HK1078779B - Substituted benzazoles and use thereof as raf kinase inhibitors - Google Patents

Description

Substituted indoles and their use as Raf kinase inhibitors

Technical Field

The present invention relates to novel substituted indole-like compounds and pharmaceutically acceptable salts, esters or prodrugs thereof, compositions of the novel compounds and pharmaceutically acceptable carriers, and the novel compounds for use in the prevention or treatment of cancer, either alone or in combination with at least one additional therapeutic agent.

Background

The Raf serine/threonine kinases are essential components of the Ras/mitogen-activated protein kinase (MAPK) signaling module of a complex transcriptional program that controls the response to external cellular stimuli. Raf genes encoding highly conserved serine-threonine specific protein kinases are known to bind to ras oncogenes. They are part of signal transduction pathways thought to consist of receptor tyrosine kinases, p21ras, Raf protein kinases, MeK1(ERK activator or MAPKK) kinases, and ERK (mapk) kinases, which ultimately phosphorylate transcription factors. In this pathway, Raf kinases are activated by ras and phosphorylate and activate two isoforms of mitogen-activated protein kinases (termed Mek1 and Mek2), which are dual specificity threonine/tyrosine kinases. Two Mek isoforms activate mitogen-activated kinases 1 and 2(MAPK, also known as extracellular ligand regulated kinases 1 and 2 or Erk1 and Erk 2). The MAPKs phosphorylate many substrates, such as transcription factors, in which case their transcription programs are established. Raf kinases are involved in the Ras/MAPK pathway to influence and regulate many cellular functions such as cell proliferation, differentiation, survival, oncogenic transformation and apoptosis.

The basic role and location of Raf in many signaling pathways has been demonstrated from studies using deregulated and dominant inhibitory Raf mutants in mammalian cells, as well as studies using biochemical and genetic technology model organisms. In many cases, activation of Raf by stimulating receptors for tyrosine phosphorylation in cells is dependent on the activity of Ras, suggesting that Ras functions upstream of Raf. Upon activation, Raf-1 phosphorylates and activates Mek1, resulting in signal transmission to downstream effectors such as MAPK (mitogen-activated protein kinase) (Crews et al (1993) Cell 74: 215). The Raf serine/threonine kinase is thought to be the major Ras effector involved in animal cell proliferation (Avruch et al (1994) Trends biochem. Sci.19: 279).

Raf kinases have three distinct isoforms, Raf-1(c-Raf), A-Raf and B-Raf, which can be distinguished by their ability to interact with Ras, the pathway for activation of MAPK kinases, tissue distribution and subcellular localization (Marias et al, biochem. J.351: 289-305, 2000; Weber et al, Oncogene 19: 169-176, 2000; Pritcard et al, mol.biol.15: 6430-cell 6442, 1995). Raf kinases are activated by Ras and phosphorylate and activate two isoforms of mitogen-activated protein kinases (designated Mek1 and Mek2, which are dual specificity threonine/tyrosine kinases). Both Mek isoforms activate mitogen-activated kinases 1 and 2(MAPK, also known as extracellular ligand regulated kinases 1 and 2 or Erk1 and Erk 2). The MAPK phosphorylates a number of substrates including the cytosolic protein and ETS family transcription factors. The involvement of Raf kinases in the Ras/MAPk pathway affects and regulates many cellular functions, such as cell proliferation, differentiation, survival, cell cycle progression and apoptosis.

Activating mutations in one of the Ras genes can be observed in-20% of all tumors and the Raf/MEK/ERK pathway is activated in-30% of all tumors (Bos et al, Cancer Res.49: 4682-4689, 1989) (Hoshino et al, Oncogene 18: 813-822, 1999). Recent studies have shown that B-Raf mutations in skin nevi are a key step in the initiation of melanoma (Pollock et al, Nature Genetics 25: 1-2, 2002). Moreover, most recent studies have shown that activating mutations in the B-Raf kinase domain are present in 66% of melanomas, 12% of colon cancers and 14% of liver cancers (Davies et al Nature 417: 949-.

Inhibitors of Raf/MEK/ERK at Raf kinase levels may be effective as therapeutic agents for the following tumors: tumors with overexpressed or mutated receptor tyrosine kinases, activated intracellular tyrosine kinases, tumors with aberrantly expressed Grb2 (adaptor protein that stimulates Ras by the Sos exchange factor), and tumors bearing Raf activating mutations themselves. In early clinical trials, inhibitors of Raf-1 kinase (which also inhibit B-Raf) have shown promise as therapeutic agents for cancer (Crump, Current Pharmaceutical Design 8: 2243-.

Disruption of Raf expression in cell lines throughout RNA antisense technology has been shown to inhibit ras and Raf-mediated tumorigenicity (Kolch et al, Nature 349: 416-428, 1991; Monia et al, Nature Medicine 2 (6): 668-675, 1996).

Several Raf kinase inhibitors have been described as being effective in inhibiting tumor cell proliferation in vitro and/or in vivo assays (see, e.g., U.S. Pat. nos. 6,391,636, 6,358,932, 6,037,136, 5,717,100, 6,458,813, 6,204,467, and 6,268,391). Other patents and patent applications suggest that Raf kinase inhibitors are useful for treating leukemia (see, e.g., U.S. patent nos. 6,268,391 and 6,204,467; and published U.S. patent application nos. 20020137774, 20020082192, 20010016194 and 20010006975), or for treating breast cancer (see, e.g., U.S. patent nos. 6,358,932, 5,717,100, 6,458,813, 6,268,391 and 6,204,467; and published U.S. patent application No. 20010014679).

Summary of The Invention

Providing a novel substituted indole compound of formula (I) and pharmaceutically acceptable salts thereof or providing an ester having a solubility enhancing moiety or prodrug thereof:

in the formula, X₁And X₂Independently selected from ═ N-, -NR₄-, -O-or-S-, with the proviso that if X₁is-NR₄-, -O-or-S-, then X₂Is ═ N-; or if X₂is-NR₄-, -O-or-S-, then X₁Is ═ N-, and X₁And X₂Neither is N-;

y is O or S;

A₁is substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, polycyclic arylalkyl, heteroaryl, biaryl, heteroarylaryl, heteroarylheteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, biarylalkyl, heteroarylarylalkyl;

A₂is a substituted or unsubstituted heteroaryl;

R₁is O or H, R₂Is NR₅R₆Or a hydroxyl group; or R₁And R₂Taken together to form a substituted or unsubstituted heterocycloalkyl or heteroaryl; wherein the dotted line represents a single bond or a double bond;

R₃is hydrogen, halogen, lower alkyl or lower alkoxy;

R₄is hydrogen, hydroxy, alkylamino, dialkylamino or alkyl;

R₅and R₆Independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkyl heterocycle, and heteroarylalkyl; or R₅And R₆Taken together to form a substituted or unsubstituted heterocycle or heteroaryl;

and pharmaceutically acceptable salts, esters, and prodrugs thereof.

In other embodiments, there are provided novel substituted indole compounds represented by the general formula (II):

in the formula, Y, Ar₁，Ar₂，R₁，R₂，R₃And R₄As described above;

and pharmaceutically acceptable salts, esters and prodrugs thereof.

In other embodiments, there are provided novel substituted indole compounds represented by the general formula (III):

in the formula, X₁，Ar₁，Ar₂，R₁，R₂And R₃As described above;

and pharmaceutically acceptable salts, esters, tautomers and prodrugs thereof.

In other embodiments, there are provided novel substituted indole compounds represented by the general formula (IV):

in the formula, X₁，Y，Ar₁，R₁，R₂And R₃As described above;

and pharmaceutically acceptable salts, esters, tautomers and prodrugs thereof.

In other embodiments, there are provided novel substituted indole compounds represented by the general formula (V):

in the formula, X₁，Ar₁，R₁，R₂And R₃As described above;

and pharmaceutically acceptable salts, esters, tautomers and prodrugs thereof.

In other aspects, the invention provides methods of treating a Raf associated disease in a human or animal subject, the treatment comprising administering to the subject an amount of a compound of formula (I), (II), (III), (IV) or (V) effective to reduce or prevent tumor growth in the subject.

In yet other aspects, the invention provides methods of treating Raf-associated diseases in a human or animal subject, said treatment comprising administering to the subject an amount of a compound of formula (I), (II), (III), (IV) or (V) in combination with at least one other agent effective to reduce or prevent tumor growth in the subject for the treatment of cancer.

In yet other aspects, the present invention provides therapeutic compositions commonly used in the treatment of cancer, said compositions comprising at least one compound of formula (I), (II), (III), (IV) or (V) in combination with one or more other agents for the treatment of cancer.

The compounds of the invention may be used to treat cancer, including cancer (e.g., lung, pancreatic, thyroid, bladder or colon cancer), myeloid disorders (e.g., myeloid leukemia) and adenomas (e.g., villous colon adenomas).

The invention also provides compositions, methods of use, and methods of manufacture, as detailed herein.

Detailed description of the preferred embodiments

In one aspect, the present invention provides novel substituted indole compounds of formula (I) and pharmaceutically acceptable salts, esters or prodrugs thereof:

in the formula, X₁And X₂Independently selected from ═ N-, -NR₄-, -O-or-S-, with the proviso that if X₁is-NR₄-, -O-or-S-, then X₂Is ═ N-; or if X₂is-NR₄-, -O-or-S-, then X₁Is ═ N-, and X₁And X₂Neither is N-; y is O or S;

y is O or S;

A₁is substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, polycyclic arylalkyl, heteroaryl, biaryl, heteroarylaryl, heteroarylheteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, biarylalkyl, heteroarylarylalkyl;

A₂is a substituted or unsubstituted heteroaryl;

R₁is O or H, and R₂Is NR₅R₆Or a hydroxyl group; or R₁And R₂Taken together to form a substituted or unsubstituted heterocycloalkyl or heteroaryl; wherein the dotted line represents a single bond or a double bond;

R₃is hydrogen, halogen, lower alkyl, or lower alkoxy;

R₄is hydrogen, hydroxy, alkylamino, dialkylamino or alkyl;

R₅and R₆Independently selected from hydrogen, and substituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxaalkyl heterocycle, and heteroarylalkyl; or R₅And R₆Taken together to form a substituted or unsubstituted heterocycle or heteroaryl;

and pharmaceutically acceptable salts, esters and prodrugs thereof.

In other embodiments, there are provided novel substituted indole compounds represented by the general formula (II):

in the formula, Y, Ar₁，Ar₂，R₁，R₂，R₃And R₄As described above;

and pharmaceutically acceptable salts, esters and prodrugs thereof.

In other embodiments, there are provided novel substituted indole compounds of the formula (III),

In the formula, X₁，Ar₁，Ar₂，R₁，R₂And R₃As described above;

and pharmaceutically acceptable salts, esters, tautomers and prodrugs thereof.

In other embodiments, there are provided novel substituted indole compounds represented by the general formula (IV):

in the formula, X₁，Y，Ar₁，R₁，R₂And R₃As described above;

and pharmaceutically acceptable salts, esters, tautomers and prodrugs thereof.

In other embodiments, there are provided novel substituted indole compounds represented by the general formula (V):

in the formula, X₁，Ar₁，R₁，R₂And R₃As described above;

and pharmaceutically acceptable salts, esters, tautomers and prodrugs thereof.

In another aspect, the invention provides a method of treating a human or animal subject suffering from a Raf-associated disease, such as cancer. Accordingly, the present invention provides a method of treating a Raf associated disease in a human or animal subject, said treatment comprising administering to the subject a therapeutically effective amount of a compound of formula I, II, III, IV or V as described above, alone or in combination with other anti-cancer agents.

In other aspects, the invention provides methods of treating a Raf associated disease in a human or animal subject, the treatment comprising administering to the subject an amount of a compound of formula (I), (II), (III), (IV) or (V) effective to reduce or prevent tumor growth in the subject.

In yet other aspects, the invention provides methods of treating Raf-associated diseases in a human or animal subject, the treatment comprising administering to the subject an amount of a compound of formula (I), (II), (III), (IV) or (V), alone or in combination with at least one additional agent for treating cancer, effective to reduce or prevent tumor growth in the subject. Many suitable anti-cancer agents for use as combination therapies are suitable for use in the methods of the invention. Indeed, the invention includes, but is not limited to, administration of a number of anti-cancer agents, such as apoptosis-inducing agents, polynucleotides (e.g., ribozymes), polypeptides (e.g., enzymes), drugs, biomimetics, alkaloids, alkylating agents, anti-tumor antibiotics, anti-metabolites, hormones, platinum compounds, and anti-cancer drug-conjugated monoclonal antibodies, toxins and/or radionuclides, biological response modifiers (e.g., interferons [ e.g., IFN-a, etc. ] and interleukins [ e.g., IL-2, etc. ]), adoptive immunotherapeutics, hematopoietic growth factors, agents that induce tumor cell differentiation (e.g., pan-trans-retinoic acid, etc.), gene therapy agents, antisense therapy agents and nucleosides, tumor vaccines, inhibitors of angiogenesis, and the like. Many other examples of chemotherapeutic compounds and anticancer agents suitable for co-administration with compounds of formula (I), (II), (III), (IV) or (V) are known to those skilled in the art.

In a preferred embodiment, the anti-cancer agent in combination with a compound of the invention comprises an agent that induces or stimulates apoptosis. Agents that induce apoptosis include, but are not limited to, radiation (e.g., W), kinase inhibitors (e.g., epidermal growth factor receptor [ EGFR ] kinase inhibitors, vascular growth factor receptor [ VGFR ] kinase inhibitors, fibroblast growth factor receptor [ FGFR ] kinase inhibitors, platelet-derived growth factor receptor [ PGER ] I kinase inhibitors, and Bcr-Ab1 kinase inhibitors such as STI-571, imatinib, and Glivec), antisense molecules, antibodies [ e.g., herceptin and rituxan ], anti-estrogens [ e.g., raloxifene and tamoxifen ], anti-androgens [ e.g., flutamide, bikrolid, finasteride, aminoglutethimide, ketoconazole, and corticosteroids ], cyclooxygenase 2(COX-2) inhibitors [ e.g., selectoria, meloxicam, NS-398, and non-steroidal anti-inflammatory drugs (NSAIDs) ] and cancer chemotherapeutics [ e.g., irinotecan (Camptosar), CPT-11, fludarabine (fludara), Dacarbazine (DTIC), dexamethasone, mitoxantrone, Mylotarg, VP-16, cisplatin, 5-FU, Adrianeb, deacetyl viol or taxol ]; a cell signaling molecule; ceramides and cytokines; and staurosporine (staurosporine) and the like.

In other aspects, the invention provides a pharmaceutical composition comprising at least one compound of formula I, II, III, IV or V together with a pharmaceutically acceptable carrier suitable for administration to a human or animal subject, either alone or in combination with other anti-cancer agents.

In other aspects, the invention provides methods of making compounds of formula I, II, III, IV or V herein.

In yet other aspects, the invention provides a compound that is an inhibitor of Raf kinase. Since the enzyme is p21^rasThe inhibitors may be used in human or veterinary pharmaceutical compositions to inhibit the raf kinase pathway, for example in the treatment of raf kinase mediated tumour and/or cancer cell growth. In particular, the compounds may be used in the treatment of human or animal, e.g. murine, cancers, since the progression of these cancers is dependent on the fas protein signalling cascade, and therefore disruption of the cascade by inhibition of raf kinase activity is therapeutically sensitive. Thus, the compounds of the invention may be used to treat solid cancers, such as carcinomas (e.g., lung, pancreatic, thyroid, bladder or colon), myeloid diseases (e.g., myeloid leukemia), or adenomas (e.g., villous colon adenomas).

As used herein, "Raf inhibitor" means that it exhibits IC as measured in the Raf/Mek filtration assay described below₅₀(ii) no more than about 100 μ M, more typically no more than about 50 μ M, relative to Raf kinase activity.Preferred isoforms of Raf kinase that are inhibited by the compounds of the invention include A-Raf, B-Raf and C-Raf (Raf-1). ' IC₅₀"is the concentration of inhibitor that reduces the activity of an enzyme (e.g., Raf kinase) to half maximal level. Representative compounds of the invention have been found to exhibit inhibitory activity against Raf. IC of Compounds of the invention versus Raf as measured in the Raf kinase assay described herein₅₀Preferably no more than 10. mu.M, more preferably no more than about 5. mu.M, even more preferably no more than about 1. mu.M, and most preferably no more than about 200 nM.

As used herein, the term "indole" includes benzimidazole, benzothiazole, and benzoxazole.

The phrase "alkyl" refers to an alkyl group that does not contain heteroatoms. Thus, the phrase includes straight chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like. The phrase also includes branched isomers of straight chain alkyl groups, including but not limited to: -CH (CH)₃)₂，-CH(CH₃)(CH₂CH₃)，-CH(CH₂CH₃)₂，-C(CH₃)₃，-C(CH₂CH₃)₃，-CH₂CH(CH₃)₂，-CH₂CH(CH₃)(CH₂CH₃)，-CH₂CH(CH₂CH₃)₂，-CH₂C(CH₃)₃，-CH₂C(CH₂CH₃)₃，-CH(CH₃)-CH(CH₃)(CH₂CH₃)，-CH₂CH₂CH(CH₃)₂，-CH₂CH₂CH(CH₃)(CH₂CH₃)，-CH₂CH₂CH(CH₂CH₃)₂，-CH₂CH₂C(CH₃)₃，-CH₂CH₂C(CH₂CH₃)₃，-CH(CH₃)CH₂-CH(CH₃)₂，-CH(CH₃)CH(CH₃)CH(CH₃)₂，-CH(CH₂CH₃)CH(CH₃)CH(CH₃)(CH₂CH₃) And the like. The phrase also includes cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, and these rings are substituted with straight and branched chain alkyl groups as described above. Thus, the phrase "alkyl" includes primary, secondary and tertiary alkyl groups. Preferred alkyl groups include straight and branched chain alkyl groups and cycloalkyl groups having 1 to 12 carbon atoms.

As used herein, "lower alkyl" includes substituted or unsubstituted, straight or branched alkyl groups having 1 to 6 carbon atoms. Representative lower alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, neopentyl, trifluoromethyl, pentafluoroethyl and the like. Lower alkyl groups may be substituted, for example, by halogen, hydroxy, amino, nitro and/or cyano groups, and the like. Representative halogen-substituted and hydroxy-substituted lower alkyl groups include chloromethyl, trichloromethyl, chloroethyl, hydroxyethyl and the like. Other suitably substituted lower alkyl moieties include, for example, aralkyl, aminoalkyl, aminoaralkyl, carbonylaminoalkyl, alkylcarbonylaminoalkyl, arylcarbonylaminoalkyl, aralkylcarbonylaminoalkyl, aminoalkoxyalkyl and arylaminoalkyl.

As used herein, "lower alkoxy" refers to RO-, wherein R is lower alkyl. Representative examples of lower alkoxy include methoxy, ethoxy, t-butoxy, trifluoromethoxy and the like.

As used herein, the term "halogen" refers to chloro, bromo, fluoro and iodo groups. "haloalkyl" refers to an alkyl group substituted with one or more halogen atoms. The term "halo-lower alkyl" refers to a lower alkyl group substituted with one or more halogen atoms. The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen atoms. The term "halo-lower-alkoxy" refers to a lower-alkoxy group substituted with one or more halogen atoms.

As used herein, "amino" refers to-NH₂. As used herein, the term "alkylamino" refers to the group-NRR ', wherein R and R' are each independently selected from hydrogen or lower alkylAnd (4) a base. As used herein, the term "arylamino" refers to the group-NRR 'where R is aryl and R' is hydrogen, lower alkyl or aryl. As used herein, the term "aralkylamino" refers to the group-NRR ', where R is loweraralkyl and R' is hydrogen, loweralkyl, aryl, or loweraralkyl.

The term "alkoxyalkyl" means-alk₁-O-alk₂In the formula, alk₁Is alkyl or alkenyl, alk₂Is an alkyl or alkenyl group. The term "lower alkoxyalkyl" refers to alkoxyalkyl, wherein alk₁Is lower alkyl or lower alkenyl, alk₂Is lower alkyl or lower alkenyl. The term "aryloxyalkyl" refers to-alkyl-O-aryl. The term "aralkoxyalkyl" refers to the group-alkylene-O-aralkyl, where aralkyl is loweraralkyl.

As used herein, the term "alkoxyalkylamino" refers to-NR- (alkoxyalkyl), where R is typically hydrogen, loweralkyl, or loweralkyl. As used herein, the term "amino lower alkoxyalkyl" refers to an aminoalkoxyalkyl group, wherein the alkoxyalkyl group is a lower alkoxyalkyl group.

As used herein, the term "aminocarbonyl" refers to the group-C (O) -NH₂. As used herein, "substituted aminocarbonyl" refers to-C (O) -NRR ', where R is lower alkyl and R' is hydrogen or lower alkyl. As used herein, the term "arylaminocarbonyl" refers to the group-C (O) -NRR 'wherein R is aryl and R' is hydrogen, lower alkyl or aryl. As used herein, "aralkylaminocarbonyl" means-C (O) -NRR 'where R is loweraralkyl and R' is hydrogen, loweralkyl, aryl, or loweraralkyl.

"aminosulfonyl" as used herein refers to-S (O)₂-NH₂. As used herein, "substituted aminosulfonyl" refers to-S (O)₂-NRR ', wherein R is lower alkyl and R' is hydrogen or lower alkyl. As used herein, the term "aralkylaminosulfonylaryl" refers to-aryl-S (O)₂-NH-aralkyl, wherein the aralkyl is lower aralkyl.

"carbonyl" refers to the divalent group-C (O) -.

"carbonyl oxygen" generally refers to-C (O) -O. These groups include esters, -C (O) -O-R, where R is lower alkyl, cycloalkyl, aryl or lower aralkyl. The term "carbonyloxycycloalkyl" generally refers to "carbonyloxycarbocycloalkyl" and "carbonyloxacycloalkyl", i.e., R is carbocycloalkyl or heterocycloalkyl, respectively. As used herein, the term "arylcarbonyl oxygen" refers to-C (O) -O-aryl, where aryl is a monocyclic or polycyclic, carbocyclic aryl, or heterocyclic aryl. As used herein, the term "aralkylcarbonyloxy" refers to the group-C (O) -O-aralkyl, where aralkyl is lower aralkyl.

As used herein, the term "sulfonyl" refers to-SO₂-. "alkylsulfonyl" means a radical of the structure-SO₂R-substituted sulfonyl, wherein R is alkyl. Alkylsulfonyl groups employed in compounds of the present invention are typically lower alkylsulfonyl groups having 1 to 6 carbon atoms in its backbone structure. Thus, typical alkylsulfonyl groups employed in compounds of the present invention include, for example, methylsulfonyl (i.e., R is methyl), ethylsulfonyl (i.e., R is ethyl), propylsulfonyl (i.e., R is propyl), and the like. As used herein, the term "arylsulfonyl" refers to-SO₂-an aryl group. As used herein, the term "aralkylsulfonyl" refers to-SO₂-aralkyl, wherein the aralkyl is loweraralkyl. As used herein, the term "sulfonamido" refers to-SO₂NH₂。

As used herein, the term "carbonylamino" refers to the divalent group-NH-C (O) -wherein the hydrogen atom of the amide nitrogen of the carbonylamino group may be substituted with a lower alkyl group, an aryl group or a lower aralkyl group. Such groups include, for example, carbamates (-NH-C (O) -O-R) and amides (-NH-C (O) -O-R), wherein R is a linear or branched lower alkyl, cycloalkyl or aryl group or a lower aralkyl group. The term "lower alkylcarbonylamino" refers to alkylcarbonylamino wherein R is a lower alkyl group having from about 1 to 6 carbon atoms in its backbone structure. The term "arylcarbonylamino" refers to-NH-C (O) -R, wherein R is an alkaryl group. Similarly, the term "aralkylcarbonylamino" refers to a carbonylamino group wherein R is a lower aralkyl group. As used herein, the term "aminocarbonyl" refers to the divalent radical-C (O) -NH-, wherein the hydrogen atom of the amide nitrogen of the carbonylamino group may be substituted for the lower alkyl, aryl or lower aralkyl group described above.

As used herein, the term "guanidino" refers to a guanidine derived from H₂N-C(＝NH)-NH₂Part (c) of (a). Such moieties include those bound to the nitrogen atom bearing the formal double bond (the "2" -position of guanidine, e.g., diaminomethyleneamino, (H)₂N)₂C ═ NH —) and those bound to any nitrogen atom bearing a formal single bond (at the "1-" and/or "3" -position of guanidine, for example H₂N-C (═ NH) -NH-). Any of the hydrogen atoms on the nitrogen may be substituted with a suitable substituent such as lower alkyl, aryl or lower aralkyl.

The term "amidino" as used herein means R-C (═ N) -NR' - (at "N)¹"group on nitrogen") and R (NR') C ═ N- (at "N²"nitrogen group"), wherein R and R' may be hydrogen, lower alkyl, aryl or lower aralkyl.

"cycloalkyl" refers to a monocyclic or polycyclic, heterocyclic, or carbocyclic alkyl substituent. Typical cycloalkyl substituents have 3-8 backbone (i.e., ring) atoms, wherein each backbone atom can be a carbon or heteroatom. As used herein, the term "heterocycloalkyl" refers to a cycloalkyl substituent having from 1 to 5, typically from 1 to 4, heteroatoms in the ring structure. Suitable heteroatoms for use in the present invention are nitrogen, oxygen and sulfur. Representative heterocycloalkyl moieties include, for example, morpholino, piperazinyl, piperidinoalkyl (piperadinyl), and the like. Carbocycloalkyl is cycloalkyl in which all ring atoms are carbon. The term "polycyclic" when used herein with cycloalkyl substituents refers to both fused and non-fused alkyl cyclic structures.

As used herein, the term "substituted heterocycle" or "heterocyclyl" or heterocycle refers to any 3-or 4-membered ring containing heteroatoms selected from nitrogen, oxygen, and sulfur, or a 5-or 6-membered ring containing 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur; wherein the 5-membered ring has 0-2 double bonds and the 6-membered ring has 0-3 double bonds; wherein the nitrogen and sulfur atoms may be optionally oxidized; wherein the nitrogen and sulfur heteroatoms may optionally be quaternized and include any bicyclic group wherein any of the above heterocycles may be independently fused to a benzene ring or other 5-or 6-membered heterocycle. Thus, the term "heterocycle" includes rings in which nitrogen is a heteroatom as well as partially and fully saturated rings. Preferred heterocycles include, for example, diazepanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolidinyl, imidazolinyl, pyridylalkyl, piperidinyl, pyrazinyl, piperazinyl, N-methylpiperazinyl, azetidinyl, N-methylazetidinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, triazolyl, and benzothienyl.

The heterocyclic moiety may be unsubstituted or mono-or di-substituted with various substituents independently selected from hydroxy, halogen, oxo (C ═ O), alkylimino (RN ═ where R is lower alkyl or lower alkoxy), amino, alkylamino, dialkylamino, acylaminoalkyl, alkoxy, thioalkoxy, polyalkoxy, lower alkyl, cycloalkyl or haloalkyl.

The heterocyclic group may be attached at various positions as will be apparent to those skilled in the organic and medicinal chemistry arts in conjunction with the disclosure herein.

Wherein R is H or a heterocyclic substituent, as described herein.

Representative heterocycles include, for example, imidazolyl, pyridyl, piperazinyl, azetidinyl, thiazolyl, furyl, triazolyl benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, 2, 3-diazanaphthyl, indolyl, naphthylpyridyl, indazolyl, and quinolinyl.

"aryl" refers to optionally substituted monocyclic and polycyclic aromatic groups having 3 to 14 backbone carbon or heteroatoms and includes carbocyclic aryl and heterocyclic aryl groups. Carbocyclic aryl is aryl in which all ring atoms in the aromatic ring are carbon. As used herein, the term "heteroaryl" refers to an aryl group having 1-4 heteroatoms as ring atoms in the aromatic ring, with the remaining ring atoms being carbon atoms. As used herein, the term "polycyclic aryl" when used with aryl substituents refers to fused and unfused cyclic structures wherein at least one cyclic structure is aromatic, such as benzodioxole (which has a heterocyclic structure fused to a phenyl group, i.e., a phenyl group)Naphthyl, and the like. Exemplary aryl moieties useful as substituents in the compounds of the present invention include phenyl, pyridyl, pyrimidinyl, thiazolyl, indolyl, imidazolyl, oxadiazolyl, tetrazolyl, pyrazinyl, triazolyl, thiophenyl, furanyl, quinolinyl, purinyl, naphthyl, benzothiazolyl, benzopyridyl, and benzimidazolyl, and the like.

"aralkyl" refers to an alkyl group substituted with an aryl group. The aralkyl groups used in the compounds of the present invention typically have from 1 to 6 carbon atoms incorporated into the alkyl portion of the aralkyl group. Suitable aralkyl groups for use in the compounds of the present invention include, for example, benzyl, picolyl, and the like.

Representative heteroaryl groups include, for example, those shown below. These heteroaryl groups may be further substituted and attached at various positions as known to those skilled in the organic and pharmaceutical chemistry arts in conjunction therewith.

Representative heteroaryl groups include, for example, imidazolyl, pyridyl, piperazinyl, azetidinyl, thiazolyl, triazolyl benzimidazolyl, benzothiazolyl, and benzoxazolyl.

