(M,4H),7.65(d,1H),7.37(t,2H),6.56(t,1H),2.13(s,3H), LC-MS (ESI) calculating mass 411.43, measured mass 412.3[ M + H ESI ] ]⁺(retention time: 1.43 minutes).

Example 71

N- (5- (5- (1H-pyrazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -4' -fluorobiphenyl-3-yl) methanesulfonamide

a)5- (5- (1H-pyrazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -4' -fluorobiphenyl-3-amine

To a solution of the compound from example 70 (0.6g,1.46mmol) in ethanol (40ml) was added aqueous sodium hydroxide (1.0g,25mmol,17.1eq.) and the mixture was heated at 85 ℃ for 5 hours. The mixture was quenched and extracted as described in example 1 (d). The combined organic layers were washed with water, brine and dried over sodium sulfate. Evaporation of the solvent gave the product in 84% yield (0.45 g).

b) N- (5- (5- (1H-pyrazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -4' -fluorobiphenyl-3-yl) methanesulfonamide

To a solution of the compound from example 71(a) (150mg,0.406mmol) in DCM was added pyridine (0.5ml,6.21mmol,15.3eq.) followed by methanesulfonyl chloride (70mg,0.609mmol,1.5 eq.). The mixture was stirred for 1 hour, the reaction was terminated and extracted as described in example 2 (b). The solvent was evaporated and the residue was purified by preparative HPLC to give the product in 17% yield (30 mg).¹HNMR(300MHz,DMSO-d₆):10.23(s,1H),8.82(s,1H),8.6(d,1H),8.24(d,1H),7.92(dd,1H),7.85-7.8(m,3H),7.76-7.71(m,2H),7.54-7.53(m,2H),7.38(t,2H),6.56(t,1H),3.19(s,3H); LC-MS (ESI): calculated mass: 447.48; measured mass: 449.1[ M + H [)]⁺(retention time: 1.575 minutes).

Example 72

N- (5- (5- (1H-pyrazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -4' -fluorobiphenyl-3-yl) ethanesulfonamide

The compound was prepared from the compound of example 70 using the procedure of example 71.¹HNMR(300MHz,DMSO-d₆) 10.3(s,1H),8.81(s,1H),8.6(d,1H),8.24(s,1H),7.93(dd,1H),7.84-7.76(M,4H),7.7-7.69(M,1H),7.55-7.53(M,2H),7.4-7.36(M,2H),6.57-6.56(M,1H),3.3 (quartet, 2H),1.27(t,3H), LC-MS (ESI): 461.51, 462.1[ M + H ], (ESI): 462.]⁺(retention time: 1.563 minutes).

Example 73

N- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (5-methylfuran-2-yl) phenyl) acetamide

a) N- [3- (5-methyl-furan-2-yl) -5-nitro-phenyl ] -acetamide

To a solution of N- (3-bromo-5-nitrophenyl) acetamide (5g,19.23mmol) from example 1(c) in 1, 2-dimethoxyethane (200ml) were added 4,4,5, 5-tetramethyl-2- (5-methylfuran-2-yl) -1,3, 2-dioxaborolane (5.9g,28.85mmol), sodium carbonate (8.15g,76.92mmol) and water (20ml) and the mixture was passed through N₂Bubbling and degassing for 15 minutes. Adding Pd (dppf) Cl₂(3.2g,3.846mmol) and the mixture was heated at 100 ℃ for 2 h. The mixture was returned to room temperature, and the reaction was terminated and extracted as described in example 1 (d). The solvent was evaporated and the residue was purified by flash column chromatography (40% ethyl acetate in hexane) to give the product in 80% yield (4.0 g). ¹HNMR(300MHz,DMSO-d₆) 10.45(s,1H),8.4(s,1H),8.2(d,2H),7.1(s,1H),6.2(s,1H),2.4(s,3H),2.15(s,3H), a calculated mass of 260.25, and an actually measured mass of 259.1[ M + H ]]⁺(RetentionTime: 1.578 minutes).

b) N- [ 3-amino-5- (5-methyl-furan-2-yl) -phenyl ] -acetamide

To a solution of the compound (4.0g,15.384mmol) from example 73(a) in methanol (50ml) was added 10% palladium on carbon (500mg) and the mixture was stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 6 hours. The mixture was filtered through a pad of celite and washed with methanol. Evaporation of the solvent gave the compound in 95% yield (3.3 g).¹HNMR(300MHz,DMSO-d₆) 9.6(s,1H),7.0(d,2H),6.45(d,2H),6.2(s,1H),5.2(s,2H),2.4(s,3H),2.15(s,3H), a calculated mass of 230.26, an actual measured mass of 231.2[ M + H ]]⁺(retention time: 0.212 minutes).

c) N- [3- (4-bromo-2-nitro-phenylamino) -5- (5-methyl-furan-2-yl) -phenyl ] -acetamide

To a solution of the compound from example 73(b) (5g,22.73mmol) in anhydrous DMF (25ml) was added 4-bromo-1-fluoro-2-nitrobenzene (7.09g,27.3mmol) and potassium fluoride (1.32g,22.73 mmol). The mixture was stirred at 100 ℃ overnight. The mixture was brought to room temperature and the DMF was removed under reduced pressure. The residue was purified by flash column chromatography (50% ethyl acetate in hexane) to give the compound in 65% yield (6 g). ¹HNMR(300MHz,DMSO-d₆) 10.2(s,1H),9.6(s,1H),8.2(s,1H),7.7(s,2H),7.5(M,1H),7.30(s,1H),7.2(s,1H),6.7(d,1H),2.9(s,1H),2.33(s,3H),2.15(s,3H), a calculated mass of 430.25, and an actually measured mass of 432[ M + H ] 430.25]⁺(retention time: 1.85 minutes).

d) N- [3- (2-amino-4-bromo-phenylamino) -5- (5-methyl-furan-2-yl) -phenyl ] -acetamide

To a solution of the compound (6.0g,13.945mmol) obtained in example 73(c) in ethanol (100ml) were added iron powder (500mg) and 50% aqueous calcium chloride solution (10 ml). The mixture was stirred at 80 ℃ for 2 hours and filtered through a pad of celite. The celite pad was washed with ethyl acetate (200 ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. The solvent was evaporated and the residue was purified by flash column chromatography (20% ethyl acetate in hexane) to give the compound in 98% yield(5.5g)。¹HNMR(300MHz,DMSO-d₆) 9.8(s,1H),7.30(d,1H),6.9(M,3H),6.7(M,2H),6.5(d,1H),5.2(s,2H),2.33(s,3H),2.15(s,3H), calculated mass 400.27, measured mass 402[ M + H [ ], M + H ], and]⁺(retention time: 1.695 min).

e) N- (3- (5-bromo-1H-benzo [ d ] imidazol-1-yl) -5- (5-methylfuran-2-yl) phenyl) acetamide

Formic acid (10ml) was added to the compound (5g,12.49mmol) of example 73(d) at room temperature, and the mixture was heated at 100 ℃ for 2 hours. Formic acid was removed and the residue was purified by flash column chromatography (3% methanol in chloroform) to give the compound in 58% yield (3.0 g). ¹HNMR(300MHz,DMSO-d₆) 10.3(s,1H),8.7(s,1H),8.0(s,1H),7.9(s,2H),7.6(M,2H),7.5(M,1H),7.0(s,1H),6.3(d,1H),2.33(s,3H),2.15(s,3H), the calculated mass is 410.26, and the measured mass is 410.2[ M + H []⁺(retention time: 1.616 min).

f) N- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (5-methylfuran-2-yl) phenyl) acetamide

To a solution of the compound from example 73(e) (100mg,0.244 mmol) in 1, 2-dimethoxyethane (10ml) were added 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (0.043g,0.341mmol), sodium carbonate (0.0755g,0.731mmol) and water (2.0ml) and the mixture was passed through N₂Bubbling and degassing for 15 minutes. Adding Pd (PPh)₃)₄(0.0563g,0.0487mmol) and the mixture was heated at 100 ℃ for 2 hours. The mixture was allowed to return to room temperature, and then the reaction was terminated and extracted as described in example 1 (d). The solvent was evaporated and the residue was purified by preparative HPLC to give the compound in 10% yield (10 mg).¹HNMR(300MHz,DMSO-d₆) 10.2(s,1H),8.6(s,1H),8.4(s,1H),7.8-8.1(s,4H),7.6-7.7(M,4H),7.0(s,1H),6.3(s,1H),3.9(M,1H),2.4(s,3H),2.15(s,4H), a calculated mass of 411.46, and an actually measured mass of 412.1[ M + H ], (M,1H)]⁺(retention time: 0.809 minutes).

Example 74

N- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (5-methylfuran-2-yl) phenyl) ethanesulfonamide

a)3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (5-methylfuran-2-yl) aniline

A mixture of KOH (0.614g,10.94mmol) and the compound from example 73 (3.0g,7.29mmol) in ethanol (5ml) and water (2ml) was heated at 60 ℃ for 2 h. The mixture was diluted with ethyl acetate (100ml) and washed with water (50ml) and brine (25 ml). The organic phase was dried over sodium sulfate and concentrated in vacuo and the residue was purified by column chromatography to give the product in 92% yield (2.5 g).

b) N- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (5-methylfuran-2-yl) phenyl) ethanesulfonamide

To a solution of the compound from example 74(a) (0.1g,0.27mmol) in pyridine (1ml) and DCM (2ml) was added ethanesulfonyl chloride (0.1ml) and the mixture was stirred at room temperature for 12 hours. The solvent was removed and the crude product was purified by preparative HPLC to give the product in 24% yield (0.03 g).¹HNMR(300MHz,CD₃OD) 9.2(s,1H),8.1(s,1H),8.0(s,1H),7.95(s,1H),7.6-7.7(m,4H),7.5(s,1H),6.8(d,1H),6.2(s,1H),4.0(s,3H),3.3(m,2H),2.4(s,3H),1.4(t, 3H). LC-MS (ESI) calculated mass 461.54 and measured mass 462.1[ M + H ]]⁺(retention time: 1.315 minutes).

Example 75

N- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (5-methylfuran-2-yl) phenyl) propane-2-sulfonamide

The compound was prepared from the compound of example 73 using the procedure of example 74.¹HNMR(300MHz,CD₃OD) 8.5(s,1H),8.0(s,1H),7.95(s,1H),7.9(s,1H),7.6-7.7(m,5H),7.5(s,1H),6.8(d,1H),6.2(s,1H),4.0(s,3H),3.5(m,1H),2.4(s,3H),1.5(d, 6H). LC-MS (ESI) calculated mass 475.56Quality measurement of 475.9[ M + H ]]⁺(retention time: 1.415 min).

Example 76

N- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (5-methylfuran-2-yl) phenyl) cyclopropanesulfonamide

This compound was prepared from the compound of example 73 using the procedure of example 74 and cyclopropanesulfonyl chloride.¹HNMR(300MHz,CD₃OD) 8.5(s,1H),8.0(s,1H),7.95(s,1H),7.9(s,1H),7.6-7.7(m,4H),7.5(s,1H),6.8(d,1H),6.2(s,1H),4.0(s,3H),2.4(s,3H),1.0-1.5(m, 4H). LC-MS (ESI) calculated mass 473.55 and measured mass 474.0[ M + H [)]⁺(retention time: 1.382 minutes).

Example 77

N- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (5-methylfuran-2-yl) phenyl) benzenesulfonamide

The compound was prepared from the compound of example 73 using the procedure of example 74. Yield 0.03g, (25%),¹HNMR(300MHz,CD₃OD) 8.55(s,1H),8.05(s,1H),7.9(m,4H),7.6-7.7(m,5H),7.5(s,2H),7.4(d,1H),7.2(t,1H),6.8(d,1H),6.2(s,1H),4.0(s,3H),2.4(s, 3H). LC-MS (ESI) for calculating mass 509.58 and measured mass 509.9M + H ]⁺(retention time: 1.482 minutes).

Example 78

1- (furan-2-ylmethyl) -3- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (5-methylfuran-2-yl) phenyl) urea

To a solution of the compound from example 74(a) (0.1g,0.271mmol) in DCM (10ml) was added phosgene (0.04g,0.406mmol) and furfuryl amine (0.029g,0.2977mmol) in that order at 0 deg.C. The mixture was heated at 60 ℃ for 2 hours and evaporatedThe residue was then purified by preparative HPLC to give compound in 15% yield (20 mg).¹HNMR(300MHz,CD₃OD) 9.6(s,1H),8.2(s,1H),8.0(s,1H),7.95(s,2H),7.6-7.7(M,5H),7.7(s,1H),7.6(s,1H),6.4(s,1H),6.3(d,1H),6.2(s,1H),4.5(s,2H),4.0(s,3H),2.4(s,3H), LC-MS (ESI) calculated mass 492.53, measured mass 493.1[ M + H ] calculated mass 493.1]⁺(retention time: 1.415 min).

Example 79

1-cyclopentyl-3- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (5-methylfuran-2-yl) phenyl) urea

This compound was prepared from the compound of example 74(a) using the method of example 78.¹HNMR(300MHz,CD₃OD) 8.7(s,1H),8.6(s,1H),8.2(s,1H),8.0(s,1H),7.95(s,1H),7.6-7.7(m,5H),7.5(s,1H),6.9(d,1H),6.3(s,2H),4.0(s,3H),2.4(s,3H),1.4-1.9(m, 8H). LC-MS (ESI) for calculating mass 480.56 and measured mass 481.2M + H ]⁺(retention time: 1.517 minutes).

Example 80

N- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (5-methylfuran-2-yl) phenyl) morpholine-4-carboxamide

This compound was prepared from the compound of example 74(a) using the method of example 78.¹HNMR(300MHz,CD₃OD) 8.5(s,1H),8.0(s,1H),7.95(s,1H),7.9(s,1H),7.8(s,2H),7.6-7.7(m,3H),7.5(s,1H),6.8(d,1H),6.2(s,1H),4.0(s,3H),2.4(s,3H),3.6(t,4H),3.8(t, 4H). LC-MS (ESI) for calculating mass 482.53 and measured mass 483.1M + H]⁺(retention time: 0.814 minutes).

Example 81

N- (3- (5- (1- (2-hydroxyethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (5-methylfuran-2-yl) phenyl) acetamide

This compound was prepared from the compound of example 73(e) using the procedure of example 73.¹HNMR(300MHz,DMSO-d₆) 10.1(s,1H),8.6(s,1H),8.4(s,1H),7.7-8.0(m,4H),7.6(m,3H),7.0(d,1H),6.8(d,1H),6.2(d,1H),4.2(t,2H),3.8(t,2H),2.4(s,3H),2.2(s, 3H). LC-MS (ESI) calculated mass 441.48 and measured mass 442.1[ M + H ]]⁺(retention time: 0.436 min).

Example 82

N- (3- (5- (1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (5-methylfuran-2-yl) phenyl) acetamide

This compound was prepared from the compound of example 73(e) using the procedure of example 73. ¹HNMR(300MHz,CD₃OD) 9.5(s,1H),8.3(s,1H),8.1(m,3H),7.95(m,4H),7.7(m,1H),6.8(d,1H),6.2(s,1H),4.20(m,2H),3.7(m,2H),3.0(s,6H),2.4(s,3H),2.2(s, 3H). LC-MS (ESI) for calculating mass 468.55 and measured mass 469.5M + H]⁺(retention time: 0.179 min).

Example 83

N- (3- (5-methylfuran-2-yl) -5- (5- (1- (2- (morpholin-4-yl) ethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide

This compound was prepared from the compound of example 73(e) using the procedure of example 73.¹HNMR(300MHz,CD₃OD) 9.5(s,1H),8.3(s,1H),8.1(m,3H),7.95(m,3H),7.7(m,1H),6.8(d,1H),6.2(d,1H),4.70(t,2H),4.0(m,3H),3.7(t,2H),3.50(m,3H),2.4(s,4H),2.2(s, 4H). LC-MS (ESI) mass 510, measured mass 511.2M + H]⁺(retention time: 0.277 min).

Example 84

N- (3- (5- (1H-pyrazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (5-methylfuran-2-yl) phenyl) acetamide

To a solution of the compound from example 73(e) (0.1g,0.243mmol) in DMF (5ml) was added pyrazole (0.022g,0.0317mmol,1.3eq.), copper (I) oxide (0.01g,0.1eq.) and cesium carbonate (0.158g,0.0487mmol,2.0eq.) and the mixture was heated at 110 ℃ for 48 hours. The mixture was quenched and extracted as described in example 1 (d). The solvent was evaporated and the residue was purified by preparative HPLC to give the product in 68% yield (0.02 g). ¹HNMR(300MHz,DMSO-d₆) 9.3(s,1H),8.4(s,1H),8.3(s,1H),7.8-8.1(M,4H),7.6-7.7(M,3H),6.80(d,1H),6.6(t,1H),6.2(d,1H),2.4(s,3H),2.2(s,3H), LC-MS (ESI). The calculated mass is 397.43, and the measured mass is 398.3[ M + H (ESI) ]]⁺(retention time: 1.382 minutes).

Example 85

N- (3- (5- (1H-imidazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (5-methylfuran-2-yl) phenyl) acetamide

The compound was prepared from the compound of example 73(e) using the procedure of example 84.¹HNMR(300MHz,DMSO-d₆) 9.5(s,1H),9.0(M,1H),8.2(M,2H),8.0(s,2H),7.8(M,4H),7.6(s,1H),6.80(d,1H),6.2(d,1H),2.4(s,3H),2.2(s,3H), LC-MS (ESI): calculated mass: 397.43; measured mass: 398.3[ M + H ] (ESI) ]]⁺(retention time: 0.179 min).

Example 86

N- (3- (5- (4H-1,2, 4-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (5-methylfuran-2-yl) phenyl) acetamide

The compound was prepared from the compound of example 73(e) using the procedure of example 84.¹HNMR(300MHz,DMSO-d₆):10.4(s,1H),9.3(s,1H),8.8(s,1H),8.4(d,2H),7.8-8.1(m,4H),7.6(s,1H),6.80(d,1H),6.2(d,1H),2.4(s,3H),2.2(s,3H)LC-MS (ESI) calculated mass 398.42, measured mass 399.2[ M + H ]]⁺(retention time: 0.914 min).

Example 87

N- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrrol-1-yl) phenyl) acetamide

a)1- (3, 5-dinitro-phenyl) -1H-pyrrole

A solution of 3, 5-dinitroaniline (10g,54.644mmol) and 2, 5-dimethoxytetrahydrofuran (18.05g,136.61mmol,2.5eq.) in acetic acid (122ml) was heated at 100 ℃ for 16 h. Completion of the reaction was monitored by TLC. The mixture was then allowed to return to room temperature and poured into ice-cold water. The precipitate was filtered, washed with water (150ml) and dried to give the product in 54% yield (8.2 g). LC-MS (ESI) for calculating mass 233.18 and measured mass 233.04M + H ]⁺(retention time: 1.667 minutes).

b) 3-nitro-5-pyrrol-1-yl-phenyl amines

To a solution of 1- (3, 5-dinitro-phenyl) -1H-pyrrole (8.2g,35.19mmol) and pyridine (10ml) in ethanol (100ml) was added a solution of 20% aqueous ammonium sulfide (38.4ml,140.76mmol,4.0eq.) in water (10ml) at 80 ℃. The mixture was stirred at the same temperature for 4 hours. The mixture was quenched with ice water (200ml) and the precipitated solid was filtered. The filtered solid was dried in vacuo to give the product in 98% yield (7.0 g).

c) N- (3-nitro-5-pyrrol-1-yl-phenyl) -acetamide

Acetic anhydride (7.0ml) was added to 3-nitro-5-pyrrol-1-yl-phenyl amine (7.0g,34.48 mmol). The mixture was stirred at room temperature for 30 minutes, and then the reaction was terminated by adding crushed ice. The precipitate formed was filtered and washed with cold water to give an off-white solid. The solid was dried under high vacuum to give the product in 89% yield (7.52 g). LC-MS (ESI) calculated mass 245.23 and measured mass 244.1M-H]⁺(retention time: 0.24 minutes).

d) N- (3-amino-5-pyrrol-1-yl-phenyl) -acetamide

To a solution of N- (3-nitro-5-pyrrol-1-yl-phenyl) acetamide (7.51g,30.61mmol) in ethanol (100ml) was added iron powder (4.273g,76.53mmol,2.5eq.) followed by a solution of calcium chloride (8.49g,76.53mmol,2.5eq.) in water (100 ml). The mixture was stirred at 80 ℃ for 2 hours and then filtered through a pad of celite. The celite pad was washed with ethyl acetate (200ml) and the combined organic layers were washed with water (100ml) and brine (25 ml). The solvent was evaporated and the residue was purified by column chromatography (20% ethyl acetate in hexane) to give the compound in 87% yield (5.7 g). ¹HNMR(300MHz,DMSO-d₆):9.9(s,1H),8.25(s,1H),7.8(d,1H),7.6(s,1H),7.05(d,1H),6.8(s,1H),6.5(m,1H),6.3(m,1H),5.15(s,2H),2.02(s,3H)。

e) N- (3- (4-bromo-2-nitrophenylamino) -5- (1H-pyrrol-1-yl) phenyl) acetamide

To a solution of N- (3-amino-5-pyrrol-1-yl-phenyl) acetamide (5g,23.23mmol) in anhydrous DMF (5ml) was added 4-bromo-1-fluoro-2-nitrobenzene (5.11g,23.23mmol) and potassium fluoride (1.35g,23.23 mmol). The mixture was stirred at 110 ℃ overnight. The mixture was then allowed to return to room temperature and the DMF was removed in vacuo. Flash column chromatography (50% ethyl acetate in hexanes) of the residue afforded the compound in 63% yield (6.1 g).

f) N- (3- (2-amino-4-bromophenylamino) -5- (1H-pyrrol-1-yl) phenyl) acetamide

To a solution of the compound from example 87(e) (6.0g,14.45mmol) in ethanol (50ml) were added iron powder (2.02g,36.12mmol,2.5eq.) and calcium chloride (4.01g,36.12mmol,2.5eq.) and 50ml of water. The mixture was stirred at 80 ℃ for 2 hours and then filtered through a pad of celite. The celite pad was washed with ethyl acetate (100ml) and the combined organic layers were washed with water (50ml) and brine (25 ml). The solvent was evaporated and the residue was purified by column chromatography (20% ethyl acetate in hexane) to give the compound in 86% yield (4.8 g). LC-MS (ESI) for calculating mass 385.26 and actually measured mass 385M + H]⁺(retention time: 1.659 minutes).

g) N- (3- (5-bromo-1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrrol-1-yl) phenyl) acetamide

Formic acid (12ml) was added to the compound (4g,10.38mmol) of example 87(f) at room temperature and the mixture was heated at 100 ℃ for 2 hours. Formic acid was removed under reduced pressure and the residue was purified by flash column chromatography (3% methanol in chloroform) to give the product in 76% yield (3.1 g). LC-MS (ESI) calculated mass 395.25 and measured mass 396.8[ M + H ]]⁺(retention time: 1.55 minutes).

h) N- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrrol-1-yl) phenyl) acetamide

To a solution of the compound from example 87(g) (2.0g,5.06mmol) in 1, 2-methoxyethane (50ml) were added 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (1.58g,7.59mmol,1.5eq.), sodium carbonate (1.34g,12.65mmol,2.5eq.) and water (5.0ml) and the mixture was degassed for 15 minutes (N.sub.0₂Bubbling). Adding Pd (PPh)₃)₄(2.92g,2.53mmol,0.5eq.) and the mixture was heated at 100 ℃ for 2 hours. The mixture was quenched and extracted as described in example 1 (d). The solvent was evaporated and the residue was purified by column chromatography to give the compound in 60% yield (1.2 g).¹H-NMR(300MHz,CD₃OD: 8.53(s,1H),8.0(s,1H),7.9(s,1H),7.82(M,2H),7.79(M,1H),7.7(d,1H),7.6(M,1H),7.48(M,1H),7.29(M,2H),6.31(M,2H),3.95(s,3H),2.15(s,3H), LC-MS (ESI): calculated mass: 396.44, measured mass: 396.8[ M + H (S,1H) ], measured mass: 396.8 ]⁺(retention time: 0.63 minutes).

Example 88

N- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrrol-1-yl) phenyl) methanesulfonamide

a)3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrrol-1-yl) aniline

A mixture of 20% sodium hydroxide (5ml) and the compound from example 87 (1.15g,2.9mmol) in 25ml ethanol was heated at 100 ℃ for 2 h. The mixture was diluted with ethyl acetate (100ml) and the organic layer was washed with water (50ml) and brine (25 ml). The solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography to give the product in 68% yield (0.7 g).

b) N- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrrol-1-yl) phenyl) methanesulfonamide

To a solution of the compound from example 88(a) (70mg,0.198mmol) in DCM (1ml) was added pyridine (0.5ml) and methanesulfonyl chloride (27mg,0.237mmol,1.2eq.) and the mixture was stirred at room temperature for 12 hours. Pyridine was removed under reduced pressure and the crude product was purified by preparative HPLC to give the product in 12% yield (10 mg).¹H-NMR(300MHz,DMSO-d₆) 10.2(s,1H),8.7(s,1H),8.21(s,1H),7.99(d,2H),7.7-7.61(M,3H),7.45(t,2H),7.38(d,2H),6.33(t,2H),3.88(s,3H),3.2(s,3H), LC-MS (ESI) calculated mass 432.5, measured mass 433.1[ M + H ] calculated mass 433.]⁺(retention time: 0.88 min).

Example 89

N- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrrol-1-yl) phenyl) cyclopropanesulfonamide

This compound was prepared from the compound of example 87 using the procedure of example 88 and cyclopropanesulfonyl chloride.¹H-NMR(300MHz,DMSO-d₆) 10.2(s,1H),8.71(s,1H),8.2(s,1H),7.99(M,1H),7.95(s,1H),7.68-7.59(M,3H),7.44-7.41(M,4H),6.31(M,2H),3.95(s,3H),2.95(M,1H),1.0(M,4H), LC-MS (ESI) calculating mass 458.54, measured mass 459.2[ M + H ESI ]]⁺(retention time: 1.29 minutes).

Example 90

N- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrrol-1-yl) phenyl) benzenesulfonamide

The compound was prepared from the compound of example 87 using the procedure of example 88.¹H-NMR(300MHz,CD₃OD) 8.35(s,1H),7.93(s,1H),7.83-7.78(M,4H),7.58-7.55(M,1H),7.51-7.47(M,3H),7.36(t,1H),7.32(d,1H),7.21t,1H),7.14(t,1H),7.12-7.11(M,2H),6.22(t,2H),3.9(s,3H), LC-MS (ESI) calculated mass 494.57, measured mass 495[ M + H ] 495]⁺(retention time: 1.71 minutes).

Example 91

1- (furan-2-ylmethyl) -3- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrrol-1-yl) phenyl) urea

To a solution of the compound from example 88(a) (70mg,0.198mmol) in DCM (1ml) was added TEA (triethylamine) (0.055ml,0.396mmol,2.0eq.) and 2- (isocyanatomethyl) furan (29mg,0.237mmol,1.2eq.) at 0 ℃. The mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give the compound in 40% yield (38 mg). ¹H-NMR(300MHz,CD₃OD) 9.0(s,1H),8.07(s,1H),7.97(s,1H),7.92(s,1H),7.81-7.74(M,3H),7.63(s,1H),7.44(M,2H),7.3(M,2H),6.36-6.31(M,4H),4.41(s,2H),3.96(s,3H), LC-MS (ESI) calculated mass 477.52, measured mass 478.1[ M + H ESI ]]⁺(retention time: 1.393 minutes).

Example 92

1-cyclopentyl-3- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrrol-1-yl) phenyl) urea

The compound was prepared from the compound of example 87 using the procedure of example 91.¹H-NMR(300MHz,CD₃OD) 9.52(s,1H),8.16(s,1H),8.03(s,1H),7.98(s,1H),7.88-7.84(M,3H),7.65(s,1H),7.47(s,1H),7.3(M,2H),6.35(M,2H),4.1(M,1H),3.95(s,3H),2.05(M,2H),1.8-1.6(M,4H),1.51-1.48(M,2H), LC-MS (ESI) calculated mass 465.55, measured mass 466.1[ M + H ] calculated mass 466.1]⁺(retention time: 1.45 minutes).

Example 93

N- (3- (5- (1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrrol-1-yl) phenyl) acetamide

This compound was prepared from the compound of example 87(g) using the procedure of example 87.¹H-NMR(300MHz,CD₃OD) 8.42(s,1H),8.0(s,1H),7.82-7.8(M,2H),7.75(s,1H),7.65(s,1H),7.6(d,1H),7.51(d,1H),7.38(s,1H),7.19(M,2H),6.21(M,2H),4.32(t,2H),3.0(t,2H),2.4(s,6H),2.08(s,3H), LC-MS (ESI): calculated mass 453.23, measured mass 453.9[ M + H (ESI): measured mass 453.9 ]⁺(retention time: 0.112 minutes).

Example 94

N- (3- (5- (1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrrol-1-yl) phenyl) benzenesulfonamide

The compound was prepared from the compound of example 93 using the procedure of example 88.¹H-NMR(300MHz,DMSO-d₆) 10.91(s,1H),8.66(s,1H),8.36(s,1H),8.14(s,1H),7.92(s,1H),7.91-7.89(M,2H),7.7-7.59(M,5H),7.36-7.29(M,4H),7.22(M,1H),6.32(t,2H),4.57(t,2H),3.64(M,2H),2.86(d,6H), LC-MS (ESI): 551.66, 552.2[ M + H ] measured mass]⁺(retention time: 0.54 minutes).

Example 95

N- (3- (5- (6-methoxypyridin-3-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrrol-1-yl) phenyl) acetamide

This compound was prepared using the procedure of example 87.¹H-NMR(300MHz,CD₃OD):9.0(s,1H),8.37(d,1H),7.96(dd,1H),7.92(s,1H),7.89-7.87(m,1H),7.78(d,1H),7.71(t,2H)7.68-7.65(M,1H),7.49(t,1H),7.2(t,2H),6.85(d,1H),6.25(t,2H),3.89(s,3H),2.1(s,3H), LC-MS (ESI) calculating mass: 423.47, measured mass: 424.1[ M + H ] in]⁺(retention time: 1.518 minutes).

Example 96

N- (3- (5- (1H-pyrazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrrol-1-yl) phenyl) acetamide

To a solution of the compound from example 87(g) (2.0g,5.06mmol) in DMF (50ml) were added pyrazole (0.69g,10.12mmol,2.0eq.), copper (I) oxide (0.145g,1.01mmol,0.2eq.) and cesium carbonate (3.3g,10.12mmol,2.0eq.) and the mixture was heated at 110 ℃ for 16 h. The mixture was quenched and extracted as described in example 1 (d). The solvent was evaporated and the residue was purified by column chromatography to give the product in 78% yield (1.5 g). ¹H-NMR(300MHz,DMSO-d₆) 10.2(s,1H),8.79(s,1H),8.61(d,1H),8.24(d,1H),7.94-7.91(M,1H),7.87-7.81(M,3H),7.76(d,1H),7.64-7.63(M,1H),7.43-7.42(M,2H),6.57(t,1H),6.33(M,2H),2.13(s,3H), LC-MS (ESI) calculated mass: 382.42, measured mass: 383.1[ M + H + M,1H ], calculated mass: 383.1]⁺(retention time: 1.376 min).

Example 97

N- (3- (5- (1H-pyrazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrrol-1-yl) phenyl) ethanesulfonamide

a)3- (5- (1H-pyrazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrrol-1-yl) aniline

A mixture of 10% NaOH (5ml) and the compound from example 96 (1.45g,3.79mmol) in 25ml ethanol was heated at 100 ℃ for 2 hours. The mixture was diluted with ethyl acetate (100ml) and the organic layer was washed with water (50ml) and brine (25 ml). The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to give the product in 85% yield (1.1 g).

b) N- (3- (5- (1H-pyrazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrrol-1-yl) phenyl) ethanesulfonamide

To a solution of the compound from example 97(a) (70mg,0.206mmol) in DCM (2ml) was added pyridine (0.033ml,0.411mmol,2.0eq.) and ethanesulfonyl chloride (32mg,0.247mmol,1.2eq.) and the mixture was stirred at room temperature for 12 hours. Pyridine was removed under reduced pressure and the residue was purified by preparative HPLC to give the product in 63% yield (56 mg). ¹H-NMR(300MHz,DMSO-d₆) 10.35(s,1H),8.83(s,1H),8.62(d,1H),8.26(d,1H),7.95(dd,1H),7.82-7.78(M,2H),7.69(s,1H),7.46-7.42(M,4H),6.58(t,1H),6.35(t,2H),3.34-3.32(M,2H),1.28(t,3H), LC-MS (ESI), calculated mass 432.5, measured mass 433.2[ M + H ] M]⁺(retention time: 1.43 minutes).

Example 98

N- (3- (5- (1H-pyrazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrrol-1-yl) phenyl) propane-2-sulfonamide

The compound was prepared from the compound of example 96 using the procedure of example 87.¹H-NMR(300MHz,DMSO-d₆) 10.3(s,1H),8.81(s,1H),8.6(d,1H),8.25(d,1H),7.95-7.92(M,1H),7.79-7.76(M,2H),7.66(M,1H),7.43(M,4H),6.57-6.56(M,1H),6.34-6.33(M,2H),3.53-3.5(M,1H),1.31(d,6H), LC-MS (ESI) and calculated mass 446.52, measured mass 447.2[ M + H ] (M,1H) and calculated mass 446.52]⁺(retention time: 1.5 minutes).

Example 99

N- (3- (5- (1-methyl-1H-1, 2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrrol-1-yl) phenyl) acetamide

a) N- (3- (4-iodo-2-nitrophenylamino) -5- (1H-pyrrol-1-yl) phenyl) acetamide

A solution of N- (3-amino-5-pyrrol-1-yl-phenyl) acetamide (5.0g,18.72mmol), 1-fluoro-4-iodo-2-nitrobenzene (4.02g,18.72mmol,1.0eq.) and potassium fluoride (1.08g,18.72mmol,1.0eq.) in DMF (30ml) from example 87(d) was heated at 130 ℃ for 5 hours. The mixture was quenched and extracted as described in example 1 (d). The solvent was evaporated and the residue was purified by column chromatography (60-120 silica gel, 50% ethyl acetate in hexane) to give the product in 49% yield (4.3 g).

b) N- (3- ((2-amino-4-iodophenyl) amino) -5- (1H-pyrrol-1-yl) phenyl) acetamide

To a solution of the compound from example 99(a) (0.5g,1.08mmol) in THF (30ml) was added a solution of ammonium chloride (0.289g,5.41mmol,5eq.) in water (5ml) and zinc (0.354g,5.41mmol,5 eq.). The mixture was stirred at room temperature for 0.5 hour and filtered. The filtrate was diluted with water and extracted as described in example 1 (d). Evaporation of the solvent gave the product in 75% yield (0.35 g).¹HNMR(300MHz,DMSO-d₆):9.88(s,1H),7.38(s,1H),7.19(s,1H),7.09-7.06(m,3H),6.84-6.8(m,3H),6.51(m,1H),6.22(t,2H),5.04(brs,2H),2.0(s,3H)。

c) N- (3- (5-iodo-1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrrol-1-yl) phenyl) acetamide

A mixture of the compound from example 99(b) (0.35g,0.81mmol) and formic acid (10ml) was heated at 100 ℃ for 30 minutes. The formic acid was evaporated under reduced pressure and the residue 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 product in 84% yield (0.3 g).¹HNMR,300MHz:(DMSO-d₆):10.4(s,1H),8.7(s,1H),8.18(s,1H),7.82(s,2H),7.67-7.54(m,3H),7.4(s,2H),6.32(m,2H),2.05(s,3H)。

d) N- (3- (1H-pyrrol-1-yl) -5- (5- ((trimethylsilyl) ethynyl) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide

The compound from example 99(c) (3.0g,7.4mmol) in DMF-Et₃The N (1:1;60ml) solution was passed through N₂Bubbling and degassing for 15 minutes. Sequentially adding Pd (PPh)₃)₄(1.2g,11.9mmol,0.1eq.), copper (I) iodide (0.2g,11.9mmol,0.1eq.) and ethynyltrimethylsilane (2.2ml,49.2mmol,2eq.) and the mixture was stirred at room temperature for 12 hours. Mixing the mixture according to The reaction was terminated and extracted as described in example 1 (d). The solvent was evaporated and the residue was purified by column chromatography (60-120 silica gel, 60% ethyl acetate in hexane) to give the product in 71% yield (2.0 g).¹HNMR,300MHz:(DMSO-d₆) 10.4(s,1H),8.85(s,1H),7.9-7.8(M,2H),7.75-7.5(M,6H),7.45(t,2H),2.05(s,3H),0.2(s,9H), LC-MS (ESI), calculated mass 412.56, measured mass 413[ M + H ] 412.56]⁺(retention time: 1.55 minutes).

e) N- (3- (5-ethynyl-1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrrol-1-yl) phenyl) acetamide

To a solution of the compound from example 99(d) (2.0g,4.85mmol) in THF was added TBAF (1M in THF; 2.0ml,9.7mmol,2eq.) at 0 deg.C and the mixture was stirred for 0.5 h. The mixture was filtered through a pad of silica and distilled to give the product in 96% yield (1.6 g). LC-MS (ESI) for calculating mass 340.38 and measured mass 341.1M + H]⁺(retention time: 1.518 minutes).

f) N- (3- (5- (1-methyl-1H-1, 2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrrol-1-yl) phenyl) acetamide

A mixture of the compound from example 99(e) (1.0g,29.4mmol), sodium azide (0.19g,29.4mmol,1.0eq.), methyl iodide (0.4g,29.4mmol,1.0eq.), sodium ascorbate (0.6g,29.4mmol,1.0eq.), and copper sulfate pentahydrate (0.36g,14.7mmol,0.5eq.) in DMSO, DCM and water (1:1:1,15:12:12ml) was stirred at room temperature for 12 hours. The mixture was quenched with water and the precipitate formed was filtered and dried to give the crude product, which was purified by preparative HPLC to give the product in 15% yield (0.02 g). LC-MS (ESI) calculated mass 397.43 and measured mass 398.1[ M + H ] ]⁺(retention time: 0.453 minutes).

Example 100

N- (3- (5- (1-methyl-1H-1, 2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrrol-1-yl) phenyl) methanesulfonamide

a)3- (5- (1-methyl-1H-1, 2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrrol-1-yl) aniline

A mixture of 20% sodium hydroxide (5ml) and the compound from example 99 (1.0g,2.52mmol) in 10ml ethanol was heated at 100 ℃ for 3 hours. The mixture was diluted with ethyl acetate (100ml) and the organic layer was washed with water (50ml) and brine (25 ml). The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to give the product in 73% yield (0.65 g). LC-MS (ESI) mass calculated 355.4 and measured 356.3M + H]⁺(retention time: 0.49 minutes).

b) N- (3- (5- (1-methyl-1H-1, 2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrrol-1-yl) phenyl) methanesulfonamide

To a solution of the compound from example 100(a) (100mg,0.281mmol) in DCM (5ml) was added pyridine (45mg,0.563mmol,2.0eq.) and methanesulfonyl chloride (26mg,0.225mmol,0.8eq.) and the mixture was stirred at room temperature for 12 h. Pyridine was removed under reduced pressure and the residue was purified by preparative HPLC to give the product in 7% yield (8 mg).¹HNMR,300MHz:(DMSO-d₆) 10.33(s,1H),9.01(s,1H),8.64(s,1H),8.27(s,1H),7.97-7.94(M,1H),7.83(d,1H),7.71(s,1H),7.46-7.42(M,4H),6.35-6.34(M,2H),4.12(s,3H),3.21(s,3H), LC-MS (ESI) calculating mass 433.49, measured mass 434.3[ M + H ] 434.3 ]⁺(retention time: 0.67 minutes).

Example 101

N- (3- (5- (1-methyl-1H-1, 2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrrol-1-yl) phenyl) ethanesulfonamide

This compound was prepared from the compound of example 99 using the procedure of example 100.¹HNMR,300MHz:(DMSO-d₆) 10.37(s,1H),8.97(s,1H),8.63(s,1H),8.26(s,1H),7.95-7.93(M,1H),7.8(d,1H),7.67(M,1H),7.45-7.42(M,4H),6.34(t,2H),4.2(s,3H),2.4(M,2H),1.2(d,3H), LC-MS (ESI), calculated mass 447.51, measured mass 449.1[ M + H + M,1H ], calculated mass]⁺(retention time: 0.97 min).

Example 102

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

This compound was prepared from the compound of example 99 using the procedure of example 100 and cyclopropanesulfonyl chloride.¹HNMR,300MHz:(DMSO-d₆) 10.3(s,1H),8.8(s,1H),8.61(s,1H),8.25(s,1H),7.91(d,1H),7.78(d,1H),7.69(s,1H),7.46-7.43(M,4H),6.34(t,2H),4.12(s,3H),2.94(M,1H),1.04-1.02(M,4H), LC-MS (ESI): calculated mass 459.52, measured mass 460.1[ M + H ] (ESI)]⁺(retention time: 1.22 minutes).

Example 103

N- (3- (5- (1-methyl-1H-1, 2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrrol-1-yl) phenyl) benzenesulfonamide

This compound was prepared from the compound of example 99 using the procedure of example 100. ¹HNMR,300MHz:(DMSO-d₆) 10.91(s,1H),8.69(s,1H),8.61(s,1H),8.21(s,1H),7.92-7.89(M,3H),7.67-7.62(M,4H),7.37-7.32(M,4H),7.20(s,1H),6.32(d,2H),4.11(s,3H), LC-MS (ESI) calculating mass 495.56, measured mass 496.1[ M + H ] for]⁺(retention time: 1.42 minutes).

Example 104

1- (furan-2-ylmethyl) -3- (3- (5- (1-methyl-1H-1, 2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrrol-1-yl) phenyl) urea

To a solution of the compound from example 100(a) (100mg,0.281mmol) in DCM (10ml) was added 2- (isocyanatomethyl) furan (35mg,0.281mmol,1.0eq.) at 0 ℃ and the mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give the compound in 13% yieldThe rate (18 mg).¹HNMR,300MHz:(DMSO-d₆) 9.05(s,1H),8.8(s,1H),8.6(s,1H),8.24(s,1H),7.92-7.9(M,1H),7.81(d,1H),7.72-7.60(M,4H),7.48-7.41(M,3H),6.89(t,1H),6.41(M,1H),6.32-6.28(M,2H),4.33(d,2H),4.12(s,3H), LC-MS (ESI) and 479.2[ M + H ] to calculate the mass 478.51 and the measured mass 479.2[ M + H ] (s,3H) ]]⁺(retention time: 1.39 minutes).

Example 105

N- (3- (5- (1- (2- (morpholin-4-yl) ethyl) -1H-1,2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrrol-1-yl) phenyl) acetamide

A mixture of the compound from example 99(e) (100mg,0.294mmol), 4- (2-azidoethyl) morpholine (55mg,0.353mmol,1.2eq.), sodium ascorbate (58mg,0.294mmol,1.0eq.), and copper sulfate pentahydrate (37mg,0.147mmol,0.5eq.) in DMSO, DCM and water (1:1:1,3ml) was stirred at room temperature for 12 hours. The mixture was quenched with water and the precipitate formed was filtered and dried to give the crude product, which was purified by preparative HPLC to give the product in 7% yield (10 mg). ¹HNMR,300MHz:(DMSO-d₆) 10.46(s,1H),8.83(s,1H),8.73(s,1H),8.28(s,1H),7.92(M,2H),7.84-7.81(M,2H),7.63(s,1H),7.43-7.42(M,2H),6.34(M,2H),4.82(t,2H),4.01(M,4H),3.7(M,2H),2.51-2.43(M,4H),2.05(s,3H), LC-MS (ESI): calculated mass 496.56, measured mass 497[ M + H ] calculated mass]⁺(retention time: 0.08 minutes).

Example 106

N-(3-(5-(Oxazol-5-yl) -1H-benzo [ d]Imidazol-1-yl) -5- (1H-pyrrol-1-yl) phenyl) acetamide

a) N- (3- (4-formyl-2-nitrophenylamino) -5- (1H-pyrrol-1-yl) phenyl) acetamide

The compound of example 87(d) ((d))A solution of 5.5g,25.7mmol), 4-fluoro-3-nitrobenzaldehyde of intermediate example 4 (3.86g,25.7mmol,1.0eq.) and potassium fluoride (1.49g,25.7mmol,1.0eq.) in DMF (5ml) was heated at 130 ℃ for 4 h. The mixture was quenched and extracted as described in example 1 (d). The solvent was evaporated and the residue was purified by column chromatography (60-120 silica gel, 40% ethyl acetate in hexane) to give the product in 38% yield (3.58 g).¹HNMR(300MHz,DMSO-d₆):10.05(s,1H),9.86(s,1H),8.71(s,1H),7.95(d,1H),7.67(m,2H),7.50(s,1H),7.32-7.29(m,5H),6.29(s,1H),2.08(s,3H)。

b) N- (3- (2-nitro-4-)(Azol-5-yl) phenylamino) -5- (1H-pyrrol-1-yl) phenyl) acetamide

To a solution of the compound from example 106(a) (2.5g,6.88mmol) in methanol (15ml) was added potassium carbonate (1.04g,7.57mmol,1,1eq.) and the mixture was stirred at room temperature for 10 min. Tosylmethylisonitrile (1.48g,7.57mmol,1.1eq.) was added and the mixture was refluxed for 4 hours. The solvent was distilled off and water was added to the crude product. The mixture was extracted as described in example 1 (d). The solvent was evaporated and the residue was purified by column chromatography (60-120 silica gel, 70% ethyl acetate in hexane) to give the product in 57% yield (1.58 g). ¹HNMR(300MHz,DMSO-d₆):10.05(d,1H),10.32(d,1H),9.87(s,1H),7.81(s,1H),7.98-7.92(m,1H),7.85-7.60(m,3H),7.55(s,1H),7.32-7.29(m,4H),7.29(s,1H),2.08(s,3H)。

c) N- (3- (2-amino-4-) (Azol-5-yl) phenylamino) -5- (1H-pyrrol-1-yl) phenyl) acetamide

To a solution of the compound from example 106(b) (1.58g,3.9mmol) in methanol (30ml) and ethyl acetate (15ml) was added 10% Pd/C (300mg,0.2eq.) and the reaction vessel purged with nitrogen for 5 minutes. Then the mixture is taken up with H₂Hydrogenation in balloon for 12 hours. Will be mixed withThe mixture was filtered through a pad of celite and the filtrate was concentrated to give the compound in 68% yield (1.0 g).

d)N-(3-(5-(Oxazol-5-yl) -1H-benzo [ d]Imidazol-1-yl) -5- (1H-pyrrol-1-yl) phenyl) acetamide

A mixture of the compound from example 106(c) (0.4g,1.07mmol) and formic acid (4ml) was heated at 100 ℃ for 30 minutes. The formic acid was evaporated off and the residue was dissolved in ethyl acetate. The ethyl acetate layer was washed with water, brine and dried over sodium sulfate. The solvent was evaporated and the residue was purified by preparative HPLC to give the product in 12% yield (50 mg).¹HNMR(300MHz,DMSO-d₆) 10.43(s,1H),8.84(s,1H),8.47(s,1H),8.17(s,1H),7.87-7.77(M,5H),7.63(s,1H),7.42(t,2H),6.34(t,2H),2.13(s,3H), LC-MS (ESI): mass 383.40 is calculated and 384.1[ M + H ] is measured]⁺(retention time: 1.108 minutes).

Example 107

N-(3-(5-(Oxazol-5-yl) -1H-benzo [ d]Imidazol-1-yl) -5- (1H-pyrrol-1-yl) phenyl) propane-2-sulfonamide

a)3-(5-(Oxazol-5-yl) -1H-benzo [ d]Imidazol-1-yl) -5- (1H-pyrrol-1-yl) anilines

To a solution of the compound from example 106 (800mg,2.1mmol) in ethanol (15ml) was added aqueous sodium hydroxide (0.72g,18.06mmol,8.6eq.) and the mixture was heated at 85 ℃ for 5 hours. The mixture was quenched and extracted as described in example 1 (d). Evaporation of the solvent gave the product in 70% yield (0.5 g).

b)N-(3-(5-(Oxazol-5-yl) -1H-benzo [ d]Imidazol-1-yl) -5- (1H-pyrrol-1-yl) phenyl) propane-2-sulfonamide

To a solution of the compound from example 107(a) (80mg,0.23mmol) in DCM (2ml) was added pyridine (37mg,0.47mmol,2.0eq.) followed by propane-2-sulfonyl chloride (39mg,0.28mmol,1.2 eq.). The mixture was stirred for 1 hour, the reaction was terminated and extracted as described in example 2 (b). The solvent was evaporated and the residue was purified by preparative HPLC to give the product in 14% yield (14 mg).¹HNMR(300MHz,DMSO-d₆) 10.29(s,1H),8.80(s,1H),8.46(s,1H),8.17(s,1H),7.82-7.86(M,3H),7.68(s,1H),7.46-7.40(M,4H),6.34(t,2H),3.30(M,1H),2.51-2.50(M,6H), LC-MS (ESI) calculating mass 447.51, measured mass 448.1[ M + H ], (M + H) calculating mass]⁺(retention time: 2.001 minutes).

Example 108

N-(3-(5-(Oxazol-5-yl) -1H-benzo [ d]Imidazol-1-yl) -5- (1H-pyrrol-1-yl) phenyl) cyclopropanesulfonamide

This compound was prepared from the compound of example 106 using the procedure of example 107 and cyclopropanesulfonyl chloride.¹HNMR(300MHz,DMSO-d₆) 10.35(s,1H),8.87(s,1H),8.52(s,1H),8.22(s,1H),7.82(d,3H),7.74-7.35(M,1H),7.5-7.45(M,4H),6.39(t,2H),3.04-2.95(M,1H),1.08-1.07(M,4H), LC-MS (ESI) calculating mass: 445.49, actual mass: 446.1[ M + H ESI ]]⁺(retention time: 1.43 minutes).

Example 109

N- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrrol-1-yl) phenyl) ethanesulfonamide

The compound was prepared from the compound of example 87 using the procedure of example 88.¹HNMR(300MHz,DMSO-d₆) 10.3(s,1H),8.67(s,1H),8.2(s,1H),8.0(s,1H),7.95(s,1H),7.67-7.61(M,3H),7.43-7.39(M,4H),6.38(s,2H),3.88(s,3H),3.32 (quartet, 2H),1.27(t,3H), LC-MS (ESI): calculated mass 446.52, measured mass 447.1[ M + H ], (ESI)]⁺(retention time: 1.25 minutes).

Example 110

N- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrrol-1-yl) phenyl) propane-2-sulfonamide

The compound was prepared from the compound of example 87 using the procedure of example 88.¹HNMR(400MHz,DMSO-d₆) 10.34(s,1H),8.89(s,1H),8.23(s,1H),8.01(s,1H),7.97(s,1H),7.69-7.65(M,3H),7.44-7.41(M,4H),7.64(d,2H),3.89(s,3H),3.51-3.50(M,1H),1.31(d,6H), LC-MS (ESI) calculating mass 460.55, measured mass 461.1[ M + H ] measured mass 461.1 ]⁺(retention time: 1.377 minutes).

Example 111

N- (3- (5- (1-cyclopentyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrrol-1-yl) phenyl) acetamide

This compound was prepared using the procedure of example 87.¹HNMR(300MHzDMSO-d₆) 10.45(s,1H),8.96(s,1H),8.34(s,1H),8.04(s,1H),7.98(s,1H),7.91(s,1H),7.83(s,1H),7.72-7.68(M,2H),7.64(s,1H),7.42(t,2H),6.34(t,2H),4.68-4.57(M,1H),2.14(s,3H),2.08-1.93(M,4H),1.87-1.73(M,2H),1.72-1.60(M,2H), LC-MS (ESI), calculated mass 450.53, measured mass 451.2[ M + H ]]⁺(retention time: 1.509 minutes).

