# Patent

## Title
Substituted benz-azoles and methods of their use as inhibitors of Raf kinase

## Abstract

New substituted benz-azole compounds, compositions and methods of inhibition of Raf kinase activity in a human or animal subject are provided. The new compounds compositions may be used either alone or in combination with at least one additional agent for the treatment of a Raf kinase mediated disorder, such as cancer.

## Background
CROSS-REFERENCE TO RELATED APPLICATION
This application is based on U.S. provisional application Ser. No. 60/369,066 filed Mar. 29, 2002.


FIELD OF THE INVENTION
The present invention relates to new substituted benz-azole-like compounds and pharmaceutically acceptable salts, esters or prodrugs thereof, compositions of the new compounds together with pharmaceutically acceptable carriers, and uses of the new compounds, either alone or in combination with at least one additional therapeutic agent, in the prophylaxis or treatment of cancer.
BACKGROUND OF THE INVENTION
The Raf serine/threonine kinases are essential components of the Ras/Mitogen-Activated Protein Kinase (MAPK) signaling module that controls a complex transcriptional program in response to external cellular stimuli. Raf genes code for highly conserved serine-threonine-specific protein kinases which are known to bind to the ras oncogene. They are part of a signal transduction pathway believed to consist of receptor tyrosine kinases, p21 ras, 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 Kinase Kinase (called Mek1 and Mek2), that are dual specificity threonine/tyrosine kinases. Both Mek isoforms activate Mitogen Activated Kinases 1 and 2 (MAPK, also called Extracellular Ligand Regulated Kinase 1 and 2 or Erk1 and Erk2). The MAPKs phosphorylate many substrates including transcription factors and in so doing set up their transcriptional program. Raf kinase participation in the Ras/MAPK pathway influences and regulates many cellular functions such as proliferation, differentiation, survival, oncogenic transformation and apoptosis.
Both the essential role and the position of Raf in many signaling pathways have been demonstrated from studies using deregulated and dominant inhibitory Raf mutants in mammalian cells as well as from studies employing biochemical and genetic techniques model organisms. In many cases, the activation of Raf by receptors that stimulate cellular tyrosine phosphorylation is dependent on the activity of Ras, indicating that Ras functions upstream of Raf. Upon activation, Raf-1 then phosphorylates and activates Mek1, resulting in the propagation of the signal to downstream effectors, such as MAPK (mitogen-activated protein kinase) (Crews et al. (1993) Cell 74:215). The Raf serine/threonine kinases are considered to be the primary Ras effectors involved in the proliferation of animal cells (Avruch et al. (1994) Trends Biochem. Sci. 19:279).
Raf kinase has three distinct isoforms, Raf-1 (c-Raf), A-Raf, and B-Raf, distinguished by their ability to interact with Ras, to activate MAPK kinase pathway, tissue distribution and sub-cellular localization (Marias et. Al., Biochem. J. 351: 289–305, 2000; Weber et. al., Oncogene 19:169–176, 2000; Pritchard et. al., Mol. Cell. Biol. 15:6430–6442, 1995). Raf kinases are activated by Ras and phosphorylate and activate two isoforms of Mitogen-Activated Protein Kinase Kinase (called Mek1 and Mek2) that are dual specificity threonine/tyrosine kinases. Both Mek isoforms activate Mitogen Activated Kinases 1 and 2 (MAPK, also called Extracellular Ligand Regulated Kinase 1 and 2 or Erk1 and Erk2). The MAPKs phosphorylate many substrates including cytosolic proteins and ETS family of transcription factors. Raf kinase participation in the Ras/MAPK pathway influences and regulates many cellular functions such as proliferation, differentiation, survival, cell cycle progression and apoptosis.
Activating mutation of one of the Ras genes can be seen 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 mutation in the skin nevi is a critical step in the initiation of melanocytic neoplasia (Pollock et. al., Nature Genetics 25: 1–2, 2002). Furthermore, most recent studies have emerged that activating mutation in the kinase domain of B-Raf occurs in  ̃66% of melanomas, 12% of colon carcinoma and 14% of liver cancer (Davies et. al., Nature 417:949–954,–2002) (Yuen et. al., Cancer Research 62:6451–6455, 2002) (Brose et. al., Cancer Research 62:6997–7000, 2002).
Inhibitors of Raf/MEK/ERK pathway at the level of Raf kinases can potentially be effective as therapeutic agents against tumors with over-expressed or mutated receptor tyrosine kinases, activated intracellular tyrosine kinases, tumors with aberrantly expressed Grb2 (an adapter protein that allows stimulation of Ras by the Sos exchange factor) as well as tumors harboring activating mutations of Raf itself. In the early clinical trails inhibitor of Raf-1 kinase that also inhibit B-Raf have shown promise as therapeutic agents in cancer therapy (Crump, Current Pharmaceutical Design 8: 2243–2248, 2002; Sebastien et. al., Current Pharmaceutical Design 8: 2249–2253, 2002).
Disruption of Raf expression in cell lines through the application of RNA antisense technology has been shown to suppress both 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 exhibiting efficacy 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 the use of Raf kinase inhibitors for treating leukemia (see, e.g., U.S. Pat. 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. Pat. 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
New substituted benz-azole compounds and pharmaceutically acceptable salts thereof or esters having a solubility enhancing moieties or prodrugs thereof are provided of the formula (I):




wherein, X1 and X2 are independently selected from ═N—, —NR4—, —O— or —S—, provided that if X1 is —NR4—, —O— or —S—, then X2 is ═N—, or if X2 is —NR4—, —O— or —S—, then X2 is ═N—, and both X1 and X2 are not ═N—;
Y is O or S;
A1 is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl, heteroarylaryl, heteroarylheteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, biarylalkyl, or heteroarylarylalkyl;
A2 is substituted or unsubstituted heteroaryl;
R1 is O or H, and R2 is NR5R6 or hydroxyl; or R1 is taken together with R2 to form a substituted or unsubstituted heterocycloalkyl or heteroaryl group; wherein, the dashed line represents a single or double bond;
R3 is hydrogen, halogen, loweralkyl, or loweralkoxy;
R4 is hydrogen, hydroxyl, alkylamino, dialkylamino or alkyl;
R5 and R6 are independently selected from hydrogen, and substituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl; or R5 and R6 are taken together to form substituted or unsubstituted heterocyclo or heteroaryl; and
the pharmaceutically acceptable salts, esters and prodrugs thereof.
In other embodiments, new substituted benz-azole compounds are provided of the formula (II):




wherein and Y, Ar1, Ar2, R1, R2, R3 and R4 are as defined above; and
the pharmaceutically acceptable salts, esters, and prodrugs thereof.
In other embodiments, new substituted benz-azole compounds are provided of the formula (III):




wherein X1, Ar1, Ar2, R1, R2 and R3 are as defined above; and
the pharmaceutically acceptable salts, esters, tautomers and prodrugs thereof.
In other embodiments, new substituted benz-azole compounds are provided of the formula (IV):




wherein X1, Y, Ar1, R1, R2 and R3 are as defined above; and
the pharmaceutically acceptable salts, esters, tautomers and prodrugs thereof.
In yet other embodiments, new substituted benz-azole compounds are provided of the formula (V):




wherein X1, Ar1, R1, R2 and R3 are as defined above; and
the pharmaceutically acceptable salts, esters, tautomers and prodrugs thereof.
In other aspects, the present invention provides methods for treating Raf related disorders in a human or animal subject in need of such treatment comprising administering to said 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 present invention provides methods for treating Raf related disorders in a human or animal subject in need of such treatment comprising administering to said 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 combination with at least one additional agent for the treatment of cancer.
In yet other aspects, the present invention provides therapeutic compositions comprising at least one compound of formula (I), (II), (III), (IV) or (V) in combination with one or more additional agents for the treatment of cancer, as are commonly employed in cancer therapy.
The compounds of the invention are useful in the treatment of cancers, including carcinomas (e.g., of the lungs, pancreas, thyroid, bladder or colon), myeloid disorders (e.g., myeloid leukemia) and adenomas (e.g., villous colon adenoma).
The invention further provides compositions, methods of use, and methods of manufacture as described in the detailed description of the invention.


DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
In accordance with one aspect of the present invention, new substituted benz-azole compounds and pharmaceutically acceptable salts, esters or prodrugs thereof are provided of the formula (I):




wherein, X1 and X2 are independently selected from ═N—, —NR4—, —O— or —S—, provided that if X1 is —NR4—, —O— or —S—, then X2 is ═N—, or if X2 is —NR4—, —O— or —S—, then X2 is ═N—, and both X1 and X2 are not ═N—;Y is O or S;
Y is O or S;
A1 is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl, heteroarylaryl, heteroarylheteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, biarylalkyl, or heteroarylarylalkyl;
A2 is substituted or unsubstituted heteroaryl;
R1 is O or H, and R2 is NR5R6 or hydroxyl; or R1 is taken together with R2 to form a substituted or unsubstituted heterocycloalkyl or heteroaryl group; wherein, the dashed line represents a single or double bond;
R3 is hydrogen, halogen, loweralkyl, or loweralkoxy;
R4 is hydrogen, hydroxyl, alkylamino, dialkylamino or alkyl;
R5 and R6 are independently selected from hydrogen, and substituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl; or R5 and R6 are taken together to form substituted or unsubstituted heterocyclo or heteroaryl; and
the pharmaceutically acceptable salts, esters and prodrugs thereof.
In other embodiments, new substituted benz-azole compounds are provided of the formula (II):




wherein and Y, Ar1, Ar2, R1, R2, R3 and R4 are as defined above; and
the pharmaceutically acceptable salts, esters, and prodrugs thereof.
In other embodiments, new substituted benz-azole compounds are provided of the formula (III):




wherein X1, Ar1, Ar2, R1, R2 and R3 are as defined above; and
the pharmaceutically acceptable salts, esters, tautomers and prodrugs thereof.
In other embodiments, new substituted benz-azole compounds are provided of the formula (IV):




wherein X1, Y, Ar1, R1, R2 and R3 are as defined above; and
the pharmaceutically acceptable salts, esters, tautomers and prodrugs thereof.
In yet other embodiments, new substituted benz-azole compounds are provided of the formula (V):




wherein X1, Ar1, R1, R2 and R3 are as defined above; and
the pharmaceutically acceptable salts, esters, tautomers and prodrugs thereof.
In another aspect, the present invention provides methods of treating human or animal subjects suffering from a Raf related disorder, such as cancer. Thus, the present invention provides methods of treating a human or animal subject in need of such treatment comprising administering to the subject a therapeutically effective amount of a compound of formula I, II, III, IV or V above, either alone or in combination with other anticancer agents.
In other aspects, the present invention provides methods for treating Raf related disorders in a human or animal subject in need of such treatment comprising administering to said 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 present invention provides methods for treating Raf related disorders in a human or animal subject in need of such treatment comprising administering to said 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 combination with at least one additional agent for the treatment of cancer. A number of suitable anticancer agents to be used as combination therapeutics are contemplated for use in the methods of the present invention. Indeed, the present invention contemplates, but is not limited to, administration of numerous anticancer agents such as: agents that induce apoptosis; polynucleotides (e.g., ribozymes); polypeptides (e.g., enzymes); drugs; biological minietics; alkaloids; alkylating agents; antitumor antibiotics; antimetabolites; hormones; platinum compounds; monoclonal antibodies conjugated with anticancer drugs, toxins, and/or radionuclides; biological response modifiers (e.g. interferons [e.g. IFN-a, etc.] and interleukins [e.g. IL-2, etc.], etc.); adoptive immunotherapy agents; hematopoietic growth factors; agents that induce tumor cell differentiation (e.g. all-trans-retinoic acid, etc.); gene therapy reagents; antisense therapy reagents and nucleotides; tumor vaccines; inhibitors of angiogenesis, and the like. Numerous other examples of chemotherapeutic compounds and anticancer therapies suitable for coadministration with the disclosed compounds of formula (I), (II), (III), (IV) or (V) are known to those skilled in the art.
In preferred embodiments, anticancer agents to be used in combination with compounds of the present invention comprise agents that induce or stimulate 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 inhibitor, Vascular Growth Factor Receptor [VGFR] kinase inhibitor, Fibroblast Growth Factor Receptor [FGFR] kinase inhibitor, Platelet-derived Growth Factor Receptor [PGFR] I kinase inhibitor, and Bcr-Abl kinase inhibitors such as STI-571, Gleevec, and Glivec]); antisense molecules; antibodies [e.g., Herceptin and Rituxan]; anti-estrogens [e.g., raloxifene and tamoxifen]; anti-androgens [e.g., flutamide, bicalutamide, finasteride, amino-glutethamide, ketoconazole, and corticosteroids]; cyclooxygenase 2 (COX-2) inhibitors [e.g., Celecoxib, meloxicam, NS-398, and non-steroidal antiinflammatory drugs (NSAIDs)]; and cancer chemotherapeutic drugs [e.g., irinotecan (Camptosar), CPT-11, fludarabine (Fludara), dacarbazine (DTIC), dexamethasone, mitoxantrone, Mylotarg, VP-16, cisplatinum, 5-FU, Doxrubicin, Taxotere or taxol]; cellular signaling molecules; ceramides and cytokines; and staurosprine, and the like.
In other aspects, the present invention provides pharmaceutical compositions 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 together with other anticancer agents.
In other aspects, the present invention provides methods of manufacture of compounds of formula I, II, III, IV or V as described herein.
In yet other aspects, the present invention provides compounds which are inhibitors of the enzyme raf kinase. Since the enzyme is a downstream effector of p21ras, the instant inhibitors are useful in pharmaceutical compositions for human or veterinary use where inhibition of the raf kinase pathway is indicated, e.g., in the treatment of tumors and/or cancerous cell growth mediated by raf kinase. In particular, the compounds are useful in the treatment of human or animal, e.g., murine cancer, since the progression of these cancers is dependent upon the ras protein signal transduction cascade and therefore is susceptible to treatment by interruption of the cascade by inhibiting raf kinase activity. Accordingly, the compounds of the invention are useful in treating solid cancers, such as, for example, carcinomas (e.g., of the lungs, pancreas, thyroid, bladder or colon, myeloid disorders (e.g., myeloid leukemia) or adenomas (e.g., villous colon adenoma).
“Raf inhibitor” is used herein to refer to a compound that exhibits an IC50 with respect to Raf Kinase activity of no more than about 100 μM and more typically not more than about 50 μM, as measured in the Raf/Mek Filtration Assay described generally hereinbelow. Preferred isoforms of Raf Kinase in which the compounds of the present invention will be shown to inhibit, include A-Raf, B-Raf, and C-Raf (Raf-1). “IC50” is that concentration of inhibitor which reduces the activity of an enzyme (e.g., Raf kinase) to half-maximal level. Representative compounds of the present invention have been discovered to exhibit inhibitory activity against Raf. Compounds of the present invention preferably exhibit an IC50 with respect to Raf of no more than about 10 μM, more preferably, no more than about 5 μM, even more preferably not more than about 1 μM, and most preferably, not more than about 200 nM, as measured in the Raf kinase assays described herein.
As used herein, the term “benz-azoles” includes benzimidazoles, benzothiazoles and benzoxazoles.
The phrase “alkyl” refets to alkyl groups that do 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 chain isomers of straight chain alkyl groups, including but not limited to, the following which are provided by way of example: —CH(CH3)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 others. The phrase also includes cyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl and such rings substituted with straight and branched chain alkyl groups as defined above. Thus the phrase alkyl groups includes primary alkyl groups, secondary alkyl groups, and tertiary alkyl groups. Preferred alkyl groups include straight and branched chain alkyl groups and cyclic alkyl groups having 1 to 12 carbon atoms.
As used herein “loweralkyl” includes both substituted or unsubstituted straight or branched chain alkyl groups having from 1 to 6 carbon atoms. Representative loweralkyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, trifluoromethyl, pentafluoroethyl and the like. Loweralkyl groups may be substituted, such as with halo, hydroxy, amino, nitro and/or cyano groups, and the like. Representative of halo-substituted and hydroxy-substituted loweralkyl include chloromethyl, trichloromethyl, chloroethyl, hydroxyethyl, and the like. Other suitable substituted loweralkyl moieties include, for example, aralkyl, aminoalkyl, aminoaralkyl, carbonylaminoalkyl, alkylcarbonylaminoalkyl, arylcarbonylaminoalkyl, aralkylcarbonyl-aminoalkyl, aminoalkoxyalkyl and arylaminoalkyl.
“Loweralkoxy” as used herein refers to RO— wherein R is loweralkyl. Representative examples of loweralkoxy groups include methoxy, ethoxy, t-butoxy, trifluoromethoxy and the like.
As used herein, the term “halogen” or “halo” refers to chloro, bromo, fluoro and iodo groups. “Haloalkyl” refers to an alkyl radical substituted with one or more halogen atoms. The term “haloloweralkyl” refers to a loweralkyl radical substituted with one or more halogen atoms. The term “haloalkoxy” refers to an alkoxy radical substituted with one or more halogen atoms. The term “haloloweralkoxy” refers to a loweralkoxy radical substituted with one or more halogen atoms.
“Amino” refers herein to the group —NH2. The term “alkylamino” refers herein to the group —NRR′ where R and R′ are each independently selected from hydrogen or a lower alkyl. The term “arylamino” refers herein to the group —NRR′ where R is aryl and R′ is hydrogen, a lower alkyl, or an aryl. The term “aralkylamino” refers herein to the group —NRR′ where R is a lower aralkyl and R′ is hydrogen, a loweralkyl, an aryl, or a loweraralkyl.
The term “alkoxyalkyl” refers to the group -alk1-O-alk2 where alk, is alkyl or alkenyl, and alk2 is alkyl or alkenyl. The term “loweralkoxyalkyl” refers to an alkoxyalkyl where alk1 is loweralkyl or loweralkenyl, and alk2 is loweralkyl or loweralkenyl. The term “aryloxyalkyl” refers to the group -alkyl-O-aryl. The term “aralkoxyalkyl” refers to the group -alkylenyl-O-aralkyl, where aralkyl is a loweraralkyl.
The term “alkoxyalkylamino” refers herein to the group —NR-(alkoxyalkyl), where R is typically hydrogen, loweraralkyl, or loweralkyl. The term “aminoloweralkoxyalkyl” refers herein to an aminoalkoxyalkyl in which the alkoxyalkyl is a loweralkoxyalkyl.
The term “aminocarbonyl” refers herein to the group —C(O)—NH2. “Substituted aminocarbonyl” refers herein to the group —C(O)—NRR′ where R is loweralkyl and R′ is hydrogen or a loweralkyl. The term “arylaminocarbonyl” refers herein to the group —C(O)—NRR′ where R is an aryl and R′ is hydrogen, loweralkyl or aryl. “aralkylaminocarbonyl” refers herein to the group —C(O)—NRR′ where R is loweraralkyl and R′ is hydrogen, loweralkyl, aryl, or loweraralkyl.
“Aminosulfonyl” refers herein to the group —S(O)2—NH2. “Substituted aminosulfonyl” refers herein to the group —S(O)2—NRR′ where R is loweralkyl and R′ is hydrogen or a loweralkyl. The term “aralkylaminosulfonlyaryl” refers herein to the group -aryl-S(O)2—NH-aralkyl, where the aralkyl is loweraralkyl.
“Carbonyl” refers to the divalent group —C(O)—.
“Carbonyloxy” refers generally to the group —C(O)—O. Such groups include esters, —C(O)—O—R, where R is loweralkyl, cycloalkyl, aryl, or loweraralkyl. The term “carbonyloxycycloalkyl” refers generally herein to both an “carbonyloxycarbocycloalkyl” and an “carbonyloxyheterocycloalkyl”, i.e., where R is a carbocycloalkyl or heterocycloalkyl, respectively. The term “arylcarbonyloxy” refers herein to the group —C(O)—O-aryl, where aryl is a mono- or polycyclic, carbocycloaryl or heterocycloaryl. The term “aralkylcarbonyloxy” refers herein to the group —C(O)—O-aralkyl, where the aralkyl is loweraralkyl.
The term “sulfonyl” refers herein to the group —SO2—. “Alkylsulfonyl” refers to a substituted sulfonyl of the structure —SO2R— in which R is alkyl. Alkylsulfonyl groups employed in compounds of the present invention are typically loweralkylsulfonyl groups having from 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., where R is methyl), ethylsulfonyl (i.e., where R is ethyl), propylsulfonyl (i.e., where R is propyl), and the like. The term “arylsulfonyl” refers herein to the group —SO2-aryl. The term “aralkylsulfonyl” refers herein to the group —SO2-aralkyl, in which the aralkyl is loweraralkyl. The term “sulfonamido” refers herein to —SO2NH2.
As used herein, the term “carbonylamino” refers to the divalent group —NH—C(O)— in which the hydrogen atom of the amide nitrogen of the carbonylamino group can be replaced a loweralkyl, aryl, or loweraralkyl group. Such groups include moieties such as carbamate esters (—NH—C(O)—O—R) and amides —NH—C(O)—O—R, where R is a straight or branched chain loweralkyl, cycloalkyl, or aryl or loweraralkyl. The term “loweralkylcarbonylamino” refers to alkylcarbonylamino where R is a loweralkyl having from 1 to about 6 carbon atoms in its backbone structure. The term “arylcarbonylamino” refers to group —NH—C(O)—R where R is an aryl. Similarly, the term “aralkylcarbonylamino” refers to carbonylamino where R is a lower aralkyl. As used herein, the term “aminocarbonyl” refers to the divalent group —C(O)—NH— in which the hydrogen atom of the amide nitrogen of the carbonylamino group can be replaced a loweralkyl, aryl, or loweraralkyl group, as described above.
As used herein, the term “guanidino” or “guanidyl” refers to moieties derived from guanidine, H2N—C(═NH)—NH2. Such moieties include those bonded at the nitrogen atom carrying the formal double bond (the “2”-position of the guanidine, e.g., diaminomethyleneamino, (H2N)2C═NH—) and those bonded at either of the nitrogen atoms carrying a formal single bond (the “1-” and/or “3”-positions of the guandine, e.g., H2N—C(═NH)—NH—). The hydrogen atoms at any of the nitrogens can be replaced with a suitable substituent, such as loweralkyl, aryl, or loweraralkyl.
As used herein, the term “amidino” refers to the moieties R—C(═N)—NR′— (the radical being at the “N1” nitrogen) and R(NR′)C═N— (the radical being at the “N2” nitrogen), where R and R′ can be hydrogen, loweralkyl, aryl, or loweraralkyl.
“Cycloalkyl” refers to a mono- or polycyclic, heterocyclic or carbocyclic alkyl substituent. Typical cycloalkyl substituents have from 3 to 8 backbone (i.e., ring) atoms in which each backbone atom is either carbon or a heteroatom. The term “heterocycloalkyl” refers herein to cycloalkyl substituents that have from 1 to 5, and more typically from 1 to 4 heteroatoms in the ring structure. Suitable heteroatoms employed in compounds of the present invention are nitrogen, oxygen, and sulfur. Representative heterocycloalkyl moieties include, for example, morpholino, piperazinyl, piperadinyl and the like. Carbocycloalkyl groups are -cycloalkyl groups in which all ring atoms are carbon. When used in connection with cycloalkyl substituents, the term “polycyclic” refers herein to fused and non-fused alkyl cyclic structures.
The term “substituted heterocycle” or “heterocyclic group” or heterocycle as used herein refers to any 3- or 4-membered ring containing a heteroatom selected from nitrogen, oxygen, and sulfur or a 5- or 6-membered ring containing from one to three heteroatoms selected from the group consisting of 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 atom maybe optionally oxidized; wherein the nitrogen and sulfur heteroatoms maybe optionally quarternized; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring or another 5- or 6-membered heterocyclic ring independently defined above. The term “heterocycle” thus includes rings in which nitrogen is the heteroatom as well as partially and fully-saturated rings. Preferred heterocycles include, for example: diazapinyl, pyrryl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazoyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, pyrazinyl, piperazinyl, N-methyl piperazinyl, azetidinyl, N-methylazetidinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, triazolyl and benzothienyl.
Heterocyclic moieties can be unsubstituted or monosubstituted or disubstituted with various substituents independently selected from hydroxy, halo, oxo (C═O), alkylimino (RN═, wherein R is a loweralkyl or loweralkoxy group), amino, alkylamino, dialkylamino, acylaminoalkyl, alkoxy, thioalkoxy, polyalkoxy, loweralkyl, cycloalkyl or haloalkyl.
The heterocyclic groups may be attached at various positions as will be apparent to those having skill in the organic and medicinal chemistry arts in conjunction with the disclosure herein.




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

Representative heterocyclics include, for example, imidazolyl, pyridyl, piperazinyl, azetidinyl, thiazolyl, furanyl, triazolyl benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, indolyl, naphthpyridinyl, indazolyl, and quinolizinyl.
“Aryl” refers to optionally substituted monocyclic and polycyclic aromatic groups having from 3 to 14 backbone carbon or hetero atoms, and includes both carbocyclic aryl groups and heterocyclic aryl groups. Carbocyclic aryl groups are aryl groups in which all ring atoms in the aromatic ring are carbon. The term “heteroaryl” refers herein to aryl groups having from 1 to 4 heteroatoms as ring atoms in an aromatic ring with the remainder of the ring atoms being carbon atoms. When used in connection with aryl substituents, the term “polycyclic aryl” refers herein to fused and non-fused cyclic structures in which at least one cyclic structure is aromatic, such as, for example, benzodioxozolo (which has a heterocyclic structure fused to a phenyl group, i.e.,




naphthyl, and the like. Exemplary aryl moieties employed as substituents in 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. Typically, aralkyl groups employed in compounds of the present invention have from 1 to 6 carbon atoms incorporated within the alkyl portion of the aralkyl group. Suitable aralkyl groups employed in 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 can be further substituted and may be attached at various positions as will be apparent to those having skill in the organic and medicinal chemistry arts in conjunction with the disclosure herein.




Representative heteroaryl's 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, which are not condensed to each other, are bound. Exemplary biaryl compounds include, for example, phenylbenzene, diphenyldiazene, 4-methylthio-1-phenylbenzene, phenoxybenzene, (2-phenylethynyl)benzene, diphenyl ketone, (4-phenylbuta-1,3-diynyl)benzene, phenylbenzylamine, (phenylmethoxy)benzene, and the like. Preferred optionally substituted biaryl groups include: 2-(phenylamino)-N-[4-(2-phenylethynyl)-phenyl]acetamide, 1,4-diphenylbenzene, N-[4-(2-phenylethynyl)phenyl]-2-[benzyl-amino]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)phenyl]acetamide, 5-phenyl-2H-benzo-[d]1,3-dioxolene, 2-chloro-1-methoxy-4-phenylbenzene, 2-[(imidazolylmethyl)amino]-N-[4-(2-phenylethynyl)phenyl]acetamide, 4-phenyl-1-phenoxybenzene, N-(2-aminoethyl)-[4-(2-phenylethynyl)phenyl]carboxamide, 2-{[(4-fluorophenyl)methyl]amino}-N-[4-(2-phenylethynyl)phenyl]acetamide, 2-{[(4-methylphenyl)methyl]amino }-N-[4-(2-phenylethynyl)phenyl]acetamide, 4-phenyl-1-(trifluoromethyl)benzene, 1-butyl-4-phenyl-benzene, 2-(cyclohexylamino)-N-[4-(2-phenylethynyl)phenyl]acetamide, 2-(ethylmethyl-amino)-N-[4-(2-phenylethynyl)phenyl]acetamide, 2-(butylamino)-N-[4-(2-phenyl-ethynyl)phenyl]acetamide, N-[4-(2-phenylethynyl)phenyl]-2-(4-pyridylamino)acetamide, N-[4-(2-phenylethynyl)phenyl]-2-(quinuclidin-3-ylamino)acetamide, N-[4-(2-phenylethynyl)phenyl]pyrrolidin-2-ylcarboxamide, 2-amino-3-methyl-N-[4-(2-phenylethynyl)-phenyl]butanamide, 4-(4-phenylbuta-1,3-diynyl)phenylamine, 2-(dimethylamino)-N-[4-(4-phenylbuta-1,3-diynyl)phenyl]acetamide, 2-(ethylamino)-N-[4-(4-phenylbuta-1,3-diynyl)phenyl]acetamide, 4-ethyl-1-phenylbenzene, 1-[4-(2-phenylethynyl)phenyl]ethan-1-one, N-(1-carbamoyl-2-hydroxypropyl)[4-(4-phenylbuta-1,3-diynyl)phenyl]carboxamide, N-[4-(2-phenylethynyl)phenyl]propanamide, 4-methoxyphenyl phenyl ketone, phenyl-N-benzamide, (tert-butoxy)-N-[(4-phenylphenyl)methyl]carboxamide, 2-(3-phenylphenoxy)ethanehydroxamic acid, 3-phenylphenyl propanoate, 1-(4-ethoxyphenyl)-4-methoxybenzene, and [4-(2-phenylethynyl)phenyl]pyrrole.
The term “heteroarylaryl” refers to a biaryl group where one of the aryl groups is a heteroaryl group. 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)pyrimidine-2-ylamine, 1-methoxy-4-(2-thienyl)benzene, 1-methoxy-3-(2-thienyl)benzene, 5-methyl-2-phenyl-pyridine, 5-methyl-3-phenylisoxazole, 2-[3-(trifluoromethyl)phenyl]furan, 3-fluoro-5-(2-furyl)-2-methoxy-1-prop-2-enylbenzene, (hydroxyimino)(5-phenyl(2-thienyl))-methane, 5-[(4-methylpiperazinyl)methyl]-2-phenylthiophene, 2-(4-ethylphenyl)thio-phene, 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 where both of the aryl groups is a heteroaryl group. Exemplary heteroarylheteroaryl groups include, for example, 3-pyridylimidazole, 2-imidazolylpyrazine, and the like. Preferred optionally substituted heteroarylheteroaryl groups 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 radical. Suitable substitution groups include, for example, hydroxyl, nitro, amino, imino, cyano, halo, thio, sulfonyl, thioamido, amidino, imidino, oxo, oxamidino, methoxamidino, imidino, guanidino, sulfonamido, carboxyl, formyl, loweralkyl, haloloweralkyl, loweralkyamino, haloloweralkylamino, loweralkoxy, haloloweralkoxy, loweralkoxyalkyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl, heteroaralkylcarbonyl, alkylthio, aminoalkyl, cyanoalkyl, aryl and the like.
The substitution group can itself be substituted. The group substituted onto the substitution group can be carboxyl, halo; nitro, amino, cyano, hydroxyl, loweralkyl, loweralkoxy, aminocarbonyl, —SR, thioamido, —SO3H, —SO2R or cycloalkyl, where R is typically hydrogen, hydroxyl or loweralkyl.
When the substituted substituent includes a straight chain group, the substitution can occur either within the chain (e.g., 2-hydroxypropyl, 2-aminobutyl, and the like) or at the chain terminus (e.g., 2-hydroxyethyl, 3-cyanopropyl, and the like). Substituted substitutents can be straight chain, branched or cyclic arrangements of covalently bonded carbon or heteroatoms.
As used herein, the term “carboxy-protecting group” refers to a carbonyl group which has been esterified with one of the commonly used carboxylic acid protecting ester groups employed to block or protect the carboxylic acid function while reactions involving other functional sites of the compound are carried out. In addition, a carboxy protecting group can be attached to a solid support whereby the compound remains connected to the solid support as the carboxylate until cleaved by hydrolytic methods to release the corresponding free acid. Representative carboxy-protecting groups include, for example, loweralkyl esters, secondary amides arid the like.
As used herein, the term “pharmaceutically acceptable salts” refers to the nontoxic acid or alkaline earth metal salts of the compounds of Formula I. These salts can be prepared in situ during the final isolation and purification of the compounds of Formula I, or by separately reacting the base or acid functions 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, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-napthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproionate, picrate, pivalate, propionate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.
Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulfuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, methanesulfonic acid, succinic acid and citric acid. Basic addition salts can be prepared in situ during the final isolation and purification of the compounds of formula (I), or separately by reacting carboxylic acid moieties with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with 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 salts and the like, as well as nontoxic 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 the formation of base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.
As used herein, the term “pharmaceutically acceptable ester” refers to esters, which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters include formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
The term “pharmaceutically acceptable prodrugs” as used herein refers to those 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 their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term “prodrug” refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery,Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
The term “cancer” refers to cancer diseases that can be beneficially treated by the inhibition of Raf kinase, including, for example, solid cancers, such as carcinomas (e.g., of the lungs, pancreas, thyroid, bladder or colon), myeloid disorders (e.g., myeloid leukemia) and adenomas (e.g., villous colon adenoma).
In illustrative embodiments of the invention, Ar1 may be, for example, phenyl which may be substituted by one or more substitutents selected from the group consisting of hydroxyl, nitro, cyano, halo, and substituted or unsubstituted amino, imino, thio, sulfonyl, thioamido, amidino, imidino, oxo, oxamidino, methoxamidino, imidino, guanidino, sulfonamido, carboxyl, formyl, loweralkyl, haloloweralkyl, loweralkyamino, haloloweralkylamino, loweralkoxy, haloloweralkoxy, loweralkoxyalkyl, alkylcarbonyl, aminocarbonyl, loweralkylaminocarbonyl, heterocycloalkylloweralkylaminocarbonyl, carboxylloweralkylaminocarbonyl, arylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl, heteroaralkylcarbonyl, alkylthio, aminoalkyl, cyanoalkyl, aryl and the like. In other illustrative-embodiments of the invention, Ar2 may be, for example, pyridyl, which may be substituted by one or more substitutents selected from the group consisting of hydroxyl, nitro, cyano, halo, and substituted or unsubstituted amino, imino, thio, sulfonyl, thioamido, amidino, imidino, oxo, oxamidino, methoxamidino, imidino, guanidino, sulfonamido, carboxyl, formyl, loweralkyl, haloloweralkyl, loweralkyamino, haloloweralkylamino, loweralkoxy, haloloweralkoxy, loweralkoxyalkyl, alkylcarbonyl, aminocarbonyl, loweralkylaminocarbonyl, heterocycloalkylloweralkylaminocarbonyl, carboxylloweralkylaminocarbonyl, 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-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-benzimidazol-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-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-methylpyridine-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, 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, 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)-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-(dimethylamino)ethyl]pyridine-2-carboxamide, 4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl }oxy)-N-(tetrahydrofuran-2-yl-methyl)pyridine-2-carboxamide, 4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-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, 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-ylpyridine-2-carboxamide, 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]pyridine-2-carboxamide, (4-{2-[(4-bromophenyl)amino]benzothiazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide, (4-{2-[(4-bromophenyl)amino]benzoxazol-5-yloxy}-(2-pyridyl))-N-methylcarboxamide, and other representative compounds set forth in the Examples.
In other aspects, the present invention relates to the processes for preparing the compounds of Formulas I, II, III, IV and V and to the synthetic intermediates useful in such processes.
The compounds of the invention comprise asymmetrically substituted carbon atoms. Such asymmetrically substituted carbon atoms can result in the compounds of the invention comprising mixtures of stereoisomers at a particular asymmetrically substituted carbon atom or a single stereoisomer. As a result, racemic mixtures, mixtures of diastereomers, as well as single diastereomers of the compounds of the invention are included in the present invention. The terms “S” and “R” configuration, as used herein, are as defined by the IUPAC 1974 RECOMMENDATIONS FOR SECTION E, FUNDAMENTAL STEREOCHEMISTRY, Pure Appl. Chem. 45:13–30 (1976). The terms α and β are employed for ring positions of cyclic compounds. The α-side of the reference plane is that side on which the preferred substituent lies at the lower numbered position. Those substituents lying on the opposite side of the reference plane are assigned β descriptor. It should be noted that this usage differs from that for cyclic stereoparents, in which “α” means “below the plane” and denotes absolute configuration. The terms α and β configuration, as used herein, are as defined by the CHEMICAL ABSTRACTS INDEX GUIDE-APPENDIX IV (1987) paragraph 203.
The present invention also relates to the processes for preparing the compounds of the invention and to the synthetic intermediates useful in such processes, as described in detail below.
Synthetic Methods
Compounds of the invention containing a benzimidazole core may be prepared using a number of methods familiar to one of skill in the art. In one method, suitably functionalized diamines may be coupled with various thioisocyanates to form the intermediate thioureas. Cyclization to form the benzimidazole moiety may be effected under known conditions such as with treatment carbodiimides or alkyl halides as in the following schemes.












Alternatively the diamines may be reacted sequentially with carbonyl diimidazole and phosphoryl chloride followed by coupling with the appropriate amine.




Compounds containing the oxazole structure may similarly be prepared according to the methods above or according to other known general procedures. Haviv et al. (J. Med. Chem. 1988, 31:1719) describes a procedure for assembling oxazole cores wherein a hydroxy aniline is treated with ethyl potassium xanthate. The resulting sulfuryl benzoxazole may then be chlorinated and coupled with an amine.




Compounds containing a benzothiazole core may also be prepared according to known methods. An ortho-halothioisocyanate may be reacted with an amine to form a thiourea. Reduction with NaH then allows formation of the thiazole ring.