The term "biaryl" refers to a group or substituent to which two aryl groups are attached, which cannot be condensed with each other. Exemplary biaryl compounds include, for example, biphenyl, diphenyldiazene, 4-methylthio-1-biphenyl, phenoxybenzene, (2-phenylethynyl) benzene, diphenylketone, (4-phenyl-1, 3-butadiynyl) benzene, phenylbenzylamine, (phenylmethoxy) benzene, and the like. Preferred optionally substituted biaryls include 2- (phenylamino) -N- [4- (2-phenylethynyl) phenyl ] acetamide, 1, 4-biphenylene, N- [4- (2-phenylethynyl) phenyl ] -2- [ benzylamino ] acetamide, 2-amino-N- [4- (2-phenylethynyl) phenyl ] propanamide, 2-amino-N- [4- (2-phenylethynyl) phenyl ] acetamide, 2- (cyclopropylamino) -N- [4- (2-phenylethynyl) phenyl ] acetamide, 2- (ethylamino) -N- [4- (2-phenylethynyl) phenyl ] acetamide, 2- [ (2-methylpropyl) amino ] -N- [4- (2-phenylethynyl) amino ] -N- [4- (2-methylpropyl) amino ] -N- [4- (2-phenylethynyl) phenyl ] acetamide -phenylethynyl) phenyl ] acetamide, 5-phenyl-2H-benzo [ d ]1, 3-dioxole, 2-chloro, -1-methoxy-4-biphenyl, 2- [ (imidazolylmethyl) amino ] -N- [4- (2-phenylethynyl) phenyl ] acetamide, 4-phenyl-1-phenoxybenzene, N- (2-aminoethyl) [4- (2-phenylethynyl) phenyl ] carbamoyl, 2- { [ (4-fluorophenyl) methyl ] amino } -N- [4- (2-phenylethynyl) phenyl ] acetamide, 2- { [ (4-methylphenyl) methyl ] amino } -N- [4- (2-phenylethynyl) phenyl ] acetamide, N- [4- (2-phenylethynyl, 4-phenyl-1- (trifluoromethyl) benzene, 1-butyl-4-biphenyl, 2- (cyclohexylamino) -N- [4- (2-phenylethynyl) phenyl ] acetamide, 2- (ethylmethylamino) -N- [4- (2-phenylethynyl) phenyl ] acetamide, 2- (butylamino) -N- [4- (2-phenylethynyl) phenyl ] acetamide, N- [4- (2-phenylethynyl) phenyl ] -2- (4-pyridinylamino) acetamide, N- [4- (2-phenylethynyl) phenyl ] -2- (quinuclidin-3-ylamino) acetamide, N- [4- (2-phenylethynyl) phenyl ] pyrrolidin-2-ylaminoacetamide Formyl, 2-amino-3-methyl-N- [4- (2-phenylethynyl) phenyl ] butanamide, 4- (4-phenyl-1, 3-butadiynyl) phenylamide, 2- (dimethylamino) -N- [4- (4-phenyl-1, 3-butadiynyl) phenyl ] acetamide, 2- (ethylamino) -N- [4- (4-phenyl-1, 3-butadiynyl) phenyl ] acetamide, 4-ethyl-1-biphenyl, 1- [4- (2-phenylethynyl) phenyl ] ethan-1-one, N- (1-carbamoyl-2-hydroxypropyl) [4- (4-phenyl-1, 3-butynedionyl) phenyl ] carboxamide, N- [4- (2-phenylethynyl) phenyl ] propionamide, 4-methoxyphenyl phenone, phenyl-N-benzamide, (tert-butoxy) -N- [ (4-phenylphenyl) methyl ] carboxamide, 2- (3-phenylphenoxy) ethanaminic acid (hydroxamic acid), 3-phenylphenyl propionate, 1- (4-ethoxyphenyl) -4-methoxybenzene and [4- (2-phenylethynyl) phenyl ] pyrrole.

The term "heteroarylaryl" refers to a biaryl group wherein one aryl group is heteroaryl. Exemplary heteroarylaryl groups include, for example, 2-phenylpyridine, phenylpyrrole, 3- (2-phenylethynyl) pyridine, phenylpyrazole, 5- (2-phenylethynyl) -1, 3-dihydropyrimidine-2, 4-dione, 4-phenyl-1, 2, 3-thiadiazole, 2- (2-phenylethynyl) pyrazine, 2-phenylthiophene, phenylimidazole, 3- (2-piperazinylphenyl) furan, 3- (2, 4-dichlorophenyl) -4-methylpyrrole, and the like. Preferred optionally substituted heteroarylaryl groups include 5- (2-phenylethynyl) pyrimidin-2-ylamine, 1-methoxy-4- (2-thienyl) benzene, 1-methoxy-3- (2-thienyl) benzene, 5-methyl-2-phenylpyridine, 5-methyl-3-phenylisoxazole, 2- [3- (trifluoromethyl) phenyl ] furan, 3-fluoro-5- (2-furyl) -2-methoxy-1-prop-2-ylbenzene, (hydroxyimino) (5-phenyl (2-thienyl)) methane, 5- [ (4-methylpiperazinyl) methyl ] -2-phenylthiophene, and, 2- (4-ethylphenyl) thiophene, 4-methylthio-1- (2-thienyl) benzene, 2- (3-nitrophenyl) thiophene, (tert-butoxy) -N- [ (5-phenyl (3-pyridyl)) methyl ] carboxamide, hydroxy-N- [ (5-phenyl (3-pyridyl)) methyl ] amide, 2- (phenylmethylthio) pyridine and benzylimidazole.

The term "heteroarylheteroaryl" refers to a biaryl group in which both aryl groups are heteroaryl. Exemplary heteroarylheteroaryl groups include, for example, 3-pyridylimidazole, 2-imidazolylpyrazine and the like. Preferred optionally substituted heteroarylheteroarylheteroaryls include 2- (4-piperazinyl-3-pyridyl) furan, diethyl (3-pyrazin-2-yl (4-pyridyl)) amine and dimethyl {2- [2- (5-methylpyrazin-2-yl) ethynyl ] (4-pyridyl) } amine.

"optionally substituted" or "substituted" refers to the replacement of hydrogen with a monovalent or divalent group. Suitable substituents include, for example, hydroxy, nitro, amino, imino, cyano, halogen, thio, sulfonyl, thioamido, amidino, imidino, oxo, oxaamidino, amidino, imidino, guanidino, sulfonamido, carboxy, formyl, lower alkyl, halo-lower alkyl, lower alkylamino, halo-lower alkylamino, lower alkoxy, halo-lower alkoxy, lower alkoxyalkyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl, heteroaralkylcarbonyl, alkylthio, aminoalkyl, cyanoalkyl, aryl, and the like.

The substituents may be themselves substituted. The group substituted on the substituent may be carboxyl, halogen, nitro, amino, cyano, hydroxyl, lower alkyl, lower alkoxy, aminocarbonyl, -SR, thioamido, -SO₃H、-SO₂R or cycloalkyl, wherein R is typically hydrogen, hydroxy or lower alkyl.

When the substituted substituent comprises a straight chain group, the substitution may occur in-chain (e.g., 2-hydroxypropyl, 2-aminobutyl, etc.) or at the chain end (e.g., 2-hydroxyethyl, 3-cyanopropyl, etc.). The substituted substituents may be a linear, branched or cyclic arrangement of covalently bonded carbon or heteroatoms.

In this context, the term "carboxyl protecting group" refers to a carbonyl group that has been esterified with a conventional carboxylic acid protecting ester group, blocking or protecting the carboxylic acid function while involving carrying out reactions at other functional sites of the compound. Alternatively, the carboxyl protecting group may be attached to a solid support, whereby the compound is attached to the solid support as a carboxylate until cleaved using a hydrolysis method to release the corresponding free acid. Representative carboxylic acid protecting groups include, for example, lower alkyl esters, secondary amides, and the like.

As used herein, the term "pharmaceutically acceptable salt" refers to a non-toxic acid or alkaline earth metal salt of a compound of formula I. These salts may be prepared in situ during the final isolation and purification of the compounds of formula I or separately by reacting the base or acid with a suitable organic or inorganic acid or base, respectively. Representative salts include, but are not limited to, the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethylsulfonate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthylsulfonate, oxalate, pamoate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. The nitrogen-containing basic groups may also be quaternized with such compounds as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and the like. Thus, a water or oil soluble or dispersible product is obtained.

Examples of acids which may be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, and organic acids such as oxalic acid, maleic acid, methanesulfonic acid, succinic acid and citric acid. Base addition salts can be prepared in situ during the final isolation and purification of the compounds of formula I, or separately by reacting the carboxylic acid moiety with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, or with aqueous ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, aluminum, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Other representative organic amines useful for forming base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.

As used herein, the term "pharmaceutically acceptable ester" refers to esters that hydrolyze in vivo and include those that break down readily in the human body away from the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, especially alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of specific esters include formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.

The term "pharmaceutically acceptable prodrug" as used herein refers to prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for the intended use, and zwitterionic forms, if any, of the compounds of the present invention. The term "prodrug" refers to a compound that rapidly converts (e.g., hydrolyzes in the blood) in vivo to yield the parent compound of the above formula. A complete discussion of the Drug Design in the context of the Bioreversible carriers in Drug Design, the American Pharmaceutical Association and pergamon Press, 1987 is provided in t.higuchi and v.stella, Pro-drugs as Novel Delivery Systems (Pro-drugs as Novel Delivery Systems), volume 14, the a.c.s.symposium Series and Edward b.roche, eds., incorporated herein by reference.

The term "cancer" refers to a cancer that can be treated by inhibition of Raf kinase, including, for example, solid cancers such as carcinomas (e.g., lung, pancreatic, thyroid, bladder or colon), myeloid diseases (e.g., myeloid leukemia), and adenomas (e.g., villous colon adenomas).

In an illustrative embodiment of the invention, Ar₁May be, for example, phenyl substituted with one or more substituents selected from the group consisting of hydroxy, nitro, cyano, halogen, substituted or unsubstituted amino, imino, thio, sulfonyl, thioamido, amidino, imidino, oxo, oxamidyl, carbamimidoyl, imidino, guanidino, sulfonamido, carboxy, formyl, lower alkyl, halolower alkyl, lower alkylamino, halolower alkylamino, lower alkoxy, halolower alkoxy, lower alkoxyalkyl, alkylcarbonyl, aminocarbonyl, lower alkylaminocarbonyl, heterocycloalkyl lower alkylaminocarbonyl, carboxylower alkylaminocarbonyl, arylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl, heteroaralkylcarbonyl, alkylthio, aminoalkyl, cyanoalkyl, aryl, and the like. In other illustrative embodiments of the invention, Ar₂May be, for example, pyridyl substituted with one or more substituents selected from the group consisting of hydroxy, nitro, cyano, halogen, substituted or unsubstituted amino, imino, thio, sulfonyl, thioamido, amidino, imidino, oxo, oxamidyl, carbamimido, iminoamino, sulfonamido, carboxy, formyl, lower alkyl, halolower alkyl, lower alkylamino, halolower alkylamino, lower alkoxy, halolower alkoxy, lower alkoxyalkyl, alkylcarbonyl, aminocarbonyl, lower alkylaminocarbonyl, heterocycloalkyl lower alkylaminocarbonyl, carboxylower alkylaminocarbonyl, arylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl, heteroaralkylcarbonyl, alkylthio, aminoalkyl, cyanoalkyl, aryl and the like.

In representative embodiments of the invention, the compounds of the invention include, for example, 4- [ (2- { [ 4-chloro-3- (trifluoromethyl) phenyl ] amino } -1H-benzimidazol-6-yl) oxy ] -N-methylpyridine-2-carboxamide, 4- ({2- [ (3-chlorophenyl) amino ] -1H-benzimidazol-6-yl } oxy) -N-methylpyridine-2-carboxamide, 4- ({2- [ (4-bromophenyl) amino ] -1H-benzimidazol-6-yl } oxy) -N-methylpyridine-2-carboxamide, 4- ({2- [ (3-chloro-4-fluorophenyl) amino ] -1H-benzimidazol-e-2-carboxamide -6-yl } oxy) -N-methylpyridine-2-carboxamide, N-methyl-4- { [2- (phenylamino) -1H-benzimidazol-6-yl ] oxy } pyridine-2-carboxamide, 4- [ (2- { [ 4-bromo-2- (trifluoromethyl) phenyl ] amino } -1H-benzimidazol-6-yl) oxy ] -N-methylpyridine-2-carboxamide, N-methyl-4- ({2- [ (2-methylpropyl) amino ] -1H-benzimidazol-6-yl } oxy) pyridine-2-carboxamide, 4- [ (2- { [4- (dimethylamino) naphthalen-1-yl ] amino } -1H-benzo Imidazol-6-yl) oxy ] -N-methylpyridine-2-carboxamide, N-methyl-4- ({2- [ (4-nitrophenyl) amino ] -1H-benzimidazol-6-yl } oxy) pyridine-2-carboxamide, N-methyl-4- ({2- [ (phenylcarbonyl) amino ] -1H-benzimidazol-6-yl } oxy) pyridine-2-carboxamide, N-methyl-4- ({2- [ (phenylmethyl) amino ] -1H-benzimidazol-6-yl } oxy) pyridine-2-carboxamide, methyl 4- { [6- ({2- [ (methylamino) carbonyl ] pyridin-4-yl } oxy) -1H-benzimidazol-one- 2-yl ] amino } benzoate, 4- ({2- [ (4-chlorophenyl) amino ] -1H-benzimidazol-6-yl } oxy) -N-methylpyridine-2-carboxamide, 4- [ (2- { [2- (ethyloxy) phenyl ] amino } -1H-benzimidazol-6-yl) oxy ] -N-methylpyridine-2-carboxamide, N-methyl-4- ({2- [ (2-morpholin-4-ylethyl) amino ] -1H-benzimidazol-6-yl } oxy) pyridine-2-carboxamide, 4- ({2- [ (4-iodophenyl) amino ] -1H-benzimidazol-6-yl } oxy) -N-methylbenzimidazol-6-yl } oxy Pyridine-2-carboxamide, N-methyl-4- [ (2- { [4- (trifluoromethyl) phenyl ] amino } -1H-benzimidazol-6-yl) oxy ] pyridine-2-carboxamide, 4- ({2- [ (furan-2-ylmethyl) amino ] -1H-benzimidazol-6-yl } oxy) -N-methylpyridine-2-carboxamide, 4- ({2- [ (4-bromo-3-methylphenyl) amino ] -1H-benzimidazol-6-yl } oxy) -N-methylpyridine-2-carboxamide, 4- ({2- [ (4-acetylphenyl) amino ] -1H-benzimidazol-6-yl } oxy) -N-methylpyridine-2-carboxamide -methylpyridine-2-carboxamide, N-methyl-4- ({2- [ (2, 4, 6-trimethylphenyl) amino ] -1H-benzimidazol-6-yl } oxy) pyridine-2-carboxamide, 4- [ (2- { [4- (1, 1-dimethylethyl) phenyl ] amino } -1H-benzimidazol-6-yl) oxy ] -N-methylpyridine-2-carboxamide, 4- ({2- [ (2-bromophenyl) amino ] -1H-benzimidazol-6-yl } oxy) -N-methylpyridine-2-carboxamide, 4- ({2- [ (3-bromophenyl) amino ] -1H-benzimidazol-6-yl } oxy) - N-methylpyridine-2-carboxamide, 4- ({2- [ (2-chlorophenyl) amino ] -1H-benzimidazol-6-yl } oxy) -N-methylpyridine-2-carboxamide, methyl 3- { [6- ({2- [ (methylamino) carbonyl ] pyridin-4-yl } oxy) -1H-benzimidazol-2-yl ] amino } thiophene-2-carboxylate, 4- ({2- [ (4-bromophenyl) amino ] -1H-benzimidazol-6-yl } oxy) -N- { (3R, 5R) -5- [ (methyloxy) methyl ] pyrrolidin-3-yl } pyridine-2-carboxamide, pharmaceutically acceptable salts thereof, and pharmaceutically acceptable salts thereof, 4- ({2- [ (4-bromophenyl) amino ] -1-methyl-1H-benzimidazol-5-yl } oxy) -N-methylpyridine-2-carboxamide, 4- [ (2- { [ 4-chloro-3- (trifluoromethyl) phenyl ] amino } -1-methyl-1H-benzimidazol-5-yl) oxy ] -N-methylpyridine-2-carboxamide, N-methyl-4- [ (1-methyl-2- { [4- (trifluoromethyl) phenyl ] amino } -1H-benzimidazol-5-yl) oxy ] pyridine-2-carboxamide, 4- ({2- [ (4-bromophenyl) amino ] -1-methyl-1H-benzimidazol-5-yl) oxy ] pyridine-2-carboxamide -benzimidazol-5-yl } oxy) -N-ethylpyridine-2-carboxamide, 4- ({2- [ (4-bromophenyl) amino ] -1-methyl-1H-benzimidazol-5-yl } oxy) -N- (2-hydroxyethyl) pyridine-2-carboxamide, 4- ({2- [ (4-bromophenyl) amino ] -1-methyl-1H-benzimidazol-5-yl } oxy) -N, N-dimethylpyridine-2-carboxamide, 4- ({2- [ (4-bromophenyl) amino ] -1-methyl-1H-benzimidazol-5-yl } oxy) -N- (2, 2, 2-trifluoroethyl) pyridine-2-carboxamide, N- (4-bromophenyl) -1-methyl-5- { [2- (pyrrolidin-1-ylcarbonyl) pyridin-4-yl ] oxy } -1H-benzimidazol-2-amine, ethyl (3R) -3- (methyloxy) -4- [ ({4- [ (2- { [4- (trifluoromethyl) phenyl ] amino } -1H-benzimidazol-5-yl) oxy ] pyridin-2-yl } carbonyl) amino ] piperidine-1-carboxylate, 4- ({2- [ (4-bromophenyl) amino ] -1-methyl-1H-benzimidazol-5-yl } oxy) -N- [2- (dimethy l) benzimidazol-5-yl } oxy Arylamino) ethyl ] pyridine-2-carboxamide, 4- ({2- [ (4-bromophenyl) amino ] -1-methyl-1H-benzimidazol-5-yl } oxy) -N- (tetrahydrofuran-2-ylmethyl) pyridine-2-carboxamide, 4- ({2- [ (4-bromophenyl) amino ] -1-methyl-1H-benzimidazol-5-yl } hetero) -N- (2-morpholin-4-ylethyl) pyridine-2-carboxamide, 4- ({2- [ (4-bromophenyl) amino ] -1-methyl-1H-benzimidazol-5-yl } oxy) -N- (piperidin-4-ylmethyl) pyridine-2-carboxamide, and pharmaceutically acceptable salts thereof -carbamoyl, 5- ({2- [ (3-aminopyrrolidin-1-yl) carbonyl ] pyridin-4-yl } oxy) -N- (4-bromophenyl) -1-methyl-1H-benzimidazol-2-amine, 4- ({2- [ (4-bromophenyl) amino ] -1-methyl-1H-benzimidazol-5-yl } oxy) -N- [1- (diphenylmethyl) azetidin-3-yl ] pyridine-2-carboxamide, 4- ({2- [ (4-bromophenyl) amino ] -1-methyl-1H-benzimidazol-5-yl } oxy) -N-piperidin-3-ylpyridin-2-carboxamide, and pharmaceutically acceptable salts thereof, 4- ({2- [ (4-bromophenyl) amino ] -1-methyl-1H-benzimidazol-5-yl } oxy) -N- (1, 3-thiazol-2-yl) pyridine-2-carboxamide and 4- ({2- [ (4-bromophenyl) amino ] -1-methyl-1H-benzimidazol-5-yl } oxy) -N- [ (1-ethylpyrrolidin-2-yl) methyl ] pyridin-2-carboxamide, (4- {2- [ (4-bromophenyl) amino ] benzothiazol-5-yloxy } (2-pyridyl)) -N-methylcarbamoyl, (4- {2- [ (4-bromophenyl) amino ] benzoxazol-5- Oxy } - (2-pyridyl)) -N-methylcarbamoyl and other representative compounds listed in the examples.

In other aspects, the invention relates to processes for preparing compounds of formula I, II, III, IV and V and synthetic intermediates useful in such processes.

The compounds of the present invention contain asymmetrically substituted carbon atoms. Such asymmetrically substituted carbon atoms may be derived from compounds of the present invention which comprise a mixture of stereoisomers at a particular asymmetrically substituted carbon atom or a single stereoisomer. Thus, the present invention includes racemic mixtures, mixtures of diastereomers, as well as individual diastereomers of the compounds of the invention. As used herein, the terms "S" and "R" configuration are in accordance with IUPAC1974R_{ECOMMENDATIONS FOR} S_ECTION E，F_UNDAMENTAL S_{TEREOCHEMISTRY}Pureepl. chem.45: 13-30 (1976). The terms α and β are used to denote the ring position of a cyclic compound. The alpha-side of the reference plane refers to the side of the preferred substituent located at the lower numbered position. Those substituents located on opposite sides of the reference plane are designated beta descriptors. It should be noted that this use is different from that of the cyclic stereogenic mother nucleus, where α means "below the plane" and indicates the absolute configuration. In this context, the terms α and β configuration are according to C_HEMICAL A_BSTRACTS I_NDEX G_UIDE-A_PPENDIXIV (1987) definition in paragraph 203.

The invention also relates to processes for preparing the compounds of the invention and to synthetic intermediates used in such processes, as described below.

Synthesis method

The benzimidazole-containing compounds of the present invention may be prepared using a number of methods familiar to those skilled in the art. In one approach, appropriately functionalized diamines may be coupled with various thioisocyanates to form thiourea intermediates. The cyclization reaction to form the benzimidazole moiety is carried out under known conditions, following the following scheme, with, for example, a carbodiimide or alkyl halide.

The process comprises the following steps:

the method comprises the following steps:

alternatively, the diamine may be reacted sequentially with carbonyldiimidazole and phosphorus oxychloride, followed by coupling with the appropriate amine.

Similarly, compounds comprising an oxazole structure can be prepared according to the methods described above or other known general procedures. Haviv et al (j.med.chem.1988, 31: 1719) describe a procedure for combining oxazole cores in which the hydroxyaniline is treated with potassium ethyl xanthate. The resulting sulfonylbenzoxazole is then chlorinated and coupled with an amine.

Compounds containing a benzothiazole core may also be prepared according to known methods. Reacting the ortho-halothioisocyanate with an amine to form a thiourea. Then, reduction with NaH forms the thiazole ring.

For example, the benzothiazoles of the present invention may be generally substituted by the synthetic routes described below:

benzoxazoles are generally synthesized by the following route:

the compounds of the invention can inhibit the growth of cancer cells in vitro or in vivo. The compounds may be used alone or in combination with a pharmaceutically acceptable carrier or excipient. Suitable pharmaceutically acceptable carriers or excipients include, for example, processing agents and drug delivery modifiers and enhancers, such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, glucose, hydroxypropyl- β -cyclodextrin, polyvinylpyrrolidone, low melting waxes, ion exchange resins, and the like, as well as combinations of any two or more thereof. Other suitable pharmaceutically acceptable excipients are described in Remington's pharmaceutical sciences, "Mack pub. Co., New Jersey (1991), which is incorporated herein by reference.

An effective amount of a compound of the invention generally includes any amount sufficient to detectably inhibit Raf activity by any of the assays described herein, other Raf kinase activity assays known to those skilled in the art, or by detecting inhibition or alleviation of symptoms of cancer.

The amount of active ingredient that is combined with the carrier materials to produce a single dosage form will vary with the subject being treated and the particular mode of administration. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy. The therapeutically effective amount in the given case is readily determined by routine experimentation and is within the skill and judgment of the ordinary clinician.

In the present invention, a therapeutically effective dose is generally the total daily dose administered to a subject in a single or divided dose and may be, for example, from 0.001 to 1000mg/kg body weight per day, more preferably from 1.0 to 30mg/kg body weight per day. Dosage unit compositions may contain amounts of submultiples thereof to compensate for the daily dosage.

The compounds of the present invention may be administered orally, parenterally, sublingually, or by nebulisation or inhalation spray, rectally, or topically in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles as required. Typical modes of administration also include transdermal administration, such as transdermal patches or iontophoresis devices. As used herein, the term "parenteral" includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.

Injectable preparations, for example sterile injectable aqueous or oleaginous suspensions, may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1, 3-propanediol. Suitable excipients and solvents which may be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectables.

Suppositories for rectal administration are prepared by mixing the drug with suitable non-irritating excipients such as cocoa butter and polyethylene glycols, which are solid at ordinary temperatures but liquid at the rectal temperature and therefore melt in the rectum and release the drug.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound may be mixed with at least one inert diluent such as sucrose, lactose or starch. As in normal practice, such dosage forms may also contain other substances in addition to inert diluents, for example lubricating agents such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Medicaments and pills may also be prepared with an enteric coating.

Oral liquid dosage forms may comprise pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, cyclodextrins, and sweetening, flavoring, and perfuming agents.

The compounds of the invention may also be administered in the form of liposomes. As is known in the art, liposomes are typically derived from phospholipids or other lipid substances. Liposomes are formed from mono-or multilamellar hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The compositions in liposome form may contain, in addition to the compounds of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are natural and synthetic phospholipids and phosphatidyl cholines (lecithins). Methods of forming liposomes are known in the art. See, for example, the eds presmott, Methods in Cell Biology, Vol.fourteenth, Academic Press, New York, N.W., p.33, et al (1976).

Although the compounds of the present invention may be administered as the sole active agent, they may also be used in combination with one or more other agents for the treatment of cancer. Representative agents for use in combination with the compounds of the invention for the treatment of cancer include, for example, irinotecan, topotecan, yersinine, 5-fluorouracil, leucovorin, carboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide, vinca alkaloids, imatinib (Gleevec), anthracyclines, rituximab, trastuzumab, and other cancer chemotherapeutic agents.

The compounds described above in combination with the compounds of the present invention are used in therapeutic amounts, as shown in the Physicians' Desk Reference (PDR), 47 th edition (1993), incorporated herein by Reference, or as known to those of skill in the art, in amounts useful for therapy.

The compounds of the invention and other anticancer agents may be administered at the recommended maximum clinical dose or at lower doses. The dosage level of the active compound in the compositions of the invention may be varied to achieve the desired therapeutic effect depending on the route of administration, the severity of the disease and the response of the patient. Administration may be as a single composition or as a single dosage form comprising both agents. When administered in combination, the therapeutic agents may be formulated as separate compositions, or the therapeutic agents may be administered as a single composition, at the same time or at different times.

Antiestrogens, such as tamoxifen, inhibit breast cancer growth by arresting the induction of the cell cycle, which requires the action of the cell cycle inhibitor p27 Kip. Recently, activation of the ras-Raf-MAP kinase pathway has been shown to alter the phosphorylation state of p27Kip, impairing the inhibitory activity of the arrested cell cycle, thereby contributing to antiestrogen resistance (Donovan et al, J.biol.chem.276: 40888, 2001). As reported by Donovan et al, inhibition of MAPK signaling altered the phosphorylation state of p27 in hormone-remodeled breast cancer cell lines during MEK inhibitor treatment, as well as restored hormone sensitivity. Thus, in one aspect, the compounds of formula (I), (II), (III), (IV) and (V) may be used to treat hormone-dependent cancers, such as breast and prostate cancer, with conventional anti-cancer agents to reverse the hormone resistance common in these cancers.

In blood cancers such as Chronic Myelogenous Leukemia (CML), chromosomal translocations are responsible for the constitutive activation of the BCR-AB1 tyrosine kinase. These afflicted patients responded to Geevec, a small molecule tyrosine kinase inhibitor, as a result of inhibition of Ab1 kinase activity. However, many patients with advanced disease initially respond to imatinib, but then relapse due to a mutation conferred by resistance in the Ab1 kinase domain. In vivo studies demonstrated that BCR-Av1 uses the Raf kinase pathway to exert its effects. Furthermore, inhibition of more than one kinase in the same pathway may provide additional protection against resistance conferring mutations. Thus, another aspect of the invention is the use of a compound of formula (I), (II), (III), (IV) and (V) in combination with at least one additional agent, such as imatinib, to reverse or prevent resistance to the at least one additional agent in the treatment of blood cancers, such as Chronic Myelogenous Leukemia (CML).

The invention will be better understood from the following examples, which are given for the purpose of illustration and are not intended to limit the invention.

Representative side chains for the compounds used in the following examples are generally prepared as follows:

example 1

Synthesis of 4- [ (2- { [ 4-chloro-3- (trifluoromethyl) phenyl ] amino } -1H-benzimidazol-6-yl) oxy ] -N-methylpyridine-2-carboxamide

Compound 4- [ (2- { [ 4-chloro-3- (trifluoromethyl) phenyl ] amino } -1H-benzimidazol-6-yl) oxy ] -N-methylpyridine-2-carboxamide was synthesized as follows:

step 1. Synthesis of 4- [ (4-amino-3-nitrophenyl) oxy ] -N-methylpyridine-2-carboxamide:

the mixture comprising 4-amino-3-nitrophenol (1 equivalent) and potassium bis (trimethylsilyl) amide (2 equivalents) was stirred in dimethylformamide at room temperature for 2 hours. To this mixture were added (4-chloro (2-pyridyl)) -N-methylcarbamoyl (1 equivalent) and potassium carbonate (1.2 equivalents), and stirred at 90 ℃ for 3 days. The reaction mixture was then concentrated and separated between ethyl acetate and water. The organic layer was separated, washed with brine, dried, filtered, and concentrated in vacuo to give a brown solid. Purification on silica gel (2% triethylamine/50% ethyl acetate in hexanes) gave 4- [ (4-amino-3-nitrophenyl) oxy ] -N-methylpyridine-2-carboxamide as an orange solid. The product had satisfactory NMR. HPLC, 3.39 min; MS: MH + ═ 289.