Example 112

N- (3- (5- (1- (3-hydroxy-3-methylbutyl) -1H-1,2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrrol-1-yl) phenyl) acetamide

A mixture of the compound from example 99(e) (0.3g,0.88mmol), 4-azido-2-methylbutan-2-ol from intermediate example 6 (0.17g,1.06mmol,1.2eq.), sodium ascorbate (L) (0.17g,0.88mmol,1.0eq.) and copper sulfate pentahydrate (0.11g,0.44mmol,0.5eq.) in DCM (2ml), DMSO (2ml) and water (2ml) was stirred at room temperature for 12 hours. The mixture was quenched with water and the precipitate was filtered and dried. The crude product was purified by preparative HPLC to give the product in 48% yield (0.2 g). ¹HNMR(300MHz,DMSO-d₆) 10.42(s,1H),8.86(s,1H),8.68(s,1H),8.23(s,1H),7.93-7.77(M,4H),7.62(s,1H),7.40(t,2H),6.31(t,2H),4.70(t,2H),3.40(brs,1H),2.48(t,2H),2.11(s,3H),1.16(s,6H), LC-MS (ESI), calculated mass 469.54, measured mass 470.2[ M + H ]]⁺(retention time: 0.666 minutes).

Example 113

N- (3- (5- (1- (3-hydroxy-3-methylbutyl) -1H-1,2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrrol-1-yl) phenyl) ethanesulfonamide

a)4- (4- (1- (3-amino-5- (1H-pyrrol-1-yl) phenyl) -1H-benzo [ d ] imidazol-5-yl) -1H-1,2, 3-triazol-1-yl) -2-methylbutan-2-ol

To a solution of the compound from example 112 (150mg,0.32mmol) in ethanol (10ml) was added aqueous sodium hydroxide (160mg,4mmol,12.5eq.) and the mixture was heated at 80 ℃ for 2 hours. The mixture was quenched and extracted as described in example 1 (d). Evaporation of the solvent gave the product in 58% yield (80 mg).

b) N- (3- (5- (1- (3-hydroxy-3-methylbutyl) -1H-1,2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrrol-1-yl) phenyl) ethanesulfonamide

To a solution of the compound from example 113(a) (100mg,0.234mmol) in DCM (5ml) was added pyridine (b)36mg,0.47mmol,2eq.), followed by ethanesulfonyl chloride (23mg,0.187mmol,0.8 eq.). The mixture was stirred for 2 hours, the reaction was terminated and extracted as described in example 2 (b). The solvent was evaporated and the residue was purified by preparative HPLC to give the product in 10% yield (12 mg). ¹HNMR(300MHz,DMSO-d₆) 10.35(s,1H),8.88(s,1H),8.70(s,1H),8.25(s,1H),7.93(dd,1H),7.78(d,1H),7.68(M,1H),7.45-7.41(M,4H),6.34(t,2H),4.52-4.46(M,2H)3.37-3.30(M,5H),1.27(t,3H),1.18(s,6H), LC-MS (ESI): 519.62, 520.2[ M + H ] measured mass]⁺(retention time: 1.17 minutes).

Example 114

N- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrazol-1-yl) phenyl) acetamide

a) N- (3-nitro-5- (1H-pyrazol-1-yl) phenyl) acetamide

To a solution of N- (3-bromo-5-nitrophenyl) acetamide (10g,38.6mmol) from example 1(c) in DMF (100ml) was added pyrazole (5.26g,77.2mmol,2.0eq.), copper (I) oxide (1.104g,7.72mmol,0.2eq.) and cesium carbonate (25.15g,77.2mmol,2.0eq.) and the mixture was heated at 120 ℃ for 16 h. The mixture was quenched and extracted as described in example 1 (d). The solvent was distilled off and the residue was purified by silica gel column chromatography (30% ethyl acetate in hexane) to give the compound in 86% yield (8.2 g).¹HNMR(300MHz,DMSO-d₆) 10.62(s,1H),8.7(d,1H),8.5-8.48(M,2H),8.32(t,1H),7.84(d,1H),6.62(t,1H),2.08(s,3H), LC-MS (ESI) calculating mass: 246.22, measured mass: 247.1[ M + H [ ]]⁺(retention time: 0.6 minutes).

b) N- (3-amino-5- (1H-pyrazol-1-yl) phenyl) acetamide

To a solution of the compound from example 114(a) (8.2g,33.3mmol) in ethanol (70ml) were added iron powder (3.72g,66.6mmol,2.0eq.) and 50% aqueous calcium chloride (15 ml). The mixture was stirred at 100 ℃ for 4 hours. The mixture was terminated as described in example 1(d)Reacted and extracted. The solvent was distilled off and the residue was purified by silica gel column chromatography to give the compound in 99% yield (7.1 g). LC-MS (ESI) for calculating mass 216.24 and actual measurement 217M + H]⁺(retention time: 0.12 minutes).

c) N- (3- ((4-bromo-2-nitrophenyl) amino) -5- (1H-pyrazol-1-yl) phenyl) acetamide

A solution of the compound from example 114(b) (6.97g,32.23mmol), 4-bromo-1-fluoro-2-nitrobenzene (7.09g,32.23mmol,1.0eq.) and potassium fluoride (1.87g,32.23mmol,1.0eq.) in DMF was heated at 150 ℃ for 4 hours. The mixture was quenched and extracted as described in example 2 (b). The solvent was distilled off to give a crude residue, which was purified by silica gel column chromatography to give the compound in 75% yield (10 g). LC-MS (ESI) calculated mass 416.23 and measured mass 417M + H]⁺(retention time: 1.65 minutes).

d) N- (3- ((2-amino-4-bromophenyl) amino) -5- (1H-pyrazol-1-yl) phenyl) acetamide

To a solution of the compound (10g,24.03mmol) obtained in example 114(c) in ethanol (70ml) were added iron powder (2.68g,48.05mmol,2.0eq.) and 50% aqueous calcium chloride (20 ml). The mixture was stirred at 100 ℃ for 4 hours. The mixture was quenched and extracted as described in example 1 (d). The solvent was distilled off and the residue was used in the next step without purification.

e) N- (3- (5-bromo-1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrazol-1-yl) phenyl) acetamide

A mixture of the compound from example 114(d) (crude product from the previous step) and formic acid (20ml) was heated at 100 ℃ for 30 minutes. 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 product in 84% yield (8.0 g).¹HNMR(300MHz,DMSO-d₆) 8.72(s,1H),8.57(d,1H),8.22(M,1H),8.11(s,1H),8.01(d,1H),7.87-7.79(M,3H),7.66(d,1H),7.51(dd,1H),6.58(t,1H),2.1(s,3H), LC-MS (ESI) calculating mass 396.24, measured mass 397[ M + H ] calculated mass]⁺(retention time: 1.38 minutes).

f) N- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrazol-1-yl) phenyl) acetamide

A solution of the compound from example 114(e) (8.0g,20.19mmol) in 1, 2-dimethoxyethane (100ml) was passed through N₂Bubbling and degassing for 5 minutes. 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (6.3g,30.29mmol,1.5eq.) was added and the mixture was degassed for an additional 5 minutes. Adding Pd (PPh)₃)₄(4.67g,4.04mmol,0.2eq.) and aqueous sodium carbonate (5.35g,50.5mmol,2.5eq.), followed by the procedure of example 1 (d). The crude residue of the product was purified by silica gel column chromatography to give the compound in 62% yield (5.0 g). ¹HNMR(300MHz,CD₃OD is 9.21(s,1H),8.35(d,1H),8.13-8.08(M,3H),8.0(s,1H),7.94(s,1H),7.88-7.76(M,4H),6.73-6.69(M,1H),3.98(s,3H),2.23(s,3H), LC-MS (ESI), calculated mass is 397.43, measured mass is 398.1[ M + H (ESI) ], calculated mass is 397.43, and measured mass is 398.1]⁺(retention time: 0.26 min).

Example 115

N- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrazol-1-yl) phenyl) methanesulfonamide

a)3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrazol-1-yl) aniline

To a solution of the compound (4.0g,10.06mmol) prepared in example 114 in ethanol (25ml) was added 20% aqueous sodium hydroxide (5ml), and the reaction mixture was heated at 100 ℃ for 2 hours. The mixture was quenched and extracted as described in example 1 (d). Evaporation of the solvent gave the product in 78% yield (2.8 g).

b) N- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrazol-1-yl) phenyl) methanesulfonamide

To a solution of the compound from example 115(a) (50mg,0.14mmol) in DCM was added pyridine (22mg,0.28mmol,2.0eq.) followed by methanesulfonyl chloride (19mg,0.169mmol,1.2 mmol)eq.). The mixture was stirred for 1 hour, the reaction was terminated and extracted as described in example 2 (b). The solvent was evaporated and the residue was purified by preparative HPLC to give the product in 20% yield (12 mg). ¹HNMR(300MHz,CD₃OD) 8.68(s,1H),8.35(d,1H),8.02(s,1H),7.92(s,1H),7.87(s,1H),7.84-7.81(M,1H),7.77-7.73(M,2H),7.71(s,1H),7.67-7.63(M,1H),7.5-7.48(M,1H),6.58-6.55(M,1H),3.93(s,3H),3.12(s,3H), LC-MS (ESI): calculated mass 433.49, actual measured mass 434.1[ M + H ESI]⁺(retention time: 0.35 minutes).

Example 116

N- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d)]Imidazol-1-yl) -5- (1H-pyrazol-1-yl) phenyl) propane_-2_-Sulfonamides

The compound was prepared from the compound of example 114 using the procedure of example 115.¹HNMR(300MHz,CD₃OD) 8.65(s,1H),8.37(d,1H),8.05(s,1H),7.96(s,1H),7.91(s,1H),7.81(M,3H),7.76-7.74(M,1H),7.69-7.67(M,1H),7.55-7.54(M,1H),6.61-6.6(M,1H),3.95(s,3H),3.54-3.49(M,1H),1.43(d,6H), LC-MS (ESI) calculated mass 461.54, measured mass 462.1[ M + H ESI ]]⁺(retention time: 0.7 minutes).

Example 117

N- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrazol-1-yl) phenyl) cyclopropanesulfonamide

This compound was prepared from the compound of example 114 using the procedure of example 115 and cyclopropanesulfonyl chloride.¹HNMR(300MHz,CD₃OD: 8.54(s,1H),8.37(d,1H),8.02(s,1H),7.93(d,1H),7.88(s,1H),7.82-7.8(M,3H),7.72(d,1H),7.65-7.62(M,1H),7.53-7.52(M,1H),6.6-6.59(M,1H),3.95(s,3H),2.81-2.78(M,1H),1.18-1.15(M,2H),1.09-1.04(M,2H), LC-MS (ESI): 459.52; 460.1[ M + H ], (M, 2H): calculated mass: 459.52; measured mass: 460.1 ]⁺(retention time: 0.58 minutes).

Example 118

N- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrazol-1-yl) phenyl) benzenesulfonamide

The compound was prepared from the compound of example 114 using the procedure of example 115.¹HNMR(300MHz,CD₃OD is 9.2(s,1H),8.29(d,1H),8.12(s,1H),8.0(s,1H),7.96-7.93(M,3H),7.83-7.75(M,4H),7.69-7.65(M,1H),7.61-7.54(M,3H),7.45(t,1H),6.58(M,1H),3.98(s,3H), LC-MS (ESI), calculated mass is 495.56, measured mass is 496.2[ M + H ], (M + H) ], calculated mass is 3.98]⁺(retention time: 1.28 minutes).

Example 119

N- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrazol-1-yl) phenyl) piperidine-1-sulfonamide

The compound was prepared from the compound of example 114 using the procedure of example 115.¹HNMR(300MHz,CD₃OD) 8.92(s,1H),8.3(d,1H),8.06(s,1H),8.0(s,1H),7.95(s,1H),7.88(s,1H),7.77-7.69(M,5H),7.45(M,1H),6.56(M,1H),3.92(s,3H),3.28-3.27(M,4H),1.6-1.49(M,6H), LC-MS (ESI) calculated mass 502.59, measured mass 503.1[ M + H ] ESI]⁺(retention time: 0.1.33 minutes).

Example 120

1- (furan-2-ylmethyl) -3- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrazol-1-yl) phenyl) urea

To a solution of the compound from example 115(a) (50mg,0.141mmol) in DCM (1ml) was added TEA (29mg,0.281mmol,2.0eq.) and 2- (isocyanatomethyl) furan (21mg,0.169mmol,1.2eq.) at 0 ℃ and the mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to yield Compound, 15% yield (10 mg).¹HNMR(300MHz,CD₃OD) 9.16(s,1H),8.35(d,1H),8.1(s,1H),8.0(s,1H),7.95-7.94(M,2H),7.91(M,1H),7.87(d,1H),7.8-7.78(M,2H),7.75-7.74(M,1H),7.46(d,1H),6.6-6.59(M,1H),6.38-6.37(M,1H),6.31-6.3(M,1H),4.43(s,2H),3.98(s,3H), LC-MS (ESI) calculated mass 478.51, measured mass 479.0[ M + H (M,1H) ], measured mass 479.0]⁺(retention time: 0.72 minutes).

Example 121

1- (4-fluorophenyl) -3- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrazol-1-yl) phenyl) urea

This compound was prepared using the procedure of example 120.¹HNMR(300MHz,CD₃OD: 9.7(s,1H),9.3(s,1H),8.67(s,1H),8.62(d,1H),8.21(s,1H),8.06(s,1H),8.0(s,1H),7.95(s,1H),7.83-7.81(M,2H),7.75-7.71(M,2H),7.63-7.6(M,1H),7.52-7.49(M,2H),7.15(t,2H),6.61-6.6(M,1H),3.88(s,3H), LC-MS (ESI): calculated mass: 492.51; measured mass: 493.2[ M + H]⁺(retention time: 1.37 minutes).

Example 122

N- (3- (5- (1H-pyrazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrazol-1-yl) phenyl) acetamide

To a solution of the compound (200mg,0.505mmol) obtained in example 114(e) in DMF (20ml) were added pyrazole (41mg,0.606mmol,1.2eq.), copper (I) oxide (0.7mg,0.0051mmol,0.01eq.) and cesium carbonate (329mg,1.01mmol,2.0eq.) and the mixture was heated at 110 ℃ for 12 hours. The mixture was quenched and extracted as described in example 1 (d). The solvent was evaporated and the residue was purified by preparative HPLC to give the product in 20% yield (37 mg). ¹HNMR(300MHz,CD₃OD is 8.9(brs,1H),8.37-8.33(M,2H),8.19(s,1H),8.13-8.12(M,1H),8.06-8.05(M,1H),7.92(M,2H),7.86-7.85(M,1H),7.8-7.78(M,2H),6.61-6.57(M,2H),2.22(s,3H), LC-MS (ESI), calculated mass is 383.41, measured mass is 384.3[ M + H ] (M, ESI)]⁺(retention time: 0.52 minutes).

Example 123

1- (3- (5- (1H-pyrazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrazol-1-yl) phenyl) -3- (furan-2-ylmethyl) urea

a)3- (5- (1H-pyrazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrazol-1-yl) aniline

To a solution of the compound from example 122 (230mg,0.6mmol) in ethanol (20ml) was added aqueous sodium hydroxide (192mg,4.8mmol,8.0eq.) and the mixture was heated at 90 ℃ for 3 hours. The mixture was quenched and extracted as described in example 1 (d). Evaporation of the solvent gave the product in 73% yield (150 mg).

b)1- (3- (5- (1H-pyrazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrazol-1-yl) phenyl) -3- (furan-2-ylmethyl) urea

To a solution of the compound from example 123(a) (50mg,0.146mmol) in DCM was added TEA (45mg,0.439mmol,3.0eq.) followed by 2- (isocyanatomethyl) furan (23mg,0.19mmol,1.3 eq.). The mixture was stirred for 1 hour, then the reaction was terminated and extracted as described in example 1 (d). The solvent was evaporated and the residue was purified by preparative HPLC to give the product in 8% yield (5 mg). ¹HNMR(300MHz,CD₃OD is 8.92(brs,1H),8.34-8.31(M,2H),8.16(s,1H),7.92-7.89(M,4H),7.77(M,2H),7.71(M,1H),7.44(M,1H),6.57(M,2H),6.36-6.35(M,1H),6.29-6.28(M,1H),4.41(s,2H), LC-MS (ESI), calculated mass is 464.48, measured mass is 465.2[ M + H ], (ESI)]⁺(retention time: 1.35 minutes).

Example 124

1- (3- (5- (1H-pyrazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrazol-1-yl) phenyl) -3-cyclopentylurea

Utilization of this Compound from the Compound of example 122123.¹HNMR(300MHz,CD₃OD is 9.21(brs,1H),8.35-8.33(M,2H),8.22(s,1H),7.98(s,2H),7.93-7.88(M,2H),7.78-7.77(M,2H),7.73-7.72(M,1H),6.59-6.58(M,2H),4.08(M,1H),1.99-1.96(M,2H),1.75-1.71(M,2H),1.68-1.33(M,2H),1.52-1.49(M,2H), LC-MS (ESI): 452.51, 453.3[ M + H ], (M, 2H): measured mass: 453.3]⁺(retention time: 1.42 minutes).

Example 125

N- (3- (5- (1H-imidazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrazol-1-yl) phenyl) acetamide

The compound was prepared from the compound of example 114(e) using the procedure of example 122.¹HNMR(300MHz,CD₃OD) 9.43(s,1H),8.77(s,1H),8.35(d,2H),8.16(M,1H),8.12(s,1H),8.09-8.08(M,1H),8.03-8.02(M,1H),8.0(s,1H),7.98(s,1H),7.83-7.82(M,1H),7.79-7.72(M,3H),6.59-6.58(M,1H),2.21(s,3H), LC-MS (ESI): calculated mass 383.41, measured mass 384.1[ M + H ESI: (ESI): calculated mass 383.41 ]⁺(retention time: 0.12 minutes).

Example 126

N- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrazol-1-yl) phenyl) ethanesulfonamide

The compound was prepared from the compound of example 114 using the procedure of example 115.¹HNMR(400MHz,CD₃OD is 9.13(s,1H),8.36(d,1H),8.10(s,1H),8.02(s,1H),7.94(s,1H),7.88-7.78(M,5H),7.58(s,1H),6.61-6.50(M,1H),3.97(s,3H),3.31 (quartet, 2H)1.40(t,3H), LC-MS (ESI) calculating mass 447.51, measured mass 448.1[ M + H ] measured mass]⁺(retention time: 0.49 minutes).

Example 127

N- (3- (5- (1- (cyclopropylmethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrazol-1-yl) phenyl) acetamide

A solution of the compound from example 114(e) (0.5g,1.26mmol) in 1, 2-dimethoxyethane (10ml) was passed through N₂Bubbling and degassing for 5 minutes. The compound of intermediate example 9 (0.47g,1.89mmol,1.5eq.) was added and the mixture was degassed for an additional 5 minutes. Adding Pd (dppf) Cl₂(0.2g,0.25mmol,0.2eq.) and aqueous sodium carbonate (0.27g,2.52mmol,2eq.) followed by the procedure of example 1 (d). The crude residue of the product was purified by preparative HPLC to give the product in 11% yield (60 mg).¹HNMR(300MHz,DMSO-d₆) 10.52(s,1H),8.82-8.73(M,1H),8.59(d,1H),8.23-8.15(M,3H),8.03-7.92(M,2H),7.83-7.74(M,2H),7.72-7.59(M,2H),6.59(s,1H),4.23(d,2H),2.12(s,3H),1.25-0.78(M,5H), LC-MS (ESI), calculated mass 437.50, measured mass 438.2[ M + H + M, calculated mass: 437.50 [ ] ]⁺(retention time:

0.812 minutes).

Example 128

N- (3- (5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrazol-1-yl) phenyl) acetamide

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

A solution of the compound from example 114(e) (0.6g,1.51mmol) in 1, 2-dimethoxyethane (20ml) was passed through N₂Bubbling and degassing for 5 minutes. The compound of intermediate example 5 (0.85g,2.27mmol,1.5eq.) was added and the mixture was degassed for an additional 5 minutes. Adding Pd (dppf) Cl₂(0.25g,0.302mmol,0.2eq.) and aqueous sodium carbonate (0.5g,4.53mmol,3.0eq.) followed by the procedure of example 1 (d). The crude residue of the product was purified by preparative HPLC to give the product in 35% yield (0.3 g).

b) N- (3- (5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrazol-1-yl) phenyl) acetamide

To a solution of the compound from example 128(a) (300mg,0.53mmol) in DCM (4ml) was added trifluoroacetic acid (0.6ml) at 0 ℃ and the mixture was stirred at room temperature for 6 h. The solvent was evaporated and the residue was purified by preparative HPLC to give the product in 89% yield (220 mg). ¹HNMR(300MHz,DMSO-d₆) 10.50(s,1H),8.84(s,1H),8.73-8.63(M,1H),8.61(d,1H),8.52-8.38(M,1H),8.35(s,1H),8.20(s,1H),8.07(d,1H),8.01(s,1H),7.87-7.83(M,2H),7.73-7.65(M,2H),6.62(t,1H),4.36(M,1H),3.50-3.35(M,2H),3.17-3.10(M,2H),2.32-2.21(M,4H),2.14(s,3H), LC-MS ESI, calculated mass (466.54), measured mass 467.2[ M + H ], (M + H)]⁺(retention time: 0.128 minutes).

Example 129

N- (3- (5- (1- (1- (methylsulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrazol-1-yl) phenyl) acetamide

To a solution of the compound from example 128 (80mg,0.171mmol) in DCM (10ml) was added pyridine (27mg,0.34mmol,2eq.) and methanesulfonyl chloride (19mg,0.171mmol,1 eq.). The mixture was stirred for 4 hours, quenched and extracted as described in example 2 (b). The solvent was evaporated and the residue was purified by preparative HPLC to give the product in 19% yield (18 mg).¹HNMR(300MHz,DMSO-d₆) 10.52(s,1H),10.06(s,1H),8.58(d,1H),8.43(s,1H),8.24(s,1H),8.06-8.00(M,3H),7.89(s,1H),7.83(d,1H),7.78-7.74(M,2H),6.62(t,1H),4.36(M,1H),3.01-2.94(M,6H),2.30(s,3H),2.13(s,3H),2.10-2.01(M,2H), LC-MS (ESI) calculating mass 544.63, measured mass 545.2[ M + H ] (M,3H) ], LC-MS (ESI)]⁺(retention time: 0.40 minutes).

Example 130

N-(3-(5-(Oxazol-5-yl) -1H-benzo [ d]Imidazol-1-yl) -5- (1H-pyrazol-1-yl) phenyl) acetamide

a) N- (3- (4-formyl-2-nitrophenylamino) -5- (1H-pyrazol-1-yl) phenyl) acetamide

A solution of the compound from example 114(b) (0.35g,1.62mmol), 4-fluoro-3-nitrobenzaldehyde (0.24g,1.62mmol,1.0eq.) and potassium fluoride (94mg,1.62mmol,1.0eq.) in DMF (2ml) was heated at 130 ℃ for 4 h. The mixture was quenched and extracted as described in example 1 (d). The solvent was evaporated and the residue was purified by column chromatography (60-120 silica gel, 40% ethyl acetate in hexane) to give the product in 51% yield (0.3 g).¹HNMR(300MHz,DMSO-d₆):10.29(s,1H),10.03(s,1H),9.87(s,1H),8.71(m,1H),8.43(d,1H),8.05(s,1H),7.92(d,1H),7.76(s,1H),7.60(s,1H),7.54(s,1H),7.27(s,1H),6.55(s,1H),2.10(s,3H)。

b) N- (3- (2-nitro-4-) (Azol-4-yl) phenylamino) -5- (1H-pyrazol-1-yl) phenyl) acetamide

To a solution of the compound from example 130(a) (0.3g,0.824mmol) in methanol (8ml) was added potassium carbonate (0.18g,0.904mmol,1.1eq.) and the mixture was stirred at room temperature for 10 min. Tosylmethylisonitrile (0.124g,0.904mmol,1.1eq.) was added and the mixture refluxed for 4 hours. The solvent was distilled off and water was added to the crude product. The mixture was extracted as described in example 1 (d). The solvent was evaporated and the residue was purified by column chromatography (60-120 silica gel, 40% ethyl acetate in hexane) to give the product in 75% yield (0.25 g). ¹HNMR(300MHz,DMSO-d₆):10.23(s,1H),9.57(s,1H),8.46-8.40(m,3H),7.94-7.89(m,2H),7.76-7.72(m,2H),7.57(s,1H),7.49(s,1H),7.42(d,1H),6.55(t,1H),2.01(s,3H)。

c) N- (3- (2-amino-4-) (Azol-4-yl) phenylamino) -5- (1H-pyrazol-1-yl) phenyl) acetamide

To a solution of the compound from example 130(b) (0.25g,0.62mmol) in methanol (15ml) and ethyl acetate (7ml) was added 10% Pd/C (30mg) and the reaction vessel was purged with nitrogen for 5 minutes. Then the mixture is taken up with H₂Hydrogenation of the balloon for 4 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated to give the compound in 86% yield (0.2 g).

d)N-(3-(5-(Oxazol-5-yl) -1H-benzo [ d]Imidazol-1-yl) -5- (1H-pyrazol-1-yl) phenyl) acetamide

A mixture of the compound from example 130(c) (0.2g,0.54mmol) and formic acid (3ml) was heated at 100 ℃ for 30 minutes. The formic acid was evaporated off and the residue was dissolved in ethyl acetate. The ethyl acetate layer was washed with water, brine and dried over sodium sulfate. The solvent was evaporated and the residue was purified by preparative HPLC to give the product in 6% yield (12 mg).¹HNMR(300MHz,DMSO-d₆) 10.47(s,1H),8.80(brs,1H),8.60(d,1H),8.46(s,1H),8.24(s,1H),8.17(s,1H),8.94(s,1H),7.86-7.81(M,3H),7.78-7.76(M,2H),6.60(t,1H)2.12(s,3H), LC-MS (ESI) calculating mass 384.39, measured mass 385.1[ M + H ] measured mass 385.1]⁺(retention time: 0.39 minutes).

Example 131

N- (2',4' -difluoro-5- (6- (1-methyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) biphenyl-3-yl) acetamide

a) N- (5- (5-bromo-3-nitropyridin-2-ylamino) -2',4' -difluorobiphenyl-3-yl) acetamide

A solution of the compound from example 1(e) (1.07g,4.08mmol), 5-bromo-2-chloro-3-nitropyridine (0.97g,4.08mmol,1.0eq.) and potassium fluoride (0.24g,4.08mmol,1.0eq.) in DMF (30ml) was heated at 130 ℃ for 5 hours. The mixture was quenched and extracted as described in example 1 (d). The solvent was distilled off to leave a crude product (1.8 g).

b) N- (5- (3-amino-5-bromopyridin-2-ylamino) -2',4' -difluorobiphenyl-3-yl) acetamide

To a solution of the compound from example 131(a) (1.8g,3.8mmol) in THF (30ml) was added a solution of ammonium chloride (0.83g,15.5mmol,4eq.) in water (15ml) and zinc (1.02g,15.5mmol,10 eq.). The mixture was stirred at room temperature for 3 hours and filtered. The mixture was quenched and extracted as described in example 1 (d). Evaporation of the solvent gave the product in 97% yield (1.6 g).

c) N- (5- (6-bromo-3H-imidazo [4,5-b ] pyridin-3-yl) -2',4' -difluorobiphenyl-3-yl) acetamide

A mixture of the compound from example 131(b) (1.6g,3.7mmol) and formic acid (15ml) was heated at 90 ℃ for 1 hour. The formic acid was then distilled 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 product in 79% yield (1.3 g). ¹HNMR(300MHz,DMSO-d₆):10.43(s,1H),9.0(s,1H),8.55(s,1H),8.24(s,1H),7.89(d,1H),7.75-7.65(m,2H),7.48-7.41(m,2H),7.27-7.26(dt,1H),2.1(s,3H)。

d) N- (2',4' -difluoro-5- (6- (1-methyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) biphenyl-3-yl) acetamide

A solution of the compound from example 131(c) (75mg,0.17mmol) in 1, 2-dimethoxyethane (10ml) was passed through N₂Bubbling and degassing for 5 minutes. 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (42mg,0.203mmol,1.2eq.) was added and the mixture was degassed for an additional 5 minutes. Adding Pd (dppf) Cl₂(28mg,0.033mmol,0.2eq.) and aqueous sodium carbonate (54mg,0.507mmol,3.0eq.) followed by the procedure of example 1 (d). The crude residue of the product was purified by preparative HPLC to give the product in 20% yield (15 mg).¹HNMR(300MHz,DMSO-d₆) 10.39(s,1H),8.94(s,1H),8.71(d,1H),8.41(d,1H),8.3(s,2H),8.05(s,1H),7.88(s,1H),7.75-7.68(M,2H),7.48-7.42(dt,1H),7.29-7.25(dt,1H),3.89(s,3H),2.1(s,3H), LC-MS (ESI), calculated mass 444.15 measured mass 445.1[ M + H ] M]⁺(retention time: 1.39 minutes).

Example 132

N- (2',4' -difluoro-5- (6- (1-methyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) biphenyl-3-yl) methanesulfonamide

a)2',4' -difluoro-5- (6- (1-methyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) biphenyl-3-amine

To a solution of the compound from example 131 (0.5g,1.1mmol) in ethanol (10ml) was added aqueous sodium hydroxide (392mg,9.79mmol,8.9eq.) and the mixture was heated at 85 ℃ for 2 hours. The mixture was quenched and extracted as described in example 1 (d). Evaporation of the solvent gave the product in 79% yield (0.35 g).

b) N- (2',4' -difluoro-5- (6- (1-methyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) biphenyl-3-yl) methanesulfonamide

To a solution of the compound from example 132(a) (70mg,0.174mmol) in DCM (5ml) was added pyridine (28mg,0.348mmol,2.0eq.) followed by methanesulfonyl chloride (22mg,0.192mmol,1.1 eq.). The reaction solution was stirred for 1 hour, and the reaction was terminated and extracted as described in example 2 (b). The solvent was evaporated and the residue was purified by preparative HPLC to give the product in 8% yield (7 mg).¹H-NMR(300MHz,CD₃OD is 8.8(brs,1H),8.7(s,1H),8.32-8.28(M,1H),8.12(s,1H),7.95(s,1H),7.9-7.85(M,1H),7.8-7.77(s,1H),7.7-7.6(M,1H),7.53-7.49(M,2H),7.18-7.05(M,2H),3.96(s,3H),3.13(s,3H), LC-MS (ESI) calculating mass 480.12, measured mass 481.3[ M + H + M ] M]⁺(retention time: 1.38 minutes).

Example 133

N- (2',4' -difluoro-5- (6- (1-methyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) biphenyl-3-yl) ethanesulfonamide

The Compound Using the method of example 132 from the Compound of example 131And (4) preparation.¹HNMR(300MHz,DMSO-d₆) 8.8(s,1H),8.7(d,1H),8.29(d,1H),8.11(s,1H),7.95(s,1H),7.86(t,1H),7.8-7.77(M,1H),7.7-7.49(M,4H),7.05-7.18(M,1H),3.96(s,3H),3.29 (quartet, 2H),1.37(t,3H), LC-MS (ESI), calculated mass 494.13, measured mass 495.1[ M + H ] and calculated mass 495.1 ]⁺(retention time: 1.46 minutes).

Example 134

N- (2',4' -difluoro-5- (6- (1-methyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) biphenyl-3-yl) benzenesulfonamide

This compound was prepared from the compound of example 131 using the procedure of example 132. LC-MS (ESI) for calculating mass 542.13 and measured mass 543.1M + H]⁺(retention time: 1.64 minutes).

Example 135

N- (5- (6- (1-cyclopentyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) -2',4' -difluorobiphenyl-3-yl) acetamide

This compound was prepared from the compound of example 131(c) using the procedure of example 131 (d).¹H-NMR(300MHz,DMSO-d₆) 10.43(s,1H),8.92(s,1H),8.73-8.74(d,1H),8.44-8.40(M,1H),8.30-8.25(M,1H),8.05(s,1H),7.25-7.9(M,6H),3.59-3.50(M,1H),2.11(s,3H),2.02-1.93(M,2H),1.88-1.83(M,4H),1.71-1.66(M,2H), LC-MS (ESI), calculated mass 498.20, measured mass 499.2[ M + H ] M,4H, M,2H)]⁺(retention time: 1.63 minutes).

Example 136

N- (2',4' -difluoro-5- (6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) biphenyl-3-yl) acetamide

a)4- (4- (3- (5-acetylamino-2 ',4' -difluorobiphenyl-3-yl) -3H-imidazo [4,5-b ] pyridin-6-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester

A solution of the compound from example 131(c) (150mg,0.338mmol) in 1, 2-dimethoxyethane (20ml) was passed through N ₂Bubbling and degassing for 5 minutes. Tert-butyl 4- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate (153mg,0.406mmol,1.2eq.) was added and the mixture was degassed for an additional 5 minutes. Adding Pd (PPh)₃)₄(55mg,0.068mmol,0.2eq.) and aqueous sodium carbonate (107mg,1.01mmol,3.0eq.), followed by the procedure of example 1 (d). The product was obtained as a crude residue in 48% yield (100 mg).

b) N- (2',4' -difluoro-5- (6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) biphenyl-3-yl) acetamide

To a solution of the compound from example 136(a) (100mg,0.16mmol) in 1, 4-dioxane (5ml) was added a solution of HCl in dioxane at 0 ℃ and stirred at room temperature for 2 hours. The solvent was evaporated and the residue was purified by preparative HPLC to give the product in 30% yield (25 mg).¹HNMR(300MHz,DMSO-d₆) 10.2(s,1H),8.95-8.91(M,1H),8.78-8.75(M,2H),8.48-8.30(M,3H),8.15-8.10(M,1H),7.84-7.64(M,3H),7.48-7.38(M,1H),7.30-7.20(M,1H),4.6-4.45(M,1H),3.2-3.0(M,4H),2.3-2.05(M,7H), LC-MS (ESI), calculated mass 513.21, measured mass 514.2[ M + H [, (ESI) ]]⁺(retention time: 0.21 minutes).

Example 137

N- (5- (6- (1H-pyrazol-1-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) -2',4' -difluorobiphenyl-3-yl) acetamide

To a solution of the compound (1.5g,3.3mmol) of example 131(c) in DMF (20ml) were added pyrazole (0.22g,3.3mmol,1eq.), copper (I) oxide (0.243g,1.69mmol,0.5eq.) and cesium carbonate (1.73g,5.3mmol,1.6eq.), followed by heating at 90 ℃ for 12 hours. The mixture was quenched and extracted as described in example 1 (d). The solvent was distilled off and the residue was purified by column chromatography (60-120 silica gel, 70% ethyl acetate in hexane) to giveProduct, 35% yield (0.5 g).¹HNMR(300MHz,DMSO-d₆) 10.4(s,1H),9.05-8.97(M,2H),8.68-8.60(M,2H),8.32-825(brs,1H),7.92-7.8(M,2H),7.75-7.65(M,2H),7.48-7.38(M,1H),7.30-7.20(M,1H),6.63-6.60(M,1H),2.1(s,3H), LC-MS (ESI), calculated mass 430.14, measured mass 431.1[ M + H ] 431.1]⁺(retention time: 1.46 minutes).

Example 138

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

a) N- (2',5' -difluoro-5-nitrobiphenyl-3-yl) acetamide

A solution of N- (3-bromo-5-nitrophenyl) acetamide from example 1(c) (0.8g,3.07mmol) in 1, 2-dimethoxyethane (15ml) was passed over N₂Bubbling and degassing for 5 minutes. 2, 5-difluorophenylboronic acid (0.58g,3.69mmol,1.2eq.) was added and the mixture was degassed for an additional 5 minutes. Adding Pd (dppf) Cl ₂(0.5g,0.615mmol,0.2eq.) and aqueous sodium carbonate (0.98g,9.23mmol,3.0eq.) followed by the procedure of example 1 (d). The crude residue of the product was purified by column chromatography (60-120 silica gel, 25% ethyl acetate in hexane) to afford the product in 67% yield (0.6 g).¹HNMR(300MHz,DMSO-d₆):10.56(s,1H),8.65(t,1H),8.14(s,1H),8.06(s,1H),7.56-7.52(m,1H),7.47-7.37(m,2H),2.12(s,3H)。

b) N- (5-amino-2 ',5' -difluorobiphenyl-3-yl) acetamide

To a solution of the compound from example 138(a) (0.6g,2.05mmol) in methanol (10ml) and ethyl acetate (3ml) was added 10% Pd/C (100mg) and the reaction vessel was purged with nitrogen for 5 minutes. Then the mixture is taken up with H₂Hydrogenation in balloon for 12 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated to give the compound in 93% yield (0.5 g).

c) N- (5- (4-bromo-2-nitrophenylamino) -2',5' -difluorobiphenyl-3-yl) acetamide

A solution of the compound from example 138(b) (0.5g,1.9mmol), 4-bromo-1-fluoro-2-nitrobenzene (0.42g,1.9mmol,1.0eq.) and potassium fluoride (0.11g,1.9mmol,1.0eq.) in DMF (2ml) was heated at 130 ℃ for 5 h. The mixture was quenched and extracted as described in example 1 (d). The solvent was evaporated and the residue was purified by column chromatography (60-120 silica gel, 30% ethyl acetate in hexane) to give the product in 57% yield (0.5 g).

d) N- (5- (2-amino-4-bromophenylamino) -2',5' -difluorobiphenyl-3-yl) acetamide

To a solution of the compound from example 138(c) (0.5g,1.08mmol) in THF (10ml) was added a solution of ammonium chloride (0.46g,8.67mmol,8eq.) in water (2ml) and zinc (0.57g,8.67mmol,8 eq.). The mixture was stirred at 45 ℃ for 2 hours and filtered. The filtrate was diluted with water and extracted as described in example 1 (d). Evaporation of the solvent gave the product in 86% yield (0.4 g).

e) N- (5- (5-bromo-1H-benzo [ d ] imidazol-1-yl) -2',5' -difluorobiphenyl-3-yl) acetamide

A mixture of the compound from example 138(d) (0.4g,0.93mmol) and formic acid (4ml) was heated at 100 ℃ for 30 minutes. The formic acid was evaporated off and the residue 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 product in 85% yield (0.35 g).¹HNMR(300MHz,DMSO-d₆):10.42(s,1H),8.75(s,1H),8.04(d,2H),7.86(s,1H),7.69(d,1H),7.64-7.56(m,3H),7.54-7.38(m,1H),7.37-7.31(m,1H),2.12(s,3H)。

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

A solution of the compound from example 138(e) (100mg,0.226mmol) in 1, 2-dimethoxyethane (10ml) was passed through N₂Bubbling and degassing for 5 minutes. 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (57mg,0.27mmol,1.2eq.) was added and the mixture was degassed for an additional 5 minutes. Adding Pd (dppf) Cl₂(37mg,0.045mmol,0.2eq.) and aqueous sodium carbonate (71mg,0.678mmol,3.0eq.) followed by example 1(d ) The method of (1). The crude residue of the product was purified by preparative HPLC to give the product in 20% yield (20 mg).¹HNMR(300MHz,DMSO-d₆) 10.4(s,1H),8.64(s,1H),8.20(s,1H),8.07(s,1H),7.99(s,1H),7.94(s,1H),7.8-7.68(M,2H),7.6-7.45(M,4H),7.27(t,1H),3.88(s,3H),2.12(s,3H), LC-MS (ESI): calculated mass: 443.45; measured mass: 444.1[ M + H ESI ]]⁺(retention time: 1.147 minutes).

Example 139

N- (2',5' -difluoro-5- (5- (1- (2- (morpholin-4-yl) ethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) acetamide

A solution of the compound from example 138(e) (5g,11.34mmol) in 1, 2-dimethoxyethane (100ml) was passed through N₂Bubbling and degassing for 5 minutes. 4- (2- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) ethyl) morpholine (4.2g,13.61mmol,1.2eq.) was added and the mixture was degassed for a further 5 minutes. Adding Pd (PPh)₃)₄(1.3g,1.13mmol,0.1eq.) and aqueous sodium carbonate (2.4g,22.67mmol,2.0eq.), followed by the procedure of example 1 (d). The crude residue of the product was purified by preparative HPLC to give the product in 37% yield (2.3 g).¹HNMR(400MHz,DMSO-d₆) 10.42(s,1H),8.87(s,1H),8.34(s,1H),8.17(s,1H),8.13(s,1H),8.05(s,1H),7.80-7.53(M,2H),7.66-7.58(M,3H),7.46-7.44(M,1H),7.38-7.32(M,1H),4.59(t,2H),3.76-3.67(M,4H),3.43-3.39(M,2H),2.54-2.44(M,4H),2.07(s,3H), LC-MS (ESI), calculated mass 542.58, measured mass 543.3[ M + H ] (M,4H) ]⁺(retention time: 0.22 minutes).

Example 140

N- (2',5' -difluoro-5- (5- (1- (2- (morpholin-4-yl) ethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) methanesulfonamide

a)2',5' -difluoro-5- (5- (1- (2- (morpholin-4-yl) ethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-amine

To a solution of the compound from example 139 (2.2g,4.0mmol) in ethanol (100ml) was added aqueous sodium hydroxide (2.0g,50mmol,12.5eq.) and the mixture was heated at 100 ℃ for 4 hours. The mixture was quenched and extracted as described in example 1 (d). Evaporation of the solvent gave the product in 90% yield (1.8 g).

b) N- (2',5' -difluoro-5- (5- (1- (2- (morpholin-4-yl) ethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) methanesulfonamide

To a solution of the compound from example 140(a) (100mg,0.2mmol) in DCM (2ml) was added pyridine (32mg,0.4mmol,2.0eq.) followed by methanesulfonyl chloride (30mg,0.26mmol,1.3 eq.). The mixture was stirred for 1 hour, the reaction was terminated and extracted as described in example 2 (b). The solvent was evaporated and the residue was purified by preparative HPLC to give the product in 26% yield (30 mg).¹HNMR(400MHz,CD₃OD) 9.34(s,1H),8.25(s,1H),8.06-8.05(M,2H),7.86.7.80(s,2H),7.74-7.73(M,1H),7.68(M,1H),7.60-7.59(M,1H),7.44-7.39(M,1H),7.33-7.27(M,1H),7.24-7.19(M,1H),4.69(t,2H),3.94-3.88(M,4H),3.76(t,2H),3.54-3.40(M,4H),3.19(s,3H), LC-MS (ESI), calculated mass 578.63, measured mass 579.3[ M + H ], (M,4H), calculated mass 579 ]⁺(retention time: 0.26 min).

Example 141

N- (2',5' -difluoro-5- (5- (1- (2- (morpholin-4-yl) ethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) ethanesulfonamide

The compound was prepared from the compound of example 139 using the procedure of example 140.¹HNMR(400MHz,DMSO-d₆) 10.34(s,1H),8.69(s,1H),8.27(s,1H),8.01(s,1H),7.98(s,1H),7.72-7.61(M,5H),7.51-7.44(M,2H),7.39-7.35(M,1H),4.27(t,2H),3.58(t,4H),3.32-3.28(M,2H),2.77(t,2H),2.45(M,4H),1.22(t,3H), LC-MS (ESI), calculated mass 592.66, measured mass 593.2[ M + H + 2H ], calculated mass 593.2]⁺(retention time: 0.332 min).

Example 142

N- (2',5' -difluoro-5- (5- (1- (2- (morpholin-4-yl) ethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) propane-2-sulfonamide

The compound was prepared from the compound of example 139 using the procedure of example 140.¹HNMR(400MHz,DMSO-d₆) 10.35(s,1H),8.79(s,1H),8.37(s,1H),8.15(s,1H),8.07(s,1H),7.74-7.62(M,5H),7.54(s,1H),7.51-7.45(M,1H),7.41-7.35(M,1H),4.61(t,2H),3.70-3.63(M,6H),3.52-3.42(M,3H),3.40-3.28(M,2H),1.43(d,6H), LC-MS (ESI) calculating mass 606.69, measured mass 607.4[ M + H ] 607.4]⁺(retention time: 0.55 minutes).

Example 143

N- (2',5' -difluoro-5- (5- (1- (2- (morpholin-4-yl) ethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) cyclopropanesulfonamide

This compound was prepared from the compound of example 139 using the procedure of example 140 and cyclopropanesulfonyl chloride.¹HNMR(400MHz,DMSO-d₆) 10.31(s,1H),8.76(s,1H),8.36(s,1H),8.14(s,1H),8.07(s,1H),7.73(d,1H),7.67-7.63(M,4H),7.55(s,1H),7.50-7.45(M,2H),4.60(t,2H),3.99-3.79(M,2H),3.69-3.63(M,6H),3.20-3.17(M,2H),2.91-2.88(M,1H),1.1-1.0(d,4H), LC-MS (ESI), calculated mass 604.67, measured mass 605.4[ M + H ] and measured mass 605.4]⁺(retention time: 0.48 minutes).

Example 144

N- (5- (5- (1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -2',5' -difluorobiphenyl-3-yl) acetamide

The compound was prepared from the compound of example 138(e) using the procedure of example 139.¹HNMR(400MHz,DMSO-d₆):10.42(s,1H),8.74(s,1H),8.34(s,1H),8.16(s,1H),8.12(s,1H),8.04(s,1H),7.79-7.73(M,2H),7.64-7.57(M,3H),7.45-7.42(M,1H),7.36-7.34(M,1H),4.56(t,2H),3.62(t,2H),3.84(s,6H),2.12(s,3H), LC-MS (ESI), calculated mass 500.54, measured mass 501.2[ M + H ], (ESI)]⁺(retention time: 0.22 minutes).

Example 145

N- (5- (5- (1H-pyrazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -2',5' -difluorobiphenyl-3-yl) acetamide

To a solution of the compound from example 138(e) (2.5g,5.67mmol,1eq.) in DMF (10ml) was added pyrazole (0.77g,11.3mmol,2eq.), copper (I) oxide (1.62g,11.3mmol,2.0eq.) and cesium carbonate (3.67g,11.3mmol,2.0eq.) and the mixture was heated at 90 ℃ for 48 h. The mixture was quenched and extracted as described in example 1 (d). The solvent was evaporated and the residue was purified by preparative HPLC to give the product in 79% yield (1.92 g). ¹HNMR(400MHz,CD₃OD is 10.43(s,1H),8.84(s,1H),8.60(d,1H),8.24(s,1H),8.12(s,1H),7.97-7.82(M,3H),7.76(s,1H),7.63-7.60(M,2H),7.49-7.32(M,1H),6.56(s,1H),2.10(s,3H), LC-MS (ESI) calculating mass 429.42, measured mass 430.2[ M + H ], (S + H)]⁺(retention time: 1.45 minutes).

Example 146

N- (5- (5- (1H-pyrrol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -2',5' -difluorobiphenyl-3-yl) acetamide

To a solution of the compound from example 138(e) (250mg,0.57mmol,1eq.) in DMF (1ml) was added pyrazole (77mg,1.13mmol,2eq.), copper (I) oxide (162mg,1.13mmol,2.0eq.) and cesium carbonate (367mg,1.13mmol,2.0eq.) and the mixture was heated at 90 ℃ for 48 hours. The mixture was quenched and extracted as described in example 1 (d). The solvent was evaporated and the residue was purified by preparative HPLC to give the product in 45% yield (110 mg).¹HNMR(400MHz,DMSO-d₆):10.45(s,1H),8.81(s,1H),8.15(s,1H),8.00(d,1H) 7.86-7.80(M,2H),7.66-7.62(M,3H),7.46-7.44(M,4H),6.29(t,2H),2.13(s,3H), LC-MS (ESI) calculating mass 428.43, and actual measuring mass 429.1[ M + H ESI ]]⁺(retention time: 1.647 min).

Example 147

N- (3- (benzofuran-2-yl) -5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide

a) N- (3- (benzofuran-2-yl) -5-nitrophenyl) acetamide

A solution of N- (3-bromo-5-nitrophenyl) acetamide from example 1(c) (2g,7.7mmol) in 1, 2-dimethoxyethane (25ml) was passed over N₂Bubbling and degassing for 5 minutes. 2- (benzofuran-2-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxolane (2.45g,10mmol,1.3eq.) is added and the mixture is degassed for a further 5 minutes. Adding Pd (dppf) Cl₂(0.63g,0.77mmol,0.1eq.) and aqueous sodium carbonate (2.45g,23.1mmol,3.0eq.) followed by the procedure of example 1 (d). The crude residue of the product was used directly in the next step.

b) N- (3-amino-5- (benzofuran-2-yl) phenyl) acetamide

To a solution of the compound from example 147(a) (1.8g,6.08mmol) in ethanol (30ml) were added calcium chloride (1.35g,12.16mmol,2eq.) and iron powder (0.7g,12.16mmol,2eq.) and the mixture was heated at 100 ℃ for 2 hours and filtered. The filtrate was diluted with water and extracted as described in example 1 (d). The solvent was evaporated and the residue was purified by column chromatography (100-200 neutral alumina, 4% methanol in chloroform) to give the product in 90% yield (1.45 g).

c) N- (3- (benzofuran-2-yl) -5- (4-bromo-2-nitrophenylamino) phenyl) acetamide

A solution of the compound from example 147(b) (1.45g,5.45mmol), 4-bromo-1-fluoro-2-nitrobenzene (1.2g,5.45mmol,1.0eq.) and potassium fluoride (0.32g,5.45mmol,1.0eq.) in DMF (5ml) was heated at 100 ℃ for 12 h. The mixture was quenched and extracted as described in example 1 (d). The solvent was evaporated and the residue was purified by column chromatography (60-120 silica gel, 40% ethyl acetate in hexane) to give the product in 59% yield (1.5 g).

d) N- (3- (2-amino-4-bromophenylamino) -5- (benzofuran-2-yl) phenyl) acetamide

To a solution of the compound from example 147(c) (1.45g,3.12mmol) in ethanol (35ml) were added calcium chloride (0.69g,6.24mmol,2eq.) and iron powder (0.36g,6.24mmol,2eq.) and the mixture was heated at 100 ℃ for 2 hours and filtered. The filtrate was diluted with water and extracted as described in example 1 (d). The solvent was distilled off and the residue was used directly in the next step.

e) N- (3- (benzofuran-2-yl) -5- (5-bromo-1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide

A mixture of the compound from example 147(d) (1.36g,3.2mmol) and formic acid (2ml) was heated at 100 ℃ for 30 minutes. The formic acid was evaporated off and the residue 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 product in 61% yield (0.85 g).

f) N- (3- (benzofuran-2-yl) -5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide

A solution of the compound from example 147(e) (0.8g,1.8mmol) in 1, 2-dimethoxyethane (20ml) was passed through N₂Bubbling and degassing for 5 minutes. 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (0.56g,2.7mmol,1.5eq.) was added and the mixture was degassed for an additional 5 minutes. Adding Pd (PPh) ₃)₄(0.207g,0.18mmol,0.1eq.) and an aqueous solution of sodium carbonate (3.8g,3.6mmol,2.0eq.), followed by the procedure of example 1 (d). The crude residue of the product was purified by preparative HPLC to give the pure product in 75% yield (0.6 g).¹HNMR(300MHz,DMSO-d₆) 10.46(s,1H),8.78(s,1H),8.21(M,2H),8.06(s,1H),8.01(s,1H),7.96(s,2H),7.74-7.64(M,3H),7.63-7.59(M,2H),7.34-7.31(M,2H),3.89(s,3H),2.15(s,3H), LC-MS (ESI) calculating mass 447.49, measured mass 448.1[ M + H ], and mass measured]⁺(at the time of retentionThe method comprises the following steps: 1.397 minutes).