Benzothiazoles may generally be substituted in accordance with the present invention, such as through the following synthetic pathway:




Benzoxzoles may generally be synthesized through the following pathway:




The compounds of-the invention are useful in vitro or in vivo in inhibiting the growth of cancer cells. The compounds may be used alone or in compositions together 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, for example, calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, dextrose, hydroxypropyl-β-cyclodextrin, polyvinyl-pyrrolidinone, 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), incorporated herein by reference.
Effective amounts of the compounds of the invention generally include any amount sufficient to detectably inhibit Raf activity by any of the assays described herein, by other Raf kinase activity assays known to those having ordinary skill in the art or by detecting an inhibition or alleviation of symptoms of cancer.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host 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 for a given situation can be readily determined by routine experimentation and is within the skill and judgment of the ordinary clinician.
For purposes of the present invention, a therapeutically effective dose will generally be a total daily dose administered to a host in single or divided doses may be in amounts, for example, of from 0.001 to 1000 mg/kg body weight daily and more preferred from 1.0 to 30 mg/kg body weight daily. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.
The compounds of the present invention may be administered orally, parenterally, sublingually, by aerosolization or inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration may also involve the use of transdermal administration such as transdermal patches or ionophoresis devices. The term parenteral as used herein 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 the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-propanediol. Among the acceptable vehicles and solvents that may be employed 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 di-glycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols, which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, cyclodextrins, and sweetening, flavoring, and perfuming agents.
The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.W., p. 33 et seq. (1976).
While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more other agents used in the treatment of cancer. Representative agents useful in combination with the compounds of the invention for the treatment of cancer include, for example, irinotecan, topotecan, gemeitabine, 5-fluorouracil, leucovorin carboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide, vinca alkaloids, imatinib (Gleevec), anthracyclines, rituximab, trastuzumab, as well as other cancer chemotherapeutic agents.
The above compounds to be employed in combination with the compounds of the invention will be used in therapeutic amounts as indicated in the Physicians' Desk Reference (PDR) 47th Edition (1993), which is incorporated herein by reference, or such therapeutically useful amounts as would be known to one of ordinary skill in the art.
The compounds of the invention and the other anticancer agents can be administered at the recommended maximum clinical dosage or at lower doses. Dosage levels of the active compounds in the compositions of the invention may be varied so as to obtain a desired therapeutic response depending on the route of administration, severity of the disease and the response of the patient. The combination can be administered as separate compositions or as a single dosage form containing both agents. When administered as a combination, the therapeutic agents can be formulated as separate compositions, which are given at the same time or different times, or the therapeutic agents, can be given as a single composition.
Antiestrogens, such as tamoxifen, inhibit breast cancer growth through induction of cell cycle arrest, that requires the action of the cell cycle inhibitor p27Kip. Recently, it has been shown that activation of the Ras-Raf-MAP Kinase pathway alters the phosphorylation status of p27Kip such that its inhibitory activity in arresting the cell cycle is attenuated, thereby contributing to antiestrogen resistance (Donovan et al, J. Biol. Chem. 276:40888, 2001). As reported by Donovan et al., inhibition of MAPK signaling through treatment with MEK inhibitor changed the phosphorylation status of p27 in hormone refactory breast cancer cell lines and in so doing restored hormone sensitivity. Accordingly, in one aspect, the compounds of formulas (I), (II), (III), (IV) and (V) may be used in the treatment of hormone dependent cancers, such as breast and prostate cancers, to reverse hormone resistance commonly seen in these cancers with conventional anticancer agents.
In hematological cancers, such as chronic myelogenous leukemia (CML), chromosomal translocation is responsible for the constitutively activated BCR-AB1 tyrosine kinase. The afflicted patients are responsive to Geevec, a small molecule tyrosine kinase inhibitor, as a result of inhibition of Ab1 kinase activity. However, many patients with advanced stage disease respond to Gleevec initially, but then relapse later due to resistance-conferring mutations in the Ab1 kinase domain. In vitro studies have demonstrated that BCR-Av1 employs the Raf kinase pathway to elicit its effects. In addition, inhibiting more than one kinase in the same pathway provides additional protection against resistance-conferring mutations. Accordingly, in another aspect of the invention, the compounds of formulas (I), (II), (III), (IV) and (V) are used in combination with at least one additional agent, such as Gleevec, in the treatment of hematological cancers, such as chronic myelogenous leukemia (CML), to reverse or prevent resistance to the at least one additional agent.
The present invention will be understood more readily by reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the present invention.
Representative side chains for use in the compounds of the following examples may generally be prepared in accordance with the following procedures:
EXAMPLE 1
Synthesis of 4-[(2-{[4-chloro-3-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-6-yl)oxy]-N-methylpyridine-2-carboxamide
The 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:
A mixture containing 4-amino-3-nitrophenol (1 eq) and potassium bis(trimethylsilyl)amide (2 eq) was stirred in dimethylformamide for 2 hours at room temperature. To this mixture was added (4-chloro(2-pyridyl))-N-methylcarboxamide (1 eq) and potassium carbonate (1.2 eq) and stirred at 90° C. for 3 days. The reaction mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried, filtered, and concentrated in vacuum to give brown solid. Purification on silica gel (2% triethyl amine/50% ethyl acetate in hexane) gave 4-[(4-amino-3-nitrophenyl)oxy]-N-methylpyridine-2-carboxamide as an orange solid. The product gave satisfactory NMR. HPLC, 3.39 min; MS: MH+=289.
Step 2. Synthesis of 4-[(3,4-diaminophenyl)oxy]-N-methylpyridine-2-carboxamide:
The mixture containing [4-(3-amino-4-nitrophenoxy)(2-pyridyl)]-N— in methanol with catalytic amount of 10% Pd/C was hydrogenated until disappearance of the yellow color to yield 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:
The mixture containing 4-[(3,4-diaminophenyl)oxy]-N-methylpyridine-2-carboxamide (1 eq) and 4-chloro-3-(trifluoromethyl)benzeneisothiocyanate (1 eq) in tetrahydrofuran was stirred at room temperature for 16 hours to give the corresponding thiourea. To the resulting mixture was added 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride (2 eq) and the mixture was stirred for another 10 hours. The mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was washed with brine and dried. Purification on HPLC gave 4-[(2-{[4-chloro-3-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-6-yl)oxy]-N-methyl-pyridine-2-carboxamide. MS: MH+=462
EXAMPLES 2–108
The compounds shown in the following Table 1 (Examples 2–108) were prepared from following the procedure described for Example 1.










TABLE 1





Example
Structure
Name
MH+


















2




4-({2-[(3-chlorophenyl)amino]-1H-benzimidazol-6-yl}oxy)-N-methyl-pyridine-2-carboxamide
394


 


3




4-({2-[(4-bromophenyl)amino]-1H-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide
440


 


4




4-({2-[(3-chloro-4-fluorophenyl)-amino]-1H-benzimidazol-6-yl}-oxy)-N-methylpyridine-2-carboxamide
412


 


5




N-methyl-4-{[2-(phenylamino)-1H-benzimidazol-6-yl]oxy}-pyridine-2-carboxamide
360


 


6




4-[(2-{[4-bromo-2-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-6-yl)oxy]-N-methyl-pyridine-2-carboxamide
508


 


7




N-methyl-4-({2-[(2-methylpropyl)-amino]-1H-benzimidazol-6-yl}-oxy)pyridine-2-carboxamide
340


 


8




4-[(2-{[4-(dimethylamino)-naphthalen-1-yl]amino}-1H-benzimidazol-6-yl)oxy]-N-methyl-pyridine-2-carboxamide
453


 


9




N-methyl-4-({2-[(4-nitrophenyl)-amino]-1H-benzimidazol-6-yl}-oxy)pyridine-2-carboxamide
405


 


10




N-methyl-4-({2-[(phenylcarbonyl)-amino]-1H-benzimidazol-6-yl}-oxy)pyridine-2-carboxamide
388


 


11




N-methyl-4-({2-[(phenylmethyl)-amino]-1H-benzimidazol-6-yl}-oxy)pyridine-2-carboxamide
374


 


12




methyl 4-{[6-({2-[(methylamino)-carbonyl]pyridin-4-yl}oxy)-1H-benzimidazol-2-yl]amino}benzoate
418


 


13




4-({2-[(4-chlorophenyl)amino]-1H-benzimidazol-6-yl}oxy)-N-methyl-pyridine-2-carboxamide
394


 


14




4-[(2-{[2-ethyloxy)phenyl]-amino}-1H-benzimidazol-6-yl)-oxy]-N-methylpyridine-2-carboxamide
404


 


15




N-methyl-4-({2-[(2-morpholin-4-ylethyl)amino]-1H-benzimidazol-6-yl}oxy)pyridine-2-carboxamide
397


 


16




4-({2-[(4-iodophenyl)amino]-1H-benzimidazol-6-yl}oxy)-N-methyl-pyridine-2-carboxamide
486


 


17




N-methyl-4-[(2-{[4-(trifluoro-methyl)phenyl]amino}-1H-benzimidazol-6-yl)oxy]pyridine-2-carboxamide
428


 


18




4-({2-[(furan-2-ylmethyl)amino]-1H-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide
364


 


19




4-({2-[(4-bromo-3-methylphenyl)-amino]-1H-benzimidazol-6-yl}-oxy)-N-methylpyridine-2-carboxamide
453


 


20




4-({2-[(4-acetylphenyl)amino]-1H-benzimidazol-6-yl}oxy)-N-methyl-pyridine-2-carboxamide
402


 


21




N-methyl-4-({2-[(2,4,6-trimethyl-phenyl)amino]-1H-benzimidazol-6-yl}oxy)pyridine-2-carboxamide
402


 


22




4-[(2-{[4-(1,1-dimethylethyl)-phenyl]amino}-1H-benzimidazol-6-yl)oxy]-N-methylpyridine-2-carboxamide
416


 


23




4-({2-[(2-bromophenyl)amino]-1H-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide
440


 


24




4-({2-[(3-bromophenyl)amino]-1H-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide
440


 


25




4-({2-[(2-chlorophenyl)amino]-1H-benzimidazol-6-yl}oxy)-N-methyl-pyridine-2-carboxamide
394


 


26




methyl 3-{[6-({2-[(methylamino)-carbonyl]pyridin-4-yl}oxy)-1H-benzimidazol-2-yl]amino}-thiophene-2-carboxylate
424


 


27




4-({2-[(4-bromophenyl)amino]-1H-benzimidazol-6-yl}oxy)-N-{(3R,5R)-5-[(methyloxy)methyl]-pyrrolidin-3-yl}pyridine-2-carboxamide
539


 


28




(4-{2-[(2,5-difluorophenyl)amino]-benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide
395.3


 


29




(4-{2-[(2,4-difluorophenyl)amino]-benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide
395.3


 


30




N-methyl[4-(2-{[2-(trifluoro-methyl)phenyl]amino}benzimidazol-5-yloxy)(2-pyridyl)]-carboxamide
427.3


 


31




(4-{2-[(3,4-dichlorophenyl)amino]-benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide
428.2


 


32




N-methyl(4-{2-[(2-methylthio-phenyl)amino]benzimidazol-5-yloxy}(2-pyridyl))carboxamide
405.4


 


33




N-methyl(4-{2-[(4-methylthio-phenyl)amino]benzimidazol-5-yloxy}(2-pyridyl))carboxamide
405.4


 


34




(4-{2-[(2-methoxyphenyl)amino]-benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide
389.4


 


35




(4-{2-[(2-fluorophenyl)amino]-benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide
377.3


 


36




N-methyl(4-{2-[(4-sulfamoyl-phenyl)amino]benzimidazol-5-yloxy}(2-pyridyl))carboxamide
438.4


 


37




N-methyl[4-(2-{[2-(trifluoro-methoxy)phenyl]amino}-benzimidazol-5-yloxy)(2-pyridyl)]-carboxamide
443.3


 


38




(4-{2-[(3,4-dimethoxyphenyl)-amino]benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide
419.4


 


39




[4-(2-{[2-fluoro-5-(trifluoro-methyl)phenyl]amino}-benzimidazol-5-yloxy)(2-pyridyl)]-N-methylcarboxamide
445.3


 


40




(4-{2-[(2,4-dichlorophenyl)amino]-benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide
428.2


 


41




N-methyl[4-(2-{[3-(trifluoro-methyl)phenyl]amino}-benzimidazol-5-yloxy)(2-pyridyl)]-carboxamide
427.3


 


42




(4-{2-[(3-methoxyphenyl)amino]-benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide
389.4


 


43




N-methyl(4-{2-[(2-phenylphenyl)-amino]benzimidazol-5-yloxy}(2-pyridyl))carboxamide
435.4


 


44




[4-(2-{[2-chloro-5-(trifluoro-methyl)phenyl]amino}-benzimidazol-5-yloxy)(2-pyridyl)]-N-methylcarboxamide
461.8


 


45




(4-{2-[(2,5-dimethoxyphenyl)-amino]benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide
419.4


 


46




(4-{2-[(3,5-difluorophenyl)amino]-benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide
395.3


 


47




(4-{2-[(2-ethylphenyl)amino]-benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide
387.4


 


48




(4-{2-[(3,5-difluorophenyl)amino]-benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide
395.4


 


49




[4-(2-{[3,5-bis(trifluoromethyl)-phenyl]amino}benzimidazol-5-yloxy)(2-pyridyl)]-N-methyl-carboxamide
495.4


 


50




(4-{2-[(2-methoxy-5-methylphenyl)amino]-benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide
403.4


 


51




(4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-6-yloxy}(2-pyridyl))-N-methylcarboxamide
452.3


 


52




N-methyl[4-(2-{[2-(methylethyl)-phenyl]amino}benzimidazol-5-yloxy)(2-pyridyl)]carboxamide
401.4


 


53




(4-{2-[(2-methoxy-4-nitrophenyl)-amino]benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide
434.4


 


54




(4-{2-[(3,5-dimethoxyphenyl)-amino]benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide
420.1


 


55




(4-{2-[(5-chloro-2,4-dimethoxy-phenyl)amino]benzimidazol-5-yloxy}(2-pyridyl))-N-methyl-carboxamide
454.1


 


56




N-methyl-4-[(2-{[2-(1-methyl-ethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide
402.5


 


57




N-methyl-4-[(2-{[2-(methyloxy)-4-nitrophenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide
435.4


 


58




4-({2-[(4-ethylphenyl)amino]-1H-benzimidazol-5-yl}oxy)-N-methyl-pyridine-2-carboxamide
388.4


 


59




4-[(2-{[3,5-bis(methyloxy)phenyl]-amino}-1H-benzimidazol-5-yl)-oxy]-N-methylpyridine-2-carboxamide
420.4


 


60




4-[(2-{[5-chloro-2,4-bis(methyloxy)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-methyl-pyridine-2-carboxamide
454.9


 


61




4-({2-[(4-cyclohexylphenyl)-amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2-carboxamide
442.5


 


62




4-({2-[(3,4-difluorophenyl)amino]-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
396.4


 


63




4-({2-[(3,4-dimethylphenyl)-amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2-carboxamide
388.4


 


64




4-({2-[(4-bromo-3-chlorophenyl)-amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2-carboxamide
473.7


 


65




4-({2-[(4-butylphenyl)amino]-1H-benzimidazol-5-yl}oxy)-N-methyl-pyridine-2-carboxamide
416.5


 


66




N-methyl-4-[(2-{[4-(1-methylethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide
402.5


 


67




4-({2-[(2,6-dichlorophenyl)amino]-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
429.3


 


68




N-methyl-4-[(2-{[4-(phenyloxy)-phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide
452.5


 


69




4-({2-[(3,5-dimethylphenyl)-amino]-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
388.4


 


70




4-[(2-{[4-(diethylamino)phenyl]-amino}-1H-benzimidazol-5-yl)-oxy]-N-methylpyridine-2-carboxamide
431.5


 


71




4-({2-[(4-chloro-2-methylphenyl)-amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2-carboxamide
408.9


 


72




4-({2-[(4-bromo-2-chlorophenyl)-amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2-carboxamide
473.7


 


73




4-[(2-{[2-bromo-4-(1-methylethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
481.4


 


74




4-({2-[(2-chloro-4-methylphenyl)-amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2-carboxamide
408.9


 


75




4-({2-[(2-bromo-4-methylphenyl)-amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2-carboxamide
453.3


 


76




4-[(2-{[2-chloro-4-(trifluoro-methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
462.8


 


77




4-({2-[(4-chloro-2-fluorophenyl)-amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2-carboxamide
412.8


 


78




4-{[2-(2,3-dihydro-1H-inden-5-ylamino)-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2-carboxamide
400.5


 


79




4-({2-[(2,5-dimethylphenyl)-amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2-carboxamide
388.4


 


80




4-({2-[(4-fluoro-2-methylphenyl)-amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2-carboxamide
392.4


 


81




N-methyl-4-({2-[(2,3,5-trifluorophenyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide
414.4


 


82




4-({2-[(2-chloro-5-fluorophenyl)-amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2-carboxamide
412.8


 


83




4-({2-[(4-bromo-3-fluorophenyl)-amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2-carboxamide
457.3


 


84




4-[(2-{[3-(1,1-dimethylethyl)-phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
416.5


 


85




4-({2-[(2,4-dibromophenyl)-amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2-carboxamide
518.2


 


86




4-({2-[(3-chloro-4-fluorophenyl)-amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2-carboxamide
412.8


 


87




4-[(2-{[4-bromo-2-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
507.3


 


88




4-({2-[(2,5-dichlorophenyl)amino]-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
429.3


 


89




N-methyl-4-{[2-({4-[(trifluoro-methyl)oxy]phenyl}amino)-1H-benzimidazol-5-yl]oxy}pyridine-2-carboxamide
444.4


 


90




4-{[2-(1,3-benzodioxol-5-yl-amino)-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2-carboxamide
404.4


 


91




4-({2-[(3-chloro-4-methylphenyl)-amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2-carboxamide
408.9


 


92




4-({2-[(4-chloro-3-methylphenyl)-amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2-carboxamide
408.9


 


93




4-[(2-{[3-chloro-4-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
462.8


 


94




4-[(2-{[4-fluoro-3-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
446.4


 


95




4-({2-[(4-chloro-3-fluorophenyl)-amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2-carboxamide
412.8


 


96




4-{[2-({4-bromo-2-[(trifluoromethyl)oxy]phenyl}amino)-1H-benzimidazol-5-yl]oxy}-N-methyl-pyridine-2-carboxamide
523.3


 


97




N-methyl-4-[(2-{[3-(methylthio)-phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide
406.5


 


98




N-methyl-4-[(2-{[4-(methyloxy)-phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide
390.4


 


99




4-({2-[(3-ethylphenyl)amino]-1H-benzimidazol-5-yl}oxy)-N-methyl-pyridine-2-carboxamide
388.4


 


100




N-methyl-4-{[2-({4-[(trifluoro-methyl)thio]phenyl}amino)-1H-benzimidazol-5-yl]oxy}pyridine-2-carboxamide
460.4


 


101




4-({2-[(4-fluorophenyl)amino]-1H-benzimidazol-5-yl}oxy)-N-methyl-pyridine-2-carboxamide
378.4


 


102




N-methyl-4-{[2-({3-[(trifluoro-methyl)thio]phenyl}amino)-1H-benzimidazol-5-yl]oxy}pyridine-2-carboxamide
460.4


 


103




N-methyl-4-[(2-{[4-methyl-3-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide
442.4


 


104




4-({2-[(4-bromo-2-fluorophenyl)-amino]-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2-carboxamide
457.3


 


105




4-[(2-{[5-chloro-2-(methyloxy)-phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
424.9


 


106




N-methyl-4-[(2-{[4-(methyloxy)-1,1′-biphenyl-3-yl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide
466.5


 


107




4-({2-[(3-fluorophenyl)amino]-1H′-benzimidazol-5-yl}oxy)-N-methyl-pyridine-2-carboxamide
378.4


 


108




4-{[2-({3-bromo-4-[(trifluoro-methyl)oxy]phenyl}amino)-1H-benzimidazol-5-yl]oxy}-N-methyl-pyridine-2-carboxamide
523.3









EXAMPLE 109
Synthesis of (4-{2-[(4-bromophenyl)amino]-benzothiazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide
Step 1. Synthesis of 2-bromo-5-methoxybenzothiazole
A solution of bromine (3.6 eq) in chloroform (0.75M) was added dropwise over a period of 1 hr to a stirred suspension of 5-methoxy-2-mercaptobenzothiazole (1 eq) in chloroform at 0° C. The mixture was stirred for 30 min before it was added slowly to water and stirred for further 20 min. The mixture was filtered to remove a cream 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 and the filtrate and washings were combined and evaporated, chromatographed (4:1 hexanes 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-methoxybenzthiazole (1 eq), 4-Bromoaniline (2 eq) and disopropylethylamine was subjected to microwave in NMP at 220° C. The resultant mixture was concentrated and partitioned 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. Synthesis of 2-[(4-bromophenyl)amino]benzothiazol-5-ol
The mixture of (4-bromophenyl)(5-mnethoxybenzothiazol-2-yl)amine and hydrobromic acid (48%) was subjected to the microwave at 150° C. for 6 mins to yield the desired product. MS: MH+=321
Step 4. Synthesis of (4-{2-[(4-bromophenyl)amino]benzothiazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide:
The mixture containing 2-[(4-bromophenyl)amino]benzothiazol-5-ol (1 eq), Potassiumbis(trimethylsilyl)amide (4 eq), was stirred in dimethylformamide for 30 min at room temperature. To this mixture was added (4-chloro(2-pyridyl)-N-methyl-carboxamide (1 eq) and Potassium carbonate (1.2 eq) and microwaved for 6 mins at 150° C. The reaction mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried, filtered and concentrated. Purification on Prep LC yielded the desired product. MS: MH+=455
Each of the Examples 110–119 shown in the following Table 2 were synthesized according to the procedure described in Example 109:










TABLE 2





Example
Structure
Name
MH+


















110




(4-{2-[(4-bromophenyl)amino]-benzothiazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide
455


 


111




(4-{2-[(4-chlorophenyl)amino]-benzothiazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide
411.1


 


112




N-methyl(4-{2-[(4-methylphenyl)-amino]benzothiazol-5-yloxy}(2-pyridyl))carboxamide
391.1


 


113




N-methyl[4-(2-{[4-(tri-fluoromethoxy)phenyl]amino}-benzothiazol-5-yloxy)(2-pyridyl)]-carboxamide
461.1


 


114




(4-{2-[(4-butylphenyl)amino]-benzothiazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide
433.2


 


115




N-methyl[4-(2-{[4-(methylethyl)-phenyl]amino}benzothiazol-5-yloxy)(2-pyridyl)]carboxamide
419.2


 


116




(4-{2-[(3,4-dichloro-phenyl)amino]-benzothiazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide
445


 


117




(4-{2-[(4-bromophenyl)amino]-benzothiazol-5-yloxy}(2-pyridyl))-N-(2-morpholin-4-ylethyl)-carboxamide
554.1


 


118




N-((3R)pyrrolidin-3-yl)(4-{2-[(4-bromophenyl)amino]benzothiazol-5-yloxy}(2-pyridyl))carboxamide
510


 


119




N-[(3R,5R)-5-(methoxy-methyl)-pyrrolidin-3-yl](4-{2-[(4-bromo-phenyl)amino]benzothiazol
554.1









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-methyl-pyridine-2-carboxamide:
A solution of 4-[(4-amino-3-nitrophenyl)oxy]-N-methylpyridine-2-carboxamide (1 eq) in methylene chloride was treated with trifluoroacetic anhydride (1 eq) and stirred for 10 minutes at 0° C. The mixture was quenched with saturated NaHCO3 solution. The organic layer was separated and washed with water, brine, dried and evaporated. MS: MH+=385.2.
To a solution of the trifluroacetamide (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 taken up in ethyl acetate, washed with water, brine, dried and evaporated. The crude product was purified by column chromatography eluting with 1:1 hexanes and ethylacetate followed by 2% triethylamine in 1:1 hexanes and ethyl acetate followed by 2% triethylamine in 1:1 hexanes and ethyl acetate to afford N-methyl-4-{[4-(methylamino)-3-nitrophenyl]oxy}pyridine-2-carboxamide as a reddish orange solid. MS: MH+=303.1.
The solution of nitromethylaniline in methanol was treated with 5% palladium on carbon and stirred under hydrogen atmosphere for 15 min. (until the disappearance of yellow coloration) at room temperature. The mixture was filtered and the filtrate was concentrated to provide 0.36 g of the 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 the diamine 4-{[3-amino-4-(methylamino)phenyl]oxy}-N-methylpyridine-2-carboxamide (1 eq) in methanol was treated with 4-bromophenylisothiocyanate (1 eq) and stirred at 60° C.–-65° C. for 2 hours. The reaction mixture was cooled down to room temperature and methyl iodide (1 eq) was added and stirred overnight at 60° C. The reaction was cooled to room temperature, evaporated, taken up in ethyl acetate, and washed with water and brine, dried, and evaporated under reduced pressure. Column chromatography using a gradient solvent system of hexanes and ethyl acetate and either 1:1 methylene chloride and acetone or 5% methanol in methylene chloride yielded the product as a half white powder. MS: MH+=452.3
EXAMPLE 120b
Alternative Synthesis of 4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
Step 1. Synthesis of N-methyl {4-[4-(methylamino)-3-aminophenoxy](2-pyridyl)}carboxamide:




A mixture containing 4-amino-3-nitrophenol 5 (1.0 g, 6.4 mmol), potassium bis(trimethylsilyl)amide (2.58 g, 12.8mmol) was stirred in DMF (50 ml) for 2 hours at rt. To this mixture was added (4-chloro(2-pyridyl))-N-methylcarboxamide 4 (1.09 g, 6.4 mmol) and potassium carbonate (0.5 g, 7.6 mmol) and stirred at 90° C. overnight. The reaction mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was separated and washed with brine (2×10 ml), dried, filtered and concentrated in vacuum to give brown solid. Purification on silica gel with 2% triethyl amine in 50% ethyl acetate in hexane gave 1.3 g (yield, 72%) of [4-(4-amino-3-nitrophenoxy)(2-pyridyl)]-N-methylcarboxamide 6 as an orange solid: 1H NMR (300 MHz, CDCl3) δ 8.40 (d, J=5.6 Hz, 1 H), 7.99 (br s, 1 H), 7.90 (d, J=2.7 Hz, 1 H), 7.64 (d, J=2.7 Hz, 1 H), 7.17 (dd, J=2.7, 9.0 Hz, 1 H), 6.95 (ddd, J=0.7, 2.5, 5.6 Hz, 1 H) 6.89 (d, J=9.0 Hz, 1 H), 6.18 (br s, 2 H), 3.00 (d, J=5.1 Hz, 3 H); mp 208–210° C. dec; LCMS m/z 289.2 (MH+), tR=1.92 min.
A 500 mL three neck round bottom flask fitted with a mechanical stirrer was charged with nitroaniline 6 (10.0 g, 34.8 mmol) and CH2Cl2 (175 ml). The resulting suspension was cooled to 0° C. and TFAA (9.5 mL, 14.1 g, 67.0 mmol) was added over 16 h while allowing the cooling bath to expire.2 After the reaction was judged complete by TLC,3 TBACl (5.2 g, 17.5 mmol)4 and dimethyl sulfate (6.7 mL, 8.9 g, 70.0 mmol) were added followed by 50% aqueous NaOH solution (140 mL). The resulting reaction mixture was cooled with an ice bath, and stirred vigorously for 1.5 h at rt.3,5,6 The reaction was then poured over ice water and the resulting phases were partitioned and separated. The aqueous phase was extracted with CH2Cl2 (3×100 mL) and the combined organic layers were washed with brine (2×100 mL), dried (MgSO4), and concentrated. The crude residue was purified by recrystallization (1:3 ethanol-water) to give 8.36 g (27.7 mmol, 79%) of 7 as fine red needles: 1H NMR (300 MHz, CDCl3) δ 8.40 (dd, J=0.5, 4.9 Hz, 1 H), 8.07 (br d, J=3.7 Hz, 1 H), 7.98 (br s, 1 H), 7.95 (d, J=2.9 Hz, 1 H), 7.62 (dd, J=0.5, 2.9 Hz, 1 H), 7.27 (ddd, J=0.5, 2.9, 9.3 Hz, 1 H), 6.98 (dd, J=2.7, 5.6 Hz, 1 H), 6.92 (d, J=9.3 Hz, 1 H), 3.07 (d, J=5.1 MHz, 3 H), 3.00 (d, J=5.1 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ 166.6, 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° C. LCMS m/z 303.4 (MH+), tR=2.37 min.
A suspension of nitroaniline 7 (5.0 g, 16.5 mmol) in methanol was sparged with N2 for 20 min after which 10% Pd/C (0.88 g, 0.8 mmol) was added. The reaction was purged with H2 and maintained under a H2 atmosphere overnight at room temperature. The reaction was purged with N2 and filtered through Celite. The collected solids were washed with EtOAc (3×50 mL), and the combined organic layers were dried (MgSO4) and concentrated to afford 4.35 g (16.0 mmol, 97%) of an off white solid as 8: 1H NMR (300 MHz, CDCl3) δ 8.30 (d, J=5.5 Hz, 1 H), 7.99 (br s, 1 H), 7.67 (d, J=2.5 Hz, 1 H), 6.91 (dd, J=2.5, 5.5 Hz, 1 H), 6.62 (d, J=8.5 Hz, 1 H), 6.53 (dd, J=2.5, 8.5 Hz, 1 H), 6.44 (d, J=2.5 Hz, 1 H), 2.98 (d, J=5.2 Hz, 3 H), 2.86 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 167.4, 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° C. dec.; LCMS m/z 273.3 (MH+), tR=1.66 min.
Step 2. Synthesis of (4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide:




A 250 mL round bottom flask was charged with 4-bromophenylisothiocyanate1 (2.17 g, 10.1 mmol), diamine 8 (2.74 g, 10.1 mmol), and MeOH (40 mL) and the reaction was maintained at rt overnight. Ferric chloride (2.43 g, 15 mmol) was added and the resulting red reaction mixture was stirred overnight. The reaction was partitioned with EtOAc (100 mL) and water (100 mL), and filtered through Celite. The layers were separated and the aqueous phase was neutralized (pH=7) with saturated Na2CO3 solution. The resulting aqueous phase was extracted with EtOAc (100 mL) and the mixture was filtered through Celite. The phases were separated and the aqueous phase was again extracted and filtered. The combined organic layers were washed with brine (250 mL), dried (MgSO4), and concentrated to give a brown solid. The crude residue was purified by trituration in hot toluene to furnish 2.22 g (4.95 mmol, 49%) of a tan solid as 1: 1H NMR (300 MHz, CDCl3) δ 8.38 (d, J=5.8 Hz, 1 H), 8.07 (br d, J=4.7 Hz, 1 H), 7.61 (d, J=2.5 Hz, 1 H), 7.44 (app dd, J=8.8, 20.6 Hz, 4 H), 7.05 (m, 3 H), 6.78 (dd, J=2.2, 8.5 Hz, 1 H), 3.51 (s, 3 H), 3.00 (d, J=5.2 Hz, 3 H); mp 251–254° C. dec; LCMS m/z 452.2 (MH+), tR=2.17 min.
EXAMPLES 121–384
The compounds shown in the following Table 3 (Examples 121–384) were prepared from following the procedure described for Example 120a.










TABLE 3





Example
Structure
Name
MH+


















121




4-[(2-{[4-chloro-3-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)-oxy]-N-methylpyridine-2-carboxamide
476.1


 


122




N-methyl-4-[(1-methyl-2-{[4-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide
442


 


123




(4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yl-oxy}(2-pyridyl))-N-methyl-carboxamide
452.0


 


124




(4-{2-[(4-chlorophenyl)amino]-1-methylbenzimidazol-5-yloxy}-(2-pyridyl))-N-methylcarboxamide
408.1


 


125




(4-{2-[(4-iodophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide
500.1


 


126




N-methyl(4-{1-methyl-2-[(4-methylphenyl)amino]benzimidazol-5-yloxy}(2-pyridyl))carboxamide
388.2


 


127




N-methyl(4-{1-methyl-2-[(4-phenoxyphenyl)amino]benzimidazol-5-yloxy}(2-pyridyl))-carboxamide
466.2


 


128




N-methyl[4-(1-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}benzimidazol-5-yloxy)(2-pyridyl)]carboxamide
458.2


 


129




(4-{2-[(4-butylphenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide
430.2


 


130




(4-{2-[(4-bromo-3-fluoro-phenyl)amino]-1-methyl-benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide
470.1


 


131




N-methyl(4-{1-methyl-2-[(4-nitrophenyl)amino]benzimidazol-5-yloxy}(2-pyridyl))-carboxamide
419.2


 


132




N-methyl[4-(1-methyl-2-{[4-(methylethyl)phenyl]amino}benzimidazol-5-yloxy)(2-pyridyl)]-carboxamide
416.3


 


133




(4-{2-[(3,4-dichlorophenyl)-amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methyl-carboxamide
442.1


 


134




(4-{2-[(4-bromo-3-methyl-phenyl)amino]-1-methyl-benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide
466.1


 


135




(4-{2-[(3,4-dimethylphenyl)-amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methyl-carboxamide
402.2


 


136




(4-{2-[(3-chloro-4-fluoro-phenyl)amino]-1-methyl-benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide
426.1


 


137




methyl 4-({1-methyl-5-[2-(N-methylcarbamoyl)(4-pyridyl-oxy)]benzimidazol-2-yl}amino)-benzoate
432.2


 


138




(4-{2-[(4-bromo-3-chloro-phenyl)amino]-1-methyl-benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide
486.0


 


139




(4-{2-[(3-bromophenyl)amino]-1-methylbenzimidazol-5-yl-oxy}(2-pyridyl))-N-methyl-carboxamide
452.1


 


140




(4-{2-[(4-acetylphenyl)amino]-1-methylbenzimidazol-5-yloxy}-(2-pyridyl))-N-methylcarboxamide
416.2


 


141




[4-(2-{[4-(tert-butyl)phenyl]-amino}-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-methyl-carboxamide
430.2


 


142




(4-{2-[(4-methoxyphenyl)-amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methyl-carboxamide
404.2


 


143




(4-{2-[(4-cyclohexylphenyl)-amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methyl-carboxamide
456.2


 


144




(4-{2-[(3,4-difluorophenyl)-amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methyl-carboxamide
410.2


 


145




(4-{2-[(4-methoxy-2-methyl-phenyl)amino]-1-methyl-benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide
418.2


 


146




(4-{2-[(3-chlorophenyl)amino]-1-methylbenzimidazol-5-yl-oxy}(2-pyridyl))-N-methyl-carboxamide
408.1


 


147




(4-{2-[(3-fluorophenyl)amino]-1-methylbenzimidazol-5-yloxy}-(2-pyridyl))-N-methylcarbox-amide
392.2


 


148




4-({1-methyl-5-[2-(N-methyl-carbamoyl)(4-pyridyloxy)]-benzimidazol-2-yl}amino)-benzoic acid
418.2


 


149




N-methyl{4-[1-methyl-2-(phenylcarbonylamino)-benzimidazol-5-yloxy](2-pyridyl)}carboxamide
402.2


 


150




[4-(2-{[2-chloro-5-(trifluoro-methyl)phenyl]amino}-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-methylcarboxamide
476.1


 


151




(4-{2-[(2,5-dimethoxyphenyl)-amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methyl-carboxamide
434.2


 


152




(4-{2-[(2,4-difluorophenyl)-amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methyl-carboxamide
410.2


 


153




(4-{2-[(3,5-difluorophenyl)-amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methyl-carboxamide
410.2


 


154




(4-{2-[(4-ethylphenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide
402.2


 


155




(4-{2-[(4-chlorophenyl)amino]-1-methylbenzimidazol-5-yloxy}-(2-pyridyl))-N-methylcarboxamide
408.1


 


156




(4-{2-[(4-bromo-3-methyl-phenyl)amino]-1-methyl-benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide
466.1


 


157




(4-{2-[(2-methoxy-4-nitro-phenyl)amino]-1-methyl-benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide
448.4


 


158




N-methyl[4-(1-methyl-2-{[2-(tri-fluoromethyl)phenyl]amino}benzimidazol-5-yloxy)(2-pyridyl)]-carboxamide
441.4


 


159




(4-{2-[(3-methoxyphenyl)-amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide
403.4


 


160




(4-{2-[(2-ethylphenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide
401.4


 


161




(4-{2-[(2,5-difluorophenyl)-amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methyl-carboxamide
409.3


 


162




(4-{2-[(2,6-dichlorophenyl)-amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methyl-carboxamide
442.3


 


163




(4-{2-[(4-ethylphenyl)amino]-benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide
388.2


 


164




N-methyl(4-{1-methyl-2-[(2-methylthiophenyl)amino]-benzimidazol-5-yloxy}(2-pyridyl))carboxamide
420.1


 


165




N-methyl(4-{1-methyl-2-[(4-methylthiophenyl)amino]-benzimidazol-5-yloxy}(2-pyridyl))carboxamide
420.1


 


166




N-methyl[4-(1-methyl-2-{[2-(trifluoromethoxy)phenyl]-amino}benzimidazol-5-yloxy)(2-pyridyl)]carboxamide
458.1


 


167




[4-(2-{[2-fluoro-5-(trifluoro-methyl)phenyl]amino}-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-methylcarboxamide
460.1


 


168




(4-{2-[(4-cyanophenyl)amino]-1-methylbenzimidazol-5-yloxy}-(2-pyridyl))-N-methyl-carboxamide
399.1


 


169




N-methyl[4-(1-methyl-2-{[3-(trifluoromethyl)phenyl]amino}-benzimidazol-5-yloxy)(2-pyridyl)]carboxamide
442.1


 


170




N-methyl[4-(1-methyl-2-{[2-(methylethyl)phenyl]amino}-benzimidazol-5-yloxy)(2-pyridyl)]carboxamide
416.2


 


171




(4-{2-[(5-chloro-2,4-dimethoxy-phenyl)amino]-1-methyl-benzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide
468.2


 


172




N-methyl(4-{1-methyl-2-[(2-phenylphenyl)amino]benzimidazol-5-yloxy}(2-pyridyl))-carboxamide
450.2


 


173




(4-{2-[(3-ethylphenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide
402.2


 


174




(4-{2-[(2-fluorophenyl)amino]-1-methylbenzimidazol-5-yloxy}-(2-pyridyl))-N-methylcarboxamide
392.1


 


175




(4-{2-[(4-bromophenyl)amino]-1-ethylbenzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide
466.1


 


176




(4-{2-[(4-aminophenyl)amino]-1-methylbenzimidazol-5-yloxy}-(2-pyridyl))-N-methylcarboxamide
389.2


 


177(synthesisas inEx 1)




N-methyl[4-(1-methyl-2-{[4-(methylamino)phenyl]amino}-benzimidazol-5-yloxy)(2-pyridyl)]carboxamide
403.2


 


178(synthesisas inEx 1)




[4-(2-{[4-(dimethylamino)-phenyl]amino}-1-methyl-benzimidazol-5-yloxy)(2-pyridyl)]-N-methylcarboxamide
417.2


 


179




N-methyl-4-[(1-methyl-2-{[5-methyl-2-(methyloxy)phenyl]-amino}-1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide
418.5


 


180




4-[(2-{[3,5-bis(methyloxy)-phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
434.5


 


181




4-({2-[(2,6-difluorophenyl)-amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N-methyl-pyridine-2-carboxamide
410.4


 


182




4-[(2-{[3,5-bis(trifluoromethyl)-phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
510.4


 


183




N-methyl-4-[(1-methyl-2-{[4-(methyloxy)-1,1′-biphenyl-3-yl]-amino}-1H-benzimidazol-5-yl)-oxy]pyridine-2-carboxamide
480.5


 


184




4-({2-[(2,4-dimethylphenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
402.5


 


185




4-({2-[(2-chloro-5-nitrophenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methyl-pyridine-2-carboxamide
453.9


 


186




N-methyl-4-[(1-methyl-2-{[4-(methyloxy)-2-nitrophenyl]-amino}-1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide
449.4


 


187




4-[(2-{[4-chloro-2-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)-oxy]-N-methylpyridine-2-carboxamide
476.9


 


188




4-({2-[(3-chloro-2-methyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
422.9


 


189




4-({2-[(4-fluorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
392.4


 


190




4-({2-[(2,3-dimethylphenyl)-amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N-methyl-pyridine-2-carboxamide
402.5


 


191




4-[(2-{[5-chloro-2-(methyloxy)-phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
438.9


 


192




N-methyl-4-[(1-methyl-2-{[4-(1,3-oxazol-5-yl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide
441.5


 


193




4-[(2-{[2-(ethyloxy)phenyl]-amino}-1-methyl-1H-benz-imidazol-5-yl)oxy]-N-methyl-pyridine-2-carboxamide
418.5


 


194




4-({2-[(2-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
453.3


 


195




4-{[2-(cyclohexylamino)-1-methyl-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2-carboxamide
380.5


 


196




N-methyl-4-({1-methyl-2-[(3-nitrophenyl)amino]-1H-benz-imidazol-5-yl}oxy)pyridine-2-carboxamide
419.4