Step 2. Synthesis of 4- [ (3, 4-diaminophenyl) oxy ] -N-methylpyridine-2-carboxamide:

a mixture containing [4- (3-amino-4-nitrophenoxy) (2-pyridyl) ] -N-in methanol was hydrogenated with a catalytic amount of 10% Pd/C until the yellow color disappeared, yielding the product amine. HPLC, 2.5 mins; MS: MH + ═ 259.

Step 3. Synthesis of 4- [ (2- { [ 4-chloro-3- (trifluoromethyl) phenyl ] amino } -1H-benzimidazol-6-yl) oxy ] -N-methylpyridine-2-carboxamide:

a mixture comprising 4- [ (3, 4-diaminophenyl) oxy ] -N-methylpyridine-2-carboxamide (1 equivalent) and 4-chloro-3- (trifluoromethyl) benzeneisothiocyanate (1 equivalent) in tetrahydrofuran was stirred at room temperature for 16 h to give the corresponding thiourea. To the resulting mixture was added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (2 eq) and the mixture was stirred for a further 10 hours. The mixture was concentrated and separated between ethyl acetate and water. The organic layer was washed with brine and dried. Purification on HPLC afforded 4- [ (2- { [ 4-chloro-3- (trifluoromethyl) phenyl ] amino } -1H-benzimidazol-6-yl) oxy ] -N-methylpyridine-2-carboxamide. MS: MH + ═ 462

Examples 2 to 108

The compounds shown in table 1 below (examples 2-108) were prepared according to the procedure described in example 1.

TABLE 1

Example 109

Synthesis of (4- {2- [ (4-bromophenyl) amino ] -benzothiazol-5-yloxy } (2-pyridyl)) -N-methylcarbamoyl

Step 1. Synthesis of 2-bromo-5-methoxybenzothiazole

At 0 deg.CA solution of bromine (3.6 equivalents) in chloroform (.75M) was added dropwise to a stirred suspension of 5-methoxy-2-mercaptobenzothiazole (1 equivalent) in chloroform over 1 hour. The mixture was stirred for 30 minutes before slowly adding it to water and for an additional 20 minutes. The mixture was filtered to remove the milky white solid. The organic phase was dried and evaporated to leave a brown solid. The brown solid was dissolved in ether and filtered. The residue was washed with ether, the filtrate and washings were combined and evaporated and chromatographed (4: 1 hexane and ethyl acetate) to give the title compound as a pale yellow solid. MS: MH⁺＝244

Step 2. Synthesis of (4-bromophenyl) (5-methoxybenzothiazol-2-yl) amine

The mixture containing 2-bromo-5-methoxybenzothiazole (1 eq), 4-bromoaniline (2 eq) and diisopropylethylamine was subjected to microwave heating in NMP at 220 ℃. The resulting mixture was concentrated and separated between ethyl acetate and water. The organic layer was washed with brine and dried. Purification on silica gel gave the desired product. MS: MH⁺＝335

Step 3, synthesizing 2- [ (4-bromophenyl) amino ] benzothiazole-5-alcohol

The mixture of (4-bromophenyl) (5-methoxybenzothiazol-2-yl) amine and hydrobromic acid (48%) was heated by microwave heating at 150 ℃ for 6 minutes to give the desired product. MS: MH⁺＝321

Step 4. synthesize (4- {2- [ (4-bromophenyl) amino ] benzothiazol-5-yloxy } (2-pyridyl)) -N-methylcarbamoyl:

stirring the mixture containing 2- [ (4-bromophenyl) amino group in dimethylformamide at room temperature]Mixture of benzothiazol-5-ol (1 equivalent) and potassium bis (trimethylsilyl) amide (4 equivalents) for 30 minutes. (4-chloro (2-pyridyl) -N-methylcarbamoyl (1 equiv.) and potassium carbonate (1.2 equiv.) are added to the mixture and heated at 150 ℃ for 6 minutes by microwave, then the reaction mixture is concentrated, and separated between ethyl acetate and water, the organic layer is separated,washed with brine, dried, filtered and concentrated. Purification on preparative liquid chromatography yielded the desired product. MS: MH⁺＝455

The procedure of example 109 was followed to synthesize the respective compounds shown in example 110-119 shown in Table 2 below:

TABLE 2

Example 120a

Synthesis of 4- ({2- [ (4-bromophenyl) amino ] -1-methyl-1H-benzimidazol-5-yl } oxy) -N-methylpyridine-2-carboxamide

The compound 4- ({2- [ (4-bromophenyl) amino ] -1-methyl-1H-benzimidazol-5-yl } oxy) -N-methylpyridine-2-carboxamide was synthesized as follows:

step 1 Synthesis of 4- { [ 3-amino-4- (methylamino) phenyl ] oxy } -N-methylpyridine-2-carboxamide:

a solution of 4- [ (4-amino-3-nitrophenyl) oxy ] -N-methylpyridine-2-carboxamide (1 equivalent) in dichloromethane was treated with trifluoroacetic anhydride (1 equivalent) and stirred at 0 ℃ for 10 minutes. The mixture was quenched with saturated NaHCO3 solution. The organic layer was separated, washed with water, brine, dried and evaporated. MS: MH + 385.2.

To a solution of trifluoroacetamide (1 eq) in a mixture of toluene, acetonitrile and sodium hydroxide solution (50%) was added benzyltrimethylammonium chloride (1 eq) and dimethyl sulfate (1.2 eq). The biphasic mixture was stirred overnight at room temperature and evaporated. The mixture was extracted in ethyl acetate, washed with water, brine, dried and evaporated. The crude product was purified by column chromatography eluting with 1: 1 hexane and ethyl acetate followed by 1: 1 hexane and 2% triethylamine in ethyl acetate to give N-methyl-4- { [4- (methylamino) -3-nitrophenyl ] oxa } pyridine-2-carboxamide as a reddish orange solid. MS: MH + 303.1.

A solution of nitromethylaniline in methanol was treated with palladium on 5% carbon at room temperature and stirred under a hydrogen atmosphere for 15 minutes (until the yellow colour disappeared). The mixture was filtered and the filtrate was concentrated to give 0.36g of diamine 4- { [ 3-amino-4- (methylamino) phenyl ] oxy } -N-methylpyridine-2-carboxamide. MS: MH + 273.3.

Step 2. Synthesis of 4- ({2- [ (4-bromophenyl) amino ] -1-methyl-1H-benzimidazol-5-yl } oxy) -N-methylpyridine-2-carboxamide:

a solution of diamine 4- { [ 3-amino-4- (methylamino) phenyl ] oxy } -N-methylpyridine-2-carboxamide (1 eq) in methanol was treated with 4-bromophenyl isothiocyanate (1 eq) and stirred at 60-65 ℃ for 2 h. The reaction mixture was cooled to room temperature, methyl iodide (1 eq) was added and stirred at 60 ℃ overnight. The reaction was cooled to room temperature, evaporated, extracted in ethyl acetate, washed with water and brine, dried and evaporated under reduced pressure. Column chromatography using a gradient solvent system of hexane and ethyl acetate with 1: 1 dichloromethane and acetone or 5% methanol in dichloromethane afforded a semi-white powder. MS: MH + ═ 452.3

Example 120b

Alternative to the Synthesis of 4- ({2- [ (4-bromophenyl) amino ] -1-methyl-1H-benzimidazol-5-yl } oxy) -N-methylpyridine-2-carboxamide

Step 1, synthesizing N-methyl {4- [4- (methylamino) -3-aminophenoxy ] (2-pyridyl) } carbamoyl:

a mixture containing 4-amino-3-nitrophenol 5(1.0g, 6.4mmol), potassium bis (trimethylsilyl) amide (2.58g, 12.8mmol) was stirred in DMF (50ml) at room temperature. To this mixture were added (4-chloro (2-pyridyl)) -N-methylcarbamoyl 4(1.09g, 6.4mmol) and potassium carbonate (0.5g, 7.6mmol), and stirred at 90 ℃ overnight. The reaction mixture was then concentrated and separated between ethyl acetate and water. The organic layer was separated and washed with brine (2X10ml), dried, filtered and concentrated in vacuo to give a brown solid. Purification on silica gel with 2% triethylamine (in 50% mixture of ethyl acetate and hexane) gave 1.3g (yield 72%) of [4- (4-amino-3-nitrophenoxy) (2-pyridyl) as an orange solid]-N-methylcarbamoyl 6:¹H NMR(300MHz，CDCl₃)δ8.40(d，J＝5.6Hz，1H)，7.99(br s，1H)，7.90(d，J＝2.7Hz，1H)，7.64(d，J＝2.7Hz，1H)，7.17(dd，J＝2.7，9.0Hz，1H)，6.95(ddd，J＝0.7，2.5，5.6Hz，1H)，6.89(d，J＝9.0Hz，1H)，6.18(br s，2H)，3.00(d，J＝5.1Hz，3H)；mp 208-210℃ dec；LCMS m/z 289.2(MH⁺)，t_R1.92 minutes.

To a 500mL three-necked round bottom flask equipped with mechanical stirring was added nitroaniline 6(10.0g, 34.8mmol) and CH₂Cl₂(175 ml). The resulting suspension was cooled to 0 ℃ and TFAA (9.5mL, 14.1g, 67.0mmol) was added over 16 hours, while the cooling bath was stopped². After the reaction was judged to be complete using TLC,³TBACl (5.2g, 17.5mmol) was added⁴And dimethyl sulfate (6.7mL, 8.9g, 70.0mmol) followed by the addition of 50% aqueous NaOH (140 mL). The resulting reaction mixture was cooled with an ice bath and stirred vigorously at room temperature for 1.5 hours.^3，5，6The reaction was then poured off with ice-water and the phases separated and separated. By CH₂Cl₂The aqueous phase was extracted (3X 100mL) and washed with brine (2X 100 m)L) washing the combined organic layers and drying (MgSO)₄) And concentrated. The crude product was purified by recrystallization (1: 3 ethanol-water) to give 8.36g (27.7mmol, 79%) red fine needles 7:¹H NMR(300MHz，CDCl₃)δ8.40(dd，J＝0.5，4.9Hz，1H)，8.07(br d，J＝3.7Hz，1H)，7.98(br s，1H)，7.95(d，J＝2.9Hz，1H)，7.62(dd，J＝0.5，2.9Hz，1H)，7.27(ddd，J＝0.5，2.9，9.3Hz，1H)，6.98(dd，J＝2.7，5.6Hz，1H)，6.92(d，J＝9.3Hz，1H)，3.07(d，J＝5.1MHz，3H)，3.00(d，J＝5.1Hz，3H)；¹³C NMR(75MHz，CDCl₃)δ166.6，164.6，152.6，150.0，144.8，142.2，130.6，118.9，115.5，114.2，109.7，30.2，26.4；mp 164-166℃。LCMS m/z 303.4(MH⁺)，t_R＝2.37min。

with N₂A suspension of nitroaniline 7(5.0g, 16.5 mmol 1) in methanol was sparged for 20 minutes followed by the addition of 10% Pd/C (0.88g, 0.8 mmol). By H₂The reaction was rinsed and kept at room temperature under a hydrogen atmosphere overnight. With N₂The reaction was washed and filtered through celite. The collected solid was washed with EtOAc (3X50mL) and dried (MgSO)₄) The combined organic layers were concentrated to give 4.35g (16.0mmol, 97%) of a cream solid 8:¹H NMR(300MHz，CDCl₃)，δ8.30(d，J＝5.5Hz，1H)，7.99(br s，1H)，7.67(d，J＝2.5Hz，1H)，6.91(dd，J＝2.5，5.5Hz，1H)，6.62(d，J＝8.5Hz，1H)，6.53(dd，J＝2.5，8.5Hz，1H)，6.44(d，J＝2.5Hz，1H)，2.98(d，J＝5.2Hz，3H)，2.86(s，3H)；¹³CNMR(75MHz，CDCl₃)δ167.4，164.9，152.2，149.6，146.0，136.6，136.3，114.0，112.3，112.0，110.2，109.0，31.6，26.5；mp 153-156℃dec.；LCMS m/z 273.3(MH⁺)，t_R＝1.66min。

step 2. synthesis of (4- {2- [ (4-bromophenyl) amino ] -1-methylbenzimidazole-5-yloxy } (2-pyridyl)) -N-methylcarbamoyl:

to a 250mL round bottom flask was added 4-bromophenyl isothiocyanate¹(2.17g, 10.1mmol), diamine 8(2.74g, 10.1mmol) and MeOH (40mL), and the reaction was left at room temperature overnight. Ferric chloride (2.43g, 15mmol) was added and the resulting red reaction mixture was stirred overnight. The reaction was separated with EtOAc (100mL) and water (100mL) and filtered through celite. The layers were separated and saturated Na was used₂CO₃The aqueous phase was neutralized in solution (pH 7). The resulting aqueous phase was extracted with EtOAc (100mL) and the mixture was filtered through celite. The phases were separated, the aqueous phase was re-extracted, and filtered. The combined organic layers were washed with brine (250mL) and dried (MgSO)₄) And concentrated to give a brown solid. The crude residue was purified by trituration in hot toluene to give 2.22g (4.95mmol, 49%) of a tan solid 1:¹H NMR(300MHz，CDCl₃)δ8.38(d，J＝5.8Hz，1H)，8.07(br d，J＝4.7Hz，1H)，7.61(d，J＝2.5Hz，1H)，7.44(app dd，J＝8.8，20.6Hz，4H)，7.05(m，3H)，6.78(dd，J＝2.2，8.5Hz，1H)，3.51(s，3H)，3.00(d，J＝5.2Hz，3H)；mp 251-254℃ dec.；LCMS m/z 452.2(MH⁺)，t_R2.17 min. .

Example 121-

The compound described in Table 3 below (example 121-384) was prepared by the procedure described in example 120 a.

TABLE 3

Example 372

Synthesis of 4- ({2- [ (4-bromophenyl) amino ] -1-methyl-1H-benzimidazol-5-yl } oxy) -N-ethylpyridin-2-carboxamide

4- ({2- [ (4-bromophenyl) amino ] -1-methyl-1H-benzimidazol-5-yl } oxy) -N-ethylpyridine-2-carboxamide was synthesized as follows:

step 1, synthesizing tert-butyl 4-chloropyridine-2-carboxylate:

4-chloropyridine-2-carbonyl chloride (1 eq) was suspended in anhydrous tetrahydrofuran. 2 equivalents of 1M potassium tert-butoxide are then slowly added dropwise to the reaction while the reaction is stirred under nitrogen. After 3-4 hours, or when the reaction was complete as determined by HPLC, the reaction was evaporated under reduced pressure and diluted with ethyl acetate. The organic layer was washed with water, followed by brine and dried over anhydrous sodium sulfate. The organic extract was evaporated under reduced pressure to give tert-butyl ester as a yellow oil. MS: MH + ═ 214.0

Step 2, synthesizing tert-butyl 4- (4-amino-3-nitrophenoxy) pyridine-2-carboxylate:

KHMDS (2 equiv.) as an anhydrous white solid powder was suspended in dimethylformamide. Red crystalline 4-amino-3-nitrophenol (1 eq) was added to the rapidly stirred solution under an inert atmosphere and the heterogeneous solution was stirred for 2 hours. Then, a solution of tert-butyl 4-chloropyridine-2-carboxylate (1 equivalent) in dimethylformamide was added dropwise. Anhydrous potassium carbonate powder (1.2 eq) was added to the reaction as an acid scavenger. The purple viscous mixture was heated to 80 ℃ for 12-15 hours until the reaction was complete as determined by HPLC. The reaction was evaporated under reduced pressure and diluted with excess ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The organic layers were mixed and washed with water then brine four times. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. Flash silica gel chromatography using a 1: 1 mixture of hexane and ethyl acetate as eluent was carried out to purify the crude material to give the desired product. MS: MH + ═ 332.

Step 3, synthesizing tert-butyl 4- [ 3-nitro-4- (2, 2, 2-trifluoroacetylamino) phenoxy ] pyridine-2-carboxylate:

trifluoroacetic anhydride (1 eq) was slowly added dropwise to a solution of the above amine in anhydrous dichloromethane under nitrogen. After 10-15 minutes, or after the reaction was complete as determined by HPLC, the reaction was quenched with an excess of saturated aqueous sodium bicarbonate. The product was extracted from the aqueous layer with dichloromethane and washed with water and brine. The extract was dried using anhydrous sodium sulfate and evaporated under reduced pressure to give the title product as a yellow solid. MS: MH⁺＝428.

Step 4, synthesizing tert-butyl 4- [ 3-nitro-4- (2, 2, 2-trifluoro-N-methylacetylamino) phenoxy ] pyridine-2-carboxylic ester:

before 2 equivalents of methyl iodide (2 equivalents) were slowly added dropwise to the reaction mass, the tert-butyl amount of 4- [ 3-nitro-4- (2, 2, 2-trifluoroacetylamino) phenoxy was stirred under nitrogen at 20 ℃]Pyridine-2-carboxylic acid ester (1 equivalent) and sodium carbonate (4 equivalents) in dimethylformamide for 30 minutes. After 2-3 hours, or after the reaction was complete as determined by HPLC, the reaction was evaporated under reduced pressure. The crude mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the title product as an orange solid. MS: MH⁺＝442。

Step 5, synthesizing tert-butyl 4- [4- (methylamino) -3-nitrophenoxy ] pyridine-2-carboxylate:

tert-butyl 4- [ 3-nitro-4- (2, 2, 2-trifluoro-N-methylacetylamino) phenoxy group was stirred at room temperature]Pyridine-2-carboxylic acid ester in ethanol. 1N sodium hydroxide was slowly added dropwise to the reaction until conversion was complete as determined by HPLC. The reaction was evaporated under reduced pressure and extracted with ethyl acetate, washed with saturated aqueous ammonium chloride solution, followed by water and brine. The organic extract was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the product as an orange solid. MS: MH⁺＝346

Step 6, synthesizing tert-butyl 4- [ 3-amino-4- (methylamino) phenoxy ] pyridine-2-carboxylate:

tert-butyl 4- [4- (methylamino) -3-nitrophenoxy group was stirred at room temperature]Pyridine-2-carboxylate (1 equivalent) and 10% palladium on carbon (0.1 equivalent) in methanol, and flushed with nitrogen. The reaction was flushed with hydrogen for 1-2 hours, or until HLPC determined the reaction was complete. The reaction was flushed with nitrogen for 15 minutes before being filtered through a pad of celite. The celite pad was washed with excess methanol, followed by concentration under reduced pressure to give the product as a pale yellow solid. MS: MH⁺＝316.

Step 7. Synthesis of tert-butyl 4- {2- [ (4-bromophenyl) amino ] -1-methylbenzimidazol-5-yloxy } pyridine-2-carboxylic acid:

a solution of the diamine (1 eq.) and 4-bromophenyl isothiocyanate (1 eq.) in anhydrous tetrahydrofuran from step 6 was stirred at 20 deg.C under nitrogen for 2-3 hours, or when the reaction was complete as determined by HLPC. The solution was treated with 3 equivalents of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride. The stirred solution was heated to 50 ℃ under nitrogen for 2-3 hours, or until the reaction was complete as determined by HLPC. The reaction was evaporated under reduced pressure and then diluted with ethyl acetate and water. The aqueous layer was back-extracted with ethyl acetate. The mixed organic layer was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, followed by drying under reduced pressure. Purifying by reverse phase high pressure liquid chromatographyCrude material, after freeze drying, gave a brown powder product. MS: MH⁺＝495.

Step 8, synthesizing 4- {2- [ (4-bromophenyl) amino ] -1-methylbenzimidazole-5-yloxy } pyridine-2-carboxylic acid

A trifluoroacetic acid solution of the product of step 7 was treated with two drops of water at room temperature for 3-4 hours, or until the reaction was complete as determined by HLPC. The reaction was evaporated under reduced pressure to give quantitatively the product as a red-orange oil. MS: MH⁺＝439.

Step 9. Synthesis of 4- ({2- [ (4-bromophenyl) amino ] -1-methyl-1H-benzimidazol-5-yl } oxy) -N-ethylpyridine-2-carboxamide:

a solution of the above (1 eq) anhydrous tetrahydrofuran (0.5ml) was treated with O-benzotriazol-1-yl N, N, N ', N' -tetramethyluronium hexafluorophosphate (2 eq), excess diisopropylethylamine and ethylamine (1 eq). The reaction was stirred under nitrogen for 12-15 hours. The reaction was evaporated under reduced pressure and diluted with ethyl acetate. The ethyl acetate layer was washed once with water and then evaporated under reduced pressure. The crude material was purified by reverse phase high pressure liquid chromatography and recovered as TFA salt after lyophilization. MS: MH⁺＝466.

Example 373-

The compounds shown in Table 4 below (example 373-447) were prepared by the procedure described in example 372.

TABLE 4

Example 450

Preparation of (4-chloro-phenyl) - {5- [2- (4, 5-dihydro-1H-imidazol-2-yl) -pyridin-4-yloxy ] -1-methyl-1H-benzimidazol-2-yl } -amine)

Step 1. synthesis of 4- (4-amino-3-nitro-phenoxy) ═ pyridine-2-carbonitrile:

potassium carbonate (9.00g) was dried under vacuum heating and cooled to room temperature under nitrogen. 4-amino-3-nitrophenol (3.355g), 4-chloro-2-cyanopyridine (3.00g) and DMSAO (30mL, anhydrous) were added. The system was stirred under nitrogen while heating to 103 ℃ and held at this temperature for 1 hour. The reaction was then cooled to room temperature and poured onto ice/H₂O (500mL), collecting the deposit, washing (H)₂O), dissolved (EtOAc), dried (Na)₂8O₄) Filtered and the solid was left behind. Suspension (Et)₂O), collected, air dried 4.1015g (73.5%), collected a second batch (0.5467gm, 10%). M/z 257(M +1)

Step 2. synthesis of N- [4- (2-cyano-pyridin-4-yloxy) -2-nitro-phenyl ] -2, 2, 2-trifluoro-N-methyl-acetamide:

potassium carbonate (1.6g) was dried under vacuum heating, cooled to room temperature, and suspended in dichloromethane (30mL) with 4- (4-amino-3-nitro-phenoxy) ═ pyridine-2-carbonitrile (2.005gm) under nitrogen. It was cooled to 0 ℃ and TFAA (2.2mL) was added. When added, the starting material quickly turned into a solution. After 10 minutes at 0 ℃, the mixture is diluted with dichloromethane and washed (H)₂O, aqueous NaCl solution), drying (K)₂CO₃) Filtering to leave yellowColored foam. And M/z is 353(M +1). The product can be used without purification.

Methyl iodide (0.53mL) was added to a suspension of potassium carbonate (1.858g) in DMF (30mL) containing Compound 2 (. about.7.8 mmole) under nitrogen. The suspension was stirred at room temperature overnight and then poured onto H₂On O (300mL), extract (Et)₂O, 3x150mL), washing the mixed extract (H)₂O, aqueous NaCl), dried (potassium carbonate), filtered and left an orange oil (7.4922 g). 367(M +1) ═ M/z

Step 3. synthesis of 4- (4-methylamino-3-nitro-phenoxy) -pyridine-2-carbonitrile:

NaOH (1mL, 1N aqueous solution) was added dropwise to N- [4- (2-cyano-pyridin-4-yloxy) -2-nitro-phenyl ] at room temperature]-2, 2, 2-trifluoro-N-methyl-acetamide (440mg) in ethanol (6 mL). After 40 minutes, with H₂The mixture was diluted with O (20mL) and cooled to 0 ℃. The bright orange crystals were collected, washed (H2O) and air dried 311.1mg (94%). M/z 271(M +1)

Step 4. Synthesis of 4- [2- (4-chloro-phenylamino) -1-methyl-1H-benzimidazol-5-yloxy ] -pyridine-2-carbonitrile:

palladium on carbon (46mg 10% w/w) was suspended in MeOH (2mL) under nitrogen. The resulting suspension was added to a suspension of 4- (4-methylamino-3-nitro-phenoxy) -pyridine-2-carbonitrile (311mg) in MeOH (3mL) at room temperature under nitrogen. The atmosphere was changed to hydrogen and the system was vigorously stirred at 1 atmosphere for 1 hour. The atmosphere was then changed to nitrogen and the mixture (celite) was filtered and the filtrate used without further purification in the next reaction. M/z 2421(M +1).

4-chlorophenyl isothiocyanate (200mg) was added to a solution of Compound 5 in MeOH (10 mL). The solution was stirred under reflux for 2 hours. Methyl iodide (71 ml) was added and stirring was continued at 67 ℃ overnight. The mixture was then cooled to room temperature, evaporated to dryness and the residue chromatographed (0.5% NH on silica gel)₄OH, 5% MeOH, 94.5% dichloromethane) was isolated to give compound Rf 0.29(325mg). crystallization from dichloromethane/ether gave 127 mg. M/z 376(M +1)

1HNMR(MeOH-d4)

9.40ppm s(b) (1H)

8.55ppm d，d H＝5.7，0.6Hz (1H)

7.62ppm m (2h)

7.42ppm d，d J＝2.5，0.6Hz (1H)

7.43ppm d (1H)

7.37ppm m (2h)

7.21ppm d J＝2.0Hz (1H)

7.15ppm d，d J＝5.9，2.5Hz (1H)

6.97ppm d，d J＝8.4，2.2hz (1H)

3.80ppm s (3H)

Step 5. synthesis of (4-chloro-phenyl) - {5- [2- (4, 5-dihydro-1H-imidazol-2-yl) -pyridin-4-yloxy ] -1-methyl-1H-benzimidazol-2-yl } -amine:

carefully remove H₂SO₄(454mg) 4- [2- (4-chloro-phenylamino) -1-methyl-1H-benzimidazol-5-yloxy-added]-pyridine-2-carbonitrile (60.0mg) in a suspension of ethylenediamine (0.50 mL). The system was shaken at room temperature for 72 hours and then poured onto ice/NaHCO₃The above. The solid product is collected and washed (H)₂O), and air-dried to give 59.8 mg. M/z 419(M +1).

Example 451

Synthesis of (4- {2- [ (4-bromophenyl) amino ] benzoxazol-5-yloxo } - (2-pyridyl)) -N-methylcarbamoyl

Step 1. Synthesis of 2-amino-4-methoxyphenol

The mixture containing 4-methoxy-2-nitrophenol in methanol was hydrogenated with a catalytic amount of 10% Pd/C until the yellow color disappeared to give 2-amino-4-methoxyphenol. MS: MH + 140.

Step 2, synthesizing 5-methoxybenzoxazole-2-thiol

The mixture comprising 2-amino-4-methoxyphenol (1 eq) and O-ethylxanthic acid, potassium salt (1.1 eq) in pyridine was refluxed for 2 hours. The resulting mixture was poured into ice/water containing hydrochloric acid to give a tan solid 5-methoxybenzoxazole-2-thiol. MS: MH + 182

Step 3, synthesizing 2-chloro-5-methoxybenzoxazole

Heating the mixture comprising 5-methoxybenzoxazole-2-thiol in thionyl chloride with one drop of DMF. The resulting mixture was concentrated and separated between ethyl acetate and water. The organic layer was washed with brine, dried and concentrated. Purifying on a silica gel column to obtain white solid 2-chloro-5-methoxybenzoxazole. MS: MH + ═ 184.

Step 4, (4-bromophenyl) (5-methoxybenzoxazole-2-yl) amine is synthesized

The mixture containing 2-chloro-5-methoxybenzoxazole (1 equivalent), 4-bromoaniline (2 equivalents) and diisopropylethylamine was refluxed in dimethylformamide. The resulting mixture was concentrated and separated between ethyl acetate and water. The organic layer was washed with brine and dried. Purification on silica gel gave (4-bromophenyl) (5-methoxybenzoxazol-2-yl) amine. MS: MH + (318)

Step 5, synthesizing 2- [ (4-bromophenyl) amino ] benzoxazole-5-ol

The mixture of (4-bromophenyl) (5-methoxybenzoxazol-2-yl) amine and hydrobromic acid (48%) was heated by microwave at 150 ℃ for 6 minutes to give 2- [ (4-bromophenyl) amino ] benzoxazol-5-ol. MS: MH + (305)

Step 6, synthesizing (4- {2- [ (4-bromophenyl) amino ] benzoxazole-5-yloxy } - (2-pyridyl)) -N-methylcarbamoyl

The mixture containing 2- [ (4-bromophenyl) amino ] benzoxazol-5-ol (1 equivalent), potassium bis (trimethylsilyl) amide (4 equivalents) was stirred in dimethylformamide at room temperature for 30 minutes. To the mixture was added (4-chloro (2-pyridyl) -N-methylcarbamoyl (1 eq) and potassium carbonate (1.2 eq) and heated at 150 ℃ for 6 minutes under microwave heating then the reaction mixture was concentrated and separated between ethyl acetate and water the organic layer was separated and washed with brine, dried, filtered and concentrated.

The compound shown in Table 5 below (example 452-481) was prepared by following the procedure of example 449-451.