Example 148

N- (5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) acetamide

a) N- (5-nitrobiphenyl-3-yl) acetamide

A solution of N- (3-bromo-5-nitrophenyl) acetamide from example 1(c) (1g,3.87mmol) in 1, 2-dimethoxyethane (20ml) was passed over N₂Bubbling and degassing for 5 minutes. Phenylboronic acid (0.61g,5.04mmol,1.3eq.) was added and the mixture was degassed for an additional 5 minutes. Adding Pd (dppf) Cl₂(0.63g,0.77mmol,0.2eq.) and aqueous sodium carbonate (1.23g,11.6mmol,3.0eq.), followed by the procedure of example 1 (d). The crude residue of the product was purified by column chromatography (60-120 silica gel, 50% ethyl acetate in hexanes) to afford the product in 61% yield (0.6 g).

b) N- (5-aminobiphenyl-3-yl) acetamide

To a solution of N- (5-nitrobiphenyl-3-yl) acetamide (1.2g,4.68mmol) in THF (10ml) was added a solution of ammonium chloride (2g,37.4mmol,8eq.) in water (2ml) and zinc (2.36g,37.4mmol,8 eq.). The mixture was stirred at 45 ℃ for 2 hours and filtered. The filtrate was diluted with water and extracted as described in example 1 (d). Evaporation of the solvent gave the product in 94% yield (1 g).

c) N- (5- (4-bromo-2-nitrophenylamino) biphenyl-3-yl) acetamide

A solution of N- (5-aminobiphenyl-3-yl) acetamide (1g,4.54mmol), 4-bromo-1-fluoro-2-nitrobenzene (1.03g,4.54mmol,1.0eq.) and potassium fluoride (0.26g,4.54mmol,1.0eq.) in DMF (5ml) was heated at 100 ℃ for 12 hours. The mixture was quenched and extracted as described in example 1 (d). The solvent was evaporated and the residue was purified by column chromatography (60-120 silica gel, 50% ethyl acetate in hexane) to give the product in 52% yield (1 g).

d) N- (5- (2-amino-4-bromophenylamino) biphenyl-3-yl) acetamide

To a solution of the compound from example 148(c) (1.0g,2.35mmol) in THF (10ml) was added a solution of ammonium chloride (1.18g,18.8mmol,8eq.) in water (2ml) and zinc (1g,18.8mmol,8 eq.). The mixture was stirred at 45 ℃ for 2 hours and filtered. The filtrate was diluted with water and extracted as described in example 1 (d). Evaporation of the solvent gave the product in 43% yield (0.4 g).

e) N- (5- (5-bromo-1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) acetamide

A mixture of the compound from example 148(d) (0.4g,1.01mmol) and formic acid (10ml) was heated at 100 ℃ for 2 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. The solvent was evaporated and the residue was purified by column chromatography (60-120 silica gel, 50% ethyl acetate in hexane) to give the product in 85% yield (0.35 g).

f) N- (5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) acetamide

A solution of the compound from example 148(e) (400mg,0.99mmol) in 1, 2-dimethoxyethane (10ml) was passed through N₂Bubbling and degassing for 5 minutes. 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (220mg,1.05mmol,1.2eq.) was added and the mixture was degassed for an additional 5 minutes. Adding Pd (PPh)₃)₄(230mg,0.197mmol,0.2eq.) and aqueous sodium carbonate (320mg,3.01mmol,3.0eq.), followed by the procedure of example 1 (d). The crude residue of the product was purified by preparative HPLC to give the product in 12% yield (50 mg).¹HNMR(300MHz,DMSO-d₆) 10.36(s,1H),8.68(s,1H),8.18(s,1H),8.02-7.97(M,2H),7.93-7.88(M,2H),7.75-7.67(s,3H),7.61-7.49(M,4H),7.43(t,1H),3.87(s,3H),2.12(s,3H), LC-MS (ESI): calculated mass 407.47; measured mass 408.1[ M + H ESI ] ]⁺(retention time: 1.67 minutes).

Example 149

N- (4' -methoxy-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) acetamide

a) N- (4' -methoxy-5-nitrobiphenyl-3-yl) acetamide

A solution of N- (3-bromo-5-nitrophenyl) acetamide from example 1(c) (1g,3.8mmol) in 1, 2-dimethoxyethane (20ml) was passed over N₂Bubbling and degassing for 5 minutes. 4-Methoxyphenylboronic acid (0.69g,4.4mmol,1.1eq.) was added and the mixture was degassed for an additional 5 minutes. Adding Pd (dppf) Cl₂(0.31g,0.38mmol,0.1eq.) and aqueous sodium carbonate (1g,9.5mmol,2.5eq.) followed by the procedure of example 1 (d). The crude residue of the product was purified by column chromatography (60-120 silica gel, 40% ethyl acetate in hexane) to afford the product in 73% yield (0.8 g).

b) N- (5-amino-4' -methoxybiphenyl-3-yl) acetamide

To a solution of N- (4' -methoxy-5-nitrobiphenyl-3-yl) acetamide (4g,13.98mmol) in ethanol (50ml) were added calcium chloride (3.1g,27.96mmol,2eq.) and iron powder (1.45g,27.96mmol,2eq.) and the mixture was heated at 100 ℃ for 2 hours and filtered. The filtrate was diluted with water and extracted as described in example 1 (d). Evaporation of the solvent gave the product in 87% yield (3.1 g).

c) N- (5- (4-bromo-2-nitrophenylamino) -4' -methoxybiphenyl-3-yl) acetamide

The compound was prepared from the compound of example 149(b) (3.1g,12.11mmol) using the method of example 148(c) to give the title product in 52% yield (2.9 g).

d) N- (5- (2-amino-4-bromophenylamino) -4' -methoxybiphenyl-3-yl) acetamide

To a solution of the compound from example 149(c) (2.9g,6.37mmol) in ethanol (30ml) were added calcium chloride (1.4g,12.74mmol,2eq.) and iron powder (0.66g,12.74mmol,2eq.) and the mixture was heated at 100 ℃ for 2 hours and filtered. The filtrate was diluted with water and extracted as described in example 1 (d). The solvent was distilled off to give a crude residue which was used directly in the next step.

e) N- (5- (5-bromo-1H-benzo [ d ] imidazol-1-yl) -4' -methoxybiphenyl-3-yl) acetamide

The compound was prepared from the compound (2.7g,6.37mmol) of example 149(d) using the method of example 148(e) to give the product in 79% yield (2.2 g).

f) N- (4' -methoxy-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) biphenyl-3-yl) acetamide

The compound was prepared from the compound of example 149(e) using the method of example 148(f) to give the product in 67% yield (0.54 g).¹HNMR(300MHz,DMSO-d₆) 8.48(s,1H),7.96-7.84(M,4H),7.74-7.45(M,7H),7.01(d,2H),3.93(s,3H),3.83(s,3H),2.19(s,3H), LC-MS (ESI), calculated mass 437.49, measured mass 437.9[ M + H ] 437.9 ]⁺(retention time: 0.89 minutes).

Example 150

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

a) N- (3',4' -difluoro-5-nitrobiphenyl-3-yl) acetamide

A solution of N- (3-bromo-5-nitrophenyl) acetamide from example 1(c) (0.7g,2.69mmol) in 1, 2-dimethoxyethane (15ml) was passed over N₂Bubbling and degassing for 5 minutes. 3, 4-difluorophenylboronic acid (0.5g,3.23mmol,1.2eq.) was added and the mixture was degassed for an additional 5 minutes. Adding Pd (dppf) Cl₂(0.44g,0.54mmol,0.2eq.) and aqueous sodium carbonate (0.86g,8.07mmol,3.0eq.) followed by the procedure of example 1 (d). The crude residue of the product was purified by column chromatography (60-120 silica gel, 25% ethyl acetate in hexane) to afford the product in 76% yield (0.6 g).

b) N- (5-amino-3 ',4' -difluorobiphenyl-3-yl) acetamide

To a solution of the compound from example 150(a) (0.6g,2.05mmol) in methanol (10ml) and ethyl acetate (2ml) was addedTo this was added 10% Pd/C (100mg) and the reaction vessel was purged with nitrogen for 5 minutes. Then the mixture is taken up with H₂Hydrogenation in balloon for 12 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to give the compound in 93% yield (0.5 g).

c) N- (5- (4-bromo-2-nitrophenylamino) -3',4' -difluorobiphenyl-3-yl) acetamide

The compound was prepared from the compound of example 150(b) (3.1g,12.11mmol) using the method of example 148(c) to give the product in 57% yield (0.5 g).¹HNMR(300MHz,DMSO-d₆):10.16(s,1H),9.43(s,1H),8.23(d,1H),7.69-7.58(m,3H),7.41-7.38(m,2H),7.29-7.26(m,2H),7.19(s,1H),2.04(s,3H)。

d) N- (5- (2-amino-4-bromophenylamino) -3',4' -difluorobiphenyl-3-yl) acetamide

The compound was prepared from the compound of example 150(c) (0.5g,1.08mmol) using the method of example 148(d) to give the product in 86% yield (0.4 g).

e) N- (5- (5-bromo-1H-benzo [ d ] imidazol-1-yl) -3',4' -difluorobiphenyl-3-yl) acetamide

The compound was prepared from the compound of example 150(d) (0.4g,0.93mmol) using the method of example 148(e) to give the product in 97% yield (0.4 g).

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

The compound was prepared from the compound of example 150(e) (0.1g,0.226mmol) using the method of example 148(f) to give the product in 30% yield (30 mg).¹HNMR(300MHz,DMSO-d₆) 10.43(s,1H),9.03(s,1H),8.24(s,1H),8.09(s,1H),8.01(s,1H),7.97(s,1H),7.90-7.85(s,2H),7.76-7.74(M,1H),7.71(s,1H),7.68-7.66(M,1H),7.61-7.59(M,2H),3.88(s,3H),2.13(s,3H), LC-MS (ESI) and calculated mass 443.45, and measured mass 444.1[ M + H ] (s,3H)]⁺(retention time: 1.3 minutes).

Example 151

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

a) N- (2',6' -difluoro-5-nitrobiphenyl-3-yl) acetamide

A solution of N- (3-bromo-5-nitrophenyl) acetamide from example 1(c) (20g,77mmol) in 1, 2-dimethoxyethane (250ml) was passed over N₂Bubbling and degassing for 5 minutes. 2, 6-difluorophenylboronic acid (14.6g,92.4mmol,1.2eq.) was added and the mixture was degassed for an additional 5 minutes. Adding Pd (dppf) Cl₂(6.28g,7.7mmol,0.1eq.) and aqueous sodium carbonate (24.49g,231mmol,3.0eq.), followed by the procedure of example 1 (d). The crude residue of the product was purified by column chromatography (60-120 silica gel, 30% ethyl acetate in hexane) to afford the product in 94% yield (21.2 g). LC-MS (ESI) for calculating mass 292.24 and measured mass 293.1M + H]⁺(retention time: 1.49 minutes).

b) N- (5-amino-2 ',6' -difluorobiphenyl-3-yl) acetamide

The compound was prepared from the compound (21g,72mmol) in example 151(a) using the method of example 148(b) to give the product in 95% yield (18 g).

c) N- (5- (4-bromo-2-nitrophenylamino) -2',6' -difluorobiphenyl-3-yl) acetamide

The compound was prepared from the compound (8g,30.5mmol) in example 151(b) using the method of example 148(c) to give the product in 96% yield (13.5 g).

d) N- (5- (2-amino-4-bromophenylamino) -2',6' -difluorobiphenyl-3-yl) acetamide

The compound was prepared from the compound of example 151(c) (13.5g,29.22mmol) using the method of example 148(d) to give the product in 95% yield (12 g).

e) N- (5- (5-bromo-1H-benzo [ d ] imidazol-1-yl) -2',6' -difluorobiphenyl-3-yl) acetamide

The compound was prepared from the compound (12g,27.84mmol) of example 151(d) using the method of example 148(e) to give the product in 96% yield (11.8 g).

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

The compound was prepared from the compound (2.5g,5.67mmol) of example 151(e) using the method of example 148(f) to give the product in 84% yield (2.1 g).¹HNMR(400MHz,DMSO-d₆) 10.39(s,1H),8.56(s,1H),8.18(s,1H),8.05(s,1H),7.97(s,1H),7.92(s,1H),7.71-7.47(M,5H),7.27(t,2H),3.85(s,3H),2.09(s,3H), LC-MS (ESI) calculating mass 443.45, measured mass 444.0[ M + H ] calculated mass 444.0]⁺(retention time: 1.34 minutes).

Example 152

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

To a solution of the compound from example 151(e) (2.5g,5.67mmol) in DMF (20ml) were added pyrazole (0.96g,14.18mmol,2.5eq.), copper (I) oxide (0.81g,5.67mmol,1eq.) and cesium carbonate (4.6g,14.18mmol,2.5eq.) and the mixture was heated at 90 ℃ for 48 h. The mixture was quenched and extracted as described in example 1 (d). The solvent was evaporated and the residue was purified by preparative HPLC to give the product in 91% yield (2.2 g). ¹HNMR(300MHz,DMSO-d₆) 10.43(s,1H),8.67(s,1H),8.57(d,1H),8.20(d,1H),8.06(s,1H),7.92-7.88(M,1H),7.77-7.74(M,3H),7.53-7.49(M,2H),7.30-7.25(M,2H),6.54(t,1H),2.1(s,3H), LC-MS (ESI): calculated mass 429.42, measured mass 430.1[ M + H ], (ESI)]⁺(retention time: 1.50 minutes).

Example 153

N- (3- (1-methyl-1H-pyrazol-4-yl) -5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide

a) N- (3- (1-methyl-1H-pyrazol-4-yl) -5-nitrophenyl) acetamide

A solution of N- (3-bromo-5-nitrophenyl) acetamide (0.5g,1.9mmol) in 1, 2-dimethoxyethane (20ml) was passed over N₂Bubbling and degassing for 5 minutes. 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (0.513g,2.47mmol,1.3eq.) was added and the mixture was degassed for an additional 5 minutes. Adding Pd (dppf) Cl₂(0.155g,0.19mmol,0.1eq.) and an aqueous solution of sodium carbonate (0.5g,4.75mmol,2.5eq.) followed by the procedure of example 1 (d). The crude residue of the product was purified by column chromatography (60-120 silica gel, 30% ethyl acetate in hexane) to afford the product in 81% yield (0.4 g).

b) N- (3-amino-5- (1-methyl-1H-pyrazol-4-yl) phenyl) acetamide

To a solution of the compound from example 153(a) (0.4g,1.54mmol) in ethanol (25ml) were added calcium chloride (0.34g,3.08mmol,2eq.) and iron powder (0.16g,3.08mmol,2eq.) and the mixture was heated at 100 ℃ for 2 hours and filtered. The filtrate was diluted with water and extracted as described in example 1 (d). Evaporation of the solvent gave the product in 85% yield (0.3 g). LC-MS (ESI) calculated mass 230.27 and measured mass 231.1[ M + H ] ]⁺(retention time: 0.225 minutes).

c) N- (3- (4-bromo-2-nitrophenylamino) -5- (1-methyl-1H-pyrazol-4-yl) phenyl) acetamide

A solution of the compound from example 153(b) (0.3g,1.3mmol), 4-bromo-1-fluoro-2-nitrobenzene (0.29g,1.3mmol,1.0eq.) and potassium fluoride (0.075g,1.3mmol,1.0eq.) in DMF (5ml) was heated at 100 ℃ for 12 h. The mixture was quenched and extracted as described in example 1 (d). The solvent was distilled off and the residue was used directly in the next step.

d) N- (3- (2-amino-4-bromophenylamino) -5- (1-methyl-1H-pyrazol-4-yl) phenyl) acetamide

To a solution of the compound from example 153(c) (0.6g,1.3mmol) in ethanol (20ml) were added calcium chloride (0.29g,2.6mmol,2eq.) and iron powder (0.14g,2.6mmol,2eq.) and the mixture was heated at 100 ℃ for 2 hours and filtered. The filtrate was diluted with water and extracted as described in example 1 (d). The solvent was distilled off and the residue was used directly in the next step.

e) N- (3- (5-bromo-1H-benzo [ d ] imidazol-1-yl) -5- (1-methyl-1H-pyrazol-4-yl) phenyl) acetamide

A mixture of the compound from example 153(d) (0.52g,1.3mmol) and formic acid (2ml) was heated at 100 ℃ for 30 minutes. The formic acid was evaporated off and the residue 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 product in 54% yield (0.28 g). LC-MS (ESI) calculated mass 410.27, measured mass 411.0[ M + H [) ]⁺(retention time: 0.84 minutes).

f) N- (3- (1-methyl-1H-pyrazol-4-yl) -5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide

A solution of the compound from example 153(e) (0.15g,0.365mmol) in 1, 2-dimethoxyethane (10ml) was passed through N₂Bubbling and degassing for 5 minutes. 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (0.091g,0.439mmol,1.2eq.) was added and the mixture was degassed for a further 5 minutes. Adding Pd (PPh)₃)₄(0.043g,0.037mmol,0.1eq.) and aqueous sodium carbonate (0.077g,0.73mmol,2.0eq.) followed by the procedure of example 1 (d). The crude residue of the product was purified by preparative HPLC to give the product in 12% yield (18 mg).¹HNMR(300MHz,CD₃OD is 9.39(s,1H),8.10-7.91(M,6H),7.80-7.77(M,3H),7.63(s,1H),3.96(s,6H),2.20(s,3H), LC-MS (ESI) calculated mass is 443.45, measured mass is 411.46[ M + H ], (M + H) ]]⁺(retention time: 0.28 minutes).

Example 154

N- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (2-oxopyridin-1 (2H) -yl) phenyl) acetamide

a) N- (3-nitro-5- (2-oxopyridin-1 (2H) -yl) phenyl) acetamide

To a solution of N- (3-bromo-5-nitrophenyl) acetamide (1g,3.85mmol), pyridin-2-ol (0.4g,4.24mmol,1.1eq.), potassium carbonate (1g,1.3mmol,1.0eq.) and copper (I) iodide (10mg) in toluene (20ml) was added trans-cyclohexyldiamine (5mg,0.039mmol,0.01eq.) and the mixture was heated at 100 ℃ for 16 hours. The mixture was quenched and extracted as described in example 1 (d). The solvent was evaporated and the residue was purified by column chromatography (60-120 silica gel, 50% ethyl acetate in hexane) to give the product in 95% yield (1 g).

b) N- (3-amino-5- (2-oxopyridin-1 (2H) -yl) phenyl) acetamide

To a solution of the compound from example 154(a) (1.2g,4.4mmol) in ethanol (20ml) and water (2ml) were added calcium chloride (0.98g,8.8mmol,2eq.) and iron powder (0.46g,8.8mmol,2eq.) and the mixture was heated at 100 ℃ for 4 hours and filtered. The filtrate was diluted with water and extracted as described in example 1 (d). Evaporation of the solvent gave the product in 89% yield (0.95 g). LC-MS (ESI) calculated mass 243.26 and measured mass 244.1[ M + H ]]⁺(Retention time: 0.19 minutes)

c) N- (3- (4-bromo-2-nitrophenylamino) -5- (2-oxopyridin-1 (2H) -yl) phenyl) acetamide

A solution of the compound from example 154(b) (0.95g,3.9mmol), 4-bromo-1-fluoro-2-nitrobenzene (0.86g,3.9mmol,1.0eq.) and potassium fluoride (0.23g,3.9mmol,1.0eq.) in DMF (1ml) was heated at 150 ℃ for 2 hours. The mixture was quenched and extracted as described in example 1 (d). The solvent was evaporated and the residue was purified by column chromatography (100-200 silica gel, 1% methanol in DCM) to give the product in 69% yield (1.2 g).

d) N- (3- (2-amino-4-bromophenylamino) -5- (2-oxopyridin-1 (2H) -yl) phenyl) acetamide

To a solution of the compound from example 154(c) (1.2g,2.7mmol) in ethanol (20ml) were added calcium chloride (0.6g,5.4mmol,2eq.) and iron powder (0.28g,5.4mmol,2eq.) and the mixture was heated at 100 ℃ for 4 hours and filtered. The mixture was quenched and extracted as described in example 1 (d). The solvent was distilled off and the crude residue was used directly in the next step.

e) N- (3- (5-bromo-1H-benzo [ d ] imidazol-1-yl) -5- (2-oxopyridin-1 (2H) -yl) phenyl) acetamide

A mixture of the compound from example 154(d) (1.12g,2.7mmol) and formic acid (1ml) was heated at 100 ℃ for 2 hours. The formic acid was evaporated off and the residue 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 product in 61% yield (0.7 g). LC-MS (ESI) for calculating mass 423.26 and measured mass 424.9M + H]⁺(retention time: 1.065 minutes).

f) N- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (2-oxopyridin-1 (2H) -yl) phenyl) acetamide

A solution of the compound from example 154(e) (0.7g,1.65mmol) in 1, 2-dimethoxyethane (10ml) was passed through N₂Bubbling and degassing for 5 minutes. 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (0.41g,1.98mmol,1.2eq.) was added and the mixture was degassed for an additional 5 minutes. Adding Pd (PPh)₃)₄(0.19g,0.165mmol,0.1eq.) and aqueous sodium carbonate (0.35g,3.3mmol,2.0eq.) followed by the procedure of example 1 (d). The crude residue of the product was purified by preparative HPLC to give the product in 64% yield (0.45 g).¹HNMR(300MHz,CD₃OD-d₆) 9.35(s,1H),8.29-8.28(M,1H),8.11(s,1H),8.00(s,1H),7.94(d,1H),7.86-7.83(M,2H),7.77-7.73(M,2H),7.67-7.63(M,1H),7.59(t,1H),6.70-6.67(M,1H),6.55(dt,1H),3.96(s,3H),2.20(s,3H), LC-MS (ESI): calculated mass 424.45, measured mass 425.2[ M + H ESI ]⁺(retention time: 0.23 min).

Example 155

N- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-1,2, 4-triazol-1-yl) phenyl) acetamide

a) N- (3-nitro-5- (1H-1,2, 4-triazol-1-yl) phenyl) acetamide

To a solution of N- (3-bromo-5-nitrophenyl) acetamide (5g,19.3mmol) in DMF (50ml) were added 1,2, 4-triazole (3.3g,48.25mmol,2.5eq.), copper (I) oxide (0.56g,3.86mmol,0.2eq.) and cesium carbonate (12.5g,38.6mmol,2eq.) and the mixture was heated at 90 ℃ for 48 hours. The mixture was quenched and extracted as described in example 1 (d). The solvent was evaporated and the residue was purified by column chromatography (60-120 silica gel, 30% ethyl acetate in hexane) to give the product in 86% yield (4.1 g). LC-MS (ESI) calculated mass 247.21 and measured mass 248.0[ M + H]⁺(retention time: 0.257 minutes).

b) N- (3-amino-5- (1H-1,2, 4-triazol-1-yl) phenyl) acetamide

To a solution of the compound from example 155(a) (4.1g,16.6mmol) in THF (50ml) and methanol (10ml) were added a solution of ammonium chloride (0.88g,16.6mmol) and zinc (1.08g,16.6 mmol). The mixture was stirred at room temperature overnight and filtered. The filtrate was diluted with water and extracted as described in example 1 (d). The solvent was evaporated and the residue was purified by column chromatography (60-120 silica gel, 3% methanol in DCM) to give the product in 94% yield (3.4 g).

c) N- (3- (4-bromo-2-nitrophenylamino) -5- (1H-1,2, 4-triazol-1-yl) phenyl) acetamide

A solution of the compound from example 155(b) (3.43g,15.67mmol), 4-bromo-1-fluoro-2-nitrobenzene (3.4g,15.67mmol,1.0eq.) and potassium fluoride (0.91g,15.67mmol,1.5eq.) in DMF (5ml) was heated at 80 ℃ for 7 hours. The mixture was quenched and extracted as described in example 1 (d). The solvent was evaporated and the residue was purified by column chromatography (60-120 silica gel, 4% methanol in DCM) to give the product in 80% yield (5.2 g).

d) N- (3- (2-amino-4-bromophenylamino) -5- (1H-1,2, 4-triazol-1-yl) phenyl) acetamide

To a solution of the compound from example 155(c) N- (3- (4-bromo-2-nitrophenylamino) -5- (1H-1,2, 4-triazol-1-yl) phenyl) acetamide (5.2g,12.5mmol) in ethanol (100ml) were added calcium chloride (2.78g,25mmol,2eq.) and iron powder (1.3g,25mmol,2eq.) and the mixture was heated at 100 ℃ for 4 hours and filtered. The filtrate was diluted with water and extracted as described in example 1 (d). The solvent was distilled off and the crude residue was used directly in the next step.

e) N- (3- (5-bromo-1H-benzo [ d ] imidazol-1-yl) -5- (1H-1,2, 4-triazol-1-yl) phenyl) acetamide

A mixture of the compound from example 155(d) (4.84g,12.5mmol) and formic acid (10ml) was heated at 80 ℃ for 2 hours. The formic acid was evaporated off and the residue 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 product in 85% yield (4.2 g).

f) N- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-1,2, 4-triazol-1-yl) phenyl) acetamide

A solution of the compound from example 155(e) (100mg,0.25mmol) in 1, 2-dimethoxyethane (10ml) was passed through N₂Bubbling and degassing for 5 minutes. 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (62mg,0.3mmol,1.2eq.) was added and the mixture was degassed for an additional 5 minutes. Adding Pd (PPh)₃)₄(35mg,0.03mmol,0.12eq.) and aqueous sodium carbonate (0.53g,0.5mmol,2.0eq.) followed by the procedure of example 1 (d). The crude residue of the product was purified by preparative HPLC to give the product in 50% yield (50 mg).¹HNMR(400MHz,DMSO-d₆) 10.50(s,1H),9.36(s,1H),8.77(s,1H),8.28(s,1H),8.19-8.18(M,2H),8.00-7.93(M,4H),7.72(d,1H),7.60(dd,1H),3.86(s,3H),2.11(s,3H), LC-MS (ESI) calculating mass: 398.42, measured mass: 399.4[ M + H ] mass]⁺(retention time: 0.13 minutes).

Example 156

N- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (thiazol-2-yl) phenyl) acetamide

a) N- (3-nitro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) acetamide

A solution of N- (3-bromo-5-nitrophenyl) acetamide (2.1g,8.1mmol) in 1, 2-dimethoxyethane (25ml) was passed over N ₂Bubbling and degassing for 5 minutes. Bis (pinacolato) diboron (3.09g,12.15mmol,1.3eq.) was added and the mixture was degassed for an additional 5 minutes. Adding Pd (dppf) Cl₂(0.066g,0.081mmol,0.1eq.) and potassium acetate (2.38g,24.3mmol,3eq.), followed by the procedure of example 1 (d). The crude residue of the product was purified by column chromatography (60-120 silica gel, 30% ethyl acetate in hexane) to afford the product in 60% yield (1.5 g).

b) N- (3-nitro-5- (thiazol-2-yl) phenyl) acetamide

A solution of the compound from example 156(a) (2.8g,9.14mmol) in 1, 2-dimethoxyethane (10ml) was passed through N₂Bubbling and degassing for 5 minutes. 2-bromothiazole (1g,9.14mmol,1eq.) was added and the mixture was degassed for an additional 5 minutes. Adding Pd (dppf) Cl₂(0.74g,0.91mmol,0.1eq.) and aqueous sodium carbonate (1.9g,18.2mmol,2eq.) followed by the procedure of example 1 (d). The crude residue of the product was purified by column chromatography (60-120 silica gel, 40% ethyl acetate in hexane) to afford the product in 33% yield (0.8 g).¹HNMR(300MHz,DMSO-d₆):10.64(s,1H),8.65(t,1H),8.55(t,1H),8.34(t,1H),8.04(d,1H),7.94(d,1H),2.13(s,3H)。

c) N- (3-amino-5- (thiazol-2-yl) phenyl) acetamide

To a solution of the compound from example 156(b) (0.8g,3.03mmol) in methanol (25ml) and ethyl acetate (10ml) was added 10% Pd/C (300mg,0.1eq.) and the reaction vessel purged with nitrogen for 5 minutes. Then the mixture is taken up with H ₂Hydrogenation in balloon for 12 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated to give the compound in 71% yield (0.5 g).¹HNMR(300MHz,DMSO-d₆):9.83(s,1H),7.86-7.85(m,1H),7.71-7.70(m,1H),7.35(s,1H),7.04(s,1H),6.88(s,1H),5.45(brs,2H),2.03(s,3H)。

d) N- (3- (4-bromo-2-nitrophenylamino) -5- (thiazol-2-yl) phenyl) acetamide

A solution of the compound from example 156(c) (0.5g,2.14mmol), 4-bromo-1-fluoro-2-nitrobenzene (0.47g,2.14mmol,1.0eq.) and potassium fluoride (0.19g,3.21mmol,1.5eq.) in DMF was heated at 80 ℃ for 7 hours. The mixture was quenched and extracted as described in example 1 (d). The solvent was evaporated and the residue was purified by column chromatography (60-120 silica gel, 40% ethyl acetate in hexane) to give the product in 24% yield (0.22 g).

e) N- (3- (2-amino-4-bromophenylamino) -5- (thiazol-2-yl) phenyl) acetamide

To a solution of the compound from example 156(d) (0.22g,0.507mmol) in THF (15ml) was added a solution of ammonium chloride (0.11g,2.02mmol,4eq.) in water (5ml) and zinc (0.13g,2.02mmol,4 eq.). The mixture was stirred at room temperature overnight and filtered. The filtrate was diluted with water and extracted as described in example 1 (d). Evaporation of the solvent gave the product in 83% yield (0.17 g).

f) N- (3- (5-bromo-1H-benzo [ d ] imidazol-1-yl) -5- (thiazol-2-yl) phenyl) acetamide

A mixture of the compound from example 156(e) (0.17g,0.42mmol) and formic acid (3ml) was heated at 80 ℃ for 2 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 product in 86% yield (0.15 g). ¹HNMR(300MHz,DMSO-d₆):10.52(s,1H),8.77(s,1H),8.32(s,1H),8.07-8.00(m,3H),7.90-7.87(m,2H),7.66-7.63(m,1H),7.55(s,1H),2.13(s,3H)。

g) N- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (thiazol-2-yl) phenyl) acetamide

A solution of the compound from example 156(f) (0.2g,0.48mmol) in 1, 2-dimethoxyethane (15ml) was passed through N₂Bubbling and degassing for 5 minutes. 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (0.15g,0.73mmol,1.5eq.) was added and the mixture was degassed for an additional 5 minutes. Adding Pd (PPh)₃)₄(0.11g,0.096mmol,0.2eq.) and aqueous sodium carbonate (0.1g,0.96mmol,2.0eq.), followed by the procedure of example 1 (d). The crude residue of the product was purified by preparative HPLC to give the product in 1.5% yield (3 mg).¹HNMR(300MHz,CD₃OD is 8.20-8.11(M,2H),8.05-7.82(M,5H),7.68-7.61(M,3H),7.55-7.45(M,1H),3.88(s,3H),2.12(s,3H), LC-MS (ESI), calculated mass 414.48, measured mass 415.0[ M + H ] 415.0]⁺(retention time: 0.31 minutes).

Example 157

N- (3- (1H-indol-3-yl) -5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide

a) N- (3-nitro-5- (1- (phenylsulfonyl) -1H-indol-3-yl) phenyl) acetamide

A solution of N- (3-bromo-5-nitrophenyl) acetamide (0.38g,1.48mmol) in 1, 2-dimethoxyethane (15ml) was passed over N₂Bubbling and degassing for 5 minutes. 1- (phenylsulfonyl) -3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indole (0.68g,1.77mmol,1.2eq.) was added and the mixture was degassed for a further 5 minutes. Adding Pd (dppf) Cl ₂(0.12g,0.148mmol,0.1eq.) and aqueous sodium carbonate (0.47g,4.45mmol,3.0eq.) followed by the procedure of example 1 (d). The crude residue of the product was purified by column chromatography (60-120 silica gel, 30% ethyl acetate in hexane) to afford the product in 77% yield (0.5 g).

b) N- (3-amino-5- (1- (phenylsulfonyl) -1H-indol-3-yl) phenyl) acetamide

To a solution of the compound from example 157(a) (1g,2.29mmol) in methanol (10ml) was added 10% Pd/C (100mg,0.1eq.) and the reaction vessel purged with nitrogen for 5 minutes. Then the mixture is taken up with H₂Hydrogenation in balloon for 12 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated to give the compound in 89% yield (0.83 g).

c) N- (3- (4-bromo-2-nitrophenylamino) -5- (1- (phenylsulfonyl) -1H-indol-3-yl) phenyl) acetamide

A solution of the compound from example 157(b) (0.83g,2.04mmol), 4-bromo-1-fluoro-2-nitrobenzene (0.45g,2.04mmol,1.0eq.) and potassium fluoride (0.12g,2.04mmol,1.0eq.) in DMF (10ml) was heated at 130 ℃ for 5 hours. The mixture was quenched and extracted as described in example 1 (d). The solvent was evaporated and the residue was purified by column chromatography (60-120 silica gel, 30% ethyl acetate in hexane) to give the product in 48% yield (0.6 g).

d) N- (3- (2-amino-4-bromophenylamino) -5- (1- (phenylsulfonyl) -1H-indol-3-yl) phenyl) acetamide

To a solution of the compound from example 157(c) (0.61g,1mmol) in THF (10ml) and methanol (10ml) was added a solution of ammonium chloride (0.53g,10mmol,10eq.) in water (5ml) and zinc (0.63g,10mmol,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 example 1 (d). Evaporation of the solvent gave the product in 70% yield (0.4 g).

e) N- (3- (5-bromo-1H-benzo [ d ] imidazol-1-yl) -5- (1- (phenylsulfonyl) -1H-indol-3-yl) phenyl) acetamide

A mixture of the compound from example 157(d) (0.4g,0.7mmol) and formic acid (10ml) was heated at 100 ℃ for 30 minutes. 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 product in 73% yield (0.3 g).

f) N- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1- (phenylsulfonyl) -1H-indol-3-yl) phenyl) acetamide

A solution of the compound from example 157(e) (0.3g,0.5mmol) in 1, 2-dimethoxyethane (15ml) was passed through N₂Bubbling and degassing for 5 minutes. 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (0.13g,0.62mmol,1.2eq.) was added and the mixture was degassed for an additional 5 minutes. Adding Pd (PPh) ₃)₄(0.057g,0.05mmol,0.1eq.) and aqueous sodium carbonate (0.16g,1.54mmol,3.0eq.) followed by the procedure of example 1 (d). Crude product is obtainedThe residue was purified by column chromatography (60-120 silica gel, 50% ethyl acetate in hexane) to give the product in 100% yield (0.29 g). LC-MS (ESI) calculated mass 586.66 and measured mass 587.2[ M + H ]]⁺(retention time: 1.53 minutes).

g) N- (3- (1H-indol-3-yl) -5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide

To a solution of the compound from example 157(f) (0.3g,0.5mmol,1eq.) in THF (10ml) and methanol (10ml) was added cesium carbonate (0.33g,1mmol,2eq.) and the mixture was stirred at room temperature for 12 hours. The mixture was quenched and extracted as described in example 1 (d). Evaporation of the solvent gave the product in 7% yield (15 mg).¹HNMR(400MHz,DMSO-d₆) 11.52(s,1H),10.33(s,1H),8.65(s,1H),8.19(s,1H),8.04-7.89(M,4H),7.68(d,1H),7.60-7.58(M,2H),7.49-7.47(M,3H),7.21-7.13(M,2H),3.88(s,3H),2.13(s,3H), LC-MS (ESI), calculated mass 446.50, measured mass 447.1[ M + H ], calculated mass 447.1 (M + H, 3H), calculated mass]⁺(retention time: 0.55 minutes).

Example 158

N- (3- (6-methoxypyridin-3-yl) -5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide

a) N- (3- (6-methoxypyridin-3-yl) -5-nitrophenyl) acetamide

A solution of N- (3-bromo-5-nitrophenyl) acetamide (1g,3.86mmol) in 1, 2-dimethoxyethane (20ml) was passed through N₂Bubbling and degassing for 5 minutes. (6-methoxypyridin-3-yl) boronic acid (0.77g,5.0mmol,1.3eq.) was added and the mixture degassed for 5 minutes. Adding Pd (dppf) Cl₂(0.630g,0.77mmol,0.2eq.) and aqueous sodium carbonate (1.23g,11.58mmol,3.0eq.) followed by the procedure of example 1 (d). The crude residue of the product was purified by column chromatography (60-120 silica gel, 40% ethyl acetate in hexane) to afford the product in 81% yield (0.9 g).

b) N- (3-amino-5- (6-methoxypyridin-3-yl) phenyl) acetamide

To a solution of the compound from example 158(a) (0.9g,3.13mmol) in methanol (50ml) was added 10% Pd/C (250mg) and the reaction vessel was purged with nitrogen for 5 minutes. Then the mixture is taken up with H₂Hydrogenation of the balloon for 4 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated to give the compound,

99% yield (0.8 g).

c) N- (3- ((4-bromo-2-nitrophenyl) amino) -5- (6-methoxypyridin-3-yl) phenyl) acetamide

A solution of the compound from example 158(b) (0.8g,3.11mmol), 4-bromo-1-fluoro-2-nitrobenzene (0.68g,3.11mmol,1.0eq.) and potassium fluoride (0.18g,3.111mmol,1.0eq.) in DMF (5ml) was heated at 90 ℃ for 20 h. The mixture was quenched and extracted as described in example 1 (d). The solvent was evaporated and the residue was purified by column chromatography (60-120 silica gel, 40% ethyl acetate in hexane) to give the product in 42% yield (0.6 g). LC-MS (ESI) calculated mass 457.28, measured mass 458.9M + H ]⁺(retention time: 1.71 minutes).

d) N- (3- ((2-amino-4-bromophenyl) amino) -5- (6-methoxypyridin-3-yl) phenyl) acetamide

To a solution of the compound from example 158(c) (0.3g,0.66mmol) in ethanol (20ml) and water (5ml) were added calcium chloride (0.73g,6.6mmol,10eq.) and iron powder (0.36g,6.6mmol,10eq.) and the mixture was heated at 90 ℃ for 6 hours and filtered. The filtrate was diluted with water and extracted as described in example 1 (d). The solvent was distilled off and the crude residue was used directly in the next step.

e) N- (3- (5-bromo-1H-benzo [ d ] imidazol-1-yl) -5- (6-methoxypyridin-3-yl) phenyl) acetamide

A mixture of the compound from example 158(d) (0.26g,0.61mmol) and formic acid (5ml) was heated at 100 ℃ for 2 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. The solvent was evaporated and the residue was purified by column chromatography (60-120 silica gel, 10% methanolChloroform solution) gave the product in 86% yield (0.23 g). LC-MS (ESI) calculated mass 437.29 and measured mass 438.0[ M + H ]]⁺(retention time: 1.52 minutes). f) N- (3- (6-methoxypyridin-3-yl) -5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d)]Imidazol-1-yl) phenyl) acetamide

A solution of the compound from example 158(e) (0.22g,0.5mmol) in 1, 2-dimethoxyethane (20ml) was passed through N₂Bubbling and degassing for 5 minutes. 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (0.11g,0.55mmol,1.1eq.) was added and the mixture was degassed for an additional 5 minutes. Adding Pd (PPh)₃)₄(0.116g,0.1mmol,0.2eq.) and aqueous sodium carbonate (0.16g,1.5mmol,3.0eq.) followed by the procedure of example 1 (d). The crude residue of the product was purified by preparative HPLC to give the product in 18% yield (40 mg).¹HNMR(300MHz,DMSO-d₆) 10.4(s,1H),8.82(s,1H),8.55(s,1H),8.23(s,1H),8.1-8.04(M,2H),7.98-7.91(M,2H),7.85(s,1H),7.74-7.65(M,3H),6.97(d,1H),3.92(s,3H),3.88(s,3H),2.12(s,3H), LC-MS (ESI), calculated mass 438.48, measured mass 439.1[ M + H ], calculated mass ESI]⁺(retention time: 0.4 minutes).

Example 159

N- (5- (5- (1H-pyrazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) propionamide

To a solution of the compound from example 29(a) (0.5g,1.3mmol) in DMF (10ml) was added HATU (0.98g,2.6mmol,2.0eq.), followed by DIPEA (0.5g,3.9mmol,3eq.) and propionic acid (0.19g,2.6mmol,2.0 eq.). The mixture was stirred for 4 hours, then the reaction was terminated and extracted as described in example 1 (d). The solvent was evaporated and the residue was purified by preparative HPLC to give the product in 9% yield (50 mg). ¹HNMR(300MHz,DMSO-d₆) 10.12(s,1H),8.9-8.8(s,1H),8.6(d,1H),8.2(s,1H),8.12(s,1H),7.95(d,1H),7.89-7.82(M,2H),7.8-7.7(M,2H),7.55(s,1H),7.45-7.40(M,1H),7.3-7.22(M,1H),6.6-6.52(s,1H),2.4 (quartet, 2H),1.15(t,3H), LC-MS (ESI): 443.45; 444.1[ M + H ], (M + H): 444.1]⁺(retention time: 1.58 minutes).

Example 160

N- (5- (5- (1H-pyrazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) isobutyramide

This compound was prepared from the compound of example 29(a) using the procedure of example 159.¹HNMR(300MHz,DMSO-d₆) 10.28(s,1H),8.8(s,1H),8.58(d,1H),8.22(d,1H),8.11(s,1H),7.95(d,1H),7.92(d,1H),7.87(d,1H),7.82(s,1H),7.78(s,1H),7.53(s,1H),7.45(d,1H),7.25(s,1H),6.55-6.54(M,1H),2.67-2.58(M,1H),1.12(d,6H), LC-MS (ESI): 457.47; 458.1[ M + H ], (M + H): 458.]⁺(retention time: 1.6 minutes).

Example 161

N- (5- (5- (1H-pyrazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) cyclopropanecarboxamide

This compound was prepared from the compound of example 29(a) using the procedure of example 159.¹HNMR(300MHz,DMSO-d₆) 10.63(s,1H),8.72(s,1H),8.57(d,1H),8.21(d,1H),8.08(s,1H),7.93-7.74(M,5H),7.52(s,1H),7.46-7.39(M,1H),7.29-7.23(M,1H),6.55(s,1H),1.85-1.79(M,1H),0.87(d,4H), LC-MS (ESI) calculated mass: 455.46, measured mass: 456.1[ M + H + M,1H) ]⁺(retention time: 1.58 minutes).

Example 162

N- (5- (5- (1H-pyrazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) pivaloamide

This compound was prepared from the compound of example 29(a) using the procedure of example 159.¹HNMR(400MHz,DMSO-d₆):9.65(s,1H),8.74(s,1H),8.0(d,1H),8.23(d,1H),8.17(s,1H) 8.01(s,1H),7.95-7.92(M,1H),7.84-7.81(M,1H),7.78-7.72(M,2H),7.54(s,1H),7.48-7.42(M,1H),7.29-7.25(M,1H),6.57-6.56(M,1H),1.27(s,9H); LC-MS (ESI) calculating mass 471.5; measured mass 472.2[ M + H + ESI ]]⁺(retention time: 1.68 minutes).

Example 163

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

To a solution of the compound from example 29(a) (0.1g,0.26mmol) in DMF (3ml) was added EDC (74mg,0.39mmol,1.5eq.), HOBt (70mg,0.52mmol,2eq.), followed by DIPEA (0.1g,0.77mmol,3eq.) and 2- (morpholin-4-yl) acetic acid (intermediate example 10) (56mg,0.39mmol,1.5 eq.). The mixture was stirred for 12 hours, then quenched and extracted as described in example 1 (d). The solvent was evaporated and the crude residue was purified by preparative HPLC to give the product in 27% yield (36 mg).¹HNMR(400MHz,D₂O8.74 (s,1H),8.60(d,1H),8.24(d,1H),8.14(s,1H),7.96-7.91(M,2H),7.84-7.76(M,3H),7.57(s,1H),7.49-7.40(M,1H),7.35-7.22(M,1H),6.56(M,1H),3.66(t,4H),3.61-3.59(M,4H),3.21(s,2H), LC-MS (ESI), calculated mass 514.53, measured mass 515.1[ M + H ESI ]⁺(retention time: 0.53 minutes).

Example 164

N- (2',4' -difluoro-5- (5- (1- (1-methylpiperidin-4-yl) -1H-1,2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) acetamide

A mixture of the compound from example 17(e) (0.7g,1.8mmol), 4-azido-1-methylpiperidine (0.3g,2.17mmol,1.2eq.), sodium ascorbate (0.35g,1.8mmol,1.0eq.) and copper sulfate pentahydrate (0.22g,0.9mmol,0.5eq.) in DMSO, DCM and water (1:1:1,3ml) was stirred at room temperature for 12 hours. The mixture was quenched with water and the precipitate formed was filtered and dried to give the crude product, which was taken up in diethyl etherRecrystallization afforded the product in 71% yield (0.67 g).¹HNMR(300MHz,DMSO-d₆) 10.41(s,1H),8.75(s,2H),8.28(d,1H),8.11(s,1H),7.95-7.92(M,1H),7.81-7.74(M,2H),7.53(s,1H),7.45(M,1H),7.27(M,1H),3.66-3.62(M,1H),3.26-3.22(M,4H),2.87(s,3H),2.27-2.22(M,4H),2.12(M,3H), LC-MS (ESI), a calculated mass of 527.57, an actually measured mass of 528.2[ M + H ] (M + H) ((M, 4H))]⁺(retention time: 0.19 minutes).

Example 165

N- (2',4' -difluoro-5- (5- (1- (1-methylpiperidin-4-yl) -1H-1,2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) ethanesulfonamide

a)2',4' -difluoro-5- (5- (1- (1-methylpiperidin-4-yl) -1H-1,2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-amine

A solution of the compound from example 164 (0.48g,0.91mmol) in 6N HCl (10ml) was heated at 70 ℃ for 3 hours. The mixture is washed with NaHCO₃The reaction was terminated with the solution and extracted as described in example 1 (d). Evaporation of the solvent gave the product in 27% yield (0.12 g).

b) N- (2',4' -difluoro-5- (5- (1- (1-methylpiperidin-4-yl) -1H-1,2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) ethanesulfonamide

To a solution of the compound from example 165(a) (60mg,0.123mmol) in DCM (2ml) was added pyridine (19mg,0.246mmol,2.0eq.) followed by ethanesulfonyl chloride (19mg,0.148mmol,1.2 eq.). The reaction was monitored by LCMS. After completion of the reaction, the solvent was removed under reduced pressure and the crude product was purified by flash chromatography (using 2% methanol in chloroform) to give the product in 13% yield (9 mg). LC-MS (ESI) for calculating mass 577.65 and measured mass 578.2M + H]⁺(retention time: 0.42 minutes).

Example 166

N- (2',4' -difluoro-5- (5- (1- (1-methylpiperidin-4-yl) -1H-1,2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) cyclopropanesulfonamide

This compound was prepared from the compound of example 164 using the procedure of example 165 and cyclopropanesulfonyl chloride. LC-MS (ESI) for calculating mass 553.61 and measured mass 554.2M + H ]⁺(retention time: 0.57 minutes).

Example 167

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

This compound was prepared from the compound of intermediate example 12 using the procedure of example 8.¹HNMR(300MHz,DMSO-d₆) 10.43(s,1H),9.12(s,1H),8.34(s,1H),8.12(s,1H),8.02-7.97(M,2H),7.81(s,1H),7.75-7.67(M,3H),7.55(s,1H),7.47-7.41(M,1H),7.29-7.22(M,1H),4.52-4.45(M,1H),2.10(s,3H),1.45(d,6H), LC-MS (ESI), calculated mass 471.5, measured mass 471.6[ M + H ] ESI]⁺(retention time: 1.4 minutes).

Example 168

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

a) N- (5- ((4-acetyl-2-nitrophenyl) amino) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) acetamide

A solution of the compound from example 1(e) (0.6g,2.28mmol), 1- (4-fluoro-3-nitrophenyl) ethanone (0.4g,2.28mmol,1.0eq.) and potassium fluoride (0.26g,4.56mmol,2.0eq.) in DMF was heated at 80 ℃ for 7 hours. The mixture was quenched and extracted as described in example 1 (d). The solvent was evaporated and the residue was purified by column chromatography (60-120 silica gel, 1% methanol in chloroform) to give the product in 68% yield (0.66 g). ¹HNMR(300MHz,DMSO-d₆):10.18(s,1H),9.83(s,1H),8.63(d,1H),8.01(m,1H),7.71(s,1H),7.59(m,2H),7.35(m,1H),7.27-7.16(m,3H),2.52(s,3H),2.05(s,3H)。

b) (E) -N- (5- ((4- (3- (dimethylamino) acryloyl) -2-nitrophenyl) amino) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) acetamide

To a solution of the compound from example 168(a) (0.66g,1.55mmol) in DMF (4ml) and ethanol (4ml) was added DMF dimethyl acetal (7ml) and stirred at 110 ℃ for 12 h. The mixture was extracted as described in example 1 (d). The solvent was distilled off to give the product in 89% yield (0.66g), which was used directly in the next step.

c) N- (2',4' -difluoro-5- ((4- (1-methyl-1H-pyrazol-3-yl) -2-nitrophenyl) amino) - [1,1' -biphenyl ] -3-yl) acetamide

To a solution of the compound from example 168(b) (0.66g,1.37mmol) in ethanol (15ml) was added methylhydrazine (7ml) and the mixture was stirred at room temperature overnight. The mixture was quenched with cold water and the solid formed was filtered, washed with water and used in the next step.¹HNMR(300MHz,DMSO-d₆):10.12(s,1H),9.52(s,1H),8.19(d,1H),7.73-7.60(m,2H),7.59-7.54(m,2H),7.46-7.35(m,3H),7.30-7.14(m,2H),6.44(d,1H),3.85(s,3H),2.05(s,3H)。

d) N- (5- ((2-amino-4- (1-methyl-1H-pyrazol-3-yl) phenyl) amino) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) acetamide

To a solution of the compound from example 168(c) (0.5g,1.07mmol) in THF (20ml) was added a solution of ammonium chloride (0.23g,4.28mmol,4eq.) in water (10ml) and zinc (0.28g,4.28mmol,4 eq.). The mixture was stirred at room temperature for 4 hours and filtered. The filtrate was diluted with water and extracted as described in example 1 (d). Evaporation of the solvent gave the product in 65% yield (0.3 g). LC-MS (ESI) calculated mass 433.45 and measured mass 434.1[ M + H ] ]⁺(retention time: 0.49 minutes).

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

Conversion of example 168(d)A mixture of compound (0.3g,0.69mmol) and formic acid (3ml) was heated at 100 ℃ for 2 hours. The formic acid was distilled off and the crude product was extracted with ethyl acetate. The solvent was evaporated and the residue was purified by preparative HPLC to give the product in 9% yield (28 mg).¹HNMR(300MHz,DMSO-d₆) 10.42(s,1H),8.81(s,1H),8.10(s,1H),7.96(s,1H),7.83-7.72(M,3H),7.54-7.42(M,4H),7.30-7.25(M,1H),6.45(d,1H),3.9(s,3H),2.13(s,3H), LC-MS (ESI) calculating mass 443.45, measured mass 443.7[ M + H ], (M + H) calculating mass]⁺(retention time: 1.37 minutes).

Example 169

N- (5- (5- (4, 5-dihydro-1H-imidazol-2-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) acetamide

a) N- (5- ((4- (4, 5-dihydro-1H-imidazol-2-yl) -2-nitrophenyl) amino) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) acetamide

To a solution of the compound from example 22(a) (200mg,0.49mmol) in DCM (10ml) was added ethylenediamine (0.036ml,0.54mmol,1.1eq.) followed by N-bromosuccinimide (95mg,0.54mmol,1.1eq.) at 0 ℃. The mixture was stirred for 12 hours, quenched with water and extracted as described in example 2 (b). The solvent was evaporated and the residue was purified by column chromatography (60-120 silica gel, 20% methanol in chloroform) to give the product in 50% yield (0.11 g). LC-MS (ESI) calculated mass 451.43 and measured mass 452.1[ M + H ] ]⁺(retention time: 0.63 minutes).

b) N- (5- ((2-amino-4- (4, 5-dihydro-1H-imidazol-2-yl) phenyl) amino) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) acetamide

To a solution of the compound from example 169(a) (0.11g,0.23mmol) in THF (10ml) was added a solution of ammonium chloride (50mg,0.93mmol,4eq.) in water (10ml) and zinc (60mg,0.93mmol,4 eq.). The mixture was stirred at room temperature for 4 hours and filtered. The filtrate was diluted with water and extracted as described in example 1 (d). Evaporation of the solvent gave the product in 88% yield (85 mg). LC-MS (ESI) calculated mass 421.44Quality measurement of 422.2M + H]⁺(retention time: 0.49 minutes).

c) N- (5- (5- (4, 5-dihydro-1H-imidazol-2-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) acetamide

A mixture of the compound from example 169(b) (80mg,0.19mmol) and formic acid (3ml) was heated at 100 ℃ for 4 hours. The formic acid was distilled off and the crude product was extracted with ethyl acetate. The solvent was evaporated and the residue was purified by preparative HPLC to give the product in 12% yield (10 mg).¹HNMR(400MHz,D₂O8.75 (s,1H),8.33(s,1H),7.96(s,1H),7.84-7.79(M,2H),7.74(s,1H),7.66-7.6(M,1H),7.47(s,1H),7.29-7.23(M,1H),7.19-7.14(M,1H),3.99(M,4H),2.06(s,3H), LC-MS (ESI), calculated mass 431.44, measured mass 432.1[ M + H ], calculated mass 432.1 ]⁺(retention time: 0.36 minutes).