 


197




4-({2-[(3-cyanophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
399.4


 


198




N-methyl-4-[(1-methyl-2-{[4-(1H-pyrazol-1-yl)phenyl]-amino}-1H-benzimidazol-5-yl)-oxy]pyridine-2-carboxamide
440.5


 


199




4-({2-[(2-chlorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
408.9


 


200




4-{[2-(cyclopropylamino)-1-methyl-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2-carboxamide
338.4


 


201




4-[(2-{[4-(ethyloxy)phenyl]-amino}-1-methyl-1H-benz-imidazol-5-yl)oxy]-N-methyl-pyridine-2-carboxamide
418.5


 


202




N-methyl-4-{[1-methyl-2-({3-[(phenylmethyl)oxy]phenyl}amino)-1H-benzimidazol-5-yl]oxy}-pyridine-2-carboxamide
480.5


 


203




4-{[2-(2,3-dihydro-1H-inden-5-ylamino)-1-methyl-1H-benz-imidazol-5-yl]oxy}-N-methyl-pyridine-2-carboxamide
414.5


 


204




4-({2-[(2-ethyl-6-methylphenyl)-amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N-methyl-pyridine-2-carboxamide
416.5


 


205




N-methyl-4-{[1-methyl-2-({4-[(4-nitrophenyl)oxy]phenyl}-amino)-1H-benzimidazol-5-yl]-oxy}pyridine-2-carboxamide
511.5


 


206




4-({2-[(cyclohexylmethyl)-amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N-methyl-pyridine-2-carboxamide
394.5


 


207




4-[(2-{[4-bromo-3-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
521.3


 


208




4-{[2-({4-[(Z)-amino(imino)-methyl]phenyl}amino)-1-methyl-1H-benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide
416.5


 


209




4-({2-[(1-acetyl-2,3-dihydro-1H-indol-6-yl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
457.5


 


210




4-[(2-{[4-fluoro-3-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
460.4


 


211




4-{[2-(cycloheptylamino)-1-methyl-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2-carboxamide
394.5


 


212




4-({2-[(3-acetylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
416.5


 


213




4-{[2-(bicyclo[2.2.1]hept-2-ylamino)-1-methyl-1H-benz-imidazol-5-yl]oxy}-N-methyl-pyridine-2-carboxamide
392.5


 


214




N-methyl-4-[(1-methyl-2-{[2-(methyloxy)-5-(trifluoromethyl)-phenyl]amino}-1H-benz-imidazol-5-yl)oxy]pyridine-2-carboxamide
472.4


 


215




4-[(2-{[4-(1-hydroxyethyl)-phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
418.5


 


216




N-methyl-4-({1-methyl-2-[(2-pyrrolidin-1-ylethyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide
395.5


 


217




N-methyl-4-({1-methyl-2-[(3-morpholin-4-ylpropyl)amino]-1H-benzimidazol-5-yl}oxy)-pyridine-2-carboxamide
425.5


 


218




N-methyl-4-[(1-methyl-2-{[3-(2-oxopyrrolidin-1-yl)propyl]-amino}-1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide
423.5


 


219




N-methyl-4-[(1-methyl-2-{[2-(1-methylpyrrolidin-2-yl)ethyl]-amino}-1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide
409.5


 


220




N-methyl-4-({1-methyl-2-[(2-morpholin-4-ylethyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide
411.5


 


221




4-[(2-{[2,4-bis(methyloxy)-phenyl]amino}-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
434.5


 


222




1,1-dimethylethyl 3-{[1-methyl-5-({2-[(methylamino)carbonyl]-pyridin-4-yl}oxy)-1H-benz-imidazol-2-yl]amino}benzoate
474.5


 


223




3-{[1-methyl-5-({2-[(methyl-amino)carbonyl]pyridin-4-yl}-oxy)-1H-benzimidazol-2-yl]-amino}benzoic acid
418.4


 


224




4-({2-[(3,5-dimethylisoxazol-4-yl)amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N-methyl-pyridine-2-carboxamide
393.4


 


225




N-methyl-4-({1-methyl-2-[(5-methyl-3-phenylisoxazol-4-yl)-amino]-1H-benzimidazol-5-yl}-oxy)pyridine-2-carboxamide
455.5


 


226




N-methyl-4-[(1-methyl-2-{[2-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide
469.6


 


227




4-({2-[(4-chloro-1H-indazol-3-yl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
448.9


 


228




N-methyl-4-{[1-methyl-2-({[4-(methyloxy)phenyl]methyl}amino)-1H-benzimidazol-5-yl]oxy}-pyridine-2-carboxamide
418.5


 


229




4-({2-[(2,3-difluorophenyl)-amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N-methyl-pyridine-2-carboxamide
410.4


 


230




N-methyl-4-({1-methyl-2-[(2-morpholin-4-ylphenyl)amino]-1H-benzimidazol-5-yl}oxy)-pyridine-2-carboxamide
459.5


 


231




4-({2-[(3-iodophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2-carboxamide
500.3


 


232




N-methyl-4-[(1-methyl-2-{[3,4,5-tris(methyloxy)phenyl]-amino}-1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide
464.5


 


233




N-methyl-4-({1-methyl-2-[(thien-2-ylmethyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide
394.5


 


234




N-methyl-4-({1-methyl-2-[(3-thien-2-yl-1H-pyrazol-5-yl)-amino]-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide
446.5


 


235




4-{[2-(1,3-benzodioxol-5-yl-amino)-1-methyl-1H-benz-imidazol-5-yl]oxy}-N-methyl-pyridine-2-carboxamide
418.4


 


236




4-({2-[(2-iodophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2-carboxamide
500.3


 


237




4-({2-[(2,6-diethylphenyl)-amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N-methyl-pyridine-2-carboxamide
430.5


 


238




4-[(2-{[3-(1-hydroxyethyl)-phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
418.5


 


239




4-[(2-{[4-(1H-imidazol-1-yl)-phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
440.5


 


240




N-methyl-4-[(1-methyl-2-{[2-(phenyloxy)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide
466.5


 


241




4-[(2-{[3,4-bis(methyloxy)-phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
434.5


 


242




N-methyl-4-[(1-methyl-2-{[2-morpholin-4-yl-5-(trifluoro-methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide
527.5


 


243




N-methyl-4-({1-methyl-2-[(tricyclo[3.3.1.1~3,7~]dec-1-ylmethyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide
446.6


 


244




4-({2-[1,1′-bi(cyclohexyl)-2-ylamino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
462.6


 


245




4-{[2-({[(1S,5S)-6,6-dimethyl-bicyclo[3.1.1]hept-2-yl]methyl}-amino)-1-methyl-1H-benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide
434.6


 


246




N-methyl-4-{[1-methyl-2-(tricyclo[3.3.1.1~3,7~]dec-1-ylamino)-1H-benzimidazol-5-yl]oxy}pyridine-2-carboxamide
432.5


 


247




N-methyl-4-({1-methyl-2-[(3-methylphenyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide
388.4


 


248




4-[(2-{[5-fluoro-2-(1H-imidazol-1-yl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
458.5


 


249




N-methyl-4-({1-methyl-2-[(5-phenyl-1H-pyrazol-3-yl)amino]-1H-benzimidazol-5-yl}oxy)-pyridine-2-carboxamide
440.5


 


250




4-{[2-({4-[(4-ethylpiperazin-1-yl)methyl]phenyl}amino)-1-methyl-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2-carboxamide
500.6


 


251




4-({2-[(1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)amino]-1-methyl-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2-carboxamide
443.4


 


252




N-methyl-4-({1-methyl-2-[(3-oxo-2,3-dihydro-1H-isoindol-5-yl)amino]-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide
429.4


 


253




4-({2-[(4-bromophenyl)-(methyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
467.3


 


254




N-methyl-4-{[1-methyl-2-(naphthalen-2-ylamino)-1H-benzimidazol-5-yl]oxy}pyridine-2-carboxamide
424.5


 


255




ethyl 1-methyl-5-({2-[(methyl-amino)carbonyl]pyridin-4-yl}-oxy)-1H-benzimidazol-2-yl-carbamate
370.4


 


256




4-[(2-{[3-(1H-imidazol-1-yl)-propyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
406.5


 


257




N-methyl-4-({1-methyl-2-[(2-methylphenyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide
388.4


 


258




4-({2-[(2,6-dimethylphenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
402.5


 


259




4-{[2-({2-[(difluoromethyl)-oxy]phenyl}amino)-1-methyl-1H-benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide
440.4


 


260




4-[(2-{[2-(1,1-dimethylethyl)-phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
430.5


 


261




N-methyl-4-({1-methyl-2-[methyl(4-methylphenyl)amino]-1H-benzimidazol-5-yl}oxy)-pyridine-2-carboxamide
402.5


 


262




N-methyl-4-[(1-methyl-2-{[3-(methylthio)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide
420.5


 


263




4-{[2-({4-cyano-2-[(trifluoro-methyl)oxy]phenyl}amino)-1-methyl-1H-benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide
483.4


 


264




N-methyl-4-({1-methyl-2-[(4-{1-[(phenylmethyl)amino]-ethyl}phenyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide
507.6


 


265




4-{[2-(1H-indol-5-ylamino)-1-methyl-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2-carboxamide
413.5


 


266




N-methyl-4-{[1-methyl-2-(phenylamino)-1H-benzimidazol-5-yl]oxy}pyridine-2-carboxamide
374.4


 


267




N-methyl-4-[(1-methyl-2-{[2-(phenylcarbonyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide
478.5


 


268




4-{[2-({4-bromo-2-[(trifluoro-methyl)oxy]phenyl}amino)-1-methyl-1H-benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide
537.3


 


269




4-({2-[(2,4-dibromo-6-fluoro-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
550.2


 


270




4-{[2-(1,3-dihydro-2 h-isoindol-2-yl)-1-methyl-1H-benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide
400.5


 


271




4-{[2-(isoquinolin-1-ylamino)-1-methyl-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2-carboxamide
425.5


 


272




N-methyl-4-[(1-methyl-2-{[2-(1H-pyrazol-1-yl)phenyl]-amino}-1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide
440.5


 


273




4-{[2-(1H-indol-6-ylamino)-1-methyl-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2-carboxamide
413.5


 


274




methyl 4-{[1-methyl-5-({2-[(methylamino)carbonyl]pyridin-4-yl}oxy)-1H-benzimidazol-2-yl]amino}-3-[(trifluoromethyl)-oxy]benzoate
516.4


 


275




4-({2-[(2-cyanophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
399.4


 


276




N-methyl-4-[(1-methyl-2-{[2-phenylthio)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide
482.6


 


277




4-[(2-{[2-[(4-chlorophenyl)oxy]-5-(trifluoromethyl)phenyl]-amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
569.0


 


278




N-methyl-4-[(1-methyl-2-{[2-[(4-methylphenyl)oxy]-5-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide
548.5


 


279




4-({2-[(4-chlorophenyl)amino]-1,7-dimethyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
422.9


 


280




4-[(2-{[3-(1,1-dimethylethyl)-phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
430.5


 


281




4-({2-[(3-cyclohexylphenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
456.6


 


282




4-({2-[(2,5-dichlorophenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
443.3


 


283




N-methyl-4-[(1-methyl-2-{[2-{[2-(methyloxy)phenyl]oxy}-5-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide
564.5


 


284




4-[(2-{[2-[(4-cyanophenyl)oxy]-5-(trifluoromethyl)phenyl]-amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
559.5


 


285




4-({2-[(2,5-dimethylphenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
402.5


 


286




4-({2-[(5-fluoro-2-methyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
406.4


 


287




4-({2-[(2-aminophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
389.4


 


288




4-({2-[(2-cyano-5-methyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
413.5


 


289




N-methyl-4-[(1-methyl-2-{[(4-methylphenyl)methyl]amino}-1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide
402.5


 


290




4-({2-[(4-bromo-2-methyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
467.3


 


291




4-({2-[(5-bromo-2-methyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
467.3


 


292




N-methyl-4-({1-methyl-2-[(4-methyl-1,1′-biphenyl-3-yl)-amino]-1H-benzimidazol-5-yl}-oxy)pyridine-2-carboxamide
464.5


 


293




4-({2-[(5-chloro-2-fluoro-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
426.8


 


294




4-[(2-{[5-cyclohexyl-2-(methyl-oxy)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
486.6


 


295




4-({2-[(4-bromo-2-fluoro-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
471.3


 


296




4-({2-[(2-amino-4-methyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
403.5


 


297




N-methyl-4-{[1-methyl-2-(5,6,7,8-tetrahydronaphthalen-1-ylamino)-1H-benzimidazol-5-yl]oxy}pyridine-2-carboxamide
428.5


 


298




N-methyl-4-[(1-methyl-2-{[4-(methylsulfonyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide
452.5


 


299




N-methyl-4-{[1-methyl-2-({3-[(trifluoromethyl)thio]phenyl}amino)-1H-benzimidazol-5-yl]-oxy}pyridine-2-carboxamide
474.5


 


300




N-methyl-4-{[1-methyl-2-({4-[(trifluoromethyl)thio]phenyl}amino)-1H-benzimidazol-5-yl]-oxy}pyridine-2-carboxamide
474.5


 


301




4-{[2-(1,1′-biphenyl-3-ylamino)-1-methyl-1H-benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide
450.5


 


302




4-({2-[(2-chloro-4-methyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
422.9


 


303




4-[(2-{[2-bromo-4-(1-methyl-ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
495.4


 


304




4-({2-[(3-ethynylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
398.4


 


305




4-{[2-(isoquinolin-7-ylamino)-1-methyl-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2-carboxamide
425.5


 


306




N-methyl-4-[(1-methyl-2-{[3-(1-methylethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide
416.5


 


307




4-({2-[(3-bromo-4-methyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
467.3


 


308




N-methyl-4-({1-methyl-2-[(phenylsulfonyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide
438.5


 


309




4-{[2-(9H-fluoren-1-ylamino)-1-methyl-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2-carboxamide
462.5


 


310




4-{[2-(9H-fluoren-2-ylamino)-1-methyl-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2-carboxamide
462.5


 


311




4-({2-[(2,2-difluoro-1,3-benzodioxol-5-yl)amino]-1-methyl-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2-carboxamide
454.4


 


312




N-methyl-4-{[1-methyl-2-({3-[(trifluoromethyl)oxy]phenyl}amino)-1H-benzimidazol-5-yl]-oxy}pyridine-2-carboxamide
458.4


 


313




N-methyl-4-({1-methyl-2-[(1-methylethyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide
340.4


 


314




N-methyl-4-({1-methyl-2-[(2-phenylethyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide
402.5


 


315




4-({2-[(3-cycloheptylphenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
470.6


 


316




N-methyl-4-[(1-methyl-2-{[(phenylmethyl)sulfonyl]amino}-1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide
452.5


 


317




4-{[2-(2,3-dihydro-1H-indol-6-ylamino)-1-methyl-1H-benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide
415.5


 


318




N-methyl-4-[(1-methyl-2-{[1-(3-pyridin-4-ylpropanoyl)-2,3-dihydro-1H-indol-6-yl]amino}-1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide
548.6


 


319




4-({2-[(3-chloro-4-methyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
422.9


 


320




4-{[2-(cyclopentylamino)-1-methyl-1H-benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide
366.4


 


321(synthesisas inEx 1)




4-[(2-{[4-(diethylamino)phenyl]-amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
445.5


 


322




N-methyl-4-[(1-methyl-2-{[2-(4-methylphenyl)ethyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide
416.5


 


323




4-[(2-{[4-bromo-2-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)-oxy]-N-methylpyridine-2-carboxamide
521.3


 


324




4-({2-[(4-chloro-2-methyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
422.9


 


325




4-[(2-{[3-(diethylamino)-propyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
411.5


 


326




4-({2-[(4-bromo-2-chloro-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
487.8


 


327




4-({2-[(3,5-dimethylphenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
402.5


 


328




4-({2-[(cyclopropylmethyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
352.4


 


329




4-{[2-(2,3-dihydro-1,4-benzodioxin-6-ylamino)-1-methyl-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2-carboxamide
432.4


 


330




N-methyl-4-[(1-methyl-2-{[4-(phenyloxy)pyridin-3-yl]-amino}-1H-benzimidazol-5-yl)-oxy]pyridine-2-carboxamide
467.5


 


331




N-methyl-4-({1-methyl-2-[(4-pyridin-2-ylphenyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide
451.5


 


332




4-({2-[(2-chloro-4-fluoro-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
426.8


 


333




4-({2-[(4-fluoro-2-methyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
406.4


 


334




N-methyl-4-({1-methyl-2-[(2,4,5-trimethylphenyl)amino]-1H-benzimidazol-5-yl}oxy)-pyridine-2-carboxamide
416.5


 


335




4-[(2-{[2-chloro-4-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)-oxy]-N-methylpyridine-2-carboxamide
476.9


 


336




4-({2-[(5-chloro-2-methyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
422.9


 


337




4-({2-[(4-chloro-2-fluoro-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
426.8


 


338




N-methyl-4-[(1-methyl-2-{[3-(1-methylpropyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide
430.5


 


339




4-({2-[(4-fluoro-3-methyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
406.4


 


340




4-({2-[(4-chloro-3-methyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
422.9


 


341




4-{[2-({3-bromo-4-[(trifluoro-methyl)oxy]phenyl}amino)-1-methyl-1H-benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide
537.3


 


342




4 {[2-({3-chloro-4-[(trifluoro-methyl)oxy]phenyl}amino)-1-methyl-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2-carboxamide
492.9


 


343




N-methyl-4-({1-methyl-2-[(4-pyridin-3-ylphenyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide
451.5


 


344




4-[(2-{[3-chloro-4-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)-oxy]-N-methylpyridine-2-carboxamide
476.9


 


345




4-({2-[(4-chloro-3-fluoro-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
426.8


 


346




4-({2-[(2-bromo-4-methyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
467.3


 


347




N-methyl-4-({1-methyl-2-[(2,3,5-trifluorophenyl)amino]-1H-benzimidazol-5-yl}oxy)-pyridine-2-carboxamide
428.4


 


348




4-({2-[(2,4-dibromophenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
532.2


 


349




4-({2-[(2-chloro-5-fluoro-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
426.8


 


350




4-{[2-({3-chloro-4-[(trifluoro-methyl)thio]phenyl}amino)-1-methyl-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2-carboxamide
508.9


 


351




4-({2-[(3-chloro-1H-indol-6-yl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
447.9


 


352




4-[(2-{[3,5-bis(1,1-dimethyl-ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
486.6


 


353




4-[(2-{[5-(1,1-dimethylethyl)-2-(methyloxy)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)-oxy]-N-methylpyridine-2-carboxamide
460.5


 


354




N-methyl-4-[(1-methyl-2-{[2-(methyloxy)-5-(1-methyl-1-phenylethyl)phenyl]amino }-1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide
522.6


 


355




4-[(2-{[4-chloro-2,5-bis(methyl-oxy)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
468.9


 


356




4-{[2-({4-fluoro-2-[(1-methyl-ethyl)oxy]phenyl}amino)-1-methyl-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2-carboxamide
450.5


 


357




N-methyl-4-{[1-methyl-2-({3-[(1-methylethyl)oxy]phenyl}-amino)-1H-benzimidazol-5-yl]-oxy}pyridine-2-carboxamide
432.5


 


358(synthesisas inEx 769)




4-({2-[(3-furan-3-ylphenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
440.5


 


359




4-[(2-{[4-chloro-5-methyl-2-(methyloxy)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
452.9


 


360




N-methyl-4-[(1-methyl-2-{[2-methyl-5-(1-methylethyl)-phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide
430.5


 


361




4-[(2-{[2,5-bis(1,1-dimethyl-ethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
486.6


 


362




4-{[2-({5-chloro-2-[(difluoro-methyl)oxy]phenyl}amino)-1-methyl-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2-carboxamide
474.9


 


363




N-methyl-4-{[1-methyl-2-({4-[(phenylmethyl)oxy]phenyl}amino)-1H-benzimidazol-5-yl]oxy}-pyridine-2-carboxamide
480.5


 


364




4-({2-[(2-{[cyclohexyl(methyl)-amino]methyl}phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}-oxy)-N-methylpyridine-2-carboxamide
499.6


 


365




N-methyl-4-({1-methyl-2-[(6-pyrrolidin-1-ylpyridin-3-yl)-amino]-1H-benzimidazol-5-yl}-oxy)pyridine-2-carboxamide
444.5


 


366




4-[(2-{[6-(dimethylamino)-pyridin-3-yl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
418.4


 


367




N-methyl-4-({1-methyl-2-[(1-methylpiperidin-4-yl)amino]-1H-benzimidazol-5-yl}oxy)-pyridine-2-carboxamide
395.4


 


368




N-methyl-4-({1-methyl-2-[(4-methylcyclohexyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide
394.4


 


369




4-({2-[(cycloheptylmethyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
408.5


 


370




N-methyl-4-({1-methyl-2-[(3,3,5-trimethylcyclohexyl)-amino]-1H-benzimidazol-5-yl}-oxy)pyridine-2-carboxamide
422.5


 


371




N-methyl-4-({1-methyl-2-[(2-methylcyclohexyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide
394.4









EXAMPLE 372
Synthesis of 4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-ethylpyridine-2-carboxamide
The compound 4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-ethylpyridine-2-carboxamide was synthesized as follows:




Step 1. Synthesis of tert-butyl 4-chloropyridine-2-carboxylate:
4-chloropyridine-2-carbonyl chloride (1 eq) was suspended in anhydrous tetrahydrofuran. Then 2 equivalents of a solution of 1 M potassium tert-butoxide was added dropwise to the reaction slowly as the reaction was stirring under nitrogen. After 3–4 hours or when the reaction was determined to be complete 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 extracts were evaporated under reduced pressure to yield the tert-butyl ester as a yellow oil. MS: MH+=214.0
Step 2. Synthesis of tert-butyl 4-(4-amino-3-nitrophenoxy)pyridine-2-carboxylate:
Solid anhydrous white powdered KHMDS (2 eq) was suspended in a solution of dimethylformamide. Red crystalline 4-amino-3-nitrophenol (1 eq) was charged to the rapidly stirring solution under an inert atmosphere and the heterogeneous solution was allowed to stir for 2 hours. Then a dimethylformamide solution of tert-butyl 4-chloropyridine-2-carboxylate (1 eq) was added dropwise. Anhydrous powdered potassium carbonate (1.2 eq) was charged to the reaction as an acid scavenger. The purple colored viscous mixture was heated to 80° C. for 12–15 hours until when it was determined to be complete by HPLC. The reaction was evaporated under reduced pressure and diluted with excess ethyl acetate and water. An extraction of the aqueous layer was made with ethyl acetate. The organic layers were combined and washed 4 times with water followed by brine. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude material was purified by flash silica gel chromatography using an eluent of 1:1 mixture of hexanes to ethyl acetate to give the desired product. MS: MH+=332.
Step 3. Synthesis of 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 methylene chloride under nitrogen. After 10–15 minutes or until the reaction was complete as determined by HPLC, the reaction was quenched with excess saturated aqueous sodium bicarbonate. The product was extracted with methylene chloride from the aqueous layer and washed with water and brine. The extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title product as a yellow solid. MS: MH+=428.
Step 4. Synthesis of tert-butyl 4-[3-nitro-4-(2,2,2-trifluoro-N-methylacetylamino) phenoxy]pyridine-2-carboxylate:
A solution of tert-butyl 4-[3-nitro-4-(2,2,2-trifluoroacetylamino)phenoxy]pyridine-2-carboxylate (1 eq) and sodium carbonate (4 eq) in dimethylformamide was stirred at 20° C. under nitrogen for thirty minutes before 2 equivalents of iodomethane (2 eq) was charged slowly dropwise to the reaction. After 2–3 hours or until it was determined to be complete 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 afford the title product as an orange solid. MS: MH+=442.
Step 5. Synthesis of tert-butyl 4-[4-(methylamino)-3-nitrophenoxy]pyridine-2-carboxylate:
A solution of tert-butyl 4-[3-nitro-4-(2,2,2-trifluoro-N-methylacetylamino) phenoxy]pyridine-2-carboxylate in ethanol was stirred at room temperature. 1N sodium hydroxide was slowly dropped into the reaction until the conversion was complete by HPLC. The reaction was evaporated under reduced conditions and then extracted with ethyl acetate and washed with a saturated aqueous solution of ammonium chloride followed by water and brine. The organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the product as an orange solid. MS: MH+=346
Step 6. Synthesis of tert-butyl 4-[3-amino-4-(methylamino)phenoxy]pyridine-2-carboxylate:
A solution of tert-butyl 4-[4-(methylamino)-3-nitrophenoxy]pyridine-2-carboxylate (1 eq) and 10% palladium on carbon (0.1 eq) in methanol was stirred at room temperature and flushed with nitrogen. Hydrogen was flushed through the reaction for 1–2 hours or until the reaction was determined to be complete by HPLC. Nitrogen was flushed through the reaction for 15 minutes before the reaction was filtered through a celite pad. The celite pad was washed with excess methanol followed by concentration under reduced pressure to afford the product as a light yellow solid. MS: MH+=316.
Step 7. Synthesis of tert-butyl 4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}pyridine-2-carboxylate:
A solution of the diamine from step 6 (1 eq) and 4-bromophenyl isothiocyanate (1 eq) in anhydrous tetrahydrofuran under nitrogen was stirred at 20° C. for 2–3 hours or when determined to be complete by HPLC. The solution was treated with 3 equivalents of 1-ethyl-(3-dimethylaminopropyl) carbodiimide HCl. The stirred solution was heated to 50° C. under nitrogen for 2–3 hrs or until the reaction is determined to be complete by HPLC. 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 combined organic layers were washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and later evaporated under reduced pressure. The crude material was purified by reverse high-pressure liquid chromatography to afford the product as a brown powder after lyophlization. MS: MH+=495.
Step 8. Synthesis of 4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yl-oxy}pyridine-2-carboxylic acid
A solution of the product of step 7 in trifluoroacetic acid was treated with two drops of water at room temperature for 3–4 hours or until the reaction was determined to be complete by HPLC. The reaction was evaporated under reduced pressure to afford the product as a red-orange oil in quantitative yield. 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 above (1 eq) in anhydrous tetrahydrofuran (0.5 ml) was treated with O-benzotriazol-1-yl N,N,N′,N′-tetramethyl uronium hexafluorophosphate (2 eq), excess diisopropylethyl amine, and ethyl amine (1 eq). The reaction was left stirring 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 high-pressure liquid chromatography and recovered as TFA salt after lyophilization. MS: MH+=466.
EXAMPLES 373–447
The compounds shown in the following Table 4 (Examples 373–447) were prepared from following the procedure described for Example 372.










TABLE 4





Example
Structure
Name
MH+


















373




4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}-oxy)-N-(2-hydroxyethyl)pyridine-2-carboxamide
482


 


374




4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}-oxy)-N,N-dimethylpyridine-2-carboxamide
466


 


375




4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}-oxy)-N-(2,2,2-trifluoroethyl)-pyridine-2-carboxamide
521


 


376




N-(4-bromophenyl)-1-methyl-5-{[2-(pyrrolidin-1-ylcarbonyl)-pyridin-4-yl]oxy}-1H-benzimidazol-2-amine
492


 


377




ethyl (3R)-3-(methyloxy)-4-[({4-[(2-{[4-(trifluoromethyl)phenyl]-amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}carbonyl)-amino]piperidine-1-carboxylate
599


 


378




4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(dimethylamino)-ethyl]pyridine-2-carboxamide
509


 


379




4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}-oxy)-N-(tetrahydrofuran-2-yl-methyl)pyridine-2-carboxamide
522


 


380




4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}-oxy)-N-(2-morpholin-4-ylethyl)-pyridine-2-carboxamide
551


 


381




4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}-oxy)-N-(piperidin-4-ylmethyl)-pyridine-2-carboxamide
535


 


382




5-({2-[(3-aminopyrrolidin-1-yl)-carbonyl]pyridin-4-yl}oxy)-N-(4-bromophenyl)-1-methyl-1H-benzimidazol-2-amine
507


 


383




4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}-oxy)-N-[1-(diphenylmethyl)-azetidin-3-yl]pyridine-2-carboxamide
659


 


384




N-((3S)pyrrolidin-3-yl)(4-{2-[(4-bromophenyl)amino]-1-methyl-benzimidazol-5-yloxy}(2-pyridyl))carboxamide
507.0


 


385




N-(2-aminoethyl)(4-{2-[(4-bromophenyl)amino]-1-methyl-benzimidazol-5-yloxy}(2-pyridyl))carboxamide
481.0


 


386




N-((3R)pyrrolidin-3-yl)(4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))carboxamide
507.0


 


387




(4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(2-piperidylethyl)-carboxamide
549.1


 


388




(4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(oxolan-2-ylmethyl)-carboxamide
522.0


 


389




(4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(2-pyrrolidinylethyl)-carboxamide
535.1


 


390




(4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(1,3-thiazol-2-yl)-carboxamide
521.0


 


391




3-aminopyrrolidinyl 4-{2-[(4-bromophenyl)amino]-1-methyl-benzimidazol-5-yloxy}(2-pyridyl)ketone
507.0


 


392




N-[(3R,5R)-5-(methoxymethyl)-pyrrolidin-3-yl](4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))carboxamide
551.1


 


393




(4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-[(1-ethylpyrrolidin-2-yl)methyl]carboxamide
549.2


 


394




(4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(3-piperidyl)-carboxamide
521.0


 


395




(4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(3-imidazolylpropyl)-carboxamide
546.4


 


396




(4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-[3-(2-oxo-pyrrolidinyl)propyl]carboxamide
563.4


 


397




4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}-pyridine-2-carboxamide
438.1


 


398




(4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(methylethyl)carboxamide
480.3


 


399




(4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(4-hydroxy-cyclohexyl)carboxamide
536.4


 


400




(4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(2-methoxyethyl)-carboxamide
496.3


 


401




N-(2 h-benzo[d]1,3-dioxolen-5-ylmethyl)(4-{2-[(4-bromophenyl)-amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))carboxamide
572.4


 


402




(4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(4-pyridylmethyl)-carboxamide
529.3


 


403




(4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(2-(4-pyridyl)ethyl)-carboxamide
543.4


 


404




(4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-[3-(4-methylpiperazinyl)propyl]carboxamide
578.5


 


405




4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl) 4-(2-oxyethyl)piperazinyl ketone
551.4


 


406




(4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(2-imidazol-4-ylethyl)carboxamide
532.4


 


407




(4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-[2-(1-methylpyrrolidin-2-yl)ethyl]carboxamide
549.1


 


408




(4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(2-oxoazaperhydro-epin-3-yl)carboxamide
549.1


 


409




(4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(2-indol-3-ylethyl)-carboxamide
581.4


 


410




(4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-piperidylcarboxamide
521.1


 


411




(4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-[2-(2-methoxyphenyl)-ethyl]carboxamide
572.1


 


412




(4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-[2-(3-methoxyphenyl)-ethyl]carboxamide
572.4


 


413




(4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-[2-(4-methoxyphenyl)-ethyl]carboxamide
572.4


 


414




(4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(4-methylpiperazinyl)-carboxamide
536.1


 


415




(4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(2-(4-piperidyl)ethyl)-carboxamide
549.4


 


416




(4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-[2-(phenylamino)-ethyl]carboxamide
557.4


 


417




N-{2-[(4-{2-[(4-bromophenyl)-amino]-1-methylbenzimidazol-5-yloxy}-2-pyridyl)carbonylamino]-ethyl}acetamide
523.4


 


418




(4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-[2-(2-oxo-imidazolidinyl)ethyl]carboxamide
550.4


 


419




methyl 2-[(4-{2-[(4-bromophenyl)-amino]-1-methylbenzimidazol-5-yloxy}-2-pyridyl)carbonylamino]-acetate
510.3


 


420




methyl (2S)-2-[(4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))carbonylamino]-3-methylbutanoate
552.4


 


421




(2S)-2-[(4-{2-[(4-bromophenyl)amino]-1-methyl-benzimidazol-5-yloxy}(2-pyridyl))carbonylamino]-3-carbamoylpropanoic acid
553.3


 


422




methyl 3-[(4-{2-[(4-bromophenyl)amino]-1-methyl-benzimidazol-5-yloxy}-2-pyridyl)-carbonylamino]propanoate
524.3


 


423




N-((2S)-2-aminopropyl)(4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))carboxamide
495.3


 


424




N-((2R)-2-aminopropyl)(4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))carboxamide
495.3


 


425




(4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(pyrrolidin-2-yl-methyl)carboxamide
521.4


 


426




(4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-propylcarboxamide
480.3


 


427




(4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-6-yloxy}(2-pyridyl))-N-methylcarboxamide
452.1


 


428




2-[(4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}-2-pyridyl)carbonylamino]acetic acid
496.31


 


429




(2S)-2-[(4-{2-[(4-bromophenyl)-amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))carbonylamino]-3-methylbutanoic acid
538.1


 


430




3-[(4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}-2-pyridyl)carbonylamino]propanoic acid
510.1


 


431




(4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(1-methyl(4-piperidyl))carboxamide
535.1


 


432




(4-{2-[(4-chlorophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(3-methoxypropyl)-carboxamide
466.1


 


433




(4-{2-[(4-chlorophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(3-imidazolylpropyl)-carboxamide
502.1


 


434




(4-{2-[(4-chlorophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(2-morpholin-4-yl-ethyl)carboxamide
507.2


 


435




(4-{2-[(4-chlorophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(2-piperidylethyl)-carboxamide
505.2


 


436




(4-{2-[(4-chlorophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(3-morpholin-4-yl-propyl)carboxamide
521.2


 


437




(4-{2-[(4-chlorophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-[3-(2-oxo-pyrrolidinyl)propyl]carboxamide
519.2


 


438




(4-{2-[(4-chlorophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-[(1-ethylpyrrolidin-2-yl)methyl]carboxamide
505.2


 


439




N-((3R)pyrrolidin-3-yl)(4-{2-[(4-chlorophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))carboxamide
463.2


 


440




N-{2-[(4-{2-[(4-chlorophenyl)-amino]-1-methylbenzimidazol-5-yloxy}-2-pyridyl)carbonylamino]-ethyl}acetamide
479.2


 


441




(4-{2-[(4-chlorophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-(2-imidazol-4-yl-ethyl)carboxamide
488.2


 


442




(4-{2-[(4-chlorophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-[2-(1-methyl-pyrrolidin-2-yl)ethyl]carboxamide
505.2


 


443




N-[(3R,5R)-5-(methoxyethyl)-pyrrolidin-3-yl](4-{2-[(4-chloro-phenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))carboxamide
507.2


 


444




(2S)-2-[(4-{2-[(4-chlorophenyl)-amino]-1-methyl-benzimidazol-5-yloxy}(2-pyridyl))carbonylamino]-propanoic acid
466.1


 


445




N-(2,3-dihydroxypropyl)(4-{2-[(4-chlorophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))carboxamide
468.1


 


446




N-((3S)pyrrolidin-3-yl)(4-{2-[(4-chlorophenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))carboxamide
463.2


 


447(synthesisas inEx 120a)




(4-{2-[(2-methoxyphenyl)amino]-1-methylbenzimidazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide
404.1


 


448(synthesisas inEx 483)




4-[(2-{[3-(2-fluoropyridin-4-yl)-4-methylphenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[2-(4-methylpiperazin-1-yl)ethyl]-pyridine-2-carboxamide
595.7


 


448(synthesisas inEx 483)




4-[(2-{[3-(2-fluoropyridin-4-yl)-4-methylphenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-(2-pyrrolidin-1-ylethyl)pyridine-2-carboxamide
566.7









EXAMPLE 450
Preparation of (4-Chloro-phenyl)-{5-[2-(4,5-dihydro-1H-imidazol-2-yl)-pyridin-4-yloxyl]-1-methyl-1H-benzoimidazol-2-yl}-amine)
Step 1. Synthesis of 4-(4-Amino-3-nitro-phenoxy)=puridine-2-carbonitrile:




Potassium carbonate (9.00 g) was dried in vacuo with heating, cooled to RT under nitrogen. 4-amino-3-ntrophenol (3.355 g), 4-chloro-2-cyanopyridine (3.00 g) and DMSAO (30 mL, anhydrous) were added. The system was stirred under nitrogen as it was heated to 103° C., and held at this temperature 1 hr. The reaction was then cooled to RT, poured onto ice/H2O (500 mL) the precipitate was collected, washed (H2O), dissolved (EtOAc), dried (Na2SO4), filtered and stripped to a solid. This was suspended (Et2O), collected, air-dried 4.1015 g (73.5%) a second crop was collected (0.5467 gm, 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 (1.6 g) was dried in vacuo with heating, cooled to RT and suspended in dichloromethane (30 mL) with 4-(4-amino-3-nitro-phenoxy)=puridine-2-carbonitrile (2.005 gm) under nitrogen. This was cooled to 0° C. and TFAA (2.2 mL) was added, neat. The starting material goes into solution rapidly as addition is made. After 10 min at 0° C., the mixture was diluted with dichloromethane, washed (H2O, aq NaCl), dried (K2CO3), filtered and stripped to a yellow foam. M/z=353 (M+1) The product was used without purification.
Iodomethane (0.53 mL) was added to a suspension of potassium carbonate (1.858 g) in DMF (30 mL containing compound 2 ( ̃7.8 mmole) under nitrogen. The suspension stirred at RT overnight, then poured onto H2O (300 mL), extracted (Et2O, 3×150 mL), the combined extracts were washed (H2O, aq. NaCl), dried (potassium carbonate), filtered and stripped to an orange oil (7.4922 g). M/z=367 (M+1)
Step 3. Synthesis of 4-(4-Methylamino-3-nitro-phenoxy)-pyridine-2-carbonitrile:




NaOH (1 mL, 1N aq) was added dropwise to a solution of N-[4-(2-cyano-pyridin-4-yloxy)-2-nitro-phenyl]-2,2,2-trifluoro-N-methyl-acetamide (440 mg) in ethanol (6 mL) at RT. After 40 min, the mixture was diluted with H2O (20 mL) and cooled to 0° C. Bright orange crystals were collected, washed (H2O) and air-dried 311.1 mg (94%). M/z=271 (M+1)
Step 4. Synthesis of 4-[2-(4-Chloro-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carbonitrile:




Palladium on carbon (46 mg 10% w/w) was suspended in MeOH (2 mL) under nitrogen. The resulting suspension was added, under nitrogen, to a suspension of 4-(4-methylamino-3-nitro-phenoxy)-pyridine-2-carbonitrile (311 mg) in MeOH (3 mL) at RT. The atmosphere was exchanged with hydrogen, and the system stirred vigorously under 1 atm hydrogen for 1 hr. The atmosphere was then exchanged for nitrogen, the mixture was filtered (celite) and the filtrate was used without further purification in the next reaction. M/z=2421 (M+1).
4-chlorophenylisothiocyanate (200 mg) was added to a solution of compound 5 in MeOH (10 mL). The solution was stirred at reflux for 2 hrs. Iodomethane (71 microliters) was added, and stirring continued at 67° C., overnight. The mixture was then cooled to RT evaporated to dryness, and the residue chromatographed (0.5% NH4OH, 5% MeOH, 94.5% dichloromethane on silica gel) to isolate a compound of Rf=0.29 (325 mg). This was crystallized from dichloromethane/ether to give 127 mg. M/z=376 (M+1)













1HNMR (MeOH-d4)





















9.40 ppm
s(b)

(1H)



8.55 ppm
d,d
H=5.7, 0.6Hz
(1H)



7.62 ppm
m

(2h)



7.42 ppm
d,d
J=2.5, 0.6Hz
(1H)



7.43 ppm
d

(1H)



7.37 ppm
m

(2h)



7.21 ppm
d
J=2.0Hz
(1H)



7.15 ppm
d,d
J=5.9, 2.5Hz
(1H)



6.97 ppm
d,d
J=8.4, 2.2hz
(1H)



3.80 ppm
s

(3H)










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




H2SO4 (454 mg) was added cautiously to a suspension of 4-[2-(4-chloro-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carbonitrile (60.0 mg) in ethylenediamine (0.50 mL). The system was shaken at room temperature for 72 hrs, then poured onto ice/NaHCO3. The solid product was collected, washed (H2O) air-dried 59.8 mg. M/z=419 (M+1).
EXAMPLE 451
Synthesis of (4-{2-[(4-bromophenyl)amino]benzoxazol-5-yloxy}-(2-pyridyl))-N-methylcarboxamide
Step 1. Synthesis of 2-amino-4-methoxyphenol
The mixture containing 4-methoxy-2-nitrophenol in methanol with catalytic amount of 10% Pd/C was hydrogenated until disappearance of yellow color to yield 2-amino-4-methoxyphenol. MS: MH+=140.
Step 2. Synthesis of 5-methoxybenzoxazole-2-thiol
The mixture containing 2-amino-4-methoxyphenol(1 eq) and O-ethylxanthic acid, potassium salt (1.1 eq) in pyridine was refluxed for two hours. The resultant mixture was poured in to ice/water containing hydrochloric acid to yield a 5-methoxybenzoxazole-2-thiol as a tan solid. MS: MH+=182
Step 3. Synthesis of 2-chloro-5-methoxybenzoxazole
The mixture containing 5-methoxybenzoxazole-2-thiol was heated in thionyl chloride with a drop of DMF. The resultant mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was washed with brine and dried and concentrated. Purification on a silica gel column gave 2-chloro-5-methoxybenzoxazole as a white solid. MS: MH+=184.
Step 4. Synthesis of (4-bromophenyl)(5-methoxybenzoxazol-2-yl)amine
The mixture containing 2-chloro-5-methoxybenzoxazole(1 eq), 4-bromoaniline (2 eq) and diisopropylethylamine was refluxed in dimethylformamide. The resultant mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was washed with brine and dried. Purification on silica gel gave (4-bromo-phenyl)(5-methoxybenzoxazol-2-yl)amine. MS: MH+=318
Step 5. Synthesis of 2-[(4-bromophenyl)amino]benzoxazol-5-ol
The mixture of (4-bromophenyl)(5-methoxybenzoxazol-2-yl)amine and hydrobromic acid (48%) was subjected to the microwave at 150° C. for 6 mins to yield 2-[(4-bromophenyl)amino]benzoxazol-5-ol. MS: MH+=305
Step 6. Synthesis of (4-{2-[(4-bromophenyl)amino]benzoxazol-5-yloxy}-(2-pyridyl))-N-methylcarboxamide
The mixture containing 2-[(4-bromophenyl)amino]benzoxazol-5-ol (1 eq), potassium bis(trimethylsilyl)amide (4 eq), was stirred in dimethylformamide for 30 min at room temperature. To this mixture was added (4-chloro(2-pyridyl)-N-methyl-carboxamide (1 eq) and Potassium carbonate (1.2 eq) and microwaved for 6 mins at 150° C. The reaction mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried, filtered and concentrated. Purification on Prep LC yielded the desired product. MS: MH+=439.
The compounds shown in the following Table 5 (Examples 452–481) were prepared from following the procedure described for Examples 449–451.