TABLE 5

Example 482

Synthesis of [4- (2- { [4- (dimethylamino) phenyl ] amino-1-methylbenzimidazol-5-yloxy) (2-pyridyl) ] -N- (2-pyrrolidinylethyl) carbamoyl

Step 1 Synthesis of 4- (2- { [4- (dimethylamino) phenylamino) -1-methylbenzimidazol-5-yloxy) pyridine-2-carboxylic acid

Tert-butyl 4- [ 3-amino-4- (methylamino) phenoxy ] to methanol]To pyridine-2-carboxylate (1 equivalent) was added 4- (dimethylamino) benzeneisothiocyanate (1 equivalent), and stirred at room temperature for 16 hours. LC/MS was performed after the formation of the corresponding thiourea. The mixture was then concentrated, and tetrahydrofuran and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (2 eq) were added thereto and stirred at room temperature for 16 hours. Extraction of butyl 4- (2- { [ 4-dimethylamino) phenyl group from the reaction mixture]Amino) -1-methylbenzimidazol-5-yloxy) pyridine-2-carboxylate. Trifluoroacetic acid was added thereto (in dichloromethane) and stirred at room temperature overnight. Purification by preparative chromatography gave 4- (2- { [ 4-dimethylamino) phenylamino) -1-methylbenzimidazol-5-yloxy) pyridine-2-carboxylic acid. MS: MH⁺＝403。

Step 2. Synthesis of [4- (2- { [4- (dimethylamino) phenylamino-1-methylbenzimidazol-5-yloxy) (2-pyridyl) ] -N- (2-pyrrolidinylethyl) carboxamide:

to 4- (2- { [4- (dimethylamino) phenylamino) -1-methylbenzimidazol-5-yloxy) pyridine-2-carboxylic acid (1 eq) in tetrahydrofuran was added 2-pyrrolidinoethylamine (2 eq), HBTU (2 eq) and N, N-diisopropylethylamine (4 eq) and stirred at room temperature for 16 h. The mixture was then concentrated and separated between ethyl acetate and water. The organic layer was concentrated and subjected to preparative chromatography to give [4- (2- { [4- (dimethylamino) phenyl ] amino]Amino-1-methylbenzimidazol-5-yloxy) (2-pyridyl)]-N- (2-pyrrolidinylethyl) carboxamide. MS: MH⁺＝498.

Example 483

Synthesis of [4- (2- { [ 4-bromo-3-methylphenyl) amino-1-methylbenzimidazol-5-yloxy) (2-pyridyl) ] -N- (2-pyrrolidinylethyl) carboxamide

Step 1. Synthesis of 4- {2- [ (4-bromo-3-methylphenyl) amino ] -1-methylbenzimidazol-5-yloxy) pyridine-2-carboxylic acid

Tert-butyl 4- [ 3-amino-4- (methylamino) phenoxy ] to methanol]Pyridine-2-carboxylate (1 equivalent) was added 4-bromo-3-methylbenzene isothiocyanate (1 equivalent), and stirred at room temperature for 16 hours. LC/MS was performed after the formation of the corresponding thiourea. Then, methyl iodide (1 equivalent) was added thereto, and heated to 60 ℃ for 2 hours. In the formation of tert-butyl 4- (2- { [ 4-bromo-3-methylphenyl)]Amino) -1-methylbenzimidazol-5-yloxy) pyridine-2-carboxylic acid butyl ester followed by LC/MS. Trifluoroacetic acid was added thereto (in dichloromethane) and stirred at room temperature overnight. Purification by preparative chromatography gave 4- (2- { [ 4-bromo-3-methylphenylamino) -1-methylbenzimidazol-5-yloxy) pyridine-2-carboxylic acid. MS: MH⁺＝452

Step 2 Synthesis of [4- (2- { [ 4-bromo-3-methylphenyl) amino-1-methylbenzimidazol-5-yloxy) (2-pyridyl) ] -N- (2-pyrrolidinylethyl) carboxamide

To 4- (2- { [ 4-bromo-3-methylphenylamino) -1-methylbenzimidazol-5-yloxy) pyridine-2-carboxylic acid (1 eq) in tetrahydrofuran was added 2-pyrrolidinoethylamine (2 eq), HBTU (2 eq) and N, N-diisopropylethylamine (4 eq) and stirred at room temperature for 16 h. The mixture was then concentrated and separated between ethyl acetate and water. The organic layer was concentrated and purified by preparative chromatography to give [4- (2- { [4 bromo-3-methylphenyl ] phenyl]Amino-1-methylbenzimidazol-5-yloxy) (2-pyridyl)]-N- (2-pyrrolidinylethyl) carboxamide. MS: MH⁺＝549.

Example 484

Synthesis of [4- (2- { [ 2-fluoro-5- (trifluoromethyl) phenyl) amino-1-methyl-benzimidazol-5-yloxy) (2-pyridyl) ] -N- (2-pyrrolidinoethyl) carboxamide

Step 1 Synthesis of 4- {2- [ (2-fluoro-5- (trifluoromethyl) phenyl) amino ] -1-methylbenzimidazol-5-yloxy) pyridine-2-carboxylic acid

Tert-butyl 4- [ 3-amino-4- (methylamino) phenoxy ] to methanol]2-fluoro-5- (trifluoromethyl) benzeneisothiocyanate (1 eq) was added to pyridine-2-carboxylate (1 eq) and stirred at room temperature for 16 h. LC/MS was performed after the formation of the corresponding thiourea. Methyl iodide (1 eq) was then added thereto and heated to 60 ℃ for 2 hours. In the formation of tert-butyl 4- (2- { [ 2-fluoro-5- (trifluoromethyl) phenyl]Amino) -1-methylbenzimidazol-5-yloxy) pyridine-2-carboxylate followed by LC/MS. Trifluoroacetic acid was added thereto (in dichloromethane) and stirred at room temperature overnight. The resulting 4- (2- { [ 2-fluoro-5- (trifluoromethyl) phenylamino) -1-methylbenzimidazol-5-yloxy) pyridine-2-carboxylic acid was purified by preparative chromatography. MS: MH⁺＝446。

Step 2. Synthesis of [4- (2- { [ 2-fluoro-5- (trifluoromethyl) phenyl) amino-1-methylbenzimidazol-5-yloxy) (2-pyridyl) ] -N- (2-pyrrolidinylethyl) carboxamide:

to 4- (2- { [ 2-fluoro-5- (trifluoromethyl) phenylamino) -1-methylbenzimidazol-5-yl in tetrahydrofuranOxy) pyridine-2-carboxylic acid (1 eq) 2-pyrrolidinylethylamine (2 eq), HBTU (2 eq) and N, N-diisopropylethylamine (4 eq) were added and stirred at room temperature for 16 h. The mixture was then concentrated and separated between ethyl acetate and water. The organic layer was concentrated and purified by preparative chromatography to give [4- (2- { [ 2-fluoro-5- (trifluoromethyl) phenyl ] methane]Amino-1-methylbenzimidazol-5-yloxy) (2-pyridyl)]-N- (2-pyrrolidinylethyl) carboxamide. MS: MH⁺＝542.

Example 485

Synthesis of [4- (2- { [ 4-bromo-3-fluorophenyl) amino-1-methyl-benzimidazol-5-yloxy) (2-pyridyl) ] -N- (2-piperidylethyl) carboxamide

Step 1. Synthesis of 4- {2- [ (4-bromo-3-fluorophenyl) amino ] -1-methylbenzimidazole-5-yloxy) pyridine-2-carboxylic acid

Tert-butyl 4- [ 3-amino-4- (methylamino) phenoxy ] to methanol]Pyridine-2-carboxylate (1 eq) was added 4-bromo-3-fluorobenzene isothiocyanate (1 eq) and stirred at room temperature for 16 h. LC/MS was performed after the formation of the corresponding thiourea. Methyl iodide (1 eq) was then added thereto and heated to 60 ℃ for 2 hours. After formation of tert-butyl 4- (2- { [ 4-bromo-3-fluorophenyl)]Amino) -1-methylbenzimidazol-5-yloxy) pyridine-2-carboxylate followed by LC/MS. Trifluoroacetic acid was added thereto (in dichloromethane) and stirred at room temperature overnight. The resulting 4- (2- { [ 4-bromo-3-fluorophenylamino) -1-methylbenzimidazol-5-yloxy) pyridine-2-carboxylic acid was purified by preparative chromatography. MS: MH⁺＝456。

Step 2. Synthesis of [4- (2- { [ 4-bromo-3-fluorophenyl) amino-1-methylbenzimidazol-5-yloxy) (2-pyridyl) ] -N- (2-piperidylethyl) carboxamide:

to 4- (2- { [ 4-bromo-3-fluorophenylamino) -1-methylbenzimidazol-5-yloxy) pyridine-2-carboxylic acid (1 eq) in tetrahydrofuran was added 2-piperidinylethylamine (2 eq), HBTU (2 eq) and N, N-diisopropylethylamine (4 eq) and stirred at room temperature for 16 h. The mixture was then concentrated and taken up in ethyl acetate and waterAnd (4) separating. The organic layer was concentrated and purified by preparative chromatography to give [4- (2- { [ 4-bromo-3-fluorophenyl ] ester]Amino-1-methylbenzimidazol-5-yloxy) (2-pyridyl)]-N- (2-piperidinylethyl) carboxamide. MS: MH⁺＝567.

Example 486

Synthesis of 4- { 1-methyl-2- [ (4-methylphenyl) amino-1-methyl-benzimidazol-5-yloxy) (2-pyridyl) ] -N- (2-pyrrolidinylethyl) carboxamide

Step 1. Synthesis of 4- { 1-methyl-2- [ (4-methylphenyl) amino ] benzimidazol-5-yloxy) pyridine-2-carboxylic acid

Tert-butyl 4- [ 3-amino-4- (methylamino) phenoxy ] to methanol]Pyridine-2-carboxylate (1 equivalent) was added with 4-methylbenzene isothiocyanate (1 equivalent), and stirred at room temperature for 16 hours. After the formation of the corresponding thiourea, LC/MS was performed, then methyl iodide (1 eq) was added thereto and heated to 60 ℃ for 2 hours. LC/MS was performed after formation of tert-butyl 4- { 1-methyl-2- [ (4-methylphenyl) amino) benzimidazol-5-yloxy) pyridine-2-carboxylate. Trifluoroacetic acid was added thereto (in dichloromethane) and stirred at room temperature overnight. The resulting 4- { 1-methyl-2- [ (4-methylphenyl) amino group was purified by preparative chromatography]Benzimidazol-5-yloxy) pyridine-2-carboxylic acid. MS: MH⁺＝374.

Step 2. Synthesis of 4- { 1-methyl-2- [ (4-methylphenyl) amino-1-methylbenzimidazol-5-yloxy) (2-pyridyl) ] -N- (2-pyrrolidinylethyl) carboxamide

To 4- { 1-methyl-2- [ (4-methylphenyl) amino group in tetrahydrofuran]To benzimidazole-5-yloxy) pyridine-2-carboxylic acid (1 eq) was added 2-pyrrolidinoethylamine (2 eq), HBTU (2 eq), and N, N-diisopropylethylamine (4 eq), and stirred at room temperature for 16 h. The mixture was then concentrated and separated between ethyl acetate and water. Concentrating the organic layer, and subjecting to preparative chromatography to obtain 4- { 1-methyl-2- [ (4-methylphenyl) amino-1-methylbenzimidazol-5-yloxy) (2-pyridyl)]-N-2 (2-pyrrolidinylethyl) carboxamide. MS: MH⁺＝470.

Example 487

Synthesis of [4- (2- { [ 4-ethylphenyl) amino-1-methylbenzimidazol-5-yloxy) (2-pyridyl) ] -N- (2-pyrrolidinoethyl) carboxamide

Step 1. Synthesis of 4- {2- [ (4-ethylphenyl) amino ] -1-methylbenzimidazol-5-yloxy) pyridine-2-carboxylic acid

Tert-butyl 4- [ 3-amino-4- (methylamino) phenoxy ] to methanol]4-Ethylbenzeneisothiocyanate (1 eq) was added to pyridine-2-carboxylate and stirred at room temperature for 16 h. LC/MS was performed after the formation of the corresponding thiourea. Methyl iodide (1 eq) was then added thereto and heated to 60 ℃ for 2 hours. In the formation of tert-butyl 4- (2- { [ 4-ethylphenyl)]Amino) -1-methylbenzimidazol-5-yloxy) pyridine-2-carboxylate followed by LC/MS. Trifluoroacetic acid was added thereto (in dichloromethane) and stirred at room temperature overnight. The resulting 4- (2- { [ 4-ethylphenylamino) -1-methylbenzimidazol-5-yloxy) pyridine-2-carboxylic acid was purified by preparative chromatography. MS: MH⁺＝388。

Step 2 Synthesis of [4- (2- { [ 4-ethylphenyl) amino-1-methylbenzimidazol-5-yloxy) (2-pyridyl) ] -N- (2-pyrrolidinylethyl) carboxamide

To 4- (2- { [ 4-ethylphenylamino) -1-methylbenzimidazol-5-yloxy) pyridine-2-carboxylic acid (1 eq) in tetrahydrofuran was added 2-pyrrolidinoethylamine (2 eq), HBTU (2 eq) and N, N-diisopropylethylamine (4 eq) and stirred at room temperature for 16 h. The mixture was concentrated and separated between ethyl acetate and water. The organic layer was concentrated and subjected to preparative chromatography to give [4- (2- { [ 4-ethylphenyl ] phenyl]Amino-1-methylbenzimidazol-5-yloxy) (2-pyridyl)]-N- (2-pyrrolidinylethyl) carboxamide. MS: MH⁺＝484.

Example 488

Synthesis of [4- (2- { [3- (tert-butyl) phenyl) amino-1-methyl-benzimidazol-5-yloxy) (2-pyridyl) ] -N- (2-piperidylethyl) carboxamide

Step 1. Synthesis of 4- {2- [ (3- (tert-butyl) phenyl) amino ] -1-methylbenzimidazol-5-yloxy) pyridine-2-carboxylic acid

Tert-butyl 4- [ 3-amino-4- (methylamino) phenoxy ] to methanol]3- (tert-butyl) benzeneisothiocyanate (1 eq) was added to pyridine-2-carboxylate (1 eq) and stirred at room temperature for 16 h. LC/MS was performed after the formation of the corresponding thiourea. Methyl iodide (1 eq) was then added thereto and heated to 60 ℃ for 2 hours. Formation of tert-butyl 4- (2- { [3- (tert-butyl) phenyl]Amino) -1-methylbenzimidazol-5-yloxy) pyridine-2-carboxylate followed by LC/MS. Trifluoroacetic acid was added thereto (in dichloromethane) and stirred at room temperature overnight. The resulting 4- (2- { [3- (tert-butyl) phenylamino) -1-methylbenzimidazol-5-yloxy) pyridine-2-carboxylic acid was purified by preparative chromatography. MS: MH⁺＝416。

Step 2 Synthesis of [4- (2- { [3- (tert-butyl) phenyl) amino-1-methylbenzimidazol-5-yloxy) (2-pyridyl) ] -N- (2-piperidylethyl) carboxamide

To 4- (2- { [3- (tert-butyl) phenylamino) -1-methylbenzimidazol-5-yloxy) pyridine-2-carboxylic acid (1 eq) in tetrahydrofuran was added 2-piperidinylethylamine (2 eq), HBTU (2 eq) and N, N-diisopropylethylamine (4 eq) and stirred at room temperature for 16 h. The mixture was then concentrated and separated between ethyl acetate and water. The organic layer was concentrated and subjected to preparative chromatography to give [4- (2- { [3- (tert-butyl) phenyl ] 4]Amino-1-methylbenzimidazol-5-yloxy) (2-pyridyl)]-N- (2-piperidinylethyl) carboxamide. MS: MH⁺＝512.

Example 489

Synthesis of [4- (2- { [ 4-chloro-3- (trifluoromethyl) phenyl) amino-1-methyl-benzimidazol-5-yloxy) (2-pyridyl) ] -N- (2-piperidylethyl) carboxamide

Step 1. Synthesis of 4- {2- [ (4-chloro-3- (trifluoromethyl) phenyl) amino ] -1-methylbenzimidazol-5-yloxy) pyridine-2-carboxylic acid

Tert-butyl 4- [ 3-amino-4- (methylamino) phenoxy ] to methanol]To pyridine-2-carboxylate (1 equivalent) was added 4-chloro-3- (trifluoromethyl) benzeneisothiocyanate (1 equivalent), and stirred at room temperature for 16 hours. LC/MS was performed after the formation of the corresponding thiourea. Methyl iodide (1 eq) was then added thereto and heated to 60 ℃ for 2 hours. In the formation of tert-butyl 4- (2- { [ 4-chloro-3- (trifluoromethyl) phenyl]Amino) -1-methylbenzimidazol-5-yloxy) pyridine-2-carboxylate followed by LC/MS. Trifluoroacetic acid was added thereto (in dichloromethane) and stirred at room temperature overnight. The resulting 4- (2- { [ 4-chloro-3- (trifluoromethyl) phenylamino) -1-methylbenzimidazol-5-yloxy) pyridine-2-carboxylic acid was purified by preparative chromatography. MS: MH⁺＝462.

Step 2 Synthesis of [4- (2- { [ 4-chloro-3- (trifluoromethyl) phenyl) amino-1-methylbenzimidazol-5-yloxy) (2-pyridyl) ] -N- (2-piperidylethyl) carboxamide

To 4- (2- { [ 4-chloro-3- (trifluoromethyl) phenylamino) -1-methylbenzimidazol-5-yloxy) pyridine-2-carboxylic acid (1 eq) in tetrahydrofuran was added 2-piperidinylethylamine (2 eq), HBTU (2 eq) and N, N-diisopropylethylamine (4 eq) and stirred at room temperature for 16 h. The mixture was then concentrated and separated between ethyl acetate and water. The organic layer was concentrated and obtained by preparative chromatography to give [4- (2- { [ 4-chloro-3-trifluoromethylphenyl ] e]Amino-1-methylbenzimidazol-5-yloxy) (2-pyridyl)]-N- (2-piperidinylethyl) carboxamide. MS: MH⁺＝558。

As shown in the right-hand column, compounds 490-626 listed in Table 6 were synthesized as described in example 482-489.

TABLE 6

Example 627

Step 1 Synthesis of [4- (2- { [4- (chloromethyl) phenyl ] carbonylamino) -1-methylbenzimidazol-5-yloxy) (2-pyridinyl) ] -N-methylcarbamoyl

A solution of sodium thiocyanate (1 eq) in acetone was slowly added to a solution of 4- (chloromethyl) benzoyl chloride (1 eq) in acetone at 0 ℃. The mixture was then filtered to {4- [ 3-amino-4- (methylamino) phenoxy [ ]](2-pyridyl) } -N-methylcarbamoyl (1 eq) in acetone. LC/MS was performed after the formation of N-acylthiourea. The mixture was concentrated, then extracted in tetrahydrofuran, and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (2 eq) was added thereto and stirred at room temperature for 16 hours. The mixture was concentrated. And separated between ethyl acetate and water. The organic layer was then dried, concentrated and yielded [4- (2- { [4- (chloromethyl) phenyl ] 4]Carbonylamino) -1-methylbenzimidazol-5-yloxy) (2-pyridyl)]-N-methylcarbamoyl. MS: MH⁺＝449.

Step 2. Synthesis of N-methyl {4- [ 1-methyl-2- ({4- [ (4-methylpiperazino) methyl ] phenyl } carbonylamino) benzimidazol-5-yloxa ] (2-pyridyl) } carboxamide

To [4- (2- { [4- (chloromethyl) phenyl)]Carbonylamino) -1-methylbenzimidazol-5-yloxy) (2-pyridyl)]Methylpiperazine (4 equivalents) was added to a tetrahydrofuran solution of-N-methylcarbamoyl (1 equivalent) and stirred at room temperature for 16 hours. The reaction mixture was concentrated and purified by preparative chromatography to give N-methyl {4- [ 1-methyl-2- ({4- [ (4-methylpiperazinyl) methyl group]Phenyl } carbonylamino) benzimidazol-5-yloxyhetero](2-pyridyl) } carbamoyl. MS: MH⁺＝512.

Example 628

Step 1. Synthesis of N-methyl [4- (1-methyl-2- {2- {4- [ (4-methylpiperazino) methylphenyl } -benzimidazol-5-yloxy) (2-pyridyl) ] carboxamide

To {4- [ 3-amino-4- (methylamino) phenoxy group](2-pyridyl) } -N-methylcarbamoyl (1 eq) in tetrahydrofuran solution 4- (chloromethyl) benzoyl chloride was addedChlorine (1 equivalent) and triethylamine (2 equivalents). The N-acylation reaction was completed in 0.5 hours. The reaction mixture was concentrated and separated between ethyl acetate and water. The organic layer was concentrated, and methylpiperazine (4 equivalents) and tetrahydrofuran were added to the crude product, which was stirred at room temperature for 16 hours. The reaction mixture was concentrated and separated between ethyl acetate and water. The organic layer was concentrated and extracted in acetic acid, heated to 60 ℃ and held for 3 hours. Preparative chromatography gave N-methyl [4- (1-methyl-2- {2- {4- [ (4-methylpiperazinyl) methylphenyl } -benzimidazol-5-yloxy) (2-pyridyl)]And (4) carbamyl. MS: MH⁺＝470.

Example 629

Step 1. Synthesis of 2-chloro-4- (3-pyridyl) pyrimidine

Nitrogen was bubbled through a solution of 2, 4-dichloropyrimidine (1 eq.) in tetrahydrofuran and water (3: 1) for 0.5 hour. Bis (diphenylphosphino) ferrocene palladium (II) chloride (0.05 eq) was added, followed by pyridine-3-boronic acid (1 eq) and sodium carbonate (3 eq) and the mixture was heated to 60 ℃ under nitrogen for 16 hours. The reaction mixture was concentrated and separated between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated. Purification on silica gel afforded 2-chloro-4- (3-pyridyl) pyrimidine. MS: MH⁺＝190。

Step 2. Synthesis of 2-nitro-4- (4- (3-pyridyl) pyrimidin-2-yloxy) phenylamine

A solution of 4-amino-3-nitro-phenol (1 eq) and 2-chloro-4- (3-pyridyl) pyrimidine (1 eq) in N, N-dimethylformamide was heated by microwave for 10 minutes at 150 ℃. The reaction mixture was separated between ethyl acetate and water. The organic layer was concentrated and purified on silica gel to give 2-nitro-4- (4- (3-pyridyl) pyrimidin-2-yloxy) phenylamine. MS: MH⁺＝309.

Step 3. Synthesis of 4- (4- (3-pyridyl) pyrimidin-2-yloxy) benzene-1, 2-diamine

Hydrogenation of the toluene with a catalytic amount of 10% Pd/CThe mixture comprising 2-nitro-4- (4- (3-pyridyl) pyrimidin-2-yloxy) phenylamine in alcohol until the yellow color disappears to give 4- (4- (3-pyridyl) pyrimidin-2-yloxy) benzene-1, 2-diamine. MS: MH⁺＝279.

Step 3, synthesizing {4- [ (4-methylpiperazino) methyl ] phenyl } -N- [5- (4- (3-pyridyl) pyrimidin-2-yloxy) benzimidazol-2-yl ] carboxamide.

A solution of sodium thiocyanate (1 eq) in acetone was slowly added to a solution of 4- (chloromethyl) benzoyl chloride (1 eq) in acetone at 0 ℃. The mixture was then filtered to a solution of 4- (4- (3-pyridyl) pyrimidin-2-yloxy) benzene-1, 2-diamine (1 eq) in acetone. LC/MS was performed after the formation of N-acylthiourea. The mixture was concentrated and extracted in tetrahydrofuran, and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (2 eq) was added thereto and stirred at room temperature for 16 hours. The mixture was concentrated and separated between ethyl acetate and water. The organic layer was then dried and concentrated to give [4- (chloromethyl) phenyl ] amine]-N- [5- (4- (3-pyridyl) pyrimidin-2-yloxy) benzimidazol-2-yl]And (4) carbamyl. Extracted in tetrahydrofuran, methylpiperazine (4 eq) was added and stirred at room temperature for 16 h. The reaction mixture was concentrated and subjected to preparative chromatography to give {4- [ (4-methylpiperazinyl) methyl group]Phenyl } -N- [5- (4- (3-pyridyl) pyrimidin-2-yloxy) benzimidazol-2-yl]And (4) carbamyl. MS: MH⁺＝520.

Example 630

Step 1. Synthesis of 4-ethyl-1- [ (4-nitrophenyl) methylpiperazine

To a solution of 4- (chloromethyl) -1-nitrobenzene (1 eq) in tetrahydrofuran was added ethylpiperazine (3 eq) and stirred at room temperature for 16 h. Concentration and passage through silica gel afforded 4-ethyl-1- [ (4-nitrophenyl) methylpiperazine. MS: MH⁺＝249

Step 2. Synthesis of 4- [ (4-ethylpiperazinyl) methyl ] phenylamine

Hydrogenation of said catalyst comprising 4-ethyl-1- [ (Pd/C) in methanol with a catalytic amount of 10% Pd/CMixture of nitrophenyl) methylpiperazine to give 4- [ (4-ethylpiperazinyl) methyl]A phenylamine. MS: MH⁺＝219.

Step 3, synthesizing 4- [ (4-ethylpiperazinyl) methyl ] benzene isothiocyanate

At 0 deg.C, to 4- [ (4-ethylpiperazinyl) methyl group]To a solution of phenylamine in acetone was added sodium bicarbonate (2 equiv.) and thiophosgene (2 equiv.). The mixture was warmed to room temperature, concentrated, and separated between ethyl acetate and water. The organic layer was dried over sodium bicarbonate and sodium sulfate and concentrated to give 4- [ (4-ethylpiperazinyl) methyl group]A benzeneisothiocyanate. MS: MH⁺＝261。

Step 4 Synthesis of [4- [ (2- { [ 4-ethylpiperazino) methyl ] phenyl ] amino) -1-methylbenzimidazol-5-yloxy) (2-pyridyl) ] -N-methylcarbamoyl

To 4- [ (4-ethylpiperazinyl) methyl group]To a solution of benzeneisothiocyanate (1 equivalent) in methanol was added {4- [ 3-amino-4- (methylamino) phenoxy ] phenol](2-pyridyl) } -N-methylcarbamoyl (1 eq) and heated to 60 ℃ for 16 hours. Preparative chromatography gave [4- [ (2- { [ 4-ethylpiperazinyl) methyl group]Phenyl radical]Amino) -1-methylbenzimidazol-5-yloxy) (2-pyridyl)]-N-methylcarbamoyl. MS: MH⁺＝499.

Example 631

Step 1. Synthesis of 4-ethyl-1- (4-nitrophenyl) piperazine

To a solution of 4-fluoro-1-nitrobenzene (1 eq) in N, N-dimethylformamide was added ethylpiperazine (2 eq) and N, N-diisopropylethylamine (2 eq) and heated at 80 ℃ for 16 h. The resulting mixture was concentrated and separated in ethyl acetate and water. The organic layer was then washed with brine, dried over sodium sulfate and concentrated. Silica gel was passed through to give 4-ethyl-1- (4-nitrophenyl) piperazine. MS: MH⁺＝235.

Step 2. Synthesis of 4- (4-ethylpiperazino) phenylamine

Hydrogenation with catalytic amount of 10% Pd/CThe mixture containing 4-ethyl-1- (4-nitrophenyl) piperazine in methanol gave 4- (4-ethylpiperazinyl) phenylamine. MS: MH⁺＝205。

Step 3, synthesizing 4- (4-ethylpiperazinyl) benzene isothiocyanate

To a solution of 4- (4-ethylpiperazinyl) phenylamine in acetone was added sodium bicarbonate (2 eq) and thiophosgene (2 eq) at 0 ℃. The mixture was warmed to room temperature, concentrated and separated between ethyl acetate and water. The organic layer was dried with sodium bicarbonate and sodium sulfate and concentrated to give 4- (4-ethylpiperazinyl) benzeneisothiocyanate. MS: MH⁺＝247。

Step 3 Synthesis of [4- (2- { [ 4-ethylpiperazino) phenyl ] amino) -1-methylbenzimidazol-5-yloxy) (2-pyridyl) ] -N-methylcarbamoyl

To a solution of 4- (4-ethylpiperazinyl) benzeneisothiocyanate (1 eq) in methanol was added {4- [ 3-amino-4- (methylamino) phenoxy ] phenoxy](2-pyridyl) } -N-methylcarbamoyl (1 eq) and heated to 60 ℃ for 16 hours. Preparative chromatography gave 4- (2- { [ 4-ethylpiperazino) phenyl]Amino) -1-methylbenzimidazol-5-yloxy) (2-pyridyl)]-N-methylcarbamoyl. MS: MH⁺＝485.

Example 632

Step 1. Synthesis of 4- (2-bromoethyl) -1-nitrobenzene

To a solution of 4- (2-bromoethyl) -1-nitrobenzene (1 eq) in tetrahydrofuran was added morpholine (3 eq) and stirred at room temperature for 16 h. Concentration and silica gel flow through afforded 4- [2- (4-nitrophenyl) ethylmorpholine. MS: MH⁺＝236.

Step 2. Synthesis of 4- (2-morpholin-4-ylethyl) phenylamine

Hydrogenation of said solution containing 4- [2- (4-nitrophenyl) ethyl in methanol with catalytic amount of 10% Pd/C]A mixture of morpholines to give 4- (2-morpholin-4-ylethyl) phenylamine. MS: MH⁺＝206.

Step 3, synthesizing 4- (2-morpholine-4-yl ethyl) benzene isothiocyanate

To a solution of 4- (2-morpholin-4-ylethyl) phenylamine in acetone was added sodium bicarbonate (2 equiv.) and thiophosgene (2 equiv.) at 0 ℃. The mixture was warmed to room temperature, concentrated and separated between ethyl acetate and water. The organic layer was dried over sodium bicarbonate and sodium sulfate and concentrated to give 4 (2-morpholin-4-ylethyl) benzeneisothiocyanate. MS: MH⁺＝252。

Step 4 Synthesis of N-methyl [4- (1-methyl-2- { [4- (2-morpholin-4-ylethyl) phenyl ] amino } -benzimidazole-5-oxa) (2-pyridinyl) ] carboxamide

To a solution of 4 (2-morpholin-4-ylethyl) benzeneisothiocyanate (1 eq) in methanol was added {4- [ 3-amino-4- (methylamino) phenoxy ] methyl](2-pyridyl) } -N-methylcarbamoyl (1 eq) and stirred at room temperature for 16 h. LC/MS was performed after the formation of the corresponding thiourea. To this was added methyl iodide (1 eq) and heated to 60 ℃ for 3 hours. Concentration followed by preparative chromatography gave N-methyl [4- (1-methyl-2- { [4- (2-morpholin-4-ylethyl) phenyl]Amino } -benzimidazole-5-oxa) (2-pyridyl)]And (4) carbamyl. MS: MH⁺＝486.