Example 170

N- (4 '-fluoro-5- (5- (6-fluoropyridin-3-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) acetamide

This compound was synthesized by the method of example 53. LC-MS (ESI) calculated mass 440.44, measured mass 441.1[ M + H ]]⁺(retention time: 1.57 minutes).

Example 171

N- (3- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrrol-1-yl) phenyl) acetamide

To a solution of the compound from example 87(g) (1.5g,3.8mmol) in 1, 2-dimethoxyethane (40ml) were added the compound from intermediate example 13 (1.68g,7.59mmol,2eq.), sodium carbonate (1g,9.5mmol,2.5eq.) and water (4ml) and the mixture was degassed for 15 min (N)₂Bubbling). Adding Pd (PPh)₃)₄(0.9g,0.76mmol,0.2eq.) and the mixture was heated at 100 ℃ for 2 hours. The mixture was quenched and extracted as described in example 1 (d). Steaming and removingThe solvent was removed and the residue was purified by column chromatography to give the compound in 74% yield (1.15 g).¹HNMR(300MHz,DMSO-d₆) 8.86(M,1H),8.26(M,1H),7.99-7.94(M,2H),7.87-7.80(M,2H),7.72-7.60(M,3H),7.39(s,2H),6.31(s,2H),4.15 (quartet, 2H),2.10(s,3H),1.40(t,3H), LC-MS (ESI) calculating mass 410.47, measured mass 411.2[ M + H ] (ESI) ]⁺(retention time: 1.11 minutes).

Example 172

N- (3- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrrol-1-yl) phenyl) ethanesulfonamide

a)3- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrrol-1-yl) aniline

A mixture of 20% NaOH (5ml) and the compound from example 171 (0.9g,2.12mmol) in 25ml ethanol was heated at 90 ℃ for 2 h. The mixture was diluted with ethyl acetate (100ml) and the organic layer was washed with water (50ml) and brine (25 ml). The solvent was distilled off and the residue was purified by silica gel column chromatography to give the compound in 78% yield (0.7 g).

b) N- (3- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrrol-1-yl) phenyl) ethanesulfonamide

To a solution of the compound from example 172(a) (75mg,0.2mmol) in DCM (1ml) was added pyridine (0.5ml) and ethanesulfonyl chloride (52mg,0.4mmol,2eq.) and the mixture was stirred at room temperature for 12 h. The pyridine was distilled off and the residue was purified by preparative HPLC to give the compound in 25% yield (23 mg).¹HNMR(300MHz,DMSO-d₆) 10.31(s,1H),8.74(s,1H),8.26(s,1H),7.98(d,2H),7.69-7.61(M,3H),7.42-7.38(M,4H),6.33(s,2H),4.15 (quartet, 2H),3.16 (quartet, 2H),1.43(t,3H),1.25(t,3H), LC-MS (ESI): calculated mass 460.55, measured mass 461.18[ M + H ], (ESI) ]⁺(retention time: 1.38 minutes).

Example 173

N- (3- (5- (1-isopropyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrrol-1-yl) phenyl) acetamide

This compound was prepared from intermediate example 12 using the procedure of example 171.¹HNMR(300MHz,DMSO-d₆) 10.40(s,1H),8.67(s,1H),8.29(s,1H),8.01(s,1H),7.94(s,1H),7.86-7.81(M,2H),7.70-7.59(M,3H),7.41(s,2H),6.32(s,2H),4.53-4.49(M,1H),2.12(s,3H),1.46(d,6H), LC-MS (ESI), calculated mass 424.5, measured mass 425.2[ M + H ] ESI]⁺(retention time: 1.34 minutes).

Example 174

N- (3- (5- (1-isopropyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrrol-1-yl) phenyl) methanesulfonamide

a)3- (5- (1-isopropyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrrol-1-yl) aniline

A mixture of 20% NaOH (5ml) and the compound from example 173 (1g,2.43mmol) in 25ml of ethanol was heated at 90 ℃ for 2 hours. The mixture was diluted with ethyl acetate (100ml) and the organic layer was washed with water (50ml) and brine (25 ml). The solvent was distilled off and the crude product was purified by silica gel column chromatography to give the compound in 93% yield (0.75 g).

b) N- (3- (5- (1-isopropyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrrol-1-yl) phenyl) methanesulfonamide

To a solution of the compound from example 174(a) (100mg,0.26mmol) in DCM (1ml) was added pyridine (0.5ml) and ethanesulfonyl chloride (60mg,0.52mmol,2eq.) and the mixture was stirred at room temperature for 12 h. The pyridine was distilled off and the residue was purified by preparative HPLC to give the compound in 8% yield (10 mg).¹HNMR(300MHz,CD₃OD: 9.20(s,1H),8.18(s,1H),8.01(s,1H),7.94(s,1H),7.80(s,2H),7.62(s,1H),7.49(m,2H),7.31(m,2H),6.35(m,2H),4.65-4.51(m,1H),3.14(s,3H),1.55(d,6H), LC-MS (ESI): calculated mass: 461.0; measured mass: LC-MS (ESI): determined by experiment)Mass 460.55[ M + H]⁺(retention time: 1.44 minutes).

Example 175

N- (3- (5- (1-isopropyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrrol-1-yl) phenyl) ethanesulfonamide

The compound was prepared from the compound of example 173 using the procedure of example 174.¹HNMR(300MHz,CD₃OD) 9.05(s,1H),8.16(s,1H),7.99-7.93(M,2H),7.77(s,2H),7.58(s,1H),7.47(M,2H),7.30(M,2H),6.35(M,2H),4.60-4.51(M,1H),3.30 (quartet, 2H),1.56-1.54(d,6H),1.38(t,3H), LC-MS (ESI) calculated mass 474.58, measured mass 475.1[ M + H ] 475.1]⁺(retention time: 1.50 minutes).

Example 176

N- (2',4' -difluoro-5- (6- (1-methyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1' -biphenyl ] -3-yl) propionamide

To a solution of propionic acid (20mg,0.274mmol) in DMF (2ml) was added HATU (155mg,0.41mmol,1.5eq.) and the mixture was stirred at room temperature for 0.5 h. The compound from example 132(a) (110mg,0.274mmol) and DIPEA (0.15ml,0.821mmol,3eq.) were added and the mixture was stirred for 12 h, quenched with water and extracted with DCM (3 × 50 ml). The combined organic layers were washed with water to give a precipitate, which was filtered. The crude product was purified by preparative HPLC to give the product (14 mg).¹HNMR(400MHz,DMSO-d₆) 10.23(s,1H),8.92(s,1H),8.72(d,1H),8.41(d,1H),8.33-8.31(M,2H),8.04(d,1H),7.89(d,1H),7.75-7.69(M,2H),7.48-7.42(M,1H),7.29-7.25(M,1H),3.90(s,3H),2.40 (quartet, 2H),1.11(t,3H), LC-MS (ESI): calculated mass 458.46, measured mass 459.1[ M + H ] (ESI) ]]⁺(retention time: 1.44 minutes).

Example 177

N- (2',4' -difluoro-5- (6- (1-methyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1' -biphenyl ] -3-yl) cyclopropanecarboxamide

This compound was prepared using the procedure of example 176.¹HNMR(400MHz,DMSO-d₆) 10.62(s,1H),8.94(s,1H),8.72(d,1H),8.41(d,1H),8.31(d,2H),8.04(s,1H),7.88(brs,1H),7.72-7.68(M,2H),7.47-7.41(M,1H),7.29-7.25(m.1H),3.89(s,3H),1.85(M,1H),0.84(d,4H), LC-MS (ESI): 470.4, 471.1[ M + H ] mass measured ]⁺(retention time: 1.52 minutes).

Example 178

N- (2',4' -difluoro-5- (6- (6-fluoropyridin-3-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1' -biphenyl ] -3-yl) acetamide

A solution of the compound from example 131(c) (330mg,0.75mmol) in 1, 2-dimethoxyethane (10ml) was passed through N₂Bubbling and degassing for 5 minutes. (6-Fluoropyridin-3-yl) boronic acid (130mg,0.9mmol,1.2eq.) was added and the mixture was degassed for an additional 5 minutes. Adding Pd (dppf) Cl₂(120mg,0.15mmol,0.2eq.) and aqueous sodium carbonate (290mg,2.7mmol,3.0eq.), followed by the procedure of example 1 (d). The crude residue of the product was purified by preparative HPLC to afford the product.¹HNMR(400MHz,DMSO-d₆) 10.40(s,1H),9.03(s,1H),8.79(d,1H),8.68(s,1H),8.60(s,1H),8.43(dt,1H),8.30(s,1H),7.87(s,1H),7.70(s,2H),7.47-7.26(M,3H),2.07(s,3H), LC-MS (ESI) calculating mass 459.4, measured mass 460.1[ M + H: (ESI) ], and mass]⁺(retention time: 1.53 minutes).

Example 179

N- (5- (6- (1H-pyrazol-1-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) -2' -fluoro-4 ' -methoxy- [1,1' -biphenyl ] -3-yl) acetamide

The compound was synthesized using the procedure of example 148 using N- (3-bromo-5-nitrophenyl) acetamide (0.8g,3.089mmol) and 2-fluoro-4-methoxyPhenylphenyl) boronic acid (0.63g,3.71mmol,1.2eq.) was prepared as starting material. ¹HNMR(400MHz,DMSO-d₆) 10.39(s,1H),9.05(s,1H),9.02(d,1H),8.67(d,2H),8.26(s,1H),7.89(s,1H),7.84(d,1H),7.68(s,1H),7.59(t,1H),7.04-6.95(M,2H),6.64(t,1H),3.85(s,3H),2.13(s,3H), LC-MS (ESI), calculated mass 442.45, measured mass 443.1[ M + H ] is used]⁺(retention time: 1.42 minutes).

Example 180

N- (2' -fluoro-4 ' -methoxy-5- (6- (1-methyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1' -biphenyl ] -3-yl) acetamide

A solution of the compound from example 179(e) (250mg,0.549mmol) in 1, 2-dimethoxyethane (10ml) was passed through N₂Bubbling and degassing for 5 minutes. 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (137mg,0.66mmol,1.2eq.) was added and the mixture was degassed for an additional 5 minutes. Adding Pd (PPh)₃)₄(63mg,0.0549mmol,0.1eq.) and aqueous sodium carbonate (117mg,1.1mmol,2.0eq.) followed by the procedure of example 1 (d). The crude residue of the product was purified by preparative HPLC to give the product in 90% yield (225 mg).¹HNMR(400MHz,DMSO-d₆) 10.39(s,1H),8.92(s,1H),8.71(d,1H),8.41(d,1H),8.30(s,1H),8.25(t,1H),8.04(s,1H),7.84(d,1H),7.67(s,1H),7.58(t,1H),7.03-6.93(M,2H),3.90(s,3H),3.84(s,3H),2.11(s,3H), LC-MS (ESI): 456.47, 456.6[ M + H ] (S, 3H): measured mass: 456.6 ]⁺(retention time: 1.07 minutes).

Example 181

N- (2',4' -difluoro-5- (6- (1- (1-methylpiperidin-4-yl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1' -biphenyl ] -3-yl) acetamide

a) N- (2',4' -difluoro-5- ((5-iodo-3-nitropyridin-2-yl) amino) - [1,1' -biphenyl ] -3-yl) acetamide

Examples of the inventionA solution of the compound of 1(e) (2.58g,9.85mmol), 2-chloro-5-iodo-3-nitropyridine of intermediate example 14 (2.8g,9.85mmol,1.0eq.) and potassium fluoride (0.57g,9.85mmol,1.0eq.) in DMF (30ml) was heated at 130 ℃ for 5 hours. The mixture was quenched and extracted as described in example 1 (d). The solvent was evaporated and the residue was purified by column chromatography (60-120 silica gel, 30% ethyl acetate in hexane) to give the product in 40% yield (2.0 g).¹HNMR(300MHz,DMSO-d₆) 10.10(s,1H),9.95(s,1H),8.74(d,1H),8.66(d,1H),7.88(s,1H),7.60-7.52(M,2H),7.42-7.34(M,2H),7.24-7.21(M,1H),2.07(s,3H), LC-MS (ESI) calculated mass: 510.2, measured mass: 510.9[ M + H (ESI) ], and mass ratio of the mass ratio to the mass ratio of the mass ratio]⁺(retention time: 1.75 minutes).

b) N- (5- ((3-amino-5-iodopyridin-2-yl) amino) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) acetamide

To a solution of the compound from example 181(a) (0.5g,0.98mmol) in THF (30ml) was added a solution of ammonium chloride (0.2g,3.92mmol,4eq.) in water (15ml) and zinc (0.25g,3.92mmol,4 eq.). The mixture was stirred at room temperature for 3 hours and filtered. The filtrate was diluted with water and extracted as described in example 1 (d). Evaporation of the solvent gave the product in 64% yield (0.3 g). ¹HNMR(400MHz,DMSO-d₆) 9.96(s,1H),7.99(s,1H),7.90(s,1H),7.61(d,1H),7.50 (quartet, 1H), 7.43(s,1H),7.39-7.33(M,1H),7.28(s,1H),7.22-7.18(M,2H),5.39(s,2H),2.05(s,3H), LC-MS (ESI): calculated mass: 480.2; measured mass: 481.1[ M + H ], (ESI): 481.1]⁺(retention time: 1.53 minutes).

c) N- (2',4' -difluoro-5- (6-iodo-3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1' -biphenyl ] -3-yl) acetamide

A mixture of the compound from example 181(b) (3.12g,1.5g) and formic acid (15ml) was heated at 90 ℃ for 1 hour. The formic acid was then distilled off and the residue 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 product in 92% yield (1.4 g).¹HNMR(300MHz,DMSO-d₆) 10.38(s,1H),8.93(s,1H),8.63(s,2H),8.21(s,1H),7.89(s,1H),7.74-7.64(m,2H),7.42(t,1H),7.26(t,1H),2.11(s,3H), LC-MS (ESI)Calculated mass 490.2, measured mass 491.1M + H]⁺(retention time: 1.60 minutes).

d) N- (2',4' -difluoro-5- (6- ((trimethylsilyl) ethynyl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1' -biphenyl ] -3-yl) acetamide

The compound from example 181(c) (1.6g,3.265mmol) in DMF-Et₃The N (1:1;60ml) solution was passed through N₂Bubbling and degassing for 15 minutes. Followed by the addition of Pd (PPh)₃)₄(0.18g,0.163mmol,0.05eq.), copper (I) iodide (62mg,0.326mmol,0.1eq.) and ethynyltrimethylsilane (0.38g,3.91mmol,1.2eq.) and the mixture was stirred at room temperature for 12 hours. The mixture was quenched and extracted as described in example 1 (d). The solvent was evaporated and the residue was purified by column chromatography (60-120 silica gel, 40% ethyl acetate in hexane) to give the product in 73% yield (1.1 g). ¹HNMR(300MHz,DMSO-d₆) 10.41(s,1H),9.02(s,1H),8.52(d,1H),8.33(d,1H),8.21(s,1H),7.91(s,1H),7.73-7.64(M,2H),7.43(M,1H),7.26(M,1H),2.11(s,3H),0.27(s,9H), LC-MS (ESI) calculating mass 460.55, measured mass 461.2[ M + H ] measured mass]⁺(retention time: 1.83 minutes).

e) N- (5- (6-ethynyl-3H-imidazo [4,5-b ] pyridin-3-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) acetamide

To a solution of the compound from example 181(d) (1.1g,2.4mmol) in THF was added TBAF (1M in THF; 0.6ml,2.4mmol,1.0eq.) at 0 deg.C and the mixture was stirred for 0.5 h. The mixture was filtered through a pad of silica and distilled to give a crude residue which was purified by column chromatography (60-120 silica gel, 5% methanol in chloroform) to give the product in 86% yield (0.8 g).¹HNMR(300MHz,DMSO-d₆) 10.39(s,1H),9.03(s,1H),8.56(d,1H),8.38(d,1H),8.23(s,1H),7.91(s,1H),7.75-7.66(M,2H),7.48-7.41(M,1H),7.30-7.24(M,1H),4.39(s,1H),2.07(s,3H), LC-MS (ESI) calculating mass 388.3, measured mass 389.2[ M + H ] measured mass 389.2]⁺(retention time: 1.49 minutes).

f) N- (2',4' -difluoro-5- (6- (1- (1-methylpiperidin-4-yl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1' -biphenyl ] -3-yl) acetamide

A mixture of the compound from example 181(e) (0.5g,1.28mmol), 4-azido-1-methylpiperidine from intermediate example 11 (0.21g,1.54mmol,1.2eq.), sodium ascorbate (0.25g,1.28mmol,1.0eq.) and copper sulfate pentahydrate (0.16g,0.6mmol,0.5eq.) in DMSO, DCM and water (2:5:2,9ml) was stirred at room temperature for 12 hours. The mixture was quenched with water and the precipitate formed was filtered and dried to give the crude product, which was purified by preparative HPLC to give the product in 74% yield (0.5 g). ¹HNMR(300MHz,CDCI₃) 8.94(d,1H),8.56(d,1H),8.43(s,1H),8.15(s,1H),7.90(s,1H),7.72(s,1H),7.65(s,2H),7.53-7.45(M,1H),7.05-7.49(M,1H),4.68-4.59(M,1H),3.18-3.13(M,4H),2.62(s,3H),2.44-2.39(M,4H),2.24(s,3H), LC-MS (ESI), a calculated mass of 558.50, an actually measured mass of 529.2[ M + H ] (ESI)]⁺(retention time: 0.39 minutes).

Example 182

N- (2',4' -difluoro-5- (6- (1- (1-methylpiperidin-4-yl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1' -biphenyl ] -3-yl) ethanesulfonamide

a)2',4' -difluoro-5- (6- (1- (1-methylpiperidin-4-yl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1' -biphenyl ] -3-amine

The compound (0.4g,0.757mmol) of example 181 was added to 6N HCl aqueous solution (10ml) at 0 ℃ and the mixture was stirred at 70 ℃ for 3 hours. The mixture was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3X 50 ml). The combined organic layers were washed with water, brine, dried over sodium sulfate and the residue was purified by column chromatography (60-120 silica gel, 10% methanol in DCM) to give the product in 30% yield (0.11 g). LC-MS (ESI) for calculating mass 486.52 and measured mass 487.3M + H]⁺(retention time: 0.22 minutes).

b) N- (2',4' -difluoro-5- (6- (1- (1-methylpiperidin-4-yl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1' -biphenyl ] -3-yl) ethanesulfonamide

To a solution of the compound from example 182(a) (55mg,0.113mmol) in DCM was added pyridine (17mg,0.226mmol,2.0eq.) followed by ethanesulfonyl chloride (17mg,0.135mmol,1.2 eq.). The reaction was monitored by LCMS. After completion of the reaction, the solvent was evaporated and the crude product was purified by preparative HPLC to give the product in 46% yield (30 mg).¹HNMR(300MHz,DMSO-d₆) 10.31(s,1H),9.01(s,1H),8.97(d,1H),8.84(s,1H),8.62(s,1H),7.93(s,1H),7.75-7.71(M,2H),7.48-7.419(M,2H),7.27(M,1H),3.45(M,1H),2.79(s,3H),2.41-2.34(M,4H),2.28-2.24 (quartet, 2H),1.27-1.22(M,4H),1.03(t,3H), LC-MS (ESI): 578.64; 578.9[ M + H ] measured mass]⁺(retention time: 0.11 minutes).

Example 183

N- (2',4' -difluoro-5- (6- (1- (1-methylpiperidin-4-yl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1' -biphenyl ] -3-yl) cyclopropanecarboxamide

To a solution of cyclopropanecarboxylic acid (14mg,0.169mmol,1.5eq.) in DMF (2ml) was added HATU (90mg,0.226mmol,2.0eq.) and the mixture was stirred at room temperature for 0.5 h. The compound from example 182(a) (55mg,0.113mmol) and DIPEA (45mg,0.339mmol,3eq.) were added and the mixture was stirred for 12 h, quenched with water and extracted with DCM (3 × 50 ml). The combined organic layers were washed with water to give a precipitate, which was filtered. The crude product was purified by preparative HPLC to give the product in 13% yield (12 mg). ¹HNMR(300MHz,DMSO-d₆) 10.68(s,1H),8.98(s,2H),8.83(s,1H),8.62(s,1H),8.33(s,1H),8.88(s,1H),7.71-7.66(M,2H),7.46-7.39(M,1H),7.28-7.23(M,1H),4.83(M,1H),3.62-3.52(M,4H),2.81(s,3H),2.30-2.26(M,4H),1.85(M,1H),0.83(d,4H), LC-MS (ESI) calculating mass 554.59, measured mass 554.9[ M + H ] 554.9]⁺(retention time: 0.183 min).

Example 184

N- (5- (5- (1H-pyrazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -2',6' -difluoro- [1,1' -biphenyl ] -3-yl) methanesulfonamide

a)5- (5- (1H-pyrazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -2',6' -difluoro- [1,1' -biphenyl ] -3-amine

To a solution of the compound (2.1g,4.895mmol) prepared in example 152 in ethanol (50ml) was added 10% aqueous sodium hydroxide (10ml) and the mixture was heated at 100 ℃ for 2 hours. The mixture was quenched and extracted as described in example 1 (d). Evaporation of the solvent gave the product in 89% yield (1.6 g).

b) N- (5- (5- (1H-pyrazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -2',6' -difluoro- [1,1' -biphenyl ] -3-yl) methanesulfonamide

To a solution of the compound from example 184(a) (50mg,0.129mmol) in DCM was added pyridine (20mg,0.258mmol,2.0eq.) followed by methanesulfonyl chloride (18mg,0.155mmol,1.2 eq.). The reaction was monitored by LCMS. After completion of the reaction, the solvent was evaporated and the crude product was purified by preparative HPLC to give the product in 50% yield (30 mg). ¹HNMR(400MHz,DMSO-d₆) 10.32(s,1H),8.76(s,1H),8.61(d,1H),8.24(d,1H),7.93(dd,1H),7.79(s,1H),7.76(d,1H),7.61-7.57(M,4H),7.37(s,1H),7.31(t,2H),3.19(s,3H), LC-MS (ESI) calculating mass 465.48, measured mass 466.1[ M + H ], (S,1H) calculating mass]⁺(retention time: 1.47 minutes).

Example 185

N- (5- (5- (1H-pyrazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -2',6' -difluoro- [1,1' -biphenyl ] -3-yl) ethanesulfonamide

The compound was prepared from the compound of example 152 using the procedure of example 184.¹HNMR(400MHz,DMSO-d₆) 10.35(s,1H),8.72(s,1H),8.60(d,1H),8.24(d,1H),7.93(dd,1H),7.76(t,2H),7.61-7.54(M,3H),7.39(s,1H),7.31(t,2H),6.56(t,1H),2.40 (quartet, 2H),1.26(t,3H), LC-MS (ESI): calculated mass 479.5, measured mass 480.0[ M + H ], (M + H): measured mass]⁺(Retention time: 151 minutes).

Example 186

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

a)2',6' -difluoro-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-amine

To a solution of the compound (2.0g,4.514mmol) prepared in example 151 in ethanol (50ml) was added 10% aqueous sodium hydroxide (2.5ml), and the mixture was heated at 100 ℃ for 2 hours. The mixture was quenched and extracted as described in example 1 (d). Evaporation of the solvent gave the product in 99% yield (1.8 g).

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

To a solution of the compound from example 186(a) (50mg,0.124mmol) in DCM was added pyridine (20mg,0.258mmol,2.0eq.) followed by methanesulfonyl chloride (29mg,0.155mmol,2.0 eq.). The reaction was monitored by LCMS. After completion of the reaction, the solvent was evaporated and the crude product was purified by preparative HPLC to give the product in 42% yield (25 mg).¹HNMR(300MHz,DMSO-d₆) 10.34(s,1H),8.76(s,1H),8.22(s,1H),7.97(d,2H),7.66-7.57(M,5H),7.36-7.30(M,3H),3.88(s,3H),3.19(s,3H), LC-MS (ESI) calculating mass 479.50, and measured mass 480.2[ M + H ]]⁺(retention time: 1.27 minutes).

Example 187

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

The compound was prepared from the compound of example 151 using the procedure of example 186.¹HNMR(400MHz,DMSO-d₆):10.37(s,1H),8.80(s,1H),8.23(s,1H),7.98(d,2H),7.67(s,2H),7.61(s,1H),7.56(s,2H),7.38(s,1H),7.30(t,2H),3.88(s,3H),3.30 (quartet, 2H),1.26(t,3H), LC-MS (ESI) calculated mass: 493.3, measured mass: 494.1[ M + H [ ], calculated mass [ + H ] ], and]⁺(retention time: 1.38 minutes).

Example 188

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

This compound was prepared using the method of example 148 starting from N- (3-bromo-5-nitrophenyl) acetamide (0.8g,3.089mmol) and (4-fluoro-2-methoxyphenyl) boronic acid (0.63g,3.71mmol,1.2 eq.).¹HNMR(400MHz,DMSO-d₆) 10.35(s,1H),8.93(s,1H),8.24(s,1H),8.07(s,1H),7.98(d,2H),7.71-7.69(M,3H),7.47-7.44(M,2H),7.08(dd,1H),6.93(dt,1H),3.88(s,3H),3.17(s,3H),2.08(s,3H), LC-MS (ESI): calculated mass 455.48, measured mass 456.1[ M + H ], calculated mass 456.1]⁺(retention time: 1.13 minutes).

Example 189

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

a) N- (2' -fluoro-4 ' -methoxy-5-nitro- [1,1' -biphenyl ] -3-yl) acetamide

The compound was prepared from the compound of example 1(c) (0.8g,3.089mmol) and (2-fluoro-4-methoxy-phenyl) boronic acid (0.63g,3.71mmol,1.2eq.) using the procedure of example 148(a) to give the product in 97% yield (0.91 g).¹HNMR(300MHz,DMSO-d₆):10.52(s,1H),8.59(s,1H),8.07(s,1H),7.97(s,1H),7.55(t,1H),7.05-6.93(m,2H),3.84(s,3H),2.11(s,3H)。

b) N- (5-amino-2 ' -fluoro-4 ' -methoxy- [1,1' -biphenyl ] -3-yl) acetamide

This compound was used from the compound (0.9g,2.96mmol) of example 189(a)Prepared by the method of example 148(b) to give the product in 97% yield (790 mg).¹HNMR(300MHz,DMSO-d₆) 9.74(s,1H),7.28(t,1H),6.91-6.78(M,4H),6.34(s,1H),5.15(brs,2H),3.77(s,3H),1.98(s,3H), LC-MS (ESI) calculated mass 274.3, measured mass 275.2[ M + H ] 275.2 ]⁺(retention time: 0.35 minutes).

c) N- (5- ((4-bromo-2-nitrophenyl) amino) -2' -fluoro-4 ' -methoxy- [1,1' -biphenyl ] -3-yl) acetamide

The compound was prepared from the compound (3g,10.95mmol) of example 189(b) using the method of example 148(c) to give the crude product in 93% yield (4.82 g).¹HNMR(300MHz,DMSO-d₆) 10.13(s,1H),9.43(s,1H),8.23(d,1H),7.68-7.64(M,2H),7.53(s,1H),7.44(t,1H),7.24(d,1H),7.11(s,1H),6.98-6.88(M,2H),3.81(s,3H),2.06(s,3H), LC-MS (ESI) calculating mass 474.3, measured mass 476.01[ M + H ESI ]]⁺(retention time: 1.85 minutes).

d) N- (5- ((2-amino-4-bromophenyl) amino) -2' -fluoro-4 ' -methoxy- [1,1' -biphenyl ] -3-yl) acetamide

The compound was prepared from the compound of example 189(c) (4.8g,10.13mmol) using the method of example 148(d) to give the product in 93% yield (4.12 g).¹HNMR(300MHz,DMSO-d₆) 10.80(s,1H),7.30(t,2H),7.11(d,1H),6.98-6.82(M,5H),6.63(dd,1H),6.52(s,1H),5.09(brs,2H),3.77(s,3H),1.98(s,3H), LC-MS (ESI) calculating mass 444.30, measured mass 441.0[ M + H ] measured mass 441.0]⁺(retention time: 1.66 minutes).

e) N- (5- (5-bromo-1H-benzo [ d ] imidazol-1-yl) -2' -fluoro-4 ' -methoxy- [1,1' -biphenyl ] -3-yl) acetamide

The compound was prepared from the compound (4g,9mmol) of example 189(d) using the method of example 148(e) to give the product in 95% yield (3.8 g). ¹HNMR(300MHz,DMSO-d₆) 10.38(s,1H),8.69(s,1H),7.99(t,2H),7.77(d,1H),7.65-7.44(M,4H),7.01-6.89(M,2H),3.81(s,3H),2.09(s,3H), LC-MS (ESI) calculating mass 454.3.30, and 456.0[ M + H ] measured mass 456]⁺(retention time: 1.68 min)A clock).

f) N- (5- (5- (1H-pyrazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -2' -fluoro-4 ' -methoxy- [1,1' -biphenyl ] -3-yl) acetamide

The compound was prepared from the compound of example 189(e) (0.8g,1.76mmol) using the method of example 148(f) to give the product in 71% yield (0.55 g).¹HNMR(400MHz,DMSO-d₆) 10.34(s,1H),8.84(s,1H),8.61(d,1H),8.24(d,1H),8.06(s,1H),7.95-7.93(M,1H),7.82-7.77(M,3H),7.61(t,1H),7.51(s,1H),7.04-6.94(M,2H),6.57(t,1H),3.84(s,3H),2.12(s,3H), LC-MS (ESI): 441.4 and 442.1[ M + H ] of measured mass 442.1]⁺(retention time: 1.44 minutes).

Example 190

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

A solution of the compound from example 189(e) (0.25g,0.55mmol) in 1, 2-dimethoxyethane (10ml) was passed through N₂Bubbling and degassing for 5 minutes. 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (0.14g,0.66mmol,1.2eq.) was added and the mixture was degassed for an additional 5 minutes. Adding Pd (PPh) ₃)₄(63mg,0.055mmol,0.1eq.) and aqueous sodium carbonate (0.12g,1.1mmol,2.0eq.), followed by the procedure of example 1 (d). The crude residue of the product was purified by preparative HPLC to give the product in 90% yield (0.23 g).¹HNMR(400MHz,DMSO-d₆) 10.42(s,1H),9.08(s,1H),8.26(s,1H),8.11(s,1H),8.02(s,1H),7.99(s,1H),7.80(s,1H),7.75-7.68(M,2H),7.58(t,1H),7.53(s,1H),7.04-6.94(M,2H),3.89(s,3H),3.84(s,3H),2.12(s,3H), LC-MS (ESI): calculated mass: 445.4, measured mass: 455.7[ M + H (S,3H) ], measured mass: 455.7]⁺(retention time: 0.75 minutes).

Example 191

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

a)5- (5-bromo-1H-benzo [ d ] imidazol-1-yl) -2' -fluoro-4 ' -methoxy- [1,1' -biphenyl ] -3-amine

To a solution of the compound from example 189(e) (2.5g,5.5mmol) in ethanol (50ml) was added aqueous sodium hydroxide (2g,50mmol,9eq.) and the mixture was heated at 90 ℃ for 2 hours. The mixture was quenched and extracted as described in example 1 (d). The solvent was then distilled off to leave the compound in 92% yield (2.1 g).

b) N- (5- (5-bromo-1H-benzo [ d ] imidazol-1-yl) -2' -fluoro-4 ' -methoxy- [1,1' -biphenyl ] -3-yl) cyclopropanesulfonamide

To a solution of the compound from example 191(a) (0.8g,1.94mmol) in DCM was added pyridine (0.8ml,10.12mmol) followed by cyclopropanesulfonyl chloride (0.326g,2.33mmol,1.2 eq.). The mixture was stirred for 16 hours, the reaction was terminated and extracted as described in example 2 (b). Evaporation of the solvent gave a crude residue which was purified by column chromatography (60-120 silica gel, 4% methanol in DCM) to give the product in 80% yield (0.8 g).

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

The compound was prepared from the compound from example 191(b) (150mg,0.295mmol) using the method of example 148(f) to give the product in 41% yield (45 mg).¹H-NMR (400MHz, DMSO-D6)8.94(bs,1H),8.25(s,1H),8.02(s,1H),7.98(s,1H),7.72-7.66(M,2H),7.64-7.560(M,3H),7.51(s,1H),7.03(D,1H),6.95(dd,1H),3.89(s,3H),3.84(s,3H),2.87(M,1H),1.02(D,4H); LC-MS (ESI); calculated mass 517.57: ESI of 518.1[ M + H [ ]]⁺(retention time: 1.39 minutes).

Example 192

Cyclopropanesulfonic acid {2 '-fluoro-4' -methoxy-5- [5- (1H-pyrazol-4-yl) -benzoimidazol-1-yl ] -biphenyl-3-yl } -amide

This compound was prepared from the compound of example 189(e) using the procedure of example 2 and cyclopropanesulfonyl chloride along with the procedure of example 148 (f). ¹H-NMR (400MHz, DMSO-D6) =10.22(s,1H),8.83(s,1H),8.17(s,2H),8.07(s,1H),7.70(s,2H),7.64-7.60(t,1H),7.56(s,2H),7.50(s,1H),7.03(D,1H),6.96(D,1H),3.85(s,3H),2.90-2.80(M,1H),1.10(t,3H),1.02(D,4H); LC-MS (ESI): mass 503.55 is calculated and mass 503.9[ M + H ] (ESI)]⁺(retention time: 1.24 minutes).

Example 193

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

a)2',4' -difluoro-5- (5- (1-methyl-1H-pyrazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-amine

The compound was prepared from the compound of example 168(e) (0.6g,1.35mmol) using the method of example 186(a) to give the product in 70% yield (0.38 g). LC-MS (ESI) calculated mass 401.41 and measured mass 402.1[ M + H ]]⁺(retention time: 1.198 min).

b) N- (2',4' -difluoro-5- (5- (1-methyl-1H-pyrazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) methanesulfonamide

The compound was prepared from the compound (85mg,0.211mmol) in example 193(a) using the method of example 186(b) to give the product in 35% yield (34 mg).¹HNMR(400MHz,DMSO-d₆) 8.73(s,1H),7.94(s,1H),7.79-7.69(M,2H),7.51-7.49(M,1H),7.42(M,2H),7.34(s,1H),7.31(s,1H),7.25(M,1H),6.44(s,1H),3.89(s,3H),3.00(s,3H), LC-MS (ESI) calculating mass 479.5, measured mass 480.1[ M + H ESI ] ]⁺(retention time: 1.34 minutes).

Example 194

N- (5- (5- (1H-1,2, 4-triazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) acetamide

a) N- (2',4' -difluoro-5- ((2-nitro-4- (1H-1,2, 4-triazol-1-yl) phenyl) amino) - [1,1' -biphenyl ] -3-yl) acetamide

To a solution of the compound from example 17(c) (0.67g,1.31mmol) in DMF (2ml) were added 1,2, 4-triazole (0.136g,1.95mmol,1.5eq.), copper (I) oxide (0.188g,1.31mmol,1eq.) and cesium carbonate (0.85g,2.62mmol,2eq.), and the mixture was heated at 90 ℃ for 12 hours. The mixture was quenched and extracted as described in example 1 (d). 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 product in 68% yield (0.4 g).

b) N- (5- ((2-amino-4- (1H-1,2, 4-triazol-1-yl) phenyl) amino) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) acetamide

To a solution of the compound from example 194(a) (0.4g,0.88mmol) in acetic acid (10ml) was added slowly iron powder (0.12g,2.2mmol,2.5eq) portionwise over 10 min at 80 deg.C (note: highly exothermic reaction). After the addition was complete, the mixture was heated at 80 ℃ for 1 hour and the reaction was stopped by adding crushed ice. The precipitate formed was filtered and washed with cold water to give a solid which was dried under high vacuum to give the product in 67.5% yield (0.25 g).

c) N- (5- (5- (1H-1,2, 4-triazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) acetamide

A mixture of the compound from example 194(b) (0.250g,0.595mmol) and formic acid (3ml) was heated at 80 ℃ for 1 h. The formic acid was evaporated off and the crude product was dissolved in ethyl acetate. The crude product was purified by preparative HPLC to give the product in 29% yield (75 mg).¹HNMR(300MHz,DMSO-d₆) 10.41(s,1H),9.36(s,1H),8.81(s,1H),8.3(s,1H),8.26(s,1H),8.08(M,1H),7.88-7.87(M,3H),7.8-7.7(M,3H),7.55(s,1H),7.5-7.4(M,1H),7.32-7.24(M,1H),2.12(s,3H), LC-MS (ESI) calculated mass: 430.41, measured mass: 430.8[ M + H + M,1H ], calculated mass: 430.8]⁺(retention time: 1.17 minutes).

Example 195

N- (5- (5- (1H-1,2, 4-triazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) ethanesulfonamide

a)5- (5- (1H-1,2, 4-triazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-amine

To a solution of the compound from example 194(c) (0.26g,0.6mmol) in ethanol (5ml) was added a 1:1HCl solution (3ml) and the mixture was heated at 80 ℃ for 1 hour. The mixture was neutralized with sodium bicarbonate solution and extracted as described in example 2 (b). Evaporation of the solvent gave the product in 56% yield (0.13 g). LC-MS (ESI) for calculating mass 388.37 and measured mass 388.8M + H ]⁺(retention time: 0.5 minutes).

b) N- (5- (5- (1H-1,2, 4-triazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) ethanesulfonamide

The compound was prepared from the compound of example 195(a) (65mg,0.167mmol) using the method of example 186(b) and ethanesulfonyl chloride (32mg,0.15mmol,1.5eq.) to give the product in 15% yield (12 mg).¹HNMR(300MHz,DMSO-d₆) 10.50(brs,1H),9.15(M,1H),8.85(s,1H),8.30-8.25(M,2H),7.83-7.76(M,3H),7.60-7.48(M,4H),7.22(M,1H),3.32(q,2H),1.27-1.24(t,3H), LC-MS (ESI), calculating mass 480.49, and measured mass 480.8[ M + H ] 480.8]⁺(retention time: 1.41 minutes).

Example 196

N- (5- (5- (1H-1,2, 4-triazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) methanesulfonamide

This compound was prepared from the compound of example 195(a) using the method of example 195.¹HNMR(300MHz,DMSO-d₆):10.30(brs,1H),9.35(M,1H),8.82(s,1H),8.29-8.25(M,2H),7.87-7.76(M,3H),7.61-7.46(M,4H),7.27(M,1H),3.18(s,3H), LC-MS (ESI) calculated mass: 466.46, measured mass: 467.8[ M + H ] 467.8]⁺(retention time: 0.71 minutes).

Example 197

N- (5- (5- (1H-1,2, 4-triazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) cyclopropanesulfonamide

This compound was prepared from the compound of example 195(a) using the method of example 195 and cyclopropanesulfonyl chloride. ¹HNMR(300MHz,DMSO-d₆) 10.40(brs,1H),9.45(M,1H),8.80(s,1H),8.35-8.25(M,2H),7.88-7.76(M,3H),7.65-7.48(M,4H),7.21(M,1H),2.96-2.9(M,1H),1.04-1.0(M,4H), LC-MS (ESI) calculating mass 492.5, measured mass 493.1[ M + H ]]⁺(retention time: 1.43 minutes).

Example 198

N- (5- (5- (1H-1,2, 4-triazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) propanamide

To a solution of the compound from example 195(a) (50mg,0.128mmol) in DMF (2ml) was added propionic acid (14mg,0.192mmol,1.5 eq.). HATU (73mg,0.192mmol,1.5eq.) was added and the mixture was stirred at room temperature for 6 hours. The mixture was quenched with cold water and the precipitate was collected to give the product in 26% yield (15 mg).¹HNMR(400MHz,CD₃OD is 9.17(s,1H),8.67(s,1H),8.24-8.22(M,2H),8.17(M,1H),7.89(s,2H),7.7-7.64(M,1H),7.55(M,1H),7.17-7.11(M,2H),2.52-2.46(q,2H),1.27-1.23(t,3H), LC-MS (ESI) calculating mass 444.44, measured mass 445.2[ M + H ], (ESI)]⁺(retention time: 1.35 minutes).

Example 199

N- (5- (5- (1H-1,2, 3-triazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) acetamide

This compound was prepared from the compound of example 17(c) using the method of example 194 and 1,2, 3-triazole.¹HNMR,300MHz:(DMSO-d₆) 10.37(s,1H),8.24(M,3H),8.11-8.08(M,3H),7.98-7.9(M,1H),7.85(s,1H),7.8-7.7(M,1H),7.55(M,1H),7.5-7.42(M,1H),7.32-7.24(M,1H),2.1(s,3H), LC-MS (ESI) calculating mass 430.41, and measured mass 431.1[ M + H ] 431.1 ]⁺(retention time: 1.53 minutes).

Example 200

N- (5- (5- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) ethanesulfonamide

a)5- (5-bromo-1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-amine

To a solution of the compound from example 1(h) (20g,45.2mmol) in ethanol (250ml) was added aqueous sodium hydroxide (5g,125mmol,2.75eq.) and the mixture was heated at 85 ℃ for 5 h.

The mixture was quenched and extracted as described in example 1 (d). Evaporation of the solvent gave the product in 99% yield (18 g).

b) N- (5- (5-bromo-1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) ethanesulfonamide

The compound was prepared from the compound of example 200(a) (3.0g,7.5mmol) using the method of example 186(b) and ethanesulfonyl chloride (4g,30.7mmol,4eq.) to give the product in 95% yield (3.5 g).

c) N- (5- (5- (1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) ethanesulfonamide

A solution of the compound from example 200(b) (2.5g,5.08mmol) in 1, 2-dimethoxyethane (75ml) was passed through N₂Bubbling and degassing for 5 minutes. Adding 4- (4,4,5, 5-tetramethyl- [1,3,2 ]]Boron dioxide pentanesCyclo-2-yl) -1H-pyrazole (1.18g,6.1mmol,1.2eq.) and degassing of the mixture was continued for 5 min. Adding Pd (PPh) ₃)₄(0.28g,0.254mmol,0.05eq.) and aqueous sodium carbonate (1.0g,9.48mmol,2.0eq.) followed by the procedure of example 1 (d). The crude residue of the product was purified by column chromatography (60-120 silica gel, 80% ethyl acetate in hexane) to afford the product in 30% yield (0.7 g).¹H-NMR (300MHz, DMSO-D6) =8.20(bs,2H),8.08(bs,1H),7.75(M,3H),7.62(s,2H),7.50(M,2H),7.30(M,1H),3.31(q,2H),1.27(t,3H) LC-MS (ESI): calculated mass: 479.5; measured mass: 480.1[ M + H ], (ESI) ]]⁺(retention time: 1.22 minutes).

d) N- (5- (5- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) ethanesulfonamide

To a solution of the compound from example 200(c) (50mg,0.104mmol) in DCM was added pyridine (0.5ml,6.32mmol) followed by cyclopropanesulfonyl chloride (22mg,0.139mmol,1.5 eq.). The reaction solution was stirred for 1 hour, and the reaction was terminated and extracted as described in example 2 (b). Evaporation of the solvent gave a crude residue which was purified by preparative HPLC to give the product in 89% yield (40 mg).¹H-NMR (400MHz, DMSO-D6) =10.36(s,1H),8.89(D,1H),8.61(s,1H),8.28(s,1H),7.86(D,1H),7.77-7.74(m,2H),7.60(s,2H),7.48-7.46(m,2H),7.29(t,1H),3.30(q,2H),3.20-3.18(m,1H),1.33-1.32(m,2H),1.26-1.23(m, 7H). LC-MS (ESI) calculated mass 583.63 and measured mass 584.1[ M + H ] ]⁺(retention time: 1.62 minutes).

Example 201

N- (2',4' -difluoro-5- (5- (pyrimidin-5-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) ethanesulfonamide

This compound was prepared from the compound of example 200(b) using the method of example 200 (c). H-NMR (300MHz, CD)₃OD) =9.10(bs,4H),8.14-8.10(m,1H),7.97-7.82(m,1H),7.80(d,1H),7.60-7.52(m,3H),7.46(s,1H),7.06-7.04(m,2H),3.25(m,2H),1.28(t,3H); LC-MS (ESI); calculated mass: 419.51; true: M;)Quality measurement of 492.1[ M + H ]]⁺(retention time: 1.43 minutes).

Example 202

N- (2',4' -difluoro-5- (5- (pyridin-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) ethanesulfonamide

This compound was prepared from the compound of example 200(b) using the method of example 200 (c). H-NMR (300MHz, CD)₃OD) =8.95(s,1H),8.84(d,2H),8.44(d,3H),8.04(d,1H),7.79(d,1H),7.64-7.56(M,1H),7.51(d,2H),7.11-7.04(dt,1H),3.21(q,2H),1.33(t,3H); LC-MS (ESI) calculating mass: 490.52; measured mass: 490.9[ M + H ]; calculated mass: 490.9[ M + ESI ]]⁺(retention time: 0.37 minutes).

Example 203

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

This compound was prepared from the compound of example 200(a) (15g,37.5mmol) using the method of example 186(b) and cyclopropanesulfonyl chloride (10ml,56.25mmol,1.5eq.) and then subjected to the method of example 200(c) to give the product in 40% yield (36 mg). ¹H-NMR (400MHz, DMSO-D6) =10.33(s,1H),8.88(s,1H),8.20(s,2H),8.09(s,1H),7.80-7.77(M,1H),7.73(s,2H),7.63(D,2H),7.53(D,1H),7.52-7.49(M,1H),7.32-7.31(M,1H),1.05(D,5H) ppm LC-MS ESI: (calculated mass: 491.51; measured mass: 492.4[ M + H ], (M,1H) = LC-MS ESI)]⁺(retention time: 1.34 minutes).

Example 204

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

This compound was prepared from the compound of example 167 using the procedure of example 2 and cyclopropanesulfonyl chloride. H-NMR (30)0MHz, DMSO-D6) =8.64(s,1H),8.30(s,1H),8.01(s,1H),7.95(s,1H),7.80-7.72(M,1H),7.65(D,2H),7.55-7.52(M,3H),7.45(M,2H),7.32-7.22(M,1H),4.52(M,1H),2.82(M,1H),1.48(s,3H),1.46(s,3H),1.01-0.99(M,4H), LC-MS (ESI): mass 533.59; mass 534.1[ M + H ], (M + H): measured mass 534.1]⁺(retention time: 1.59 minutes).

Example 205

N- (2',4' -difluoro-5- (5- (1-isopropyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) -2-methoxyacetamide

a) N- (5- (5-bromo-1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) -2-methoxyacetamide

To a solution of the compound from example 200(a) (250mg,0.625mmol) in DCM was added TEA (0.5ml,3.46mmol,5.5eq.) followed by 2-methoxyacetyl chloride (81mg,0.75mmol,1.2 eq.). The mixture was stirred for 2 hours, the reaction was terminated and extracted as described in example 1 (d). The solvent was evaporated to give a crude residue which was purified by column chromatography (60-120 silica gel, 20% ethyl acetate in hexane, 68% yield (200 mg).

b) N- (2',4' -difluoro-5- (5- (1-isopropyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) -2-methoxyacetamide

Prepared from the compound of example 205(a) (100mg,0.212mmol) using the method of example 200(c) and 1-isopropyl-4- (4,4,5, 5-tetra-methyl-1, 3, 2-dioxolan-2-yl) -1H-pyrazole (70mg,0.297mmol,1.4eq.) to give the title product in 57% yield (60 mg).¹H-NMR (300MHz, DMSO-D6) =8.64(s,1H),8.30(s,1H),8.01(s,1H),7.95(s,1H),7.80-7.72(M,1H),7.65(D,2H),7.55-7.52(M,3H),7.45(M,2H),7.32-7.22(M,1H),4.52(M,1H),2.82(M,1H),1.48(s,3H),1.46(s,3H),1.01-0.99(M,4H); LC-MS (ESI): mass 501.53; mass measured mass 502.1[ M + H ], (ESI): mass 501.53; mass measured]⁺(retention time: 1.55 minutes).

Example 206

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

To a solution of the compound from example 203 (50mg,0.101mmol) in DCM (1ml) was added TEA (0.1ml,0.69mmol,6.9eq.) followed by acetyl chloride (12mg,0.142mmol,1.4 eq.). The mixture was stirred for 2 hours, quenched and extracted as described in example 1 (d). Evaporation of the solvent gave a crude residue which was purified by preparative HPLC to give the product in 74% yield (40 mg). ¹H-NMR (300MHz, DMSO-D6) =8.93(bs,1H),8.72(s,1H),8.50(s,1H),8.24(s,1H),7.83(D,1H),7.76-7.70(M,2H),7.58(bs,2H),7.50-7.40(M,2H),7.30-7.20(M,1H),3.15(s,3H),2.90-2.80(M,1H),2.67(s,3H),1.01(D,4H); LC-MS (ESI): mass calculated 533.55; measured mass 534.1[ M + H ] (ESI): measured mass 534.1: (M + H) =]⁺(retention time: 1.55 minutes).

Example 207

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

To a solution of the compound from example 203 (50mg,0.101mmol) in DCM was added pyridine (16mg,0.202mmol,2.0eq.) followed by methanesulfonyl chloride (14mg,0.122mmol,1.2 eq.). The mixture was stirred for 1 hour, the reaction was terminated and extracted as described in example 2 (b). Evaporation of the solvent gave a crude residue which was purified by preparative HPLC to give the product in 60% yield (40 mg). H-NMR (400MHz, DMSO-D6) =10.32(s,1H),8.95(s,1H),8.90(s,1H),8.62(s,1H),8.29(s,1H),7.88(D,1H),7.76(dd,2H),7.63(D,2H),7.52(s,1H),7.50-7.47(M,1H),7.30-7.29(dt,1H),3.61(s,3H),2.90-2.86(M,1H),1.04-1.02(D,4H); LC-MS (ESI): calculated mass 569.6; measured mass 569.9[ M + H ], (ESI)]⁺(retention time: 0.64 min).

Example 208

N- (5- (5- (1-cyclopentyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) methanesulfonamide

a) N- (5- (5-bromo-1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) methanesulfonamide

To a solution of the compound from example 200(a) (3.0g,7.5mmol) in DCM was added pyridine (5ml,63.2mmol,8.4eq.) followed by methanesulfonyl chloride (1.3g,11.25mmol,1.5 eq.). The mixture was stirred for 1 hour, the reaction was terminated and extracted as described in example 2 (b). Evaporation of the solvent gave a crude residue which was purified by preparative HPLC to give the product in 95% yield (3.5 g).

b) N- (5- (5- (1-cyclopentyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) methanesulfonamide

Prepared from the compound of example 208(a) (100mg,0.209mmol) using the method of example 200(c) and 1-cyclopentyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (82mg,0.313mmol,1.5eq.) to give the title product in 33% yield (30 mg). H-NMR (300MHz, DMSO-D6) =10.28(s,1H),8.63(s,1H),8.28(s,1H),8.00(s,1H),7.94(s,1H),7.80-7.70(M,1H),7.70-7.60(M,2H),7.54(D,2H),7.50-7.40(M,2H),7.30-7.20(dt,1H),4.72-4.65(M,1H),3.94(s,1H),3.16(s,3H),2.15-2.05(M,2H),2.00-1.90(M,2H),1.85-1.75(M,2H),1.70-1.60(M,2H), LC-MS ESI, calculated mass: 533.59: 534.3M + M.38 measured mass: (LC-MS ESI): 534.3: (M, 534.3) ]⁺(retention time: 1.12 minutes).