TABLE 5





Example
Structure
Name
MH+







452




N-(2-aminoethyl)-4-({2-[(4-bromo-phenyl)amino]-1,3-benzoxazol-5-yl}oxy)pyridine-2-carboxamide
469.3


 


453




4-({2-[(4-bromophenyl)amino]-1,3-benzoxazol-5-yl}oxy)-N-(2-morpholin-4-ylethyl)pyridine-2-carboxamide
539.4


 


454




4-({2-[(4-bromophenyl)amino]-1,3-benzoxazol-5-yl}oxy)-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide
495.3


 


455




4-({2-[(4-bromophenyl)amino]-1,3-benzoxazol-5-yl}oxy)-N-{(3R,5R)-5-[(methyloxy)methyl]pyrrolidin-3-yl}pyridine-2-carboxamide
539.4


 


456




4-({2-[(4-chlorophenyl)amino]-1,3-benzoxazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
395.8


 


457




4-({2-[(3,5-difluorophenyl)amino]-1,3-benzoxazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
397.4


 


458




N-methyl-4-[(2-{[2-(trifluoro-methyl)phenyl]amino}-1,3-benzoxazol-5-yl)oxy]pyridine-2-carboxamide
429.4


 


459




4-({2-[(2-fluorophenyl)amino]-1,3-benzoxazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
379.4


 


460




4-({2-[(2,6-difluorophenyl)amino]-1,3-benzoxazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
397.4


 


461




N-methyl-4-[(2-{[3-(trifluoro-methyl)phenyl]amino}-1,3-benzoxazol-5-yl)oxy]pyridine-2-carboxamide
429.4


 


462




4-({2-[(2-chlorophenyl)amino]-1,3-benzoxazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
395.8


 


463




4-({2-[(2-ethylphenyl)amino]-1,3-benzoxazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
389.4


 


464




N-methyl-4-[(2-{[4-(1-methyl-ethyl)phenyl]amino}-1,3-benzoxazol-5-yl)oxy]pyridine-2-carboxamide
403.5


 


465




4-({2-[(3-chlorophenyl)amino]-1,3-benzoxazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
395.8


 


466




N-methyl-4-{[2-({4-[(trifluoro-methyl)oxy]phenyl}amino)-1,3-benzoxazol-5-yl]oxy}pyridine-2-carboxamide
445.4


 


467




N-methyl-4-[(2-{[2-(1-methyl-ethyl)phenyl]amino}-1,3-benz-oxazol-5-yl)oxy]pyridine-2-carboxamide
403.5


 


468




4-({2-[(3,4-dichlorophenyl)amino]-1,3-benzoxazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
430.3


 


469




4-({2-[(4-ethylphenyl)amino]-1,3-benzoxazol-5-yl}oxy)-N-methyl-pyridine-2-carboxamide
389.4


 


470




4-[(2-{[4-(1-methylethyl)phenyl]-amino}-1,3-benzoxazol-5-yl)oxy]-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide
458.5


 


471




4-({2-[(2,5-dimethylphenyl)amino]-1,3-benzoxazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
389.4


 


472




4-({2-[(4-bromophenyl)(methyl)-amino]-1,3-benzoxazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
454.3


 


473




N-methyl-4-{[2-(phenylamino)-1,3-benzoxazol-5-yl]oxy}pyridine-2-carboxamide
361.4


 


474




4-[(2-{[4-(dimethylamino)phenyl]-amino}-1,3-benzoxazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
404.4


 


475




4-[(2-{[4-(4-ethylpiperazin-1-yl)-phenyl]amino}-1,3-benzoxazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
473.5


 


476




4-({2-[(4-butylphenyl)amino]-1,3-benzoxazol-5-yl}oxy)-N-methyl-pyridine-2-carboxamide
417.5


 


477




N-methyl-4-[(2-{[4-(phenyloxy)-phenyl]amino}-1,3-benzoxazol-5-yl)oxy]pyridine-2-carboxamide
453.5


 


478




4-[(2-{[4-(1-methylethyl)phenyl]-amino}-1,3-benzoxazol-5-yl)oxy]-N-(2-morpholin-4-ylethyl)pyridine-2-carboxamide
502.6


 


479




N-[1-(1-methylethyl)azetidin-3-yl]-4-[(2-{[4-(1-methylethyl)phenyl]-amino}-1,3-benzoxazol-5-yl)oxy]-pyridine-2-carboxamide
486.6


 


480




4-({2-[(4-bromo-3-fluorophenyl)-amino]-1,3-benzoxazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
458.3


 


481




4-[(2-{[4-(1-methylethyl)phenyl]-amino}-1,3-benzoxazol-5-yl)oxy]-N-[2-(2-oxoimidazolidin-1-yl)-ethyl]pyridine-2-carboxamide
501.6









EXAMPLE 482
Synthesis of [4-(2-{[4-(dimethylamino)phenyl]amino-1-methyl benzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamide
Step 1. Synthesis of 4-(2-{[4-(dimethylamino)phenylamino)-1-methyl-benzimidazol-5-yloxy)pyridinr-2-carboxylic acid
To tert-butyl4-[3-amino-4-(methylamino)phenoxy]pyridine-2-carboxylate (1 eq) in methanol was added 4-(dimethylamino)benzeneisothiocyanate (1 eq) and stir at ambient temperature for 16 h. Formation of the corresponding thiourea was followed by LC/MS. The mixture was then concentrated and to it was added tetrahydrofuran and 1-ethyl-(3-dimethylaminopropyl)carbodimidehydrochloride (2 eq) and stir at ambient temperature for 16 h. tert-butyl4-(2-{[4-dimethylamino)phenyl]amino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylate crashes out of the reaction mixture. To it in methylene chloride was added trifluroacetic acid and stirred at ambient temperature overnight. Resulting 4-(2-{[4-dimethylamino)phenyl]amino)-1-methylbenzimidazol-5-yloxy)-pyridine-2-carboxylic acid was purified by preparative chromatography. MS: MH+=403.
Step 2. Synthesis of [4-(2-{[4-(dimethylamino)phenylamino-1-methyl-benzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamide:
To 4-(2-{[4-(dimethylamino)pheylamino)-1-methylbenzimidazol-5-yloxy)-pyridine-2-carboxylic acid (1 eq) in tetrahydrofuran was added 2-pyrrolidinylethylamine (2 eq), HBTU (2 eq) and N,N-diisopropylethylamine (4 eq) and stir at ambient temperature for 16 h. The mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was concentrated and preparative chromatography yielded [4-(2-{[4-(dimethylamino)phenyl]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-methyl benzimidazol-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
To tert-butyl4-[3-amino-4-(methylamino)phenoxy]pyridine-2-carboxylate (1 eq) in methanol was added 4-bromo-3-methylbenzeneisothiocyanate (1 eq) and stir at ambient temperature for 16 h. Formation of the corresponding thiourea was followed by LC/MS. To it was then added iodomethane (1 eq) and heated to 60° C. for 2 h. Formation of tert-butyl4-(2-{[4-bromo-3-methylphenyl]amino)-1-methylbenzimidazol-5-yloxy)pyridine -2-carboxylate was followed by LC/MS. To it in methylene chloride was added trifluroacetic acid and stirred at ambient temperature overnight. Resulting 4-(2-{[4-bromo-3-methylphenylamino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylic acid was purified by preparative chromatography. MS: MH+=452
Step 2. Synthesis of [4-(2-{[4-bromo-3-methylphenyl)amino-1-methyl-benzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamide
To 4-(2-{[4-bromo-3-methylpheylamino)-1-methylbenzimidazol-5-yloxy)-pyridine-2-carboxylic acid(1 eq) in tetrahydrofuran was added 2-pyrrolidinylethylamine (2 eq), HBTU (2 eq) and N,N-diisopropylethylamine (4 eq) and stir at ambient temperature for 16 h. The mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was concentrated and preparative chromatography yielded [4-(2-{[4bromo-3-methylphenyl]amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamide. MS: MH+=549.
EXAMPLE 484
Synthesis of [4-(2-{[2-fluro-5-(trifluromethyl)phenyl)amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamide
Step 1. Synthesis of 4-{2-[(2-fluro-5-(trifluromethyl)phenyl)amino]-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylic acid
To tert-butyl4-[3-amino-4-(methylamino)phenoxy]pyridine-2-carboxylate (1 eq) in methanol was added 2-fluro-5-(trifluromethyl)benzeneisothiocyanate (1 eq) and stir at ambient temperature for 16 h. Formation of the corresponding thiourea was followed by LC/MS. To it was then added iodomethane (1 eq) and heated to 60° C. for 2 h. Formation of tert-butyl4-(2-{[2-fluro-5-(trifluromethyl)phenyl]amino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylate was followed by LC/MS. To it in methylene chloride was added trifluroacetic acid and stirred at ambient temperature overnight. Resulting 4-(2-{[2-fluro-5-(trifluromethyl)phenylamino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylic acid was purified by preparative chromatography. MS: MH+=446.
Step 2. Synthesis of [4-(2-{[2-fluro-5-(trifluromethyl)phenyl)amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamide:
To 4-(2-{[2-fluro-5-(trifluromethyl)phenylamino)-1-methylbenzimidazol-5-yl-oxy)pyridine-2-carboxylic acid (1 eq) in tetrahydrofuran was added 2-pyrrolidinylethylamine (2 eq), HBTU (2 eq) and N,N-diisopropylethylamine (4 eq) and stir at ambient temperature for 16 h. The mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was concentrated and preparative chromatography yielded [4-(2-{[2-fluro-5-(trifluromethyl)phenyl]amino-1-methylbenzimidazol-5-yloxy)-(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamide. MS: MH+=542.
EXAMPLE 485
Synthesis of [4-(2-{[4-bromo-3-flurophenyl)amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-piperidylethyl)carboxamide
Step 1. Synthesis of 4-{2-[(4-bromo-3-flurophenyl)amino]-1-methyl-benzimidazol-5-yloxy)pyridine-2-carboxylic acid
To tert-butyl4-[3-amino-4-(methylamino)phenoxy]pyridine-2-carboxylate (1 eq) in methanol was added 4-bromo-3-flurobenzeneisothiocyanate (1 eq) and stir at ambient temperature for 16 h. Formation of the corresponding thiourea was followed by LC/MS. To it was then added iodomethane (1 eq) and heated to 60° C. for 2 h. Formation of tert-butyl4-(2-{[4-bromo-3-flurophenyl]amino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylate was followed by LC/MS. To it in methylene chloride was added trifluroacetic acid and stirred at ambient temperature overnight. Resulting 4-(2-{[4-bromo-3-flurophenylamino)-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-flurophenyl)amino-1-methyl-benzimidazol-5-yloxy)(2-pyridyl)]-N-(2-piperidylethyl)carboxamide:
To 4-(2-{[4-bromo-3-fluropheylamino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylic acid (1 eq) in tetrahydrofuran was added 2-piperidylethylamine (2 eq), HBTU (2 eq) and N,N-diisopropylethylamine (4 eq) and stir at ambient temperature for 16 h. The mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was concentrated and preparative chromatography yielded [4-(2-{[4-bromo-3-flurophenyl]amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-piperidylethyl)-carboxamide. MS: MH+=567.
EXAMPLE 486
Synthesis of 4-{1-methyl-2-[(4-methylphenyl)amino-1-methylbenzimidazol-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
To tert-butyl-4-[3-amino-4-(methylamino)phenoxy]pyridine-2-carboxylate (1 eq) in methanol was added 4-methylbenzeneisothiocyanate (1 eq) and stir at ambient temperature for 16 h. Formation of the corresponding thiourea was followed by LC/MS. To it was then added iodomethane (1 eq) and heated to 60° C. for 2 h. Formation of tert-butyl-4-{1-methyl-2-[(4-methylphenyl)amino)benzimidazol-5-yloxy)pyridine-2-carboxylate was followed by LC/MS. To it in methylene chloride was added trifluroacetic acid and stirred at ambient temperature overnight. Resulting 4-{1-methyl-2-[(4-methylphenyl)amino]benzimidazol-5-yloxy)pyridine-2-carboxylic acid was purified by preparative chromatography. 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]benzimidazol-5-yloxy)pyridine-2-carboxylic acid (1 eq) in tetrahydrofuran was added 2-pyrrolidinylethylamine (2 eq), HBTU (2 eq) and N,N-diisopropylethylamine (4 eq) and stir at ambient temperature for 16 h. The mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was concentrated and preparative chromatography yielded 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-methyl benzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamide
Step 1. Synthesis of 4-{2-[(4-ethylphenyl)amino]-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylic acid
To tert-butyl4-[3-amino-4-(methylamino)phenoxy]pyridine-2-carboxylate (1 eq) in methanol was added 4-ethylbenzeneisothiocyanate (1 eq) and stir at ambient temperature for 16 h. Formation of the corresponding thiourea was followed by LC/MS. To it was then added iodomethane (1 eq) and heated to 60° C. for 2 h. Formation of tert-butyl4-(2-{[4-ethylphenyl]amino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylate was followed by LC/MS. To it in methylene chloride was added trifluroacetic acid and stirred at ambient temperature overnight. 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-ethylpheyl]amino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylic acid (1 eq) in tetrahydrofuran was added 2-pyrrolidinylethylamine (2 eq), HBTU (2 eq) and N,N-diisopropylethylamine (4 eq) and stir at ambient temperature for 16 h. The mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was concentrated and preparative chromatography yielded [4-(2-{[4-ethylphenyl]amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinyl-ethyl)carboxamide MS: MH+=484.
EXAMPLE 488
Synthesis of [4-(2-{[3-(tert-butyl)phenyl)amino-1-methylbenzimidazol-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
To tert-butyl4-[3-amino-4-(methylamino)phenoxy]pyridine-2-carboxylate (1 eq) in methanol was added 3-(tert-butyl)benzeneisothiocyanate (1 eq) and stir at ambient temperature for 16 h. Formation of the corresponding thiourea was followed by LC/MS. To it was then added iodomethane (1 eq) and heated to 60° C. for 2 h. Formation of tert-butyl4-(2-{[3-(tert-butyl)phenyl]amino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylate was followed by LC/MS. To it in methylene chloride was added trifluroacetic acid and stirred at ambient temperature overnight. 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-piperidylethylamine (2 eq), HBTU (2 eq) and N,N-diisopropylethylamine (4 eq) and stir at ambient temperature for 16 h. The mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was concentrated and preparative chromatography yielded [4-(2-{[3-(tert-butyl)phenyl]amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-piperidylethyl)-carboxamide. MS: MH+=512.
EXAMPLE 489
Synthesis of [4-(2-{[4-chloro-3-(trifluromethyl)phenyl)amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-piperidylethyl)carboxamide
Step 1. Synthesis of 4-{2-[(4-chloro-3-(trifluromethyl)phenyl)amino]-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylic acid
To tert-butyl4-[3-amino-4-(methylamino)phenoxy]pyridine-2-carboxylate (1 eq) in methanol was added 4-chloro-3-(trifluromethyl)benzeneisothiocyanate (1 eq) and stir at ambient temperature for 16 h. Formation of the corresponding thiourea was followed by LC/MS. To it was then added iodomethane (1 eq) and heated to 60° C. for 2 h. Formation of tert-butyl4-(2-{[4-chloro-3-(trifluromethyl)phenyl]amino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylate was followed by LC/MS. To it in methylene chloride was added trifluroacetic acid and stirred at ambient temperature overnight. Resulting 4-(2-{[4-chloro-3-(trifluromethyl)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-(trifluromethyl)phenyl)amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-piperidylethyl)carboxamide
To 4-(2-{[4-chlro-3-(trifluromethyl)pheylamino)-1-methylbenzimidazol-5-yloxy)-pyridine-2-carboxylic acid(1 eq) in tetrahydrofuran was added 2-piperidylethylamine (2 eq), HBTU (2 eq) and N,N-diisopropylethylamine (4 eq) and stir at ambient temperature for 16 h. The mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was concentrated and preparative chromatography yielded [4-(2-{[4-chloro-3-trifluromethylphenyl]amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-piperidylethyl)carboxamide. MS: MH+=558.
Each of the compounds 490–626 listed below in Table 6, were synthesized as indicated in the right hand column by the method described in one of the Examples 482–489.











TABLE 6









Synthesized






as in


Example
Molecular Structure
Name
MH+
Example:



















490




4-[(2-{[4-(dimethylamino)-phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[(1-ethylpyrrolidin-2-yl)-methyl]pyridine-2-carboxamide
514.6
482


 


491




4-[(2-{[4-(dimethylamino)-phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-(2-morpholin-4-ylethyl)-pyridine-2-carboxamide
516.6
482


 


492




4-[(2-{[4-(dimethylamino)-phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[3-(4-methylpiperazin-1-yl)propyl]pyridine-2-carboxamide
543.7
482


 


493




4-[(2-{[4-(dimethylamino)-phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-1,3-thiazol-2-ylpyridine-2-carboxamide
486.6
482


 


494




4-[(2-{[4-(dimethylamino)-phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[2-(1-methylpyrrolidin-2-yl)ethyl]pyridine-2-carboxamide
514.6
482


 


495




4-[(2-{[4-(dimethylamino)-phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-(2-pyrrolidin-1-ylethyl)-pyridine-2-carboxamide
500.6
482


 


496




4-[(2-{[4-(dimethylamino)-phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[3-(1H-imidazol-1-yl)-propyl]pyridine-2-carboxamide
511.6
482


 


497




4-[(2-{[4-(dimethylamino)-phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[2-(methyloxy)ethyl]-pyridine-2-carboxamide
461.5
482


 


498




4-[(2-{[4-(dimethylamino)-phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-(2-hydroxyethyl)-pyridine-2-carboxamide
447.5
482


 


499




4-[(2-{[4-(dimethylamino)-phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-(2-piperidin-1-ylethyl)-pyridine-2-carboxamide
514.6
482


 


500




4-[(2-{[4-(dimethylamino)-phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-(3-piperidin-1-ylpropyl)-pyridine-2-carboxamide
528.7
482


 


501




4-[(2-{[4-(dimethylamino)-phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-(3-pyrrolidin-1-ylpropyl)-pyridine-2-carboxamide
514.6
482


 


502




4-[(2-{[4-(dimethylamino)-phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-(2-pyridin-4-ylethyl)-pyridine-2-carboxamide
508.6
482


 


503




4-[(2-{[4-(dimethylamino)-phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-propylpyridine-2-carboxamide
445.5
482


 


504




4-[(2-{[4-(dimethylamino)-phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-(2-piperazin-1-ylethyl)-pyridine-2-carboxamide
515.6
482


 


505




4-[(2-{[4-(dimethylamino)-phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[3-(methyloxy)propyl]-pyridine-2-carboxamide
475.6
482


 


506




4-[(2-{[4-(dimethylamino)-phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-ethylpyridine-2-carboxamide
431.5
482


 


507




N-[2-(acetylamino)ethyl]-4-[(2-{[4-(dimethylamino)-phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide
488.6
482


 


508




4-[(2-{[4-(dimethylamino)-phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[2-(2-oxoimidazolidin-1-yl)ethyl]pyridine-2-carboxamide
515.6
482


 


509




4-[(2-{[4-(dimethylamino)-phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[(3R)-pyrrolidin-3-yl]-pyridine-2-carboxamide
472.6
482


 


510




4-[(2-{[4-(dimethylamino)-phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[3-(2-oxo-pyrrolidin-1-yl)propyl]pyridine-2-carboxamide
528.6
482


 


511




4-({2-[(4-bromo-3-methylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[3-(2-oxopyrrolidin-1-yl)propyl]pyridine-2-carboxamide
578.5
483


 


512




N-[2-(acetylamino)ethyl]-4-({2-[(4-bromo-3-methylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide
538.4
483


 


513




4-({2-[(4-bromo-3-methylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-ethylpyridine-2-carboxamide
481.4
483


 


514




4-({2-[(4-bromo-3-methylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-morpholin-4-ylethyl)pyridine-2-carboxamide
566.5
483


 


515




4-({2-[(4-bromo-3-methylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(methyloxy)ethyl]pyridine-2-carboxamide
511.4
483


 


516




4-({2-[(4-bromo-3-methylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[3-(4-methylpiperazin-1-yl)propyl]pyridine-2-carboxamide
593.5
483


 


517




4-({2-[(4-bromo-3-methylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide
522.4
483


 


518




4-({2-[(4-bromo-3-methylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(1-methyl-pyrrolidin-2-yl)ethyl]-pyridine-2-carboxamide
564.5
483


 


519




4-({2-[(4-bromo-3-methylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[3-(1H-imidazol-1-yl)propyl]pyridine-2-carboxamide
561.5
483


 


520




4-({2-[(4-bromo-3-methylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-1,3-thiazol-2-yl-pyridine-2-carboxamide
536.4
483


 


521




4-({2-[(4-bromo-3-methylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-propylpyridine-2-carboxamide
495.4
483


 


522




4-({2-[(4-bromo-3-methylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-pyrrolidin-1-ylethyl)pyridine-2-carboxamide
550.5
483


 


523




4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-(2-hydroxyethyl)pyridine-2-carboxamide
490.4
484


 


524




4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[3-(2-oxopyrrolidin-1-yl)propyl]pyridine-2-carboxamide
571.5
484


 


525




N-[2-(acetylamino)ethyl]-4-[(2-{[2-fluoro-5-(trifluoromethyl)-phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide
531.5
484


 


526




N-ethyl-4-[(2-{[2-fluoro-5-(trifluoromethyl)-phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide
474.4
484


 


527




4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-(2-morpholin-4-yl-ethyl)pyridine-2-carboxamide
559.5
484


 


528




4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[2-(methyloxy)ethyl]-pyridine-2-carboxamide
504.5
484


 


529




4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[3-(4-methylpiperazin-1-yl)propyl]pyridine-2-carboxamide
586.6
484


 


530




4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[2-(1-methylpyrrolidin-2-yl)ethyl]pyridine-2-carboxamide
557.6
484


 


531




4-[2-(dimethylamino)-ethyl]-4-[(2-{[2-fluoro-5-(trifluoromethyl)-phenyl]amino }-1-methyl-1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide
517.5
484


 


532




4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[3-(1H-imidazol-1-yl)-propyl]pyridine-2-carboxamide
554.5
484


 


533




4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazo1-5-yl)oxy]-N-1,3-thiazol-2-ylpyridine-2-carboxamide
529.5
484


 


534




4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-(2-pyridin-4-ylethyl)-pyridine-2-carboxamide
551.5
484


 


535




4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-propylpyridine-2-carboxamide
488.5
484


 


536




4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-(2-pyrrolidin-1-ylethyl)-pyridine-2-carboxamide
543.5
484


 


537




4-({2-[(4-bromo-3-fluorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[(1-ethylpyrrolidin-2-yl)methyl]pyridine-2-carboxamide
568.5
485


 


538




4-({2-[(4-bromo-3-fluorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-pyridine-2-carboxamide
568.5
485


 


539




4-({2-[(4-bromo-3-fluorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(methyloxy)ethyl]pyridine-2-carboxamide
515.4
485


 


540




4-({2-[(4-bromo-3-fluorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-piperidin-1-ylethyl)pyridine-2-carboxamide
568.5
485


 


541




4-({2-[(4-bromo-3-fluorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-pyridin-4-ylethyl)pyridine-2-carboxamide
562.4
485


 


542




4-({2-[(4-bromo-3-fluorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[3-(methyloxy)-propyl]pyridine-2-carboxamide
529.4
485


 


543




4-({2-[(4-bromo-3-fluorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-propylpyridine-2-carboxamide
499.4
485


 


544




4-({2-[(4-bromo-3-fluorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-ethylpyridine-2-carboxamide
485.3
485


 


545




4-({2-[(4-bromo-3-fluorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide
526.4
485


 


546




4-({2-[(4-bromo-3-fluorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[3-(2-oxopyrrolidin-1-yl)propyl]pyridine-2-carboxamide
582.4
485


 


547




N-[(1-ethylpyrrolidin-2-yl)methyl]-4-({1-methyl-2-[(4-methylphenyl)amino]-1H-benzimidazol-5-yl}-oxy)pyridine-2-carboxamide
485.6
486


 


548




4-({1-methyl-2-[(4-methylphenyl)amino]-1H-benzimidazol-5-yl}oxy)-N-(2-morpholin-4-ylethyl)pyridine-2-carboxamide
487.6
486


 


549




4-({1-methyl-2-[(4-methylphenyl)amino]-1H-benzimidazol-5-yl}oxy)-N-[3-(4-methylpiperazin-1-yl)propyl]pyridine-2-carboxamide
514.6
486


 


550




4-({1-methyl-2-[(4-methylphenyl)amino]-1H-benzimidazol-5-yl}oxy)-N-1,3-thiazol-2-ylpyridine-2-carboxamide
457.5
486


 


551




4-({1-methyl-2-[(4-methylphenyl)amino]-1H-benzimidazol-5-yl}oxy)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]pyridine-2-carboxamide
485.6
486


 


552




4-({1-methyl-2-[(4-methylphenyl)amino]-1H-benzimidazol-5-yl}oxy)-N-(2-pyrrolidin-1-ylethyl)pyridine-2-carboxamide
471.6
486


 


553




N-[2-(dimethylamino)-ethyl]-4-({1-methyl-2-[(4-methylphenyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide
445.5
486


 


554




N-[3-(1H-imidazol-1-yl)propyl]-4-({1-methyl-2-[(4-methylphenyl)amino]-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide
482.6
486


 


555




4-({1-methyl-2-[(4-methylphenyl)amino]-1H-benzimidazol-5-yl}oxy)-N-[2-(methyloxy)ethyl]-pyridine-2-carboxamide
432.5
486


 


556




N-(2-hydroxyethyl)-4-({1-methyl-2-[(4-methyl-phenyl)amino]-1H-benzimidazol-5-yl}oxy)-pyridine-2-carboxamide
418.5
486


 


557




4-({1-methyl-2-[(4-methylphenyl)amino]-1H-benzimidazol-5-yl}oxy)-N-(2-piperidin-1-ylethyl)pyridine-2-carboxamide
485.6
486


 


558




4-({1-methyl-2-[(4-methylphenyl)amino]-1H-benzimidazol-5-yl}oxy)-N-[3-(2-oxopyrrolidin-1-yl)propyl]pyridine-2-carboxamide
499.6
486


 


559




4-({1-methyl-2-[(4-methylphenyl)amino]-1H-benzimidazol-5-yl}oxy)-N-(3-piperidin-1-ylpropyl)pyridine-2-carboxamide
499.6
486


 


560




4-({1-methyl-2-[(4-methylphenyl)amino]-1H-benzimidazol-5-yl}oxy)-N-(3-pyrrolidin-1-ylpropyl)pyridine-2-carboxamide
485.6
486


 


561




4-({1-methyl-2-[(4-methylphenyl)amino]-1H-benzimidazol-5-yl}oxy)-N-(2-pyridin-4-yl-ethyl)pyridine-2-carboxamide
479.6
486


 


562




4-({1-methyl-2-[(4-methylphenyl)amino]-1H-benzimidazol-5-yl}oxy)-N-(2-piperazin-1-yl-ethyl)pyridine-2-carboxamide
486.6
486


 


563




4-({1-methyl-2-[(4-methylphenyl)amino]-1H-benzimidazol-5-yl}oxy)-N-[3-(methyloxy)-propyl]pyridine-2-carboxamide
446.5
486


 


564




4-({1-methyl-2-[(4-methylphenyl)amino]-1H-benzimidazol-5-yl}oxy)-N-propylpyridine-2-carboxamide
416.5
486


 


565




N-ethyl-4-({1-methyl-2-[(4-methylphenyl)amino]-1H-benzimidazol-5-yl}oxy)-pyridine-2-carboxamide
402.5
486


 


566




N-[2-(acetylamino)ethyl]-4-({1-methyl-2-[(4-methylphenyl)amino]-1H-benzimidazol-5-yl}oxy)-pyridine-2-carboxamide
459.5
486


 


567




4-({1-methyl-2-[(4-methylphenyl)amino]-1H-benzimidazol-5-yl}oxy)-N-[2-(2-oxoimidazolidin-1-yl)ethyl]pyridine-2-carboxamide
486.5
486


 


568




4-({1-methyl-2-[(4-methylphenyl)amino]-1H-benzimidazol-5-yl}oxy)-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide
443.5
486


 


569




4-({2-[(4-ethylphenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[(1-ethylpyrrolidin-2-yl)methyl]pyridine-2-carboxamide
499.6
487


 


570




4-({2-[(4-ethylphenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-morpholin-4-ylethyl)-pyridine-2-carboxamide
501.6
487


 


571




4-({2-[(4-ethylphenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[3-(4-methylpiperazin-1-yl)propyl]pyridine-2-carboxamide
528.7
487


 


572




4-({2-[(4-ethylphenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-1,3-thiazol-2-ylpyridine-2-carboxamide
471.6
487


 


573




4-({2-[(4-ethylphenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]pyridine-2-carboxamide
499.6
487


 


574




4-({2-[(4-ethylphenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-pyrrolidin-1-ylethyl)-pyridine-2-carboxamide
485.6
487


 


575




N-[2-(dimethylamino)-ethyl]-4-({2-[(4-ethyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}-oxy)pyridine-2-carboxamide
459.6
487


 


576




4-({2-[(4-ethylphenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[3-(1H-imidazol-1-yl)-propyl]pyridine-2-carboxamide
496.6
487


 


577




4-({2-[(4-ethylphenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(methyloxy)ethyl]-pyridine-2-carboxamide
446.5
487


 


578




4-({2-[(4-ethylphenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-hydroxyethyl)pyridine-2-carboxamide
432.5
487


 


579




4-({2-[(4-ethylphenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-piperidin-1-ylethyl)-pyridine-2-carboxamide
499.6
487


 


580




4-({2-[(4-ethylphenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(3-piperidin-1-ylpropyl)-pyridine-2-carboxamide
513.7
487


 


581




4-({2-[(4-ethylphenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(3-pyrrolidin-1-yl-propyl)pyridine-2-carboxamide
499.6
487


 


582




4-({2-[(4-ethylphenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-pyridin-4-ylethyl)-pyridine-2-carboxamide
493.6
487


 


583




4-({2-[(4-ethylphenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-piperazin-1-ylethyl)-pyridine-2-carboxamide
500.6
487


 


584




4-({2-[(4-ethylphenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[3-(methyloxy)propyl]-pyridine-2-carboxamide
460.5
487


 


585




4-({2-[(4-ethylphenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-propylpyridine-2-carboxamide
430.5
487


 


586




N-ethyl-4-({2-[(4-ethylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}-oxy)pyridine-2-carboxamide
416.5
487


 


587




N-[2-(acetylamino)ethyl]-4-({2-[(4-ethylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide
473.5
487


 


588




4-({2-[(4-ethylphenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(2-oxoimidazolidin-1-yl)ethyl]pyridine-2-carboxamide
500.6
487


 


589




4-[(2-{[3-(1,1-dimethylethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[(1-ethyl-pyrrolidin-2-yl)methyl]-pyridine-2-carboxamide
527.7
488


 


590




4-[(2-{[3-(1,1-dimethylethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-(2-morpholin-4-ylethyl)pyridine-2-carboxamide
529.7
488


 


591




4-[(2-{[3-(1,1-dimethylethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[3-(4-methylpiperazin-1-yl)propyl]pyridine-2-carboxamide
556.7
488


 


592




4-[(2-{[3-(1,1-dimethylethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-1,3-thiazol-2-yl-pyridine-2-carboxamide
499.6
488


 


593




4-[(2-{[3-(1,1-dimethylethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[2-(2-methyl-pyrrolidin-2-yl)ethyl]-pyridine-2-carboxamide
527.7
488


 


594




4-[(2-{[3-(1,1-dimethylethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-(2-pyrrolidin-1-ylethyl)pyridine-2-carboxamide
513.7
488


 


595




4-[(2-{[3-(1,1-dimethylethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[3-(1H-imidazol-1-yl)propyl]pyridine-2-carboxamide
524.6
488


 


596




4-[(2-{[3-(1,1-dimethylethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[2-(methyloxy)ethyl]pyridine-2-carboxamide
474.6
488


 


597




4-[(2-{[3-(1,1-dimethylethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-(2-hydroxyethyl)pyridine-2-carboxamide
460.5
488


 


598




4-[(2-{[3-(1,1-dimethylethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-(2-piperidin-1-yl-ethyl)pyridine-2-carboxamide
527.7
488


 


599




4-[(2-{[3-(1,1-dimethylethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[3-(2-oxopyrrolidin-1-yl)propyl]pyridine-2-carboxamide
541.7
488


 


600




4-[(2-{[3-(1,1-dimethylethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-(3-piperidin-1-yl-propyl)pyridine-2-carboxamide
541.7
488


 


601




4-[(2-{[3-(1,1-dimethylethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-(3-pyrrolidin-1-ylpropyl)pyridine-2-carboxamide
527.7
488


 


602




4-[(2-{[3-(1,1-dimethylethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-(2-pyridin-4-ylethyl)pyridine-2-carboxamide
521.6
488


 


603




4-[(2-{[3-(1,1-dimethylethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-(2-piperazin-1-ylethyl)pyridine-2-carboxamide
528.7
488


 


604




4-[(2-{[3-(1,1-dimethylethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[3-(methyloxy)-propyl]pyridine-2-carboxamide
488.6
488


 


605




4-[(2-{[3-(1,1-dimethylethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-propylpyridine-2-carboxamide
458.6
488


 


606




4-[(2-{[3-(1,1-dimethylethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-ethylpyridine-2-carboxamide
444.5
488


 


607




N-[2-(acetylamino)ethyl]-4-[(2-{[3-(1,1-di-methylethyl)phenyl]-amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide
501.6
488


 


608




4-[(2-{[3-(1,1-dimethylethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[2-(2-oxo-imidazolidin-1-yl)ethyl]-pyridine-2-carboxamide
528.6
488


 


609




4-[(2-{[3-(1,1-dimethylethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide
485.6
489


 


610




4-[(2-{[4-chloro-3-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[2-(1-methylpyrrolidin-2-yl)ethyl]pyridine-2-carboxamide
574.0
489


 


611




4-[(2-{[4-chloro-3-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[3-(1H-imidazol-1-yl)propyl]pyridine-2-carboxamide
571.0
489


 


612




4-[(2-{[4-chloro-3-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[2-(dimethylamino)-ethyl]pyridine-2-carboxamide
534.0
489


 


613




4-[(2-{[4-chloro-3-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[3-(methyloxy)propyl]-pyridine-2-carboxamide
534.9
489


 


614




4-[(2-{[4-chloro-3-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-propylpyridine-2-carboxamide
504.9
489


 


615




4-[(2-{[4-chloro-3-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-ethylpyridine-2-carboxamide
490.9
489


 


616




N-[2-(acetylamino)ethyl]-4-[(2-{[4-chloro-3-(trifluoromethyl)-phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide
547.9
489


 


617




4-[(2-{[4-chloro-3-(trifluoromethyl)phenyl]-amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-(2-morpholin-4-yl-ethyl)pyridine-2-carboxamide
576.0
489


 


618




4-[(2-{[4-chloro-3-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[3-(4-methylpiperazin-1-yl)propyl]pyridine-2-carboxamide
603.1
489


 


619




4-[(2-{[4-chloro-3-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-(2-pyrrolidin-1-ylethyl)pyridine-2-carboxamide
560.0
489


 


620




4-[(2-{[4-chloro-3-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[2-(methyloxy)ethyl]-pyridine-2-carboxamide
520.9
489


 


621




4-[(2-{[4-chloro-3-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-(2-piperidin-1-ylethyl)-pyridine-2-carboxamide
574.0
489


 


622




4-[(2-{[4-chloro-3-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-(3-piperidin-1-yl-propyl)pyridine-2-carboxamide
588.0
489


 


623




4-[(2-{[4-chloro-3-(trifluoromethyl)phenyl]-amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-(2-pyridin-4-ylethyl)-pyridine-2-carboxamide
568.0
489


 


624




4-[(2-{[4-chloro-3-(trifluoromethyl)phenyl]-amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-(2-piperazin-1-ylethyl)-pyridine-2-carboxamide
575.0
489


 


625




4-[(2-{[4-chloro-3-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[(3R)-pyrrolidin-3-yl]-pyridine-2-carboxamide
531.9
489


 


626




4-[(2-{[4-chloro-3-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[3-(2-oxopyrrolidin-1-yl)propyl]pyridine-2-carboxamide
588.0
489









EXAMPLE 627
Step 1. Synthesis of [4-(2-{[4-(chloromethyl)phenyl]carbonylamino}-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-methylcarboxamide
A solution of sodium thiocyanate (1 eq) in acetone was added slowly in to a solution of 4-(chloromethyl)benzoylchloride (1 eq) in acetone at 0° C. The mixture was then filtered in to a solution of {4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide (1 eq) in acetone. Formation of N-acylthiourea was followed by LC/MS. The mixture was concentrated and taken in tetrahydrofuran and to it was added 1-ethyl-(3-dimethylaminopropyl)carbodimidehydrochloride (2 eq) and stirred at ambient temperature for 16 h. The mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was then dried and concentrated to yield [4-(2-{[4-(chloromethyl)phenyl]carbonylamino}-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-methylcarboxamide. MS: MH+=449.
Step 2. Synthesis of N-methyl{4-[1-methyl-2-({4-[(4methylpiperazinyl)methyl]phenyl}carbonylamino)benzimidazol-5-yloxy](2-pyridyl)}carboxamide.