Example 633

Step 1. Synthesis of [ (4-nitrophenyl) ethyl ] benzylamine

To a solution of 1- (4-nitrophenyl) ethan-1-one (1 equivalent) and phenylmethylamine (1 equivalent) in methanol was added sodium triethoxyborohydride (1.2 equivalents). The resulting mixture was stirred at room temperature for 16 hours. The mixture was concentrated and separated between ethyl acetate and water. Concentrating the organic layer and performing preparative chromatography to give [ (4-nitrophenyl) ethyl group]Benzylamine. MS: MH⁺＝256。

Step 2. Synthesis of [ (4-aminophenyl) ethyl ] benzylamine

Hydrogenation of said catalyst comprising [ (4-nitrophenyl) ethyl ] in methanol with a catalytic amount of 10% Pd/C]Mixture of benzylamines until the yellow color disappears to give [ (4-amino)Phenyl) ethyl]Benzylamine. MS: MH⁺＝226.

Step 3 Synthesis of 4- { [ benzylamino ] ethyl } benzene isothiocyanate

At 0 deg.C to [ (4-nitrophenyl) ethyl group]To a solution of benzylamine in acetone was added sodium bicarbonate (2 equiv.) and thiophosgene (2 equiv.). The mixture was warmed to room temperature, concentrated and separated in ethyl acetate and water. The organic layer was dried over sodium bicarbonate and sodium sulfate and concentrated to give 4- { [ benzylamino]Ethyl benzene isothiocyanate. MS: MH⁺＝268。

Step 4 Synthesis of N-methyl (4- { 1-methyl-2-2 [ (4- { [ benzylamino ] ethyl } phenyl) amino) benzimidazol-5-yloxy) - (2-pyridyl)) carboxamide

To [4- (3, 4-diaminophenoxy) (2-pyridyl) ]]To a solution of (1 eq) N-methylcarbamoyl in methanol was added 4- { [ benzylamino { (S) }]Ethyl } benzeneisothiocyanate (1 eq) was heated to 60 ℃ for 3 hours. Preparative chromatography was performed to give N-methyl (4- { 1-methyl-2-2- [ (4- { [ benzylamino ] amino]Ethyl } phenyl) amino) benzimidazol-5-yloxy) - (2-pyridyl)) carboxamide. MS: MH⁺＝506。

Example 634

Step 1 Synthesis of (5-fluoro-2-nitrophenyl) methylamine

A solution of 5-fluoro-2-nitrophenylamine (1 eq) in dichloromethane was treated with trifluoroacetic anhydride (1 eq) and stirred at 0 ℃ for 10 minutes. The mixture was quenched with saturated sodium bicarbonate solution. The organic layer was separated and washed with water, brine, dried and evaporated. To a solution of trifluoroacetamide (1 eq) in a mixture of toluene, acetonitrile and sodium hydroxide solution (50%) was added benzyltrimethylammonium chloride (1 eq) and dimethyl sulfate (1.2 eq). The biphasic mixture was stirred at room temperature overnight and evaporated. The mixture was extracted in ethyl acetate, washed with water, brine, dried and evaporated. Purifying the crude product by column chromatography eluting with 1: 1 hexane and ethyl acetate to give (5-fluoro-2-nitrophenyl) methylAn amine. MS: MH⁺＝170.

Step 2, synthesizing {4- [ 4-amino-3- (methylamino) phenoxy ] (2-pyridyl) } -N-methylcarbamoyl

The mixture comprising 5-fluoro-2-nitrophenylamine (1 equivalent), potassium bis (trimethylsilyl) amide (2 equivalents) was stirred in dimethylformamide at room temperature for 2 hours. To this mixture was added (3-hydroxyphenyl) -N-methylcarbamoyl (1 eq) and potassium carbonate (1.2 eq) and stirred at 90 ℃ for 16 h. The reaction mixture was then concentrated and separated between ethyl acetate and water. The organic layer was separated and washed with brine, dried, filtered and concentrated in vacuo to give a brown solid. Purifying on silica gel to obtain N-methyl {4- [3- (methylamino) -4-nitrophenoxy](2-pyridyl)) carbamoyl. Extracted in methanol and hydrogenated with a catalytic amount of 10% Pd/C to give {4- [ 4-amino-3- (methylamino) phenoxy [ ] -](2-pyridyl) } -N-methylcarbamoyl. MS: MH⁺＝272.

Step 3 Synthesis of (4- {2- [ (4-bromophenyl) amino ] -1-methylbenzimidazol-6-yloxo) - (2-pyridyl) -N-methylcarbamoyl

Treatment of {4- [ 4-amino-3- (methylamino) phenoxy ] with 4-bromophenyl isothiocyanate (1 eq.)](2-pyridyl) } -N-methylcarbamoyl (1 eq) in methanol and stirred at 60 ℃ for 2 hours. The reaction mixture was cooled to room temperature and methyl iodide (1 eq) was added and stirred at 60 ℃ overnight. The reaction was concentrated and subjected to preparative chromatography to give (4- {2- [ (4-bromophenyl) amino group]-1-methylbenzimidazol-6-yloxa) - (2-pyridyl) -N-methylcarbamoyl. MS: MH⁺＝452。

Example 635

Step 1 Synthesis of ((5-aminobenzimidazole-2-yl) (4-bromophenylamine)

A solution of 4-nitrophenyl-1, 2-diamine in methanol was treated with 4-bromophenyl isothiocyanate (1 eq) and stirred at 60 ℃ for 2 hours. The reaction mixture was cooled to room temperature and methyl iodide was added(1 eq.) and stirred at 60 ℃ overnight. The reaction was concentrated and purified on silica gel to give (4-bromophenyl) (5-nitrobenzimidazol-2-yl) amine. The crude product was extracted in methanol and hydrogenated with a catalytic amount of 10% Pd/C to give ((5-aminobenzimidazol-2-yl) (4-bromophenylamine). MS: MH⁺＝302。

Step 2 Synthesis of [4- ({2- [ (4-bromophenyl) amino } benzimidazol-5-yl } amino) (2-pyridyl-N-methylcarbamoyl)

To a solution of ((5-aminobenzimidazol-2-yl) (4-bromophenylamine (1 eq) in N, N-dimethylformamide was added sodium hydride (2 eq) and the mixture was heated at 220 ℃ for 8 minutes under microwave separation of the reaction mixture between ethyl acetate and water, drying of the organic layer over sodium sulfate and concentration preparative chromatography gave [4- ({2- [ (4-bromophenyl) amino } benzimidazol-5-yl } amino) (2-pyridyl-N-methylcarbamoyl.MS: MH⁺＝437

Example 636

Step 1. Synthesis of (4- {2- [ (4-bromophenyl) methyl ] -1-methylbenzimidazol-5-yloxy) - (2-pyridyl)) -N-methylcarbamoyl

To a solution of 4-bromophenylacetic acid (1 eq) in dichloromethane containing one drop of N, N-dimethylformamide was added oxalyl chloride (1.2 eq) at 0 ℃. Then, the resulting mixture was heated to room temperature and stirred for 2 hours. Concentrating the mixture, and adding tetrahydrofuran, [4- (3, 4-diaminophenoxy) (2-pyridyl) thereto]N-methylcarbamoyl (1 equivalent) and triethylamine (1 equivalent), and stirred for 2 hours. LC/MS was performed after the formation of the N-acylated product. The mixture was concentrated and separated between ethyl acetate and water. The organic layer was dried over sodium sulfate, concentrated and extracted in acetic acid, heated to 60 ℃ for 2 hours. Preparative chromatography was performed to give (4- {2- [ (4-bromophenyl) methyl group)]-1-methylbenzimidazol-5-yloxy) - (2-pyridyl)) -N-methylcarbamoyl. MS: MH⁺＝451。

Example 637

Step 1 Synthesis of 4- ({ 1-methyl-5- [2- (N-methylcarbamoyl) (4-pyridyloxy)) ] benzimidazol-2-yl } amino) benzoic acid

To {4- [ 3-amino-4- (methylamino) phenoxy group](2-pyridyl) } -N-methylcarbamoyl (1 eq) in methanol 4-isothiocyanatobenzoic acid (1 eq) was added and stirred at 60 ℃ for 3 hours. Then, methyl iodide (1 equivalent) was added thereto, and heated to 60 ℃ for 3 hours, the solvent was concentrated and purified on silica gel to obtain 4- ({ 1-methyl-5- [2- (N-methylcarbamoyl) (4-pyridyloxy))]Benzimidazol-2-yl } amino) benzoic acid. MS: MH⁺＝417.

Step 2 Synthesis of N-methyl [4- (1-methyl-2- { [4- (2-morpholin-4-ylethyl) phenyl ] amino-benzoimidazol-5-oxy) (2-pyridinyl) ] carboxamide CHIR-164277

To 4- ({ 1-methyl-5- [2- (N-methylcarbamoyl) (4-pyridyloxy))]To a solution of benzimidazol-2-yl } amino) benzoic acid (1 eq) in tetrahydrofuran was added morpholine (2 eq) and N, N-diisopropylethylamine (4 eq) and HBTU (2 eq) and stirred at room temperature for 16 h. The mixture was concentrated and separated between ethyl acetate and water. The organic layer was washed with brine and dried over sodium sulfate. Preparative chromatography gave N-methyl [4- (1-methyl-2- { [4- (2-morpholin-4-ylethyl) phenyl]Amino-benzimidazole-5-oxa) (2-pyridyl)]And (4) carbamyl. MS: MH⁺＝529.

Example 638

Step 1 Synthesis of 3- ({ 1-methyl-5- [2- (N-methylcarbamoyl) (4-pyridyloxy)) ] benzimidazol-2-yl } amino) benzoic acid

To a methanol solution of 4- [ 3-amino-4- (methylamino) phenoxy ] (2-pyridyl) } -N-methylcarbamoyl (1 eq) was added 3-isothiocyanatobenzoic acid (1 eq) and stirred at 60 ℃ for 3 hours. Then, methyl iodide (1 equivalent) was added thereto, and heated to 60 ℃ for 3 hours, and the solvent was concentrated and purified on silica gel to obtain 3- ({ 1-methyl-5- [2- (N-methylcarbamoyl) (4-pyridyloxy)) ] benzimidazol-2-yl } amino) benzoic acid. MS: MH + ═ 417.

Step 2 Synthesis of N-methyl [3- (1-methyl-2- { [4- (2-morpholin-4-ylethyl) phenyl ] amino-benzimidazol-5-oxy) (2-pyridinyl) ] carboxamide

To a solution of 3- ({ 1-methyl-5- [2- (N-methylcarbamoyl) (4-pyridyloxy)) ] benzimidazol-2-yl } amino) benzoic acid (1 eq) in tetrahydrofuran was added morpholine (2 eq) and N, N-diisopropylethylamine (4 eq), EDCI (2 eq), HOAT (1.2 eq) and stirred at room temperature for 16 h. The mixture was concentrated and separated between ethyl acetate and water. The organic layer was washed with brine and dried over sodium sulfate. Preparative chromatography gave N-methyl [3- (1-methyl-2- { [4- (2-morpholin-4-ylethyl) phenyl ] amino-benzoimidazol-5-oxy) (2-pyridinyl) ] carboxamide. MS: MH + ═ 529.

As shown in the right-hand column, compounds 639-698 listed in Table 7 were synthesized according to the method described above 627-638 or as otherwise indicated.

TABLE 7

Example 699

Step 1, synthesizing {4- [ 2-methoxy-4- (methylamino) -5-nitrophenoxy ] (2-pyridyl) } -N-methylcarbamoyl

2 h-benzo [ d ] is added to a stirred solution of concentrated nitric acid (22 equivalents) at 0-10 ℃ over a period of 0.5 h]1, 3-dioxolane (1 eq) and stirred for a further 0.5 h. Concentrated sulfuric acid (0.06 eq) was then added dropwise to the reaction mixture over 0.5 hours at 0-10C and stirred at 20C for 0.5 hours. Then it is poured onto crushed ice and the separated solid is filtered, washed with water and dried to give 5, 6-dinitro-2 h-benzo 1[ d]1, 3-dioxolane. MS: MH⁺212。

Step 2 Synthesis of methyl (6-nitro (2 h-benzo [3, 4-d ]1, 3-dioxolan-5-yl) amine

To a stirred solution of methylamine ether and ethanol (1.5: 1) was added 5, 6-dinitro-2 h-benzo 1[ d]1, 3-dioxolane, and stirred at room temperature for 24 hours. The solvent was evaporated under vacuum and the solid was washed with water and dried to give methyl (6-nitro (2 h-benzo [ 3.4-d)]1, 3-dioxolan-5-yl)) amine. MS: MH⁺196。

Step 3, synthesizing 2-methoxy-4- (methylamino) -5-nitrophenol

To the stirred methanol solution was slowly added sodium metal (4.8 equivalents) followed by methyl (6-nitro (2 h-benzo [3, 4-d ]1, 3-dioxolan-5-yl)) amine (1 equivalent) and stirred for 2 hours at room temperature. The mixture was then refluxed for 0.5 hours and diluted with water. After cooling to room temperature, the isolated solid was filtered and dried to give 2-methoxy-4- (methylamino) -5-nitrophenol as a red solid. MS: MH +198

Step 4, synthesizing {4- [ 2-methoxy-4- (methylamino) -5-nitrophenoxy ] (2-pyridyl) } -N-methylcarbamoyl

To a stirred solution of 2-methoxy-4- (methylamino) -5-nitrophenol (1 eq) in N, N-dimethylacetamide was added potassium tert-butoxide (1.2 eq) and stirring was continued at room temperature until solidification. Then, (3-chlorophenyl) -N-methylcarbamoyl (1 equivalent) and anhydrous potassium carbonate (1 equivalent) were added thereto, and the resulting mixture was heated to 50 ℃, whereby the solid was liquefied. It was then heated to 110 ℃ for 12 hours. After cooling to room temperature, the solvent was distilled off and the solid was extracted with ethyl acetate in a soxhlet apparatus for 48 hours. The organic layer was cooled to 0 ℃ and the product was crystallized from ethyl acetate to give {4- [ 2-methoxy-4- (methylamino) -5-nitrophenoxy ] (2-pyridyl) } -N-methylcarbamoyl. MS: MH + 332.

Step 5. Synthesis of 4- {2- [ (4-chlorophenyl) amino ] -6-methoxy- -1-methylbenzimidazole-5-yloxy) pyridine-2-carboxylic acid

To a methanol solution of tert-butyl 4- [ 3-amino-6-methoxy-4- (methylamino) phenoxy ] pyridine-2-carboxylate (1 equivalent) was added 4-chlorophenyl isothiocyanate (1 equivalent), and stirred at room temperature for 16 hours. LC/MS was performed after the formation of the corresponding thiourea. Then, methyl iodide (1 equivalent) was added thereto, and heated to 60 ℃ for 2 hours. LC/MS was performed after formation of tert-butyl 4- (2- { [ 4-chlorophenyl ] amino) -1-methylbenzimidazol-5-yloxy) pyridine-2-carboxylate. Trifluoroacetic acid was added thereto (in dichloromethane) and stirred at room temperature overnight. The resulting 4- (2- { [ 4-chlorophenylamino) -6-methoxy-1-methylbenzimidazol-5-yloxy) pyridine-2-carboxylic acid was purified by preparative chromatography. MS: MH + 424.

Step 6 Synthesis of [4- (2- { [ 4-chlorophenyl) amino-6-methoxy-1-methylbenzimidazol-5-yloxy) (2-pyridyl) ] -N- (2-pyrrolidinylethyl) carboxamide

To a solution of 4- (2- { [ 4-chlorophenylamino) -6-methoxy-1-methylbenzimidazol-5-yloxy) pyridine-2-carboxylic acid (1 eq) in tetrahydrofuran was added 2-pyrrolidinoethylamine (2 eq), HBTU (2 eq) and N, N-diisopropylethylamine (4 eq) and stirred at room temperature for 16 h. The mixture was then concentrated and separated between ethyl acetate and water. The organic layer was concentrated and subjected to preparative chromatography to give [4- (2- { [ 4-chlorophenyl ] amino-6-methoxy-1-methylbenzimidazol-5-yloxy) (2-pyridyl) ] -N- (2-pyrrolidinylethyl) carbamoyl. MS: MH + ═ 522.

Example 700

Step 1. Synthesis of 4- {2- [ (4-bromo-3-methylphenyl) amino ] -6-methoxy-1-methylbenzimidazol-5-yloxy) pyridine-2-carboxylic acid

To a solution of tert-butyl 4- [ 3-amino-6-methoxy-4- (methylamino) phenoxy ] pyridine-2-carboxylate (1 eq) in methanol was added 4-bromo-3-methylphenyl isothiocyanate (1 eq) and stirred at room temperature for 16 h. LC/MS was performed after the formation of the corresponding thiourea. Methyl iodide (1 eq) was then added thereto and heated to 60 ℃ for 2 hours. LC/MS was performed after formation of butyl 4- (2- { [ 4-bromo-3-methylphenyl ] amino) -1-methylbenzimidazol-5-yloxy) pyridine-2-carboxylate. Trifluoroacetic acid was added thereto (in dichloromethane) and stirred at room temperature overnight. The resulting 4- (2- { [ 4-bromo-3-methylphenylamino) -6-methoxy-1-methylbenzimidazol-5-yloxy) pyridine-2-carboxylic acid was purified by preparative chromatography. MS: MH + ═ 482.

Step 2 Synthesis of [4- (2- { [ 4-bromo-3-methylphenyl) amino-6-methoxy-1-methylbenzimidazol-5-yloxy) (2-pyridyl) ] -N- (2-pyrrolidinylethyl) carboxamide

To a solution of 4- (2- { [ 4-bromo-3-methylphenylamino) -6-methoxy-1-methylbenzimidazol-5-yloxy) pyridine-2-carboxylic acid (1 eq) in tetrahydrofuran was added 2-pyrrolidinoethylamine (2 eq), HBTU (2 eq) and N, N-diisopropylethylamine (4 eq) and stirred at room temperature for 16 h. The mixture was then concentrated and separated between ethyl acetate and water. The organic layer was concentrated and subjected to preparative chromatography to give [4- (2- { [ 4-bromo-3-methylphenyl ] amino-6-methoxy-1-methylbenzimidazol-5-yloxy) (2-pyridyl) ] -N- (2-pyrrolidinylethyl) carbamoyl. MS: MH + ═ 579.

Example 701

Step 1 Synthesis of 4- {3- [3- (3-isopropyl-phenyl) -thioureido ] -4-methylamino-phenoxy } -pyridine-2-carboxylic acid

To a solution of tert-butyl 4- [ 3-amino-4- (methylamino) phenoxy ] pyridine-2-carboxylate (1 eq) in methanol was added 3-isopropylphenyl isothiocyanate (1 eq) and stirred at room temperature for 16 hours. LC/MS was performed after the formation of the corresponding thiourea. Methyl iodide (1 eq) was then added thereto and heated to 60 ℃ for 2 hours. LC/MS was performed after formation of 4- {3- [3- (3-isopropyl-phenyl) -thioureido ] -4-methylamino-phenoxy } -pyridine-2-carboxylate. Trifluoroacetic acid was added thereto (in dichloromethane) and stirred at room temperature overnight.

The resulting 4- (2- { [ 4-bromo-3-methylphenylamino) -1-methylbenzimidazol-5-yloxy) pyridine-2-carboxylic acid was purified by preparative chromatography. MS: MH + (437)

Step 2 Synthesis of 4- [2- (3-isopropyl-phenylamino) -1-methyl-1H-benzimidazol-5-yloxy ] -pyridine-2-carboxylic acid) 2-pyrrolidin-1-yl-ethyl) -amide

To a solution of 4- {3- [3- (3-isopropyl-phenyl) -thioureido ] -4-methylamino-phenoxy } -pyridine-2-carboxylic acid (1 eq) in tetrahydrofuran was added 2-pyrrolidinoethylamine (2 eq), EDCI (2 eq), HOAT (1.2 eq) and N, N-diisopropylethylamine (4 eq) and stirred at room temperature for 16 h. The mixture was then concentrated and separated between ethyl acetate and water. The organic layer was concentrated and subjected to preparative chromatography to give 4- [2- (3-isopropyl-phenylamino) -1-methyl-1H-benzimidazol-5-yloxy ] -pyridine-2-carboxylic acid) 2-pyrrolidin-1-yl-ethyl) -amide. MS: MH + ═ 499.

Example 702

Step 1. Synthesis of 3-chloro-4- (2-methyl-5-nitrophenyl) pyridine

Nitrogen was bubbled through a solution of 2-bromo-1-methyl-4-nitrobenzene (1 eq) in dimethoxyethane and water (3: 1) for 0.5 h. Bis (biphenylphosphine) ferrocenepalladium (II) chloride (0.05 eq) was added followed by 3-chloro-4-pyridineboronic acid hydrate (1 eq) and sodium carbonate (3 eq) and the mixture was heated to 60 ℃ under nitrogen for 16 hours. The reaction mixture was concentrated and separated between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated. Purification on silica gel gave 3-chloro-4- (2-methyl-5-nitrophenyl) pyridine. MS: MH + (248).

Note that: the same procedure can be used to perform the Suzuki reaction between halopyridine and nitrophenylboronic acid.

If not commercially available, the boronic acid can be synthesized using the following steps:

step 1a Synthesis of 2-Fluoropyridine boronic acid

Toluene and tetrahydrofuran (4: 1) were added to a flame-dried flask, followed by 4-bromo-2-fluoropyridine (1 equivalent) and triisopropyl borate (1.2 equivalent), and the flask was cooled to-70 ℃. N-butyllithium (1.2 equiv.) was then added dropwise over 0.5 hour, and the mixture was stirred at-70 ℃ for 0.5 hour. The reaction mixture was then cooled to-20 ℃ and 2N hydrochloric acid was added. The formation of 2-fluoropyridine boronic acid was observed by LC/MS during heating of the mixture to room temperature. The mixture was separated between ethyl acetate and water. The organic layer was dried over sodium sulfate and concentrated to give 2-fluoropyridineboronic acid. MS: MH + ═ 141.

Step 2. Synthesis of 3- (3-chloro (4-pyridyl) -4-methylphenylamine

To the mixture containing 3-chloro-4- (2-methyl-5-nitrophenyl) pyridine in acetic acid was added iron powder (5 equivalents) and the resulting mixture was stirred at room temperature for 6 hours. Then, saturated sodium carbonate was added thereto, made neutral, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and passed through silica gel to give 3- (3-chloro (4-pyridyl)) -4-methylphenylamine. MS: MH + ═ 218.

Step 3, synthesizing 3- (3-chloro (4-pyridyl)) -4-methylbenzene isothiocyanate

To 3- (3-chloro (4-pyridyl)) -4-methylphenyl amine in acetone was added sodium bicarbonate (2 equivalents) and thiophosgene (2 equivalents) at 0 ℃. The mixture was warmed to room temperature, concentrated and separated between ethyl acetate and water. The organic layer was dried over sodium bicarbonate and sodium sulfate and concentrated to give 3- (3-chloro (4-pyridyl)) -4-methylbenzene isothiocyanate. MS: MH + 260.

Step 4 Synthesis of {4- (2- { [3- (3-chloro (4-pyridyl)) -4-methylphenyl ] amino) -1-methylbenzimidazol-5-yloxy) (2-pyridyl) ] -N-methylcarbamoyl

To 3- (3-chloro (4-pyridyl)) -4-methylbenzenethiocyanate (1 eq) in methanol was added {4- [ 3-amino-4- (methylamino) phenoxy ] (2-pyridyl) } -N-methylcarbamoyl (1 eq) and the resulting mixture was stirred at room temperature for 16 h. LC/MS showed the formation of the corresponding thiourea. Then, anhydrous ferric chloride (1.5 eq) was added to it (in methanol) and stirred for 3 hours. The reaction mixture was then concentrated to half its volume and the pH was made neutral with 1N sodium hydroxide. Then extracted with ethyl acetate, and the organic layer was washed with brine and dried with sodium carbonate. The crude product was then titrated with hot methanol to give {4- (2- { [3- (3-chloro (4-pyridyl)) -4-methylphenyl ] amino) -1-methylbenzimidazol-5-yloxy) (2-pyridyl) ] -N-methylcarbamoyl. MS: MH + ═ 498.

Example 703

1. Synthesis of {4- [ 2-methoxy-4- (methylamino) -5-nitrophenoxy ] (2-pyridyl) } -N-methylcarbamoyl

To the stirred solution of concentrated nitric acid (22 eq.) was added 2 h-benzo [ d ]1, 3-dioxolane (1 eq.) at 0-10 ℃ over 0.5 h and stirred for a further 0.5 h. To this reaction mixture was added concentrated sulfuric acid (0.06 eq) dropwise over 0.5 h at 0-10 ℃ and stirred at 20 ℃ for 0.5 h. Then it is poured onto crushed ice and the separated solid is filtered, washed with water and dried to give 5, 6-dinitro-2 h-benzo 1[ d ]1, 3-dioxolane. MS: MH + 212.

Step 2 Synthesis of methyl (6-nitro (2 h-benzo [3, 4-d ]1, 3-dioxolan-5-yl) amine

To a stirred solution of methylamine ether and ethanol (1.5: 1) was added 5, 6-dinitro-2 h-benzo 1[ d ]1, 3-dioxolane and stirred at room temperature for 24 hours. The solvent was evaporated under vacuum and the solid was washed with water and dried to give methyl (6-nitro (2 h-benzo [3.4-d ]1, 3-dioxolan-5-yl)) amine. MS: MH + 196.

Step 3, synthesizing 2-methoxy-4- (methylamino) -5-nitrophenol

To the stirred methanol solution was slowly added sodium metal (4.8 equivalents) followed by methyl (6-nitro (2 h-benzo [3, 4-d ]1, 3-dioxolan-5-yl)) amine (1 equivalent) and stirred for 2 hours at room temperature. The mixture was then refluxed for 0.5 hours and diluted with water. After cooling to room temperature, the isolated solid was filtered and dried to give 2-methoxy-4- (methylamino) -5-nitrophenol as a red solid. MS: MH + ═ 198.

Step 4, synthesizing {4- [ 2-methoxy-4- (methylamino) -5-nitrophenoxy ] (2-pyridyl) } -N-methylcarbamoyl

To a stirred solution of 2-methoxy-4- (methylamino) -5-nitrophenol (1 eq) in N, N-dimethylacetamide was added potassium tert-butoxide (1.2 eq) and stirring was continued at room temperature until solidification. Then, (3-chlorophenyl) -N-methylcarbamoyl (1 equivalent) and anhydrous potassium carbonate (1 equivalent) were added thereto, and the resulting mixture was heated to 50 ℃, whereby the solid was liquefied. It was then heated to 110 ℃ for 12 hours. After cooling to room temperature, the solvent was distilled off, and the resulting solid was extracted with ethyl acetate in a soxhlet apparatus for 48 hours. The organic layer was cooled to 0 ℃ and the product was crystallized from ethyl acetate to give {4- [ 2-methoxy-4- (methylamino) -5-nitrophenoxy ] (2-pyridyl) } -N-methylcarbamoyl. MS: MH + 332.

Step 5, synthesizing {4- [ 3-amino-6-methoxy-4- (methylamino) phenoxy ] (2-pyridyl) } -N-methylcarbamoyl

The {4- [ 2-methoxy-4- (methylamino) -5-nitrophenoxy ] (2-pyridyl) } -N-methylcarbamoyl solution in methanol was hydrogenated with 10% Pd/C. The catalyst was filtered off and the solvent was concentrated to give {4- [ 3-amino-6-methoxy-4- (methylamino) phenoxy ] (2-pyridyl) } -N-methylcarbamoyl. MS: MH +: 302.

step 6, synthesizing (4- {2- [ (4-bromo-3-methylphenyl) amino) ] -6-methoxy-1-methylbenzimidazole-5-yloxy } - (2-pyridyl)) -N-methylcarbamoyl

To a solution of {4- [ 3-amino-6-methoxy-4- (methylamino) phenoxy ] (2-pyridyl) } -N-methylcarbamoyl (1 eq) in methanol was added 4-bromo-3-methylphenyl isothiocyanate (1 eq) and stirred at 60 ℃ for 2 hours. LC/MS was performed after thiourea formation. To this was added methyl iodide (1 eq) and heated to 60 ℃ for 3 hours. The mixture was concentrated and purified by preparative chromatography to give (4- {2- [ (4-bromo-3-methylphenyl) amino) ] -6-methoxy-1-methylbenzimidazol-5-yloxy } - (2-pyridyl)) -N-methylcarbamoyl. MS: MH +496.