Example 209

N- (2',6' -difluoro-5- (6- (1-methyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1' -biphenyl ] -3-yl) cyclopropanecarboxamide

a) N- (5- ((5-bromo-3-nitropyridin-2-yl) amino) -2',6' -difluoro- [1,1' -biphenyl ] -3-yl) acetamide

A solution of N- (5-amino-2 ',6' -difluoro- [1,1' -biphenyl ] -3-yl) acetamide (1.4g,6.1mmol), 5-bromo-2-chloro-3-nitropyridine (1.6g,6.1mmol,1.0eq.) and potassium fluoride (0.53g,9.0mmol,1.5eq.) in DMF (8ml) was heated at 110 ℃ for 4 hours. The mixture was quenched and extracted as described in example 1 (d). Evaporation of the solvent gave a crude product which was purified by column chromatography (60-120 silica gel, 30% ethyl acetate in hexane) to afford the title product in 28% yield (0.8 g).

b) N- (5- ((5-bromo-3-nitropyridin-2-yl) amino) -2',6' -difluoro- [1,1' -biphenyl ] -3-yl) acetamide

To a solution of the compound from example 209(a) (0.8g,1.73mmol) in THF (25ml) and methanol (5ml) was added a solution of ammonium chloride (0.37g,6.92mmol,4eq.) in water (5ml) and zinc (0.45g,6.92mmol,4 eq.). The mixture was stirred at room temperature for 1 hour and filtered. The filtrate was diluted with water and extracted as described in example 1 (d). Evaporation of the solvent gave the product in 80% yield (0.6 g).

c) N- (5- (6-bromo-3H-imidazo [4,5-b ] pyridin-3-yl) -2',6' -difluoro- [1,1' -biphenyl ] -3-yl) acetamide

A mixture of the compound from example 209(b) (0.6g,1.38mmol) and formic acid (3ml) was heated at 80 ℃ for 1 hour. The methanol was then distilled off 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 evaporated and the crude product was washed with hexane to give the title product in 98% yield (0.5 g).

d) N- (2',6' -difluoro-5- (6- (1-methyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1' -biphenyl ] -3-yl) acetamide

Prepared from the compound of example 209(c) (1.3g,2.94mmol) using the method of example 200(c) and 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (0.91g,4.41mmol,1.5eq.) to give the title product in 61% yield (0.8 g).

e)2',6' -difluoro-5- (6- (1-methyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1' -biphenyl ] -3-amine

To a solution of the compound from example 209(d) (0.8g,1.8mmol) in ethanol (10ml) was added aqueous sodium hydroxide (0.2g,5.4mmol,3eq.) and the mixture was heated at 80 ℃ for 12 h.

The mixture was quenched with water and a solid precipitated out. This was purified by column chromatography on basic alumina using 2% methanol in chloroform as eluent to give the product in 20% yield (0.15 g).

f) N- (2',6' -difluoro-5- (6- (1-methyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1' -biphenyl ] -3-yl) cyclopropanecarboxamide

To a solution of the compound from example 209(e) (15mg,0.37mmol) in DMF (2ml) was added cyclopropanecarboxylic acid (40mg,0.55 mmol). HATU (200mg,0.55mmol) was added and stirred at room temperature for 4 h. The mixture was quenched with cold water and the precipitate was collected and purified by preparative HPLC to give the title product in 10% yield (17 mg).¹HNMR(400MHz,DMSO-d₆) 10.7(s,1H),8.89(s,1H),8.73-8.72(d,1H),8.42(d,1H),8.35-8.34(t,1H),8.31(s,1H),8.04(s,1H),7.82(s,1H),7.69(s,1H),7.57-7.51(M1H),7.31-7.27(t,2H),3.89(s,3H),1.86-1.83(M,1H),0.85-0.84(d,4H), LC-MS (ESI) calculating mass 470.47 and actually measuring mass 471.2[ M + H ] (M + H) ]]⁺(retention time: 1.43 minutes).

Example 210

3- (2',4' -difluoro-5- (5- (1-isopropyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1 '-biphenyl ] -3-yl) -N, N' -dimethylsulphamic acid diamide

a)3- (5- (5-bromo-1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1 '-biphenyl ] -3-yl) -N, N' -dimethylsulphamic acid diamide

To a solution of the compound from example 200(a) (4.0g,10.0mmol) in DCM (50ml) was added pyridine (5ml,63.29mmol,6.3eq.) followed by dimethylsulfamoyl chloride (2.0g,14.0mmol,1.4 eq.). The mixture was stirred for 16 hours, quenched and extracted as described in example 1 (d). Evaporation of the solvent gave a crude product which was purified by column chromatography (60-120 silica gel, 2% methanol in DCM) to give the desired title product in 81% yield (4.1 g).

b)3- (2',4' -difluoro-5- (5- (1-isopropyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1 '-biphenyl ] -3-yl) -N, N' -dimethylsulphamic acid diamide

This compound was prepared from the compound of example 210(a) (200mg,0.394mmol) using the method of example 200(c) and 1-isopropyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (121mg,0.383mmol,1.3eq.) to give the title product in 23% yield (50 mg). H-NMR (300MHz, DMSO-D6) =10.45(s,1H),8.95(s,1H),8.35(s,1H),8.04(s,1H),7.98(s,1H),7.78-7.68(M,3H),7.57(s,2H),7.47(M,2H),7.34-7.24(dt,1H),2.80(s,6H),1.47(D,6H); LC-MS (ESI); calculated mass: 536.6: measured mass: 537.1[ M + H ESI ]]⁺(retention time: 1.57 minutes).

Example 211

3- (5- (5- (6- (benzyloxy) pyridin-3-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1 '-biphenyl ] -3-yl) -N, N' -dimethylsulfuric acid diamide

This compound was prepared from the compound of example 210(a) using the method of example 200(c) and 2- (benzyloxy) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine.¹HNMR(300MHz,DMSO-d₆) 10.29(s,1H),8.81(s,1H),8.22(s,1H),7.99(s,1H),7.95(s,1H),7.75-7.56(M,5H),7.48-7.43(M,2H),7.27(M,1H),3.88(s,3H),3.48-3.44(M,1H),1.3(d,6H), LC-MS (ESI) calculating mass 611.66, measured mass 612.1[ M + H ] measured mass ]⁺(retention time: 1.87 minutes).

Example 212

3- (2',4' -difluoro-5- (5- (6-oxo-1, 6-dihydropyridin-3-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1 '-biphenyl ] -3-yl) -N, N' -dimethylsulphamic acid diamide

To a solution of the compound from example 211 (250mg,0.391mmol) in 1, 4-dioxane (10ml) was added TFA (0.2ml) and the mixture was heated at 70 ℃ for 2 hours. The reaction mass was completely concentrated and the crude product was purified by preparative HPLC to afford the title product in 70% yield (80 mg).¹H-NMR (300MHz, DMSO-D6) =8.96(s,1H),8.02(s,1H),7.80(dd,1H),7.82(D,1H),7.80-7.70(M,2H),7.70-7.62(D,1H),7.57(s,2H),7.51-7.44(M,2H),7.29(dt,1H),6.47(D,1H),2.80(s,6H); LC-MS (ESI); calculated mass: 521.54; measured mass: 522.2[ M + H + M522H ]]⁺(retention time: 0.87 minutes).

Example 213

N- (5- (6- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) acetamide

a) N- (5- (6- (1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) acetamide

Prepared from N- (5- (6-bromo-3H-imidazo [4,5-b ] pyridin-3-yl) -2',4' -difluorobiphenyl-3-yl) acetamide (2.1g,4.74mmol) using the method of example 200(c) to give the desired title product in 95% yield (1.9 g).

b) N- (5- (6- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) acetamide

The compound was prepared from the compound (50mg,0.125mmol) in example 213(a) using the method of example 200(d) to give the product in 33% yield (20 mg). H-NMR (400MHz, CD)₃OD) =8.80(dd,2H),8.73(s,1H),8.44(d,1H),8.40(s,1H),8.27(t,1H),7.81(d,1H),7.76(s,1H),7.66-7.64(M,1H),7.14-7.09(M,2H),3.03-2.99(M,1H),2.20(s,3H),1.47-1.44(M,2H),1.25-1.23(M,2H) ppm calculated mass 534.54, measured mass 534.8[ M + H ] M,2H]⁺(retention time: 1.55 minutes).

Example 214

N- (2',4' -difluoro-5- (6- (1- (methylsulfonyl) -1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1' -biphenyl ] -3-yl) acetamide

This compound was prepared from the compound of example 213(a) using the procedure of example 200 (d). H-NMR (400MHz, DMSO-D6+ D2O) =9.01(s,1H),8.99(s,1H),8.92(D,1H),8.69-8.68(M,2H),8.31(t,1H),7.90(M,1H),7.73(M,2H),7.46(dt,1H),7.29(dt,1H),3.63(s,3H),2.14(s,3H); LC-MS (ESI); calculated mass 508.5; measured mass 508.7[ M + H + D2H); calculated mass]⁺(retention time: 1.46 minutes).

Example 215

N- (5- (6- (1- (ethylsulfonyl) -1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) acetamide

This compound was prepared from the compound of example 213(a) using the procedure of example 200 (d).¹H-NMR (400MHz, DMSO-D6) =10.41(s,1H),9.03(s,1H),8.98(s,1H),8.92(D,1H),8.69(s,1H),8.31(s,1H),7.88(s,1H),7.71(M,2H),7.47(dt,1H),7.28(dt,1H),3.77(q,2H),1.16(t,3H),2.12(s,3H), LC-MS (ESI): calculated mass 522.53; measured mass 523.2[ M + H + M ], (ESI): calculated mass 522.53]⁺(retention time: 1.56 minutes).

Example 216

N- (2', 4' -difluoro-5- (6- (1-methyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1 '-biphenyl ] -3-yl) -N, N' -dimethylsulphamic acid diamide

a) N- (2', 4' -difluoro-5- ((6-bromo) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1 '-biphenyl ] -3-yl) -N, N' -dimethyldisulphate

To a solution of N- (2',4 ' -difluoro-5- ((6-bromo) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1 ' -biphenyl ] -3-yl) amine (3.0g,7.48mmol) in DCM (10ml) was added pyridine (3ml,37.9mmol,2eq.) followed by dimethylsulfamoyl chloride (1.6g,11.22mmol,1.5 eq.). The mixture was stirred for 16 hours, the reaction was terminated and extracted as described in example 1 (d). Evaporation of the solvent gave the crude product which was purified by preparative HPLC to give the title product in 55% yield (2.1 g).

b) N- (2', 4' -difluoro-5- (6- (1-methyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1 '-biphenyl ] -3-yl) -N, N' -dimethylsulphamic acid diamide

Prepared from the compound of example 216(a) (150mg,0.295mmol) using the method of example 200(c) and 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole to give the title product in 41% yield (45 mg).¹HNMR(300MHz,DMSO-d₆) =8.95(s,1H),8.72(s,1H),7.41(d,1H),8.32(s,1H),8.05(s,1H),7.98(M,1H),7.72(M,1H),7.50-7.42(M,2H),7.32-7.24(M,2H),3.90(s,3H),2.81(s,6H); LC-MS (ESI); calculated mass 509.53: measured mass 510.1[ M + H ESI ]]⁺(retention time: 1.49 minutes).

Example 217

N- (2', 4' -difluoro-5- (6- (1-isopropyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1 '-biphenyl ] -3-yl) -N, N' -dimethyldisulphate diamide

This compound was prepared from the compound of example 216(a) using the method of example 200(c) and 1-isopropyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole.¹H-NMR (300MHz, DMSO-D6) =10.40(s,1H),8.94(s,1H),8.75(D,1H),8.40(M,2H),8.06(s,1H),7.99(t,1H),7.76-7.68(M,2H),7.50-7.40(M,2H),7.32-7.24(dt,1H),4.60-4.50(M,1H),2.81(s,6H),1.48(s,6H); LC-MS (ESI); calculated mass 537.58; measured mass 538.1[ M + H ESI ]]⁺(retention time: 1.62 minutes).

Example 218

N- (2', 4' -difluoro-5- (6-oxo-1, 6-dihydropyridin-3-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1 '-biphenyl ] -3-yl) -N, N' -dimethylsulphamic acid diamide

a) N- (2', 4' -difluoro-5- (6- (benzyloxy) pyridin-3-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1 '-biphenyl ] -3-yl) -N, N' -dimethylsulphamic acid diamide

A solution of the compound from example 216(a) (300mg,0.59mmol) in 1, 2-dimethoxyethane (10ml) was passed through N₂Bubbling and degassing for 5 minutes. 2- (benzyloxy) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (220mg,0.708mmol,1.2eq.) was added and the mixture was degassed for an additional 5 minutes. Adding Pd (PPh)₃)₄(34mg,0.0295mmol,0.05eq.) and aqueous sodium carbonate (125mg,1.179mmol,2.0eq.) followed by the procedure of example 1 (d). The crude residue of the product was purified by preparative HPLC to afford the title product in 69% yield (250 mg).¹HNMR(300MHz,DMSO-d₆) 10.39(s,1H),9.03(s,1H),8.78(s,1H),8.64(s,1H),8.55(s,1H),8.25-8.2(M,1H),7.98(s,1H),7.74(M,2H),7.7-7.5(M,2H),7.5-7.25(M,1H),7.08-7.0(d,1H),5.43(s,2H),2.81(s,6H), LC-MS (ESI), calculated mass 614.2: measured mass 613.2[ M-H ] M-H]⁺(retention time: 1.4 minutes).

b) N- (2', 4' -difluoro-5- (6-oxo-1, 6-dihydropyridin-3-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1 '-biphenyl ] -3-yl) -N, N' -dimethylsulphamic acid diamide

To a solution of the compound (240mg,0.391mmol) obtained in example 218(a) in 1, 4-dioxane (10ml) was added (0.8ml) and the mixture was heated at 70 ℃ for 2 hours. The reaction mass was completely concentrated and the crude product was purified by preparative HPLC to afford the title product in 50% yield (80 mg). H-NMR (300MHz, DMSO-D6) =10.40(s,1H),8.99(s,1H),8.67(D,1H),8.42(D,1H),8.00-7.95(M,2H),7.88(s,1H),7.73(M,2H),7.50-7.43(M,2H),7.32-7.26(dt,1H),6.48(D,1H),2.81(s,6H); LC-MS (ESI); calculated mass 522.53: measured mass 523.1[ M + H ]; calculated mass 522.53 ]⁺(retention time: 1.39 minutes).

Example 219

N- (2',4' -difluoro-5- (5- (1- (3-hydroxy-3-methylbutyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) acetamide

This compound was prepared from the compound of example 1(H) (0.2g,0.452mmol) using the method of example 200(c) and 2-methyl-4- (3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) butan-2-ol to give the title product in 55.79% yield (0.13 g).¹HNMR (300MHz, DMSO-d6):10.42(s,1H),8.96(s,1H),8.11(s,1H),8.01(s,2H),7.82(s,1H),7.71(M,3H),7.54-7.41(M,2H),7.29-7.25(M,1H),4.24-4.18(t,2H),2.155(s,3H),1.98-1.92(s,2H), calculated mass: 515.55; measured mass: 516.3[ M + H + M ] is measured]⁺(retention time: 1.2 minutes).

Example 220

N- (4 '-fluoro-5- (5- (1- (3-hydroxy-3-methylbutyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) acetamide

The compound is prepared from N- (5- (5-bromo-1H-benzo [ d)]Imidazol-1-yl) -4 '-fluoro- [1,1' -biphenyl]-3-yl) acetamide (0.07g,0.164mmol) prepared using the procedure of example 200(c) and 2-methyl-4- (3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) butan-2-ol (0.092g,0.329mmol,2.0eq.) to give the title product in 22.2% yield (0.018 g). ¹HNMR(300MHz,DMSO-d₆) 10.42(s,1H),8.68(s,1H),8.25(s,1H),7.99(d,2H),7.93(s,1H),7.83(s,1H),7.69(M,2H),7.65(M,1H),7.61(M,2H),7.36(t,2H),4.48(s,1H), 4.26(M,2H), 2.12(s,3H), 1.91(M,2H), 1.15(s,6H), LC-MS (ESI): calculated mass 497.56 measured mass 497.9[ M + H ], (ESI)]⁺(retention time: 0.9 minutes).

Example 221

N- (2',4 ' -difluoro-5- (5- (3-fluoropyridin-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) acetamide

This compound was prepared from the compound of example 1(h) using the method of example 200 (c).¹HNMR(400MHz,DMSO-d₆) 10.42(s,1H),8.85(s,1H),8.70(s,1H),8.541-8.53(d,1H),8.14-8.11(d,2H),7.88-7.84(M,2H),7.79-7.69(M,3H),7.56(s,1H),7.48-7.46(t,1H),2.155(s,3H),2.12(s,3H), calculated mass 458.43, measured mass 459.2[ M + H ], (s,1H), measured mass 458.43]⁺(retention time: 1.55 minutes).

Example 222

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

The compound was prepared from the compound of example 1(h) using the method of example 220.¹HNMR (300MHz, DMSO-d6):10.32(s,1H)8.80(s,1H),8.40(s,1H),8.37(s,1H),8.16(s,1H),7.97-7.91(d,1H),7.90-7.76(M,3H),7.56(d,1H),7.47(M,1H),7.30(M,1H),2.25(s,3H),2.10(s,3H); LC-MS ESI): mass 443.45; mass 444.2[ M + H + M, 2.25: (S,3H); (LC-MS ESI) ]⁺(retention time: 0.69 minutes).

Example 223

3- ((2',4 ' -difluoro-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1 ' -biphenyl ] -3-yl) amino) -3-oxopropanoic acid ethyl ester

To a solution of the compound from example 2(a) (80mg,0.1995mmol) in DCM was added TEA (40mg,0.399mmol,2.0eq.) followed by ethyl 3-chloro-3-oxopropanoate (32.9mg,0.219mmol,1.1 eq). The mixture was stirred for 2 hours, quenched and extracted as described in example 1 (d). Evaporation of the solvent gave a crude residue which was purified by preparative HPLC to give the pure product in 20% yield (20 mg).¹HNMR(400MHz,DMSO-d₆):10.7(s,1H),8.77(s,1H),8.23(s,1H),8.10(s,1H),8.01(s,1H),7.97(s,1H),7.83(s,1H),7.78(d,1H),7.73(d,1H),7.65(d,1H),7.59(s,1H),7.49(t,1H),7.3(t,1H),3.90(s,3H),3.82(q,2H),1.4(t,3H),3.45(s,2H);LC-MS(ESI):Calculated mass 515.51, measured mass 516.4[ M + H]⁺(retention time: 0.96 minutes).

Example 224

3- ((2',4 ' -difluoro-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1 ' -biphenyl ] -3-yl) amino) -3-oxopropanoic acid

To a solution of example 223(20mg,0.0388mmol) in THF (10ml) was added aqueous lithium hydroxide (4mg,0.0776mmol,2eq) and the mixture was stirred at room temperature for 2 h. The mixture was quenched and extracted as described in example 1 (d). Evaporation of the solvent gave a crude residue which was purified by preparative HPLC to give the pure product in 90% yield (25 mg). ¹HNMR(400MHz,DMSO-d₆) 10.7(s,1H),8.77(s,1H),8.23(s,1H),8.10(s,1H),8.01(s,1H),7.97(s,1H),7.83(s,1H),7.78(d,1H),7.73(d,1H),7.65(d,1H),7.59(s,1H),7.49(t,1H),7.3(t,1H),3.90(s,3H),3.45(s,2H), LC-MS (ESI): calculated mass 487.15, measured mass 488.0[ M + H + E]⁺(retention time: 0.638 min).

Example 225

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

To a solution of the compound from example 2(a) (100mg,0.249mmol) in DMF was added 2- (1H-1,2, 4-triazol-1-yl) acetic acid (47mg,0.374, mmol,1.5eq.) followed by HATU (189mg,0.498mmol,2.0 eq.) and DIPEA (96.5mg,0.74mmol,3.0 eq.). The mixture was stirred for 16 hours, quenched and extracted as described in example 1 (d). Evaporation of the solvent gave a crude residue which was purified by preparative HPLC to give the product in 71.4% yield (90 mg).¹HNMR(400MHz,DMSO-d₆):10.9(s,1H),8.66(s,1H),8.59(s,1H),8.19(s,1H),8.06(s,1H),8.02(s,1H),8.00(d,1H),7.93(s,1H),7.80-7.75(m,2H),7.7(d,1H),7.61-7.59(m,2H),7.48-7.42(m,1H),7.3(m,1H)4.12(s,1H),3.87(s,3H), LC-MS (ESI), calculated mass 510.17, measured mass 511.2[ M + H ]]⁺(retention time: 0.386 minutes).

Example 226

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

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

To a solution of the compound from example 2(a) (100mg,0.249mmol) in DMF was added cyanoacetic acid (25.6mg,0.299mmol,1.2eq), followed by HATU (184mg,0.485mmol,2.0eq) and DIPEA (0.15ml,0.74mmol,3.0 eq). The mixture was stirred for 16 hours, quenched and extracted as described in example 1 (d). Evaporation of the solvent gave a crude residue which was purified by column chromatography to give the product in 19% yield (80 mg). LC-MS (ESI) calculating mass 468, and measuring mass 469.3M + H]⁺(retention time: 0.88 min).

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

To a solution of example 226(a) (80mg,0.170mmol) in DMF was added sodium azide (11mg,0.170mmol,1.eq) followed by ammonium chloride (10mg,0.188mmol,1.1 eq). The mixture was stirred at 80 ℃ for 16 hours, quenched and extracted as described in example 1 (d). Evaporation of the solvent gave a crude residue which was purified by preparative HPLC to give the product in 6.8% yield (6 mg).¹HNMR(400MHz,CD₃OD) 8.51(s,1H),8.16(s,1H),8.02(s,1H),7.92(s,1H),7.88(s,1H),7.80(s,1H),7.73-7.60(M,3H),7.53(s,1H),7.16-7.10(M,2H),4.12(s,2H),3.96(s,3H), LC-MS (ESI): calculated mass 511.17, measured mass 512.1[ M + H ESI ] ]⁺(retention time: 0.874 minutes).

Example 227

(3S,5R) -N- (2',4' -difluoro-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) -3, 5-dimethylpiperazine-1-carboxamide

To a solution of the compound from example 2(a) (80mg,0.2mmol) in DCM was added a 20% phosgene solution in toluene (0.2ml,0.4mmol,2eq.) at 0 ℃. The mixture was stirred for 1 hour and excess phosgene was removed by purging with nitrogen, then 2, 6-dimethylpiperazine (34mg,0.3mmol,1.5eq.) was added. The mixture was stirred overnight, the reaction was terminated and extracted as described in example 1 (d). Evaporation of the solvent gave a crude residue which was purified by preparative HPLC to give the pure product in 7% yield (7 mg).¹HNMR(300MHz,CD₃OD is 8.48(s,1H),8.0(s,1H),7.9(s,1H),7.86-7.85(M,2H),7.72-7.65(d,1H),7.65-7.59(M,4H),7.43(s,1H),7.11(M,1H),4.2(d,2H),3.1-3.0(br,2H),2.7-2.6(t,1H),1.23-1.17(d,6H), LC-MS (ESI) calculated mass is 541.59, measured mass is 542.2[ M + H [ ]]⁺(retention time: 0.632 minutes).

Example 228

N- (2',4' -difluoro-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) -4-methylpiperazine-1-carboxamide

This compound was prepared from the compound of example 2(a) using the procedure of example 227. ¹HNMR(300MHz,CD₃OD is 8.48(s,1H),8.0(s,1H),7.9(s,1H),7.86-7.85(M,2H),7.72-7.65(d,1H),7.65-7.59(M,4H),7.43(s,1H),7.11-7.09(M,2H),3.94(s,3H),3.63-3.60(M,4H),2.55-2.53(M,4H),2.36(s,3H), LC-MS (ESI) calculated mass is 527.57, measured mass is 528.1[ M + H ] (measured mass)]⁺(retention time: 0.632 minutes).

Example 229

N- (2',4' -difluoro-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) -2- ((3S,5R) -3, 5-dimethylpiperazin-1-yl) acetamide

This compound was prepared from the compound of example 2(a) using the procedure of example 226.¹HNMR(300MHz,DMSO-d₆) 8.4(brs,1H),8.14(M,1H),8.01(s,1H),7.92(s,1H),7.86(s,1H),7.83(M,1H),7.72-7.70(d,1H),7.66-7.59(M,2H),7.55(s,1H),7.15-7.11(M,2H),3.94(s,3H),3.37(s,2H),2.269(M,2H),1.27(s,3H),1.25(s,3H), LC-MS (ESI). The calculated mass is 555.62. the measured mass is 556.2[ M + H ] in the measured mass is 555.62]⁺(retention time: 0.75 minutes).

Example 230

1- (2',4' -difluoro-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) -3- (furan-2-ylmethyl) urea

To a solution of the compound from example 2(a) (20mg,0.049mmol) in DCM was added furfuryl isocyanate (7mg,0.059mmol,1.2eq.) followed by DIPEA (0.01ml,0.0747mmol,1.5 eq.). The mixture was stirred overnight, the reaction was terminated and extracted as described in example 1 (d). Evaporation of the solvent gave a crude residue which was purified by preparative HPLC to give the product in 92% yield (24 mg). ¹HNMR(400MHz,DMSO-d₆) 9.07(s,1H),8.95(brs,1H),8.24(s,1H),7.99(s,1H),7.97-7.96(M,2H),7.75-7.59(M,5H),7.40(M,2H),7.26(M,1H),6.82(t,1H),6.4(M,1H),6.27(M,1H),4.32-4.31(d,2H),3.88(s,3H), LC-MS (ESI): 524.52 and 525.1[ M + H ] mass]⁺(retention time: 0.75 minutes).

Example 231

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

a)4- (2- ((2',4' -difluoro-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) amino) -2-oxoethyl) piperazine-1-carboxylic acid tert-butyl ester

To a solution of the compound from example 2(a) (100mg,0.249mmol) in DMF was added 2- (4- (tert-butoxycarbonyl) piperazin-1-yl) acetic acid (121mg,0.498mmol,2eq.) followed by HATU (190mg,0.498mmol,2eq.) and DIPEA (0.17ml,0.996mmol,4 eq.). The mixture was stirred for 16 hours, quenched and extracted as described in example 1 (d). Evaporation of the solvent gave a crude residue which was purified by preparative HPLC to give the product in 25% yield (25 mg).

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

To a solution of example 231(a) (23mg,0.038mmol) in DCM (1ml) was added TFA (1ml) at 0 ℃ and the mixture was stirred at room temperature overnight. The solvent was evaporated to give a crude residue which was recrystallized from diethyl ether to give the product in 70% yield (18 mg).¹HNMR (400MHz, DMSO-d6):10.29(s,1H),8.75(s,1H),8.62(brs,2H),8.21(s,1H),8.14(s,1H),8.0(s,1H),7.95(s,1H),7.9(s,1H),7.75-7.7(M,2H),7.63-7.58(M,2H),7.48-7.44(t,1H),7.3-7.26(t,1H), LC-MS (ESI): calculating mass 527.22; measured mass 528.1[ M + H6 ]]⁺(retention time: 0.632 minutes).

Example 232

(2',4' -difluoro-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) carbamic acid methyl ester

To a solution of the compound from example 2(a) (60mg,0.15mmol) in chloroform (5ml) was added methyl chloroformate (14mg,0.15mmol,1eq.) and pyridine (0.024ml,0.3mmol,2eq.) at 0 ℃. The mixture was stirred at room temperature for 1 hour, then quenched with water and extracted with chloroform (3X 50 ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. Evaporation of the solvent gave the title compound in 37% yield (25 mg).¹HNMR(300MHz,DMSO-d₆):10.13(s,1H),8.63(s,1H),8.20(s,1H),7.98-7.92(m,3H),7.70-7.67(m,3H),7.60(m,1H),746(M,2H),7.27(M,1H),3.87(M,3H),3.72(s,3H), LC-MS (ESI) calculated mass 459.15, measured mass 460.2[ M + H ] ]⁺(retention time: 0.94 min).

Example 233

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

The compound was prepared from the compound of example 2(a) (100mg,0.249mmol) using the method of example 225 and 2- (morpholin-4-yl) acetic acid (54mg,0.373, mmol,1.5eq.) to give the product in 19% yield (25 mg).¹HNMR(300MHz,DMSO-d₆) 10.42(s,1H),8.91(s,1H),8.20(s,1H),8.08(s,1H),8.00(s,1H),7.95(s,1H),7.82(s,1H),7.77-7.71(M,2H),7.66-7.64(M,2H),7.46-7.40(M,1H),7.29-7.25(M,1H), 4.25(s,2H),3.9(s,3H),3.87-3.15(M,8H), LC-MS (ESI) calculating mass 528.55 measured mass 529.3[ M + H ], (M,8H) }]⁺(retention time: 0.38 minutes).

Example 234

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

The compound was prepared from the compound of example 2(a) using the method of example 225.¹HNMR(400MHz,DMSO-d₆) 8.91(s,1H),8.18(s,1H),8.05(s,1H),7.99(s,1H),7.94(s,1H),7.81(s,1H),7.75-7.70(M,2H),7.67-7.63(M,2H),7.42-7.37(t,1H),7.27-7.23(t,1H),4.12(s,2H),3.86(s,3H),3.50-3.35(M,2H),3.05-2.99(t,2H),1.79-1.68(M,5H),1.40(s,1H), LC-MS (ESI), calculated mass 526.58, measured mass 527.1[ M + H ], calculated mass of ]⁺(retention time: 0.36 minutes).

Example 235

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

The compound was prepared from the compound of example 2(a) using the method of example 225.¹HNMR(400MHz,DMSO-d₆) 11.02(s,1H),10.31(s,1H),8.80(s,1H),8.22 (s,1H),8.10(s,1H),8.01(s,1H),7.96(s,1H),7.79-7.73(M,2H),7.70(d,1H),7.63-7.61(M,2H),7.49-7.47(t,1H),7.31-7.29(t,1H),4.34-4.32(d,2H),3.88(s,3H),3.16(M,1H),2.03-1.91(M,4H), a calculated mass 512.55, and an actually measured mass 513.5[ M + H]⁺(retention time: 0.28 minutes).

Example 236

N- (2',4 ' -difluoro-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -2',3' -dihydro- [1,1' -biphenyl ] -3-yl) -4-ethylpiperazine-1-carboxamide

This compound was prepared from the compound of example 2(a) using the procedure of example 227. NMR (400MHz, DMSO-D6):9.53(brs,1H),9.22(s,1H),8.75(s,1H),8.22(s,1H),7.98(t,2H),7.77-7.72(M,3H),7.63(dd,1H),7.49-7.44(M,2H),7.283(dt,1H),4.35(D,2H),3.89(s,3H),3.57(D,3H),3.24-3.18(M,3H),3.07-3.02(M,2H),1.26(t,3H): LC-MS (ESI): calculated mass: 543.6; measured mass: 543.2M + H]⁺(retention time: 0.224 minutes).

Example 237

N- (2',4' -difluoro-5- (6- (1-methyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1' -biphenyl ] -3-yl) -2- (pyrrolidin-1-yl) acetamide

The compound was prepared from the compound of example 132(a) (100mg,0.248mmol) using the method of example 225 and 2- (pyrrolidin-1-yl) acetic acid (35mg,0.273mmol,1.1eq) to give the product in 7.08% yield (9 mg).¹HNMR(400MHz,DMSO-d₆):8.89(s,1H),8.6(s,1H),8.29(s,2H),8.10(s,1H),7.93(s,1H),7.85(s,1H),7.78(s,1H),7.67-7.61(m,1H),7.14-7.08(M,2H),4.29(s,2H),3.95(s,3H),3.80(s,2H),3.29(t,2H),2.14(t,4H); LC-MS (ESI) calculated mass 513.21; measured mass 514.4[ M + H ]; measured mass]⁺(retention time: 0.27 min).

Example 238

N- (2',4' -difluoro-5- (6- (1-methyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1' -biphenyl ] -3-yl) -2- (morpholin-4-yl) acetamide

The compound was prepared from the compound of example 132(a) using the procedure of example 225.¹HNMR(400MHz,DMSO-d₆) 11.1(s,1H),8.99(s,1H),8.70(s,1H),8.42(d,2H),8.31(s,1H),8.05(s,1H),7.90(s,1H),7.83(s,1H),7.77-7.75(M,1H),7.47(t,1H),7.30(t,1H),4.27(s,2H),3.90(s,3H),3.82(t,4H),2.50(t,4H), LC-MS (ESI), calculated mass 529.20, measured mass 530.4[ M + H ] calculated mass 530.4]⁺(retention time: 0.23 min).

Example 239

N- (2',4' -difluoro-5- (6- (1-methyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1' -biphenyl ] -3-yl) -2- (piperidin-1-yl) acetamide

The compound was prepared from the compound of example 132(a) using the procedure of example 225.¹HNMR(400MHz,DMSO-d₆) 11.0(s,1H),9.73(s,1H),8.99(s,1H),8.70(d,1H),8.43(t,2H),8.31(s,1H),8.05(s,1H),7.90(s,1H),7.83(s,1H),7.79-7.73(M,1H),7.49-7.44(M,1H),7.30(t,1H),4.20(s,2H),3.90(s,3H),3.37(t,4H),1.80-1.69(M,6H), LC-MS (ESI): 527.57, 528.6[ M + H ] measured mass]⁺(retention time: 0.32 minutes).

Example 240

N- (2',4 ' -difluoro-5- (6- (1-methyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1 ' -biphenyl ] -3-yl) piperidine-4-carboxamide

a)4- ((2',4 ' -difluoro-5- (6- (1-methyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1 ' -biphenyl ] -3-yl) carbamoyl) piperidine-1-carboxylic acid tert-butyl ester

The compound was prepared from the compound of example 132(a) (100mg,0.248mmol) using the method of example 225 and 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid (56mg,0.248mmol,2eq) to give the product in 26.3% yield (40 mg). LC-MS (ESI) calculated mass 513.21 and measured mass 514.4[ M + H ]]⁺(retention time: 0.68 minutes).

b) N- (2',4 ' -difluoro-5- (6- (1-methyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1 ' -biphenyl ] -3-yl) piperidine-4-carboxamide

To a solution of the compound from example 240(a) (30mg,0.0489mmol) in DCM was added TFA (1ml) and stirred at room temperature for 16 h. The mixture was concentrated to give the product in 98% yield (25 mg).¹HNMR(400MHz,DMSO-d₆) 10.50(s,1H),8.94(s,1H),8.72-8.66(M,2H),8.40-8.35(M,3H),8.29(s,1H),8.03(s,1H),7.90-7.89(d,1H),7.73-7.67(M,2H),7.46-7.41(M,1H),7.28-7.23(M,1H),3.88(s,3H),3.37-3.34(d,2H),2.99-2.90(M,2H),2.73-2.68(M,1H),2.01-1.98(d,2H),1.85-1.77(M,2H), LC-MS (ESI) (calculated mass 513.21; measured mass: 513.4 [ M + 514H ], (M,1H)]⁺(retention time: 0.68 minutes).

Example 241

The compound was prepared from example 132(a) using the procedure of example 225.¹HNMR(400MHz,DMSO-d₆) 10.9(s,1H),9.0(s,1H),8.73(s,1H),8.6(s,1H),8.3(s,1H),8.4(d,1H),8.03(d,1H),7.87(s,1H),7.75(M,1H),7.48(M,1H),7.29(M,1H),5.23(s,1H),3.95(s,3H), LC-MS ESI, calculated mass 511.49, measured mass 512.1[ M + H ] (S,1H), calculated mass]⁺(Retention time: 1.01 min)。

Example 242

N- (2',4 ' -difluoro-5- (6- (1-methyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1 ' -biphenyl ] -3-yl) -3, 5-dimethylpiperazine-1-carboxamide

To a solution of the compound from example 132(a) (100mg,0.248mmol) in DCM was added 20% phosgene (73.4mg,0.748mmol,3eq) followed by 1-ethylpiperazine (28.3mg,0.248mmol,1 eq.). The mixture was stirred for 16 hours, the reaction was terminated and extracted as described in example 2 (b). Evaporation of the solvent gave a crude residue which was purified by preparative HPLC to give the product in 5.9% yield (8 mg).¹HNMR(400MHz,DMSO-d₆) 9.13(s,2H),8.90(1,1H),8.70-8.69(d,1H),8.40-8.39(d,1H),8.29(s,1H),8.18(t,1H),8.03(s,1H),7.74-7.63(M,3H),7.46-7.40(M,1H),7.28-7.22(M1H),4.32-4.29(d,2H),3.88(s,3H),3.34(M,2H),2.80(t,2H),1.24(s,3H),1.22(s,3H), LC-MS (ESI) calculated mass 542.24, measured mass 543.3[ M + H + ESI)]⁺(retention time: 0.67 minutes).

Example 243

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

To a solution of the compound from example 132(a) (60mg,0.1492mmol) in DCM was added TEA (30mg,0.298mmol,2.0eq) followed by acryloyl chloride (16.1mg,0.179mmol,1.2 eq). The mixture was stirred for 4 hours, quenched and extracted as described in example 2 (b). Evaporation of the solvent gave a crude residue which was purified by preparative HPLC to give the product in 41% yield (28 mg). ¹HNMR(400MHz,DMSO-d₆) 10.7(s,1H),8.97(s,1H),8.754(d,1H),8.44(t,1H),8.33(s,1H),8.069(d,2H),7.79-7.75(M,2H),7.48(t,1H),7.30(t,1H),6.55-6.51(M,1H),6.32(d,1H),5.84(d,1H),3.92(s,3H), LC-MS (ESI), calculated mass 456.15, measured mass 457.1[ M + H + M [, (M,1H) ]]⁺(at the time of retentionThe method comprises the following steps: 1.456 minutes).

Example 244

N-cyclopropyl-N '- (2',4 '-difluoro-5- (6- (1-methyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1, 1' -biphenyl ] -3-yl) -sulfuric acid diamide

To a solution of the compound from example 132(a) (60mg,0.149mmol) in pyridine was added N-cyclopropyl-2-oxoOxazolidine-3-sulfonamide (49mg,0.238mmol,1.6 eq). The mixture was stirred at 50 ℃ for 16 hours, quenched and extracted as described in example 1 (d). Evaporation of the solvent gave a crude residue which was purified by preparative HPLC to give the product in 19.4% yield (15 mg).¹HNMR(400MHz,CD₃OD is 8.89(s,1H),8.71(s,1H),8.32(s,1H),8.14(s,1H),7.96(s,1H),7.77(t,1H),7.71(d,1H),7.71-7.63(M,1H),7.47(t,1H),7.15-7.09(M,2H),3.98(s,3H),2.48-2.44(M,1H),0.65-0.55(M,4H), LC-MS (ESI) calculated mass 521.14, measured mass 522.1[ M + H ] 522]⁺(retention time: 1.480 minutes).

Example 245

N- (2', 4' -difluoro-5- (6- (1-methyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1 '-biphenyl ] -3-yl) -N' - (furan-2-ylmethyl) sulfuric acid diamide

To a solution of the compound from example 132(a) (100mg,0.248mmol) in pyridine was added N- (furan-2-ylmethyl) -2-oxoOxazolidine-3-sulfonamide (97mg,0.398mmol,1.6 eq). The mixture was stirred at 50 ℃ for 16 hours, quenched and extracted as described in example 1 (d). Evaporation of the solvent gave a crude residue which was purified by preparative HPLC to give the productYield 18% (25 mg).¹HNMR(400MHz,DMSO-d₆) 10.24(s,1H),8.89(s,1H),8.70(d,1H),8.40(d,1H),8.31-8.28(M,2H),8.03(d,1H),7.71-7.64(M,3H),7.46-7.43(M,2H),7.32(d,1H),7.29-7.24(M,1H),6.28-6.27(M,1H),6.23(d1H),4.10-4.09(d,2H),3.88(s,3H), LC-MS (ESI) calculating mass 561.14 and actually measuring mass 562.1[ M + H ] 561.14]⁺(retention time: 1.513 minutes).

Example 246

N- (5- (6- (2-aminopyridin-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) acetamide

a) (4- (3- (5-acetylamino-2 ',4' -difluoro- [1,1' -biphenyl ] -3-yl) -3H-imidazo [4,5-b ] pyridin-6-yl) pyridin-2-yl) carbamic acid tert-butyl ester

This compound was prepared from the compound of example 131(c) using the procedure of example 131 (d).

b) N- (5- (6- (2-aminopyridin-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) acetamide

To a solution of the compound from example 246(a) (0.2g,0.359mmol) in DCM (5ml) was added TFA (1.2ml) at 0 ℃. The mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo, quenched with sodium bicarbonate and extracted as described in example 1 (d). Evaporation of the solvent gave the product in 17.7% yield (0.29 g).¹HNMR(400MHz,DMSO-d₆) 10.41(s,1H),9.09(s,1H),8.87(d,1H),8.70-8.69(d,2H),8.34(s,1H),8.10-8.08(d,1H),8.12(s,1H),7.86(s,1H),7.71(M,2H),7.52(M,1H),7.41-7.39(d,1H),7.31(M,2H),2.12(s,3H), a calculated mass 456.48, an actually measured mass 457.3[ M + H ], (s,1H)]⁺(retention time: 0.19 minutes).

Example 247

N- (2',4' -difluoro-5- (6- (thiazol-2-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1' -biphenyl ] -3-yl) acetamide

This compound was prepared from a solution of the compound from example 131(c) (100mg,0.225mmol) in THF (6ml) using the method of example 200(c) and thiazol-2-yl zinc (II) bromide (155mg,0.677mmol,3.0eq.) to give the product in 25% yield (25 mg).¹HNMR (400MHz, DMSO-D6):10.42(s,1H),9.08(D,2H),8.72(D,1H),8.30(s,1H),8.01(D,1H),7.93(s,1H),7.90(D,1H),7.75-7.72(M,2H),7.46(t,1H),7.28(t,1H),2.13(s,3H); LC-MS (ESI): calculated mass 447.46; measured mass 448.0[ M + H ]: measured mass 448.0 ]⁺

Example 248

N- (5- (6- (6-aminopyridin-3-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) acetamide

This compound was prepared from the compound of example 131(c) using the procedure of example 246.¹HNMR(300MHz,DMSO-d₆) 10.43(s,1H),9.02(s,1H),8.76(d,1H),8.55(d,1H),8.44-8.34(M,3H),8.04(brs,2H),7.84(s,1H),7.75-7.67(M,2H),7.49-7.42(M,1H),7.30-7.25(M,1H),7.10-7.07(M,1H),2.12(s,3H), LC-MS (ESI), calculated mass 456.15, measured mass 457.2[ M + H ] M]⁺(retention time: 0.20 minutes).

Example 249

N- (5- (5- (4-aminophenyl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) acetamide

This compound was prepared from the compound of example 131(c) using the procedure of example 246.¹HNMR(300MHz,DMSO-d₆) 10.41(s,1H),8.98(s,1H),8.68(s,1H),8.37(s,1H),8.31(s,1H),7.89(s,1H),7.71-7.68(M,1H),7.62-7.59(M,2H),7.48-7.42(M,1H),7.29-7.24(M,2H),7.12(s,1H),6.95-6.90(M,3H),2.12(s,3H), LC-MS (ESI), calculated mass 455.16, measured mass 456.3[ M + H ESI ]]⁺(retention time: 0.78 min).

Example 250

N- (5- (5- (2-aminopyridin-4-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) acetamide

The compound was prepared from the compound of example 1(h) using the method of example 246 to give the product in 97.6% yield (0.40 g). ¹HNMR(400MHzCD₃OD is 8.68(s,1H),8.21-8.20(d,2H),7.91-7.88 (t,2H),7.84-7.81(dd,1H),7.70-7.68(d,1H),7.66-7.64(M,1H),7.54(d,1H),7.34-7.30(M,2H),7.15-7.10(M,2H),3.33(s,1H),2.19(s,3H), calculated mass 455.46, measured mass 456.3[ M + H ] M + H]⁺(retention time: 0.29 minutes).

Example 251

N- (2',4' -difluoro-5- (5- (thiazol-2-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) acetamide

This compound was prepared from a solution of the compound from example 1(h) (200mg,0.452mmol) in THF (6ml) using the method of example 200(c) and thiazol-2-yl zinc (II) bromide (310mg,1.35mmol,3.0eq) to give the product in 25% yield (50 mg).

Example 252

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

This compound was prepared from the compound of example 1(h) using the method of example 1 (i).¹HNMR(300MHz,CD₃OD is 8.25(d,1H),8.08(s,2H),7.96(s,1H),7.82(s,1H),7.59-7.51(M,3H),7.42(s,1H),7.05-6.99(M,4H),2.1(s,3H), LC-MS (ESI) calculated mass is 455.16, measured mass is 456.1[ M + H ]]⁺(retention time: 0.21 minutes).

Example 253

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

a) (4- (1- (5-acetylamino-2 ',4' -difluoro- [1,1' -biphenyl ] -3-yl) -1H-benzo [ d ] imidazol-5-yl) -1-methyl-1H-pyrazol-5-yl) carbamic acid tert-butyl ester

This compound was prepared from the compound of example 1(h) using the method described in example 1 (i).

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

To a solution of the compound from example 253(a) (15mg,0.02mmol) in DCM was added TFA (1 ml). The mixture was stirred at room temperature for 16 h and concentrated to give the product in 50.4% yield (6 mg).¹HNMR(400MHz,CD₃OD) 8.49(s,1H),8.11-8.10(d,1H),7.86(s,1H),7.73-7.60(m,4H),7.53-7.49(m,2H),7.16-7.09(m,2H),3.76(s,3H),2.20(s,3H),1.97(s, 2H). LC-MS (ESI) for calculating mass 458.46 and measured mass 459.0M + H]⁺(retention time: 0.43 minutes).

Example 254

N- (5- (5- (2-aminothiazol-5-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) acetamide

To N- (5- (5- (2-bromoacetyl) -1H-benzo [ d ]]Imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl]To a solution of (100mg,0.20mmol) of (E) -3-yl) acetamide in ethanol was added thiourea (20mg,0.30mmol,1.5 eq). The mixture was stirred at 60 ℃ for 3 hours. The mixture was quenched and extracted as described in example 1 (d). Evaporation of the solvent gave a crude residue which was purified by preparative HPLC to give the product in 14.7% yield (14 mg). ¹HNMR(300MHz,CD₃OD is 8.73(s,1H),8.11(s,1H),8.01(s,1H),7.73-7.69(m,2H),7.62-7.50(m,2H),7.45(d,1H),7.10-6.99(m,3H),2.10(s,3H), LC-MS (ESI): calculated mass: 461.4; measured mass: 462.1[ ]M+H]⁺(retention time: 0.80 minutes).

Example 255

N- (5- (5- (2-aminopyrimidin-5-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) acetamide

This compound was prepared from the compound of example 1(h) using the method of example 246.¹HNMR(300MHz,CD₃OD is 8.84(s,1H),8.70(s,1H),8.18(s,1H),7.99(s,1H),7.86-7.83(M,1H),7.72-7.61(M,3H),7.53(d,1H),7.13-7.01(M,2H),2.13(s,3H), LC-MS (ESI) is calculated as 456.4, measured as 457.1[ M + H ], (ESI)]⁺(retention time: 0.56 minutes).

Example 256

N- (5- (5- (1H-pyrazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) -1-methylpiperidine-4-carboxamide

The compound was prepared from the compound of example 29(a) (50mg,0.128mmol) using the method of example 225 using 1-methylpiperidinecarboxylic acid (22mg,0.154mmol,1.2eq.) to give the product in 30% yield (20 mg).¹HNMR(300MHz,CD₃OD) 8.59(s,1H),8.27(d,1H),8.15-8.14(t,1H),8.11(m,1H),7.82-7.75(m,4H),7.66-7.56(m,1H),7.56(m,1H),7.13-7.11(m,1H),6.56(t,1H),3.53-3.47(m,2H),3.0(m,2H),2.82(s,3H),2.7(m,1H),2.14-2.0(m, 4H). LC-MS (ESI) calculated mass 512.55 and measured mass 513.1[ M + H ]⁺(retention time: 1.245 minutes).

Example 257

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

The compound was prepared from the compound of example 29(a) using the method of example 225.¹HNMR(400MHz,DMSO-d₆) 10.12(s,1H),8.73(s,1H),8.58(d,1H),8.22(d,1H),8.13(t,1H),7.95-7.9(M,2H),7.82-7.71(M,3H),7.55(s,1H),7.47-7.41(M,1H),7.28-7.23(dt,1H),6.55-6.54(M,1H),3.45(s,2H),3.17(s,3H),2.48-2.32(M,8H), LC-MS (ESI) calculating mass 527.57, measured mass 528.2[ M + H ] 528.2]⁺(retention time: 0.36 minutes).

Example 258

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

The compound was prepared from the compound of example 29(a) using the method of example 225.¹HNMR(400MHz,DMSO-d₆) 11.2(s,1H),8.75(s,1H),8.57(s,1H),8.22(d,1H),8.07(t,1H),8.0(s,1H),7.92-7.85(m,2H),7.8-7.73(m,3H),7.59(s,1H),7.47-7.41(dt,1H),7.28-7.23(dt,1H),6.54(m,1H),5.24(s, 2H). LC-MS (ESI) for calculating mass 496.47 and measured mass 497.0M + H]⁺(retention time: 0.17 minutes).

Example 259

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

The compound was prepared from the compound of example 29(a) using the method of example 225 and 2- (piperidin-1-yl) acetic acid (41mg,0.290mmol,1.5eq.) to give the product in 10.1% yield (10 mg).¹HNMR(400MHz,DMSO-d₆) 10.11(s,1H),8.75(s,1H),8.60(d,1H),8.24-8.21(d,1H),8.15(s,1H),7.98(s,1H),7.94-7.92(dd,1H),7.84-7.82(d,1H),7.79-7.77(M,2H),7.56(s,1H),7.49-7.43(t,1H),6.57-6.56(t,1H),3.14(s,2H), 2.67(s,1H), 2.33(s,1H), 1.90(s,1H), 1.60-1.59(t,5H), 1.40(s,2H) LC-MS (ESI), calculated mass: 512.55; measured mass: 513.M + H]⁺(retention time: 0.3 minutes).

Example 260

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

The compound was prepared from the compound of example 29(a) using the method of example 225.¹HNMR(600MHz,CD₃OD) 8.62(s,1H),8.29-8.28(d,1H),8.17-8.16(t,1H),8.12(s,1H),7.85-7.83(dd,3H),7.77-7.76(d,1H),7.68-7.67(M,1H),7.59(s,1H),7.15-7.12(M,2H),6.58-6.57(t,1H),3.73(s,2H), 3.02(t,4H), 2.00-1.94(M,7H), LC-MS (ESI) calculating mass 498.53, measured mass 499.6[ M + H ], (M,1H)]⁺(retention time: 0.6 minutes).

Example 261

N- (2',4' -difluoro-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) -1-ethylpiperidine-3-carboxamide

The compound was prepared from the compound of example 2(a) using the method of example 225.¹HNMR (300MHz, DMSO):10.6(d,1H),9.50(s,1H),8.79(d,1H),8.22(s,1H),8.10(s,1H),8.00-7.96(d,2H),7.80-7.70(M,3H),7.64-7.59(M,1H),7.46(M,1H),7.28(M,1H),3.81(s,3H),3.60-3.56(d,3H),3.43-3.37(M,1H),3.14-3.04(d,2H),3.0-2.89(t,2H),2.13(d,1H),2.00-1.95(d,1H),1.73-1.69(d,1H),1.55(d, 1H): ESI: (LC, 541.2): calculated mass ratio (LC, M,1H), calculated mass ratio of (M,1H), 3.7-3.7H), 3.1.7 (d,1H),1.55 (MS, 1H), ESI, 35540: (M, 2H)]⁺(retention time: 0.22 minutes).

Example 262

N- (2',4' -difluoro-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) -1-methylpiperidine-3-carboxamide

This compound was prepared from the compound of example 2(a) using the method of example 255.¹HNMR(300MHz,DMSO):10.6(d,1H),9.50(s,1H),8.79(d,1H),8.22(s,1H),8.10(s,1H),8.00-7.96(d,2H),7.80-7.70(M,3H),7.64-7.59(M,1H),7.46(M,1H),7.28(M,1H),3.81(s,3H),3.60-3.56(d,3H),3.43-3.37(M,1H),3.14-3.04(d,2H),3.0-2.89(t,2H),2.13(d,1H),2.00-1.95(d,1H),1.73-1.69(d,1H),1.55(d,1H), LC-MS (ESI): calculated mass 526.58; measured mass 527.2[ M + H ], (M + H)]⁺(retention time: 0.15 minutes).