To a solution of [4-(2-{[4-(chloromethyl)phenyl]carbonylamino)-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-methylcarboxamide[4-(2-{[4-(chloromethyl)phenyl]carbonylamino}-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-methylcarboxamide (1 eq) in tetrahydrofuran was added methylpiperazine (4 eq) and stirred at ambient temperature for 16 h. The reaction mixture was concentrated and purified on preparative chromatography to yield N-methyl {4-[1-methyl-2-({4-[(4methylpiperazinyl)methyl]phenyl}-carbonylamino)benzimidazol-5-yloxy](2-pyridyl)]carboxamide. MS: MH+=512.
EXAMPLE 628
Step 1. Synthesis of N-methyl[4-(1-methyl-2-{2-{4-[(4-methylpiperazinyl)-methylphenyl}-benzimidazol-5-yloxy)(2-pyridyl)]carboxamide
To a solution of {4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide (1 eq) in tetrahydrofuran was added 4-(chloromethyl)-benzoylchloride (1 eq) and triethylamine (2 eq). N-acylation is completed in 0.5 h. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was concentrated and to the crude product was added methylpiperazine (4 eq) and tetrahydrofuran and stir for 16 h at ambient temperature. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was concentrated and taken in acetic acid and heated to 60° C. for 3 h. Preparative chromatography yielded N-methyl[4-(1-methyl-2-{2-{4-[(4-methylpiperazinyl)methyl-phenyl}-benzimidazol-5-yloxy)(2-pyridyl)]carboxamide. 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 h. Bis(diphenylphosphino)ferrocene Palladium(II)chloride (0.05 eq) followed by pyridine-3-boronic acid (1 eq) and sodium carbonate (3 eq) was added and the mixture was heated to 60° C. for 16 h under nitrogen. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was washed with brine and dried with sodium sulfate and concentrated. Purification on silica gel gave 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 microwaved at 150° C. for 10 mins. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was concentrated and purified on silica gel to yield 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
The mixture containing 2-nitro-4-(4-(3-pyridyl)pyrimidin-2-yloxy)phenylamine in methanol with catalytic amount of 10% Pd/C was hydrogenated until disappearance of yellow color to yield 4-(4-(3-pyridyl)pyrimidin-2-yloxy)benzene-1,2-diamine. MS: MH+=279.
Step 4. Synthesis of {4-[(4-methylpiperazinyl)methyl]phenyl}-N-[5-(4-(3-pyridyl)pyrimidin-2-yloxy)benzimidazol-2-yl]carboxamide.




A solution of sodium thiocyanate (1 eq) in acetone was added slowly in to a solution of 4-(chloromethyl)benzoylchloride (1 eq) in acetone at 0° C. The mixture was then filtered in to a solution of 4-(4-(3-pyridyl)pyrimidin-2-yloxy)benzene-1,2-diamine (1 eq) in acetone. Formation of N-acylthiourea was followed by LC/MS. The mixture was concentrated and taken in tetrahydrofuran and to it was added 1-ethyl-(3-dimethylaminopropyl)carbodimidehydrochloride (2 eq) and stirred at ambient temperature for 16 h. The mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was then dried and concentrated to yield [4-(chloromethyl)phenyl]-N-[5-(4-(3-pyridyl)pyrimidin-2-yloxy)benzimidazol-2-yl]carboxamide. It was taken in tetrahydrofuran and added methylpiperazine (4 eq) and stirred at ambient temperature for 16 h. The reaction mixture was concentrated and purified on preparative chromatography to yield {4-[(4-methylpiperazinyl)methyl]phenyl}-N-[5-(4-(3-pyridyl)pyrimidin-2-yloxy)benzimidazol-2-yl]carboxamide. MS: MH+=520.
EXAMPLE 630
Step 1. Synthesis of 4-ethyl-1-[(4-nitrophenyl)methylpiperazine
To 4-(chloromethyl)-1-nitrobenzene(1 eq) in tetrahydrofuran was added Ethylpiperazine (3 eq) and stir for 16 h at ambient temperature. Concentrating and passing through a plug of silica gave 4-ethyl-1-[(4-nitrophenyl)methylpiperazine. MS: MH+=249
Step 2. Synthesis of 4-[(4-ethylpiperazinyl)methyl]phenylamine
The mixture containing 4-ethyl-1-[(nitrophenyl)methylpiperazine in methanol with catalytic amount of 10% Pd/C was hydrogenated to yield 4-[(4-ethyl-piperazinyl)methyl]phenylamine. MS: MH+=219.
Step 3. Synthesis of 4-[(4-ethylpiperazinyl)methyl]benzeneisothiocyanate
To 4-[(4-ethylpiperazinyl)methyl]phenylamine in acetone at 0° C. was added sodium bicarbonate (2 eq) and thiophosgene (2 eq). The mixture was brought to ambient temperature and concentrated and partitioned between ethyl acetate and water. The organic layer was dried with sodium bicarbonate and sodium sulfate and concentrated to yield 4-[(4-ethylpiperazinyl)methyl]benzeneisothiocyanate. MS: MH+=261.
Step 4. Synthesis of [4-[(2-{[4-ethylpiperazinyl)methyl]phenyl]amino)-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-methylcarboxamide
To 4-[(4-ethylpiperazinyl)methyl]benzeneisothiocyanate(1 eq) in methanol was added {4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide (1 eq) and heated to 60° C. for 16 h. Preparative chromatography yielded [4-[(2-{[4-ethylpiperazinyl)methyl]phenyl]amino)-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-methylcarboxamide. MS: MH+=499.
EXAMPLE 631
Step 1. Synthesis of 4-Ethyl-1-(4-nitrophenyl)piperazine
To 4-fluro-1-nitrobenzene(1 eq) in N,N-dimethylformamide was added Ethyl piperazine (2 eq) and N,N-diisopropylethyl amine (2 eq) and heated at 80° C. for 16 h. Concentrated the resultant mixture and partitioned between ethyl acetate and water. The organic layer was then washed with brine and dried with sodium sulfate and concentrated. Passed through a plug of silica to yield 4-Ethyl-1-(4-nitrophenyl)piperazine. MS: MH+=235.
Step 2. Synthesis of 4-(4-ethylpiperazinyl)phenylamine
The mixture containing 4-ethyl-1-(4-nitrophenyl)piperazine in methanol with catalytic amount of 10% Pd/C was hydrogenated to yield 4-(4-ethylpiperazinyl)phenylamine. MS: MH+=205.
Step 3. Synthesis of 4-(4-ethylpiperazinyl)benzeneisothiocyanate
To 4-(4-ethylpiperazinyl)phenylamine in acetone at 0° C. was added sodium bicarbonate (2 eq) and thiophosgene (2 eq). The mixture was brought to ambient temperature and concentrated and partitioned between ethyl acetate and water. The organic layer was dried with sodium bicarbonate and sodium sulfate and concentrated to yield 4-(4-ethylpiperazinyl)benzeneisothiocyanate. MS: MH+=247.
Step 4. Synthesis of [4-(2-{[4-ethylpiperazinyl)phenyl]amino)-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-methylcarboxamide
To 4-(4-ethylpiperazinyl)benzeneisothiocyanate (1 eq) in methanol was added {4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide (1 eq) and heated to 60° C. for 16 h. Preparative purification yielded [4-(2-{[4-ethylpiperazinyl)phenyl]-amino)-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-methylcarboxamide. MS: MH+=485.
EXAMPLE 632
Step 1. Synthesis of 4-(2-bromoethyl)-1-nitrobenzene
To 4-(2-bromoethyl)-1-nitrobenzene(1 eq) in tetrahydrofuran was added morpholine (3 eq) and stir for 16 h at ambient temperature. Concentrating and passing through a plug of silica gave 4-[2-(4-nitrophenyl)ethylmorpholine. MS: MH+=236.
Step 2. Synthesis of 4-(2-morpholin-4-ylethyl)phenylamine
The mixture containing 4-[2-(4-nitrophenyl)ethyl]morpholine in methanol with catalytic amount of 10% Pd/C was hydrogenated to yield 4-(2-morpholin-4-ylethyl)phenylamine. MS: MH+=206.
Step 3. Synthesis of 4-(2-morpholin-4-ylethyl)benzeneisothiocyanate
To 4-(2-morpholin-4-ylethyl)phenylamine in acetone at 0° C. was added sodium bicarbonate (2 eq) and thiophosgene (2 eq). The mixture was brought to ambient temperature and concentrated and partitioned between ethyl acetate and water. The organic layer was dried with sodium bicarbonate and sodium sulfate and concentrated to yield 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}-benzimidazol-5-oxy)(2-pyridyl)]carboxamide




To 4(2-morpholin-4-ylethyl)benzeneisothiocyanate (1 eq) in methanol was added {4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide (1 eq) and stirred at ambient temperature for 16 h. The corresponding thiourea formation was followed by LC/MS. To it was the added iodomethane(1 eq) and heated to 60° C. for 3 h. Concentration followed by preparative chromatography yielded N-methyl[4-(1-methyl-2-{[4-(2-morpholin-4-ylethyl)phenyl]amino}-benzimidazol-5-oxy)(2-pyridyl)]carboxamide. MS: MH+=486.
EXAMPLE 633
Step 1. Synthesis of [(4-nitrophenyl)ethyl]benzylamine
To a solution of 1-(4-nitrophenyl)ethan-1-one (1 eq) and phenylmethylamine (1 eq) in methanol was added sodiumtriacetoxyborohydride (1.2 eq). The resulting mixture was stirred at ambient temperature for 16 h. The mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was concentrated and preparative purification yielded [(4-nitrophenyl)ethyl]benzylamine. MS: MH+=256.
Step 2. Synthesis of [(4-aminophenyl)ethyl]benzylamine
The mixture containing [(4-nitrophenyl)ethyl]benzylamine in methanol with catalytic amount of 10% Pd/C was hydrogenated until disappearance of yellow color to yield [(4-aminophenyl)ethyl]benzylamine. MS: MH+=226.
Step 3. Synthesis of 4-{[benzylamino]ethyl}benzeneisothiocyanate
To [(4-nitrophenyl)ethyl]benzylamine in acetone at 0° C. was added sodium bicarbonate (2 eq) and thiophosgene (2 eq). The mixture was brought to ambient temperature and concentrated and partitioned between ethyl acetate and water. The organic layer was dried with sodium bicarbonate and sodium sulfate and concentrated to yield 4-{[benzylamino]ethyl}benzeneisothiocyanate. 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 a solution of [4-(3,4-diaminophenoxy)(2-pyridyl))]-N-methylcarboxamide(1 eq) in methanol was added 4-{[benzylamino]ethyl}benzeneisothiocyanate (1 eq) and heated to 60° C. for 3 h. Preparative chromatography yielded N-methyl(4-{1-methyl-2-2-[(4-{[benzylamino]ethyl}phenyl)amino)benzimidazol-5-yloxy)-(2-pyridyl))-carboxamide. MS: MH+=506.
EXAMPLE 634
Step 1. Synthesis of (5-fluro-2-nitrophenyl)methylamine
A solution of 5-fluro-2-nitrophenylamine (1 eq) in methylenechloride was treated with trifluoroacetic anhydride (1 eq) and stirred for 10 minutes at 0° C. The mixture was quenched with saturated sodium bicarbonate solution. The organic layer was separated and washed with water, brine, dried and evaporated. To the solution of the trifluroacetamide (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 taken up in ethyl acetate, washed with water, brine, dried and evaporated. The crude was purified by column chromatography eluting with 1:1 hexanes and ethyl acetate to afford (5-fluro-2-nitrophenyl)methylamine. MS: MH+=170.
Step 2. Synthesis of {4-[4-amino-3-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide
The mixture containing 5-fluro-2-nitrophenylamine (1 eq), Potassium bis(trimethylsilyl)amide (2 eq) was stirred in dimethylformamide for 2 hours at room temperature. To this mixture was added (3-hydroxyphenyl)-N-methylcarboxamide (1 eq) and Potassium carbonate (1.2 eq) and stirred at 90° C. for 16 h. The reaction mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried, filtered and concentrated in vacuum to give brown solid. Purification on silica gel gave N-methyl {4-[3-(methylamino)-4-nitro-phenoxy](2-pyridyl))carboxamide. It was taken in methanol and hydrogenated with catalytic amount of 10% Pd/C to give {4-[4-amino-3-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide. MS: MH+=272.
Step 3. (4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-6-yloxy}-(2-pyridyl)-N-methylcarboxamide




A solution of the {4-[4-amino-3-(methylamino)phenoxy](2-pyridyl)}-N-methyl-carboxamide(1 eq) in methanol was treated with 4-bromophenylisothiocyanate (1 eq) and stirred at 60° C. for 2 hours. The reaction mixture was cooled down to room temperature and iodomethane (1 eq) was added and stirred overnight at 60° C. The reaction was concentrated and preparative chromatography gave (4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-6-yloxy}-(2-pyridyl)-N-methylcarboxamide. MS: MH+=452.
EXAMPLE 635
Step 1. Synthesis of ((5-aminobenzimidazol-2-yl)(4-bromophenylamine)
A solution of the 4-nitrobenzene-1,2-diamine in methanol was treated with 4-bromo phenyl isothiocyanate (1 eq) and stirred at 60° C. for 2 hours. The reaction mixture was cooled down to room temperature and iodomethane (1 eq) was added and stirred overnight at 60° C. The reaction was concentrated and purified on silica gel to yield (4-bromophenyl)(5-nitrobenzimidazol-2-yl)amine. The product was taken in methanol and hydrogenated with 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-methylcarboxamide




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 microwaved for 8 mins at 220° C. The reaction mixture was partitioned between ethyl acetate and water and the organic layer was dried with sodium sulfate and concentrated. Preparative chromatography yielded [4-({2-[(4-bromophenyl)amino]benzimidazol-5-yl}amino)(2-pyridyl)]-N-methylcarboxamide. MS: MH+=437.
EXAMPLE 636
Step 1. Synthesis of [4-{2-[(4-bromophenyl)methyl]-1-methylbenzimidazol-5-yloxy}-(2-pyridyl)]-N-methylcarboxamide




To 4-bromophenyl acetic acid (1 eq) in dichoromethane containing a drop of N,N-dimethyl formamide at 0° C. was added oxalyl chloride (1.2 eq). The resulting mixture was then brought to ambient temperature and stirred for 2 h. The mixture was concentrated and to it was added tetrahydrofuran and [4-(3,4-diaminophenoxy)(2-pyridyl)]-N-methylcarboxamide (1 eq) and triethyl amine (1 eq) and stirred for 2 h. Formation of the N-acylated product was followed by LC/MS. The mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was dried with sodium sulfate and concentrated and taken in acetic acid and heated to 60° C. for 2 h. Preparative chromatography yielded [4-{2-[(4-bromophenyl)methyl]-1-methylbenzimidazol-5-yloxy}(2-pyridyl)]-N-methylcarboxamide. MS: MH+=451.
EXAMPLE 637
Step 1. Synthesis of 4-({1-methyl-5-[2-(N-methylcarbamoyl)(4-pyridyl-oxy))]benzimidazol-2-yl}amino)benzoic acid
To {4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide (1 eq) in methanol was added 4-isothiocyanatobenzoic acid (1 eq) and stirred at 60° C. for 3 h. To it was then added iodomethane (1 eq) and heated to 60° C. for 3 h. and concentrated the solvent and purified on silica gel to yield 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-benzimidazol-5-oxy)(2-pyridyl)]carboxamide CHIR-164277
To 4-({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) and HBTU(2 eq) and stir at ambient temperature for 16 h. The mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was washed with brine and dried with sodium sulfate. Preparative chromatography gave N-methyl[4-(1-methyl-2-{[4-(2-morpholin-4-ylethyl)phenyl]-amino-benzimidazol-5-oxy)(2-pyridyl)]carboxamide. 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 4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide (1 eq) in methanol was added 3-isothiocyanatobenzoic acid (1 eq) and stirred at 60° C. for 3 h. To it was then added iodomethane (1 eq) and heated to 60° C. for 3 h and concentrated the solvent and purified on silica gel to yield 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-pyridyl)]carboxamide
To 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 stir at ambient temperature for 16 h. The mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was washed with brine and dried with sodium sulfate. Preparative chromatography gave N-methyl[3-(1-methyl-2-{[4-(2-morpholin-4-ylethyl)-phenyl]amino-benzimidazol-5-oxy)(2-pyridyl)]carboxamide. MS: MH+=529.
Each of the compounds 639–698, listed in Table 7 were synthesized as indicated in the right hand column by the method described in one of the Examples 627–638 or as otherwise indicated.











TABLE 7









Synthesis as


Example
Structure
Name
MH+
in Example:







639




4-({2-[(4-bromophenyl)-methyl]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
452.3
636


 


640




4-({2-[(4-bromophenyl)-amino]-1H-benzimidazol-6-yl}amino)-N-methylpyridine-2-carboxamide
438.3
635


 


641




4-({2-[(4-bromophenyl)-amino]-1-methyl-1H-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide
453.3
634


 


642




N-methyl-4-({1-methyl-2-[(4-{1-[(phenylmethyl)-amino]ethyl}phenyl)amino]-1H-benzimidazol-5-yl}oxy)-pyridine-2-carboxamide
507.6
633


 


643




4-({2-[(4-{[2-(dimethyl-amino)ethyl]oxy}phenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
461.5
631


 


644




N-methyl-4-{[1-methyl-2-({4-[(methylamino)-carbonyl]phenyl}amino)-1H-benzimidazol-5-yl]oxy}-pyridine-2-carboxamide
431.5
637


 


645




N-methyl-4-({1-methyl-2-[(4-{[(2-morpholin-4-yl-ethyl)amino]carbonyl}-phenyl)amino]-1H-benzimidazol-5-yl}oxy)-pyridine-2-carboxamide
530.6
637


 


646




4-{[2-({4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-amino)-1-methyl-1H-benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide
514.6
637


 


647




N-methyl-4-({1-methyl-2-[(4-{[(2-pyridin-4-ylethyl)-amino]carbonyl}phenyl)amino]-1H-benzimidazol-5-yl}-oxy)pyridine-2-carboxamide
522.6
637


 


648




4-[(2-{[4-({[2-(dimethyl-amino)ethyl]amino}-carbonyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
488.6
637


 


649




4-({2-[(4-{[3-(dimethyl-amino)pyrrolidin-1-yl]-carbonyl}phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
514.6
637


 


650




N-methyl-4-({1-methyl-2-[(4-{[(1-methylethyl)amino]-carbonyl}phenyl)amino]-1H-benzimidazol-5-yl}oxy)-pyridine-2-carboxamide
459.5
637


 


651




4-[(2-{[4-(2,6-dimethyl-morpholin-4-yl)phenyl]-amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
487.6
 120a


 


652




N-methyl-4-({1-methyl-2-[(4-piperidin-1-ylphenyl)-amino]-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide
457.5
 120a


 


653




N-methyl-4-[(1-methyl-2-{[4-({[2-(1-methylpyrrolidin-2-yl)ethyl]amino}carbonyl)-phenyl]amino}-1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide
528.6
637


 


654




N-methyl-4-({1-methyl-2-[(4-{[(2-piperidin-1-ylethyl)-amino]carbonyl}phenyl)amino]-1H-benzimidazol-5-yl}-oxy)pyridine-2-carboxamide
528.6
637


 


655




4-[(2-{[4-({[3-(1H-imidazol-1-yl)propyl]amino}carbonyl)-phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
525.6
637


 


656




4-[(2-{[4-({[(1-ethyl-pyrrolidin-2-yl)methyl]-amino}carbonyl)phenyl]-amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
528.6
637


 


657




N-methyl-4-({1-methyl-2-[(4-{[(2-pyrrolidin-1-yl-ethyl)amino]carbonyl}-phenyl)amino]-1H-benzimidazol-5-yl}oxy)-pyridine-2-carboxamide
514.6
637


 


658




N-methyl-4-({1-methyl-2-[(4-{[(pyridin-4-ylmethyl)-amino]carbonyl}phenyl)-amino]-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide
508.6
637


 


659




N-methyl-4-{[1-methyl-2-({4-[(1,3-thiazol-2-yl-amino)carbonyl]phenyl}amino)-1H-benzimidazol-5-yl]-oxy}pyridine-2-carboxamide
500.6
637


 


660




N-methyl-4-[(1-methyl-2-{[4-({[3-(4-methylpiperazin-1-yl)propyl]amino}carbonyl)-phenyl]amino}-1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide
557.7
637


 


661




4-{[2-({4-[(1-aza-bicyclo[2.2.2]oct-3-ylamino)-carbonyl]phenyl}amino)-1-methyl-1H-benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide
526.6
637


 


662




4-({2-[(4-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
526.6
637


 


663




N-methyl-4-{[1-methyl-2-({4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}amino)-1H-benzimidazol-5-yl]oxy}-pyridine-2-carboxamide
500.6
637


 


664




N-methyl-4-{[1-methyl-2-({4-[(4-methyl-1,4-diazepan-1-yl)carbonyl]phenyl}-amino)-1H-benzimidazol-5-yl]oxy}pyridine-2-carboxamide
514.6
637


 


665




N-methyl-4-[(1-methyl-2-{[4-({[3-(2-oxopyrrolidin-1-yl)propyl]amino}carbonyl)-phenyl]amino}-1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide
542.6
637


 


666




4-({2-[(4-{[(3R)-3-hydroxy-pyrrolidin-1-yl]carbonyl}-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
487.5
637


 


667




4-({2-[(4-{[(3S)-3-hydroxy-pyrrolidin-1-yl]carbonyl}-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
487.5
637


 


668




4-({2-[(4-{[4-(2-hydroxy-ethyl)piperazin-1-yl]-carbonyl}phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
530.6
637


 


669




4-{[2-({4-[(4-acetylpiperazin-1-yl)carbonyl]phenyl}-amino)-1-methyl-1H-benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide
528.6
637


 


670




4-({2-[(4-{[(3R)-3-(dimethyl-amino)pyrrolidin-1-yl]-carbonyl}phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
514.6
637


 


671




4-({2-[(4-{[(3R)-3-(dimethyl-amino)pyrrolidin-1-yl]-carbonyl}phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
514.6
637


 


672




N-methyl-4-({1-methyl-2-[(4-{[(tetrahydrofuran-2-ylmethyl)amino]carbonyl}-phenyl)amino]-1H-benzimidazol-5-yl}oxy)-pyridine-2-carboxamide
501.6
637


 


673




4-({2-[(4-{[(3R)-3-(acetyl-amino)pyrrolidin-1-yl]-carbonyl}phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
528.6
637


 


674




4-[(2-{[4-(1,4′-bipiperidin-1′-ylcarbonyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
568.7
637


 


675




N-methyl-4-[(1-methyl-2-{[4-(morpholin-4-yl-carbonyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide
487.5
637


 


676




4-({2-[(4-{[(3R,5S)-3,5-dimethylpiperazin-1-yl]-carbonyl}phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
514.6
637


 


677




N-methyl-4-[(1-methyl-2-{[4-(pyrrolidin-1-yl-carbonyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide
471.5
637


 


678




4-({2-[(4-{[(2R)-2-(amino-carbonyl)pyrrolidin-1-yl]-carbonyl}phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
514.6
637


 


679




N-methyl-4-({1-methyl-2-[(4-{[4-(1-methylethyl)-piperazin-1-yl]carbonyl}-phenyl)amino]-1H-benzimidazol-5-yl}oxy)-pyridine-2-carboxamide
528.6
637


 


680




4-[(2-{[4-({(2R,5S)-2-[(dimethylamino)methyl]-5-methylmorpholin-4-yl}-carbonyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
558.7
637


 


681




N-methyl-4-({1-methyl-2-[(4-{[(1-methylpiperidin-4-yl)amino]carbonyl}phenyl)-amino]-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide
514.6
637


 


682




4-[(2-{[4-({2-[(dimethyl-amino)methyl]morpholin-4-yl}-carbonyl)-phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
544.6
637


 


683




4-{[2-({4-[(4-ethylpiperazin-1-yl)methyl]phenyl}amino)-1-methyl-1H-benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide
500.6
630


 


684




N-methyl-4-{[1-methyl-2-({4-[methyl(1-methyl-pyrrolidin-3-yl)amino]-phenyl}amino)-1H-benzimidazol-5-yl]oxy}-pyridine-2-carboxamide
486.6
631


 


685




4-{[2-({4-[[2-(dimethyl-amino)ethyl](methyl)amino]-phenyl}amino)-1-methyl-1H-benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide
474.6
631


 


686




4-[(2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
486.6
631


 


687




4-{[2-({4-[2-(4-ethylpiperazin-1-yl)ethyl]phenyl}amino)-1-methyl-1H-benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide
514.6
632


 


688




N-methyl-4-[(1-methyl-2-{[4-(2-morpholin-4-ylethyl)-phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide
487.6
632


 


689




N-methyl-4-[(1-methyl-2-{[4-(2-piperidin-1-ylethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide
485.6
632


 


690




N-methyl-4-[(1-methyl-2-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide
471.6
628


 


691




N-methyl-4-({1-methyl-2-[({4-[(4-methylpiperazin-1-yl)methyl]phenyl}carbonyl)-amino]-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide
514.6
627


 


692




N-methyl-4-{[1-methyl-2-({[4-(morpholin-4-ylmethyl)-phenyl]carbonyl}amino)-1H-benzimidazol-5-yl]oxy}-pyridine-2-carboxamide
501.6
627


 


693




N-methyl-4-{[1-methyl-2-({[4-(piperidin-1-ylmethyl)phenyl]carbonyl}-amino)-1H-benzimidazol-5-yl]oxy}pyridine-2-carboxamide
499.6
627


 


694




N-methyl-4-({1-methyl-2-[4-(morpholin-4-ylmethyl)phenyl]-1H-benzimidazol-5-yl}oxy)-pyridine-2-carboxamide
458.5
628


 


695




N-methyl-4-({1-methyl-2-[4-(piperidin-1-ylmethyl)phenyl]-1H-benzimidazol-5-yl}oxy)-pyridine-2-carboxamide
456.6
628


 


696




4-({2-[4-({[2-(dimethyl-amino)ethyl]amino}methyl)-phenyl]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
459.6
628


 


697




4-{[2-(4-{[[2-(dimethyl-amino)ethyl](methyl)amino]-methyl}phenyl)-1-methyl-1H-benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide
473.6
628


 


698




4-[(4-methylpiperazin-1-yl)methyl]-N-{5-[(4-pyridin-3-ylpyrimidin-2-yl)oxy]-1H-benzimidazol-2-yl}benzamide
521.6
629









EXAMPLE 699
Step 1. Synthesis of {4-[2-methoxy-4-(methylamino)-5-nitrophenoxy](2-pyridyl)}-N-methylcarboxamide
To a stirred solution of concentrated nitric acid (22 eq) was added 2 h-benzo[d]1,3-dioxolane(1 eq) at 0–10° C. for 0.5 h and stirred for another 0.5 h. To this reaction mixture was then added concentrated sulfuric acid (0.06 eq) drop-wise at 0–10° C. for 0.5 h and stirred at 20° C. for 0.5 h. It was then poured on to crushed ice, and the separated solid was filtered washed with water and dried to give 5,6-dinitro-2 h-benzol[d]1,3-dioxalane. MS:MH+ 212
Step 2. Synthesis of methyl(6-nitro(2 h-benzo[3,4-d]1,3-dioxalan-5-yl)amine
To a stirred solution of methyl amine in ether and ethanol (1.5:1) was added 5,6-dinitro-2 h-benzol[d]1,3-dioxalane and stirred at ambient temperature for 24 h. 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-dioxaln-5-yl))amine. MS: MH+ 196
Step 3. Synthesis of 2-methoxy-4-(methylamino)-5-nitrophenol
To a stirred solution of methanol was added sodium metal (4.8 eq) slowly at ambient temperature followed by methyl(6-nitro(2 h-benzo[3,4-d]1,3-dioxalan-5-yl))amine (1 eq) and stirred for 2 h. The mixture was then refluxed for 0.5 h and diluted with water. After cooling it to ambient temperature the separated solid was filtered and dried to give 2-methoxy-4-(methylamino)-5-nitrophenol as a red solid. MS:MH+ 198
Step 4. Synthesis of {4-[2-methoxy-4-(methylamino)-5-nitrophenoxy](2-pyridyl)}-N-methylcarboxamide
To a stirred solution of 2-methoxy-4-(methylamino)-5-nitrophenol(1 eq) in N,N-dimethylacetamide was added potassium-t-butoxide (1.2 eq) and continued stirring at ambient temperature until it solidified. To it was then added (3-chlorophenyl)-N-methylcarboxamide (1 eq) and anhydrous potassium carbonate (1 eq) and the resulting mixture was heated to 50° C. whereby the solid liquified. It was then heated to 110° C. for 12 h. After cooling to ambient temperature the solvent was distilled off and the resulting solid was extracted using ethyl acetate in a soxhlet apparatus for 48 h. the organic layer was cooled to 0° C., when the product crystallized from the ethyl acetate to give {4-[2-methoxy-4-(methylamino)-5-nitrophenoxy](2-pyridyl)}-N-methylcarboxamide. MS:MH+ 332
Step 5. Synthesis of 4-{2-[(4-chlrophenyl)amino]-6-methoxy-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylic acid
To tert-butyl4-[3-amino-6-methoxy-4-(methylamino)phenoxy]pyridine-2-carboxylate(1 eq) in methanol was added 4-chlorobenzeneisothiocyanate (1 eq) and stir at ambient temperature for 16 h. Formation of the corresponding thiourea was followed by LC/MS. To it was then added iodomethane (1 eq) and heated to 60° C. for 2 h. Formation of tert-butyl4-(2-{[4-chlorophenyl]amino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylate was followed by LC/MS. To it in methylene chloride was added trifluroacetic acid and stirred at ambient temperature overnight. 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 4-(2-{[4-chloropheylamino)-6-methoxy-1-methylbenzimidazol-5-yloxy)-pyridine-2-carboxylic acid(1 eq) in tetrahydrofuran was added 2-pyrrolidinylethylamine (2 eq), HBTU (2 eq) and N,N-diisopropylethylamine (4 eq) and stir at ambient temperature for 16 h. The mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was concentrated and preparative chromatography yielded [4-(2-{[4-chlorophenyl]amino}-6-methoxy-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamide. 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 tert-butyl4-[3-amino-6-methoxy-4-(methylamino)phenoxy]pyridine-2-carboxylate(1 eq) in methanol was added 4-bromo-3-methylbenzeneisothiocyanate (1 eq) and stir at ambient temperature for 16 h. Formation of the corresponding thiourea was followed by LC/MS. To it was then added iodomethane (1 eq) and heated to 60° C. for 2 h. Formation of tert-butyl4-(2-{[4-bromo-3-methylphenyl]amino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylate was followed by LC/MS. To it in methylene chloride was added trifluroacetic acid and stirred at ambient temperature overnight. 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 4-(2-{[4-bromo-3-methylpheylamino)-6-methoxy-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylic acid(1 eq) in tetrahydrofuran was added 2-pyrrolidinylethylamine (2 eq), HBTU (2 eq) and N,N-diisopropylethylamine (4 eq) and stir at ambient temperature for 16 h. The mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was concentrated and preparative chromatography yielded [4-(2-{(4-bromo-3-methylphenyl)amino}-6-methoxy-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamide. MS: MH+=579.
EXAMPLE 701
Step 1. Synthesis of 4-{3-[3-(3-Isopropyl-phenyl)-thioureaido]-4-methylamino-phenoxy}-pyridine-2-carboxylic acid
To tert-butyl4-[3-amino-4-(methylamino)phenoxy]pyridine-2-carboxylate (1 eq) in methanol was added 3-isopropylbenzeneisothiocyanate (1 eq) and stir at ambient temperature for 16 h. Formation of the corresponding thiourea was followed by LC/MS. To it was then added iodomethane (1 eq) and heated to 60° C. for 2 h. Formation of 4-{3-[3-(3-Isopropyl-phenyl)-thioureaido]-4-methylamino-phenoxy}-pyridine-2-carboxylate was followed by LC/MS. To it in methylene chloride was added trifluoroacetic acid and stirred at ambient temperature overnight. 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-benzoimidazol-5-yloxy]-pyridine-2-carboxylicacid) 2-pyrrolidin-1-yl-ethyl)-amide
To 4-{3-[3-(3-Isopropyl-phenyl)-thioureaido]-4-methylamino-phenoxy}-pyridine-2-carboxylic acid (1 eq) in tetrahydrofuran was added 2-pyrrolidinylethylamine (2 eq), EDCI (2 eq), HOAT (1.2 eq) and N,N-diisopropylethylamine (4 eq) and stir at ambient temperature for 16 h. The mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was concentrated and preparative chromatography yielded 4-[2-(3-Isopropyl-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylicacid) 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(diphenylphosphino)ferrocene Palladium(II)chloride (0.05 eq) followed by 3-chloro-4-pyridine boronic acid hydrate (1 eq) and sodium carbonate (3 eq) was added and the mixture was heated to 90° C. for 16 h under nitrogen. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was washed with brine and dried with sodium sulfate and concentrated. Purification on silica gel gave 3-chloro-4-(2-methyl-5-nitrophenyl)pyridine. MS: MH+=248.
Note: The same procedure was used for Suzuki reaction between the halopyridines and the nitrophenylboronic acids.
Boronic acids were synthesized using the following procedure if commercially unavailable.
Step 1a. Synthesis of 2-fluropyridine boronic acid
A flame-dried flask was charged with toluene and tetrahydrofuran (4:1) and then with 4-bromo-2-fluropyridine(1 eq) and triisopropylborate (1.2 eq) and the flask was cooled to −70° C. Then n-butyllithium (1.2 eq) was added dropwise over 0.5 h and the mixture was stirred for 0.5 h at −70° C. The reaction mixture was then brought to −20° C. and 2N hydrochloric acid was added to it. Formation of 2-fluropyridine boronic acid was seen by LC/MS on warming the mixture to ambient temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was dried with sodium sulfate and concentrated to yield 2-fluropyridine boronic 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 Fe dust (5 eq) and the resulting mixture was stirred at ambient temperature for 6 h. To it was then added saturated sodium carbonate to bring it to neutral pH and extracted with ethyl acetate. The organic layer was washed with brine and dried with sodium sulfate and concentrated and passed through a plug of silica to yield 3-(3-chloro(4-pyridyl))-4-methylphenylamine. MS: MH+=218.
Step 3. Synthesis of 3-(3-chlro(4-pyridyl))-4-methylbenzeneisothiocyanate
To 3-(3-chloro(4-pyridyl))-4-methylphenylamine in acetone at 0° C. was added sodium bicarbonate (2 eq) and thiophosgene (2 eq). The mixture was brought to ambient temperature and concentrated and partitioned between ethyl acetate and water. The organic layer was dried with sodium bicarbonate and sodium sulfate and concentrated to yield 3-(3-chloro(4-pyridyl))-4-methylbenzeneisothiocyanate. MS: MH+=260.
Step 4. Synthesis of {4-(2-{[3-(3-chloro(4-pyridyl))-4-methylphenyl]amino)-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-methylcarboxamide
Step 4. Synthesis of [4-(2-{[3-(3-chloro(4-pyridyl))-4-methylphenyl]amino}-1-methylbenzimidazol-5-yloxy](2-pyridyl)]-N-methylcarboxamide