Example 704

Synthesis of (5- {2- [ (4-bromophenyl) amino ] -1-methylbenzimidazol-5-yloxy) - (3-pyridyl)) -N-methylcarbamoyl

Step 1, synthesizing methyl 5- (4-nitrophenoxy) pyridine-3-carboxylic ester

The mixture comprising methyl-5-hydroxypyridine-3-carboxylic acid ester (1 equivalent), potassium bis (trimethylsilyl) amide (1.2 equivalents) was stirred in N, N-dimethylformamide at room temperature for 2 hours. To the mixture was added 1-fluoro-4-nitrobenzene (1.1 eq), potassium carbonate (1.2 eq) and stirred at 80 ℃ for 16 hours. Then, the reaction mixture was concentrated and separated between ethyl acetate and water. The organic layer was separated, washed with brine, dried, filtered and concentrated in vacuo to give a brown solid. Methyl 5- (4-nitrophenoxy) pyridine-3-carboxylate was purified on silica gel. MS: MH + ═ 274.

Step 2, synthesizing methyl 5- [ 4-aminophenoxy ] pyridine-3-carboxylic ester

The mixture comprising methyl 5- (4-nitrophenoxy) pyridine-3-carboxylate in methanol was hydrogenated with a catalytic amount of 10% Pd/C to give 5- [ 4-aminophenoxy ] pyridine-3-carboxylate. MS: MH + ═ 244.

Step 3, synthesizing methyl 5- [4- (2, 2, 2-trifluoroacetylamino) phenoxy ] pyridine-3-carboxylic ester

A solution of methyl-5- [ 4-aminophenoxy ] pyridine-3-carboxylate (1 equivalent) in methylene chloride was treated with trifluoroacetic anhydride (1 equivalent) and stirred at 0 ℃ for 10 minutes. The mixture was quenched with saturated sodium bicarbonate solution. The organic layer was separated, washed with water, brine, dried and evaporated to give methyl 5- [4- (2, 2, 2-trifluoroacetylamino) phenoxy ] pyridine-3-carboxylate. MS: MH + ═ 340.

Step 4, synthesizing methyl 5- [ 3-nitro-4- (2, 2, 2-trifluoroacetylamino) phenoxy ] pyridine-3-carboxylic ester

To a solution of methyl 5- [4- (2, 2, 2-trifluoroacetylamino) phenoxy ] pyridine-3-carboxylate in acetic acid and acetic anhydride (1: 1) at 0 ℃ is added nitric acid followed by sulfuric acid. After completion of the reaction was confirmed by LC, separation was performed between ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give methyl 5- [ 3-nitro-4- (2, 2, 2-trifluoroacetylamino) phenoxy ] pyridine-3-carboxylate. MS: MH + ═ 385

Step 5, synthesizing methyl 4- [4- (methylamino) -3-nitrophenoxy ] pyridine-3-carboxylic ester

To a solution of methyl 5- [ 3-nitro-4- (2, 2, 2-trifluoroacetylamino) phenoxy ] pyridine-3-carboxylate (1 eq) in a mixture of toluene, acetonitrile and sodium hydroxide solution (50%) was added benzyltrimethylammonium chloride (1 eq) and dimethyl sulfate (1.2 eq). The biphasic mixture was stirred at room temperature overnight and evaporated. The mixture was extracted in ethyl acetate and washed with water, brine, dried and evaporated. The crude product was purified by column chromatography to give methyl 4- [4- (methylamino) -3-nitrophenoxy ] pyridine-3-carboxylate. MS: MH + 303.

Step 6, synthesizing methyl 5- [ 3-amino-4- (methylamino) phenoxy ] pyridine-3-carboxylic ester

Hydrogenating the mixture comprising methyl 4- [4- (alpha-methylamino) -3-nitrophenoxy ] pyridine-3-carboxylate with 10% Pd/C to obtain methyl 5- [ 3-amino-4- (methylamino) phenoxy ] pyridine-3-carboxylate. MS: MH + ═ 273.

Step 7, synthesizing methyl 5- {2- [ (4-bromophenyl) amino ] -1-methylbenzimidazole-5-yloxy } pyridine-3-carboxylate

A solution of methyl 5- [ 3-amino-4- (methylamino) phenoxy ] pyridine-3-carboxylate (1 eq) in methanol (8ml) was treated with 4-bromophenyl isothiocyanate (1 eq) and stirred at 60 deg.C-65 deg.C for 2 hours. The reaction mixture was cooled to room temperature, methyl iodide (1 eq) was added and stirred at 60 ℃ overnight. The reaction was cooled to room temperature, evaporated, extracted in ethyl acetate, washed with water and brine, dried and evaporated under reduced pressure. Performing column chromatography to obtain methyl 5- {2- [ (4-bromophenyl) amino ] -1-methylbenzimidazole-5-yloxy } pyridine-3-carboxylate. MS: MH + 452.

Step 8, synthesizing (5- {2- [ (4-bromophenyl) amino ] -1-methylbenzimidazole-5-yloxy) - (3-pyridyl)) -N-methylcarbamoyl

To methyl 5- {2- [ (4-bromophenyl) amino ] -1-methylbenzimidazol-5-yloxy } pyridine-3-carboxylate was added methylamine, and the resulting mixture was stirred at room temperature for 16 hours. It was then concentrated and purified by preparative chromatography to give (5- {2- [ (4-bromophenyl) amino ] -1-methylbenzimidazol-5-yloxy) - (3-pyridyl)) -N-methylcarbamoyl. MS: MH + 452.

As shown in the right-hand column, each of the compounds listed in Table 8 was synthesized according to the method shown in example 699 or 700.

TABLE 8

Unless otherwise indicated, each of the compounds 747-782 listed in the table below was synthesized according to the procedure described in one of examples 702 or 703, as shown in the right hand column.

TABLE 9

Example 783

Synthesis of [4- (2- { [6- (dimethylamino) (3-pyridyl) ] amino } -1-methylbenzimidazol-5-yloxy) (2-pyridyl) ] -N-methylcarbamoyl

Step 1. Synthesis of 2- (dimethylamino) -5-nitropyridine:

2-chloro-5-nitropyridine (1.0 equivalent) and dimethylamine (2M in EtOH, 4.6 equivalents) in NMP were heated at 100 ℃ for 2 hours. The solution was poured slowly into H2O. The filtrate thus formed was filtered and dried to give 2- (dimethylamino) -5-nitropyridine.

Step 2, synthesizing 2- (dimethylamino-5-aminopyridine:

a mixture of 2- (dimethylamino) -5-nitropyridine (1 eq) and 5% palladium on carbon (0.3 eq) in ethanol was stirred at room temperature and flushed with nitrogen. The reaction vessel was evacuated and purged three times with hydrogen. The reaction mixture was placed under a hydrogen atmosphere overnight. The reaction was flushed with nitrogen and then filtered through a pad of celite. Before removing the solvent by evaporation under reduced pressure, the celite pad was washed with excess ethanol to give 2- (dimethylamino) -5-aminopyridine.

Step 3, synthesizing 2- (dimethylamino) -5-isothiocyanate pyridine:

2- (dimethylamino) -5-aminopyridine (1.0 eq) was extracted in acetone and cooled to 0C. Thiophosgene (1.6 equivalents) was added dropwise and the reaction was stirred at 0 ℃ for 30 minutes before excess thiophosgene and acetone were removed by evaporation under reduced pressure.

Step 4 Synthesis of [4- (2- { [6- (dimethylamino) (3-pyridyl) ] amino } -1-methylbenzimidazol-5-yloxy) (2-pyridyl) ] -N-methylcarbamoyl

A solution of {4- [ 3-amino-4- (methylamino) phenoxy ] (2-pyridyl) } -N-methylcarbamoyl (1.1 eq) in methanol was treated with 2- (dimethylamino) -5-isothiocyanatopyridine (1.0 eq) and stirred at 60 ℃ for 2 hours. Methyl iodide (1 eq) was added and stirred at 60 ℃ overnight. The reaction was cooled to room temperature, evaporated and purified by reverse phase HPLC. MS: MH + ═ 418.3

Example 784

Step 1

A solution of 1(1 eq) and 10% palladium on carbon (0.1 eq) in ethyl acetate was stirred at room temperature and flushed with nitrogen. The reaction was flushed with hydrogen for 2-3 hours, or until the reaction was complete as determined by HPLC. The reaction was flushed with nitrogen for 15 minutes before filtering the reaction through a pad of celite. Before removing the mixed organic solution by evaporation under reduced pressure, the celite pad was washed with excess ethyl acetate and dichloromethane to give solid 2. MS: MH + ═ 207.

Step 2

A solution of 2(1 eq) and sodium carbonate (1.5 eq) in acetone was stirred in an ice bath under nitrogen. Thiophosgene (1.5 equivalents) was added dropwise over 30 minutes. The reaction in the ice bath was stirred for an additional 30 minutes before being removed and warmed to room temperature. The reaction was stirred at room temperature for 1.5 hours before the reaction solution was concentrated under vacuum. Toluene was added to the crude product and removed under vacuum to azeotropically remove any residual thiophosgene to provide product 3. MS: MH + ═ 249.

Step 3

A solution of 3(1.0 eq) and 4(1.0 eq) in MeOH was stirred at room temperature overnight. Ferric chloride (1.2 eq) was added and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum. The crude product was separated between EtOAc and water and filtered. The layers were separated and saturated Na was used₂CO₃The aqueous phase was neutralized (pH 7) with the solution. The resulting aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine and dried (Na)₂SO₄) And concentrated to give the desired product 5. MS: MH + ═ 487

Step 4

The solution was degassed by bubbling argon through a DME/H2O (3: 1) solution of 5(1 eq), 6(1 eq) and sodium carbonate (1.2 eq) for 10 minutes. To the reaction solution was added pd (ii) (dppf) Cl 2-MeCl 2(0.1 eq) and the reaction was sealed. The reaction was heated at 100 ℃ overnight. The reaction was cooled to room temperature, and ethyl acetate and water were added. The organic and aqueous layers were separated. The aqueous layer was washed once more with ethyl acetate. The organic layers were mixed and dried (Na)₂SO₄) And concentrated under vacuum to give the desired product 7. MS: MH + ═ 469.

Step 5

The reaction flask was flame dried and cooled under nitrogen. To the reaction was added a solution of 8(1.0 equiv) in THF followed by triisopropyl borate (1.2 equiv). The reaction solution was added to a dry ice/acetone bath and stirred at about-72 ℃. N-butyllithium (1.5 eq, 2.5M solution in hexanes) was added dropwise over 40 minutes. The reaction solution was stirred in a dry ice/acetone bath for an additional 30 minutes. The reaction solution was then transferred to a saturated NaCl/dry ice bath and stirred at about-25 ℃ for 20 minutes before adding 2N HCl (2.0 equivalents). Then, the reaction solution was taken out of the bath and heated to room temperature. The organic and aqueous layers were separated. The aqueous layer was washed once with ethyl acetate. The organic layers were mixed and dried (Na)₂SO₄) And concentrated under vacuum to give the desired product 9. MS: MH + ═ 141.

As shown in the right-hand column, each of the compounds 785-802 listed in the following table was synthesized according to the method described in example 783 or 784.

Watch 10

Example 803

Step 1.4- [2- (3-isopropyl-phenylamino) -1-methyl-1H-benzimidazol-5-yloxy ] -pyridine-2-carboxylic acid (2-phenylmethanesulfonylamino-ethyl) -amide

To the solution containing 4- [2- (3-isopropyl-phenylamino) -1-methyl-1H-benzimidazol-5-yloxy group by syringe]-pyridine-2-carboxylic acid (2-amino-ethyl) -amide (1 equivalent) (prepared using the method described in example 3 above), K₂CO₃To a mixture (5 equivalents) (0.2M in a 5: 1 mixture of acetonitrile and water) was added α -toluenesulfonyl chloride (1 equivalent). The resulting heterogeneous mixture was stirred at room temperature for 1 hour. The mixture was then diluted with water and extracted with dichloromethane. The organics were washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to a viscous oil. Purification by chromatography gives 4- [2- (3-isopropyl-phenylamino) -1-methyl-1H-benzimidazol-5-yloxy]-pyridine-2-carboxylic acid (2-phenylmethanesulfonylamino-ethyl) -amide. MS: MH +599

The compounds shown in the following table (example 804-812) were prepared according to the procedure described in example 803 below.

TABLE 11

Example 813

Step 1.4- {2- (3- (1-benzyl-1H- [1, 2, 3] triazol-4-yl) -phenylamino ] -1-methyl-1H-benzimidazol-5-yloxy } -pyridine-2-carboxylic acid carboxamide

To a mixture of 4- [2- (3-ethynyl-phenylamino) -1-methyl-1H-benzimidazol-5-yloxy ] -pyridine-2-carboxylic acid carboxamide (1 equivalent) (prepared as described in previous example 2), benzyl azide (1 equivalent) in t-butanol (0.1M) was added sodium ascorbate (0.05 equivalent) and copper sulfate (II) pentahydrate (0.01 equivalent). The resulting mixture was stirred at room temperature for 1 hour. The mixture was then diluted with water and the solid was collected by suction filtration. MS: MH +531

Example 814

Step 1. Synthesis of 6-Nitro-indole-1-carboxylic acid tert-butyl ester

To a stirred solution of 6-nitroindole (1 eq) in dichloromethane (0.3M) and DMF (3.1M) was added di-tert-butyl dicarbonate (2 eq) followed by 4- (dimethylamino) pyridine (1 eq). The resulting solution was stirred at room temperature overnight. Then, dichloromethane was removed in a rotary evaporator, and the remaining solution was diluted with water and extracted with ethyl acetate. The organic was washed with 10% citric acid solution, saturated sodium chloride solution, saturated sodium bicarbonate solution, saturated sodium chloride solution and dried over sodium sulfate. Then, the ethyl acetate was removed in vacuo. Then, diethyl ether was added and a brown solid was collected by suction filtration to give 6-nitro-indole-1-carboxylic acid tert-butyl ester. MS: MH +263

Step 2. Synthesis of 6-amino-2, 3-dihydro-indole-1-carboxylic acid tert-butyl ester

6-Nitro-indole-1-carboxylate (1 equiv.) was dissolved in methanol (0.1M) and palladium on carbon (0.1 equiv.) in methanol was added to the solution under nitrogen. Then, hydrogen gas was introduced, and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was then filtered through celite and the solvent was removed in vacuo to give 6-amino-2, 3-dihydro-indole-1-carboxylic acid tert-butyl ester as a white solid. MS: MH + 235.

Step 3. Synthesis of 6-isothiocyanato-2, 3-dihydro-indole-1-carboxylic acid tert-butyl ester

Thiophosgene (1.1 eq) was added to a stirred suspension of 6-amino-2, 3-dihydro-indole-1-carboxylic acid tert-butyl ester (1 eq), sodium carbonate (10 eq) and dichloromethane: water (3: 1 by volume) at 0 ℃. The resulting mixture was stirred at 0 ℃ for 2 hours. The mixture was diluted with water, the organics separated and washed with water, saturated sodium chloride solution, dried over sodium sulfate and the solvent removed in vacuo to give the orange oil, tert-butyl 6-isothiocyanate-2, 3-dihydro-indole-1-carboxylate.

Step 4. Synthesis of 4- [2- (2, 3-dihydro-1H-indol-6-ylamino) -1-methyl-1H-benzimidazol-5-yloxy ] -pyridine-2-carboxylic acid carboxamide.

To a solution of 4- (4-methylamino 3-nitro-phenoxy) -pyridine-2-carboxylic acid carboxamide (1 eq) in methanol (0.1M) under nitrogen was added palladium on carbon (0.1 eq). The atmosphere was changed to hydrogen (1atm), and the resulting suspension was stirred at room temperature for 2 hours. The mixture was filtered through celite and added to 6-isothiocyanate-2, 3-dihydro-indole-1-carboxylate (1 equivalent). The resulting solution was stirred overnight. Iron (III) chloride containing methanol (2 eq) was added and the solution turned dark red. The solution was stirred at room temperature for 3 hours. Then, methanol was removed in vacuo, and the resulting oil was diluted with water and extracted with dichloromethane. The organics were washed with saturated sodium bicarbonate solution, water and saturated sodium chloride solution and dried over sodium sulfate. The solvent was removed in vacuo. Toluene was added to the resulting oil and heated to reflux, the solution was cooled to room temperature and the solid was collected after 3 days of suction filtration to give 4- [2- (2, 3-dihydro-1H-indol-6-ylamino) -1-methyl-1H-benzimidazol-5-yloxy ] -pyridine-2-carboxylic acid carboxamide. MS: MH +415

Example 815

Step 1 Synthesis of 4- { 1-methyl-2- [1- (4-morpholin-4-yl-butyryl) -2, 3-dihydro-1H-indol-6-ylamino ] -1H-benzimidazol-5-yloxy } -pyridine-2-carboxylic acid carboxamide

To the mixture containing 4- [2- (2, 3-dihydro-1H-indol-6-ylamino) -1-methyl-1H-benzimidazol-5-yloxy ] -pyridine-2-carboxylic acid carboxamide (1 equivalent) (prepared as described in example 1), EDCI (2 equivalents), HOAT (1.2 equivalents), DIEA (4 equivalents) was added THF. The mixture was stirred under nitrogen at room temperature overnight. Then, the mixture was diluted with water and extracted with ethyl acetate. The organics were washed with water, then with saturated sodium chloride solution, dried over sodium sulfate, filtered and the solvent removed in vacuo. Purification by chromatography gave 4- { 1-methyl-2- [1- (4-morpholin-4-yl-butyryl) -2, 3-dihydro-1H-indol-6-ylamino ] -1H-benzimidazol-5-yloxy } -pyridine-2-carboxylic acid carboxamide. MS: MH +570

The compounds shown in the following table (example 816-819) were prepared according to the procedure described in example 815.

TABLE 12

Example 820

Step 1. synthesis of 4- (4-methylamino-3-nitro-phenoxy) -pyridine-2-carboxylic acid:

two drops of water were treated at room temperature to a stirred solution of 4- (4-methylamino-3-nitro-phenoxy) -pyridine-2-carboxylic acid tert-butyl ester in trifluoroacetic acid for 3-4 hours, or the reaction was confirmed to be complete by HPLC. The reaction was evaporated under reduced pressure to give a red-orange oil product. Diethyl ether was added, sonicated, and filtered to give a pale pink solid. LCMS m/z 290.1(MH +), tR 1.71 min.

Step 2. synthesis of 4- (4-methylamino-3-nitro-phenoxy) -pyridine-2-carboxylic acid (2-hydroxy-ethyl) -amide:

to a suspension of 4- (4-methylamino-3-nitro-phenoxy) -pyridine-2-carboxylic acid (1 eq) in anhydrous THF was added EDC-HCl (1.2 eq), HOAT (1.2 eq) and diisopropylethylamine (3 eq). The suspension was stirred for 10 minutes at which time 2, 2-dimethyl-oxazolidine (1.1 equiv.) was added and the solution was stirred overnight. The mixture was then diluted with ethyl acetate and washed with water. The aqueous layer was washed with ethyl acetate, the organic layers were combined, dried over MgS04, filtered and concentrated. LCMS m/z 333.2(MH +), tR 2.1 min.

Step 3.4- (3-amino-4-methylamino-phenoxy) -pyridine-2-carboxylic acid (2-hydroxy-ethyl) -amide:

a solution of 4- (4-methylamino-3-nitro-phenoxy) -pyridine-2-carboxylic acid (2-hydroxy-ethyl) -amide (1 eq) and 10% palladium on carbon (0.1 eq) in methanol was stirred at room temperature and flushed with nitrogen. The reaction was flushed with hydrogen for 1-2 hours, or until the reaction was complete as determined by HPLC. The reaction was flushed with nitrogen for 15 minutes before being filtered through celite. The celite pad was washed with excess methanol before being evaporated under reduced pressure to give a pale yellow solid product. LCMS m/z 303.2(MH +), tR 1.5 min.

Step 4.4- [ 1-methyl-2- (3-trifluoromethylsulfanyl-phenylamino) -1H-benzimidazol-5-yloxy ] -pyridine-2-carboxylic acid (2-hydroxy-ethyl) -amide:

to the flask was added 3- (trifluoromethylthio) phenyl isothiocyanate (1 equivalent), 4- (3-amino-4-methylamino-phenoxy) -pyridine-2-carboxylic acid (2-hydroxy-ethyl) -amide (1 equivalent) and MeOH. The reaction was kept at room temperature overnight. Ferric chloride (1.5 eq) was added and the resulting red reaction was stirred overnight. The reaction was separated with EtOAc and water and filtered through celite. The layers were separated and saturated Na was used₂CO₃The aqueous phase is neutralized in solution. The resulting aqueous phase was extracted with EtOAc and the mixture was filtered through celite. The layers were separated, the aqueous phase was re-extracted and filtered. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated to give a brown solid. The crude residue was purified by reverse phase HPLC. LCMS m/z 504.1(MH +), tR 3.7 min.

Example 821

Step 1. Synthesis of 4- [2- (4-fluoro-phenylamino) -1-methyl-1H-benzimidazol-5-yloxy ] -pyridine-2-carboxylic acid tert-butyl ester:

to a round bottom flask was added 4-fluorophenyl isothiocyanate (1 equivalent), 4- (3-amino-4-methylamino-phenoxy) -pyridine-2-carboxylate (1 equivalent) and MeOH. The reaction was kept at room temperature overnight. Ferric chloride (1.5 eq) was added and the resulting mixture was stirred overnight. The reaction was separated with EtOAc and water and filtered through celite. The layers were separated and saturated Na was used₂CO₃The aqueous phase is neutralized in solution. The resulting aqueous phase was extracted with EtOAc and the mixture was filtered through celite. The phases were separated and the aqueous phase was re-extracted and filtered. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to give a brown solid. The crude residue was purified by trituration in hot toluene to give the desired product. LCMS m/z 435.6(MH +), tR 2.12 min.

Step 2. Synthesis of 4- [2- (4-fluoro-phenylamino) -1-methyl-1H-benzimidazol-5-yloxy ] -pyridine-2-carboxylic acid:

a stirred solution of 4- [2- (4-fluoro-phenylamino) -1-methyl-1H-benzimidazol-5-yloxy ] -pyridine-2-carboxylic acid tert-butyl ester in trifluoroacetic acid was treated with two drops of water at room temperature for 3-4 hours or the reaction was confirmed to be complete by HPLC. The reaction was evaporated under reduced pressure, and then diethyl ether was added to the residue, followed by sonication for 30 minutes. Filtration and washing with ether gave the desired acid quantitatively. LCMS m/z 379.4(MH +), tR 1.74 min.

Step 3 synthesis of {5- [2- (1H-benzoimidazol-2-yl) -pyridin-4-yloxy ] -1-methyl-1H-benzoimidazol-2-yl } - (4-fluoro-phenyl) -amine:

to a solution of 4- [2- (4-fluoro-phenylamino) -1-methyl-1H-benzimidazol-5-yloxy ] -pyridine-2-carboxylic acid (1 eq) in anhydrous THF were added EDC-HCl (1.2 eq), HOAT (1.2 eq) and diisopropylethylamine (3 eq). The suspension was stirred for 10 minutes at which time phenylenediamine (1.1 equiv.) was added and the solution was stirred overnight. The mixture was then diluted with ethyl acetate and washed with water. The aqueous layer was washed with ethyl acetate, the organic layers were combined, dried over MgSO4, filtered, and concentrated. Acetic acid was added to the residue followed by sodium acetate (1.1 eq). The mixture was heated at 70 ℃ for 3 hours, the solution was concentrated, and the residue was purified by HPLC to give the desired product. LCMS m/z 451.5(MH +), tR 1.92 min.

Synthesis of the side chain

Ether-substituted phenylenediamine:

4- (3-bromopropoxy) -2-nitrophenylamine:

to the flask was added 4-amino-3-nitrophenol 1(1 eq), K₂CO₃(2 eq.) and 2-butanone. 1, 3-dibromopropane 2(1.5 equiv.) is added and the mixture is heated at 80 ℃ for 18 hours. After cooling, the mixture was filtered and water was added. Then, using CH₂Cl₂(x3) the solution was extracted, the organic layer was concentrated and the recovered solid was washed with pentane to give the desired product 3. LCMS m/z 275.1(MH +), R_t2.74 minutes.

2-nitro-4- (3-pyrrolidinylpropoxy) phenylamine:

in the presence of Cs₂CO₃(2 eq.) and Bu₄NI (0.1 equiv.) in MeCN, 4- (3-bromopropoxy) -2-nitrophenylamine 1(1 equiv.) and pyrrolidine 2(5 equiv.) were heated to 70 ℃ for 48 hours.The reaction mixture was cooled, filtered and concentrated. Dissolving the residue in CH₂Cl₂And washed with water. The organic layer was concentrated to give the desired product 3. LCMS m/z 266.2(MH +), R_t1.51 minutes.

4- (3-pyrrolidinylpropoxy) benzene-1, 2-diamine:

to a solution of 2-nitro-4- (3-pyrrolidinopropoxy) phenylamine 1 in EtOH was added Pd/C (0.1 equiv.). The reaction vessel was repeatedly purged (x3) with nitrogen and then stirred under an atmosphere of hydrogen for 18 hours. The product was filtered through celite and washed with 25mL EtOH to give 2. LCMS 236.2R_t0.94 minute.

3-fluoro-4-amino substituted phenylenediamine:

1. synthesis of 2-fluoro-3- (4-methyl-piperazin-1-yl) -6-nitro-phenylamine.

N-methylpiperazine (1.0 equivalent), NMP, triethylamine (3.0 equivalents) and 5, 6-difluoro-2-nitroaniline (1.0 equivalent) were heated at 90 ℃ for 1 hour. The reaction was cooled to room temperature, then poured into water and allowed to stand for 1 hour. The resulting solid was collected, dried and used without further purification. MH + ═ 255.3

2. To synthesize 3-fluoro-4- (4-methyl-piperazin-1-yl) -benzene-1, 2-diamine.

To the synthetic 2-fluoro-3- (4-methyl-piperazin-1-yl) -6-nitro-phenylamine in EtOH was added Pd/C (0.1 eq). The reaction vessel was repeatedly purged (X3) with nitrogen and then stirred under a hydrogen atmosphere for 18 hours. The product was filtered through celite and washed with 25mL EtOH to afford the desired diamine. CMS 225.3Rt 0.45 min.

4-amino-substituted phenylenediamine (a):

synthesis of 5- (4-methyl-piperazin-1-yl) -2-nitro-phenylamine

N-methylpiperazine (1.0 equivalent), NMP, triethylamine (3.0 equivalents) and 5-fluoro-2-nitrophenylamine (1.0 equivalent) were heated at 90 ℃ for 1 hour. The reaction was cooled to room temperature, then poured into water and allowed to stand for 12 hours. The resulting solid was collected, dried and used without further purification. MH + ═ 237.3.

Synthesis of 4- (4-methyl-piperazin-1-yl) -benzene-1, 2-diamine:

to a solution of 5- (4-methyl-piperazin-1-yl) -2-nitro-phenylamine in EtOH was added Pd/C (0.1 eq). The reaction vessel was repeatedly purged (x3) with nitrogen and then stirred under an atmosphere of hydrogen for 18 hours. The product was filtered through celite and washed with 25mL EtOH to afford the desired diamine. LCMS 207.3Rt 0.25 min.

4-amino-substituted phenylenediamine (b):

synthesis of 5- (4-cyclopentyl-piperazin-1-yl) -2-nitro-phenylamine

1. N-cyclopentylpiperazine (1.0 equivalent), NMP, triethylamine (3.0 equivalents) and 5-fluoro-2-nitrophenylamine (1.0 equivalent) were heated at 90 ℃ for 1 hour. The reaction was cooled to room temperature, then poured into water and allowed to stand for 12 hours. The resulting solid was collected, dried and used without further purification. MH + ═ 291.4.

2. Synthesis of 4- (4-cyclopentyl-piperazin-1-yl) -benzene-1, 2-diamine:

to a solution of 5- (4-cyclopentyl-piperazin-1-yl) -2-nitro-phenylamine in EtOH was added Pd/C (0.1 equiv). The reaction vessel was repeatedly purged (x3) with nitrogen and then stirred under an atmosphere of hydrogen for 18 hours. The product was filtered through celite and washed with 25mL EtOH to afford the desired diamine. MH + ═ 261.3.

Example 822

Step 1, synthesizing 4-chloro-pyridine-2-carboxylic acid dimethylamide:

a solution of 4-chloro-pyridine-2-carbonyl chloride (1 eq) in dichloromethane was cooled to 0 ℃, at which point triethylamine (2 eq) was added followed by dimethylamine (2 eq, 2M solution in THF). The solution was warmed to room temperature and stirred overnight. Then, it was washed with 1M NaOH. The separated organic layer was dried over MgSO4, filtered and concentrated to give the desired product. HPLC, 1.82 min; MS: MH + ═ 185.6

Step 2. synthesis of 4- (4-amino-3-nitro-phenoxy) -pyridine-2-carboxylic acid dimethylamide:

the mixture comprising 4-amino-3-nitrophenol (1 equivalent) and potassium bis (trimethylsilyl) amide (2 equivalents) was stirred in dimethylformamide at room temperature for 2 hours. To the mixture was added 4-chloro-pyridine-2-carboxylic acid dimethylamide (1 eq) and potassium carbonate (1.2 eq), followed by stirring at 90 ℃ for 3 days. The reaction mixture was then concentrated before separation between ethyl acetate and water. The organic layer was separated, washed with brine, dried, filtered and concentrated in vacuo to give a brown solid. Purification by flash chromatography using ethyl acetate and hexane (1: 1) gave the desired product as a yellow slurry. HPLC, 1.69 min; MS: MH + 303.1.