Example 263

N- (2',4' -difluoro-5- (5- (1- (tetrahydro-2H-pyran-4-yl) -1H-1,2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) acetamide

A mixture of the compound (250mg,0.644mmol) obtained in example 17(e), 4-azidotetrahydro-2H-pyran (90mg,0.77mmol,1.2eq.), copper iodide (12mg,0.06mmol,0.1eq.) in DMF was stirred at 90 ℃ for 16 hours. The mixture was quenched with water, the precipitate formed was filtered and dried to give the crude product, which was purified by preparative HPLC to give the product in 45% yield (150 mg).¹HNMR (300MHz, DMSO) 10.4(s,1H)8.77(s,1H),8.69(s,1H),8.25(s,1H),8.06(d,1H),7.94-7.90(M,1H),7.83-7.76(M,3H),7.53(s,1H),7.40-7.52(M,1H),7.34-7.22(M,1H),4.80(M,1H),4.02(M,2H),3.50-3.52(M,2H),2.10(s,3H),2.0-2.12(M,4H), LC-MS (ESI), calculated mass 514.5, measured mass 514.8[ M + H + E]⁺(retention time: 1.32 minutes).

Example 264

N- (5- (5- (1H-1,2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) acetamide

A mixture of the compound (300mg,0.77mmol) from example 17(e), sodium azide (150mg,2.32mmol,3.0eq.), copper iodide (14mg,0.07mmol,0.1eq.) in DMF was stirred at room temperature for 16 hours. The mixture was quenched with water, the precipitate formed was filtered and dried to give the crude product, which was purified by preparative HPLC to give the product in 64.3% yield (200 mg). ¹HNMR(300MHzDMSO 10.4(s,1H),8.80(s,1H),8.40(s,1H),8.32(s,1H),8.11(s,1H),7.97-7.94(d,1H),7.85-7.76(M,3H),7.56(d,1H),7.47(M,1H),7.30(M,1H),2.10(s,3H), LC-MS (ESI) calculating mass 430.4, measured mass 431.2[ M + H ], (ESI)]⁺(retention time: 0.69 minutes).

Example 265

N- (5- (5- (1- (cyclopropylmethyl) -1H-1,2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) acetamide

A mixture of the compound (100mg,0.25mmol) of example 17(e), sodium azide (25mg,0.387mmol,1.5eq.), (bromomethyl) cyclopropane (41mg,0.310mmol,1.2eq.), copper iodide (5mg,0.025mmol,0.1eq.) in DMF was stirred at room temperature for 16 hours. The mixture was quenched with water, the precipitate formed was filtered and dried to give the crude product, which was purified by preparative HPLC to give the product in 80.6% yield (100 mg).¹HNMR(300MHz,CD₃OD is 10.4(s,1H),8.68(d,1H),8.05(s,1H),7.90-7.88(M,2H),7.81-7.69(M,3H),7.51-7.39(M,3H),7.28-7.22(M,1H),4.25(d,2H),2.10(s,3H),1.34(M,1H),0.63-0.56(2H, d),0.50-0.46(2H, d), LC-MS (ESI) calculating mass 484.5, measured mass 484.8[ M + H ] M]⁺(retention time: 1.42 minutes).

Example 266

N- (2',4' -difluoro-5- (5- (1- (tetrahydro-2H-pyran-4-yl) -1H-1,2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) ethanesulfonamide

To 2',4' -difluoro-5- (5- (1- (tetrahydro-2H-pyran-4-yl) -1H-1,2, 3-triazol-4-yl) -1H-benzo [ d]Imidazol-1-yl) - [1,1' -biphenyl]Pyridine (19mg,2.52mmol,2.0eq.) followed by ethanesulfonyl chloride (19mg,0.152mmol,1.2 eq.) is added to a solution of-3-amine (60mg,0.126mmol) in DCM. After completion of the reaction, the solvent was evaporated and the crude product was purified by preparative HPLC to give the product in 42% yield (30 mg).¹HNMR(300MHz,CD₃OD):8.92(s,1H)8.3(d,1H),8.06(s,1H),8.0(s,1H),7.95(s,1H),7.88(s,1H),7.77-7.69(M,5H),7.45(M,1H),6.56(M,1H),3.92(s,3H),3.28-3.27(M,4H),1.6-1.49(M,6H); LC-MS (ESI): mass 564.6 is calculated and measured mass 565.4[ M + H ], (M + H), is measured]⁺(retention time: 1.46 minutes).

Example 267

N- (5- (5- (1H-1,2, 3-triazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) ethanesulfonamide

To a solution of 5- (6- (1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-amine (70mg,0.18mmol) in DCM was added pyridine (42mg,0.54mmol,3.0eq.) followed by ethanesulfonyl chloride (27mg,0.216mmol,1.2 eq.). The reaction was monitored by LCMS. After completion of the reaction, the solvent was evaporated and the crude product was purified by preparative HPLC to give the product in 2.3% yield (2 mg).

Example 268

N- (5- (6- (1- (cyclopropylmethyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) acetamide

Mixing N- (5- (6-ethynyl-3H-imidazo [4,5-b ]]Pyridin-3-yl) -2',4' -difluoro- [1,1' -biphenyl]A mixture of-3-yl) acetamide (300mg,0.77mmol), sodium azide (76mg,1.15mmol,1.5eq.), (bromomethyl) cyclopropane (125mg,0.92mmol,1.2eq.), (bromomethyl) copper iodide (14mg,0.07mmol,0.1eq.) in DMF was stirred at room temperature for 16 h. The mixture was quenched with water and the precipitate formed was filtered and dried to give the crude product, which was purified by preparative HPLC to give the product in 82.6% yield (310 mg).¹HNMR (300MHz, DMSO) 10.4(s,1H),8.99(d,2H),8.80(s,1H),8.63(d,1H),8.30(s,1H),7.91(d,1H),7.76-7.68(M,2H),7.49-7.41(M,1H),7.30-7.25(M,1H),4.21(M,2H),2.12(s,3H),1.23(M,1H),0.63-0.60(2H, d)0.50-0.48(2H, d), LC-MS (ESI) calculating mass 485.4, measured mass 486.1[ M + H, d ]]⁺(retention time: 1.52 minutes).

Example 269

N- (2',4' -difluoro-5- (6- (1- (tetrahydro-2H-pyran-4-yl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1' -biphenyl ] -3-yl) acetamide

Mixing N- (5- (6-ethynyl-3H-imidazo [4,5-b ] ]Pyridin-3-yl) -2',4' -difluoro- [1,1' -biphenyl]A mixture of (E) -3-yl) acetamide (250mg,0.644mmol), 4-azidotetrahydro-2H-pyran (90mg,0.77mmol,1.2eq.), copper iodide (12mg,0.06mmol,0.1eq.) in DMF was stirred at 90 ℃ for 16H. The mixture was quenched with water and the precipitate formed was filtered and dried to give the crude product, which was purified by preparative HPLC to give the product in 45% yield (150 mg).¹HNMR (300MHz, DMSO) 10.4(s,1H),8.99-8.97(M,2H),8.88(s,1H),8.61-8.60(M,1H),8.32-8.29(M,1H),7.91(d,1H),7.76-7.68(M,2H),7.48-7.41(M,1H),7.3-7.24(M,1H),4.80(M,1H),4.02(M,2H),3.50-3.60(M,2H),2.10(s,3H),2.0-2.12(M,4H), LC-MS (ESI), calculated mass 515.5, measured mass 516.5[ M + H ], (M,1H)]⁺(retention time: 1.37 minutes).

Example 270

2- (4- (3- (5-acetylamino-2 ',4' -difluoro- [1,1' -biphenyl ] -3-yl) -3H-imidazo [4,5-b ] pyridin-6-yl) -1H-1,2, 3-triazol-1-yl) acetic acid ethyl ester

Reacting N- (5- (5-ethynyl-1H-benzo [ d ]]A mixture of imidazol-1-yl) -2',4' -difluorobiphenyl-3-yl) acetamide (200mg,0.51mmol), sodium azide (90mg,1.5mmol,3.0eq.), ethyl 2-bromoacetate (100mg,0.61mmol,1.2eq.), sodium ascorbate (100mg,0.51mmol,1.0eq.), and copper sulfate pentahydrate (45.9mg,0.255mmol,0.5eq.) in DMSO, THF, and water (1:1:1,3ml) was stirred at room temperature for 12 hours. The mixture was quenched with water and the precipitate formed was filtered and dried to give the crude product, which was purified by preparative HPLC to give the product in 76% yield (200 mg). ¹HNMR(300MHz,DMSO):10.4(s,1H),9.02-8.99(d,2H),8.75(s,1H),8.64(d,1H),8.29(s,1H),7.92(d,1H),7.71-7.70(M,2H),7.50-7.40(M,1H),7.27(M,1H),5.55(s,2H),4.22(q,2H),2.10(s,3H),1.24(t,3H); LC-MS (ESI): calculated mass: 517.45; measured mass: 517.8[ M + H ] (ESI): 517.8]⁺(retention time: 1.47 minutes).

Example 271

2- (4- (3- (5-acetylamino-2 ',4' -difluoro- [1,1' -biphenyl ] -3-yl) -3H-imidazo [4,5-b ] pyridin-6-yl) -1H-1,2, 3-triazol-1-yl) acetamide

To a mixture of the compound from example 270 (100mg,0.19mmol) in methanol at 0 ℃ was added methanolic ammonia solution and the mixture was stirred at room temperature for 16 h. The mixture was evaporated to completion and the crude product was purified by preparative HPLC to give the product in 13% yield (12 mg). 10.5(s,1H)9.14-8.97(d,2H),8.82(s,1H),8.76(d,1H),8.35(s,1H),7.89(d,1H),7.81-7.80(M,2H),7.65-7.55(M,1H),7.27(M,1H),5.55(s,2H),2.8(s,2H),2.10(s,3H), LC-MS (ESI): calculated mass: 515.5; measured mass: 516.5[ M + H ] (S, 2H): measured mass: 516.5]⁺(retention time: 1.37 minutes).

Example 272

N- (5- (6- (1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) acetamide

A mixture of N- (5- (6-ethynyl-3H-imidazo [4,5-b ] pyridin-3-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) acetamide (300mg,0.77mmol), sodium azide (75mg,1.15mmol,1.5eq.), copper iodide (14mg,0.07mmol,0.1eq.) in DMF was stirred at room temperature for 16 hours. The mixture was quenched with water and the precipitate formed was filtered and dried to give the crude product, which was purified by preparative HPLC to give the product in 90% yield (300 mg).

Example 273

N- (5- (6- (1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) ethanesulfonamide

To 5- (6- (1H-1,2, 3-triazol-4-yl) -3H-imidazo [4, 5-b)]Pyridin-3-yl) -2',4' -difluoro- [1,1' -biphenyl]Pyridine (42mg,0.53mmol,3.0eq.) and then ethanesulfonyl chloride (20mg,0.179mmol,1.0eq.) are added to a solution of-3-amine (70mg,0.179mmol) in DCM. The reaction was monitored by LCMS. After completion of the reaction, the solvent was evaporated and the crude product was purified by preparative HPLC to give the product in 9.3% yield (8 mg).¹HNMR (300MHz, DMSO) 10.4(s,1H),9.0-8.97(M,2H),8.64(d,1H),7.92(s,1H),7.75-7.64(M,3H),7.47-7.43(M,3H),3.31-3.24(q,2H),1.39-1.34(t,3H), LC-MS (ESI) calculating mass 481.4, measured mass 481.8[ M + H ] 481.8]⁺(retention time: 1.36 minutes).

Example 274

N- (2',4' -difluoro-5- (6- (1- (tetrahydro-2H-pyran-4-yl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1' -biphenyl ] -3-yl) ethanesulfonamide

To 2',4' -difluoro-5- (6- (1- (tetrahydro-2H-pyran-4-yl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b]Pyridin-3-yl) - [1,1' -Biphenyl]Pyridine (21mg,2.72mmol,2.0eq.) followed by ethanesulfonyl chloride (21mg,0.164mmol,1.2eq.) is added to a solution of-3-amine (65mg,0.136mmol) in DCM. After completion of the reaction, the solvent was evaporated and the crude product was purified by preparative HPLC to give the product in 42% yield (30 mg). ¹HNMR (300MHz, DMSO):10.4(s,1H),9.04(s,1H),8.99-8.98(d,1H),8.90(d,1H),8.63-8.61(d,1H),7.95(d,1H),7.76-7.70(M,2H),7.49(M,2H),7.35(d,1H),4.82(M,1H),3.95(d,2H),3.58-3.55(t,2H),3.36-3.28(M,2H),2.12(M,2H),1.29-1.24(t,3H),1.08-1.06(t,2H); LC-MS (ESI 565.5) calculated mass: 565.9[ M + H ]; measured mass: 565.9[ M + H: (M,1H)]⁺(retention time: 1.44 minutes).

Example 275

N- (5- (6- (1- (cyclopropylmethyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) ethanesulfonamide

To 5- (6- (1- (cyclopropylmethyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b]Pyridin-3-yl) -2',4' -difluoro- [1,1' -biphenyl]Pyridine (26mg,0.33mmol,3.0eq.) and ethanesulfonyl chloride (17mg,0.135mmol,1.2eq.) are added to a solution of-3-amine (50mg,0.112mmol) in DCM. After completion of the reaction, the solvent was evaporated and the crude product was purified by preparative HPLC to give the product in 33% yield (20 mg).¹HNMR (300MHz, DMSO) 10.3(s,1H)9.02-8.99(M,2H),8.81(d,1H),8.63-8.61(d,1H),7.95(d,1H),7.77-7.69(M,2H),7.49-7.42(M,2H),7.31-7.25(d,1H),4.33(d,2H),3.42-3.26(M,2H),1.34-1.24(t,3H),0.63-0.60(t,2H),0.49-0.48(t,2H), LC-MS (ESI) calculating mass 535.5, measured mass 535.8[ M + H ] 535.5 ]⁺(retention time: 0.1.33 minutes).

Example 276

N- (5- (6- (1- (cyclopropylmethyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) cyclopropanecarboxamide

To 5- (6- (1- (cyclopropylmethyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b]Pyridin-3-yl) -2',4' -difluoro- [1,1' -biphenyl]-3-amine (50mg,0.11mmol) in DMF cyclopropanecarboxylic acid (11mg,0.13 mmol,1.2eq.) was added followed by HATU (91mg,0.24mmol,2.0eq.) and DIPEA (43mg,0.33mmol,3.0 eq.). The mixture was stirred for 16 hours, quenched and extracted as described in example 1 (d). Evaporation of the solvent gave a crude residue which was purified by column chromatography to give the product in 51% yield (25 mg).¹HNMR (300MHz, DMSO):10.6(s,1H),8.99(d,2H),8.88(d,1H),8.62(d,1H),8.31(d,1H),7.92(d,1H),7.76-7.71(M,2H),7.47-7.40(M,1H),7.29-7.24(M,1H),4.33-4.30(d,2H),3.64-3.62(M,2H),3.12-3.09(M,2H),1.87-1.83(M,1H),0.63-0.61(t,2H),0.49-0.48(t,2H); LC-MS (ESI calculated mass: 511.5; measured mass: 511.8[ M + H ]; measured]⁺(retention time: 1.63 minutes).

Example 277

N- (3- (3-fluoropyridin-4-yl) -5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide

a) N- (3-bromo-5- ((4- (1-methyl-1H-pyrazol-4-yl) -2-nitrophenyl) amino) phenyl) acetamide

A solution of 4- (4-fluoro-3-nitrophenyl) -1-methyl-1H-pyrazole (1.6g,7.239mmol), N- (3-amino-5-bromophenyl) acetamide (1.98g,8.687mmol) and potassium fluoride (0.503g,8.687mmol) in DMF was heated at 130 ℃ for 48H. The mixture was quenched and extracted as described in example 1 (d). 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 35% yield (1.1g); LC-MS (API): calculated mass: 430.1; measured mass: 432[ M + H]⁺(retention time: 1.50 minutes).

b) N- (3- ((2-amino-4- (1-methyl-1H-pyrazol-4-yl) -phenyl) amino) -5-bromophenyl) acetamide

To a solution of example 277(a) (1.0g,2.32mmol) in THF (20ml) and methanol (20ml) was added a solution of ammonium chloride (1.24g,23.20mmol,10eq.) in water (15ml) and zinc (1.5g,23.20mmol,10 eq.). The mixture was stirred at room temperature for 4 hours and filtered. The filtrate was diluted with water and extracted as described in example 1 (d). Evaporation of the solvent gave the title product in 90% yield (0.9g), LC-MS (API) calculated mass 399.1, measured mass 400.0[ M + H ]]⁺(retention time: 0.61 min).

c) N- (3-bromo-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide

A mixture of the compound from example 277(b) (1.0g,2.50mmol) and formic acid (10ml) was heated at 90 ℃ for 2 hours. The formic acid was evaporated off and the residue was dissolved in ethyl acetate. The ethyl acetate layer was washed with water, brine and dried over sodium sulfate. The solvent was distilled off to give the product in 85% yield (0.9g), LC-MS (ESI) calculated mass 410.1, measured mass 412.1[ M + H ]]⁺(retention time: 0.403 minutes). d) N- (3- (3-fluoropyridine-)4-yl) -5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d]Imidazol-1-yl) phenyl) acetamide

A solution of the compound from example 277(c) (0.1g,0.243mmol) in 1, 2-dimethoxyethane (4ml) was passed through N₂Bubbling and degassing for 5 minutes. (3-Fluoropyridin-4-yl) boronic acid (0.041g,0.292mmol,1.2eq.) was added and the mixture was degassed for an additional 5 minutes. Adding Pd (dppf) Cl₂(0.020g,0.024mmol,0.1eq.) and aqueous sodium carbonate (0.077g,0.731mmol,3.0eq.) followed by the procedure of example 1 (d). The crude residue of the product was purified by preparative HPLC to give the product in 21% yield.¹HNMR(300MHz,DMSO-d₆) 10.5(s,1H),8.97(s,1H),8.75(s,1H),8.59(d,1H),8.24(s,1H),8.20(s,1H),8.01(s,1H),7.97(d,2H),7.80-7.65(M,4H),3.89(s,3H),2.13(s,3H), LC-MS (ESI) calculating mass 426.16, measured mass 427.1[ M + H ] mass ]⁺(retention time: 0.20 minutes).

Example 278

N- (3- (3-fluoropyridin-4-yl) -5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) ethanesulfonamide

This compound was prepared from the compound of example 277 (0.9g,2.11mmol,1eq.) using the method of example 2 and ethanesulfonyl chloride (60mg,0.46mmol,1.2eq.) to give the product in 15.13% yield (28 mg).¹HNMR(400MHz,DMSO-d₆) 8.69-8.68(d,1H),8.58(s,1H),8.54-8.52(d,1H),8.18(s,1H),7.97(s,1H),7.93(s,1H),7.74-7.71(t,1H),7.67-7.64(d,1H),7.58-7.56(d,1H),7.44-7.43(t,1H),7.36-7.33(d,2H),3.87(s,3H),3.07-3.02 (quartet, 2H),1.22-1.18(t,3H), LC-MS (ESI), calculated mass: 476.14, measured mass: 476.9[ M + H ] (M, M]⁺(retention time: 0.36 minutes).

Example 279

N- (3- (3-chloropyridin-4-yl) -5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide

The compound was prepared from the compound of example 277(c) using the procedure of example 277 (d).¹HNMR(400MHz,DMSO-d₆) 10.5(s,1H),8.80(M,2H),8.66-8.63(M,2H),8.20(s,1H),8.13(s,1H),7.99(s,1H),7.94(s,1H),7.81(s,1H),7.72(d,1H),7.65(d,1H),7.60(d,1H),7.53(s,1H),3.88(s,3H),2.13(s,3H), LC-MS (ESI): 442.13 and 443.1[ M + H ] (ESI): 443.1]⁺(retention time: 0.28 minutes).

Example 280

N- (2', 4' -difluoro-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) pyrimidin-2-amine

1- (5-bromo-2 ',4' -difluoro- [1,1' -biphenyl)]-3-yl) -5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d]A solution of imidazole (0.075g,0.161mmol) in 1, 4-dioxane (3ml) was passed over N₂Bubbling and degassing for 5 minutes. Pyrimidin-2-amine (0.018g,0.193mmol,1.2eq.) was added and the mixture was degassed for an additional 5 minutes. Followed by the addition of Pd₂(dba)₃(0.014g,0.016mmol,0.1eq.) and Xantphos (0.037g,0.064mmol,0.4eq.) and Cs₂CO₃(0.209g,0.644mmol,4.0eq) and the mixture was further degassed for 5 minutes and then heated at 110 ℃ for 16 hours. The mixture was filtered over a celite bed, the reaction was terminated and extracted as described in example 1 (d). Evaporation of the solvent gave a crude residue which was purified by column chromatography (60-120 silica gel, 2% methanol in ethyl acetate) to give the title product in 11.6% yield (0.09 g).¹HNMR(400MHz,DMSO-d₆) 10.15(s,1H),8.83(s,1H),8.57-8.56(d,2H),8.35(s,1H),8.24(s,1H),8.01-7.97(s,3H),7.84-7.81(d,1H),7.70-7.68(M,2H),7.46-7.432(M,2H),7.280-7.286(M,1H),6.95-6.32(t,1H),3.88(s,1H), LC-MS (ESI) calculating mass 479.48, and actual measuring mass 480.1[ M + H]⁺(retention time: 1.52 minutes).

Example 281

N- (2', 4' -difluoro-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) thiazol-2-amine

The compound is prepared from 1- (5-bromo-2 ',4' -difluoro- [1,1' -biphenyl)]-3-yl) -5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d]Imidazole (0.05g,0.107mmol) was prepared using the method of example 280 and thiazol-2-amine (0.01g,0.10mmol,1.0eq.) to give the title product in 11.7% yield (0.06 g).¹HNMR(400MHz,CD₃OD) 9.45(s,1H),8.39(s,1H),8.11(s,1H),8.01(s,1H),7.94(s,1H),7.86-7.83(m,2H),7.74(s,1H),7.67-7.65(m,1H),7.45(s,1H),7.28-7.27(d,1H),7.16-7.11(m,2H),6.89(d,1H),3.95(s, 3H). LC-MS (ESI) for calculating mass 484.52 and measured mass 485.2M + H]⁺(retention time: 1.01 min).

Example 282

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

The compound is prepared from 1- (5-bromo-2 ',4' -difluoro- [1,1' -biphenyl)]-3-yl) -5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d]Imidazole was prepared using the method of example 280.¹HNMR(400MHzCD₃OD) 8.72(s,1H),8.19(s,1H),7.97-7.90(m,3H),7.79-7.77(d,1H),7.70(m,1H),7.63-7.61(d,1H),7.56-7.55(d,1H),7.45-7.40(m,2H),7.23(m,1H),7.13(s,1H),5.86-5.85(d,1H),3.87(s,3H),3.74(s, 3H). LC-MS (ESI) calculated mass 481.50 and measured mass 482.1[ M + H ] ]⁺(retention time: 1.45 minutes).

Example 283

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

The compound is prepared from 1- (5-bromo-2 ',4' -difluoro- [1,1' -biphenyl)]-3-yl) -5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d]Imidazole was prepared using the method of example 280.¹HNMR(400MHz,DMSO-d₆) 9.13(s,1H),8.27(s,1H),8.11(s,1H),8.02-8.00(d,2H),7.821(s,1H),7.74-7.70(M,3H),7.48(M,2H),7.29(M,1H),7.09-7.04(M,3H),3.92(s,3H),3.84(s,3H), calculated mass: 481.50 measured mass: 482.1[ M + H ], (M,3H)]⁺(retention time: 1.36 minutes).

Example 284

N- (2',4' -difluoro-5- (5- (1- (3-hydroxy-3-methylbutyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) ethanesulfonamide

The compound is prepared from 4- (4- (1- (5-amino-2 ',4' -difluoro- [1,1' -biphenyl)]-3-yl) -1H-benzo [ d]Imidazol-5-yl) -1H-pyrazol-1-yl) -2-methylbutan-2-ol (88mg,0.185mmol) was prepared using the method of example 2(b) and ethanesulfonyl chloride (28.6mg,0.370mmol,1.2eq.) to give the product in 33.6% yield (35 mg).¹HNMR(300MHz,DMSO-d₆) 10.42(s,1H),8.92(s,1H),8.30(s,1H), 8.01-7.97 (d,2H),7.69(M,3H),7.59(d,2H),7.56(M,2H),7.32(M,1H),4.30(M,2H),3.31-3.28(M,4H),1.8(M,2H),1.28-1.24(t,3H),1.15(s,6H), calculated mass 565.63, measured mass 566.2[ M + H ] is ]⁺(retention time: 1.40 minutes).

Example 285

N- (2',4' -difluoro-5- (6- (6-oxo-1, 6-dihydropyridin-3-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1' -biphenyl ] -3-yl) acetamide

Reacting N- (5- (6- (6- (benzyloxy) pyridine-3-yl) -3H-imidazo [4, 5-b)]Pyridin-3-yl) -2',4' -difluoro- [1,1' -biphenyl]A solution of-3-yl) acetamide (0.10g,0.182mmol) in TFA (4ml) was stirred at room temperature for 16 h. The mixture was concentrated in vacuo, quenched with sodium bicarbonate and extracted as described in example 1 (d). Evaporation of the solvent gave the product in 84.3% yield (0.70 g).¹HNMR(400MHz,DMSO-d₆):10.42(s,1H),8.98(s,1H),8.68-8.67(d,1H),8.43(d,1H),8.31(s,1H),7.99-7.96(dd,1H),7.89(s,2H),7.76-7.70(m,2H),7.49-7.43(m,1H),7.31-7.26(m,1H),6.51-6.48(d,1H) 2.13(s,3H); LC-MS (ESI): calculated mass 457.43: measured mass 458.1[ M + H ]]⁺(retention time: 0.68 minutes).

Example 286

N- (2',4' -difluoro-5- (6- (6-oxo-1, 6-dihydropyridin-3-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1' -biphenyl ] -3-yl) ethanesulfonamide

Reacting N- (5- (6- (6- (benzyloxy) pyridine-3-yl) -3H-imidazo [4, 5-b)]Pyridin-3-yl) -2',4' -difluoro- [1,1' -biphenyl]A solution of-3-yl) ethanesulfonamide (0.140g,0.234mmol) in TFA (5ml) was stirred at room temperature for 16 h. The mixture was concentrated in vacuo, quenched with sodium bicarbonate and extracted as described in example 1 (d). The solvent was evaporated to give the product in 23.7% yield (0.028 g). ¹HNMR(400MHz,DMSO-d₆) 10.35(s,1H),9.07(s,1H),8.70(s,1H),8.44(s,1H),8.01(d,1H),7.93(s,2H),7.78-7.72(M,2H),7.48-7.45(d,2H),7.30-7.26(t,1H),6.52-6.50(d,1H),3.30-3.28(q,2H),1.28-1.25(t,3H), LC-MS (ESI) wherein the calculated mass is 507.51 and the measured mass is 508.1[ M + H ] (M + H)]⁺(retention time: 0.1 min).

Example 287

N- (2', 4' -difluoro-5- (5- (6-oxo-1, 6-dihydropyridin-3-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) acetamide

The compound is prepared from N- (5- (5- (6- (benzyloxy) pyridine-3-yl) -1H-benzo [ d]Imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl]-3-yl) acetamide (0.15g,0.274mmol) was prepared as in example 286 in 11.2% yield (0.014 g).¹HNMR(400MHz,CD₃OD is 8.92(s,1H),8.20-8.19(s,1H),8.05-8.02(dd,1H),7.94(s,1H),7.83-7.78(M,2H),7.74(s,1H),7.67-7.61(M,2H),7.55(s,1H),7.16-7.09(M,2H),6.69-6.67(d,1H),2.65(s,5H),2.19(s,3H), LC-MS (ESI), and mass 456.44 is calculated as measured mass 457.1[ M + H ] (S, ESI) ]]⁺(retention time: 0.68 minutes).

Example 288

N- (2', 4' -difluoro-5- (5- (6-oxo-1, 6-dihydropyridin-3-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) ethanesulfonamide

The compound is prepared from N- (5- (5- (6- (benzyloxy) pyridine-3-yl) -1H-benzo [ d ]Imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl]-3-yl) ethanesulfonamide (0.25g,0.419mmol) was prepared using the method of example 286 affording the product (0.175g) in 82.5% yield.¹HNMR(400MHz,DMSO-d₆) 10.38(s,1H),9.06(s,1H),8.025-7.954(M,2H),7.83-7.84(d,1H),7.82-7.72(M,2H),7.68-7.66(d,1H),7.61(s,2H),7.50-7.43(M,2H),7.31-7.26(t,1H),6.50-6.47(d,1H),3.33-3.27(q,2H),1.28-1.24(t,3H), LC-MS (ESI): mass 506.52 is calculated, and 507.0[ M + H ] is actually measured]⁺(retention time: 0.085 min).

Example 289

N- (2',4' -difluoro-5- (5- (6-oxo-1, 6-dihydropyridin-3-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) cyclopropanesulfonamide

The compound is prepared from N- (5- (5- (6- (benzyloxy) pyridine-3-yl) -1H-benzo [ d]Imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl]-3-yl) cyclopropanesulfonamide (0.145g,0.238mmol) was prepared using the method of example 286 to give the product in 6.1% yield (0.09 g).¹HNMR(400MHz,CD₃OD) 9.19(s,1H),8.07-8.04(dd,1H),7.99(s,1H),7.85-7.82(dd,2H),7.76-7.71(M,2H),7.90(M,2H),7.64-7.59(M,1H),7.15-7.13(M,2H),6.71-7.68(d,1H),2.76-2.72(M,1H),1.17-1.12(M,2H),1.06-1.02(M,2H), calculated mass 518.53, measured mass 519.3[ M + H ] 518.53]⁺(retention time: 0.8 minutes).

Example 290

N- (5- (6- (2-aminopyridin-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) cyclopropanesulfonamide

To (5- (3- (5- (cyclopropanesulfonylamino) -2',4' -difluoro- [1,1' -biphenyl)]-3-yl) -3H-imidazo [4,5-b]Pyridin-6-yl) pyridin-2-yl) carbamic acid tert-butyl ester (0.2g,0.32mmol) in DCM (5ml) was added TFA (1.2ml) at 0 ℃. The mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo, quenched with sodium bicarbonate and extracted as described in example 1 (d). Evaporation of the solvent gave the product in 17.9% yield (0.30 g).¹HNMR(400MHz,DMSO-d₆) 10.15(s,1H),9.09(s,1H),8.90(s,1H),8.69(s,1H),8.04-8.03(d,1H),7.93(s,1H),7.79(s,1H),7.74-7.72(d,1H),7.50(s,1H),7.45-7.38(M,2H),7.34(s,1H),7.30-7.26(t,1H),2.76-2.72(M,1H),1.17-1.12(M,2H),1.06-1.02(M,2H), LC-MS (ESI), calculated mass 518.54, measured mass 519.2[ M + H ] (M,1H)]⁺(retention time: 0.71 minutes).

Example 291

N- (5- (5- (2-aminopyridin-4-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) cyclopropanesulfonamide

The compound is prepared from (5- (1- (5- (cyclopropanesulfonyl amido) -2',4' -difluoro- [1,1' -biphenyl)]-3-yl) -1H-benzo [ d ]Imidazol-5-yl) pyridin-2-yl) carbamic acid tert-butyl ester (0.2g,0.32mmol) was prepared using the method of example 290 to give the product in 9.0% yield (0.18 g).¹HNMR(400MHz,DMSO-d₆) 10.32(s,1H),8.84(s,1H),8.30(s,1H),8.05-8.03 (s,3H),7.88-7.86(d,1H),7.82-7.79(M,2H),7.62-7.60(d,2H),7.52-7.47(M,2H),7.39-7.38(d,1H),7.31-7.29(M,2H),1.03-1.01(d,4H), calculated mass: 517.55, measured mass: 518.1[ M + H ] in measured mass]⁺(retention time: 0.41 minutes).

Example 292

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

Reacting N- (2',4' -difluoro-5- (5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-benzo [ d]Imidazol-1-yl) - [1,1' -biphenyl]Passing a solution of (3-yl) cyclopropanesulfonamide (0.15g,0.272mmol) in 1, 2-dimethoxyethane (5ml) over N₂Bubbling and degassing for 5 minutes. 2-bromo-5-methyl-1, 3, 4-thiadiazole (0.058g,0.326mmol,1.2eq.) was added and the mixture was degassed for an additional 5 minutes. Adding Pd (dppf) Cl₂(0.011,0.013mmol,0.05eq.) and aqueous sodium carbonate (0.072,0.680mmol,2.5eq.) followed by the procedure of example 1 (d). The crude residue of the product was purified by column chromatography (60-120 silica gel, 80% ethyl acetate in hexanes) to afford the desired title product in 4.2% yield (0.006 g). ¹HNMR(400MHz,DMSO-d₆) 10.21(s,1H),8.81(s,1H),8.34-8.33(s,1H),8.00-7.98(dd,1H),7.84(d,1H),7.79-7.73(M,1H),7.54(s,1H),7.49-7.42(M,2H),7.29-7.24(M,1H),3.17-3.16(d,2H),2.85-2.84(M,1H),2.79(s,3H),1.01-0.99(M,4H), LC-MS (ESI) calculating mass 523.58, measured mass 523.7[ M + H ] 523.7]⁺(retention time: 1.50 minutes).

Example 293

N- (2',4' -difluoro-5- (5- (5-fluoropyridin-2-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) cyclopropanesulfonamide

Reacting N- (2',4' -difluoro-5- (5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-benzo [ d]Imidazol-1-yl) - [1,1' -biphenyl]Passing a solution of (3-yl) cyclopropanesulfonamide (0.15g,0.272mmol) in 1, 2-dimethoxyethane (5ml) over N₂Bubbling and degassing for 5 minutes. 2-bromo-5-fluoropyridine (0.057g,0.326mmol,1.2eq.) was added and the mixture was degassed for an additional 5 minutes. Adding Pd (dppf) Cl₂(0.011,0.013mmol,0.05eq.) and aqueous sodium carbonate (0.072,0.680mmol,2.5eq.) followed by the procedure of example 1 (d). The crude residue of the product was purified by column chromatography (60-120 silica gel, 80% ethyl acetate in hexane) to give the title product in 14.1% yield (0.02 g).¹HNMR(400MHz,DMSO-d₆):10.23(s,1H),8.75(s,1H),8.68-8.67(d,1H),8.48(d,1H),8.20-8.13(m,2H),7.86-7.743(m,3H),7.61-760(d,2H),7.51-7.43(M,2H),7.30-7.25(M,1H),2.89-2.86(t,1H),1.03-1.02(d,4H), LC-MS (ESI) calculated mass 520.53, measured mass 521.2[ M + H [ ] ]⁺(retention time: 1.64 minutes).

Example 294

N- (3- (3-fluoropyridin-2-yl) -5- (5- (1- (2- (morpholin-4-yl) ethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) methanesulfonamide

To degassing (N)₂Bubbling) N- (3-bromo-5-nitrophenyl) acetamide (25g,96.89mmol) in 1, 4-dioxane (150ml) was added 4,4,4',4',5,5,5',5' -octamethyl-2, 2' -bis (1,3, 2-dioxolane) (29.5g,116.27mmol,1.2eq), Pd (dppf) Cl₂(7.9g,9.68mmol,0.1eq.) and potassium acetate (28.5g,290.69mmol,3 eq.). The mixture was heated in a sealed tube at 100 ℃ for 6 hours. The mixture was diluted with ethyl acetate and filtered through a pad of celite. The solvent was distilled off to leave the product (24 g).¹HNMR(300MHz,DMSO-d₆):10.44(s,1H),8.72(t,1H),8.18-8.15(m,1H),8.03(d,1H),2.08(s,1H),1.30(s,9H)。

b) N- (3- (3-fluoropyridin-2-yl) -5-nitrophenyl) acetamide

A solution of N- (3-nitro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenylacetamide (10g,32.67mmol) in 1, 2-dimethoxyethane (100ml) was passed through N₂Bubbling and degassing for 5 minutes. 2-chloro-3-fluoropyridine (4.29g,32.67mmol) was added and the mixture was degassed for an additional 5 minutes. Adding Pd (dppf) Cl₂(2.6g,3.26mmol) and an aqueous solution of sodium carbonate (10.39g,98.03mmol), followed by the procedure of example 1 (d). The crude residue of the product was purified by column chromatography (60-120 silica gel, 3% methanol in chloroform) to give the title product in 70% yield (6.3 g). ¹HNMR(300MHz,DMSO-d₆) 10.64(s,1H),8.74(m,1H),8.62(m,1H),8.55(brs,1H),8.44(brs,1H),7.93(m,1H),7.60(m,1H),2.12(s, 3H). c) N- (3-Ammonia)Yl-5- (3-fluoropyridin-2-yl) phenyl) acetamide

To a solution of N- (3- (3-fluoropyridin-2-yl) -5-nitrophenyl) acetamide (5g,18.18mmol) in THF (50ml) was added Zn (11.8g,181.18mmol) followed by a slow addition of NH₄20ml of Cl (9.7g,181.18mmol) in water. The mixture was stirred at room temperature for 1 hour. The mixture was filtered through a celite bed and washed with ethyl acetate. The mixture was diluted with ethyl acetate and washed with water and brine solution, dried over sodium sulfate and evaporated to give the product in 90% yield (4.2 g). LC-MS (ESI) calculating mass 245, and measured mass 246.1[ M + H ]]⁺(retention time: 0.21 minutes).

d) N- (3- ((4-bromo-2-nitrophenyl) amino) -5- (3-fluoropyridin-2-yl) phenyl) acetamide

A solution of 4-bromo-1-fluoro-2-nitrobenzene (3.0g,13.63mmol), N- (3-amino-5- (3-fluoropyridin-2-yl) phenyl) acetamide (4.0g,16.36mmol) and potassium fluoride (0.95g,16.36mmol) in DMF was heated at 130 ℃ for 16 h. The mixture was quenched and extracted as described in example 1 (d). Evaporation of the solvent gave 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 (3.4 g). ¹HNMR(300MHz,DMSO-d₆):8.55(brs,1H),8.23(brs,1H),7.96(m,2H),7.85(m,2H),7.67(d,1H),7.51(m,2H),7.21(d,1H),2.07(s,3H)。

e) N- (3- ((2-amino-4-bromophenyl) amino) -5- (3-fluoropyridin-2-yl) phenyl) acetamide

To a solution of example 294(d) (3.4g,7.64mmol) in THF (35ml) was added a solution of ammonium chloride (4.08g,76.40mmol,10eq.) in water (15ml) and zinc (4.98g,76.40mmol,10 eq.). The mixture was stirred at room temperature for 4 hours and filtered. The filtrate was diluted with water and extracted as described in example 1 (d). Evaporation of the solvent gave the title product in 75% yield (2.4 g). LC-MS (API) calculated mass 415.2, measured mass 417.1[ M + H [ ]]⁺(retention time: 1.35 minutes). f) N- (3- (5-bromo-1H-benzo [ d ]]Imidazol-1-yl) -5- (3-fluoropyridin-2-yl) phenyl) acetamide

A mixture of the compound from example 294(e) (2.4g,5.78mmol) and formic acid (24ml) was heated at 90 ℃ for 6 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 73% yield (1.8 g). LC-MS (ESI) calculated mass: 425.2, measured mass: 426.7[ M + H [)]⁺(retention time: 1.38 minutes).

g)3- (5-bromo-1H-benzo [ d ] imidazol-1-yl) -5- (3-fluoropyridin-2-yl) aniline

To a solution of the compound from example 294(f) (0.6g,1.41mmol) in ethanol (20ml) was added 5ml of aqueous NaOH (0.56g,14.11mmol) and the mixture was heated at 90 ℃ for 2 h. The mixture was concentrated and the crude residue was quenched with water and extracted as described in example 1 (d). Evaporation of the solvent gave the product in 55% yield (0.3 g). LC-MS (API) calculated mass 382.0 and measured mass 385.1M + H ]⁺(retention time: 1.32 minutes).

h) N- (3- (5-bromo-1H-benzo [ d ] imidazol-1-yl) -5- (3-fluoropyridin-2-yl) phenylmethanesulfonamide

To a solution of example 294(g) (0.15g,0.39mmol) in DCM was added pyridine (0.093g,1.17mmol) followed by methanesulfonyl chloride (0.054g,0.47 mmol). The mixture was stirred for 3 hours, quenched with water and extracted as described in example 2 (b). The solvent was evaporated to give a crude residue which was purified through 60-120 mesh silica gel to give the product in 60% yield (120 mg). LC-MS (ESI) calculated mass 460.1 and measured mass 460.2M + H]⁺(retention time: 1.54 minutes).

i) N- (3- (3-fluoropyridin-2-yl) -5- (5- (1- (2- (morpholin-4-yl) ethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) methanesulfonamide

A solution of the compound from example 294(h) (0.12g,0.260mmol) in 1, 2-dimethoxyethane (8ml) was passed over N₂Bubbling and degassing for 5 minutes. 4- (2- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) ethyl) morpholine (0.096g,0.313mmol) was added and the mixture was degassed for an additional 5 minutes. Adding intoAqueous sodium carbonate (0.083g,0.782mmol) and Pd (dppf) Cl₂(0.021g,0.026mmol) and then the procedure of example 1(d) was carried out. The crude residue of the product was purified by preparative HPLC to afford the title product in 10% yield (15 mg). ¹HNMR(400MHz,CD₃OD is 8.56(d,2H),8.11(s,1H),7.94-7.90(M,4H),7.80-7.72(M,2H),7.66-7.62(M,2H),7.52-7.50(M,1H),4.33(t,2H),3.68-3.64(M,4H),3.12(s,3H),2.85(M,2H),2.52(M,4H), LC-MS ESI (calculated mass: 561.2), measured mass: 561.8[ M + H + M ] ESI (calculated mass: 561.8 [)]⁺(retention time: 0.10 minutes).

Example 295

N- (3- (3-fluoropyridin-2-yl) -5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) cyclopropanesulfonamide

The compound is prepared from N- (3- (5-bromo-1H-benzo [ d)]Imidazol-1-yl) -5- (3-fluoropyridin-2-yl) phenyl) cyclopropanesulfonamide (150mg,0.30mmol) was prepared using the method of example 1(i) to give the product in 15% yield (10 mg).¹HNMR(400MHz,CDCl₃) 8.53(d,1H),7.92(d,3H),7.80(s,1H),7.72(d,2H),7.6.3-7.55(M,4H),7.41-7.28(M,1H),3.92(s,3H),2.85-2.80(M,1H),1.31-1.17(M,2H)1.03-1.01(M,2H), LC-MS (ESI) calculating mass 488.5, measured mass 489.0[ M + H ] measured mass]⁺(retention time: 0.59 minutes).

Example 296

N- (3- (3-methoxypyridin-2-yl) -5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) cyclopropanesulfonamide

The compound is prepared from N- (3- (5-bromo-1H-benzo [ d)]Imidazol-1-yl) -5- (3-methoxypyridin-2-yl) phenyl) cyclopropanesulfonamide (200mg,0.40mmol) was prepared using the method of example 1(i) to give the title product in 20% yield (20 mg). ¹HNMR(400MHz,DMSO):10.3(s,1H),8.60(d,1H),8.32-8.31(d,1H),8.20(s,1H)7.99(d,1H),7.94(s,1H),7.92-7.89(d,2H),7.66-7.63(m,3H),7.54(d,1H),7.47-7.43(m,1H),4.33(d,2H),3.42-3.26(M,2H),1.34-1.24(t,3H),0.63-0.60(t,2H),0.49-0.48(t,2H), LC-MS (ESI) calculating mass 500.5, and measured mass 500.8[ M + H ] M]⁺(retention time: 0.45 minutes).

Example 297

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

a) N- (2',4' -difluoro-5- (5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) acetamide

To degassing (N)₂Bubbling) A solution of the compound (0.3g,0.68mmol) of example 1(h) in 1, 2-dimethoxyethane (10ml) was added 4,4,4',4',5,5,5',5' -octamethyl-2, 2' -bis (1,3, 2-dioxolane) (0.26g,1.02mmol,1.5eq.), Pd (dppf) Cl₂(55mg,0.068mmol,0.1eq.) and potassium acetate (0.2g,2.04mmol,3eq.) and the mixture was heated in a sealed tube at 80 ℃ for 3 hours. The mixture was diluted with ethyl acetate and filtered through a pad of celite. 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 60% yield (0.2 g). LC-MS (ESI) calculated mass 489.32, measured mass 490.5[ (M + H)]⁺(retention time: 1.83 minutes).

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

A solution of the compound from example 297(a) (0.1g,0.204mmol) in 1, 2-dimethoxyethane (15ml) was passed through N₂Bubbling and degassing for 5 minutes. 4-bromo-1-methylimidazole (49mg,0.306mmol,1.5eq.) was added and the mixture was degassed for an additional 5 minutes. Adding Pd (dppf) Cl₂(16mg,0.0204mmol,0.1eq.) and aqueous sodium carbonate (65mg,0.612mmol,3.0eq.), followed by the procedure of example 1 (d). The crude residue of the product was purified by column chromatography (60-120 silica gel, 5% methanol in chloroform) to give the title product in 11% yield (10 mg).¹HNMR (400MHz, DMSO-d6):10.5(s,1H),9.05-9.0(brs,1H),8.8(s,1H),8.26(s,1H),8.18(s,1H),8.13(s,1H),7.87-7.76(M,5H),7.56(s,1H),7.48(dt,1H),7.3-7.29(dt,1H),3.9(s,3H),2.15(s,3H); LC-MS (ESI): 443.45; and 444.1[ M + H + H ] measured mass]⁺(retention time: 0.632 minutes).

Example 298

1- (2',4' -difluoro-5- (5- (1-methyl-1H-imidazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) -3- (furan-2-ylmethyl) urea

a)2',4' -difluoro-5- (5- (1-methyl-1H-imidazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-amine

The compound was prepared from the compound of example 297 (0.4g,2.26mmol) using the method of example 2(a) to give the product in 27% yield (0.1 g). LC-MS (ESI) calculated mass 401.41 and measured mass 402.1[ M + H ] ]⁺(retention time: 1.198 min).

b)1- (2',4' -difluoro-5- (5- (1-methyl-1H-imidazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) -3- (furan-2-ylmethyl) urea

To a solution of the compound from example 298(a) (50mg,0.124mmol) in DCM was added furfuryl isocyanate (0.01ml,0.149mmol,1.2eq.) followed by DIPEA (0.06ml,0.37mmol,3 eq.). The mixture was stirred overnight, the reaction was terminated and extracted as described in example 1 (d). Evaporation of the solvent gave a crude residue which was purified by preparative HPLC to give the product in 40% yield (20 mg).¹HNMR (300MHz, DMSO-d6):9.16(s,1H),9.14(s,1H),8.8(s,1H),8.27-8.22(d,2H),7.99(s,1H),7.89(s,1H),7.87(s,1H),7.81-7.73(m,2H),7.62(s,2H),7.49-7.42(m,2H),7.31-7.26(dt,1H),6.91-6.88(t,1H),6.44-6.42(m,1H),6.3-6.29(m,1H),4.35-4.33(d,2H),3.94(s, 3H). LC-MS (ESI) for calculating mass 524.52 and actual measurement mass 525M + H]⁺(retention time: 0.632 minutes).

Example 299

N- (2',4' -difluoro-5- (5- (1-methyl-1H-imidazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) ethanesulfonamide

The compound was prepared from the compound of example 298(a) using the procedure of example 294 (h).¹HNMR(300MHz,CD₃OD is 8.4(S,1H),8.0(S,1H),7.71-7.69(dd,1H),7.59-7.41(M,6H),7.04-7.01(M,2H),3.69(S,3H),3.22-3.13(q,2H),1.29-1.26(t,3H), LC-MS (ESI) is calculated 493.53, measured 494[ M + H + ESI ] ]⁺(retention time: 0.632 minutes).

Example 300

N- (2',4' -difluoro-5- (5- (1-methyl-1H-imidazol-5-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) ethanesulfonamide

The compound was prepared from example 200(b) (0.5g,1.02mmol) using the method of example 297 to give the title product in 16% yield (15 mg).¹HNMR(300MHz,CD₃OD is 9.01(s,1H),8.73(s,1H),8.01(s,1H),7.88-7.86(d,1H),7.71-7.70(M,1H),7.65-7.56(M,4H),7.51-7.5(M,1H),7.13-7.09(M,2H),3.91(s,3H),3.28-3.22(M,2H),1.38-1.35(t,3H), LC-MS ESI, (493.53) calculated mass, 493.9[ M + H + M) measured mass]⁺(retention time: 1.232 min).

Example 301

The title compound was prepared from the title compound of example 294(f) using the procedure of example 294 (i).¹HNMR(400MHz,DMSO-d₆):10.43(s,1H),8.25(s,1H),8.21(s,1H),8.16(s,1H),7.99(s,1H),7.95(s,1H),7.94-7.88(m,1H),7.86(s,1H),7.67-7.65(m,1H),7.61-7.57(m,2H),4.26-4.23(t,2H),3.57-3.55(t,4H),2.77-2.67(t,2H),2.43(M,4H),2.13(s,3H): LC-MS (ESI): calculated mass: 525.58; measured mass: 526.3[ M + H ]]⁺(retention time: 0.11 minutes).

Example 302

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

To a solution of the compound from example 1(H) (120mg,0.271mmol) in DMF (20ml) was added N- (1H-pyrazol-4-yl) acetamide (50mg,0.407mmol,1.5eq), copper (I) oxide (4.9mg,0.027mmol,0.1eq) and cesium carbonate (176mg,0.5429mmol,2.0eq), followed by heating at 110 ℃ for 48 hours. The mixture was quenched and extracted as described in example 1 (d). Evaporation of the solvent gave a crude residue which was purified by preparative HPLC to give the title product in 12.8% yield (16 mg). ¹HNMR(400MHz,DMSO-d₆) 10.41(s,1H),10.15(s,1H),8.85(s,1H),8.54(s,1H),8.14(d,1H),8.07(t,1H),7.87-7.71(M,5H),7.53(s,1H),7.47-7.41(M,1H),7.28-7.23(M,1H),2.11(s,3H),2.02(s,3H), LC-MS (ESI), calculated mass 461.54, measured mass 462.1[ M + H + ESI ]]⁺(retention time: 0.7 minutes).

Example 303

The title compound was prepared from the title compound of example 131(c) using the procedure of example 131 (d).¹HNMR(400MHz,DMSO-d₆) 8.71(s,1H),8.64(s,1H),8.26(s,1H),8.07(s,1H),7.93(s,1H),7.91(s,1H),7.84(s,1H),7.78-7.73(M,2H),7.54(s,1H),7.48-7.42(M,1H),7.29-7.24(dt,1H),5.48(s,2H),4.25-4.19(q,2H),2.13(s,3H),1.27-1.24(t,3H): LC-MS (ESI): calculated mass 517.49; measured mass 518.4[ M + H ] (M + H): calculated mass: 517.49; measured mass: 518.4]⁺(retention time: 1.37 minutes).

Example 304

N- (4 '-fluoro-5- (6- (thiazol-2-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1' -biphenyl ] -3-yl) acetamide

Mixing N- (5- (6-bromo-3H-imidazo [4,5-b ]]Pyridin-3-yl) -4 '-fluoro- [1,1' -biphenyl]Passing a solution of (3-yl) acetamide (300mg,0.705mmol) in THF (8ml) through N₂Bubbling and degassing for 5 minutes. Thiazol-2-ylzinc (II) bromide (485mg,2.11mmol,3.0eq.) was added and the mixture was degassed for an additional 5 minutes. Adding Pd (dppf) Cl ₂(57mg,0.070mmol,0.1eq.) of aqueous sodium carbonate solution, followed by the procedure of example 1 (d). The crude residue of the product was purified by preparative HPLC to give the title product in 40% yield (120mg)¹HNMR (400MHz, DMSO-D6):10.43(s,1H),8.78(s,1H),8.45(s,1H),8.08(s,1H),8.01(D,1H),7.94(D,1H),7.85-7.73(M,4H),7.55(s,1H),7.45(t,1H),7.27(t,1H),2.13(s,3H), LC-MS (ESI): calculated mass 429.47, measured mass 430.00[ M + H ], (ESI)]⁺(retention time: 1.33 minutes).