To 3-(3-chloro(4-pyridyl))-4-methylbenzeneisothiocyanate(1 eq) in methanol was added {4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide (1 eq) and the resulting mixture was stirred at ambient temperature for 16 h. LC/MS shows formation of the corresponding thiourea. To it in methanol was then added anhydrous ferric chloride (1.5 eq) and stirred for 3 h. The reaction mixture was then concentrated to half its volume and brought to neutral pH with 1N sodium hydroxide. It was then extracted with ethyl acetate and the organic layer was washed with brine and dried with sodium sulfate. The crude was then titurated with hot methanol to yield [4-[2-{[3-(3-chloro(4-pyridyl))-4-methylphenyl]amino}-1-methylbenzimidazol-5-yloxy](2-pyridyl)]-N-methylcarboxamide. MS: MH+=498.
EXAMPLE 703
1. Synthesis of {4-[2-methoxy-4-(methylamino)-5-nitrophenoxy](2-pyridyl)}-N-methylcarboxamide
To a stirred solution of concentrated nitric acid (22 eq) was added 2 h-benzo[d]1,3-dioxolane(1 eq) at 0–10° C. for 0.5 h and stirred for another 0.5 h. To this reaction mixture was then added concentrated sulfuric acid (0.06 eq) drop-wise at 0–10° C. for 0.5 h and stirred at 20° C. for 0.5 h. It was then poured on to crushed ice, and the separated solid was filtered washed with water and dried to give 5,6-dinitro-2 h-benzol[d]1,3-dioxalane. MS:MH+ 212
Step 2. Synthesis of methyl(6-nitro(2 h-benzo[3,4-d]1,3-dioxalan-5-yl)amine
To a stirred solution of methyl amine in ether and ethanol (1.5:1) was added 5,6-dinitro-2 h-benzol[d]1,3-dioxalane and stirred at ambient temperature for 24 h. 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-dioxaln-5-yl))amine. MS: MH+ 196
Step 3. Synthesis of 2-methoxy-4-(methylamino)-5-nitrophenol
To a stirred solution of methanol was added sodium metal (4.8 eq) slowly at ambient temperature followed by methyl(6-nitro(2 h-benzo[3,4-d]1,3-dioxalan-5-yl))amine (1 eq) and stirred for 2 h. The mixture was then refluxed for 0.5 h and diluted with water. After cooling it to ambient temperature the separated solid was filtered and dried to give 2-methoxy-4-(methylamino)-5-nitrophenol as a red solid. MS:MH+ 198
Step 4. Synthesis of {4-[2-methoxy-4-(methylamino)-5-nitrophenoxy](2-pyridyl)}-N-methylcarboxamide
To a stirred solution of 2-methoxy-4-(methylamino)-5-nitrophenol(1 eq) in N,N-dimethylacetamide was added potassium-t-butoxide (1.2 eq) and continued stirring at ambient temperature until it solidified. To it was then added (3-chlorophenyl)-N-methylcarboxamide (1 eq) and anhydrous potassium carbonate (1 eq) and the resulting mixture was heated to 50° C. whereby the solid liquified. It was then heated to 110° C. for 12 h. After cooling to ambient temperature the solvent was distilled off and the resulting solid was extracted using ethyl acetate in a soxhlet apparatus for 48 h. The organic layer was cooled to 0° C., when the product crystallized from the ethyl acetate to give {4-[2-methoxy-4-(methylamino)-5-nitrophenoxy](2-pyridyl)}-N-methylcarboxamide. MS:MH+332
Step 5. Synthesis of {4-[3-amino-6-methoxy-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide
A solution of {4-[2-methoxy-4-(methylamino)-5-nitrophenoxy](2-pyridyl)}-N-methylcarboxamide. In methanol was hydrogenated with 10% Pd/C. The catalyst was filtered off and the solvent was concentrated to yield {4-[3-amino-6-methoxy-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide. MS :MH+: 302.
Step 6. Synthesis of (4-{2-[(4-bromo-3-methylphenyl)amino]-6-methoxy-1-methylbenzimidazol-5-yloxy}-(2-pyridyl))-N-methylcarboxamide




To a solution of {4-[3-amino-6-methoxy-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide (1 eq) in methanol was added 4-bromo-3-methylbenzeneisothiocyanate (1 eq) and stirred at 60° C. for 2 h. Formation of thiourea was followed by LC/MS. To it was added iodomethane (1 eq) and heated to 60° C. for 3 h. The mixture was concentrated and purified on preparative chromatography to yield (4-{2-[(4-bromo-3-methylphenyl)amino]-6-methoxy-1-methylbenzimidazol-5-yloxy}-(2-pyridyl))-N-methylcarboxamide. MS:MH+ 496.
EXAMPLE 704
Synthesis of (5-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy)-(3-pyridyl))-N-methylcarboxamide




Step 1. Synthesis of methyl-5-(4-nitrophenoxy)pyridine-3-carboxylate
The mixture containing methyl-5-hydroxypyridine-3-carboxylate (1 eq), Potassium bis(trimethylsilyl)amide (1.2 eq) was stirred in N,N-dimethylformamide for 2 hours at room temperature. To this mixture was added 1-fluro-4-nitrobenzene (1.1 eq) and Potassium carbonate (1.2 eq) and stirred at 80° C. for 16 h. The reaction mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried, filtered and concentrated in vacuum to give brown solid. Purification on silica gel methyl-5-(4-nitrophenoxy)pyridine-3-carboxylate. MS: MH+=274.
Step 2. Synthesis of methyl5-[4-aminophenoxy]pyridine-3-carboxylate
The mixture containing methyl-5-(4-nitrophenoxy)pyridine-3-carboxylate in methanol with catalytic amount of 10% Pd/C was hydrogenated to yield methyl5-[4-aminophenoxy]pyridine-3-carboxylate. MS: MH+=244.
Step 3. Synthesis of methyl-5-[4-(2,2,2-trifluroacetamino)phenoxy]pyridine-3-carboxylate
A solution of methyl-5-[4-aminophenoxy]pyridine-3-carboxylate (1 eq) in methylene chloride was treated with trifluoroacetic anhydride (1 eq) and stirred for 10 minutes at 0° C. The mixture was quenched with saturated sodium bicarbonate solution. The organic layer was separated and washed with water, brine, dried and evaporated to yield methyl-5-[4-(2,2,2-trifluroacetamino)phenoxy]pyridine-3-carboxylate. MS: MH+=340.
Step 4. Synthesis of methyl5-[3-nitro-4-(2,2,2-trifluroacetylamino)phenoxy]-pyridine-3-carboxylate
To a solution of methyl-5-[4-(2,2,2-trifluroacetamino)phenoxy]pyridine-3-carboxylate in acetic acid and acetic anhydride(1:1) at 0° C. was added nitric acid followed by sulfuric acid. Followed the reaction by LC and once complete it was partitioned between ethyl acetate. The organic layer was washed with brine and dried with sodium sulfate and concentrated to yield methyl5-[3-nitro-4-(2,2,2-trifluroacetylamino)phenoxy]-pyridine-3-carboxylate. MS: MH+=385.
Step 5. Synthesis of methyl4-[4-(methylamino)-3-nitrophenoxy]pyridine-3-carboxylate
To the solution of the methyl5-[3-nitro-4-(2,2,2-trifluroacetylamino)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 overnight at room temperature and evaporated. The mixture was taken up in ethyl acetate, washed with water, brine, dried and evaporated. The crude was purified by column chromatography to afford methyl4-[4-(methylamino)-3-nitrophenoxy]pyridine-3-carboxylate. MS: MH+=303.
Step 6. Synthesis of methyl5-[3-amino-4-(methylamino)phenoxy]pyridine-3-carboxylate
The mixture containing methyl4-[4-(amethylamino)-3-nitrophenoxy]pyridine-3-carboxylate was hydrogenated with 10% Pd/C to yield methyl5-[3-amino-4-(methylamino)phenoxy]pyridine-3-carboxylate. MS: MH+=273.
Step 7. Synthesis of methyl5-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}pyridine-3-carboxylate
A solution of the methyl5-[3-amino-4-(methylamino)phenoxy]pyridine-3-carboxylate (1 eq) in methanol (8 ml) was treated with 4-bromophenylisothiocyanate (1 eq) and stirred at 60° C.–65° C. for 2 hours. The reaction mixture was cooled down to room temperature and methyl iodide (1 eq) was added and stirred overnight at 60° C. The reaction was cooled down to room temperature, evaporated, taken up in ethyl acetate and washed with water and brine, dried, evaporated under reduced pressure. Column chromatography yielded methyl5-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}pyridine-3-carboxylate. MS: MH+=452
Step 8. Synthesis of (5-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy)-(3-pyridyl))-N-methylcarboxamide
To a solution of methyl5-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}pyridine-3-carboxylate in added methylamine and the resulting mixture was stirred at ambient temperature for 16 h. It was then concentrated and purified by preparative chromatography to yield (5-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy)-(3-pyridyl))-N-methylcarboxamide. MS: MH+=452.
Each of the compounds 705–746, listed in Table 8 were synthesized as indicated in the right hand column by the method described in one of the Examples 699 or 700.











TABLE 8





Ex-



Synthe-


am-



sized as in


ple
Molecular Structure
Name
MH+
Example:







705




4-{[2-[(4-bromo-3-methyl-phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N-[(1-ethyl-pyrrolidin-2-yl)methyl]-pyridine-2-carboxamide
594.5
700


 


706




4-{[2-[(4-bromo-3-methyl-phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N-(2-morpholin-4-ylethyl)pyridine-2-carboxamide
596.5
700


 


707




4-{[2-[(4-bromo-3-methyl-phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N-[3-(4-methyl-piperazin-1-yl)propyl]pyridine-carboxamide
623.6
700


 


708




4-{[2-[(4-bromo-3-methyl-phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N-1,3-thiazol-2-ylpyridine-2-carboxamide
566.5
700


 


709




4-{[2-[(4-bromo-3-methyl-phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N-[2-(1-methyl-pyrrolidin-2-yl)ethyl]pyridine-2-carboxamide
594.5
700


 


710




4-{[2-[(4-bromo-3-methyl-phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N-(2-pyrrolidin-1-ylethyl)pyridine-2-carboxamide
580.5
700


 


711




4-{[2-[(4-bromo-3-methyl-phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N-[3-(1H-imidazol-1-yl)propyl]pyridine-2-carboxamide
591.5
700


 


712




4-{[2-[(4-bromo-3-methyl-phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N-[2-(methyloxy)-ethyl]pyridine-2-carboxamide
541.4
700


 


713




4-{[2-[(4-bromo-3-methyl-phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N-(2-hydroxyethyl)-pyridine-2-carboxamide
527.4
700


 


714




4-{[2-[(4-bromo-3-methy-phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N-(2-piperidin-1-ylethyl)pyridine-2-carboxamide
594.5
700


 


715




4-{[2-[(4-bromo-3-methyl-phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N-(3-piperidin-1-ylpropyl)pyridine-2-carboxamide
608.5
700


 


716




4-{[2-[(4-bromo-3-methyl-phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N-[3-(4-methyl-piperazin-1-yl)propyl]pyridine-2-carboxamide
623.6
700


 


717




4-{[2-[(4-bromo-3-methyl-phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N-(2-pyridin-4-yl-ethyl)pyridine-2-carboxamide
588.5
700


 


718




4-{[2-[(4-bromo-3-methyl-phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N-(2-piperazin-1-yl-ethyl)pyridine-2-carboxamide
595.5
700


 


719




4-{[2-[(4-bromo-3-methyl-phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N-[3-(methyloxy)-propyl]pyridine-2-carboxamide
555.4
700


 


720




4-{[2-[(4-bromo-3-methyl-phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N-propylpyridine-2-carboxamide
525.4
700


 


721




4-{[2-[(4-bromo-3-methyl-phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N-ethylpyridine-2-carboxamide
511.4
700


 


722




N-[2-(acetylamino)ethyl]-4-{[2-[(4-bromo-3-methyl-phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}pyridine-2-carboxamide
568.4
700


 


723




4-{[2-[(4-bromo-3-methyl-phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N-[2-(2-oxo-imidazolidin-1-yl)ethyl]-pyridine-2-carboxamide
595.5
700


 


724




4-{[2-[(4-bromo-3-methyl-phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N-[3-(2-oxo-pyrrolidin-1-yl)propyl]-pyridine-2-carboxamide
608.5
700


 


725




4-{[2-[(4-chlorophenyl)-amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]-oxy}-N-[(1-ethylpyrrolidin-2-yl)methyl]pyridine-2-carboxamide
536.0
699


 


726




4-{[2-[(4-chlorophenyl)-amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]-oxy}-N-(2-morpholin-4-yl-ethyl)pyridine-2-carboxamide
538.0
699


 


727




4-{[2-[(4-chlorophenyl)-amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]-oxy}-N-[3-(4-methylpiperazin-1-yl)propyl]pyridine-2-carboxamide
565.1
699


 


728




4-{[2-[(4-chlorophenyl)-amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]-oxy}-N-1,3-thiazol-2-yl-pyridine-2-carboxamide
508.0
699


 


729




4-{[2-[(4-chlorophenyl)-amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]oxy}-N-[2-(1-methyl-pyrrolidin-2-yl)ethyl]pyridine-2-carboxamide
536.0
699


 


730




4-{[2-[(4-chlorophenyl)-amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]-oxy}-N-(2-pyrrolidin-1-yl-ethyl)pyridine-2-carboxamide
522.0
699


 


731




4-{[2-[(4-chlorophenyl)-amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]-oxy}-N-[2-(dimethylamino)-ethyl]pyridine-2-carboxamide
496.0
699


 


732




4-{[2-[(4-chlorophenyl)-amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]-oxy}-N-[3-(1H-imidazol-1-yl)-propyl]pyridine-2-carboxamide
533.0
699


 


733




4-{[2-[(4-chlorophenyl)-amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]-oxy}-N-[2-(methyloxy)ethyl]-pyridine-2-carboxamide
482.9
699


 


734




4-{[2-[(4-chlorophenyl)-amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]-oxy}-N-(2-hydroxyethyl)-pyridine-2-carboxamide
468.9
699


 


735




4-{[2-[(4-chlorophenyl)-amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]-oxy}-N-(2-piperidin-1-ylethyl)pyridine-2-carboxamide
536.0
699


 


736




4-{[2-[(4-chlorophenyl)-amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]-oxy}-N-(3-piperidin-1-yl-propyl)pyridine-2-carboxamide
550.1
699


 


737




4-{[2-[(4-chlorophenyl)-amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]-oxy}-N-(3-pyrrolidin-1-yl-propyl)pyridine-2-carboxamide
536.0
699


 


738




4-{[2-[(4-chlorophenyl)-amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]-oxy}-N-(2-pyridin-4-ylethyl)-pyridine-2-carboxamide
530.0
699


 


739




4-{[2-[(4-chlorophenyl)]-1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N-(2-piperazin-1-ylethyl)pyridine-2-carboxamide
537.0
699


 


740




4-{[2-[(4-chlorophenyl)-amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]oxy}-N-[3-(methyloxy)-propyl]pyridine-2-carboxamide
497.0
699


 


741




4-{[2-[(4-chlorophenyl)-amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]-oxy}-N-propylpyridine-2-carboxamide
466.9
699


 


742




4-{[2-[(4-chlorophenyl)-amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]-oxy}-N-ethylpyridine-2-carboxamide
452.9
699


 


743




N-[2-(acetylamino)ethyl]-4-{[2-[(4-chlorophenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-pyridine-2-carboxamide
510.0
699


 


744




4-{[2-[(4-chlorophenyl)-amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]oxy}-N-[2-(2-oxo-imidazolidin-1-yl)ethyl]-pyridine-2-carboxamide
537.0
699


 


745




4-{[2-[(4-chlorophenyl)-amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]-oxy}-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide
494.0
699


 


746




4-{[2-[(4-chlorophenyl)-amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]-oxy}-N-[3-(2-oxopyrrolidin-1-yl)propyl]pyridine-2-carboxamide
550.0
699









Each of the compounds 747–782, listed in the below table were synthesized as indicated in the right hand column by the method described in one of the Examples 702 or 703 unless indicated otherwise.











TABLE 9





Ex-



Synthe-


am-



sized as in


ple
Structure
Name
MH+
Example:



















747




4-{[2-[(4-chlorophenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide
438.9
703


 


748




4-{[2-[(3-chlorophenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide
438.9
703


 


749




4-{[2-[(4-bromo-3-methyl-phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide
497.4
703


 


750




N-methyl-4-({1-methyl-6-(methyloxy)-2-[(4-methyl-phenyl)amino]-1H-benzimidazol-5-yl}oxy)-pyridine-2-carboxamide
418.5
703


 


751




4-{[2-(2,3-dihydro-1H-inden-5-ylamino)-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2-carboxamide
444.5
703


 


752




N-methyl-4-{[1-methyl-6-(methyloxy)-2-(pyridin-3-yl-amino)-1H-benzimidazol-5-yl]-oxy}pyridine-2-carboxamide
405.4
703


 


753




4-{[2-{[4-(1,1-dimethylethyl)-phenyl]amino}-1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide
460.5
703


 


754




4-{[2-[(2,5-dichlorophenyl)-amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2-carboxamide
473.3
703


 


755




4-{[2-(1,3-benzodioxol-5-ylamino)-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2-carboxamide
448.4
703


 


756




4-{[2-[(3-chloro-2-methyl-phenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide
452.9
703


 


757




4-{[2-[(4-ethylphenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide
432.5
703


 


758




4-{[2-[(4-bromophenyl)amino]-1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide
483.3
703


 


759




N-methyl-4-{[1-methyl-6-(methyloxy)-2-({4-[(trifluoro-methyl)oxy]phenyl}amino)-1H-benzimidazol-5-yl]oxy}-pyridine-2-carboxamide
488.4
703


 


760




4-{[2-[(2,4-dimethylphenyl)-amino]-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]-oxy}-N-methylpyridine-2-carboxamide
432.5
703


 


761




N-methyl-4-(3-{[1-methyl-5-({2-[(methylamino)carbonyl]-pyridin-4-yl}oxy)-1H-benzimidazol-2-yl]amino}-phenyl)pyridine-2-carboxamide
508.6
703


 


762




4-[(2-{[3-(3-chloropyridin-4-yl)-4-methylphenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
500.0
702


 


763




4-[(2-{[3-(2-fluoropyridin-4-yl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
469.5
702


 


764




N-methyl-4-[(1-methyl-2-{[3-(1-methylpiperidin-4-yl)-phenyl]amino}-1H-benz-imidazol-5-yl)oxy]pyridine-2-carboxamide
471.6
702


 


765




4-[(2-{[3-(2-fluoropyridin-4-yl)-4-methylphenyl]amino}-1-methyl-1H-benzimidazol-5-yl)-oxy]-N-methylpyridine-2-carboxamide
483.5
702


 


766




N-methyl-4-{[1-methyl-2-({3-[3-(trifluoromethyl)pyridin-4-yl]phenyl}amino)-1H-benzimidazol-5-yl]oxy}-pyridine-2-carboxamide
519.5
702


 


767




N-methyl-4-[(1-methyl-2-{[3-(2-methylpyridin-4-yl)phenyl]-amino}-1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide
465.5
702


 


768




N-methyl-4-[(1-methyl-2-{[3-(4-methylpiperazin-1-yl)phenyl]amino}-1H-benz-imidazol-5-yl)oxy]pyridine-2-carboxamide
472.6
702


 


769




4-[(2-{[4-chloro-3-(4-methyl-piperazin-1-yl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
507.0
702


 


770




4-[(2-{[3-(3-chloropyridin-4-yl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
485.9
702


 


771




4-[(2-{[3-(dimethylamino)-phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
417.5
702


 


772




4-{[2-({3-(3-chloropyridin-4-yl)-4-[(trifluoromethyl)oxy]-phenyl}amino)-1-methyl-1H-benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide
569.9
702


 


773




N-methyl-4-[(1-methyl-6-(methyloxy)-2-{[3-(2-methyl-pyridin-4-yl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide
495.6
702


 


774




N-methyl-4-{[1-methyl-6-(methyloxy)-2-({3-[3-(trifluoro-methyl)pyridin-4-yl]phenyl}-amino)-1H-benzimidazol-5-yl]-oxy}pyridine-2-carboxamide
549.5
702


 


775




4-{[2-{[3-(3-chloropyridin-4-yl)-4-methylphenyl]amino}-1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide
530.0
702


 


776




4-{[2-{[3-(2-fluoropyridin-4-yl)phenyl]amino}-1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide
499.5
702


 


777




4-[(2-{[3-(dimethylamino)-4-methylphenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
431.5
1


 


778




N-methyl-4-({1-methyl-2-[(3-pyrimidin-5-ylphenyl)amino]-1H-benzimidazol-5-yl}oxy)-pyridine-2-carboxamide
452.5
702


 


779




4-{[2-({3-(2-fluoropyridin-4-yl)-4-[(trifluoromethyl)oxy]-phenyl}amino)-1-methyl-1H-benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide
553.5
702


 


780




4-{[2-({3-(3-fluoropyridin-4-yl)-4-[(trifluoromethyl)oxy]-phenyl}amino)-1-methyl-1H-benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide
553.5
702


 


781




N-methyl-4-({1-methyl-2-[(3-thien-2-ylphenyl)amino]-1H-benzimidazol-5-yl}oxy)-pyridine-2-carboxamide
456.5
702


 


782




N-methyl-4-({1-methyl-2-[(3-quinolin-3-ylphenyl)amino]-1H-benzimidazol-5-yl}oxy)-pyridine-2-carboxamide
501.6
702









EXAMPLE 783
Synthesis of [4-(2-{[6-(dimethylamino)(3-pyridyl)]amino}-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-methylcarboxamide




Step 1. Synthesis of 2-(Dimethylamino-5-nitropyridine:
2-Chloro-5-nitropyridine (1.0 eq) and dimethylamine (2 M in EtOH, 4.6 eq) in NMP were heated for 2 h at 100° C. The solution was then poured slowly into H2O. The filtrate that formed was filtered and dried to give 2-(dimethylamino)-5-nitropyridine.
Step 2. Synthesis of 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 with hydrogen three times. The reaction mixture was left under an atmosphere of hydrogen overnight. Nitrogen was flushed through the reaction and then the reaction was filtered through a celite pad. The celite pad was washed with excess ethanol before the solvent was removed by evaporation under reduced pressure to afford 2-(dimethylamino)-5-aminopyridine.




Step 3. Synthesis of 2-(Dimethylamino)-5-isothiocynanate pyridine:
2-(Dimethylamino)-5-aminopyridine (1.0 eq) was taken up in acetone and cooled to 0 C. Thiophosgene (1.6 eq) was added dropwise and the reaction was stirred for 30 minutes at 0 C. before the 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-methylcarboxamide
A solution of the {4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide (1.1 eq) in methanol was treated with 2-(dimethylamino)-5-isothiocynanate pyridine (1.0 eq) and stirred at 60° C. for 2 hours. Methyl iodide (1 eq) was added and stirred overnight at 60° C. The reaction was cooled down 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. Hydrogen was flushed through the reaction for 2–3 hours or until the reaction was determined to be complete by HPLC. Nitrogen was flushed through the reaction for 15 minutes before the reaction was filtered through a celite pad. The celite pad was washed with excess ethyl acetate and methylene chloride before the combined organic solution was removed by evaporation under reduced pressure to afford the product as a solid 2. MS: MH+=207
Step 2




A solution of 2 (1 eq) and sodium carbonate (1.5 eq) in acetone was stirred under nitrogen in an ice bath. Thiophosgene (1.5 eq) was added drop wise over 30 minutes. The reaction was stirred for another 30 minutes in the ice bath before being removed and allowed to warm to RT. The reaction was stirred at RT for 1.5 h before the reaction solution, was concentrated under vacuum. Toluene was added to the crude product and removed under vacuum to azetrope off any residual thiophoisgene and afford the product 3. MS: MH+=249
Step 3




A solution of 3 (1.0 eq) and 4 (1.0 eq) in MeOH was stirred at RT overnight. Ferric chloride (1.2 eq) was added and the resulting reaction mixture was stirred overnight at RT. The reaction mixture was concentrated under vacuum. The crude product was partitioned with EtOAc and water and filtered. The layers were separated and the aqueous phase was neutralized (pH=7) with saturated Na2CO3 solution. The resulting aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), and concentrated to give the desired product 5. MS: MH+=487
Step 4




A solution of 5 (1 eq), 6 (1 eq), and sodium carbonate (1.2 eq) in DME/H2O (3:1) was degassed by bubbling argon through the solution for 10 minutes. Pd(II)(dppf)Cl2.MeCl2 (0.1 eq) was added to the reaction solution and the reaction was sealed. The reaction was heated at 100° C. overnight. The reaction was cooled to RT and ethyl acetate and water were added. The organic layer was separated from the aqueous layer. The aqueous layer was washed once more with ethyl acetate. The organic layers were combined, dried (Na2SO4), and concentrated under vacuum to yield the desired product 7. MS: MH+=469
Step 5




The reaction flask was flame dried and cooled under nitrogen. A solution of 8 (1.0 eq) in THF was added to the reaction flask followed by triisopropyl borate (1.2 eq). The reaction solution was placed in a dry ice/acetone bath to stir at approximately −72° C. N-butyl lithium (1.5 eq, 2.5M solution in hexane) was added drop wise over 40 minutes. The reaction solution was stirred for another 30 minutes in the dry ice/acetone bath. The reaction solution was then transferred to a saturated NaCl/dry ice bath to stir at approx. −25° C. and stirred for 20 minutes before 2N HCl (2.0 eq) was added. The reaction solution was then removed from the bath to stir and warm to RT. The organic and aqueous layers were separated. The aqueous layer was washed once with ethyl acetate. The organic layers were combined, dried (Na2SO4), and concentrated under vacuum to yield the desired product 9. MS: MH+=141
Each of the compounds 785–802, listed in the below table were synthesized as indicated in the right hand column by the method described in one of the Examples 783 or 784.











TABLE 10









Synthesized


Example
Structure
Name
MH+
as in Example:



















785




4-({2-[(4-fluoro-3-pyridin-3-ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
469.5
784


 


786




4-({2-[(4-fluoro-3-pyridin-4-ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
469.5
784


 


787




4-({2-[(4-chloro-3-pyridin-4-ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
485.9
784


 


788




4-[(2-{[4-chloro-3-(2-fluoropyridin-4-yl)phenyl]-amino}-1-methyl-1H-benz-imidazol-5-yl)oxy]-N-methyl-pyridine-2-carboxamide
503.9
784


 


789




4-({2-[(4-chloro-3-pyridin-2-ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
485.9
784


 


790




4-({2-[(4-chloro-3-pyridin-3-ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
485.9
784


 


791




4-[(2-{[4-chloro-3-(3-fluoropyridin-4-yl)phenyl]-amino}-1-methyl-1H-benz-imidazol-5-yl)oxy]-N-methyl-pyridine-2-carboxamide
503.9
784


 


792




4-[(2-{[4-chloro-3-(6-fluoropyridin-3-yl)phenyl]-amino}-1-methyl-1H-benz-imidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
503.9
784


 


793




4-{[2-({4-chloro-3-[6-(methyloxy)pyridin-3-yl]-phenyl}amino)-1-methyl-1H-benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide
516
784


 


794




4-[(2-{[3-(6-fluoropyridin-3-yl)-5-(trifluoromethyl)phenyl]-amino}-1-methyl-1H-benz-imidazol-5-yl)oxy]-N-methyl-pyridine-2-carboxamide
537.5
784


 


795




4-[(2-{[3-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)phenyl]-amino}-1-methyl-1H-benz-imidazol-5-yl)oxy]-N-methyl-pyridine-2-carboxamide
537.5
784


 


796




4-[(2-{[3-(2-fluoropyridin-4-yl)-5-(trifluoromethyl)phenyl]-amino}-1-methyl-1H-benz-imidazol-5-yl)oxy]-N-methyl-pyridine-2-carboxamide
537.5
784


 


797




N-methyl-4-[(1-methyl-2-{[3-[6-(methyloxy)pyridin-3-yl]-5-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide
549.5
784


 


798




N-methyl-4-[(1-methyl-2-{[3-pyridin-2-yl-5-(trifluoromethyl)-phenyl]amino}-1H-benz-imidazol-5-yl)oxy]pyridine-2-carboxamide
519.5
784


 


799




N-methyl-4-[(1-methyl-2-{[3-pyridin-3-yl-5-(trifluoromethyl)-phenyl]amino}-1H-benz-imidazol-5-yl)oxy]pyridine-2-carboxamide
519.5
784


 


800




N-methyl-4-[(1-methyl-2-{[3-pyridin-4-yl-5-(trifluoromethyl)-phenyl]amino}-1H-benz-imidazol-5-yl)oxy]pyridine-2-carboxamide
519.5
784


 


801




4-[(2-{[6-(dimethylamino)-pyridin-3-yl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
418.5
783


 


802




N-methyl-4-({1-methyl-2-[(6-pyrrolidin-1-ylpyridin-3-yl)-amino]-1H-benzimidazol-5-yl}-oxy)pyridine-2-carboxamide
444.5
783









EXAMPLE 803




Step 1. 4-[2-(3-Isopropyl-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylic acid (2-phenylmethanesulfonylamino-ethyl)-amide
To a mixture containing 4-[2-(3-Isopropyl-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylic acid (2-amino-ethyl)-amide (1 eq) (prepared using previously described example 3), K2CO3 (5 eq), (0.2 M in a 5:1 mixture of acetonitrile and water) were added α-toluenesulfonyl chloride (1 eq) via syringe. The resulting heterogeneous mixture was allowed to stir for 1 hour at room temperature. The mixture was then diluted with water and extracted with dichloromethane. The organics were washed with water and a saturated solution of sodium chloride, dried with sodium sulfate and concentrated in vacuo to viscous oil. Purification by chromatography yielded 4-[2-(3-Isopropyl-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylic acid (2-phenylmethanesulfonylamino-ethyl)-amide. MS: MH+599
The compounds shown in the following Table (Examples 804–812) were prepared from following the procedure described for Example 803.










TABLE 11





Exam-





ple
Structure
Name
MH+







804




4-[(1-methyl-2-{[3-(1-methyl-ethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-{2-[(methylsulfonyl)amino]-ethyl}pyridine-2-carboxamide
523.6


 


805




4-[(1-methyl-2-{[3-(1-methyl-ethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-(2-{[(phenylmethyl)sulfonyl]-amino}ethyl)pyridine-2-carboxamide
599.7


 


806




4-[(1-methyl-2-{[3-(1-methyl-ethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-(2-{[(trifluoromethyl)sulfonyl]-amino}ethyl)pyridine-2-carboxamide
577.6


 


807




4-[(1-methyl-2-{[3-(1-methyl-ethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-{2-[(phenylsulfonyl)amino]ethyl}-pyridine-2-carboxamide
585.7


 


808




4-[(1-methyl-2-{[3-(1-methyl-ethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-{2-[(propylsulfonyl)amino]-ethyl}pyridine-2-carboxamide
551.7


 


809




4-[(1-methyl-2-{[3-(1-methyl-ethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-(2-{[(4-methylphenyl)sulfonyl]-amino}ethyl)pyridine-2-carboxamide
599.7


 


810




4-[(1-methyl-2-{[3-(1-methyl-ethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-{2-[(thien-2-ylsulfonyl)amino]-ethyl}pyridine-2-carboxamide
591.7


 


811




N-(2-{[(1-methylethyl)-sulfonyl]amino}ethyl)-4-[(1-methyl-2-{[3-(1-methylethyl)-phenyl]amino}-1H-benz-imidazol-5-yl)oxy]pyridine-2-carboxamide
551.7


 


812




N-(2-{[(5-chlorothien-2-yl)-sulfonyl]amino}ethyl)-4-[(1-methyl-2-{[3-(1-methylethyl)-phenyl]amino}-1H-benz-imidazol-5-yl)oxy]pyridine-2-carboxamide
626.2









EXAMPLE 813




Step 1. 4-{2-(3-(1-Benzyl-1H-[1,2,3]triazol-4-yl)-phenyl amino]-1-methyl-1H-benzoimidazol-5-yloxy}-pyridine-2-carboxylic acid methyl amide
To a mixture of 4-[2-(3-Ethynl-phenylamino)-1-methyl-1H-benzoimidazol-5-yl-oxy]-pyridine-2-carboxylic acid methylamide (1 eq)(prepared using previously described example 2), benzyl azide (1 eq) in t-butanol (0.1M) was added sodium ascorbate (0.05 eq), and copper (II) sulfate pentahydrate (0.01 eq). The resulting mixture was allowed to stir for 1 hour at room temperature. The mixture was then diluted with water and the solid collect via suction filtration. MS: MH+531
EXAMPLE 814




Step 1. Synthesis of 6-Nitro-indole-1-carboxylic acid t-butyl ester
To a stirring solution of 6-nitroindole (1 eq) in dichloromethane (0.3M) and DMF (3.1M), was added di-t-butyl dicarbonate (2 eq) followed by the addition of 4-(dimethyl amino) pyridine (1 eq). Resulting solution was allowed to stir overnight at room temperature. The dichloromethane was then removed on a rotovap and remaining solution diluted with water and extracted with ethyl acetate. Organics were washed with 10% citric acid solution, saturated solution of sodium chloride, saturated solution of sodium bicarbonate, saturated solution of sodium chloride and dried with sodium sulfate. Ethyl acetate was then removed in vacuo. Ethyl ether was then added and a brown solid was collected by suction filtration to yield 6-Nitro-indole-1-carboxylic acid t-butyl ester. MS: MH+263




Step 2. Synthesis of 6-Amino-2,3-dihdro-indole-1-carboxylic acid t-butyl ester
6-Nitro-indole-1-carboxylic acid t-butyl ester (1 eq) was dissolved in methanol (0.1M), to this solution was added palladium on carbon (0.1 eq) in methanol under nitrogen. A hydrogen atmosphere was then inserted and resulting mixture allowed to stir for 3 hours at room temperature. The reaction mixture was then filtered through celite and solvent removed in vacuo to afford 6-Amino-2,3-dihdro-indole-1-carboxylic acid t-butyl ester as a white solid. MS: MH+235




Step 3. Synthesis of 6-Isothiocyanate-2, 3-dihydro-indole-1-carboxylic acid t-butyl ester
Thiophosgene (1.1 eq) was added to a stirred suspension of 6-Amino-2,3-dihdro-indole-1-carboxylic acid t-butyl ester (1 eq), sodium carbonate (10 eq), and dichloromethane: water 3:1 by volume at 0° C. The resulting mixture was allowed to stir for 2 hours at 0° C. The mixture was diluted with water and organics separated and washed with water, saturated solution of sodium chloride and dried with sodium sulfate, solvent removed in vacuo to afford 6-Isothiocyanate-2, 3-dihydro-indole-1-carboxylic acid t-butyl ester as orange oil.




Step 4. Synthesis of 4-[2-(2,3-Dihydro-1H-indol-6-ylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylic acid methylamide.
To a solution of 4-(4-Methylamino3-nitro-phenoxy)-pyridine-2-carboxylic acid methylamide (1 eq), in methanol (0.1M) was added palladium on carbon (0.1 eq) under nitrogen. The atmosphere was exchanged for hydrogen (1 atm) and the resulting suspension allowed to stir for 2 hours at room temperature. The mixture was filtered through celite and added to 6-Isothiocyanate-2,3-dihydro-indole-1-carboxylic acid t-butyl ester (1 eq). The resulting solution was allowed to stir overnight. Iron (III) chloride(2 eq) in methanol was added and the solution turns deep red in color. This solution was allowed to stir for 3 hours at room temperature. Methanol was then removed in vacuo; the resulting oil was diluted with water and extracted with dichloromethane. Organics were washed with saturated sodium bicarbonate solution, water, and saturated sodium chloride solution and dried with sodium sulfate. Solvent was removed in vacuo. To the resulting oil was added toluene and heated to reflux, solution was cooled to room temperature and a solid was collected after 3 days by suction filtration to afford 4-[2-(2,3-Dihydro-1H-indol-6-ylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylic acid methylamide. MS: MH+415
EXAMPLE 815




Step 1. Synthesis of 4-{1-Methyl-2-[1-(4-morpholin-4-yl-butylryl)-2,3-dihydro-1H-indol-6-ylamino]-1H-benzoimidazol-5-yloxy}-pyridine-2-carboxylic acid methylamide
To mixture containing 4-[2-(2,3-Dihydro-1H-indol-6-ylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylic acid methylamide (1 eq)(previously prepared using example 1), EDCI (2 eq), HOAT (1.2 eq), DIEA (4 eq) was added THF. The mixture was allowed to stir overnight at room temperature under nitrogen. The mixture was then diluted with water, extracted with ethyl acetate. Organics were washed with water, then saturated solution of sodium chloride and dried with sodium sulfate, filtered and the solvent was removed in vacuo. Purification by chromatography yielded 4-{1-Methyl-2-[1-(4-morpholin-4-yl-butylryl)-2,3-dihydro-1H-indol-6-ylamino]-1H-benzoimidazol-5-yloxy}-pyridine-2-carboxylic acid methylamide. MS: MH+570
The compounds shown in the following table (Examples 816–819) were prepared from following the procedure described for Example 815.










TABLE 12





Example
Structure
Name
MH+







816




4-{[2-(2,3-dihydro-1H-indol-6-yl-amino)-1-methyl-1H-benzimidazol-5-yl]oxy}-N-methyl-pyridine-2-carboxamide
415.5


 


817




N-methyl-4-[(1-methyl-2-{[1-(3-pyridin-4-yl-propanoyl)-2,3-dihydro-1H-indol-6-yl]amino}-1H-benz-imidazol-5-yl)oxy]-pyridine-2-carbox-amide
548.6


 


818




4-{[2-({1-[3-(1H-imidazol-4-yl)-propanoyl]-2,3-di-hydro-1H-indol-6-yl}amino)-1-methyl-1H-benzimidazol-5-yl]oxy}-N-methyl-pyridine-2-carbox-amide
537.6


 


819




N-methyl-4-[(1-methyl-2-{[1-(4-morpholin-4-ylbu-tanoyl)-2,3-dihydro-1H-indol-6-yl]-amino}-1H-benz-imidazol-5-yl)oxy]-pyridine-2-carbox-amide
570.7









EXAMPLE 820




Step 1. Synthesis of 4-(4-Methylamino-3-nitro-phenoxy)-pyridine-2-carboxylic acid:
A stirring solution of 4-(4-Methylamino-3-nitro-phenoxy)-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 when the reaction was determined to be complete by HPLC. The reaction was evaporated under reduced pressure to afford the product as a red-orange oil. Addition of ethyl ether, sonication, and filtration captures the product as a light 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 the 4-(4-methylamino-3-nitro-phenoxy)-pyridine-2-carboxylic acid (1 eq) in dry THF, EDC-HCl (1.2 eq), HOAT (1.2 eq), and diisopropylethylamine (3 eq) were added. The suspension was stirred for 10 minutes whereupon 2,2-dimethyloxazolidine (1.1 eq) was added and the solution is allowed to stir overnight. The mixture was then diluted with ethyl acetate and washed with water. The aqueous layer was washed with ethyl acetate, the organic layers combined, dried over MgSO4, 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. Hydrogen was flushed through the reaction for 1–2 hours or until the reaction was determined to be complete by HPLC. Nitrogen was flushed through the reaction for 15 minutes before the reaction was filtered through a celite pad. The celite pad was washed with excess methanol before it was all removed by evaporation under reduced pressure to afford the product as a light yellow solid. LCMS m/z 303.2 (MH+), tR=1.5 min.
Step 4. 4-[1-Methyl-2-(3-trifluoromethylsulfanyl-phenylamino)-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylic acid (2-hydroxy-ethyl)-amide:
A flask was charged with 3-(trifluoromethylthio)phenylisothiocyanate (1 eq), 4-(3-amino-4-methylamino-phenoxy)-pyridine-2-carboxylic acid (2-hydroxy-ethyl)-amide (1 eq), and MeOH. The reaction was maintained at rt overnight. Ferric chloride, (1.5 eq) was added and the resulting red reaction mixture was stirred overnight. The reaction was partitioned with EtOAc and water, and filtered through Celite. The layers were separated and the aqueous phase was neutralized with saturated Na2CO3 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 again 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-benzoimidazol-5-yloxy]-pyridine-2-carboxylic acid tert-butyl ester:
A round bottom flask was charged with 4-fluorophenylisothiocyanate (1 eq), 4-(3-Amino-4-methylamino-phenoxy)-pyridine-2-carboxylic acid tert-butyl ester (1 eq), and MeOH. The reaction was maintained stirring at room temperature overnight. Ferric chloride, (1.5 eq) was added and the resulting mixture was stirred overnight. The reaction was partitioned with EtOAc and water, and filtered through Celite. The layers were separated and the aqueous phase was neutralized with saturated Na2CO3 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 again extracted and filtered. The combined organic layers were 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 furnish 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-benzoimidazol-5-yloxy]-pyridine-2-carboxylic acid:
A stirring solution of 4-[2-(4-Fluoro-phenylamino)-1-methyl-1H-benzoimidazol-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 when the reaction was determined to be complete by HPLC. The reaction was evaporated under reduced pressure and then ether was added to the residue, which was then sonicated for 30 minutes. Filtration and washing with ether yields the desired acid in quantitative yield. LCMS m/z 379.4 (MH+), tR=1.74 min.
Step3. Synthesis of {5-[2-(1H-Benzoimidazol-2-yl)-pyridin-4-yloxy]-1-methyl-1H-benzoimidazol-2-yl}-(4-fluoro-phenyl)-amine:
To a suspension of 4-[2-(4-Fluoro-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylic acid (1 eq) in dry THF, EDC-HCl (1.2 eq), HOAT (1.2 eq), and diisopropylethylamine (3 eq) were added. The suspension was stirred for 10 minutes whereupon phenylenediamine (1.1 eq) was added and the solution is allowed to stir overnight. The mixture was then diluted with ethyl acetate and washed with water. The aqueous layer was washed with ethyl acetate, the organic layers 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 for 3 hours at 70° C., whereupon the solution is concentrated and the residue purified by reverse phase HPLC to afford the desired product. LCMS m/z 451.5 (MH+), tR=1.92 min.
Synthesis of Side Chains
Ether Substituted Phenylenediamines:




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

A flask is charged with 4-amino-3-nitrophenol 1 (1 eq), K2CO3 (2 eq), and 2-butanone. 1,3-dibromopropane 2 (1.5 eq) is added and the mixture is heated at 80° C. for 18 hours. After cooling, the mixture is filtered concentrated and water is added. The solution is then extracted with CH2Cl2 (×3), the organic layer concentrated, and the solid recovered washed with pentane to yield the desired product 3. LCMS m/z 275.1 (MH+), Rt 2.74 minutes.