Step 3. synthesis of 4- (4-methylamino-3-nitro-phenoxy) -pyridine-2-carboxylic acid dimethylamide:

a solution of 4- (4-amino-3-nitro-phenoxy) -pyridine-2-carboxylic acid dimethylamide (1 eq) in dichloromethane was treated with trifluoroacetic anhydride (1 eq) and stirred at 0 ℃ for 10 min. The mixture was quenched with saturated NaHCO3 solution. The organic layer was separated and washed with water, brine, dried, filtered and evaporated. MS: MH + ═ 399.0

To a solution of trifluoroacetamide (1 eq) in a mixture of toluene, acetonitrile and sodium hydroxide solution (50%) was added benzyltrimethylammonium chloride (1 eq) and dimethyl sulfate (1.2 eq). The biphasic mixture was stirred at room temperature overnight. The mixture was extracted in ethyl acetate, washed with water, brine, dried and evaporated. The crude product was purified by flash chromatography, eluting with 5% methanol in dichloromethane, to afford the desired product. HPLC, 2.14 min; MS: MH + ═ 317.3

Step 4. synthesis of 4- (3-amino-4-methylamino-phenoxy) -pyridine-2-carboxylic acid dimethylamide:

a solution of 4- (4-methylamino-3-nitro-phenoxy) -pyridine-2-carboxylic acid dimethylamide in methanol was treated with 10% palladium on carbon and stirred at room temperature under a hydrogen atmosphere for 3 hours. The mixture was flushed with nitrogen and then filtered through celite, and the filtrate was concentrated to give the desired diamine. HPLC, 1.17 min; MS: MH + ═ 287.1

Step 5. Synthesis of 4- [2- (2, 6-difluoro-phenylamino) -1-methyl-1H-benzimidazol-5-yloxy ] -pyridine-2-carboxylic acid dimethylamide:

a solution of 4- (3-amino-4-methylamino-phenoxy) -pyridine-2-carboxylic acid dimethylamide (1 eq) in methanol was treated with 2, 6-difluorophenyl isothiocyanate (1 eq) and stirred overnight. Methyl iodide (1 eq) was added to the reaction mixture and stirred at 60 ℃ overnight. The reaction was cooled to room temperature, evaporated and the residue purified by reverse phase HPLC. HPLC, 1.66 min; MS: MH + 424.1.

As described in the right hand column, compounds 823-984, listed in the table below, were synthesized according to the procedure described herein.

Watch 13

Example 985: synthesis of oxime series: 4- [2- (4-bromo-phenylamino) -1-methyl-1H-benzimidazol-5-yloxy ] -pyridine-2-carbaldehyde oxime

Step 1 Synthesis of [4- (4-methylamino-3-nitro-phenoxy) -pyridin-2-yl ] -methanol

A flame-dried 500mL three-necked round-bottomed flask was purged with nitrogen, and LAH (2.32g, 58.0mmol) and anhydrous THF (60mL) were added. The resulting suspension was cooled to 0 ℃ and a solution of tert-butyl ester 1(10.0g, 29.0mmol) in dry THF (60mL) was added slowly while the internal reaction temperature was kept below 5 ℃. The reaction was stirred at 0 ℃ for 30 minutes and then at room temperature for 30 minutes. After judging the reaction was complete, the mixture was treated by dropping water (2.3mL), 10% NaOH (2.3mL) and water (7.2mL) successively. Tong (Chinese character of 'tong')The resulting suspension was filtered through celite, washed with ethyl acetate and methanol, and the collected organics were concentrated. The crude product was adsorbed onto silica gel and purified by flash chromatography (97: 3 CH)₂Cl₂MeOH) gave orange solid 2:¹H NMR(300MHz，CDCl₃)δ8.40(d，J＝5.5Hz，1H)，8.05(br s，1H)，7.96(d，J＝2.75Hz，1H)，7.29(d，J＝2.75Hz，1H)，6.92(d，J＝9.35Hz，1H)，6.75(m，2H)，4.68(s，2H)，3.07(d，J＝5.23Hz，3H).

step 2. Synthesis of 4- (4-methylamino-3-nitro-phenoxy) -pyridine-2-carbaldehyde

To a 250mL reaction tube was added benzyl alcohol 1(1.0g, 3.6mmol), MnO₂(4.7g, 54mmol) and EtOAc (20 mL). The reaction tube was sealed and heated to 120 ℃ with stirring for 2 hours. The reaction was cooled to room temperature, then filtered through celite, and washed successively with EtOAc, MeOH, and EtOH, and the combined organics were concentrated to give 936mg (3.4mmol, 94%) of orange solid 2:¹H NMR(300MHz，CDCl₃)δ10.01(s，1H)，8.64(d，J＝5.5Hz，1H)，8.09(br s，1H)，7.96(d，J＝2.75Hz，1H)，7.37(d，J＝2.48Hz，1H)，7.29(d，J＝2.75Hz，1H)，7.08(dd，J＝2.47，5.5Hz，1H)，6.94(d，J＝9.35Hz，1H)，3.08(d，J＝5.23Hz，3H).

step 3. Synthesis of 4- (4-methylamino-3-nitro-phenoxy) -pyridine-2-carbaldoxime

To a 50mL round bottom flask was added 1(680mg, 2.5mmol), hydroxylamine hydrochloride (191mg, 2.75mmol), pyridine (0.25mL, 3.0mmol), and ethanol (10 mL).The resulting reaction mixture was stirred at room temperature overnight. The crude product was concentrated, adsorbed on silica gel and purified by flash chromatography (97: 3 CH)₂Cl₂MeOH) gave orange solid 2. LCMS m/z 289.2 (MH)⁺)，t_R2.06 minutes.

Step 4, synthesizing 4- (3-amino-4-methylamino-phenoxy) -pyridine-2-carbaldehyde oxime

A suspension of 1(330mg, 1.15mmol) and Lindlar catalyst (245mg, 10 mol%) in methanol (5mL) was added to the reaction tube, sealed, and placed on a Parr shaker. H for reactants₂(60psi) pressurized and maintained for 1 hour. The reaction was filtered through celite, the remaining solid was washed with MeOH, and the combined organics were concentrated to give a brown semi-solid 2 which was used without further purification.

Step 5 Synthesis of 4- [2- (4-bromo-phenylamino) -1-methyl-1H-benzimidazol-5-yloxy ] -pyridine-2-carbaldehyde oxime

4-bromophenyl isothiocyanate (54mg, 0.25mmol), diamine 1(65mg, 0.25mmol) and MeOH (1mL) were added to a 5mL round-bottom flask. The resulting reaction was kept at room temperature overnight. To the reaction was added methyl iodide (20 μ L, 0.33mmol) and stirred overnight. The reaction was concentrated and the resulting residue was purified by reverse phase HPLC. LCMS m/z 438.1 (MH)⁺)，t_R1.87 min.

Example 986: synthesis of O-methyl-oxime series: 4- [ 1-methyl-2- (4-trifluoromethylsulfanyl-phenylamino) -1H-benzimidazol-5-yloxy ] -pyridine-2-carbaldehyde O-methyl-oxime

Step 1. Synthesis of 4- (4-methylamino-3-nitro-phenoxy) -pyridine-2-carbaldehyde O-methyl-oxime

A suspension of 1(600mg, 2.2mmol), methoxylamine hydrochloride (202mg, 2.42mmol) and pyridine (0.22mL, 2.6mmol) in ethanol (9mL) was added to a 25mL round bottom flask. The resulting reaction mixture was stirred at room temperature overnight. The crude product was concentrated, adsorbed onto silica gel and purified by flash chromatography (97: 3 CH)₂Cl₂MeOH) gave an orange solid. LCMS m/z 303.2 (MH)⁺)，t_R2.40 min.

Step 2. Synthesis of 4- (3-amino-4-methylamino-phenoxy) -pyridine-2-carbaldehyde O-carbaryl-oxime

A suspension of 1(270mg, 0.9mmol) and Lindlar catalyst (192mg, 10 mol%) in methanol (5mL) was added to the reaction tube, which was then placed on a Parr shaker. H for reactants₂(60psi) pressurized and maintained for 1 hour. The reaction was filtered through celite and the remaining solid was washed with methanol. The combined organics were concentrated to give a brown semi-solid 2 which was not further purified. LCMS m/z 273.3 (MH)⁺)，t_R1.56 minutes.

Step 3 Synthesis of 4- [ 1-methyl-2- (4-trifluoromethylsulfonyl-phenylamino) -1H-benzimidazol-5-yloxy ] -pyridine-2-carbaldehyde O-methyl-oxime

4-Trifluoromethylthiophenyl isothiocyanate (24mg, 0.1mmol), diamine 1(27mg, 0.1mmol), and MeOH (0.5mL) were added to a 5mL round-bottom flask. The reaction was kept at room temperature overnight, followed by the addition of methyl iodide (8 μ L, 0.13 mmol). After 16 h, the reaction was concentrated and the residue was purified by reverse phase HPLC. LCMS m/z 474.3 (MH)⁺)，t_R2.42 min.

Example 987

The synthesis was performed as described in example 986, step 3, using 4-bromobenzene isothiocyanate. LCMS m/z402.4 (MH)⁺)，t_R2.15 min.

Example 988

The synthesis was performed as described in example 986, step 3, using 4-ethylphenyl isothiocyanate. LCMS m/z402.4 (MH)⁺)，t_R2.15 min.

Example 989

The synthesis was performed as described in example 986, step 3, using 4-bromo-2-trifluoromethoxyphenyl isothiocyanate. LCMS m/z 536.2 (MH)⁺)，t_R2.38 minutes.

Example 990

The synthesis was performed as described in example 986, step 3, using 2, 4-dimethylphenyl isothiocyanate. LCMS m/z402, (MH)⁺)，t_R2.07 min.

Example 991: synthesis of benzyl alcohol series: {4- [2- (4-chloro-phenylamino) -1-methyl-1H-benzimidazol-5-yloxy ] -pyridin-2-yl } -methanol

Step 1 Synthesis of [4- (3-amino-4-methylamino-phenoxy) -pyridin-2-yl ] -methanol

With N₂A methanol suspension of nitroaniline 1(550mg, 2.0mmol) was sparged for 20 minutes followed by the addition of 10% Pd/C (106mg, 0.1 mmol). Adding H to the reaction mass₂And kept overnight at room temperature under a hydrogen atmosphere. With N₂The reaction was sparged and filtered through celite. The collected solids were washed with EtOAc (3X50mL) and the combined organic layers were dried (MgSO)₄) Concentration gave 2, which was used without further purification.

Step 2. Synthesis of {4- [2- (4-chloro-phenylamino) -1-methyl-1H-benzimidazol-5-yloxy ] -pyridin-2-yl } -methanol.

4-chlorophenyl isothiocyanate (34g, 0.2mmol), diamine 1(49mg, 0.2mmol), and MeOH (1mL) were added to a 5mL round-bottom flask, and the reaction was allowed to stand at room temperature overnight. Ferric chloride (16mg, 0.1mmol) was added and the red mixture was washed with brineStir overnight. The reaction was separated between EtOAc and water, the layers were separated and saturated Na was used₂CO₃The aqueous phase was neutralized with an aqueous solution (pH 7). The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated to give a brown solid. The reaction was concentrated and the resulting residue was purified by reverse phase HPLC. LCMS m/z 381.3 (MH)⁺)，t_R2.27 min.

Example 992.

The synthesis was performed as described in example 1058, step 2, using 4-fluorophenyl isothiocyanate. LCMS m/z 365.4 (MH)⁺)，t_R2.04 min.

Example 993

The synthesis was performed as described in example 1058, step 2, using 4-bromo-3-methylphenyl isothiocyanate. LCMS m/z439.3 (MH)⁺)，t_R2.79 min.

Example 994

The synthesis was performed as described in example 991, step 2, using 4-bromo-2-trifluoromethoxyphenyl isothiocyanate. LCMS m/z 511.3 (MH)⁺)，t_R3.08 min.

Example 995

The synthesis was performed as described in example 991, step 2, using 4-methylthiophenyl isothiocyanate. LCMS m/z393.4 (MH)⁺)，t_R2.46 min.

Example 995

The synthesis was performed as described in example 991, step 2, using 3-ethylphenyl isothiocyanate. LCMS m/z 375.4 (MH)⁺)，t_R2.57 min.

Example 996

The synthesis was performed as described in example 991, step 2, using 4-trifluoromethylthiophenyl isothiocyanate. LCMSM/z 447.3 (MH)⁺)，t_R3.21 min.

Example 997

The synthesis was performed as described in example 991, step 2, using 3-iodophenyl isothiocyanate. LCMS m/z 473.2 (MH)⁺)，t_R2.57 min.

Example 998

The synthesis was performed as described in example 991, step 2, using 3-trifluoromethylthiophenyl isothiocyanate. LCMSM/z 447.3 (MH)⁺)，t_R3.08 min.

Example 999: 4- [2- (4-bromo-phenylamino) -1-methyl-1H-benzimidazol-5-yloxy ] -pyridine-2-carboxylic acid phenylamide

Synthesis of the Anilide series (4-Br and 3-iPr Western terminal)

Synthesis of 4- [2- (4-bromo-phenylamino) -1-methyl-1H-benzimidazol-5-yloxy ] -pyridine-2-carboxylic acid phenylamide.

A suspension of 1(44mg, 0.1mmol), HBTU (46mg, 0.12mmol) and DIEA (43uL, 0.25mmol) in NMP (0.5mL) was shaken at room temperature for 30 min. Aniline was added and the reaction was shaken overnight. The crude product was purified by reverse phase HPLC. LCMS m/z 515.2 (MH)⁺)，t_R2.75 min.

Example 1000

The synthesis was performed as described in example 999 using N, O-dimethylhydroxylamine hydrochloride. LCMS m/z 483.3 (MH)⁺)，t_R2.07 min.

Example 1001

The synthesis was performed as described in example 999 using 4-bromoaniline. LCMS m/z 594.0 (MH)⁺)，t_R5.39 min.

Example 1002

The synthesis was performed as described in example 999 using 3, 4-dimethylaniline. LCMS m/z 543.2 (MH)⁺)，t_R5.39 min.

Example 1003

The synthesis was performed as described in example 999 using 3-trifluoromethylaniline. LCMS m/z 583.1 (MH)⁺)，t_R3.12 min.

Example 1004

The synthesis was carried out as described in example 999 using 3-chloroaniline. LCMS m/z 550.1 (MH)⁺)，t_R5.28 min.

Example 1005

3-Ethylbenzene was used as described in example 999And (4) synthesizing amine. LCMS m/z 543.2 (MH)⁺)，t_R3.16 min.

Example 1006

The synthesis was performed as described in example 1067, using 4-methylaniline. LCMS m/z 529.2 (MH)⁺)，t_R5.15 min.

Example 1007

The synthesis was performed as described in example 999 using 3-isopropylaniline. LCMS m/z 520.3 (MH)⁺)，t_R5.98 min.

Example 1008

The synthesis was performed as described in example 999 using 3-tert-butylaniline. LCMS m/z 534.3 (MH)⁺)，t_R3.32 min.

Example 1009

The synthesis was carried out as described in example 999 using 3-trifluoromethoxyaniline. LCMS m/z 562.2 (MH)⁺)，t_R3.15 min.

Example 1010

The synthesis was performed as described in example 999 using 3-diphenylamine. LCMS m/z 554.3 (MH)⁺)，t_R3.28 min.

Example 1011

The synthesis was performed as described in example 999 using 4-bromoaniline. LCMS m/z 557.2 (MH)⁺)，t_R5.65 minutes.

Example 1012

The synthesis was performed as described in example 999 using 3-trifluoromethylaniline. LCMS m/z 546.3 (MH)⁺)，t_R5.74 min.

Example 1013

The synthesis was performed as described in example 999 using 3-iodoaniline. LCMS m/z 604.2 (MH)⁺)，t_R5.81 minutes.

Example 1014: 4- [ 1-methyl-2- (3-phenoxy-phenylamino) -1H-benzimidazol-5-yloxy ] -pyridine-2-carboxylic acid carboxamide

Step 1. Synthesis of 3-phenoxyphenyl isothiocyanate

To a stirred solution of 3-phenoxyaniline (185mg, 1.0mmol) in acetone (4.0mL) at 0 deg.C was added thiophosgene (0.23mL, 3.0mmol) and the resulting reaction was held for 30 minutes. Completion of the reaction was confirmed by TLC (4: 1 hexane/EtOAc). The reaction was concentrated, azeotroped with toluene and used without further purification.

Step 2. Synthesis of 4- [ 1-methyl-2- (3-phenoxy-phenylamino) -1H-benzimidazol-5-yloxy ] -pyridine-2-carboxylic acid carboxamide

A solution of 3-phenoxyphenyl isothiocyanate (23mg, 0.1mmol), diamine 1(27mg, 0.1mmol), and MeOH (0.5mL) was added to a1 dram vial and the reaction was shaken at room temperature overnight. Methyl iodide (8uL, 0.13mmol) was added and the mixture was shaken overnight. The reaction was concentrated and the resulting residue was purified by reverse phase HPLC. LCMS m/z 466.3 (MH)⁺)，t_R2.40 min.

Example 1015

The synthesis was performed as described in example 1014, step 2, using 4-trifluoromethylthiophenyl isothiocyanate. LCMSM/z 474.5 (MH)⁺)，t_R3.76 min.

Example 1016

The synthesis was performed as described in example 1014, step 2, using 3-trifluoromethylthiophenyl isothiocyanate. LCMSM/z 474.5 (MH)⁺)，t_R3.65 minutes.

Example 1017

The synthesis was performed as described in example 1014, step 2, using 4-1-isothiocyanato-4-methanesulfonyl-benzene prepared in step 1. LCMS m/z 452.5 (MH)⁺)，t_R2.86 min.

Example 1018

The synthesis was performed as described in example 1014, step 2, using 4- (2-isothiocyanato-4-trifluoromethyl-phenoxy) -benzonitrile prepared in step 1. LCMS m/z 559.6 (MH)⁺)，t_R4.22 minutes.

Example 1019

The synthesis was performed as described in example 1014, step 2, using 2- (2-methoxy-phenoxy) -5-trifluoromethyl-phenyl isothiocyanate prepared in step 1. LCMSm/z 564.6(MH⁺)，t_R4.42 min.

Example 1020.

The synthesis was performed as described in example 1014, step 2, using 2-phenylsulfonyl-phenyl isothiocyanate prepared in step 1. LCMS m/z 482.5 (MH)⁺)，t_R3.85 min.

Example 1021.

The synthesis was performed as described in example 1014, step 2, using 4-isothiocyanato-3-trifluoromethoxy-benzonitrile prepared in step 1. LCMS m/z 483.4 (MH)⁺)，t_R2.35 min.

Example 1022.

The synthesis was performed as described in example 1014, step 2, using 2, 4-dibromo-6-fluorophenyl isothiocyanate. LCMSM/z 550.3 (MH)⁺)，t_R3.50 min.

Example 1023.

4-bromo-2-isothiocyanates were used as described in example 1014, step 2And (3) synthesizing the trifluoromethoxy-phenyl ester. LCMS m/z 537.3 (MH)⁺)，t_R3.89 min.

Example 1024.

The synthesis was performed as described in example 1014, step 2, using phenylisothiocyanate. LCMS m/z 374.5 (MH)⁺)，t_R2.84 min.

Example 1025.

The synthesis was performed as described in example 1014, step 2, using the 2-phenoxy-phenyl isothiocyanate prepared in step 1. LCMS m/z 466.5 (MH)⁺)，t_R2.37 minutes.

Example 1026.

The synthesis was performed as described in example 1014, step 2, using 2-methyl-phenyl isothiocyanate. LCMS m/z388.5 (MH)⁺)，t_R2.99 min.

Example 1027.

Synthesis of 2-difluoromethoxy-phenyl isothiocyanate as described in example 1014, step 2And (4) obtaining. LCMSM/z 440.5 (MH)⁺)，t_R3.13 min.

Example 1028.

The synthesis was performed as described in example 1014, step 2, using 2-iodo-phenyl isothiocyanate. LCMS m/z 500.4 (MH)⁺)，t_R2.07 min.

Example 1029.

The synthesis was performed as described in example 1014, step 2, using 2, 6-diisopropyl-phenyl isothiocyanate. LCMSM/z 430.5 (MH)⁺)，t_R2.27 min.

Example 1030

4- [2- (4-bromophenyl) -1-methyl-1H-benzimidazol-5-yloxy ] -pyridine-2-carboxylic acid carboxamide.

A mixture of diamine 1(137mg, 0.36mmol) and 4-bromobenzaldehyde (66mg, 0.50mmol) in anhydrous dioxane (2mL) was heated to 100 ℃ for 16 hours. The reaction mixture was cooled to room temperature and then concentrated. The resulting residue was purified by reverse phase HPLC to give 2: LCMS m/z 437.1, t_R2.16 min.

Example 1031

4- [ 1-methyl-2- (4-methylbenzylamino) -1H-benzimidazol-5-yloxy ] -pyridine-2-carboxylic acid carboxamide.

Prepared as described in example 120b using 4-methylbenzyl thioisocyanate: LCMS m/z 402.2 (MH)⁺)，t_R1.91 min.

Example 1032

4- [2- (4-bromophenylamino) -1-methyl-1H-benzimidazol-5-yloxy ] -pyridine-2-carboxylic acid (3-pyrrolidin-1-yl-propyl) -amide.

Prepared as described in example 371 using amido-1- (3-aminopropyl) pyrrolidine: LCMS m/z 549.5 (MH)⁺)，t_R2.97 min.

Example 1033.

(4-bromophenyl) - [ 1-methyl-5- (pyridin-4-yloxy) -1H-benzo 1-imidazol-2-yl ] -amine

A solution of acid 1(44mg, 0.1mmol) in dry NMP (1mL) was heated at 200 ℃ for 20 minutes. The reaction was cooled to room temperature and the crude reaction mixture was directly purified by reverse phase HPLC to give 2:¹H NMR(300MHz，CD3OD)δ8.67(d，J＝7.4Hz，2H)，7.70(d，J＝8.5Hz，1H)，7.68(d，J＝8.8Hz，2H)，7.45(d，J＝8.8Hz，2H)，7.42(d，J＝7.4Hz，2H)，7.32(d，J＝2.2Hz，1H)，7.26(dd，J＝2.2，8.5Hz，1H)，3.86(s，3H)；LCMSm/z 395.0(MH⁺)，t_R1.48 minutes.

Example 1034

LCMS m/z 359.3(MH⁺)，t_R1.91 min.

Example 1035

{4- [2- (4-Bromophenylamino) -1-methyl-1H-benzo 1-imidazol-5-yloxy ] -pyridin-2-yl } -methanol

A suspension of tert-butyl ester 1(496mg, 1.0mmol) in dry THF (3mL) was added to a stirred suspension of LAH (61mg, 1.6mmol) in dry THF (2mL) at-78 deg.C. The reaction was warmed to room temperature over 3 hours. After the reaction was judged complete by LCMS, water (30ul, 1.7mmol) and NaF (270mg, 6.4mmol) were added and the resulting mixture was stirred vigorously at room temperature. The crude mixture was filtered through celite and the remaining solid was washed with EtOAc. The combined organic fractions were concentrated and a portion of the resulting residue was purified by reverse phase HPLC to give alcohol 2 as a TFA salt:¹H NMR(300MHz，CD3OD)δ8.56(d，J＝7.2Hz，1H)，7.72(d，J＝8.5Hz，1H)，7.69(d，J＝8.8Hz，2H)，7.45(d，J＝8.8Hz，2H)，7.33(m，3H)，7.28(dd，J＝2.2，8.5Hz，1H)，4.86(app s，2H)，3.87(s，3H)；LCMS m/z 425.1，t_R1.49 minutes.

Example 1036: (4-bromophenyl) - [ 1-methyl-5- (2-methylaminomethyl-pyridin-4-yloxy) -1H-benzimidazol-2-yl ] -amine

General preparation of benzylamine

Step 1.4- [2- (4-Bromophenylamino) -1-methyl-1H-benzimidazol-5-yloxy ] -pyridine-2-carboxaldehyde

Anhydrous DMSO (0.1mL, 1.4mmol) was added to a solution of oxalyl chloride (0.11mL, 1.3mmol) in anhydrous THF (2mL) at-78 deg.C and the resulting solution was held at-78 deg.C for 30 minutes. Then, a solution of alcohol 1 in dry THF (2mL) was added and the resulting reaction was held at-78 deg.C for 30 minutes and then at-50 deg.C for 45 minutes. Triethylamine (0.5mL, 3.6mmol) was added and the reaction was allowed to warm to room temperature over 1 hour. The reaction was quenched with water and separated with EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (3 ×). The organic phase was washed with brine and dried (MgSO)₄) And concentrated. The resulting residue was not further purified.

Step 2. (4-bromophenyl) - [ 1-methyl-5- (2-methylaminomethyl-pyridin-4-yloxy) -1H-benzimidazol-2-yl ] -amine.

Methylamine (0.3mL, 0.6mmol, 2.0M in MeOH) was added to a solution of aldehyde 1 in MeOH (1mL) and the reaction was held at room temperature for 2 days. The reaction was acidified by the addition of acetic acid (pH 3-4) and excess NaBH was added₃And (C) CN. The reaction was held for 2 days and then concentrated. The crude reaction mixture was dissolved in EtOAc and separated into yb with saturated aqueous NaHCO 3. The layers were separated and the aqueous phase was extracted with EtOAc (3 ×). The combined organic portions were washed with brine and dried (MgSO)₄) And concentrated. The resulting residue was purified by reverse phase HPLC to give N-methylamine 2 as TFA salt:¹H NMR(300MHz，CD₃OD)δ8.48(d，J＝5.8Hz，1H)，7.72(d，J＝8.8Hz，2H)，7.67(d，J＝9.4Hz，1H)，7.43(d，J＝8.8Hz，2h)，7.20(dd，J＝2.2，9.4Hz，1H)，7.19(d，J＝2.2Hz，1H)，7.02(d，J＝2.2，1H)，6.90(dd，J＝2.2，5.8Hz，1H)，4.27(s，2H)，3.86(s，3H)，2.76(s，3H)；LCMS m/z 438.5(MH⁺)，t_R1.85 min.

The following benzylamines were prepared according to the procedure described for example 1036 using the appropriate amines.

TABLE 14

Example 1053

[5- (2-aminomethyl-pyridin-4-yloxy) -1-methyl-1H-benzimidazol-2-yl ] - (4-bromophenyl) -amine.

LAH (98mg, 2.5mmol) was added portionwise to a stirred solution of oxime 1(225mg, 0.5mmol) in dry THF (3mL) at 0 ℃. After addition, the cooling bath was removed and the reaction was allowed to warm to room temperature overnight. The reaction was quenched by the addition of water (0.1mL), 10% w/w aqueous NaOH (0.1mL), and water (0.3 mL). The resulting slurry was stirred at room temperature for 1 hour and filtered through celite. The remaining solid was washed with EtOAc, the organic portions were mixed and concentrated. The crude residue was purified by reverse phase HPLC to give as TFA salts: LCMS m/z 424.1 (MH)⁺)，t_R1.87 min.

Example 1054

{4- [2- (4-bromophenylamino) -1-methyl-1H-benzimidazol-5-yloxy ] -pyridin-2-yl-methyl ] -carbamic acid methyl ester.

Chloroformate (6. mu.L, 0.08mmol) was added to a solution of benzylamine 1(21mg, 0.05mmol) and triethylamine (69. mu.L, 0.5mmol) in dry THF (1mL) at 0 ℃. The reaction was held at 0 ℃ for 20 minutes and then at room temperature for 2 hours. The reaction mixture was concentrated and purified by reverse phase HPLC to give methyl carbamate 2 as TFA salt: LCMS m/z 482.2 (MH)⁺)，t_R1.96 minutes.

Example 1055

N- {4- [2- (4-bromophenylamino) -1-methyl-1H-benzimidazol-5-yloxy ] -pyridin-2-ylmethyl } acetamide

A solution of benzylamine 1(17mg, 0.04mmol) in anhydrous NMP (2mL) was added to triethylamine (0.06mL, 0.4mmol) and acetic anhydride (0.04mL, 0.4 mmol). The resulting reaction was kept at room temperature overnight and purified by reverse phase HPLC to give acetamide 2 as a TFA salt: LCMS m/z 466.3 (MH)⁺)，t_R1.78 min.

Example 1056: 4- [2- (3-ethylphenylamino) -1-methyl-1H-benzimidazol-5-yloxy ] -pyridine-2-carboxylic acid [3- (2-oxo-pyrrolidinyl) -propyl ] -amide

General preparation of N- (3-aminopropyl) -pyrrolidone amide

Step 1: 4-chloro-pyridine-2-carboxylic acid [3- (2-oxo-pyrrolidin-1-yl) -propyl ] -amide

Acid chloride 1(2.12g, 10mmol) was treated with N-methylmorpholine (4.5mL, 41mmol) and N- (3-aminopropyl) -pyrrolidone 2(1.6mL, 11mmol) in anhydrous THF (40 mL). The reaction was kept overnight and concentrated. The residue was dissolved in EtOAc and separated with water. The aqueous portion was extracted with EtOAc (3X) and the combined organic phases were washed with brine and dried (MgSO)₄) And concentrated. The crude residue was purified by Kugelrohr distillation (0.5mmHg, 170-.

Step 2: 4- (4-methylamino-3-nitrophenoxy) -pyridine-2-carboxylic acid [3- (2-oxo-pyrrolidinyl) -propyl ] -amide

Prepared as described in example 120b with appropriate substitutions. By flash chromatography (95: 5 CH)₂Cl₂MeOH) purified amide 3. Further purification can also be achieved by recrystallization from MeCN.

And step 3: 4- (3-amino-4-methylamino-phenoxy) -pyridine-2-carboxylic acid [3- (2-oxo-pyrrolidinyl) -propyl ] -amide

Prepared as described in example 120 b.