Example 305

N- (2',4' -difluoro-5- (5- (thiazol-2-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) methanesulfonamide

This compound was prepared using the method of example 304 and starting from the compound of example 208(a) to give the product in 10.4% yield (12 mg).¹HNMR (400MHz, DMSO-D6):10.31(s,1H),8.80(s,1H),8.35(s,1H),8.02(D,1H),7.94(D,1H),7.83-7.75(m,3H),7.61(s,1H),7.57(D,1H),7.49-7.43(m,2H),7.28(dt,1H),3.19(s,3H), LC-MS (ESI): calculated mass: 482.53; found mass: 483.2.

Example 306

N- (2',4' -difluoro-5- (5- (thiazol-2-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) ethanesulfonamide

The compound is prepared fromThe compound of example 200(b) was prepared using the method of example 304 to give the product in 9.6% yield (15 mg). ¹HNMR (400MHz, DMSO-D6):10.35(s,1H),8.81(s,1H),8.35(s,1H),8.01(D,1H),7.93(s,1H),7.81-7.76(M,3H),7.58(D,2H),7.49-7.44(M,2H),7.29(t,1H),3.30(q,2H),1.26(t,3H), LC-MS (ESI): calculated mass 496.55; measured mass 497.0[ M + H ] calculated mass 496.55; measured mass 497.0]⁺(retention time: 1.12 minutes).

Example 307

N- (2',4' -difluoro-5- (5- (1-isopropyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) methanesulfonamide

This compound was prepared from the compound of example 208(a) using the method of example 208(b) and 1-isopropyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole to give the product in 9% yield (18 mg).¹HNMR(300MHz,DMSO-d₆) 10.28(s,1H),8.63(s,1H),8.28(s,1H),7.99(s,1H),7.92(s,1H),7.77(d,1H),7.70-7.61(M,2H),7.60-7.51(M,2H),7.50-7.38(M,2H),7.30-7.29(M,1H),4.60-4.40(M,1H),3.15(s,3H),1.44(d,6H), LC-MS (API) calculated mass 507.15, measured mass 508.0[ M + H ] measured mass 508.0]⁺(retention time: 1.00 min).

Example 308

N- (2',4' -difluoro-5- (5- (1-isopropyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) ethanesulfonamide

This compound was prepared from the compound of example 200(b) using the method of example 200 (c).¹HNMR(400MHz,DMSO-d₆) 10.31(s,1H),8.64(s,1H),8.30(s,1H),8.01(s,1H),7.95(s,1H),7.75(q,1H),7.65(q,2H),7.56(m,2H),7.46(m,2H),7.27(m,1H),4.51(m,1H),3.28(q,2H),1.46(d,6H),1.25(t, 3H). LC-MS (ESI) calculated mass 521.17 and measured mass 522.1[ M + H ]⁺(retention time: 1.55 minutes).

Example 309

N- (2',4' -difluoro-5- (6- (1-isopropyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1' -biphenyl ] -3-yl) ethanesulfonamide

Mixing N- (5- (6-bromo-3H-imidazo [4,5-b ]]Pyridin-3-yl) -2',4' -difluoro- [1,1' -biphenyl]Passing a solution of (3-yl) ethanesulfonamide (0.2g,0.405mmol) in 1, 2-dimethoxyethane (5ml) over N₂Bubbling and degassing for 5 minutes. 1-isopropyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (0.191g,0.810mmol,2.0eq.) was added and the mixture was degassed for an additional 5 minutes. Adding Pd (dppf) Cl₂(0.032g,0.040mmol,0.1eq.) and aqueous sodium carbonate (0.17g,1.012mmol,2.5eq.) followed by the procedure of example 1 (d). The crude residue of the product was purified by column chromatography (60-120 silica gel, 80% ethyl acetate in hexane) to afford the product in 52.1% yield (0.11 g).¹HNMR(400MHz,DMSO-d₆) 10.42(s,1H),8.94(s,1H),8.75(d,1H),8.44-8.42(dd,2H),8.05(s,1H),7.95(s,1H),7.77-7.70(M,2H),7.48-7.43(M,2H),7.30-7.26(M,1H),4.54-4.51(M,1H),4.13-4.11(M,1H), 3.28-3.26(M,2H),3.17-3.16(d,1H),1.48-1.46(d,6H),1.28-1.25(t,3H), LC-MS (ESI) calculated mass 522.57 measured mass 523.0[ M + H ], [ 523.0 (M + H) ]]⁺(retention time: 1.52 minutes).

Example 310

N- (5- (5- (6-aminopyridin-3-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) methanesulfonamide

The title compound was prepared from the title compound of example 208(a) using the method of example 246.¹HNMR(300MHz,DMSO-d₆) 10.43(s,1H),9.05(s,1H),8.42(s,2H),8.17(s,2H),7.84(s,1H),7.78-7.73(M,3H),7.62(M,2H),7.49(M,2H),7.31-7.27(M,1H),7.15-7.12(M,1H),3.19(s,3H), LC-MS (ESI) calculating mass 491.12, measured mass 492.2[ M + H ] measured mass]⁺(retention time: 0.28 minutes).

Example 311

N- (5- (5- (6-aminopyridin-3-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) ethanesulfonamide

This compound was prepared from the compound of example 200(b) using the method of example 246.¹HNMR(300MHz,DMSO-d₆) 10.43(s,1H),8.75(s,1H),8.38-8.36(M,2H),8.12(s,1H),7.80-7.42(M,3H),7.72-7.66(M,2H),7.58-7.57(M,2H),7.49-7.42(M,2H),7.31-7.27(M,1H),7.06-7.02(M,1H),3.29 (quartet, 2H),1.26(s,3H), LC-MS (ESI): calculated mass 505.14, measured mass 506.3[ M + H, 1H ], (M, 1H): calculated mass) and]⁺(retention time: 0.37 minutes).

Example 312

1- (5-acetylamino-2 ',4' -difluoro- [1,1' -biphenyl ] -3-yl) -1H-benzo [ d ] imidazole-5-carboxamide

a)1- (5-amino-2 ',4' -difluoro- [1,1' -biphenyl ] -3-yl) -1H-benzo [ d ] imidazole-5-carboxamide

To N- (5- (5-cyano-1H-benzo [ d ]]Imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl]-3-yl) acetamide (0.5g,1.28mmol,1eq.) in ethanol (10ml) 20% aqueous potassium hydroxide (0.721g,12.88mmol,10eq.) was added and the mixture was heated at 85 ℃ for 5 hours. The mixture was quenched and extracted as described in example 1 (d). Evaporation of the solvent gave the title product in 71% yield (0.32 g). LC-MS (ESI) for calculating mass 364.11 and measured mass 365.1M + H]⁺(retention time: 0.59 minutes).

b)1- (5-acetylamino-2 ',4' -difluoro- [1,1' -biphenyl ] -3-yl) -1H-benzo [ d ] imidazole-5-carboxamide

Acetic anhydride (0.1ml,1vol.) was added dropwise to the compound of example 312(a) (0.1g) at 0 ℃. The mixture was stirred at room temperature for 30 minutes, and then the reaction was terminated by adding crushed ice. The precipitate formed was filtered and washed with cold water to give an off-white solid. The solid was dried in vacuo to give the product in 28.8% yield(32mg)。¹HNMR(400MHz,DMSO-d₆) 10.48(s,1H),8.80(s,1H),8.42(s,1H),8.10(s,1H),7.99-7.97(d,1H),7.88(s,1H),7.80-7.76(M,2H),7.57(s,1H),7.49(t,1H),7.41(s,1H),7.31-7.29(t,1H),2.18(s,3H), LC-MS (ESI), calculated mass 406.12, measured mass 407.2[ M + H ] ESI]⁺(retention time: 0.47 minutes).

Example 313

N- (2',4' -difluoro-5- (5- (5-methyl-1, 2, 4-)Oxadiazol-3-yl) -1H-benzo [ d]Imidazol-1-yl) - [1,1' -biphenyl]-3-yl) acetamide

a) N- (5- ((4-cyano-2-nitrophenyl) amino) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) acetamide

A solution of N- (5-aminobiphenyl-3-yl) acetamide (1.5g,5.72mmol), 4-fluoro-3-nitrobenzonitrile (0.95g,5.72mmol,1.0eq.) and potassium fluoride (0.33g,5.72mmol,1.0eq.) in DMF (15ml) was heated at 130 ℃ for 12 hours. The mixture was quenched and extracted as described in example 1 (d). 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 43% yield (1 g).

b) N- (5- ((2-amino-4-cyanophenyl) amino) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) acetamide

To a solution of the compound from example 313(a) (1.0g,2.45mmol) in THF (15ml) was added a solution of ammonium chloride (0.52g,9.8mmol,4eq.) in water (5ml) and zinc (0.64g,9.8mmol,4 eq.). The mixture was stirred at 45 ℃ for 2 hours and filtered. The filtrate was diluted with water and extracted as described in example 1 (d). Evaporation of the solvent gave the title product in 86% yield (0.8 g).

c) N- (5- (5-cyano-1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) acetamide

A mixture of the compound from example 313(b) (0.8g,2.11mmol) and formic acid (10ml) was heated at 100 ℃ for 4 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 a crude residue in 97% yield (0.8 g).

d) N- (2',4' -difluoro-5- (5- (N-hydroxycarbamimidoyl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) acetamide

To a solution of the compound from example 313(c) (0.1g,0.25mmol) in ethanol was added hydroxylamine hydrochloride (20mg,0.28mmol,1.1eq.) and Et₃N (0.1ml,0.75mmol,3eq.) and the mixture was heated at 80 ℃ for 3 hours. The volatiles were distilled off and the resulting crude solid was washed several times with diethyl ether to give the title compound in 100% yield (0.11 g).

e) N- (2',4' -difluoro-5- (5- (5-methyl-1, 2, 4-)Oxadiazol-3-yl) -1H-benzo [ d]Imidazol-1-yl) - [1,1' -biphenyl]-3-yl) acetamide

To a solution of the compound from example 313(d) (0.1g,0.237mmol) in TFA (1ml) was added trimethyl orthoacetate (5ml) and the mixture was heated at 100 ℃ for 4 hours. The volatiles were distilled off and the resulting crude product was extracted with ethyl acetate and water, dried over sodium sulfate and the residue was purified by preparative HPLC to give the pure product in 6.6% yield (6.6 mg). LC-MS (ESI) calculated mass 445.14 and measured mass 446.1[ M + H ] ]⁺(retention time: 1.15 minutes).

Example 314

N- (2',4' -difluoro-5- (6- (1-methyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1' -biphenyl ] -3-yl) -2- (3, 5-dimethylpiperazin-1-yl) acetamide

This compound was prepared from the compound (60mg,0.149mmol) in example 132(a) by the method of example 225 and 2- (3, 5-dimethylpiperazin-1-yl) acetic acid(30mg,0.179mmol,1.2eq) to give the product in 21.9% yield (18 mg). LC-MS (ESI) calculated mass 556.25 and measured mass 557.2[ M + H ]]⁺(retention time: 0.67 minutes).

Example 315

N- (2',4' -difluoro-5- (6- (1-methyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) -2',3' -dihydro- [1,1' -biphenyl ] -3-yl) -2- (4-ethylpiperazin-1-yl) acetamide

The compound was prepared from N- (5- (6-bromo-3H-imidazo [4,5-b ] pyridin-3-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) -2- (4-ethylpiperazin-1-yl) acetamide (300mg,0.540mmol) using the method of example 1(i), and the product was obtained in 11.6% yield (35 mg). NMR (400MHz, DMSO-D6) 9.40(brs,1H),8.96(s,1H),8.740(D,1H),8.44(D,1H),8.38(s,1H),8.33(s,1H),8.07(s,1H),8.97(s,1H),7.794-7.713(M,2H),7.48(t,1H),7.31(t,1H),3.93(s,3H),3.44(s,2H),3.19-3.12(M,8H),2.71(q,2H),1.24(t,3H), LC-MS (ESI): mass calculated 558.6; measured mass 557.0[ M-H ] - (retention time: 0.21 min).

Example 316

N- (2',4 ' -difluoro-5- (6- (1-methyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1 ' -biphenyl ] -3-yl) -2- (4-methylpiperazin-1-yl) acetamide

Prepared from the compound of example 132(a) (75mg,0.186mmol) using the method of example 225 and 2- (4-methylpiperazin-1-yl) acetic acid (44.2mg,0.279mmol,1.5eq) to give the product in 34.6% yield (35 mg).¹HNMR(400MHz,DMSO-d₆) 10.29(s,1H),8.94(s,1H),8.72(d,1H),8.42-8.31(d,3H),8.05(s,1H),7.93(s,1H),7.77-7.71(M,2H),7.49-7.43(M,1H),7.29(t,1H),3.90(s,3H),3.17-3.11(M,4H),2.80(s,3H),2.67(M,2H),2.50(M,4H), LC-MS (ESI), calculated mass 542.58, measured mass 543.1[ M + H + 3H ], calculated mass 543.1]⁺(retention time: 0.252 minutes).

Example 317

1-cyclopentyl-3- (2',4 ' -difluoro-5- (6- (1-methyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1 ' -biphenyl ] -3-yl) urea

To a solution of the compound from example 132(a) (65mg,0.1616mmol) in DCM was added diisopropylamine (89mg,0.485mmol,3eq) and cyclopentyl isocyanate (19.7mg,0.1778mmol,1.1 eq). The mixture was stirred for 16 hours, the reaction was terminated and extracted as described in example 2 (b). Evaporation of the solvent gave a crude residue which was purified by preparative HPLC to give the product in 12% yield (10 mg). ¹HNMR(400MHz,DMSO-d₆) 8.92(s,1H),8.71(t,1H),8.41(d,1H),8.30(s,1H),8.05(t,1H),7.72-7.66(M,1H),7.56(s,1H),7.46-7.40(M,1H),7.27-7.24(M,2H),6.30(s,1H),3.93(s,3H),3.10(M,1H),1.87-1.81(M,2H),1.65-1.53(M,4H),1.43-1.37(M,2H), LC-MS (ESI) calculating mass 513.54, measured mass 514.5[ M + H ], [ 514.5]⁺(retention time: 1.56 minutes).

Example 318

N- (2',4 ' -difluoro-5- (6- (1-methyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1 ' -biphenyl ] -3-yl) -2- (piperazin-1-yl) acetamide

a)4- (2- ((2',4 ' -difluoro-5- (6- (1-methyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1 ' -biphenyl ] -3-yl) amino) -2-oxoethyl) piperazine-1-carboxylic acid tert-butyl ester

The compound was prepared from the compound of example 132(a) (120mg,0.298mmol) using the method of example 225 and 2- (4- (tert-butoxycarbonyl) piperazin-1-yl) acetic acid (145mg,0.597mmol,2eq) to give the product in 10.6% yield (20 mg). LC-MS (ESI) for calculating mass 628 and actually measuring mass 629.1M + H]⁺(retention time: 1.056 minutes).

b) N- (2',4 ' -difluoro-5- (6- (1-methyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1 ' -biphenyl ] -3-yl) -2- (piperazin-1-yl) acetamide

To a solution of the compound from example 318(a) (12mg,0.0191mmol) in DCM was added TFA (1ml) and the mixture was stirred at room temperature for 16 h. The mixture was concentrated to give the product in 98% yield (10 mg). ¹HNMR(400MHz,DMSO-d₆) 10.3(s,1H),8.93(s,1H),8.70(d,2H),8.41-8.07(d,1H),8.35(t,1H),8.29(s,1H),8.03(s,1H),7.94-7.93(d,1H),7.76-7.68(M,2H),7.47-7.42(M,1H),7.30-7.25(M,1H),3.89(s,3H),3.50(s,2H),3.21(s,4H),2.92(s,4H), LC-MS (ESI): 528.22, 529.2[ M + H + 4H ] measured mass]⁺(retention time: 0.182 min).

Example 319

N- (2',4 ' -difluoro-5- (6- (1-methyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1' -biphenyl ] -3-yl) -1-methylpiperidine-4-carboxamide

The compound was prepared from example 132(a) (75mg,0.1865mmol) using the method of example 225 and 1-methylpiperidine-4-carboxylic acid (40mg,0.27mmol,1.5eq) to give the product in 15% yield (15 mg).¹HNMR(400MHz,CD₃OD) 8.97(s,1H),8.67(s,1H),8.31(t,1H),8.28(s,1H),8.10(s,1H),7.93(s,1H),7.81(t,1H),7.74(s,1H),7.65-7.59(M,1H),7.13-7.07(M,2H),3.96(s,3H),3.66-3.63(M,2H),3.14-3.07(M,2H),2.92(s,3H),2.79-2.73(M,1H),2.24-2.01(M,4H), LC-MS (ESI) calculated mass 527.22, measured mass 528.0[ M + H ] calculated mass 527.22]⁺(retention time: 0.20 minutes).

Example 320

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

The compound was prepared from the compound of example 132(a) (100mg,0.249mmol) using the method of example 225 and 2- (4-ethylpiperazin-1-yl) acetic acid (85mg,0.498, mmol,2.0eq.) to give the product in 38% yield (40 mg).

Example 321

N- (5- (5- (4-ethylpiperazin-1-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) cyclopropanesulfonamide

To N- (5- (5-bromo-1H-benzo [ d ]]Imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl]To a DMSO solution of (3-yl) cyclopropanesulfonamide (110mg,0.198mmol) was added potassium carbonate (54mg,0.391mmol,2.0 eq.). Passing the mixture through N₂Bubbling was degassed for 10 min, then 1-ethylpiperazine (68mg,0.595mmol,3.0eq.) and L-proline (4.5mg) and CuI (3mg) were added. The sealed tube was then closed and the mixture was held at 95 ℃ for 24 hours. The mixture was quenched and extracted as described in example 1 (d). Evaporation of the solvent gave a crude residue which was purified by preparative HPLC to give the product in 18% yield (20 mg).¹HNMR (400MHz, DMSO-D6):10.3(s,1H),8.98(s,1H),7.77(M,1H),7.66(s,1H),7.60(brs,2H),7.50(brs,2H),7.41(s,1H),7.33-7.27(M,2H),3.60(M,4H),3.29-3.20(M,4H),3.02(q,2H),2.90(t,1H),1.30(t,3H),1.04(q,4H), LC-MS (ESI): mass 537.62 is calculated and mass 538.1[ M + H ] (ESI) is measured ]⁺

Example 322

N- (2',4' -difluoro-5- (5- (3-hydroxypyrrolidin-1-yl) -1H-benzo [ d ] imidazol-1-yl) -2',3' -dihydro- [1,1' -biphenyl ] -3-yl) cyclopropanesulfonamide

This compound was prepared according to the procedure for example 321 using (S) -pyrrolidin-3-ol to give the pure product in 12% yield (12 mg). NMR (400MHz, DMSO-D6) 8.52(s,1H),7.77(q,1H),7.56(D,3H),7.51-7.46(M,2H),7.29(t,1H),6.82(s,1H),6.73(D,1H),5.01(D,1H),4.45(s,1H),3.52(q,1H),3.35(s,1H),3.14(D,1H),2.87(q,1H),2.12-2.09(M,1H),1.96-1.94(M,1H),1.03(D,4H), LC-MS (ESI): calculated mass: 512.1; measured mass: 510[ M-H ] - (retention time: 0.42 min).

Example 323

N- (5- (5- (1-cyclopentyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) ethanesulfonamide

The title compound was prepared from the title compound of example 200(b) using the procedure of example 1 (i).¹HNMR(400MHz,CD₃OD) 8.51(s,1H),8.09(s,1H),7.92(s,1H),7.88(s,1H),7.68-7.62(M,3H),7.58(d,1H),7.51(dd,2H),7.15-7.10(M,2H),4.75-4.72(M,1H),3.24 (quartet, 2H),2.23-2.19(M,2H),2.06-2.01(M,2H),1.94-1.90(M,2H),1.77-1.73(M,2H),1.36(t,2H), LC-MS (ESI), calculated mass 547.19, measured mass 548.1[ M + H ], (M,2H + M,2H) ]⁺(retention time: 1.66 minutes).

Example 324

N- (5- (6- (1-cyclopentyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) ethanesulfonamide

a) N- (5- (6-bromo-3H-imidazo [4,5-b ] pyridin-3-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) -ethanesulfonamide

To 5- (6-bromo-3H-imidazo [4, 5-b)]Pyridin-3-yl) -2',4' -difluoro- [1,1' -biphenyl]Pyridine (52mg,0.66mmol,2.0eq.) followed by ethanesulfonyl chloride (76mg,0.66mmol,2.0eq.) is added to a solution of-3-amine (133mg,0.33mmol) in DCM. The mixture was stirred for 1 hour, the reaction was terminated and extracted as described in example 2 (b). The solvent was distilled off to give a crude residue which was used in the next step without further purification in a yield of 76.68% (125mg), LC-MS (ESI) calculated mass 492.01, measured mass 493.0M + H]⁺(retention time: 1.72 minutes).

b) N- (5- (6- (1-cyclopentyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) ethanesulfonamide

This compound was prepared from the compound of example 324(a) (125mg,0.25mmol) using the procedure of example 200(c) and 1-cyclopentylYl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (136mg,0.50mmol,2.0eq.) was prepared to give the product in 21.73% yield (30 mg). ¹HNMR (400MHz, DMSO-d6):10.32(s,1H),8.96(s,1H),8.76-8.75(d,1H),8.45-8.42(t,2H),8.06(s,1H),7.95-7.94(t,1H),7.77-7.70(M,2H),7.49-7.43(M,2H),7.28(t,1H),4.74-4.70(t,1H),3.31-3.26(q,2H),2.14-2.09(M,2H),2.00-1.95(M,2H),1.84-1.81(M,2H),1.68-1.65(M,2H),1.28-1.24(t,3H), LC-MS ESI 548.18: 3525 [ M + H ], (35 549.1: (M, 3H): 548.18: (LC-MS ESI)]⁺(retention time: 1.70 minutes).

Example 325

2- (4- (1- (5-amino-2 ',4' -difluoro- [1,1' -biphenyl ] -3-yl) -1H-benzo [ d ] imidazol-5-yl) -1H-pyrazol-1-yl) ethanol

To N- (2',4' -difluoro-5- (5- (1- (2- ((tetrahydro-2H-pyran-2-yl) oxy) ethyl) -1H-pyrazol-4-yl) -1H-benzo [ d]Imidazol-1-yl) - [1,1' -biphenyl]-3-yl) acetamide (0.12g,0.125mmol) in methanol (5ml) acetyl chloride was added (1ml) at 0 ℃. The mixture was stirred at room temperature for 16 hours. The mixture was quenched and extracted as described in example 1 (d). Evaporation of the solvent gave the product in 28% yield (0.026 g).¹HNMR(400MHz,DMSO-d₆) 8.53(s,1H),8.20(s,1H),7.97-7.95(d,2H),7.69-7.64(M,2H),7.59-7.56(dd,1H),7.39-7.36(M,1H),6.88(s,2H),6.82(d,1H),5.70(s,2H),4.95(s,1H),4.19-4.16(t,2H),3.81-3.78(t,2H), LC-MS (ESI) and 432.2[ M + H ] measured mass 431.44 ]⁺(retention time: 0.4 minutes).

Example 326

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

The compound was prepared from the title compound of example 1(h) using the procedure of example 1 (i).¹HNMR(400MHz,DMSO-d₆):10.43(s,1H),9.0(s,1H),8.17(s,2H),8.13(M,1H),8.06(s,1H),7.82(s,1H),7.74-7.73(M,3H),7.55(s,1H),7.5-7.42(M,1H),7.3-7.26(dt,1H),2.12(s,3H) LC-MS (ESI), calculated mass: 429.42, measured mass: 429.8[ M + H ] (ESI) ]]⁺(retention time: 0.6 minutes).

Example 327

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

The title compound was prepared from the title compound of example 1(h) using the procedure of example 1 (i).

Example 328

N- (2', 4' -difluoro-5- (5- (6-oxo-1, 6-dihydropyridin-3-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) -2- (1H-1,2, 4-triazol-1-yl) acetamide

a) N- (5- (5- (6- (benzyloxy) -1, 6-dihydropyridin-3-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) acetamide

This compound was prepared from the compound of example 1(h) (2g,4.5mmol) using the method of example 200(c) and 2- (benzyloxy) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2-dihydropyridine (1.68g,5.4mmol,1.2eq) to give the product in 50% yield (1.2 g). LC-MS (ESI) for calculating mass 548.2 and measured mass 549.4M + H ]⁺(retention time: 0.302 min).

b)5- (5- (6- (benzyloxy) -1, 6-dihydropyridin-3-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-amine

The compound was prepared from the compound from example 328(a) (1.1g,2.00mmol) using the method of example 2(a) to give the product in 50% yield (0.7 g).

c) N- (5- (5- (6- (benzyloxy) -1, 6-dihydropyridin-3-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) -2- (1H-1,2, 4-triazol-1-yl) acetamide

The compound was prepared from the compound of example 328(b) (100mg,0.1984mmol) using the method of example 225 to give the product in 65% yield (80 mg). LC-MS (ESI) calculated mass 613 measured mass 614M + H]⁺(retention time: 1.681 minutes).

d) N- (2', 4' -difluoro-5- (5- (6-oxo-1, 6-dihydropyridin-3-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) -2- (1H-1,2, 4-triazol-1-yl) acetamide

A solution of the compound from example 328(c) (60mg,0.0975mmol) in TFA was heated at 50 ℃ for 16 h. The mixture was concentrated to give the product in 50% yield (30 mg).¹HNMR(400MHz,DMSO-d₆) 8.94(s,1H),8.61(s,1H),8.11(s,1H),8.04-7.94(M,3H),7.81-7.75(M,4H),7.63(d,2H),7.49-7.44(M,1H),7.28(t,1H),6.46(d,1H),5.24(s,2H), LC-MS (ESI) calculating mass 523.16, measured mass 524.1[ M + H ] 524.1 ]⁺(retention time: 0.343 min).

Example 329

1- (2',4' -difluoro-5- (5- (6-oxo-1, 6-dihydropyridin-3-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) -3- (furan-2-ylmethyl) urea

a)1- (5- (5- (6- (benzyloxy) pyridin-3-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) -3- (furan-2-ylmethyl) urea

To a solution of 5- (5- (6- (benzyloxy) -1, 6-dihydropyridin-3-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-amine (75mg,0.148mmol) in DCM was added furfuryl isocyanate (19mg,0.163mmol,1.1 eq.). The mixture was stirred overnight, the reaction was terminated and extracted as described in example 2 (b). The solvent was evaporated to give a crude residue which was recrystallized from ether to give the title compound in 86% yield (80 mg).

b)1- (2',4' -difluoro-5- (5- (6-oxo-1, 6-dihydropyridin-3-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) -3- (furan-2-ylmethyl) urea

To a solution of the compound from example 329(a) (80mg) in THF (5ml) and ethanol (5ml) was added 10% palladium on carbon (10mg), followed by 20% palladium hydroxide (10 mg). The mixture was stirred under hydrogen atmosphere for 2 hours. The reaction was filtered through a bed of celite and concentrated to give the crude product, which was purified by column chromatography on silica gel (60-120) eluting with 6% MeOH in chloroform as eluent to give the product in 58% yield (40 mg).

Example 330

N- (2',4' -difluoro-5- (5- (1- (2-hydroxyethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) methanesulfonamide

Following the procedure of example 1(d), to N- (2',4' -difluoro-5- (5- (1- (2- ((tetrahydro-2H-pyran-2-yl) oxy) ethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] is added]Imidazol-1-yl) - [1,1' -biphenyl]To a solution of (3-yl) methanesulfonamide (0.15g,0.252mmol) in methanol (5ml) was added acetyl chloride (1ml) at 0 ℃. The solvent was distilled off to leave the product (0.063 g).¹HNMR(300MHz,DMSO-d₆) 8.64(s,1H),8.22(s,1H),8.00-7.97(d,2H),7.80-7.69(M,2H),7.67-7.61(M,1H),7.59-7.60(d,1H),7.53(s,2H),7.47-7.41(M,2H),7.29-7.25(t,1H),4.97-4.95(t,1H),4.18-4.15(M,2H),3.80-3.78(M,2H),3.14(s,3H) calculated mass 509.1, measured mass 510.3[ M + H ] calculated mass 509.1]⁺(retention time: 1.18 minutes).

Example 331

N- (2',6' -difluoro-5- (6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1' -biphenyl ] -3-yl) acetamide

a)4- (4- (3- (5-acetylamino-2 ',6' -difluoro- [1,1' -biphenyl ] -3-yl) -3H-imidazo [4,5-b ] pyridin-6-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester

The title compound was prepared from the title compound of example 209(c) using the method of example 209 (d).

b) N- (2',6' -difluoro-5- (6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1' -biphenyl ] -3-yl) acetamide

A solution of the compound from example 331(a) (180mg,0.293mmol) in TFA was stirred at room temperature for 16 h. The mixture was concentrated to give the crude product, which was purified by preparative HPLC to give the product in 13% yield (20 mg).¹HNMR(400MHz,DMSO-d₆) 10.41(s,1H),8.87(s,1H),8.77-8.76(d,1H),8.7-8.5(br,1H),8.42(s,1H),8.36(m,1H),8.14(s,1H),7.75(s,1H),7.69(s,1H),7.55(m,1H),7.31-7.27(t,2H),4.58-4.44(m,1H),3.17-3.09(m,4H),2.32-2.16(m,4H),2.11(s, 3H). Calculated mass 513.54, measured mass 514.3[ M + H ]]⁺(retention time: 1.32 minutes).

Example 332

1- (5-acetylamino-2 ',4' -difluoro- [1,1' -biphenyl ] -3-yl) -1H-benzo [ d ] imidazole-5-carboxylic acid

a)4- ((5-Acetylamino-2 ',4' -difluoro- [1,1' -biphenyl ] -3-yl) amino) -3-nitrobenzoic acid methyl ester

A solution of N- (5-amino-2 ',4' -difluoro- [1,1' -biphenyl ] -3-yl) acetamide (1.0g,3.813mmol), methyl 4-fluoro-3-nitrobenzoate (0.835g,4.194mmol,1.1eq.) and potassium fluoride (0.265g,4.457mmol,1.2eq.) in DMF was heated at 130 ℃ for 16 h. The mixture was quenched and extracted as described in example 1 (d). Evaporation of the solvent gave a crude residue which was purified by column chromatography (60-120 silica gel, 40% ethyl acetate in hexane) to give the product in 48.78% yield (0.82 g).

b)1- (5-Acetylamino-2 ',4' -difluoro- [1,1' -biphenyl ] -3-yl) -1H-benzo [ d ] imidazole-5-carboxylic acid methyl ester

The compound was prepared from the compound of example 332(a) using the procedures of examples 1(g) and 1(h) to give the product in 91.3% yield (0.58 g).¹HNMR(300MHz,DMSO-d₆) 10.21(s,1H),8.89(s,1H),8.38(s,1H),8.14(s,1H),8.03(s,1H),7.86-7.83(d,2H),7.79-7.75(M,2H),7.53(s,2H),7.26-7.25(M,1H),2.10(s,3H), LC-MS (ESI) calculating mass 421.4, measured mass 422[ M + H + E [ ]]⁺(retention time: 1.52 minutes).

c)1- (5-acetylamino-2 ',4' -difluoro- [1,1' -biphenyl ] -3-yl) -1H-benzo [ d ] imidazole-5-carboxylic acid

To a solution of example 332(b) (0.1g,0.24mmol,1eq.) in THF (10ml), methanol (6ml) and water (4ml) was added LiOH (0.049g,1.18mmol,5eq.) and the mixture was stirred at room temperature overnight. The reaction was diluted with water and extracted as described in example 1 (d). Evaporation of the solvent gave the product in 26% yield (0.025 g).¹HNMR(400MHz,DMSO-d₆) 12.92(s,1H),10.38(s,1H),8.79(s,1H),8.34(s,1H),8.07(s,1H),7.98-7.96(d,1H),7.87(s,1H),7.78-7.73(M,2H),7.52-7.41(M,2H),7.28-7.24(t,1H),2.11(s,3H), LC-MS (ESI), calculated mass 407.11, measured mass 408.4[ M + H + T,1H ], calculated mass]⁺(retention time: 1.01 min).

Example 333

N- (5- (5- (4-bromo-1H-pyrazol-1-yl) -1H-benzo [ d ] imidazol-1-yl) -4 '-fluoro- [1,1' -biphenyl ] -3-yl) acetamide

To a solution of the compound (4g,9.73mmol) obtained in example 70 in acetic acid (40ml) was added dropwise a solution of bromine (1.53g,9.73mmol) in acetic acid (10ml) at room temperature. The reaction was stirred at room temperature for 1 hour, cold water was added and the resulting solid was filtered and dried to give the title product in 63.15% yield (3 g).¹HNMR(300MHz,DMSO-d₆) 10.42(s,1H),8.88(s,2H),8.24(s,1H),8.23(s,1H),8.0(s,1H),7.92-7.85(M,3H),7.85-7.78(M,3H),7.66(s,1H),7.4-7.3(M,2H),2.13(s,3H), LC-MS (ESI) calculating mass 490.33, measured mass 491.7[ M + H ], (M + H) calculating mass]⁺(retention time: 1.66 minutes).

Example 334

N- (5- (6- (1-cyclopentyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) methanesulfonamide

a) N- (5- (6-bromo-3H-imidazo [4,5-b ] pyridin-3-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) -methanesulfonamide

To 5- (6-bromo-3H-imidazo [4, 5-b)]Pyridin-3-yl) -2',4' -difluoro- [1,1' -biphenyl]Pyridine (52mg,0.66mmol,2.0eq.) followed by methanesulfonyl chloride (76mg,0.66mmol,2eq.) is added to a solution of-3-amine (133mg,0.33mmol) in DCM. The reaction solution was stirred for 1 hour, and the reaction was terminated and extracted as described in example 2 (b). The solvent was evaporated to give a crude residue which was used in the next step without further purification. Yield 75.0% (120 mg). ¹HNMR(300MHz,DMSO-d₆) 10.30(s,1H),9.30(s,1H),8.56(s,1H),7.83(s,1H),7.45(s,1H),7.44(s,2H),3.16(s,3H), LC-MS (ESI) calculating mass 479.5, and actually measuring mass 480.2[ M + H [ ]]⁺(retention time: 1.59 minutes).

b) N- (5- (6- (1-cyclopentyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) methanesulfonamide

Prepared from the compound of example 334(a) (0.120g,0.25mmol) using the method of example 200(c) and 1-cyclopentyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (0.253g,0.50mmol,2.0eq) to give a crude residue which is purified by preparative HPLC to give the product in 19% yield (0.026 g).¹HNMR(400MHz,DMSO-d₆) 10.29(s,1H),8.96(s,1H),8.75(d,1H),8.44-8.41(d,2H),8.05(s,1H),7.93(s,1H),7.79(s,1H),7.74-7.72(M,1H),7.46-7.41(M,2H),7.28(t,1H),4.74-4.70(t,1H),3.17(s,3H),2.14-2.09(M,2H),2.00-1.95(M,2H),1.84-1.80(M,2H),1.68-1.65(M,2H), LC-MS (ESI) calculated mass 534.16, 535.1[ M + H ], (M + H)]⁺(retention time: 1.70 minutes).

Example 335

N- (5- (6- (1-cyclopentyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) cyclopropanesulfonamide

This compound was synthesized using the procedure of example 334 using 5- (6-bromo-3H-imidazo [4,5-b ] ]Pyridin-3-yl) -2',4' -difluoro- [1,1' -biphenyl]-3-amine (133mg,0.33mmol) cyclopropanesulphonyl chloride (20mg,0.66mmol,2.0eq.) and 1-cyclopentyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxolan-2-yl) -1H-pyrazole (0.115g,0.43mmol,2.0eq.) as starting materials were prepared to give a crude residue which was purified by preparative HPLC to give the product in 27.86% yield (34 mg).¹HNMR(400MHz,DMSO-d₆) 10.26(s,1H),8.96(s,1H),8.76-8.75(d,1H),8.45-8.42(t,2H),8.06(s,1H),8.00-7.99(d,1H),7.78-7.70(M,2H),7.49-7.43(M,2H),7.31-7.26(t,1H),4.74-4.70(t,1H),2.84(M,1H),2.14-2.08(M,2H),2.00-1.96(M,2H),1.84-1.81(M,2H),1.69-1.65(M,2H),1.09-1.02(M,4H), LC-MS (ESI), calculated mass: 560.18, measured mass: 561.2[ M + H ] (M,2H) ], 561.2]⁺(retention time: 1.70 minutes).

Example 336

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

The title compound was prepared from the compound of example 2(a) using the method of example 205.¹HNMR(300MHz,DMSO-d₆) 10.28(s,1H),8.99(s,1H),8.23(d,2H),8.03-7.98(M,3H),7.80-7.67(M,3H),7.60(s,1H),7.47(t,1H),7.29(t,1H),4.09(s,3H),3.89(s,3H),3.42(s,2H), LC-MS (API): calculated mass: 473.17; measured mass: 474.1[ M + H ], (API): 474.1 ]⁺(retention time: 0.90 minutes).

Example 337

N- (5- (5- (1H-pyrazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro [1,1' -biphenyl ] -3-yl) ethanesulfonamide

a) N- (2',4' -difluoro-5- ((2-nitro-4- (1H-pyrazol-3-yl) phenyl) amino) - [1,1' -biphenyl ] -3-yl) acetamide

To a solution of the compound from example 168(b) (0.8g,1.66mmol) in ethanol (15ml) was added hydrazine (7ml) and stirred at room temperature overnight. The mixture was purified by chromatography on silica gel eluting with 1% MeOH in chloroform to give the product in 62% yield (0.46 g).

b) N- (5- ((2-amino-4- (1H-pyrazol-3-yl) phenyl) amino) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) acetamide

To a solution of the compound from example 337(a) (0.46g,1.02mmol) in THF (3ml) and methanol (3ml) was added 10% palladium on carbon. The mixture was stirred under hydrogen atmosphere for 4 hours. The mixture was filtered through celite bed and concentrated to give the product in 66% yield (0.28 g).

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

A mixture of the compound from example 337(b) (0.3g,0.69mmol) and formic acid (3ml) was heated at 80 ℃ for 2 hours. The formic acid was distilled off and the crude product was extracted with DCM. Evaporation of the solvent gave the product in 95% yield (0.3 g).

d)5- (5- (1H-pyrazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-amine

To a solution of the compound from example 337(c) (0.26g,0.465mmol) in ethanol (3ml) was added 1:1HCl solution and heated at 80 ℃ for 1 h. The mixture was washed with saturated NaHCO₃The solution was basified and extracted with DCM (2 × 15 ml). The DCM layer was concentrated to give the product in 80% yield (0.28 g).

e) N- (5- (5- (1H-pyrazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) ethanesulfonamide

To a solution of the compound from example 337(d) (100mg,0.25mmol) in DCM was added pyridine 0.2ml followed by ethanesulfonyl chloride (33mg,0.25mmol,1.0 eq.). The mixture was stirred for 1 hour, quenched with water and extracted with DCM (3X 10 ml). The combined organic layers were concentrated and the crude product was taken up in 10% NaOH solution (3ml)Stirred for 1 hour, then washed with water, brine and dried over sodium sulfate. The aqueous layer was extracted with DCM (2 × 10 ml). The solvent was evaporated to give the crude product, which was purified by preparative HPLC to give the title product.¹HNMR(400MHz,DMSO-d₆) 13-12.5(brs,1H),10.4-10.2(brs,1H),8.69(s,1H),8.21(s,1H),7.87-7.86(M,1H),7.79-7.71(M,3H),7.56(M,2),7.42-7.42(M,2H),7.3-7.25(dt,1H),6.81(d,1H),3.35-3.25(q,2H),1.27-1.24(t,3H), LC-MS API (LC-MS API) (calculated mass: 479.5; measured mass: 480.3[ M + H: (M + H)) ]⁺(retention time: 1.32 minutes).

Example 338

N- (5- (5- (1H-pyrazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) methanesulfonamide

This compound was prepared from the compound of example 208(a) using the procedure of example 208 (b).¹HNMR(400MHz,DMSO-d₆) 8.68(s,1H),8.2(s,1H),7.87-7.85(M,1H),7.76-7.72(M,3H),7.51-7.49(M,2H),7.44-7.4(M,2H),7.3-7.22(dt,1H),6.81-6.8(d,1H),3.11(s,3H), LC-MS (API) calculated mass 465.48, measured mass 466.32[ M + H ] (API)]⁺(retention time: 1.4 minutes).

Example 339

N- (5- (6- (6-aminopyridin-3-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) methanesulfonamide

This compound was prepared from the compound of example 334(a) using the method of example 246.¹HNMR(300MHz,CD₃OD is 8.73(s,1H),8.56(s,1H),8.17(d,2H),7.79-7.71(M,3H),7.59-7.57(M,1H),7.42(M,1H),7.08-7.03(M,2H),6.65-6.62(M,1H),3.04(s,3H), LC-MS (ESI) calculating mass 492.12, measured mass 493.0[ M + H + E ]]⁺(retention time: 0.20 minutes).

Example 340

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

This compound was prepared from 2',5' -difluoro-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-amine (70mg,0.175mmol) using the method of example 2(b) and ethanesulfonyl chloride (26mg,0.21mmol,1.2eq.) to give the pure product in 16.2% yield (14 mg). NMR (400MHz, DMSO-D6):10.35(s,1H),8.80(s,1H),8.23(s,1H),8.00(s,1H),7.96(s,1H),7.70(D,1H),7.65-7.60(M,4H),7.51(s,2H),7.49-7.39(M,1H),3.88(s,3H),3.30(q,2H),1.26(t,3H), LC-MS (ESI): calculated mass: 493.53; measured mass: 494.2[ M + H ] + (retention time: 0.1.33 min).

Example 341

N- (5- (6- (2-aminopyridin-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) -2', 4' -difluoro- [1,1' -biphenyl ] -3-yl) methanesulfonamide

To (5- (3- (2',4' -difluoro-5- (methylsulfonylamino) - [1,1' -biphenyl)]-3-yl) -3H-imidazo [4,5-b]Pyridin-6-yl) pyridin-2-yl) carbamic acid tert-butyl ester (0.2g,0.33mmol) in DCM (5ml) was added TFA (1.2ml) at 0 ℃. The mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo, quenched with sodium bicarbonate and extracted as described in example 1 (d). Evaporation of the solvent gave the product in 16.9% yield (0.28 g).¹HNMR(300MHz,DMSO-d₆) 10.30(s,1H),9.04(s,1H),8.73(s,1H),8.46(s,1H),8.00(d,1H),7.91(s,1H),7.79(M,2H),7.44(M,2H),7.30(M,1H),6.95(d,1H),6.82(s,1H),6.06(s,2H),3.17(s,3H), LC-MS ESI, calculated mass: 492.50, measured mass: 493.1[ M + H ], calculated mass: 493.1]⁺(retention time: 0.39 minutes).

Example 342

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

The compound was prepared from the compound of example 29(a) (75mg,0.193mmol) using the method of example 225 and 2- (pyrrolidin-1-yl) acetic acid (37.3mg,0.289mmol,1.5eq.) to give the product in 31.18% yield (30 mg). ¹HNMR(600MHz,CD₃OD) 8.62(s,1H),8.29-8.28(d,1H),8.17-8.16(t,1H),8.12(s,1H),7.85-7.83(dd,3H),7.77-7.76(d,1H),7.68-7.67(M,1H),7.59(s,1H),7.15-7.12(M,2H),6.58-6.57(t,1H),3.73(s,2H), 3.02(t,4H), 2.00-1.94(M,4H), LC-MS (ESI) calculating mass 498.53, measured mass 499.6[ M + H ], (M,4H)]⁺(retention time: 0.6 minutes).

Example 343

N- (5- (5- (2-aminopyridin-4-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) methanesulfonamide

The compound is prepared from 5- (1- (5-amino-2 ',4' -difluoro- [1,1' -biphenyl)]-3-yl) -1H-benzo [ d]Imidazol-5-yl) pyridin-2-amine (50mg,0.121mmol) was prepared using the method of example 2(b) and methanesulfonyl chloride (27.7mg,0.242mmol,2.0eq) to give the product in 37.2% yield (22 mg).¹HNMR(400MHz,DMSO-d₆) 10.42(s,1H),8.84(s,1H),8.29(s,1H),8.04-8.20(d,3H),7.89-7.87(d,1H),7.81-7.74(M,2H),7.61(s,1H),7.57(s,1H),7.47-7.44(d,2H),7.39-7.38(d,1H),7.31-7.26(M,1H),3.19(s,3H), LC-MS (ESI) and calculated mass 491.51 measured mass 492.2[ M + H ] 492.2]⁺(retention time: 0.24 minutes).

Example 344

N- (5- (5- (4-amino-3-fluorophenyl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) acetamide

This compound was prepared from the compound of example 1(h) using the method of example 246. ¹HNMR(300MHz,DMSO-d₆):10.46(s,1H),8.86(s,1H),8.07(s,1H),7.95(s,1H),7.81-7.71(m,3H),7.59(d,1H),7.51-7.40(m,3H),7.33-7.24(m,2H),6.88-6.82(m1H),5.25(brs,2H),2.12(s,3H), LC-MS (ESI), calculated mass 472.15, measured mass 473.5[ M + H ]]⁺(retention time: 1.47 minutes).

Example 345

N- (5- (5- (2-aminopyridin-4-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) ethanesulfonamide

This compound was prepared as described in example 343 using ethanesulfonyl chloride (46.8mg,0.363mmol,2.0eq.) to give the product in 36.1% yield (33 mg).¹HNMR(400MHz,DMSO-d₆) 10.35(s,1H),8.84(s,1H),8.29(s,1H),8.04-7.99(t,3H),7.88-7.86(d,1H),7.81-7.73(M,2H),7.59-7.58(d,1H),7.48-7.44(M,2H),7.39-7.31(d,1H),7.31-7.26(M,2H),3.32-3.27(q,2H),1.28-1.24(t,3H), LC-MS (ESI): calculation of mass: 505.54; measured mass: 506.3[ M + H ], (ESI): calculation of mass: 505.54; measured mass: 506.3[ M + H ], (M + H)]⁺(retention time: 0.2 minutes).

Example 346

N- (5- (6- (2-aminopyridin-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) ethanesulfonamide

The compound is prepared from (5- (3- (5- (ethylsulfonylamino) -2',4' -difluoro- [1,1' -biphenyl)]-3-yl) -3H-imidazo [4,5-b]Pyridin-6-yl) pyridin-2-yl) carbamic acid tert-butyl ester (0.2g,0.33mmol) was prepared according to the method of example 290 to give the product in 17.9% yield (0.30 g).¹HNMR(300MHz,DMSO-d₆) 10.42(s,1H),9.01(s,1H),8.85(s,1H),8.64 (s,1H),7.96(d,1H),7.81-7.73(M,3H),7.44-7.32(M,4H),7.21(M,2H),3.25-3.23(q,2H),1.26-1.23(t,3H), the calculated mass is 506.53, and the measured mass is 507.3[ M + H ] (M + H) ]⁺(retention time: 0.2 minutes).

Example 347

N- (5- (6- (6-aminopyridin-3-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) ethanesulfonamide

The title compound was synthesized from N- (5- (6-bromo-3H-imidazo [4, 5-b) according to the procedure described for example 340]Pyridin-3-yl) -2',4' -difluoro- [1,1' -biphenyl]-3-yl) ethanesulfonamide as starting material.¹HNMR(300MHz,CD₃OD is 8.73(s,1H),8.56(s,1H),8.17(d,2H),7.79-7.71(M,3H),7.59-7.57(M,1H),7.42(M,1H),7.08-7.03(M,2H),6.65-6.62(M,1H),3.04(s,3H), LC-MS (ESI) calculating mass 492.12, measured mass 493.0[ M + H + E ]]⁺(retention time: 0.20 minutes).

Example 348

1- (2',4' -difluoro-5- (6- (1-methyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1' -biphenyl ] -3-yl) -3- (furan-2-ylmethyl) urea

To a solution of example 132(a) (60mg,0.149mmol) in DCM was added DIPEA (0.1ml,0.447mmol,3eq.) followed by 2- (isocyanatomethyl) furan (22mg,0.179mmol,1.2 eq.). The mixture was stirred for 16 hours, the reaction was terminated and extracted as described in example 2 (b). Evaporation of the solvent gave a crude residue which was purified by preparative HPLC to give the product in 44.87% yield (35 mg).¹HNMR(400MHz,DMSO-d₆) 9.02(s,1H),8.92(s,1H),8.71(s,1H),8.4(s,1H),8.30(s,1H),8.10(s,1H),8.04(s,1H),7.72-7.67(M,2H),7.60(d,2H),7.43(t,1H),7.25(t,1H),6.73(t,1H),6.41(s,1H),6.3(d,2H),4.3(d,2H),3.90(s,3H), LC-MS (ESI) calculating mass 525.17, measured mass 526.3[ M + H ] (S, 1H); measured mass 526.3 ]⁺(retention time: 1.49 minutes).

Example 349

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

This compound was prepared from the compound of example 203(a) using the method of example 203 (b).¹HNMR(400MHz, DMSO-d6, 10.3(s,1H),8.96(s,1H),8.25(s,1H),8.02(s,1H),7.98(s,1H),7.77-7.66(M,2H),7.62(s,2H),7.52-7.44(M,2H),1.0(s,4H), LC-MS (ESI), calculated mass 505.14, measured mass 506.0[ M + H ], (ESI)]⁺(retention time: 0.632 minutes).

Example 350

N- (2',4' -difluoro-5- (5- (pyridin-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) cyclopropanesulfonamide

The compound was prepared from the title compound of example 203(a) using the procedure of example 203 (b).¹HNMR(300MHz,DMSO-d₆) 8.62-8.59(M,3H),8.18(s,1H),7.84-7.81(M,4H),7.67-7.56(M,4H),7.15-7.1(M,2H),2.7(M,1H),1.2-1.1(M,4H), LC-MS (API) calculated mass 502.54, measured mass 503.2[ M + H [, (API) ]]⁺(retention time: 1.15 minutes).

Example 351

1- (5- (cyclopropanesulfonamido) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) -1H-benzo [ d ] imidazole-5-carboxamide

The compound was prepared from the compound of example 312(a) (100mg,0.27mmol) using the method of example 2(b) and cyclopropanesulfonyl chloride (42mg,0.30mmol,2.0eq.) to give the product in 27.34% yield (35 mg). ¹HNMR (400MHz, DMSO-d6):10.35(s,1H),8.82(s,1H),8.37(s,1H),8.08(s,1H),7.96-7.94(d,1H),7.77-7.72(M,2H),7.60-7.58(d,2H),7.51(s,1H),7.48-7.43(M,1H),7.38(s,1H),7.29-7.24(M,1H),2.89-2.86(t,1H),1.02-1.01(d,4H); LC-MS (ESI): 468.11; 469.1[ M + H + E; ]measured mass: (LC-MS]⁺(retention time: 1.23 minutes).

Example 352

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

The compound is prepared from N- (2',4' -difluoro-5- (5- (1- (2- ((tetrahydro-2H-pyran-2-yl) oxy) ethyl) -1H-pyrazol-4-yl) -1H-benzo [ d]Imidazol-1-yl) - [1,1' -biphenyl]-3-yl) cyclopropanesulfonamide (0.15g,0.242mmol) was prepared using the method of example 330 to give the product in 78% yield (0.063 g).¹HNMR(400MHz,DMSO-d₆) 10.15(s,1H),8.65(s,1H),8.22(s,1H),8.00-7.97(d,2H),7.75(s,1H),7.76-7.62(d,2H),7.56(M,2H),7.47(s,3H),7.27(s,1H),4.95(s,1H),4.17(s,1H),3.79(s,1H),1.01(M,5H), LC-MS (ESI) calculated mass: 535.57, measured mass: 536.4[ M + H ] (M + H)]⁺(retention time: 1.0 min).

Example 353

N- (2',4' -difluoro-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1 '-biphenyl ] -3-yl) -N, N' -dimethylsulphamic acid diamide

The compound was prepared from the title compound of example 210(a) using the procedure of example 210 (b).¹HNMR(300MHz,CD₃OD is 9.4(s,1H),8.02(s,1H),7.92(s,1H),7.85(s,1H),7.78-7.67(M,3H),7.55-7.46(M,4H),7.06-7.03(d,2H),3.86(s,3H),2.77(s,6H), LC-MS (ESI) calculated mass is 508.54, measured mass is 509.0[ M + H ] calculated mass is 508.54]⁺(retention time: 0.96 minutes).