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

4-(3-bromopropoxy)-2-nitrophenylamine 1 (1 eq) was heated to 70° C. with pyrrolidine 2 (5 eq) in MeCN with Cs2CO3 (2 eq) and Bu4NI (0.1 eq) for 48 hours. The reaction mixture was cooled, filtered, and concentrated. The residue is dissolved in CH2Cl2, and washed with water. The organic layer is concentrated yielding the desired product 3. LCMS m/z 266.2 (MH+), Rt 1.51 minutes.




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

To a solution 2-Nitro-4-(3-pyrrolidinylpropoxy)phenylamine 1 in EtOH, Pd/C (0.1 eq) is added. The reaction vessel is repeatedly purged (×3) with nitrogen, and then stirred under a hydrogen atmosphere for 18 h. The product is filtered through a Celite plug, and the plug washed with 25 mL of EtOH, to yield 2. LCMS 236.2 Rt 0.94 min.
3-Fluoro-4-amino substituted phenylenediamines:




1. Synthesis of 2-Fluoro-3-(4-methyl-piperazin-1-yl)-6-nitro-phenylamine.
A solution of N-methylpiperazine (1.0 eq), NMP, triethylamine (3.0 eq) and 5,6-difluoro-2-nitroaniline (1.0 eq) were heated at 90° C. for 1 hour. The reaction was allowed to cool to room temperature and then poured into water and let stand for 1 hour. The resulting solid was collected and dried and utilized without further purification. MH+=255.3
2. Synthesis of 3-Fluoro-4-(4-methyl-piperazin-1-yl)-benzene-1,2-diamine.
To a solution Synthesis of 2-fluoro-3-(4-methyl-piperazin-1-yl)-6-nitrophenylamine in EtOH, Pd/C (0.1 eq) is added. The reaction vessel is repeatedly purged (×3) with nitrogen, and then stirred under a hydrogen atmosphere for 18 h. The product is filtered through a Celite plug, the plug washed with 25 mL of EtOH, to yield the desired diamine. LCMS 225.3 Rt 0.45 min.
4-Amino substituted phenylenediamines (a):




Synthesis of 5-(4-Methyl-piperazin-1-yl)-2-nitro-phenylamine
A solution of N-methylpiperazine (1.0 eq), NMP, triethylamine (3.0 eq) and 5-fluoro-2-nitrophenylamine (1.0 eq) were heated at 90° C. for 1 hours. The reaction was allowed to cool to room temperature and then poured into water and let stand for 12 hours. The resulting solid was collected and dried and utilized without further purification. MH+=237.3.
Synthesis of 4-(4-Methyl-piperazin-1-yl)-benzene-1,2-diamine:
To a solution 5-(4-Methyl-piperazin-1-yl)-2-nitro-phenylamine in EtOH, Pd/C (0.1 eq) is added. The reaction vessel is repeatedly purged (×3) with nitrogen, then stirred under a hydrogen atmosphere for 18 h. The product is filtered through a Celite plug, the plug washed with 25 mL of EtOH, to yield the desired diamine. LCMS 207.3 Rt 0.25 min.
4-Amino substituted phenylenediamines (b):




Synthesis of 5-(4-Cyclopentyl-piperazin-1-yl)-2-nitro-phenylamine
1. A solution of N-cyclopentylpiperazine (1.0 eq), NMP, triethylamine (3.0 eq) and 5-fluoro-2-nitrophenylamine (1.0 eq) were heated at 90° C. for 1 hours. The reaction was allowed to cool to room temperature and then poured into water and let stand for 12 hours. The resulting solid was collected and dried and utilized without further purification. MH+=291.4.
2. Synthesis of 4-(4-Cyclopentyl-piperazin-1-yl)-benzene-1,2-diamine:
To a solution 5-(4-Cyclopentyl-piperazin-1-yl)-2-nitro-phenylamine in EtOH, Pd/C (0.1 eq) is added. The reaction vessel is repeatedly purged (×3) with nitrogen, then stirred under a hydrogen atmosphere for 18 h. The product is filtered through a Celite plug, the plug washed with 25 mL of EtOH, to yield the desired diamine. MH+=261.3.
EXAMPLE 822




Step 1. Synthesis of 4-Chloro-pyridine-2-carboxylic acid dimethylamide:
A solution of 4-chloro-pyridine-2-carbonyl chloride (1 eq) in dichloromethane was cooled to 0° C., whereupon triethylamine (2 eq) was added followed by dimethylamine (2 eq, 2M solution in THF). The solution was allowed to warm to room temperature and let stir overnight. It was then washed with 1M NaOH. The separated organic layer is dried over MgSO4, filtered, and concentrated to yield 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:
A mixture containing 4-amino-3-nitrophenol (1 eq) and potassium bis(trimethylsilyl)amide (2 eq) was stirred in dimethylformamide for 2 hours at room temperature. To this mixture was added 4-Chloro-pyridine-2-carboxylic acid dimethylamide (1 eq) and potassium carbonate (1.2 eq) and then it was stirred at 90° C. for 3 days. The reaction mixture was then concentrated before partitioning between ethyl acetate and water. The organic layer was separated, washed with brine, dried, filtered and concentrated in vacuum to give brown solid. Purification by flash chromatography with ethyl acetate and hexane (1:1) gave the desired product as a yellow syrup. 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 methylene chloride was treated with trifluoroacetic anhydride (1 eq) and stirred for 10 minutes at 0° C. The mixture was quenched with satd. NaHCO3 solution. The organic layer was separated and washed with water, brine, dried, filtered and evaporated. MS: MH+=399.0
To the solution of the trifluroacetamide (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. The mixture was taken up in ethyl acetate, washed with water, brine, dried and evaporated. The crude 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:
The solution of 4-(4-Methylamino-3-nitro-phenoxy)-pyridine-2-carboxylic acid dimethylamide in methanol was treated with 10% palladium on carbon and stirred under hydrogen atmosphere for 3 hours at room temperature. The mixture was purged with nitrogen and then was filtered through celite and the filtrate was concentrated to provide the diamine. HPLC, 1.17 min; MS: MH+=287.1
Step 5. Synthesis of 4-[2-(2,6-Difluoro-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylic acid dimethylamide:
A solution of the 4-(3-Amino-4-methylamino-phenoxy)-pyridine-2-carboxylic acid dimethylamide (1 eq) in methanol was treated with 2,6-difluorophenylisothiocyanate (1 eq) and stirred overnight. To the reaction mixture, methyl iodide (1 eq) was added and stirred overnight at 60° C. The reaction was cooled down to room temperature, evaporated, and the residue purified by reverse phase HPLC. HPLC, 1.66 min; MS: MH+=424.1
Each of the compounds 823–984, listed in the below table were synthesized as indicated in the right hand column by the method described herein.











TABLE 13









Synthesized


Example
Structure
Name
MH+
as in Ex.:







823




4-({2-[(2,6-difluoro-phenyl)amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N,N-dimethyl-pyridine-2-carbox-amide
424.1
822


 


824




N,N-dimethyl-4-[(1-methyl-2-{[2-(tri-fluoromethyl)-phenyl]amino}-1H-benzimidazol-5-yl)-oxy]pyridine-2-carboxamide
456.4
822


 


825




4-({2-[(4-ethyl-phenyl)amino]-1-methyl-1H-benz-imidazol-5-yl}-oxy)-N,N-dimethyl-pyridine-2-carbox-amide
416.5
822


 


826




4-({2-[(3,5-difluoro-phenyl)amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N,N-dimethyl-pyridine-2-carbox-amide
424.4
822


 


827




4-({2-[(2,4-di-methylphenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N,N-di-methylpyridine-2-carboxamide
416.5
822


 


828




N,N-dimethyl-4-{[1-methyl-2-({2-[(trifluoromethyl)-oxy]phenyl}amino)-1H-benzimidazol-5-yl]oxy}pyridine-2-carboxamide
472.4
822


 


829




4-({2-[(2,5-difluoro-phenyl)amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N,N-dimethyl-pyridine-2-carbox-amide
424.4
822


 


830




4-({2-[(3-ethyl-phenyl)amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N,N-dimethyl-pyridine-2-carbox-amide
416.5
822


 


831




4-[(2-{[2-chloro-5-(trifluoromethyl)-phenyl]amino}-1-methyl-1H-benz-imidazol-5-yl)oxy]-N,N-dimethyl-pyridine-2-carbox-amide
490.9
822


 


832




4-[(2-{[2-fluoro-5-(trifluoromethyl)-phenyl]amino}-1-methyl-1H-benz-imidazol-5-yl)oxy]-N,N-dimethyl-pyridine-2-carbox-amide
474.4
822


 


833




N,N-dimethyl-4-[(1-methyl-2-{[2-(methylthio)phenyl]-amino}-1H-benz-imidazol-5-yl)oxy]-pyridine-2-carbox-amide
434.5
822


 


834




4-({2-[(2,4-difluoro-phenyl)amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N,N-dimethyl-pyridine-2-carbox-amide
424.4
822


 


835




4-({2-[(2,3-dimethyl-phenyl)amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N,N-dimethyl-pyridine-2-carbox-amide
416.5
822


 


836




4-[(2-{[4-chloro-2-(trifluoromethyl)-phenyl]amino}-1-methyl-1H-benz-imidazol-5-yl)oxy]-N,N-dimethyl-pyridine-2-carbox-amide
490.9
822


 


837




4-({2-[(3-chloro-2-methylphenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N,N-di-methylpyridine-2-carboxamide
436.9
822


 


838




4-[(2-{[5-chloro-2-(methyloxy)phenyl]-amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N,N-di-methylpyridine-2-carboxamide
452.9
822


 


839




4-[(2-{[3,5-bis-(methyloxy)phenyl]-amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N,N-di-methylpyridine-2-carboxamide
448.5
822


 


840




N,N-dimethyl-4-[(1-methyl-2-{[5-methyl-2-(methyl-oxy)-phenyl]-amino}-1H-benz-imidazol-5-yl)oxy]-pyridine-2-carbox-amide
432.5
822


 


841




N,N-dimethyl-4-[(1-methyl-2-{[4-(methyloxy)-1,1′-biphenyl-3-yl]-amino}-1H-benz-imidazol-5-yl)oxy]pyridine-2-carbox-amide
494.6
822


 


842




4-[(2-{[3,4-bis-(methyloxy)phenyl]-amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N,N-di-methylpyridine-2-carboxamide
448.5
822


 


843




N,N-dimethyl-4-[(1-methyl-2-{[2-(methyloxy)phenyl]-amino}-1H-benz-imidazol-5-yl)oxy]-pyridine-2-carbox-amide
418.5
822


 


844




4-[(2-{[5-chloro-2,4-bis(methyloxy)-phenyl]amino}-1-methyl-1H-benz-imidazol-5-yl)oxy]-N,N-dimethyl-pyridine-2-carbox-amide
482.9
822


 


845




4-[(2-{[3,5-bis-(methyloxy)phenyl]-amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-pyridine-2-carboxamide
531.6
372


 


846




4-[(2-{[3,5-bis-(methyloxy)phenyl]-amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[2-(di-methylamino)ethyl]-pyridine-2-carbox-amide
491.6
372


 


847




4-[(2-{[3,5-bis-(methyloxy)phenyl]-amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[3-(methyloxy)propyl]-pyridine-2-carbox-amide
492.5
372


 


848




4-[(2-{[3,5-bis-(methyloxy)phenyl]-amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[2-(methyloxy)ethyl]-pyridine-2-carbox-amide
478.5
372


 


849




4-[(2-{[3,5-bis-(methyloxy)phenyl]-amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[3-(4-methylpiperazin-1-yl)propyl]pyridine-2-carboxamide
560.7
372


 


850




4-[(2-{[3,5-bis-(methyloxy)phenyl]-amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-(3-mor-pholin-4-ylpropyl)-pyridine-2-carbox-amide
547.6
372


 


851




4-[(2-{[3,5-bis-(methyloxy)phenyl]-amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-(1,2,2,6,6-penta-methylpiperidin-4-yl)pyridine-2-car-boxamide
573.7
372


 


852




4-[(2-{[3,5-bis-(methyloxy)phenyl]-amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-2-(mor-pholin-4-ylethyl)-pyridine-2-carbox-amide
533.6
372


 


853




4-[(2-{[3,5-bis-(methyloxy)phenyl]-amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methyl-N-propylpyridine-2-carboxamide
476.5
372


 


854




4-[(2-{[3,5-bis-(methyloxy)phenyl]-amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methyl-N-[2-(methyloxy)-ethyl]pyridine-2-carboxamide
492.5
372


 


855




4-[(2-{[3,5-bis-(methyloxy)phenyl]-amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-[2-(di-methylamino)ethyl]-N-methylpyridine-2-carboxamide
505.6
372


 


856




5-{[2-(1H-benzimid-azol-2-yl)pyrinin-4-yl]oxy}-N-[3,5-bis(methyloxy)-phenyl]-1-methyl-1H-benzimidazol-2-amine
493.5
821


 


857




4-({2-[(2-fluoro-phenyl)amino]-1-methyl-1H-benz-imadazol-5-yl}oxy)-N-[2-(1H-imidazol-4-yl)ethyl]pyridine-2-carboxamide
472.5
372


 


858




N-[2-(dimethyl-amino)ethyl]-4-({2-[2-fluorophenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide
449.5
372


 


859




4-({2-[(2-fluoro-phenyl)amino]-1-methyl-1H-benz-imadazol-5-yl}oxy)-N-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]pyridine-2-carboxamide
489.6
372


 


860




4-({2-[(2-fluoro-phenyl)amino]-1-methyl-1H-benz-imadazol-5-yl}oxy)-N-[2-(1H-indol-3-yl)ethyl]pyridine-2-carboxamide
521.6
372


 


861




4-({2-[(2-fluoro-phenyl)amino]-1-methyl-1H-benz-imadazol-5-yl}oxy)-N-[3-(methyloxy)-propyl]pyridine-2-carboxamide
450.5
372


 


862




4-({2-[(2-fluoro-phenyl)amino]-1-methyl-1H-benz-imadazol-5-yl}oxy)-N-[2-(methyloxy)-ethyl]pyridine-2-carboxamide
436.5
372


 


863




4-({2-[(2-fluoro-phenyl)amino]-1-methyl-1H-benz-imadazol-5-yl}oxy)-N-[(2-pyridin-4-yl-ethyl)pyridine-2-carboxamide
483.5
372


 


864




4-({2-[(2-fluoro-phenyl)amino]-1-methyl-1H-benz-imadazol-5-yl}oxy)-N-[3-(4-methyl-piperazin-1-yl)-propyl]pyridine-2-carboxamide
518.6
372


 


865




4-({2-[(2-fluoro-phenyl)amino]-1-methyl-1H-benz-imadazol-5-yl}oxy)-N-(3-morpholin-4-yl-propyl)pyridine-2-carboxamide
505.6
372


 


866




4-({2-[(2-fluoro-phenyl)amino]-1-methyl-1H-benz-imadazol-5-yl}oxy)-N-methyl-N-(2-pyridin-4-ylethyl)-pyridine-2-carbox-amide
497.5
372


 


867




N-[(1-ethylpyrroli-din-2-yl)-methyl]-4-({2-[(2-fluoro-phenyl)amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-pyridine-2-carbox-amide
489.6
372


 


868




4-({2-[(2-fluoro-phenyl)amino]-1-methyl-1H-benz-imadazol-5-yl}oxy)-N-(1,2,2,6,6-penta-methylpiperidin-4-yl)pyridine-2-carbox-amide
531.6
372


 


869




4-({2-[(2-fluoro-phenyl)amino]-1-methyl-1H-benz-imadazol-5-yl}oxy)-N-methyl-N-propyl-pyridine-2-carbox-amide
434.5
372


 


870




4-({2-[(2-fluoro-phenyl)amino]-1-methyl-1H-benz-imadazol-5-yl}oxy)-N-(2-morpholin-4-yl-ethyl)pyridine-2-carboxamide
491.5
372


 


871




4-({2-[(2-fluoro-phenyl)amino]-1-methyl-1H-benz-imadazol-5-yl}oxy)-N-methyl-N-[2-(methyloxy)ethyl]-pyridine-2-carbox-amide
450.5
372


 


872




4-({2-[(2-fluoro-phenyl)amino]-1-methyl-1H-benz-imadazol-5-yl}oxy)-N-methyl-N-(1-methylpiperidin-4-yl)pyridine-2-carboxamide
489.6
372


 


873




N-[2-(dimethyl-amino)ethyl]-4-({2-[(2-fluorophenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}-oxy)-N-methyl-pyridine-2-carbox-amide
463.5
372


 


874




N-[2-(1H-imidazol-4-yl)ethyl]-4-[(1-methyl-2-{[2-(methyloxy)phenyl]-amino}-1H-benz-imidazol-5-yl)oxy]-pyridine-2-carbox-amide
484.5
372


 


875




N-[2-(dimethyl-amino)ethyl]-4-[(1-methyl-2-{[2-(methyloxy)phenyl]-amino}-1H-benz-imidazol-5-yl)oxy]-pyridine-2-carbox-amide
461.5
372


 


876




4-[(1-methyl-2-{[2-(methyloxy)phenyl]-amino}-1H-benz-imidazol-5-yl)oxy]-N-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-pyridine-2-carboxamide
501.6
372


 


877




N-[2-(1H-indol-3-yl)ethyl]-4-[(1-methyl-2-{[2-(methyloxy)phenyl]-amino}-1H-benz-imidazol-5-yl)oxy]-pyridine-2-carbox-amide
533.6
372


 


878




4-[(1-methyl-2-{[2-(methyloxy)phenyl]-amino}-1H-benz-imidazol-5-yl)oxy]-N-[3-(methyloxy)-propyl]pyridine-2-carboxamide
462.5
372


 


879




4-[(1-methyl-2-{[2-(methyloxy)phenyl]-amino}-1H-benz-imidazol-5-yl)oxy]-N-[2-(methyloxy)-ethyl]pyridine-2-carboxamide
448.5
372


 


880




4-[(1-methyl-2-{[2-(methyloxy)phenyl]-amino}-1H-benz-imidazol-5-yl)oxy]-N-(2-pyridin-4-yl-ethyl)pyridine-2-carboxamide
495.6
372


 


881




4-[(1-methyl-2-{[2-(methyloxy)phenyl]-amino}-1H-benz-imidazol-5-yl)oxy]-N-[3-(4-methyl-piperazin-1-yl)-propyl]-pyridine-2-carboxamide
530.6
372


 


882




4-[(1-methyl-2-{[2-(methyloxy)phenyl]-amino}-1H-benz-imidazol-5-yl)oxy]-N-(3-morpholin-4-ylpropyl)pyridine-2-carboxamide
517.6
372


 


883




N-methyl-4-[(1-methyl-2-{[2-(methyloxy)phenyl]-amino}-1H-benz-imidazol-5-yl)oxy]-N-(2-pyridin-4-yl-ethyl)pyridine-2-carboxamide
509.6
372


 


884




N-[(1-ethyl-pyrrolidin-2-yl)-methyl]-4-[(1-methyl-2-{[2-(methyloxy)phenyl]-amino}-1H-benz-imidazol-5-yl)oxy]-pyridine-2-carbox-amide
501.6
372


 


885




4-[(1-methyl-2-{[2-(methyloxy)phenyl]-amino}-1H-benz-imidazol-5-yl)oxy]-N-(1,2,2,6,6-penta-methylpiperidin-4-yl)pyridine-2-carbox-amide
543.7
372


 


886




N-methyl-4-[(1-methyl-2-{[2-(methyloxy)phenyl]-amino}-1H-benz-imidazol-5-yl)oxy]-N-[2-(methyloxy)-ethyl]pyridine-2-carboxamide
462.5
372


 


887




4-[(1-methyl-2-{[2-(methyloxy)phenyl]-amino}-1H-benz-imidazol-5-yl)oxy]-N-(2-morpholin-4-ylethyl)pyridine-2-carboxamide
503.6
372


 


888




N-methyl-4-[(1-methyl-2-{[2-(methyloxy)phenyl]-amino}-1H-benz-imidazol-5-yl)oxy]-N-propylpyridine-2-carboxamide
446.5
372


 


889




N-methyl-4-[(1-methyl-2-{[2-(methyloxy)phenyl]-amino}-1H-benz-imidazol-5-yl)oxy]-N-(1-methylpiperi-din-4-yl)pyridine-2-carboxamide
501.6
372


 


890




N-[2-(dimethy-lamino)ethyl]-N-methyl-4-[(1-methyl-2-{[2-(methyloxy)phenyl]-amino}-1H-benz-imidazol-5-yl)oxy]-pyridine-2-carbox-amide
475.6
372


 


891




5-{[2-(1H-benz-imidazol-2-yl)-pyridin-4-yl]oxy}-1-methyl-N-[2-(methyloxy)phenyl]-1H-benzimidazol-2-amine
463.5
372


 


892




5-{[2-(1H-benz-imidazol-2-yl)-pyridin-4-yl]oxy}-N-(2-fluorophenyl)-1-methyl-1H-benz-imidazol-2-amine
451.5
372


 


893




4-({2-[(4-fluoro-phenyl)amino]-1-methyl-1H-benz-imadazol-5-yl}oxy)-N-[2-(1H-imidazol-4-yl)ethyl]pyridine-2-carboxamide
472.5
372


 


894




4-({2-[(4-fluoro-phenyl)amino]-1-methyl-1H-benz-imadazol-5-yl}oxy)-N-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]pyridine-2-carboxamide
489.6
372


 


895




N-[2-(dimethyl-amino)ethyl]-4-({2-[(4-flourophenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridine-2-carboxamide
449.6
372


 


896




4-({2-[(4-fluoro-phenyl)amino]-1-methyl-1H-benz-imadazol-5-yl}oxy)-N-[2-(1H-indol-3-yl)ethyl]pyridine-2-carboxamide
521.6
372


 


897




4-({2-[(4-fluoro-phenyl)amino]-1-methyl-1H-benz-imadazol-5-yl}oxy)-N-[3-(methyloxy)-propyl]pyridine-2-carboxamide
450.5
372


 


898




4-({2-[(4-fluoro-phenyl)amino]-1-methyl-1H-benz-imadazol-5-yl}oxy)-N-[2-(methyloxy)-ethyl]pyridine-2-carboxamide
436.5
372


 


899




4-({2-[(4-fluoro-phenyl)amino]-1-methyl-1H-benz-imadazol-5-yl}oxy)-N-(2-pyridin-4-yl-ethyl)pyridine-2-carboxamide
483.6
372


 


900




4-({2-[(4-fluoro-phenyl)amino]-1-methyl-1H-benz-imadazol-5-yl}oxy)-N-[3-(4-methyl-piperazin-1-yl)-propyl]pyridine-2-carboxamide
518.6
372


 


901




5-{[2-({(2R,5R)-2-[(dimethylamino)-methyl]-5-methyl-morpholin-4-yl}-carbonyl)pyridin-4-yl]oxy}-N-(4-fluorophenyl)-1-methyl-1H-benz-imidazol-2-amine
519.6
372


 


902




4-({2-[(4-fluoro-phenyl)amino]-1-methyl-1H-benz-imadazol-5-yl}oxy)-N-(3-morpholin-4-yl-propyl)pyridine-2-carboxamide
505.6
372


 


903




4-({2-[(4-fluoro-phenyl)amino]-1-methyl-1H-benz-imadazol-5-yl}oxy)-N-methyl-N-(2-pyridin-4-ylethyl)-pyridine-2-carbox-amide
497.6
372


 


904




N-[(1-ethylpyrroli-din-2-yl)methyl]-4-({2-[(4-fluoro-phenyl)amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-pyridine-2-carbox-amide
489.6
372


 


905




4-({2-[(4-fluoro-phenyl)amino]-1-methyl-1H-benz-imadazol-5-yl}oxy)-N-(1,2,2,6,6-penta-methylpiperidin-4-yl)pyridine-2-car-boxamide
531.7
372


 


906




4-({2-[(4-fluoro-phenyl)amino]-1-methyl-1H-benz-imadazol-5-yl}oxy)-N-methyl-N-[2-(methyloxy)ethyl]-pyridine-2-carbox-amide
450.6
372


 


907




4-({2-[(4-fluoro-phenyl)amino]-1-methyl-1H-benz-imadazol-5-yl}oxy)-N-(2-morpholin-4-ylethyl)pyridine-2-carboxamide
491.6
372


 


908




4-({2-[(4-fluoro-phenyl)amino]-1-methyl-1H-benz-imadazol-5-yl}oxy)-N-propylpyridine-2-carboxamide
434.6
372


 


909




4-({2-[(4-fluoro-phenyl)amino]-1-methyl-1H-benz-imadazol-5-yl}oxy)-N-methyl-N(1-methylpiperadin-4-yl)pyridine-2-car-boxamide
489.6
372


 


910




N-[2-(dimethyl-amino)ethyl]-4-({2-[(4-flourophenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methyl-pyridine-2-carbox-amide
463.6
372


 


911




5-{[2-({(2R,5S)-2-[(dimethylamino)-methyl]-5-methyl-morpholin-4-yl}-carbonyl)pyridin-4-yl]oxy}-N-(4-fluorophenyl)-1-methyl-1H-benz-imidazol-2-amine
519.6
372


 


912




5-{[2-(1H-benz-imidazol-2-yl)-pyridin-4-yl]oxy}-N-(4-fluorophenyl)-1-methyl-1H-benz-imidazol-2-amine
451.5
821


 


913




4-({2-[(4-bromo-2-fluorophenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methyl-pyridine-2-carbox-amide
471.3
 120a


 


914




4-({2-[(4-chloro-phenyl)amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N-(2-phenylethyl)-pyridine-2-carbox-amide
499.0
372


 


915




4-({2-[(4-chloro-phenyl)amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N-{2-[(2-methyl-oxy)phenyl]ethyl}-pyridine-2-carbox-amide
529.0
372


 


916




4-({2-[(4-chloro-phenyl)amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N-[2-(dimethyl-amino)ethyl]-pyridine-2-carbox-amide
466.0
372


 


917




4-({2-[(4-chloro-phenyl)amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N-(2-pyridin-4-ylethyl)pyridine-2-carboxamide
500.0
372


 


918




N-(4-chlorophenyl)-5-{[2-({(2R,5R)-2-[(dimethylamino)-methyl]-5-methyl-morpholin-4-yl}-carbonyl)pyridin-4-yl]oxy}-1-methyl-1H-benzimidazol-2-amine
536.0
372


 


919




4-({2-[(4-chloro-phenyl)amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N-methyl-N-(2-pyridin-4-ylethyl)-pyridine-2-carbox-amide
514.0
372


 


920




4-({2-[(4-chloro-phenyl)amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N-(1,2,2,6,6-penta-methylpiperidin-4-yl)pyridine-2-carboxamide
548.1
372


 


921




4-({2-[(4-chloro-phenyl)amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N-methyl-N-propyl-pyridine-2-carbox-amide
450.9
372


 


922




4-({2-[(4-chloro-phenyl)amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N-methyl-N-(1-methylpiperidin-4-yl)pyridine-2-carboxamide
506.0
372


 


923




4-({2-[(4-chloro-phenyl)amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N-[2-(dimethyl-amino)ethyl]N-methylpyridine-2-carboxamide
480.0
372


 


924




N-(4-chlorophenyl)-5-{[2-({(2R,5S)-2-[(dimethylamino)-methyl]-5-methyl-morpholin-4-yl}car-bonyl)pyridin-4-yl]-oxy}-1-methyl-1H-benzimidazol-2-amine
536.0
372


 


925




4-({2-[(4-chloro-phenyl)amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N-methyl-N-[2-(methyloxy)ethyl]-pyridine-2-carbox-amide
466.9
372


 


926




N-(4-fluorophenyl)-5-{[2-(3H-imidazo-[4,5-b]pyridin-2-yl)-pyridin-4-yl]oxy}-1-methyl-1H-benz-imidazol-2-amine
452.5
821


 


927




N-(4-fluorophenyl)-1-methyl-5-{[2-(1H-naphtho[2,3-d]-imidazol-2-yl)-pyridin-4-yl]oxy}-1H-benzimidazol-2-amine
501.5
821


 


928




N-(4-fluorophenyl)-1-methyl-5-{[2-(5-methyl-1H-benz-imidazol-2-yl)-pyridin-4-yl]oxy}-1H-benzimidazol-2-amine
465.5
821


 


929




N-(4-fluorophenyl)-1-methyl-5-({2-[5-(4-methylpiperazin-1-yl)-1H-benz-imidazol-2-yl]py-ridine-4-yl}oxy)-1H-benzimidazol-2-amine
549.6
821


 


930




N-(4-fluorophenyl)-1-methyl-5-{[2-(1-methyl-1H-benz-imidazol-2-yl)py-ridin-4-yl]oxy}-1H-benzimidazol-2-amine
465.5
821


 


931




5-({2-[5-(1,1-di-methylethyl)-1H-benzimidazol-2-yl]-pyridin-4-yl}oxy)-N-(4-fluorophenyl)-1-methyl-1H-benz-imidazol-2-amine
507.6
821


 


932




N-[(1-ethylpyrroli-din-2-yl)methyl]-4-[(1-methyl-2-{[3-(trifluoromethyl)-phenyl]amino}-1H-benzimidazol-5-yl)-oxy]pyridine-2-carboxamide
539.3
372


 


933




4-[(1-methyl-2-{[3-(trifluromethyl)-phenyl]amino}-1H-benzimidazol-5-yl)-oxy]-N-(2-mor-pholin-4-ylethyl)-pyridine-2-carbox-amide
541.3
372


 


934




N-[3-(4-methyl-piperazin-1-yl)-propyl]-4-[(1-methyl-2-{[3-(tri-fluoromethyl)-phenyl]amino}-1H-benzimidazol-5-yl)-oxy]pyridine-2-carboxamide
568.4
372


 


935




4-[(1-methyl-2-{[3-(trifluoromethyl)-phenyl]amino}-1H-benzimidazol-5-yl)-oxy]-N-1,3-thiazol-2-ylpyridine-2-carboxamide
511.2
372


 


936




N-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-4-[(1-methyl-2-{[3-(trifluoro-methyl)phenyl]-amino}-1H-benz-imidazol-5-yl)oxy]-pyridine-2-carbox-amide
539.3
372


 


937




4-[(1-methyl-2-{[3-(trifluoromethyl)-phenyl]amino}-1H-benzimidazol-5-yl)-oxy]-N-[2-(2-oxo-imidazolidin-1-yl)-ethyl]pyridine-2-carboxamide
540.3
372


 


938




4-[(1-methyl-1-{[3-(trifluoromethyl)-phenyl]amino}-1H-benzimidazol-5-yl)-oxy]-N-(2-pyrroli-din-1-ylethyl)pyridine-2-carbox-amide
525.3
372


 


939




N-[3-(1H-imidazol-1-yl)propyl]-4-[(1-methyl-2-{[3-(tri-fluoromethyl)-phenyl]amino}-1H-benzimidazol-5-yl)-oxy]pyridine-2-carboxamide
536.3
372


 


940




N-[2-(methyloxy)-ethyl]-4-[(1-methyl-2-{[3-(triofluoro-methyl)phenyl]-amino}-1H-benz-imidazol-5-yl)oxy]-pyridine-2-carbox-amide
486.3
372


 


941




N-(2-hydroxyethyl)-4-[(1-methyl-2-{[3-(trifluoromethyl)-phenyl]amino}-1H-benzimidazol-5-yl)-oxy]pyridine-2-carboxamide
472.2
372


 


942




4-[(1-methyl-2-{[3-(trifluoromethyl)-phenyl]amino}-1H-benzimidazol-5-yl)-oxy]-N-(2-piperidin-1-ylethyl)pyridine-2-carboxamide
539.3
372


 


943




4-[(1-methyl-2-{[3-(trifluoromethyl)-phenyl]amino}-1H-benzimidazol-5-yl)-oxy]-N-(3-piperidin-1-ylpropyl)pyridine-2-carboxamide
553.3
372


 


944




4-[(1-methyl-2-{[3-(trifluoromethyl)-phenyl]amino}-1H-benzimidazol-5-yl)-oxy]-N-(3-pyrroli-din-1-ylpropyl)py-ridine-2-carbox-amide
539.3
372


 


945




4-[(1-methyl-2-{[3-(trifluoromethyl)-phenyl]amino}-1H-benzimidazol-5-yl)-oxy]-N-(2-pyridin-4-ylethyl)pyridine-2-carboxamide
533.3
372


 


946




4-[(1-methyl-2-{[3-(trifluoromethyl)-phenyl]amino}-1H-benzimidazol-5-yl)-oxy]-N-(2-pipera-zin-1-ylethyl)pyridine-2-carbox-amide
540.2
372


 


947




N-[3-(methyloxy)-propyl]-4-[(1-methyl-2-{[3-(tri-fluoromethyl)-phenyl]amino}-1H-benzimidazol-5-yl)-oxy]pyridine-2-carboxamide
500.2
372


 


948




N-[2-(acetylamino)-ethyl]-4-[(1-methyl-2-{[3-(trifluoro-methyl)phenyl]-amino}-1H-benz-imidazol-5-yl)oxy]-pyridine-2-carbox-amide
513.3
372


 


949




4-[(1-methyl-2-{[3-(trifluoromethyl)-phenyl]amino}-1H-benzimidazol-5-yl)-oxy]-N-pyrrolidin-3-ylpyridine-2-carboxamide
497.2
372


 


950




4-[(1-methyl-2-{[3-(trifluoromethyl)-phenyl]amino}-1H-benzimidazol-5-yl)-oxy]-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]pyridine-2-carboxamide
553.3
372


 


951




4-[(1-methyl-2-{[3-(trifluoromethyl)-phenyl]amino}-1H-benzimidazol-5-yl)-oxy]-N-propyl-pyridine-2-carbox-amide
470.3
372


 


952




N-ethyl-4-[(1-methyl-2-{[3-(tri-fluoromethyl)-phenyl]amino}-1H-benzimidazol-5-yl)-oxy]pyridine-2-carboxamide
456.2
372


 


953




5-{[2-(1H-benz-imidazol-2-yl)py-ridin-4-yl]oxy}-1-methyl-N-[3-(tri-fluoromethyl)-phenyl]-1H-benz-imidazol-2-amine
501.2
821


 


954




5-{[2-(1H-benz-imidazol-2-yl)py-ridin-4-yl]oxy}-1-methyl-N-[3-(methylethyl)-phenyl]-1H-benz-imidazol-2-amine
abran
821


 


955




1-methyl-5-{[2-(5-methyl-1H-benz-imidazol-2-yl)py-ridin-4-yl]oxy}-N[3-(trifluoro-methyl)phenyl]-1H-benzimidazol-2-amine
515.2
821


 


956




1-methyl-5-{[2-(1H-naphtho[2,3-d]-imidazol-2-yl)py-ridin-4-yl]oxy}-N[3-(trifluoro-methyl)phenyl]-1H-benzimidazol-2-amine
551.3
821


 


957




1-methyl-5-{[2-(1-methyl-1H-benz-imidazol-2-yl)py-ridin-4-yl]oxy}-N[3-(trifluoro-methyl)phenyl]-1H-benzimidazol-2-amine
515.2
821


 


958




(2-{4-[(1-methyl-2-{[3-(trifluoro-methyl)phenyl]-amino}-1H-benz-imidazol-5-yl)oxy]-pyridine-2-yl}-1H-benzimidazol-5-yl-(phenyl)methanone
605.2
821


 


959




5-{[2-(5-bromo-1H-benzimidazol-2-yl)-pyridin-4-yl]oxy}-1-methyl-N-[3-(tri-fluoromethyl)-phenyl]-1H-benz-imidazol-2-amine
579.1
821


 


960




5-{[2-(5-chloro-6-fluoro-1H-benz-imidazol-2-yl)py-ridin-4-yl]oxy}-1-methyl-N-[3-(tri-fluoromethyl)-phenyl]-1H-benz-imidazol-2-amine
553.2
821


 


961




5-{[2-(5-chloro-1H-benzimidazol-2-yl)-pyridin-4-yl]oxy}-1-methyl-N-[3-(tri-fluoromethyl)-phenyl]-1H-benz-imidazol-2-amine
535.2
821


 


962




5-{[2-(5-fluoro-1H-benzimidazol-2-yl)-pyridin-4-yl]oxy}-1-methyl-N-[3-(tri-fluoromethyl)-phenyl]-1H-benz-imidazol-2-amine
519.4
821


 


963




1-methyl-5-({2-[5-(trifluoromethyl)-1H-benzimidazol-2-yl]pyridin-4-yl}-oxy)-N-[3-(trifluoro-methyl)phenyl]-1H-benzimidazol-2-amine
569.2
821


 


964




methyl 2-{4-[(1-methyl-2-{[3-(tri-fluoromethyl)-phenyl]amino}-1H-benzimidazol-5-yl)-oxy]pyridin-2-yl}-1H-benzimidazole-5-carboxylate
559.2
821


 


965




5-{[2-(5,6-dichloro-1H-benzimidazol-2-yl)pyridin-4-yl]-oxy}-1-methyl-N-[3-(trifluoromethyl)-phenyl]-1H-benz-imidazol-2-amine
569.1
821