And 4, step 4: 4- [2- (3-ethylphenylamino) -1-methyl-1H-benzimidazol-5-yloxy ] -pyridine-2-carboxylic acid [3- (2-oxo-pyrrolidinyl) -propyl ] -amide.

Preparation of benzimidazole 2 as TFA salt as described in example 120 b: LCMS m/z 513.3 (MH)⁺)，t_R2.22 minutes.

Example 1057

As described in example 1056, preparation of: LCMS m/z 563.2 (MH)⁺)，t_R2.15 min.

Example 1058

As described in example 1056, preparation of: LCMS t_R＝585.3(MH⁺)，t_R2.55 min.

Example 1059

As described in example 1056, preparation of: LCMS m/z 563.2 (MH)⁺)，t_R2.50 min.

The following other compounds were prepared according to the procedure of the examples.

Watch 15

General preparation of phenol-containing benzimidazoles

3-amino-4-methylaminophenol

Diamine 2 was prepared from nitroaniline 1 as shown in example 120 b.

Example 1095

2- (3-bromophenylamino) -1-methyl-1H-benzimidazol-5-ol

Benzimidazole 2 was prepared as described in example 120 b: LCMS m/z 318.1 (MH)⁺)，t_R2.07 min.

Example 1096

LCMS m/z 332.1(MH⁺)，t_R＝2.22min

Example 1097

LCMS m/z 366.1(MH⁺)，t_R＝2.13min

Example 1098

LCMS m/z 340.2(MH⁺)，t_R＝2.39min

Example 1099

Preparation of symmetrical bis-benzimidazoles

Step 1: 4,4 '-dimethylamino-3, 3' -dinitrodiphenyl ether

Diphenyl ether 2 was prepared using the procedure described in example 120 b:¹H NMR(300MHz，CDCl₃)δ7.98(br s，2H)，7.75(d，J＝3.0Hz，2H)，7.29(app d，J＝3.0Hz，1H)，6.87(d，J＝9.5Hz，2H)，3.05(d，J＝5.2Hz，6H).

step 2: 4,4 '-dimethylamino-3, 3' -diaminodiphenyl ether

Tetramine 2 was prepared using the method described in example 120 b:¹H NMR(300MHz，CDCl₃)δ6.59(d，J＝8.5Hz，2H)，6.47(dd，J＝2.8，8.5Hz，2H)，6.41(d，J＝2.8Hz，2H)，3.40(br s，4H)，3.06(br s，2H)，2.84(d，J＝5.5Hz，6H).

example 1100

Bis-5- [2- (3-bromophenylamino) -1-methyl-1H-benzimidazole ] -ether.

As described in example 120b, preparation: LCMS m/z 617.1 (MH)⁺)，t_R＝2.27min

Example 1101

As described in example 120b, preparation: LCMS m/z 573.4 (MH)⁺)，t_R＝2.78min

Example 1102

As described in example 120b, preparation: LCMS m/z 661.2 (MH)⁺)，t_R＝2.83min

Example 1103

As described in example 120b, preparation: LCMS m/z 545.4 (MH)⁺)，t_R＝2.73min

Example 1104

As described in example 120b, preparation: LCMS m/z 461.3 (MH)⁺)，t_R＝1.98min

Example 1105

Preparation of benzo derivatives

2- (N-phthalimido) -4-fluoronitrobenzene

A suspension of 2, 4 difluoronitrobenzene (15.9g, 100mmol) and potassium phthalimide (16.5g, 100mmol) was stirred in anhydrous NMP (50mL) for 3 days. The reaction solution was poured into MTBE, and the resulting precipitate was collected by filtration. The solid was washed with MTBE (3X) and the mother liquor was extracted with MTBE (3X). The combined organic fractions were washed with water (3X) and concentrated to give a yellow solid which was combined with the initially obtained precipitate. The mixed crude solid was purified from hot toluene by recrystallization and the crystals were washed with cold MTBE:¹H NMR(300MHz，d⁶-DMSO)δ8.31(dd，J＝5.2，9.1Hz，1H)，7.98(m，4H)，7.69(dd，J＝2.8，9.1Hz，1H)，7.62(ddd，J＝1.7，2.8，7.7Hz，1H).

example 1106

2- (N-phthalimido) -4-phenoxynitrobenzene

2- (N-phthalimido) -4-phenoxynitrobenzene 2 was prepared using a similar procedure as described in example 120 b.

Example 1107

2- (N-phthalimido) -4-phenoxyaniline

2- (N-phthalimido) -4-phenoxyaniline 2 was obtained by reduction of 2- (N-phthalimido) -4-phenoxynitrobenzene 1 as described in example 120 b.

Example 1108

N- [2- (N-phthalimido) -4-phenoxy-phenyl ] -carboxamides

A mixture of formic acid (0.12mL, 5.3mmol) and acetic anhydride (0.24mL, 2.5mmol) was heated to 60 deg.C and held for 2 hours. After cooling to room temperature, aniline 1(387mg, 1.0mmol) in dry THF (1mL) was added and the reaction was kept overnight. The reaction was concentrated and the resulting crude residue was used directly in the next step.

Example 1109

N-methyl- [2- (N-phthalimido) -4-phenoxy ] -aniline

Using BH₃DMS solution (2.0M in CH)₂Cl₂0.5mL, 1.0mL) of formamide 1 was treated and the reaction was allowed to warm to room temperature overnight. The reaction was concentrated and the residue was dissolved in EtOAc. With saturated NaHCO₃Aqueous solution the solution was separated and the layers were separated. The aqueous phase was extracted with EtOAc (3X), and the combined organic phases were washed with brine and dried (MgSO)₄) And adsorbing to SiO₂Purification by flash chromatography (4: 1 hexanes-EtOAc) afforded colorless residue 2.

Example 1110

N1-methyl-4-phenoxybenzene-1, 2-diamine

Hydrazine monohydrate (0)13mL, 2.7mmol) was added to a solution of phthalimide 1(134mg, 0.39mmol) in ethanol (4 mL). The reaction was kept at room temperature overnight and then filtered through celite. The filter cake was washed with EtOAc (3X), and the organic portions were combined and concentrated to give diamine 2 without further purification. LCMS m/z 215.1 (MH)⁺)，t_R1.77 min.

Example 1111

Synthesizing (4-bromophenyl) - (1-methyl-5-phenoxy-1H-benzimidazole-2-yl) -amine.

Benzimidazole 2 was prepared as described in example 120 b:¹H NMR(300MHz，CD₃OD)δ7.68(appddd，J＝2.9，4.9，8.8Hz，2H)，7.53(app d，J＝8.8Hz，1H)，7.41(app ddd，J＝2.9，4.9，8.8Hz，2H)，7.40(app ddd，J＝1.0，2.0，8.5Hz，2h)，7.24(app ddd，J＝1.0，2.0，8.5Hz，1H)，7.07(app dd，J＝2.2，8.8Hz，1H)，7.00(app d，J＝2.2Hz，1H)，7.00(appddd，J＝1.0，2.0，8.5Hz，2H)，3.82(s，3H)；LCMS m/z 394.0(MH+)，t_R2.36 min.

Example 1112

The solution of 1 in MeCN was treated with 1N HC aqueous solution and lyophilized. The resulting residue was purified by reverse phase HPLC to give vinyl chloride 2 as TFA salt: LCMS m/z 434.2 (MH)⁺)，t_R2.48 minutes.

Example 1113

4- [2- (3-furan-3-yl-phenylamino) -1-methyl-1H-benzimidazol-5-yloxy ] -4-indolizine-2-carboxylic acid carboxamide

Stirring Pd (OAc) at room temperature₂(4.5mg, 0.02mmol) and triphenylphosphine (13.1mg, 0.05mmol) in dry NMP (1mL) for 20 min. Aryliodide 1(100mg, 0.2mmol), 3-furylboronic acid (45mg, 0.4mmol) and triethylamine (0.11mL, 0.8mmol) were added and the resulting solution degassed and washed with Ar. Heating the reactants to 100 ℃ for 2 hours; LCMS indicated no conversion. The reaction was cooled to room temperature under Ar and Pd (dppf) Cl was added₂CH2Cl₂And diisopropylethylamine (0.14 mL). The reaction was heated to 100 ℃ and held overnight. The reaction was cooled to room temperature and LCMS indicated complete conversion. The reaction was quenched with saturated NaHCO₃The aqueous solution and EtOAc were separated and the resulting mixture was filtered through celite. The remaining solid was washed with water and EtOAc. Separating the mixed cleaning solution and separating. The aqueous phase was extracted with EtOAc (3X) and saturated Na₂CO₃The combined organic portions were washed with aqueous, brine and dried (MgSO)₄) And concentrated. The crude residue was purified by reverse phase HPLC to give 2: LCMS m/z 440.3 (MH)⁺)，t_R2.35 min.

Example 1114

Prepared as described in example 120 b.

Example 1115

Prepared as described in example 120b

Example 1116

Raf/Mek filtration assay

Buffer solution

Determination of buffer: 50mM Tris, pH7.5, 15mM MgCl₂，0.1mM EDTA，1mM DTT

Washing buffer solution: 25mM Hepes, pH7.4, 50mM sodium pyrophosphate, 500mM NaCl

Stopping the reagent: 30mM EDTA

Material

Raf, active: upstate Biotech #14-352

Mek, inactivated: upstate Biotech #14-205

³³P-ATP：NEN Perkin Elmer#NEG 602h

96-well assay plate: falcon U-bottom polypropylene plates #35-1190

A filtering device: millipore # MAVM 096 or

96-well filter plate: millipore Immobilon 1# MAIP NOB

Scintillation fluid: wallac Optiphase "Supermix" #1200-

Measurement conditions

Raf about 120pM

Mek about 60nM

³³P-ATP 100nM

Reaction time: 45-60 minutes at room temperature

Assay protocol

In assay buffer (50mM Tris, pH7.5, 15mM MgCl)₂0.1mM EDTA and 1mM DTT), Raf and Mek were mixed at 2-fold final concentration and 15. mu.l was dispersed in each well of a polypropylene assay plate (Falcon U-bottom propylene96 well assay plates # 35-1190). Background levels were determined in wells containing Mek and DMSO but no Raf.

To wells containing Raf/Mek was added 3. mu.l of 10X Raf kinase inhibitor test compound (diluted with 100% DMSO). By adding 12. mu.l of 2.5 Xs per well³³P-ATP (diluted in assay buffer) to initiate the Raf kinase activity reaction. After 45-60 minutes, the reaction was stopped by adding 70. mu.l of stop reagent (30mM EDTA). The filter plate was pre-wetted with 70% ethanol for 5 minutes and then washed by filtration with wash buffer. Samples (90. mu.l) from the reaction wells were then transferred to the filter plate. The filter plates were washed 6 times with wash buffer using a Millipore filtration device. The plates were dried and 100. mu.l scintillation fluid (Wallac Optiphase "SuperMix" #1200-439) was added to each well. The CPM was then determined using a Wallac Microbeta1450 reader.

Example 1117

And (3) determination 2: biotinylated Raf screening

In vitro Raf screening

The activity of various isoforms of Raf serine/threonine kinases can be determined by providing ATP, MEK substrates, and measuring the transfer of phosphate moieties to MEK residues. Raf recombinant allotypes were obtained by purification from sf9 insect cells infected with human Raf recombinant baculovirus expression vectors. Recombinant kinase-inactivated MEK was expressed in e.coli, purified and labeled with biotin. For each assay, test compounds were serially diluted in DMSO and then mixed with Raf (0.50nM) and kinase inactive biotin-MEK (50nM) in reaction buffer and ATP (1 uM). The reaction was incubated for an additional 2 hours at room temperature and stopped by the addition of 0.5M EDTA. Transferring the stopped reaction mixture to a neutravidin-coated plate (pierce) and incubated for 1 hour. Phosphorylation products were measured by DELFIA time-resolved fluorescence system (Wallac) using rabbit anti-p-MEK (cell signaling) as primary antibody and europium-labeled anti-rabbit as secondary antibody. Time resolved fluorescence was read on a Wallac1232 DELFIA fluorometer. 50% Inhibition (IC) of each compound was calculated by non-linear regression using XL fitting data analysis software₅₀) Concentrating.

Using the procedures of example 1116 or 1117, the compounds of examples 1-1094 were shown to have Raf kinase inhibitory activity (IC)₅₀Less than 5 μ M).

While the preferred embodiment of the invention has been illustrated, it will be appreciated that various changes can be made therein without departing from the spirit and scope of the invention.

Claims (30)

1. A compound of the general formula (I):

in the formula, X₁And X₂Independently selected from ═ N-, -NR₄-, -O-or-S-, with the proviso that if X₁is-NR₄-, -O-or-S-, then X₂Is ═ N-; or if X₂is-NR₄-, -O-or-S-, then X₁Is ═N-, and X₁And X₂Neither is N-;

y is O;

A₁is substituted or unsubstituted C₁-C₁₂Alkyl radical, C₃-C₈Cycloalkyl radical, C₃-C₈Heterocycloalkyl radical, C₃-C₁₄Aryl, polycyclic C₃-C₁₄Aryl, polycyclic C₃-C₁₄Aryl radical C₁-C₁₂Alkyl radical, C₃-C₁₄Heteroaryl group, C₃-C₁₄Biaryl radical, C₃-C₁₄Heteroaryl C₃-C₁₄Aryl radical, C₃-C₁₄Heteroaryl C₃-C₁₄Heteroaryl group, C₃-C₈Cycloalkyl radical C₁-C₁₂Alkyl radical, C₃-C₈Heterocycloalkyl radical C₁-C₁₂Alkyl radical, C₃-C₁₄Aryl radical C₁-C₁₂Alkyl radical, C₃-C₁₄Heteroaryl C₁-C₁₂Alkyl radical, C₃-C₁₄Biaryl radical C₁-C₁₂Alkyl, or C₃-C₁₄Heteroaryl C₃-C₁₄Aryl radical C₁-C₁₂An alkyl group;

A₂is a substituted or unsubstituted pyridyl;

R₁is O or H, R₂Is NR₅R₆Or a hydroxyl group; or R₁And R₂Taken together to form a substituted or unsubstituted C₃-C₈Heterocycloalkyl or C₃-C₁₄A heteroaryl group; wherein the dotted line represents a single bond or a double bond;

R₃is hydrogen, halogen, C₁-C₆Alkyl or C₁-C₆An alkoxy group;

R₄is hydrogen, hydroxy, C₁-C₁₂Alkylamino, di-C₁-C₁₂Alkylamino or C₁-C₁₂An alkyl group;

R₅and R₆Independently selected from hydrogen, substituted or unsubstituted C₁-C₁₂Alkyl radical, C₁-C₁₂Alkoxy radical C₁-C₁₂Alkyl, amino C₁-C₁₂Alkyl, acylamino C₁-C₁₂Alkyl, acyl, C₃-C₈Cycloalkyl radical, C₃-C₈Heterocycloalkyl radical, C₃-C₁₄Aryl radical, C₃-C₁₄Heteroaryl group, C₁-C₁₂Alkyl oxygen C₁-C₁₂Alkyl radical C₃-C₈Heterocycle and C₃-C₁₄Heteroaryl C₁-C₁₂An alkyl group; or R₅And R₆Taken together to form a substituted or unsubstituted C₃-C₈Heterocyclic or C₃-C₁₄A heteroaryl group;

and pharmaceutically acceptable salts and esters.

2. A compound represented by the general formula (II):

wherein Y is O;

A₁is substituted or unsubstituted C₃-C₈Cycloalkyl radical, C₃-C₈Heterocycloalkyl radical, C₃-C₁₄Aryl, polycyclic C₃-C₁₄Aryl, polycyclic C₃-C₁₄Aryl radical C₁-C₁₂Alkyl radical, C₃-C₁₄Heteroaryl group, C₃-C₁₄Biaryl radical, C₃-C₁₄Heteroaryl C₃-C₁₄Aryl radical, C₃-C₁₄Heteroaryl C₃-C₁₄Heteroaryl group, C₃-C₈Cycloalkyl radical C₁-C₁₂Alkyl radical, C₃-C₈Heterocycloalkyl radical C₁-C₁₂Alkyl radical, C₃-C₁₄Aryl radical C₁-C₁₂Alkyl radical, C₃-C₁₄Heteroaryl C₁-C₁₂Alkyl radical, C₃-C₁₄Biaryl radical C₁-C₁₂Alkyl radical, C₃-C₁₄Heteroaryl C₃-C₁₄Aryl radical C₁-C₁₂An alkyl group;

A₂is a substituted or unsubstituted pyridyl;

R₁is O and R₂Is NR₅R₆(ii) a Or R₁And R₂Taken together to form a substituted or unsubstituted C₃-C₈Heterocycloalkyl or C₃-C₁₄A heteroaryl group; wherein the dotted line represents a single bond or a double bond;

R₃is hydrogen, halogen, C₁-C₆Alkyl or C₁-C₆An alkoxy group;

R₄is hydrogen or C₁-C₆An alkyl group;

R₅and R₆Independently selected from hydrogen, substituted or unsubstituted C₁-C₁₂Alkyl radical, C₁-C₁₂Alkoxy radical C₁-C₁₂Alkyl, amino C₁-C₁₂Alkyl, acylamino C₁-C₁₂Alkyl, acyl, C₃-C₈Cycloalkyl radical, C₃-C₈Heterocycloalkyl radical, C₃-C₁₄Aryl radical, C₃-C₁₄Heteroaryl group, C₁-C₁₂Alkyl oxygen C₁-C₁₂Alkyl radical C₃-C₈Heterocycle and C₃-C₁₄Heteroaryl C₁-C₁₂An alkyl group; or R₅And R₆Taken together to form a substituted or unsubstituted C₃-C₈Heterocyclic or C₃-C₁₄A heteroaryl group;

and pharmaceutically acceptable salts and esters.

3. A compound represented by the general formula (III):

wherein X is NR₄O or S;

A₁is substituted or unsubstituted C₃-C₈Cycloalkyl radical, C₃-C₈Heterocycloalkyl radical, C₃-C₁₄Aryl, polycyclic C₃-C₁₄Aryl, polycyclic C₃-C₁₄Aryl radical C₁-C₁₂Alkyl radical, C₃-C₁₄Heteroaryl group, C₃-C₁₄Biaryl radical, C₃-C₁₄Heteroaryl C₃-C₁₄Aryl radical, C₃-C₁₄Heteroaryl C₃-C₁₄Heteroaryl group, C₃-C₈Cycloalkyl radical C₁-C₁₂Alkyl radical, C₃-C₈Heterocycloalkyl radical C₁-C₁₂Alkyl radical, C₃-C₁₄Aryl radical C₁-C₁₂Alkyl radical, C₃-C₁₄Heteroaryl C₁-C₁₂Alkyl radical, C₃-C₁₄Biaryl radical C₁-C₁₂Alkyl radical, C₃-C₁₄Heteroaryl C₃-C₁₄Aryl radical C₁-C₁₂An alkyl group;

A₂is a substituted or unsubstituted pyridyl;

R₁is O and R₂Is NR₅R₆(ii) a Or R₁And R₂Taken together to form a substituted or unsubstituted C₃-C₈Heterocycloalkyl or C₃-C₁₄A heteroaryl group; wherein the dotted line represents a single bond or a double bond;

R₃is hydrogen, halogen, C₁-C₆Alkyl or C₁-C₆An alkoxy group;

R₄is hydrogen or C₁-C₆An alkyl group;

R₅and R₆Independently selected from hydrogen, substituted or unsubstituted C₁-C₁₂Alkyl radical, C₁-C₁₂Alkoxy radical C₁-C₁₂Alkyl, amino C₁-C₁₂Alkyl, acylamino C₁-C₁₂Alkyl, acyl, C₃-C₈Cycloalkyl radical, C₃-C₈Heterocycloalkyl radical, C₃-C₁₄Aryl radical, C₃-C₁₄Heteroaryl group, C₁-C₁₂Alkyl oxygen C₁-C₁₂Alkyl radical C₃-C₈Heterocycle and C₃-C₁₄Heteroaryl radicalC₁-C₁₂An alkyl group; or R₅And R₆Taken together to form a substituted or unsubstituted C₃-C₈Heterocyclic or C₃-C₁₄A heteroaryl group;

and pharmaceutically acceptable salts and esters.

4. A compound of claim 1, 2 or 3 wherein R is₁Is O and the dotted line represents a single or double bond.

5. A compound represented by the general formula (V):

wherein X is NR₄O or S;

A₁is substituted or unsubstituted C₃-C₈Cycloalkyl radical, C₃-C₈Heterocycloalkyl radical, C₃-C₁₄Aryl, polycyclic C₃-C₁₄Aryl, polycyclic C₃-C₁₄Aryl radical C₁-C₁₂Alkyl radical, C₃-C₁₄Heteroaryl group, C₃-C₁₄Biaryl radical, C₃-C₁₄Heteroaryl C₃-C₁₄Aryl radical, C₃-C₁₄Heteroaryl C₃-C₁₄Heteroaryl group, C₃-C₈Cycloalkyl radical C₁-C₁₂Alkyl radical, C₃-C₈Heterocycloalkyl radical C₁-C₁₂Alkyl radical, C₃-C₁₄Aryl radical C₁-C₁₂Alkyl radical, C₃-C₁₄Heteroaryl C₁-C₁₂Alkyl radical, C₃-C₁₄Biaryl radical C₁-C₁₂Alkyl radical, C₃-C₁₄Heteroaryl C₃-C₁₄Aryl radical C₁-C₁₂An alkyl group;

R₁is O and R₂Is NR₅R₆(ii) a Or R₁And R₂Taken together to form a substituted or unsubstitutedSubstituted C₃-C₈Heterocycloalkyl or C₃-C₁₄A heteroaryl group; wherein the dotted line represents a single bond or a double bond;

R₃is hydrogen, halogen, C₁-C₆Alkyl or C₁-C₆An alkoxy group;

R₄is hydrogen or C₁-C₆An alkyl group;

R₅and R₆Independently selected from hydrogen, substituted or unsubstituted C₁-C₁₂Alkyl radical, C₁-C₁₂Alkoxy radical C₁-C₁₂Alkyl, amino C₁-C₁₂Alkyl, acylamino C₁-C₁₂Alkyl, acyl, C₃-C₈Cycloalkyl radical, C₃-C₈Heterocycloalkyl radical, C₃-C₁₄Aryl radical, C₃-C₁₄Heteroaryl group, C₁-C₁₂Alkyl oxygen C₁-C₁₂Alkyl radical C₃-C₈Heterocycle and C₃-C₁₄Heteroaryl C₁-C₁₂An alkyl group; or R₅And R₆Taken together to form a substituted or unsubstituted C₃-C₈Heterocyclic or C₃-C₁₄A heteroaryl group;

and pharmaceutically acceptable salts and esters.

6. The compound of claim 1, wherein X is₁Is NR₄。

7. A compound according to claim 3 or 5, wherein X is NR₄。

8. A compound according to claim 6 or 7, wherein R is₄Is hydrogen.

9. A compound according to claim 6 or 7, wherein R is₄Is methyl.

10. The compound of claim 1, 2, 3, 4 or 5, wherein A is₁Selected from substituted or unsubstituted phenyl, pyridyl, pyrimidyl, phenyl C₁-C₁₂Alkyl, pyridyl C₁-C₁₂Alkyl, pyrimidinyl C₁-C₁₂Alkyl, heterocyclic carbonylphenyl, heterocyclic phenyl, heterocyclic C₁-C₁₂Alkylphenyl, chlorophenyl, fluorophenyl, bromophenyl, iodophenyl, dihalophenyl, nitrophenyl, 4-bromophenyl, 4-chlorophenyl, C₁-C₁₂Alkyl benzoates, C₁-C₁₂Alkoxyphenyl, di-C₁-C₁₂Alkoxyphenyl, di-C₁-C₁₂Alkylphenyl, tri-C₁-C₁₂Alkylphenyl, thiophene-2-carboxylic acid ester, C₁-C₁₂Alkylphenylthio, trifluoromethylphenyl, acetylphenyl, sulfamoylphenyl, diphenyl, cyclohexylphenyl, phenyloxyphenyl, di-C₁-C₁₂Alkylamino phenyl radical, C₁-C₁₂Alkyl bromophenyl radical, C₁-C₁₂Alkyl chlorophenyl, C₁-C₁₂Alkylfluorophenyl, trifluoromethylchlorophenyl, trifluoromethylbromophenylindenyl, 2, 3-dihydroindenyl, 1, 2, 3, 4-tetrahydronaphthyl, trifluorophenyl, (trifluoromethyl) phenylthio, C₁-C₁₂Alkoxydiphenyl, morpholinyl, N-piperazinyl, N-morpholinyl C₁-C₁₂Alkyl, piperazinyl C₁-C₁₂Alkyl, cyclohexyl C₁-C₁₂Alkyl, indolyl, 2, 3-indolinyl, 1-acetyl-2, 3-indolinyl, cycloheptyl, bicyclo [2.2.1]Hept-2-yl, hydroxyphenyl, hydroxy C₁-C₁₂Alkylphenyl, pyrrolidinyl, pyrrolidin-1-yl C₁-C₁₂Alkyl, 4-amino (imino) methylphenyl, isoxazolyl, indazolyl, adamantyl, dicyclohexyl, quinuclidinyl, imidazolyl, benzimidazolyl, imidazolylphenyl, phenylimidazolyl, phthalandiyl, naphthyl, benzophenone, anilino, benzyl ether, quinolyl, and the like,Quinolino, phenylsulfonyl, phenyl C₁-C₁₂Alkylsulfonyl, 9H-fluoren-1-yl, piperidin-1-yl C₁-C₁₂Alkyl, cyclopropyl C₁-C₁₂Alkyl, pyrimidin-5-ylphenyl, quinolinylphenyl, furanyl, furanylphenyl, N-methylpiperidin-4-yl, pyrrolidin-4-ylpyridinyl, 4-benzodiazepine-1-yl, hydroxypyrrolidin-1-yl, di-C₁-C₁₂Alkylaminopyrrolidin-1-yl, 1, 4 '-dipiperidin-1' -yl and (1, 4 '-dipiperidin-1' -ylcarbonyl) phenyl.

11. A compound of claim 5, wherein R is₁Is O and the dotted line represents a single or double bond.

12. A compound of claim 1, 2, 3, 4 or 5 wherein R is₂Is NR₅R₆，R₅Is hydrogen, R₆Selected from hydrogen, substituted or unsubstituted C₁-C₁₂Alkyl radical, C₁-C₁₂Alkoxy radical C₁-C₁₂Alkyl, amino C₁-C₁₂Alkyl, acylamino C₁-C₁₂Alkyl, acyl, C₃-C₈Cycloalkyl radical, C₃-C₈Heterocycloalkyl radical, C₃-C₁₄Aryl radical, C₃-C₁₄Heteroaryl group, C₁-C₁₂Alkyl oxygen C₁-C₁₂Alkyl radical C₃-C₈Heterocycle and C₃-C₁₄Heteroaryl C₁-C₁₂An alkyl group.

13. A compound of claim 1, 2, 3, 4 or 5 wherein R is₁And R₂Taken together to form a substituted or unsubstituted C₃-C₈Heterocycloalkyl or C₃-C₁₄A heteroaryl group.

14. A compound of claim 1, 2, 3, 4 or 5 wherein R is₃Is hydrogen.

15. A compound of claim 1, 2, 3, 4 or 5 wherein R is₃Is C₁-C₆An alkoxy group.

16. The compound of claim 15, wherein R is₃Is methoxy.

17. A compound of claim 1, 2, 3, 4 or 5 wherein R is₄Is C₁-C₆An alkyl group.

18. The compound of claim 17, wherein R is₄Is methyl.

19. A compound of claim 1, 2, 3, 4 or 5 wherein R is₁Is O, R₂Is NR₅R₆，R₅Is hydrogen, R₆Is methyl.

20. A composition comprising a compound of claim 1, 2, 3, 4 or 5, which compound is effective to inhibit Raf activity in a human or animal subject when administered together with a pharmaceutically acceptable carrier.

21. The composition of claim 20, further comprising at least one additional agent for treating cancer.

22. The composition of claim 21, wherein the at least one other agent for treating cancer is selected from the group consisting of irinotecan, topotecan, yersinine, 5-fluorouracil, leucovorin, carboplatin, cisplatin, taxane, tezacitabine, cyclophosphamide, vinca alkaloids, imatinib (Gleevec), anthracyclines, rituximab, trastuzumab.

23. Use of a compound according to claim 1, 2, 3, 4 or 5 in the manufacture of a medicament for inhibiting Raf kinase activity in a human or animal subject.

24. Use of a compound of claim 1, 2, 3, 4 or 5 in the manufacture of a medicament for the treatment of cancer in a human or animal subject.

25. Use of a compound of claim 1, 2, 3, 4 or 5 in the manufacture of a medicament for the treatment of hormone dependent cancer in a human or animal subject.

26. The use of claim 25, wherein the hormone-dependent cancer is breast or prostate cancer.

27. Use of a compound according to claim 1, 2, 3, 4 or 5 in the manufacture of a medicament for the treatment of leukemia in a human or animal subject.

28. The use of claim 24, 25, 26 or 27, wherein the medicament is used in combination with at least one other agent for the treatment of cancer.

29. The use of claim 28, wherein the at least one other agent for treating cancer is selected from the group consisting of ipomoea batatas, topotecan, yersinine, 5-fluorouracil, leucovorin, carboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide, vinca alkaloids, imatinib (Gleevec), anthracyclines, rituximab, trastuzumab.

30. Use of a compound according to any one of claims 1 to 19 in the manufacture of a medicament for the treatment of cancer.