Example 354

N- (2',4' -difluoro-5- (6- (1-isopropyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1' -biphenyl ] -3-yl) acetamide

The compound was prepared from the title compound of example 131(c) using the procedure of example 131 (d).¹HNMR(400MHz,DMSO-d₆) 13.0(br,1H),10.2(br,1H),8.69(s,1H),8.20(s,1H),7.87-7.71(M,4H),7.56(M,2H),7.48-7.42(s,1H),7.3-7.25(dt,1H),6.81(d,1H),3.35-3.25(q,2H),1.27-1.24(t,3H) LC-MS (ESI), calculated mass 479.5, measured mass 480.2[ M + H + M ] and calculated mass]⁺(at the time of retentionThe method comprises the following steps: 1.42 minutes).

Example 355

N- (2 '-fluoro-4' -methoxy-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1 '-biphenyl ] -3-yl) -N, N' -dimethylsulphamic acid diamide

This compound was prepared from the compound of example 191(c) using the methods of examples 210(a) and (b).¹HNMR,400MHz:(DMSO-d₆) 10.42(s,1H),8.95(s,1H),8.25(s,1H),8.02(s,1H),7.98(s,1H),7.68(s,2H),7.6(t,1H),7.52-7.47(M,3H),7.04-7.00(dd,1H),6.97-6.94(s,1H),3.88(s,3H),3.84(s,3H),2.8(s,6H), LC-MS (ESI): 520.58, 521[ M + H ] is measured as mass ]⁺(retention time: 1.38 minutes).

Example 356

N- (2', 4' -difluoro-5- (6- (1-isopropyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1' -biphenyl ] -3-yl) methanesulfonamide

This compound was prepared from the compound of example 334(a) (0.2g,0.417mmol) using the method of example 200(c) and 1-isopropyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (0.196g,0.834mmol,2.0eq.) to give the product in 45% yield (0.095 g).¹HNMR(400MHz,DMSO-d₆) 10.30(s,1H),8.97(s,1H),8.766-8.762(d,1H),8.44-8,42(dd,2H),8.06(s,1H),7.942-7.93(s,1H),7.80-7.71(M,2H),7.49-7.42(M,2H),7.31-7.27(M,1H),4.53(M,1H),3.18(s,1H),1.48-1.47(d,6H), LC-MS (ESI), calculated mass 508.54, measured mass 509.1[ M + H]⁺(retention time: 1.55 minutes).

Example 357

This compound was prepared from the compound of example 1(h) using the method of example 246.¹HNMR(300MHz,DMSO-d₆) 10.41(s,1H),8.83(s,1H),8.11(s,1H),7.98(s,1H),7.79-7.75(M,3H),7.65.7.63(M,4H),7.52(s,1H),7.49-7.39(M,2H),7.29-7.22(M,1H),7.04-7.02(M,2H),2.1(s,3H), calculated mass 454.16, measured mass 454.8[ M + H ] 454.16 ]⁺(retention time: 0.58 minutes).

Example 358

N- (5- (6- (4-amino-3-fluorophenyl) -3H-imidazo [4,5-b ] pyridin-3-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) acetamide

This compound was prepared from the compound of example 131(c) using the procedure of example 246.¹HNMR(300MHz,DMSO-d₆) 10.39(s,1H),8.94(s,1H),8.68(s,1H),8.37(d,1H),8.29(s,1H),7.89(s,1H),7.71(M,2H),7.55-7.25(M,4H),6.85(M,1H),5.35(brs,2H),2.12(s,3H), LC-MS (ESI) calculating mass: 473.15, measured mass: 474.4[ M + H ], (ESI)]⁺(retention time: 1.51 minutes).

Example 359

1-cyclopropyl-3- (2',4' -difluoro-5- (5- (6-oxo-1, 6-dihydropyridin-3-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) sulfuric acid diamide

a)1- (5- (5- (6- (benzyloxy) pyridin-3-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) -3-cyclopropylsulfuric acid diamide

To 5- (5- (6- (benzyloxy) -1, 6-dihydropyridin-3-yl) -1H-benzo [ d]Imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl]-3-amine (120mg,0.2380mmol) in pyridine was added N-cyclopropyl-2-oxoOxazolidine-3-sulfonamide (78mg,0.380mmol,1.6 eq.). The mixture was stirred at 50 ℃ for 16 hours and quenched with waterThe reaction was taken up and extracted with ethyl acetate (3X 50 ml). The combined organic layers were washed with 1n hcl and 1n naoh, water, brine and dried over sodium sulfate. Evaporation of the solvent gave a crude residue which was purified by preparative HPLC to give the product in 10% yield (15 mg).

b) 1-cyclopropyl-3- (2',4' -difluoro-5- (5- (6-oxo-1, 6-dihydropyridin-3-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) sulfuric acid diamide

A solution of the compound from example 359(a) (14mg,0.0224mmol) in TFA (1ml) was heated at 50 ℃ for 16 h. The mixture was concentrated to give the product in 83% yield (10 mg).¹HNMR(400MHz,CD₃OD is 11.8(s,1H),10.37(s,1H),8.73(s,1H),8.16(d,1H),7.97-7.91(M,2H),7.76-7.68(M,3H),7.58-7.55(M,1H),7.50(t,1H),7.46-7.38(M,3H),7.28-7.22(M,1H),6.44(d,1H),2.31(M,1H),0.56-0.53(M,2H),0.45-0.42(M,2H), LC-MS (ESI) calculating mass 533.13, measured mass 534.1[ M + H ], (M + H)]⁺(retention time: 1.195 minutes).

Example 360

1-cyclopropyl-3- (2',4' -difluoro-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) sulfate diamide

The compound was prepared from the compound of example 2(a) (50mg,0.1246mmol) using the method of example 359(a) to give the product in 9.3% yield (6 mg).¹HNMR(400MHz,CD₃OD) 9.06(s,1H),8.09(s,1H),7.99(s,1H),7.93(s,1H),7.77(s,2H),7.69-7.49(M,4H),7.18-7.11(M,2H),3.97(s,3H),2.48-2.44(M,1H),0.66-0.53(M,4H), LC-MS (ESI): calculated mass 520.0, measured mass 521.2[ M + H ESI ]]⁺(retention time: 0.94 min).

Example 361

N- (2',4' -difluoro-5- (6- (3-fluoropyridin-4-yl) -3H-imidazo [4,5-b ] pyridin-3-yl) - [1,1' -biphenyl ] -3-yl) acetamide

The compound was prepared from the title compound of example 131(c) using the procedure of example 131 (d).¹HNMR(400MHz,DMSO-d₆) 10.41(s,1H),9.08(s,1H),8.75(s,2H),8.57(s,2H),8.31(s,1H),7.91(s,1H),7.83(s,1H),7.71(s,2H),7.47-7.42(t,1H),7.29-7.25(t,1H),2.12(s,3H), LC-MS (ESI): calculated mass: 459.13, measured mass: 460.1[ M + H ESI ]]⁺(retention time: 1.50 minutes).

Example 362

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

Reacting N- (2',4' -difluoro-5- (5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-benzo [ d]Imidazol-1-yl) - [1,1' -biphenyl]-3-yl) cyclopropanesulfonamide (100mg,0.181mmol) in THF/EtOH/water (5:5:2) was passed through N₂Bubbling and degassing for 5 minutes. 4-bromo-1-methyl-1H-pyrazol-3-amine (35mg,0.19mmol,1.1eq.) was added and the mixture was degassed for an additional 5 minutes. Bis (tri-tert-butylphosphine) palladium (0) (5mg,0.009mmol,0.05eq.) and cesium carbonate (170mg,0.54mmol,3.0eq.) were then added and the mixture was further degassed for 5 minutes and heated at 90 ℃ for 16 hours. The mixture was quenched and extracted as described in example 1 (d). Evaporation of the solvent gave a crude residue which was purified by preparative HPLC to give the product in 27% yield (25 mg). ¹HNMR (300MHz, DMSO) 10.3(s,1H)8.79(s,1H),7.95-7.92(M,2H),7.77-7.07(M,2H),7.59(s,2H),7.53-7.47(M,3H),7.29(M,1H),3.75(s,3H),2.91(M,1H),1.5-1.49(d,2H),1.30-1.26(t,2H),1.03-1.01(t,2H), LC-MS (ESI): calculated mass 520.5, measured mass 521.0[ M + H (M, 1H): calculated mass]⁺(retention time: 0.676 minutes).

Example 363

N- (5- (5- (3-amino-1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) ethanesulfonamide

The compound was prepared from the compound of example 200(b) using the method of example 200(c) to give the title product in 12% yield (8 mg).¹HNMR(300MHz,CD₃OD is 8.89(s,1H),7.90(s,1H),7.78-7.74(M,2H),7.65-7.54(M,4H),7.51(d,1H),7.15-7.05(M,2H),3.81(s,3H),3.31-3.24(q,2H),1.39-1.34(t,3H), LC-MS (ESI) calculating mass 508.54, measured mass 509.0[ M + H ] M + ESI]+ (Retention time: 0.85 min).

Example 364

(Z) -N- (2',4' -difluoro-5- (5- (1- (hydroxyimino) ethyl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) cyclopropanesulfonamide

To N- (5- (5-acetyl-1H-benzo [ d ]]Imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl]-3-yl) cyclopropanesulfonamide (110mg,0.235mmol) in ethanol hydroxylamine hydrochloride (24.7mg,0.353mmol) was added and the mixture was heated at 80 ℃ for 2 hours. The mixture was concentrated in vacuo and washed with diethyl ether to give the product in 49% yield (55 mg). ¹HNMR(400MHz,DMSO-d₆) 9.00(s,1H),8.03(s,1H),7.82-7.70(M,3H),7.60-7.58(d,2H),7.52(s,1H),7.46-7.40(M,1H),7.27-7.24(M,1H),2.86-2.83(M,1H),2.25(s,3H),1.01-1.00(M,4H), LC-MS (ESI), calculated mass 482.5, measured mass 483.1[ M + H (M + H) ], and measured mass 483.1]⁺(retention time: 1.475 minutes).

Example 365

2- (5- (1- (5-acetylamino-2 ',4' -difluoro- [1,1' -biphenyl ] -3-yl) -1H-benzo [ d ] imidazol-5-yl) -1H-1,2, 3-triazol-1-yl) acetamide

a)2- (5- (1- (5-acetylamino-2 ',4' -difluoro- [1,1' -biphenyl ] -3-yl) -1H-benzo [ d ] imidazol-5-yl) -1H-1,2, 3-triazol-1-yl) acetic acid ethyl ester

A mixture of N- (5- (5-ethynyl-1H-benzo [ d ] imidazol-1-yl) -2',4' -difluorobiphenyl-3-yl) acetamide (258mg,0.6mmol), ethyl 2-azidoacetate (180mg,0.8mmol,1.3eq.), sodium ascorbate (125mg,0.6mmol,1.0eq.), and copper sulfate pentahydrate (80mg,0.32mmol,0.5eq.) in tert-butanol and water (1:1,3ml) was stirred at room temperature for 12 hours. The mixture was quenched with water and the precipitate formed was filtered and dried to give the product in 75% yield (250 mg).

b)2- (5- (1- (5-acetylamino-2 ',4' -difluoro- [1,1' -biphenyl ] -3-yl) -1H-benzo [ d ] imidazol-5-yl) -1H-1,2, 3-triazol-1-yl) acetic acid

To a solution of the compound from example 365(a) (250mg,0.48mmol) in THF/methanol/water (1:1:0.5,5ml) was added LiOH ₂O (40mg,0.968mmol,2eq.) and the mixture was stirred at room temperature for 12 hours. The mixture was concentrated and the resulting crude product was extracted with ethyl acetate and water and dried over sodium sulfate to give the product in 42% yield (100 mg).

c)2- (5- (1- (5-acetylamino-2 ',4' -difluoro- [1,1' -biphenyl ] -3-yl) -1H-benzo [ d ] imidazol-5-yl) -1H-1,2, 3-triazol-1-yl) acetamide

To a solution of the compound from example 365(b) (100mg,0.2mmol) in DMF was added HOBt (30mg,0.224mmol,1.1eq.) followed by EDC (40mg,0.224mmol,1.1 eq.). The mixture was stirred at room temperature for 12 hours, then 25% aqueous ammonia solution was added to the pre-cooled reaction and stirred for 4 hours. The mixture was then quenched and extracted as described in example 1 (d). Evaporation of the solvent gave a crude residue which was purified by preparative TLC to give the product in 5% yield (5 mg).

Example 366

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

This compound was prepared from the compound from example 2(a) (50mg,0.125mmol) in THF using the method of example 2(b) and 2-chloroethanesulfonyl chloride (30mg,0.187mmol,1.5eq.) to give the product in 29% yield (18 mg). ¹HNMR(400MHz,CD₃OD):9.1(s,1H),8.08(s,1H),7.98(s,1H),7.92(s,1H),7.76-7.74(M,2H),7.63-7.59(M,3H),7.50(s,1H),7.14-7.12(M,2H),6.80-6.78(M,1H),6.31-6.27(d,1H),6.09-6.06(d,1H),3.95(s,3H), LC-MS (ESI) calculating mass 491.5, measured mass 492.1[ M + H [ ]]⁺(retention time: 1.413 minutes).

Example 367

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

a)2- (benzyloxy) -N- (2',4' -difluoro-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) ethanesulfonamide

This compound was prepared from the compound from example 2(a) (100mg,0.249mmol) in THF using the method of example 2(b) and 2- (benzyloxy) ethanesulfonyl chloride (87mg,0.374mmol,1.5eq.) to give the product in 69% yield (100 mg). LC-MS (ESI) calculated mass: 512.55, measured mass: 513.1[ M + H ] + (retention time: 0.632 min).

b) N- (2',4' -difluoro-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) -2-hydroxyethanesulfonamide

To a solution of the compound from example 367(a) (100mg,0.17mmol) in methanol (2ml) and THF (1ml) were added 10% Pd/C (10mg,0.1eq.) and palladium hydroxide on carbon (10mg,0.1 eq). N for reaction vessel₂And purifying for 5 minutes. Then the mixture is taken up with H ₂Hydrogenation for 12 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated to give the compound in 13% yield (11 mg).¹HNMR(400MHz,DMSO-d₆) 10.3(s,1H),8.9(s,1H),8.23(s,1H),8.00-7.97(d,2H),7.76-7.58(m,5H),7.48(s,2H),7.29(d,1H),3.88(s,3H),3.81(t, 4H). LC-MS (ESI) calculated mass 509.53 and measured mass 510.1[ M + H ]]⁺(retention time: 0.853 minutes).

Example 368

N- (2',4' -difluoro-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) piperidine-4-carboxamide

The title compound was prepared from the compound of example 2(a) using the method of example 240.¹HNMR(400MHz,CD₃OD: 8.49(s,1H),8.11(s,1H),8.0(s,1H),7.91(s,1H),7.86(s,1H),7.75(s,1H),7.71(s,1H),7.69(s,1H),7.65-7.59(M,2H),7.52(M,1H),7.14-7.1(M,2H),3.94(s,1H),2.89(t,4H),2.7(M,1H),2.04-1.84(M,4H): LC-MS (ESI). The mass: 512.55 is calculated, and the measured mass: 513.2[ M + H ] (LC-ESI)]⁺(retention time: 1.0 min).

Example 369

N- (5- (5- (4, 5-dihydro)Oxazol-2-yl) -1H-benzo [ d]Imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl]-3-yl) acetamide

a) N- (5- ((4- (4, 5-dihydro)Azol-2-yl) -2-nitrophenyl) amino) -2',4' -difluoro- [1,1' -biphenyl]-3-yl) acetamide

To a solution of the compound from example 22(a) (0.25g,0.608mmol) in tert-butanol was added 2-aminoethanol (0.05ml,0.912mmol,1.5eq.) and stirred at room temperature for 30 min. Iodine (0.25g,1.82mmol,3eq.) and K were added ₂CO₃(0.25g,1.82mmol,3eq.) and the mixture was stirred at 75 ℃ for 24 h. The mixture was quenched with sodium thiocyanate solution and extracted with ethyl acetate (3X 50 ml). Evaporation of the solvent gave a crude residue which was purified by Combiflash chromatography (5% methanol in chloroform) to give the product in 60% yield (0.15 g).

b) N- (5- ((2-amino-4- (4, 5-dihydro)Oxazol-2-yl) phenyl) amino) -2',4' -difluoro- [1,1' -biphenyl]-3-yl) acetamide

To a solution of the compound from example 369(a) (150mg,0.33mmol) in THF (3ml) was added a solution of ammonium chloride (70mg,1.32mmol,4eq.) in water (1ml) and zinc (86mg,1.32mmol,4 eq.). The mixture was stirred at room temperature for 2 hours and filtered. The filtrate was diluted with water and extracted as described in example 1 (d). Evaporation of the solvent gave the product in 78% yield (0.11 g).

c) N- (5- (5- (4, 5-dihydro)Oxazol-2-yl) -1H-benzo [ d]Imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl]-3-yl) acetamide

The compound was prepared from the compound of example 369(b) using the method of example 22(d) to give the product in 78% yield (0.11 g).¹HNMR(400MHz,DMSO-d₆) 10.5(s,1H),8.84(s,1H),8.7(d,1H),8.13(t,1H),8.10-8.05(m,3H),7.85-7.72(m,3H),7.54(s,1H),7.49-7.43(m,1H),4.47(t,2H),3.31(t,2H),2.12(s, 3H). LC-MS (ESI) calculated mass 432.4 and measured mass 432.8M + H ]⁺(retention time: 0.288 minutes).

Example 370

N-(5-(5-(1,2,4-Oxadiazol-3-yl) -1H-benzo [ d]Imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl]-3-yl) acetamide

This compound was prepared from the compound of example 313(d) using the procedure of example 313 (e).¹HNMR(400MHz,DMSO-d₆) 10.49(s,1H),9.73(s,1H),8.83(s,1H),8.43(s,1H),8.06(t,2H),7.88(t,2H),7.79-7.73(M,1H),7.55(s,1H),7.49-7.43(M,1H),7.29-7.25(M,1H),2.12(s,3H), LC-MS (ESI) calculating mass: 431.4, measured mass: 432.8[ M + H + M ] measured mass]⁺(guarantee)Retention time: 1.485 minutes).

Example 371

N- (5- (5- (4, 5-dihydro)Oxazol-2-yl) -1H-benzo [ d]Imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl]-3-yl) ethanesulfonamide

The compound was prepared from the compound of example 369 using the method of example 2.¹HNMR(300MHz,CD₃OD) 8.59(s,1H),8.27(d,1H),8.15-8.14(t,1H),8.11(m,1H),7.82-7.75(m,4H),7.66-7.56(m,1H),7.56(m,1H),7.13-7.11(m,1H),6.56(t,1H),3.53-3.47(m,2H),3.0(m,2H),2.82(s,3H),2.7(m,1H),2.14-2.0(m, 4H). LC-MS (ESI) calculated mass 512.55 and measured mass 513.1[ M + H]⁺(retention time: 0.632 minutes).

Example 372

1- (2',4' -difluoro-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) -3- (furan-2-ylmethyl) sulfuric acid diamide

The compound was prepared from the compound of example 2(a) using the procedure of example 245 to give the pure product in a yield of 10% (7 mg).¹HNMR(300MHz,DMSO-d₆) 10.26(s,1H),8.66(s,1H),8.2(s,1H),7.98(s,1H),7.94(s,1H),7.75-7.67(M,2H),7.57(t,3H),7.45-7.43(M,2H),7.29-7.25(M,2H),7.22(M,2H),3.87(s,3H),3.17(s,2H), LC-MS (ESI), 479.5, 480.2[ M + H ] for measured mass]⁺(retention time: 1.34 minutes).

Example 373

N- (2',4' -difluoro-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) -1-methylpiperidine-4-carboxamide

The compound was prepared from the compound of example 2(a) using the method of example 233.¹HNMR(400MHz,CD₃OD: 9.11(s,1H),8.23(t,1H),8.07(s,1H),7.98(s,1H),7.91(s,1H),7.80-7.77(M,3H),7.65-7.61(M,2H),7.14-7.12(M,2H),3.96(s,3H),3.63-3.60(M,2H),3.088-3.082(M,2H),2.90(s,3H),2.79-2.73(M,1H),2.24-2.01(M,4H), LC-MS (ESI): 526.58; measured mass: 527.2[ M + H ], (M, 1H): 527.]⁺(retention time: 0.183 min).

Example 374

2',4' -difluoro-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-ol

a) 1-bromo-3-methoxy-5-nitrobenzene

To a solution of 1-bromo-3, 5-dinitrobenzene (5g,20.2mmol) in methanol (50ml) was added sodium methoxide (1.3g,24.3mmol,1.2eq.) and the mixture was heated under reflux for 12 hours, then the reaction was quenched with 10% HCl. The solid formed was filtered and dried to give the compound in 65% yield (3 g).

b) 3-bromo-5-methoxyaniline

To a solution of 1-bromo-3-methoxy-5-nitrobenzene (1g,4.33mmol) in THF (10ml) was added a solution of ammonium chloride (1.83g,34.6mmol,8eq.) in water (5ml) and zinc (1.93g,34.6mmol,8 eq.). The mixture was stirred at room temperature for 30 minutes and filtered. The filtrate was diluted with water and extracted as described in example 1 (d). Evaporation of the solvent gave the product in 92% yield (0.8 g).

c) N- (3-bromo-5-methoxyphenyl) -4- (1-methyl-1H-pyrazol-4-yl) -2-nitroaniline

A solution of the compound from example 374(b) (1g,4.78mmol,1.2eq.) and 3-bromo-5-methoxyaniline (0.8g,3.98mmol) and potassium fluoride (0.23g,3.98mmol,1eq.) in DMF was heated at 120 ℃ for 12 h. The mixture was quenched and extracted as described in example 1 (d). 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 product in 42% yield (0.81 g).

d)1- (3-bromo-5-methoxyphenyl) -5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazole

This compound was prepared using the procedures of examples 1(g) and 1(h) using the compound from example 374(c) (0.81g,2.02mmol) as the starting material and was obtained in 52% yield (0.35 g).

e)1- (2',4' -difluoro-5-methoxy- [1,1' -biphenyl ] -3-yl) -5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazole

Prepared from the compound from example 374(d) (0.35g,0.92mmol) using the method of example 277(d) and 2, 4-difluorophenylboronic acid (0.17g,1.09mmol,1.2eq.) to give the product in 25% yield (95 mg).

f)2',4' -difluoro-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-ol

To a slurry of aluminium chloride (77mg,0.576mmol) and thiourea (15mg,0.192mmol) in DCM (5ml) was added a solution of the compound from example 374(e) (80mg,0.192mmol) in DCM (3 ml). The mixture was heated at 50 ℃ for 5 hours. The mixture was quenched and extracted as described in example 2(d) with anhydrous Na₂SO₄Drying and concentration gave the product in 17% yield (15 mg).¹HNMR(400MHz,CD₃OD) 9.2(s,1H),8.07(s,1H),7.99(s,1H),7.91(s,1H),7.77(s,2H),7.64-7.58(m,1H),7.30(s,1H),7.17-7.07(m,4H),3.95(s, 3H). LC-MS (ESI) mass calculated 402.4 and measured mass 403.1[ M + H ]]⁺(retention time: 1.282 minutes).

Example 375

N- (2',4' -difluoro-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) pyrazin-2-amine

A solution of the compound from example 2(a) (100mg,0.24mmol) in toluene (6ml) was passed through N₂Bubbling and degassing for 5 minutes. 2-chloropyrazine (34g,0.29mmol,1.2eq.) was added and the mixture was degassed for an additional 5 minutes. Followed by the addition of Pd ₂(dba)₃(22mg,0.02mmol,0.1eq.), Xantphos (28mg,0.04mmol,0.2eq.), and Cs₂CO₃(242mg,0.74mmol,3.0eq) and the mixture was further degassed for 5 minutes and then heated at 110 ℃ for 16 hours. The mixture was filtered over a celite bed, the reaction was terminated and extracted as described in example 1 (d). Evaporation of the solvent gave a crude residue which was purified by preparative HPLC to give the product in 10% yield (11 mg).¹HNMR(400MHz,DMSO-d₆) 9.99(s,1H),8.65(s,1H),8.31(s,1H),8.26-8.25(m,1H),8.19(m,2H),8.00-7.98(m,3H),7.93(s,1H),7.85(d,1H),7.79-7.34(m,2H),7.62-7.59(dd,1H),7.47-7.4(m,2H),7.28-7.24(dt,1H),3.87(s, 3H). LC-MS (ESI) for calculating mass 479.48 and measured mass 480.1M + H]⁺(retention time: 1.54 minutes).

Example 376

N- (2',4' -difluoro-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d]Imidazol-1-yl) - [1,1' -biphenyl]-3-yl) isoAzole-3-amines

a)1- (5-bromo-2 ',4' -difluoro- [1,1' -biphenyl ] -3-yl) -5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazole

To a solution of the compound from example 2(a) (0.80g,1.995mmol) in HBr (8ml) was added NaNO₂Aqueous solution (0.26g of 2ml aqueous solution) and the mixture was stirred at 0 ℃ for 20 minutes. A solution of CuBr in HBr (0.572g,3.99mmol,2.0eq in 3ml HBr) was then added at 0 ℃ and the mixture was stirred at 50 ℃ for 10 min. The mixture was quenched and extracted as described in example 1 (d). The solvent was evaporated under reduced pressure to give the product in 80.9% yield (0.750 g). LC-MS (ESI) with calculated mass of 465.2 and measured mass of 467.0M + H ]⁺(retention time: 1.75 minutes).

b) N- (2',4' -difluoro-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d]Imidazol-1-yl) - [1,1' -biphenyl]-3-yl) isoAzole-3-amines

This compound was prepared from the compound of example 376(a) according to the method of example 280.¹HNMR(400MHz,CD₃OD) 8.53(s,1H),8.43-8.42(d,1H),8.03(s,1H),7.95-7.93(m,2H),7.89(s,1H),7.76-7.45(d,1H),7.68-7.62(m,3H),7.33-7.32(d,1H),7.16-7.11(m,2H),6.23-6.22(d,1H),6.23-6.27(m,1H),3.97(s, 3H). LC-MS (ESI) for calculating mass 468.46 and measured mass 468.46M + H]⁺(retention time: 1.282 minutes).

Example 377

N- (2',4' -difluoro-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) pyridazin-3-amine

This compound was prepared from the compound of example 376(a) according to the method described for example 280.¹HNMR(400MHz,DMSO-d₆) 9.75(s,1H),8.74-8.73(d,2H),8.65(s,1H),8.34-8.33(m,1H),8.19(s,1H),7.98(s,1H),7.94(m,2H),7.78-7.75(m,2H),7.6-7.57(dd,1H),7.53-7.4(m,3H),7.4-7.2(m,2H),3.87(s, 3H). LC-MS (ESI) calculated mass 479.48 and measured mass 403.1[ M + H ]]⁺(retention time: 1.282 minutes).

Example 378

N- (4 '-cyano-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) cyclopropanesulfonamide

a) 3-bromo-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) aniline

To a solution of the compound from example 277(c) (1.6g,3.89mmol) in ethanol (15ml) was added aqueous sodium hydroxide (1.56g,38.9mmol,10.0eq.) and the mixture was heated at 85 ℃ for 5 hours. The mixture was quenched and extracted as described in example 1 (d). The solvent was evaporated under reduced pressure to give the product in 90% yield (1.3 g).

b) N- (3-bromo-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) cyclopropanesulfonamide

To a solution of the compound from example 378(a) (200mg,0.54mmol) in DCM was added pyridine (86mg,1.08mmol,2.0eq.) followed by cyclopropanesulfonyl chloride (93mg,0.65mmol,1.2 eq.). The mixture was stirred for 1 hour, the reaction was terminated and extracted as described in example 2 (b). The solvent was evaporated under reduced pressure to give the product in 59% yield (75 mg).

c) N- (4 '-cyano-5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) cyclopropanesulfonamide

Prepared from the compound of example 378(b) (100mg,0.21mmol) using the method of example 200(c) and 4-cyanophenylboronic acid (38mg,0.32mmol,2.5eq.) to give the product in 24% yield (25 mg). ¹HNMR(400MHz,DMSO-d₆) 10.2-10.3(brs,1H),8.71(s,1H),8.19(s,1H),8.02-7.94(m,6H),7.77(s,1H),7.69-7.67(d,1H),7.6-7.58(m,3H),3.87(s,3H),2.91-2.88(m,1H),1.0(d, 4H). LC-MS (ESI) for calculating mass 494.59 and measured mass 495.15M + H]⁺(retention time: 1.4 minutes).

Example 379

N- (2',4' -difluoro-5- (5- (4-methylpiperazine-1-carbonyl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) acetamide

To a solution of the compound from example 332(b) (100mg,0.23mmol,1.0eq.) in 1, 4-dioxane (5ml) was added trimethylaluminum (49mg,0.59mmol,2.5 eq). The mixture was stirred for 10 minutes, then N-methylpiperazine (35mg,0.35mmol,1.5eq.) was added and the mixture was heated in a sealed test tube at 110 ℃ for 12 hours. Cooling the mixture to room temperature and filtering through celite, concentrating the filtrate to obtainTo the crude product, it was purified by preparative HPLC to give the product in 21% yield (24 mg).¹HNMR(400MHz,CD₃OD) 8.61(s,1H),8.1(s,1H),7.86(s,1H),7.79.7.77(d,1H),7.75(d,1H),7.68-7.6(m,1H),7.51(d,1H),7.48-7.46(d,1H),7.14-7.08(m,2H),3.8-3.5(br,4H),2.6-2.4(br,4H),2.35(s,3H),2.18(s, 3H). LC-MS (ESI) calculated mass 489.52 and measured mass 489.8M + H]⁺(retention time: 0.15 minutes).

Example 381

N- (5- (5-cyano-1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) ethanesulfonamide

a)1- (5-amino-2 ',4' -difluoro- [1,1' -biphenyl ] -3-yl) -1H-benzo [ d ] imidazole-5-carbonitrile

To a solution of the compound from example 313(c) (1.0g,2.88mmol,1.0eq.) in ethanol (20ml) was added a 20% aqueous solution of KOH (0.486g,8.66mmol,3.0eq.) and the mixture was heated at 80 ℃ for 6 hours. The solvent was evaporated under reduced pressure and the crude product was stirred with water and ethyl acetate. The ethyl acetate layer was dried over sodium sulfate and concentrated to give the product in 78% yield (0.7 g).

b) N- (5- (5-cyano-1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) ethanesulfonamide

The compound was prepared from the compound of example 380(a) (100mg,0.28mmol) and ethanesulfonyl chloride (40mg,0.31mmol,1.1eq.) using the procedure of example 2(b) to give the product in 16% yield (22 mg).¹HNMR(400MHz,DMSO-d₆) 8.91(s,1H),8.4(s,1H),7.86-7.73(m,3H),7.58-7.45(m,4H),7.29-7.25(t,1H),3.3(m,2H),1.27-1.24(t, 3H). LC-MS (ESI) for calculating mass 438.45 and measured mass 438.9M + H]⁺(retention time: 1.5 minutes).

Example 381

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

a)2, 4-difluoro-5 '-methyl-3' -nitro-biphenyl

Prepared from 1-bromo-3-methyl-5-nitro-benzene (1.5g,6.94mmol) and difluorophenylboronic acid (1.3g,8.33mmol,1.2eq.) using the method of example 1(d) to give the product in 27% yield (0.65 g).

b)2',4' -difluoro-5-methyl- [1,1' -biphenyl ] -3-amine

To a solution of the compound from example 381(a) (1.4g,5.62mmol) in THF (20ml) was added a solution of ammonium chloride (2.4g,44.9mmol,8eq.) in water (8ml) and zinc (2.92g,44.9mmol,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 example 1 (d). Evaporation of the solvent gave the product in 92% yield (1.3 g).

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

This compound was prepared from the compound of example 381(b) (1.3g,5.93mmol) using the procedures of example 1 steps (f) through (i) to give the product in 10% yield (20 mg).¹HNMR(400MHz,DMSO-d₆) 8.96(s,1H),8.24(s,1H),8.00-7.97(d,2H),7.77-7.72(m,2H),7.67-7.62(m,3H),7.53(s,1H),7.5-7.4(t,1H),7.3-7.2(t,1H),3.9(s, 6H). LC-MS (ESI) calculated mass 400.42 and measured mass 401.1[ M + H ]]⁺(retention time: 1.6 minutes).

Example 382

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

The compound was prepared from the compound of example 277(c) using the procedure described in example 277 (d).¹HNMR(400MHz,DMSO-d₆):9.1(s,1H),8.65(d,1H),8.25(s,1H),8.22(s,1H),8.17(s,1H),8.03(s,1H),7.98(s,2H),7.94-7.92(d,1H),7.81-7.8(d,1H),7.77-7.5(d,1H),7.7-764(m,4H),6.59(s,1H),2.1(s, 1H). LC-MS (ESI) calculated mass 473.53 and measured mass 474.2[ M + H ]]⁺(retention time: 0.47 minutes).

Example 383

N- (5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -4'- (1H-pyrrol-1-yl) - [1,1' -biphenyl ] -3-yl) acetamide

The compound was prepared from the compound of example 277(c) using the procedure described in example 277 (d).¹HNMR(400MHz,DMSO-d₆) 8.71(s,1H),8.2(s,1H),8.03(s,1H),7.99(s,1H),7.94-7.93(M,2H),7.86-7.83(M,2H),7.76-7.68(M,4H),7.6-7.48(M,3H),6.3(d,1H),3.88(s,3H),2.14(s,3H) LC-MS (ESI), calculated mass 472.54, measured mass 473.1[ M + H ], (S,1H), calculated mass 473.1]⁺(retention time: 1.39 minutes).

Example 384

N- (2',4' -difluoro-5- (5- (morpholin-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) cyclopropanesulfonamide

The compound is prepared from N- (5- (5-bromo-1H-benzo [ d)]Imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl]-3-yl) cyclopropanesulfonamide was prepared using the procedure described in example 321.¹HNMR(400MHz,DMSO-d₆) 10.38(s,1H),9.0(s,1H),7.79-7.73(M,1H),7.67(s,1H),7.64(s,1H),7.61(s,1H),7.53-7.46(M,2H),7.33-7.26(M,3H),3.9(s,4H),3.2(s,4H),2.9(M1H),1.05(d,4H): LC-MS (ESI), calculated mass 510.56, measured mass 473.1[ M + H ] ESI ]⁺(retention time: 1.39 minutes).

Example 385

(E) -N- (2',4' -difluoro-5- (5- (1- (methoxyimino) ethyl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) cyclopropanesulfonamide

The compound is prepared from N- (5- (5-acetyl)radical-1H-benzo [ d]Imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl]-3-yl) cyclopropanesulfonamide was prepared using the procedure described in example 364.¹HNMR(400MHz,DMSO-d₆) 8.69(s,1H),9.0(s,1H),8.03(d,1H),7.76-7.67(m,3H),7.54(m,2H),7.47(m,1H),7.45-7.42(m,2H),7.28-7.22(m,3H),7.25-7.24(dt,1H),3.92(s,3H),2.84-2.81(m,1H),2.26(s,3H),1.0(d, 4H). LC-MS (ESI) for calculating mass 496.53 and measured mass 497.0M + H]⁺(retention time: 1.68 minutes).

Example 386

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

The compound is prepared from N- (5- (5-bromo-1H-benzo [ d)]Imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl]-3-yl) cyclopropanesulfonamide was prepared using the procedure described in example 200 (c).¹HNMR(400MHz,DMSO-d₆) 8.4(s,1H),8.33(s,1H),8.03(s,1H),7.98(s,1H),7.8-7.7(m,1H),7.69(s,1H),7.61(m,2H),7.5-7.4(m,2H),7.32-7.25(dt,1H),4.8-4.65(m,1H),2.95-2.15-1.6(m,8H),1.02(d, 4H). LC-MS (ESI) calculated mass 559.63 and measured mass 560.3[ M + H ] ]⁺(retention time: 1.19 minutes).

Example 387

N- (2',4' -difluoro-5- (5- (2-oxopyrrolidin-1-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) cyclopropanesulfonamide

Reacting N- (5- (5-bromo-1H-benzo [ d ]]Imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl]A DMSO (2ml) solution of-3-yl) cyclopropanesulfonamide (50mg,0.099mmol,1eq.) was degassed by nitrogen bubbling for 10 minutes. Copper (I) iodide (11.3mg,0.059mmol,0.6eq.) and K were added₂CO₃(42mg,0.298mmol,3eq.) N, N-dimethylglycine HCl (11mg,0.079mmol) and 2-pyrrolidone (42mg,0.49mmol,5eq.) and the mixture was further degassed for 10 minutes and then heated at 110 ℃ for 16 hours. Cooling the mixtureCool to room temperature and dilute with ethyl acetate, filter through a bed of celite and wash with water and brine solution. The ethyl acetate layer was dried over sodium sulfate. Evaporation of the solvent gave a crude residue which was purified by preparative HPLC to give the product in 90% yield (45 mg).¹HNMR(400MHz,DMSO-d₆) 8.65(s,1H),7.96(d,1H),7.78-7.65(M,3H),7.54(M,2H),7.45-7.42(M,2H),7.28-7.24(dt,1H),3.9(t,2H),2.88-2.8(M,1H),2.12-2.02(M,2H),1.0(M,4H): LC-MS (ESI): calculated mass: 508.54; measured mass: 508.7[ M + H ], (M, 2H): LC-MS (ESI): measured mass: 508.7]⁺(retention time: 1.46 minutes).

Example 388

N- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (1H-pyrazol-4-yl) phenyl) acetamide

The compound was prepared from the compound of example 277(c) using the procedure described in example 277 (d).¹HNMR(400MHz,DMSO-d₆) 10.3(s,1H),8.61(s,1H),8.2(s,1H),8.11(br,1H),7.98(s,1H),7.94(s,1H),7.88(s,1H),7.76(s,1H),7.66-7.57(M,3H),3.88(s,3H),1.84(s,3H): LC-MS (ESI): calculated mass: 397.43; measured mass: 398.22[ M + H ] (M + H): LC-MS (ESI): calculated mass: 397.43; measured mass: 398.22]⁺(retention time: 1.46 minutes).

Example 389

The compound was prepared from the compound of example 277(c) using the procedure described in example 277 (d).¹HNMR(400MHz,DMSO-d₆) 10.5(s,1H),8.97(s,1H),8.76(s,1H),8.59(s,1H),8.58(s,1H),8.24(s,1H),8.2(s,1H),8.02(s,1H),7.97-7.96(M,2H),7.8-7.65(M,4H),3.89(s,3H),2.13(s,3H), LC-MS (ESI), calculated mass 426.45, measured mass 427.1[ M + H ], calculated mass 427.1]⁺(retention time: 0.26 min).

Example 390

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

To a solution of the compound from example 326 (50mg,0.116mmol) in DCM was added pyridine (0.5ml) followed by cyclopropanesulfonyl chloride (20mg,0.139mmol,1.2 eq.). The mixture was stirred for 1 hour, the reaction was terminated and extracted as described in example 2 (b). Evaporation of the solvent gave a crude residue which was purified by preparative HPLC to give the product in 90% yield (42 mg). ¹HNMR(400MHz,CD₃OD: 8.58(s,1H),8.52(s,1H),8.33(s,1H),8.09(s,1H),8.05(s,1H),7.74-7.62(M,4H),7.49(s,1H),7.17-7.08(M,2H),3.0(M,1H),2.2(s,3H),1.1(d,4H), LC-MS (ESI): calculated mass: 533.5; measured mass: 534.1[ M + H ESI ]]⁺(retention time: 1.61 minutes).

Example 391

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

The compound is prepared from N- (2 '-fluoro-5-nitro- [1,1' -biphenyl)]-3-yl) acetamide was prepared using the procedures of examples 1, 2 and 200(c) to give the product in 26.6% yield (20 mg).¹HNMR(400MHz,CD₃OD is 8.52(s,1H),8.03(s,1H),7.94(s,1H),7.89(s,1H),7.71-7.69(M,1H),7.65-7.6(M,5H),7.53-7.49(M,2H),7.35-7.25(M,2H),3.96(s,3H),2.78-2.73(M,1H),1.17-1.0(M,4H), LC-MS (ESI) is calculated as 487.55, and measured as 488.6[ M + H ] is calculated as 487.55]⁺(retention time: 1.45 minutes).

Example 392

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

a)4- (4- (1- (5- (cyclopropanesulfonamido) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) -1H-benzo [ d ] imidazol-5-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester

Prepared from N- (5- (5-bromo-1H-benzo [ d ] imidazol-1-yl) -2',4' -difluoro- [1,1' -biphenyl ] -3-yl) cyclopropanesulfonamide (100mg,0.19mmol) using the method of example 200(c), the title product was obtained in 26.6% yield (20 mg).

b) N- (2',4' -difluoro-5- (5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) - [1,1' -biphenyl ] -3-yl) cyclopropanesulfonamide

The compound was prepared from the compound of example 392(a) (60mg,0.08mmol) using the procedure of 331(b) to give the product in 40% yield (0.020 g).¹HNMR(400MHz,DMSO-d₆) 8.64(s,1H),8.30(s,1H),8.03(s,1H),7.90(s,1H),7.76-7.74(M,1H),7.69-7.62(M,2H),7.54-7.53(t,1H),7.49(s,1H),7.46-7.43(M,1H),7.27(t,3H),4.23(M,1H),3.12-3.09(d,2H),2.81(M,1H),2.70-2.64(t,2H),2.04-2.01(d,2H),1.88-1.84(M,2H),1.23(s,2H),1.00-0.99(M,2H),0.97(s,1H), LC-ESI: (8584): calculated mass: 3585M, 83: (M,2H), calculated mass: (LC-ESI): 8584: (M, 3H): 574.20: (M,2H)]⁺(retention time: 0.27 min).

Example 393

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

This compound was prepared using the procedure of example 392.¹HNMR(400MHz,DMSO-d₆) 8.64(s,1H),8.33(s,1H),8.03(s,1H),7.98(s,1H),7.78-7.72(q,1H),7.69-7.62(q,2H),7.55-7.52(d,2H),7.48-7.42(M,2H),7.30-7.25(M,1H),4.87-4.82(M,1H),3.34-3.16(M,2H),3.14-2.94(M,3H),2.93-2.80(M,2H),2.26-2.21(M,1H),2.14-2.07(M,1H),1.01-0.98(d,4H), LC-MS (ESI), calculated mass: 560.62, measured mass: 561.m + H3H ]⁺(retention time: 0.39 minutes).

Example 394

The compound was prepared from the compound of example 1(h) using the method of example 253.¹HNMR(300MHz,DMSO-d₆) 10.46(s,1H),8.86(s,1H),8.07(s,1H),7.95(s,1H),7.81-7.71(M,3H),7.59(d,1H),7.51-7.40(M,3H),7.33-7.24(M,2H),6.88-6.82(M,1H),5.25(brs,2H),2.12(s,3H), LC-MS (ESI), calculated mass 472.15, measured mass 473.5[ M + H, 2H ], and mass of]⁺(retention time: 1.47 minutes).

Example 395

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

The compound was prepared from the compound of example 2(a) using the method of example 233.¹HNMR(300MHz,DMSO-d₆) 10.37(s,1H),8.89(s,1H),8.23(s,1H),8.14(s,1H),8.01(s,1H),7.97(s,1H),7.89(s,1H),7.76-7.72(M,2H),7.66-7.64(M,2H),7.6(s,1H),7.49-7.44(M,1H),7.31-7.26(dt,1H),3.88(s,3H),3.46(s,3H),3.5-3.4(br,2H),3.16(s,4H),2.8(s,4H), LC-MS (ESI) calculated mass 541.59, measured mass 542.1[ M + H ] (M + H) ], LC-MS (ESI)]⁺(retention time: 0.1 min).

Example 396

N- (3- (5-fluoropyridin-2-yl) -5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) cyclopropanesulfonamide

a) N- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) acetamide

A solution of the compound from example 277(c) (0.9g,2.2mmol) in 1, 4-dioxane (20ml) was passed through N₂Bubbling and degassing for 5 min. Bis (pinacolato) diboron (0.67g,0.1855mmol,1.2eq.) was added and degassing of the mixture continued for 5 minutes. Followed by the addition of Pd (dppf) Cl₂(0.0107g,0.0131mmol,0.05eq.) and potassium acetate (0.539g,5.49mmol,2.5eq.) and the mixture was further degassed for 5 minutes and then heated at 100 ℃ for 12 hours. The mixture was quenched and extracted as described in example 1 (d). The solvent was distilled off to give a crude residue, which was washed with hexane to give the title crude product (1.1 g).¹HNMR (300MHz, DMSO-d6):10.31(s,1H),8.58(s,1H),8.19-8.18(M,1H),7.98-7.94(M,3H),7.58(M,2H),7.49(M,1H),3.89(s,3H),2.10(s,3H),1.33(s,6H),1.17(s,6H), LC-MS (ESI): calculated mass 457.23 and measured mass 457.90[ M + H + 6H ], (ESI)]⁺(retention time: 0.480-0.493 minutes).

b) N- (3- (5-fluoropyridin-2-yl) -5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide

A solution of 2-bromo-5-fluoropyridine (0.2g,1.136mmol) in 1, 2-dimethoxyethane (16ml) was passed through N ₂Bubbling and degassing for 5 minutes. The compound from example 396(a) (1.03g,2.253mmol,2.0eq.) was added and the mixture was degassed for an additional 5 minutes. Followed by the addition of Pd (dppf) Cl₂(0.0463g,0.0567mmol,0.05eq.) and aqueous sodium carbonate (0.3g,2.83mmol,2.5eq.) and the mixture was further degassed for 5 minutes and then heated at 90 ℃ for 3 hours. The mixture was quenched and extracted as described in example 1 (d). Evaporation of the solvent gave a crude residue which was purified by column chromatography (60-120 silica gel, 3% methanol in DCM) to give the title product in 52% yield (250 mg).¹HNMR (400MHz, DMSO-d6):8.59(m,1H),8.53(s,1H),8.19(m,1H),8.13(m,1H),8.03-8.01(m,1H),7.96-7.91(m,1H),7.88(m,1H),7.76-7.71(m,1H),7.65-7.57(m,3H),7.56-7.48(m,1H),3.89(s,3H),2.10(s, 3H). LC-MS (ESI) for calculating mass 426.16, and measured mass 427.1M + H]⁺(retention time: 0.491 min).

c)3- (5-Fluoropyridin-2-yl) -5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) aniline

To a solution of the compound from example 396(b) (250mg,0.586mmol) in ethanol (30ml) was addedAqueous sodium hydroxide (230mg,5.75mmol,10eq.) and the mixture was heated at 85 ℃ for 16 h. The mixture was quenched and extracted as described in example 1 (d). The solvent was evaporated to give a crude residue which was used in the next step without further purification. The yield thereof was found to be 250 mg. LC-MS (API) calculated mass 384.15 and measured mass 385.2M + H ]⁺(retention time: 0.312 to 0.413 min).

d) N- (3- (5-fluoropyridin-2-yl) -5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) cyclopropanesulfonamide

To a solution of the compound from example 396(c) (250mg,0.651mmol) in THF (15ml) was added pyridine (0.154g,1.946mmol,3.0eq.) followed by cyclopropanesulfonyl chloride (0.11g,0.7746mmol,1.2 eq.). The reaction solution was stirred at room temperature for 12 hours, and the reaction was terminated and extracted as described in example 1 (d). Evaporation of the solvent gave a crude residue which was purified by preparative HPLC to give the product in 5% yield (15.6 mg).¹HNMR(400MHz,DMSO-d₆) 10.25(s,1H),8.74-8.73(d,1H),8.70(s,1H),8.22-8.18(M,2H),8.07-8.00(M,3H),7.94-7.91(M,2H),7.67-7.65(M,1H),7.61-7.59(M,2H),3.87(s,3H),2.84(M,1H),1.01-0.996(M,4H), LC-MS (ESI), calculated mass 488.14, measured mass 489.1[ M + H ] (M,1H)]⁺(retention time: 0.847 to 1.048 minutes).

Abbreviations:

RT-Room temperature

rt-Retention time

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

DMF-N, N-dimethylformamide

THF-tetrahydrofuran

TEA-Triethylamine

DCM-dichloromethane

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-butylamino 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

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

Wherein

Z is CH or N;

g is a radical of the formula

Wherein A is a benzene ring or a 5-12 membered heterocyclic ring, and

R₂is H, halogen, C_1-7Alkyl or oxo;

b is a 5-12 membered carbocyclic or heterocyclic ring selected from any one of the following groups or tautomers thereof

R₄is H, halogen, C_1-7Alkyl or oxo;

m is-NHR₅；

R₅Is H, -C (O) R₇、-SO₂R₈or-C (O) -D-R₉；

R₆Is an optionally substituted 5-6 membered heterocyclic ring;

R₇is C_1-7Alkyl radical, C_2-7Alkenyl radical, C_3-7Cycloalkyl 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；

R₉is phenyl or an optionally substituted 5-6 membered heterocyclic ring;

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

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

R₁₂and R₂₁Is C_1-7An alkyl group;

R₁₃Is C_1-7Alkoxy, amino or hydroxy;

R₁₄is C_1-7Alkyl or C_3-7A cycloalkyl group;

R₁₈and R₁₉Independently is H, C_1-7Alkyl or C_3-7A cycloalkyl group;

R₂₀is phenyl or an optionally substituted 5-6 membered heterocyclic ring;

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

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

X₁and X₂Independently is a bond or C_1-7An alkyl group.

2. The compound of claim 1, wherein ring a is any one of the following groups or tautomers thereof

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

4. The compound of claim 1 or 2, wherein Z is N.

5. The compound of claim 1, wherein

G is a radical of the formula

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;

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_1-7Alkoxy or cyano;

R₄is H or halogen;

m is-NHR₅；

R₅is-C (O) R₇、-SO₂R₈or-C (O) -D-R₉；

R₇Is C_1-7Alkyl radical, C_2-7Alkenyl, -NH-R₁₀or-NH-X₁-R₁₁；

R₈Is C_1-7Alkyl radical, C_2-7Alkenyl radical, C_3-7Cycloalkyl, hydroxy C _1-7Alkyl, -NR₁₈R₁₉、-NH-X₂-R₂₀Phenyl or a group of the formula

R₉Is phenyl or any one of the following groups

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

R₁₁is phenyl, 4-fluorophenyl or any one of the following groups

R₁₈And R₁₉Independently is H, C_1-7Alkyl or C_3-7A cycloalkyl group;

R₂₀is a group

X₁And X₂Independently is a bond or C_1-7Alkyl radical, and

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

6. The compound of claim 1, 2 or 5, wherein B is a ring of formula (1 ") or (6").

7. The compound of claim 1, 2 or 5, wherein A is a ring of formula (1 '), (2'), (4 '), (7'), (10 '), (14'), (16 ') or (20').

8. The compound of claim 1, 2 or 5, wherein B is phenyl, R₃Is halogen and R₄Is H or halogen.

9. The compound of claim 1, 2 or 5, wherein M is-NHC (O) R₇Wherein R is₇Is C_1-7Alkyl radical, C_2-7Alkenyl radical, C_3-7Cycloalkyl, -NH-R₁₀or-NH-X₁-R₁₁Wherein R is₁₀Is C_1-7Alkyl or C_3-7Cycloalkyl radical, X₁Is a bond or C_1-7Alkyl, and R₁₁Is optionally substituted by one or two C_1-7An alkyl-substituted 5-6 membered heterocyclic ring.

10. The compound of claim 1, 2 or 5, wherein M is-NHSO₂R₈Wherein R is₈Is C_1-7Alkyl radical, C_2-7Alkenyl radical, C_3-7Cycloalkyl, phenyl or NR₁₈R₁₉Wherein R is₁₈And R₁₉Independently is H, C _1-7Alkyl or C_3-7A cycloalkyl group.

11. The compound of claim 1, 2 or 5, wherein M is-NHC (O) -D-R₉Wherein D is a bond or C_1-7Alkyl and R₉Is optionally substituted by one or two C_1-7An alkyl-substituted 5-6 membered heterocyclic ring.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

13. Use of a compound according to any one of claims 1 to 11, 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.

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