 


966




5-{2-[(5-(1,1-di-methylethyl)-1H-benzimidazol-2-yl]-pyridin-4-yl}oxy)-1-methyl-N-[3-(tri-fluoromethyl)-phenyl]-1H-benz-imidazol-2-amine
557.3
821


 


967




1-methyl-5-{[2-(3-(phenyl-1,2,4-oxadi-azol-5-yl)pyridin-4-yl]oxy}-N-[3-(tri-fluoromethyl)-phenyl]-1H-benz-imidazol-2-amine
529.2
821


 


968




5-({2-[7-fluoro-6-(4-methylpiperazin-1-yl)-1H-benzimida-zol-2-yl]pyridin-4-yl}oxy)-1-methyl-N-[3-(1-methyl-ethyl)phenyl]-1H-benzimidazol-2-amine
591.3
821


 


969




1-methyl-N-[3-(1-methylethyl)-phenyl]-5-[(2-{5-[(3-pyrrolidin-1-yl-propyl)oxy]-1H-benzimidazol-2-yl}-pyridin-4-yl)oxy]-1H-benzimidazol-2-amine
602.7
821


 


970




N-(2-hydroxyethyl)-4-{[1-methyl-2-({3-[trifluoro-methyl)thio]-phenyl}amino)-1H-benzimidazol-5-yl]-oxy}pyridine-2-carboxamide
504.1
820


 


971




N-(2-hydroxyethyl)-4-{[1-methyl-2-({4-[trifluoro-methyl)thio]-phenyl}amino)-1H-benzimidazol-5-yl]-oxy}pyridine-2-carboxamide
504.1
820


 


972




4-({2-[(3-fluoro-4-methylphenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-hy-droxyethyl)pyridine-2-carboxamide
436.2
820


 


973




4-({2-[(4-bromo-3-chlorophenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-hy-droxyethyl)pyridine-2-carboxamide
516  
820


 


974




4-({2-[(4-chloro-3-methylphenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-hy-droxyethyl)pyridine-2-carboxamide
452.2
820


 


975




4-({2-[(4-fluoro-phenyl)amino]-1-methyl-1H-benz-imidazol-5-yl}oxy)-N-(2-hydroxyethyl)-pyridine-2-carbox-amide
422.2
820


 


976




4-({2-[(3-chloro-4-fluorophenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-hy-droxyethyl)pyridine-2-carboxamide
456.2
820


 


977




N-(2-hydroxyethyl)-4-[(1-methyl-2-{[4-methyl-3-(trifluoro-methyl)phenyl]-amino}-1H-benz-imidazol-5-yl)oxy]-pyridine-2-carbox-amide
486.2
820


 


978




4-({2-[(3-chloro-4-methylphenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-hy-droxyethyl)pyridine-2-carboxamide
452.2
820


 


979




4-({2-[(4-bromo-3-fluorophenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-hy-droxyethyl)pyridine-2-carboxamide
502.1
820


 


980




5-({2-[4-fluoro-5-(4-methylpiperazin-1-yl)-1H-benzimida-zol-2-yl]pyridin-4-yl}oxy)-1-methyl-N[3-(trifluoro-methyl)phenyl]-1H-benzimidazol-2-amine
428.2
821


 


981




5-{[2-(1H-benz-imidazol-2-yl)-pyridine-4-yl]oxy}-N-(4-chloro-3-py-ridine-4-ylphenyl)-1-methyl-1H-benz-imidazol-2-amine
545.0
821


 


982




1-methyl-5-{[2-(5-{[2-(methyloxy)-ethyl]oxy}-1H-benzimidazol-2-yl)-pyridin-4-yl]oxy}-N-{3-[(trifluoro-methyl)thio]-phenyl}-1H-benz-imidazol-2-amine
607.2
821


 


983




5-({2-[5-(4-cyclo-pentylpiperazin-1-yl)-1H-benzimida-zol-2-yl]pyridin-4-yl}oxy)-1-methyl-N-{3-[(trifluoro-methyl)thio]-phenyl}-1H-benz-imidazol-2-amine
685.3
821


 


984




1-methyl-N-(3-pyridin-4-yl-phenyl)-5-({2-[5-(trifluoromethyl)-1H-benzimidazol-2-yl]pyridin-4-yl}-oxy)-1H-benzimida-zol-2-amine
578.3
821









EXAMPLE 985
Synthesis of Oxime Series: 4-[2-(4-Bromo-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxyl-pyridine-2-carbaldehyde oxime
Step 1. Synthesis of [4-(4-Methylamino-3-nitro-phenoxy)-pyridin-2-yl]-methanol




A flame dried 500 mL three-necked round bottom flask purged with N2 was charged with LAH (2.32 g, 58.0 mmol) and dry THF (60 mL). The resulting suspension was cooled to 0° C. and a suspension of t-butyl ester 1 (10.0 g, 29.0 mmol) in dry THF (60 mL) was slowly added while keeping the internal reaction temperature under 5° C. The reaction was stirred at 0° C. for 30 min then at rt for 30 min. After the reaction was judged complete, the mixture was treated with successive dropwise addition of water (2.3 mL), 10% NaOH (2.3 mL), and water (7.2 mL). The resulting suspension was filtered through Celite, washed with ethyl acetate and methanol, and the collected organics concentrated. The crude product was absorbed onto silica gel and purified by flash chromatography (97:3 CH2Cl2/MeOH) to give 2 as an orange solid: 1H NMR (300 MHz, CDCl3) δ 8.40 (d, J=5.5 Hz, 1 H), 8.05 (br s, 1H), 7.96 (d, J=2.75 Hz, 1 H), 7.29 (d, J=2.75 Hz, 1 H), 6.92 (d, J=9.35 Hz, 1 H), 6.75 (m, 2 H), 4.68 (s, 2 H), 3.07 (d, J=5.23 Hz, 3 H).
Step 2. Synthesis of 4-(4-Methylamino-3-nitro-phenoxy)-pyridine-2-carbaldehyde




A 250 mL reaction tube was charged with benzyl alcohol 1 (1.0 g, 3.6 mmol), MnO2 (4.7 g, 54 mmol) and EtOAc (20 mL). The reaction tube was sealed was heated to 120° C. with stirring for 2 h. The reaction was allowed to cool to rt, then filtered through Celite and washed successively with EtOAc, MeOH, and EtOH. The combine organics were concentrated to give 936 mg (3.4 mmol, 94%) of 2 as an orange solid: 1H NMR (300 MHz, CDCl3) δ 10.01 (s, 1 H), 8.64 (d, J=5.5 Hz, 1 H), 8.09 (br s, 1 H), 7.96 (d, J=2.75 Hz, 1 H), 7.37 (d, J=2.48 Hz, 1 H), 7.29 (d, J=2.75 Hz, 1 H), 7.08 (dd, J=2.47, 5.5 Hz, 1 H), 6.94 (d, J=9.35 Hz, 1 H), 3.08 (d, J=5.23 Hz, 3 H).
Step 3. Synthesis of 4-(4-Methylamino-3-nitro-phenoxy)-pyridine-2-carbaldehyde oxime




A 50 mL round bottom flask was charged with 1 (680 mg, 2.5 mmol), hydroxylamine HCl (191 mg, 2.75 mmol), pyridine (0.25 mL, 3.0 mmol) and ethanol (10 mL). The resulting reaction mixture was stirred at rt overnight. The crude product was concentrated, absorbed onto silica gel, and purified by flash chromatography (97:3 CH2Cl2/MeOH to give 2 as an orange solid. LCMS m/z 289.2 (MH+), tR=2.06 min.
Step 4. Synthesis of 4-(3-Amino-4-methylamino-phenoxy)-pyridine-2-carbaldehyde oxime




A reaction tube was charged with suspension of 1 (330 mg, 1.15 mmol) and Lindlar catalyst (245 mg, 10 mol %) in methanol (5 mL), sealed, and placed on a Parr shaker. The reaction was pressurized with H2 (60 psi) and maintained for 1 h. The reaction was filtered through Celite and the remaining solids were washed with MeOH. The combined organics were concentrated to give 2 as a brown semi-solid which was taken on without further purification.
Step 5. Synthesis of 4-[2-(4-Bromo-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carbaldehyde oxime




A 5 mL round bottom flask was charged with 4-bromophenylisothiocyanate (54 mg, 0.25 mmol), diamine 1 (65 mg, 0.25 mmol), and MeOH (1 mL). The resulting reaction was maintained at rt overnight. Methyl iodide (20 μL, 0.33 mmol) was added to the reaction and stirred overnight. The reaction was concentrated and the resulting residue was purified by reverse-phase HPLC. LCMS m/z 438.1 (MH+), tR=1.87 min.
EXAMPLE 986
Synthesis of O-methyl-oxime Series: 4-[1-Methyl-2-(4-trifluoromethylsulfanyl-phenylamino)-1H-benzoimidazol-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 25 mL round bottom flask was charged with a suspension of 1 (600 mg, 2.2 mmol), methoxylamine HCl (202 mg, 2.42 mmol), and pyridine (0.22 mL, 2.6 mmol) in ethanol (9 mL). The resulting reaction mixture was stirred at rt overnight. The crude product was concentrated, absorbed onto silica gel, and purified by flash chromatography (97:3 CH2Cl2/MeOH) to give 2 as an orange solid. LCMS m/z 303.2 (MH+), tR=2.40 min.
Step 2. Synthesis of 4-(3-Amino-4-methylamino-phenoxy)-pyridine-2-carbaldehyde O-methyl-oxime




A reaction tube was charged with a suspension of 1 (270 mg, 0.9 mmol) and Lindlar catalyst (192 mg, 10 mol %) in methanol (5 mL), and was then placed on a Parr shaker. The was reaction pressurized with H2 (60 psi) and maintained for 1 h. The reaction was filtered through Celite and the remained solids were washed with methanol. The combined organics were concentrated to give 2 as a brown semi-solid which was carried forward without further purification LCMS m/z 273.3 (MH+), tR=1.56 min.
Step 3. Synthesis of 4-[1-Methyl-2-(4-trifluoromethylsulfanyl-phenylamino)-1H-benzoimidazol-5-yloxy]-pyridine-2-carbaldehyde O-methyl-oxime




A 5 mL round bottom flask was charged with 4-trifluoromethylthio-phenylisothiocyanate (24 mg, 0.1 mmol), diamine 1 (27 mg, 0.1 mmol), and MeOH (0.5 mL). The reaction was maintained at rt overnight, after which methyl iodide (8 μL, 0.13 mmol) was added. After 16 h, the reaction was concentrated and the resulting residue was purified by reverse-phase HPLC. LCMS m/z 474.3 (MH+), tR=2.42 min.
EXAMPLE 987




Synthesized as described in Example 986 step 3 using 4-bromophenyl isothiocyanate. LCMS m/z 402.4 (MH+), tR=2.15 min.
EXAMPLE 988




Synthesized as described in Example 986 step 3 using 4-ethylphenylisiothiocyanate. LCMS m/z 402.4 (MH+), tR=2.15 min.
EXAMPLE 989




Synthesized as described in Example 986 step 3 using 4-bromo-2-trifluoromethoxyphenylisothiocyanate. LCMS m/z 536.2 (MH+), tR=2.38 min.
EXAMPLE 990




Synthesized as described in Example 986 step 3 using 2,4-dimethylphenylisothiocyanate. LCMS m/z 402, (MH+), tR=2.07 min.
EXAMPLE 991
Synthesis of Benzyl Alcohol Series: {4-[2-(4-Chloro-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridin-2-yl}-methanol
Step 1. Synthesis of [4-(3-Amino-4-methylamino-phenoxy)-pyridin-2-yl]-methanol




A suspension of nitroaniline 1 (550 mg, 2.0 mmol) in methanol was sparged with N2 for 20 min after which 10% Pd/C (106 mg, 0.1 mmol) was added. The reaction was charged with H2 and maintained under a H2 atmosphere overnight at rt. The reaction was sparged with N2 and filtered through Celite. The collected solids were washed with EtOAc (3×50 mL), and the combined organic layers were dried (MgSO4) and concentrated to afford 2, which was taken on without further purification.
Step 2. Synthesis of {4-[2-(4-Chloro-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridin-2-yl}-methanol.




A 5 mL round bottom flask was charged with 4-chlorophenylisothiocyanate (34 g, 0.2 mmol), diamine 1 (49 mg, 0.2 mmol), and MeOH (1 mL) and the resulting reaction was maintained at rt overnight. Ferric chloride (16 mg, 0.1 mmol) was added and the red reaction mixture was stirred overnight. The reaction was partitioned with EtOAc and water, the layers were separated and the aqueous phase was neutralized (pH=7) with saturated aqueous Na2CO3 solution. 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 purified on reverse-phase HPLC. LCMS m/z 381.3 (MH+), tR=2.27 min.
EXAMPLE 992




Synthesized as described in Example 1058 step 2 using 4-fluorophenylisiothiocyanate. LCMS m/z 365.4 (MH+), tR=2.04 min.
EXAMPLE 993




Synthesized as described in Example 991 step 2 using 4-bromo-3-methylphenylisiothiocyanate. LCMS m/z 439.3 (MH+), tR=2.79 min.
EXAMPLE 994




Synthesized as described in Example 991 step 2 using 4-bromo-2-trifluoromethoxyphenylisothiocyanate. LCMS m/z 511.3 (MH+), tR=3.08 min.
EXAMPLE 995




Synthesized as described in Example 991 step 2 using 4-methylthiophenylisiothiocyanate. LCMS m/z 393.4 (MH+), tR=2.46 min.
EXAMPLE 995




Synthesized as described in Example 991 step 2 using 3-ethylphenylisiothiocyanate. LCMS m/z 375.4 (MH+), tR=2.57 min.
EXAMPLE 996




Synthesized as described in Example 991 step 2 using 4-trifluoromethylthiophenylisiothiocyanate. LCMS m/z 447.3 (MH+), tR=3.21 min.
EXAMPLE 997




Synthesized as described in Example 991 step 2 using 3-iodophenylisiothiocyanate. LCMS m/z 473.2 (MH+), tR=2.57 min.
EXAMPLE 998




Synthesized as described in Example 991 step 2 using 3-trifluoromethylthiophenylisothiocyanate. LCMS m/z 447.3 (MH+), tR=3.08 min.
EXAMPLE 999
4-[2-(4-Bromo-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylic acid phenylamide
Procedure for Synthesis of Anilide Series (4-Br and 3-iPr west-ends)
Synthesis of 4-[2-(4-Bromo-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylic acid phenylamide.




A suspension of 1 (44 mg, 0.1 mmol), HBTU (46 mg, 0.12 mmol), and DIEA (43 uL, 0.25 mmol) in NMP (0.5 mL) was shaken for 30 min at rt. Aniline was added and the reaction was shaken overnight. The crude product purified on reverse-phase HPLC. LCMS m/z 515.2 (MH+), tR=2.75 min.
EXAMPLE 1000




Synthesized as described in Example 999 using N, O-dimethylhydroxylamine HCl. LCMS m/z 483.3 (MH+), tR=2.07 min.
EXAMPLE 1001




Synthesized as described in Example 999 using 4-bromoaniline. LCMS m/z 594.0 (MH+), tR=5.39 min.
EXAMPLE 1002




Synthesized as described in Example 999 using 3,4-dimethylaniline. LCMS m/z 543.2 (MH+), tR=5.39 min.
EXAMPLE 1003




Synthesized as described in Example 999 using 3-trifluoromethylaniline. LCMS m/z 583.1 (MH+), tR=3.12 min.
EXAMPLE 1004




Synthesized as described in Example 999 using 3-chloroaniline. LCMS m/z 550.1 (MH+), tR=5.28 min.
EXAMPLE 1005




Synthesized as described in Example 999 using 3-ethylaniline. LCMS m/z 543.2 (MH+), tR=3.16 min.
EXAMPLE 1006




Synthesized as described in Example 1067 using 4-methylaniline. LCMS m/z 529.2 (MH+), tR=5.15 min.
EXAMPLE 1007




Synthesized as described in Example 999 using 3-isopropylaniline. LCMS m/z 520.3 (MH+), tR=5.98 min.
EXAMPLE 1008




Synthesized as described in Example 999 using 3-tert-butylaniline. LCMS m/z 534.3 (MH+), tR=3.32 min.
EXAMPLE 1009




Synthesized as described in Example 999 using 3-trifluoromethoxyaniline. LCMS m/z 562.2 (MH+), tR=3.15 min.
EXAMPLE 1010




Synthesized as described in Example 999 using 3-biphenylamine. LCMS m/z 554.3 (MH+), tR=3.28 min.
EXAMPLE 1011




Synthesized as described in Example 999 using 4-bromoaniline. LCMS m/z 557.2 (MH+), tR=5.65 min.
EXAMPLE 1012




Synthesized as described in Example 999 using 3-trifluoromethylaniline. LCMS m/z 546.3 (MH+), tR=5.74 min.
EXAMPLE 1013




Synthesized as described above in Example 999 using 3-iodoaniline. LCMS m/z 604.2 (MH+), tR=5.81 min.
EXAMPLE 1014
4-[1-Methyl-2-(3-phenoxy-phenylamino)-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylic acid methylamide
Step 1. Synthesis of 3-phenoxyphenylisothiocyanate




To a stirring solution of 3-phenoxyaniline (185 mg, 1.0 mmol) in acetone (4.0 mL) at 0° C. was added thiophosgene (0.23 mL, 3.0 mmol) and the resulting reaction maintained for 30 min. The reaction determined complete by TLC (4:1 hexane/EtOAc). The reaction was concentrated, azeotroped with toluene and taken on without further purification.
Step 2. Synthesis of 4-[1-Methyl-2-(3-phenoxy-phenylamino)-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylic acid methylamide




A 1 dram vial was charged with a solution of 3-phenoxyphenylisothiocyanate (23 mg, 0.1 mmol), diamine 1 (27 mg, 0.1 mmol), and MeOH (0.5 mL) and the reaction was shaken at rt overnight. Methyl iodide (8 uL, 0.13 mmol) was added and the mixture shaken overnight. The reaction was concentrated and the resulting residue purified on reverse phase HPLC. LCMS m/z 466.3 (MH+), tR=2.40 min.
EXAMPLE 1015




Synthesized as described in Example 1014 step 2 using 4-trifluoromethylthiophenylisothiocyanate. LCMS m/z 474.5 (MH+), tR=3.76 min.
EXAMPLE 1016




Synthesized as described in Example 1014 step 2 using 3-trifluoromethylthiophenylisothiocyanate. LCMS m/z 474.5 (MH+), tR=3.65 min.
EXAMPLE 1017




Synthesized as described in Example 1014 step 2 using 4-1-isothiocyanato-4-methanesulfonyl-benzene, prepared as in step 1. LCMS m/z 452.5 (MH+), tR=2.86 min.
EXAMPLE 1018




Synthesized as described in Example 1014 step 2 using 4-(2-isothiocyanato-4-trifluoromethyl-phenoxy)-benzonitrile, prepared as in step 1. LCMS m/z 559.6 (MH+), tR=4.22 min.
EXAMPLE 1019




Synthesized as described in Example 1014 step 2 using 2-(2-methoxy-phenoxy)-5-trifluoromethyl-phenylisothiocyanate, prepared as in step 1. LCMS m/z 564.6 (MH+), tR=4.42 min.




Synthesized as described in Example 1014 step 2 using 2-phenylsulfanyl-phenylisothiocyanate, prepared as in step 1. LCMS m/z 482.5 (MH+), tR=3.85 min.
EXAMPLE 1021




Synthesized as described in Example 1014 step 2 using 4-isothiocyanato-3-trifluoromethoxy-benzonitrile, prepared as in step 1. LCMS m/z 483.4 (MH+), tR=2.35 min.
EXAMPLE 1022




Synthesized as described in Example 1014 step 2 using 2,4-dibromo-6-fluorophenylisothiocyanate. LCMS m/z 550.3 (MH+), tR=3.50 min.
EXAMPLE 1023




Synthesized as described. in Example 1014 step 2 using 4-bromo-2-trifluoromethoxy-phenylisothiocyanate. LCMS m/z 537.3 (MH+), tR=3.89 min.
EXAMPLE 1024




Synthesized as described in Example 1014 step 2 using phenylisothiocyanate. LCMS m/z 374.5 (MH+), tR=2.84 min.
EXAMPLE 1025




Synthesized as described in Example 1014 step 2 using 2-phenoxyphenylisothiocyanate, prepared as in step 1. LCMS m/z 466.5 (MH+), tR=2.37 min.
EXAMPLE 1026




Synthesized as described in Example 1014 step 2 using 2-methylphenylisothiocyanate. LCMS m/z 388.5 (MH+), tR=2.99 min.
EXAMPLE 1027




Synthesized as described in Example 1014 step 2 using 2-difluoromethoxyphenylisothiocyanate. LCMS m/z 440.5 (MH+), tR=3.13 min.
EXAMPLE 1028




Synthesized as described in Example 1014 step 2 using 2-iodo-phenylisothiocyanate. LCMS m/z 500.4 (MH+), tR=2.07 min.
EXAMPLE 1029




Synthesized as described in Example 1014 step 2 using 2,6-diisopropyl-phenylisothiocyanate LCMS m/z 430.5 (MH+), tR=2.27 min.
EXAMPLE 1030
4-[2-(4-Bromophenyl)-1-methyl-1H-benzimidazol-5-yloxy]-pyridine-2-carboxylic acid methylamide.




A mixture of diamine 1 (137 mg, 0.36 mmol) and 4-bromobenzaldehyde (66 mg, 0.50 mmol) in dry dioxane (2 mL) was heated to 100° C. for 16 h. The reaction mixture was allowed to cool to rt and was then concentrated. The resulting residue was purified by reverse phase HPLC to finish 2 as the TFA salt: LCMS m/z 437.1, tR=2.16 min.
EXAMPLE 1031
4-[1-Methyl-2-(4-methylbenzylamino)-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylic acid methylamide




Prepared as per Example 120b using 4-methylbenzyl thioisocyanate: LCMS m/z 402.2 (MH+), tR=1.91 min.
EXAMPLE 1032
4-[2-(4-Bromophenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylic acid (3-pyrrolidin-1-yl-propyl)-amide




Prepared as per Example 371 using amido-1-(3-aminopropyl)pyrrolidine: LCMS m/z 549.5 (MH+), tR=2.97 min.
EXAMPLE 1033
(4-Bromophenyl)-[1-methyl-5-(pyridin-4-yloxy)-1H-benzolimidazol-2-yl]-amine




A solution of acid 1 (44 mg, 0.1 mmol) in dry NMP (1 mL) was heated at 200° C. for 20 min. The reaction was allowed to cool to rt and the crude reaction mixture was directly purified on reverse-phase HPLC to provide 2 as a TFA salt: 1H NMR (300 MHz, CD3OD) δ 8.67 (d, J=7.4 Hz, 2 H), 7.70 (d, J=8.5 Hz, 1 H), 7.68 (d, J=8.8 Hz, 2 H), 7.45 (d, J=8.8 Hz, 2 H), 7.42 (d, J=7.4 Hz, 2 H), 7.32 (d, J=2.2 Hz, 1 H), 7.26 (dd, J=2.2, 8.5 Hz, 1 H), 3.86 (s, 3 H); LCMS m/z 395.0 (MH+), tR=1.48 min.
EXAMPLE 1034




LCMS m/z 359.3 (MH+), tR=1.91 min.
EXAMPLE 1035
{4-[2-(4-Bromophenylamino)-1-methyl-1H-benzolimidazol-5-yloxy]-pyridin-2-yl}-methanol




A suspension of t-butyl ester 1 (496 mg, 1.0 mmol) in dry THF (3 mL) was added to a stirring suspension of LAH (61 mg, 1.6 mmol) in dry THF (2 mL) at −78° C. The reaction was allowed to warm to rt over 3 h. After the reaction was judged complete by LCMS, water (30 ul, 1.7 mmol) and NaF (270 mg, 6.4 mmol) were added and the resulting mixture was stirred vigorously overnight at rt. The crude mixture was filtered through Celite and the remaining solids were rinsed with EtOAc. The combined organic portions were concentrated and a portion of the resulting residue was purified by reverse-phase HPLC to furnish alcohol 2 as a TFA salt: 1H NMR (300 MHz, CD3OD) δ 8.56 (d, J=7.2 Hz, 1 H), 7.72 (d, J=8.5 Hz, 1 H), 7.69 (d, J=8.8 Hz, 2 H), 7.45 (d, J=8.8 Hz, 2 H), 7.33 (m, 3 H), 7.28 (dd, J=2.2, 8.5 Hz, 1 H), 4.86 (app s, 2 H), 3.87 (s, 3 H); LCMS m/z 425.1, tR=1.49 min.
EXAMPLE 1036
(4-Bromophenyl)-[1-methyl-5-(2-methylaminomethyl-pyridin-4-yloxy)-1H benzoimidazol-2-yl]-amine
General Preparation for Benzyl Amines
Step 1. 4-[2-(4-Bromophenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxaldehyde




Dry DMSO (0.1 mL, 1.4 mmol) was added to a solution of oxalyl chloride (0.11 mL, 1.3 mmol) in dry THF (2 mL) at −78 ° C. and the resulting solution was maintained at −78 ° C. for 30 min. A solution of alcohol 1 in dry THF (2 mL) was then introduced and the resulting reaction was maintained at −78 ° C. for 30 min, then at −50 ° C. for 45 min. Triethylamine (0.5 mL, 3.6 mmol) was added and the reaction was allowed to warm to rt over 1 h. The reaction was quenched with water and partitioned with EtOAc. The layers were separated and the aqueous portion was extracted with EtOAc (3×). The combined organic phases were washed with brine, dried (MgSO4), and concentrated. The resulting residue was carried forward without further purification.
Step 2. (4-Bromophenyl)-[1-methyl-5-(2-methylaminomethyl-pyridin-4-yloxy)-1H benzoimidazol-2-yl]-amine.




Methyl amine (0.3 mL, 0.6 mmol, 2.0 M in MeOH) was added to a solution of aldehyde 1 in MeOH (1 mL) and the reaction was maintained at rt for 2 d. The reaction was acidified by addition of acetic acid (pH=3–4), and an excess of NaBH3CN was added. The reaction was maintained for 2 d then concentrated. The crude reaction mixture was dissolved in EtOAc and partitioned with aqueous saturated NaHCO3 solution. The layers were separated and the aqueous phase was extracted with EtOAc (3×). The combined organic portions were washed with brine, dried (MgSO4), and concentrated. The resulting residue was purified by reverse-phase HPLC to afford N-methyl amine 2 as a TFA salt: 1H NMR (300 MHz, CD3OD) δ 8.48 (d, J=5.8 Hz, 1H), 7.72 (d, J=8.8 Hz, 2 H), 7.67 (d, J=9.4 Hz, 1 H), 7.43 (d, J=8.8 Hz, 2 h), 7.20 (dd, J=2.2, 9.4 Hz, 1 H), 7.19 (d, J=2.2 Hz, 1H), 7.02 (d, J=2.2, 1 H), 6.90 (dd, J=2.2, 5.8 Hz, 1 H), 4.27 (s, 2 H), 3.86 (s, 3 H), 2.76 (s, 3 H); LCMS m/z 438.5 (MH+), tR=1.85 min.
The following tabulated benzyl amines were prepared by the above method as in Example 1036 using the appropriate amine.










TABLE 14







LCMS
TIME


Example
Structure
(MH+) m/z
tR (mm)


















1037




549.1
1.62


 


1038




482.2
1.94


 


1039




494.1
1.59


 


1040




468.2
1.87


 


1041




483.3
1.83


 


1042




536.2
1.87


 


1043




552.2
1.84


 


1044




536.4
1.80


 


1045




522.3
1.76


 


1046




550.4
1.80


 


1047




452.3
2.70*


 


1048




521.4
3.63*


 


1049




465.3
2.75*


 


1050




467.3
2.86*


 


1051




494.2
1.82


 


1052




497.2
2.04









EXAMPLE 1053
[5-(2-Aminomethyl-pyridin-4-yloxy)-1-methyl-1H-benzoimidazol-2-yl]-(4-bromophenyl)-amine




LAH (98 mg, 2.5 mmol) was added portionwise to a stirring solution of oxime 1 (225 mg, 0.5 mmol) in dry THF (3 mL) at 0° C. After addition, the cooling bath was removed and the reaction was allowed to warm to rt overnight. The reaction was quenched by addition of water (0.1 mL), 10% w/w aqueous NaOH solution (0.1 mL), and water (0.3 mL). The resulting slurry was stirred at rt for 1 h and filtered through Celite. The remaining solids were rinsed with EtOAc and the organic portions were combined and concentrated. The crude residue was purified by reverse-phase HPLC to provide benzyl amine 2 as a TFA salt: LCMS m/z 424.1 (MH+), tR=1.87 min.
EXAMPLE 1054
{4-[2-(4-Bromophenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridin-2-yl-methyl]-carbamic acid methyl ester




Methyl chloroformate (6 μL, 0.08 mmol) was added to a solution of benzyl amine 1 (21 mg, 0.05 mmol) and triethylamine (69 μL, 0.5 mmol) in dry THF (1 mL) at 0° C. The reaction was maintained at 0° C. for 20 min, then at rt for 2 h. The reaction mixture was concentrated and purified by reverse-phase HPLC to provide methyl carbamate 2 as a TFA salt: LCMS m/z 482.2 (MH+), tR=1.96 min.
EXAMPLE 1055
N-{4-[2-(4-Bromophenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridin-2-ylmethyl}acetamide




To a solution of benzyl amine 1 (17 mg, 0.04 mmol) in dry NMP (2 mL) was added triethylamine (0.06 mL, 0.4 mmol) and acetic anhydride (0.04 mL, 0.4 mmol). The resulting reaction was maintained at rt overnight and purified directly by reverse-phase HPLC to furnish acetamide 2 as a TFA salt: LCMS m/z 466.3 (MH+), tR=1.78 min.
EXAMPLE 1056
4-[2-(3-Ethylphenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pryidine-2-carboxylic acid [3-(2-oxo-pyrrolidin-yl)-propyl]-amide
General Preparation for N-(3-Aminopropyl)-pyrrolidinone Amides
Step 1: 4-Chloro-pyridine-2-carboxylic acid [3-(2-oxo-pyrrolidin-1-yl)-propyl]-amide




Acid chloride 1 (2.12 g, 10 mmol) was treated with N-methylmorpholine (4.5 mL, 41 mmol) and N-(3-aminopropyl)-pyrrolidinone 2 (1.6 mL, 11 mmol) in dry THF (40 mL). The reaction was maintained overnight and concentrated. The residue was dissolved in EtOAc and partitioned with water. The aqueous portion was extracted with EtOAc (3×) and the combined organic phases were washed with brine, dried (MgSO4), and concentrated. The crude residue was purified by Kugelrohr distillation (0.5 mmHg, 170–200° C.) to provide 3.
Step 2: 4-(4-Methylamino-3-nitrophenoxy)-pyridine-2-carboxylic acid [3-(2-oxo-pyrrolidin-yl)-propyl]-amide




Prepared as per Example 120b with the appropriate substitutions. Amide 3 can be purified by flash chromatography (95:5 CH2Cl2-MeOH). It can also be further purified by recrystallization from MeCN.
Step 3: 4-(3-Amino-4-methylamino-phenoxy)-pyridine-2-carboxlic acid [3-(2-oxo-pyrrolidin-yl)-propyl]-amide




Prepared as per Example 120b.
Step 4: 4-[2-(3-Ethylphenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pryidine-2-carboxylic acid [3-(2-oxo-pyrrolidin-yl)-propyl]-amide.




Prepared as per Example 120b to provide benzimidazole 2 as a TFA salt: LCMS m/z 513.3 (MH+), tR=2.22 min.
EXAMPLE 1057




Prepared as per Example 1056: LCMS m/z 563.2 (MH+), tR=2.15 min.
EXAMPLE 1058




Prepared as per Example 1056: LCMS tR=585.3 (MH+), tR=2.55 min.
EXAMPLE 1059




Prepared as per Example 1056: LCMS m/z 563.2 (MH+), tR=2.50 min.
The following additional compounds were prepared following the procedures of the indicated Examples:











TABLE 15









Synthe-






sized


Exam-



as in


ple
Structure
Name
MH+
Ex.:







1060




N-methyl-4-[(2-{[3-(2-methyl-pyridin-4-yl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide
451.5
702


 


1061




N-methyl-4-[(1-methyl-6-(methyloxy)-2-{[3-(2-methyl-pyridin-4-yl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide
495.6
702


 


1062




N-methyl-4-{[2-({3-[3-(tri-fluoromethyl)pyridin-4-yl]-phenyl}amino)-1H-benz-imidazol-5-yl]oxy}pyridine-2-carboxamide
505.5
702


 


1063




N-methyl-4-{[1-methyl-6-(methyloxy)-2-({3-[3-(trifluoro-methyl)pyridin-4-yl]phenyl}-amino)-1H-benzimidazol-5-yl]-oxy}pyridine-2-carboxamide
549.5
702


 


1064




4-[(2-{[3-(2-fluoropyridin-4-yl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
455.5
702


 


1065




4-{[2-{[3-(2-fluoropyridin-4-yl)phenyl]amino}-1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide
499.5
702


 


1066




4-[(2-{[3-(2-fluoropyridin-4-yl)-4-methylphenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide
469.5
702


 


1067




4-{[2-({3-(2-fluoropyridin-4-yl)-4-[(trifluoromethyl)oxy]-phenyl}amino)-1H-benz-imidazol-5-yl]oxy}-N-methyl-pyridine-2-carboxamide
539.5
702


 


1068




4-[(2-{[3-(2-fluoropyridin-4-yl)-4-methylphenyl]amino}-1-methyl-1H-benzimidazol-5-yl)-oxy]-N-(2-hydroxyethyl)-pyridine-2-carboxamide
513.5
483


 


1069




4-[(2-{[3-(2-fluoropyridin-4-yl)-4-methylphenyl]amino}-1-methyl-1H-benzimidazol-5-yl)-oxy]-N-[3-(2-oxopyrrolidin-1-yl)propyl]pyridine-2-carboxamide
594.7
483


 


1070




N-[2-(dimethyl-amino)ethyl]-4-[(2-{[3-(2-fluoropyridin-4-yl)-4-methylphenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide
540.6
483


 


1071




4-[(2-{[3-(2-fluoropyridin-4-yl)-4-methylphenyl]amino}-1-methyl-1H-benzimidazol-5-yl)-oxy]-N-(2-morpholin-4-ylethyl)-pyridine-2-carboxamide
582.6
483


 


1072




4-[(2-{[3-(2-fluoropyridin-4-yl)-4-methylphenyl]amino}-1-methyl-1H-benzimidazol-5-yl)-oxy]-N-(2,2,2-trifluoroethyl)-pyridine-2-carboxamide
551.5
483


 


1073




4-[(2-{[3-(2-fluoropyridin-4-yl)-methylphenyl]amino}-1-methyl-1H-benzimidazol-5-yl)-oxy]-N-(2-piperazin-1-ylethyl)pyridine-2-carboxamide
581.7
483


 


1074




N-[2-(acetyl-amino)ethyl]-4-[(2-{[3-(2-fluoropyridin-4-yl)-4-methylphenyl[-amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide
554.6
483


 


1075




4-[(2-{[3-(2-fluoropyridin-4-yl)-4-methylphenyl]amino}-1-methyl-1H-benzimidazol-5-yl)-oxy]-N-(2-piperidin-1-ylethyl)pyridine-2-carboxamide
580.7
483


 


1076




4-[(2-{[3-(2-fluoropyridin-4-yl)-4-methylphenyl]amino}-1-methyl-1H-benzimidazol-5-yl)-oxy]-N-[1-(1-methylethyl)azetidin-3-yl]pyridine-2-carboxamide
566.7
636


 


1077




4-[(2-{[3-(2-fluoropyridin-4-yl)-4-(methyl-oxy)phenyl]methyl}-1-methyl-1H-benzimidazol-5-yl)-oxy]-N-methyl-pyridine-2-carboxamide
498.5
636


 


1078




N-methyl-4-({1-methyl-2-[(4-methylphenyl)methyl]-1H-benzimidazol-5-yl}oxy)-pyridine-2-carboxamide
387.5
636


 


1079




N-methyl-4-[(1-methyl-2-{[4-(methyl-oxy)phenyl]methyl}-1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide
403.5
636


 


1080




N-methyl-4-[(1-methyl-2-{[4-(1-methyl-ethyl)phenyl]methyl}-1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide
415.5
636


 


1081




N-methyl-4-{[1-methyl-2-({4-[(trifluoro-methyl)oxy]phenyl}methyl)-1H-benzimidazol-5-yl]-oxy}pyridine-2-carboxamide
457.4
636


 


1082




4-({2-[(4-chlorophenyl)methyl]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide
407.9
636


 


1083




N-methyl-4-[(1-methyl-2-{[4-(trifluoromethyl)phenyl]methyl}-1H-benzimidazol-5-yl)oxy]-pyridine-2-carboxamide
441.4
636


 


1084




4-{[2-{[3-(1,1-dimethylethyl)-phenyl]amino}-1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide
460.5
703


 


1085




N-methyl-4-{[1-methyl-2-{[3-(1-methylethyl)phenyl]-amino}-6-(methyloxy)-1H-benz-imidazol-5-yl]oxy}pyridine-2-carboxamide
446.5
703


 


1086




N-methyl-4-[(2-{[3-(1-methyl-ethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide
402.5
 1


 


1087




4-[(2-{[4-(1,1-dimethylethyl)-3-(2-fluoropyridin-4-yl)phenyl]-amino}-1-methyl-1H-benz-imidazol-5-yl)oxy]-N-methyl-pyridine-2-carboxamide
525.6
702


 


1088




4-{[2-{[4-(1,1-dimethylethyl)-3-(2-fluoropyridin-4-yl)phenyl]-amino}-1-methyl-6-(methyl-oxy)-1H-benzimidazol-5-yl]-oxy}-N-methyl-pyridine-2-carboxamide
555.6
702


 


1089




4-[(2-{[4-(1,1-dimethylethyl)-3-(2-fluoropyridin-4-yl)phenyl]-amino}-1H-benzimidazol-5-yl)-oxy]-N-methylpyridine-2-carboxamide
511.6
702


 


1090




4-{[2-{[3-(2-fluoropyridin-4-yl)-4-methylphenyl]amino}-1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide
513.5
702


 


1091




4-[(2-{[3-(2,6-dimethylpyridin-4-yl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)-oxy]-N-methyl-pyridine-2-carboxa-mide
479.6
702


 


1092




4-[(2-{[3-(2,6-dimethylpyridin-4-yl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]-N-methyl-pyridine-2-carboxamide
465.5
702


 


1093




4-{[2-{[3-(2,6-dimethylpyridin-4-yl)phenyl]amino}-1-methyl-6-(methyloxy)-1H-benzimidazol-5-yl]oxy}-N-methylpyridine-2-carboxamide
509.6
702


 


1094a




N-methyl-4-({1-methyl-2-[(4-methyl-3-thien-2-ylphenyl)-amino]-1H-benzimidazol-5-yl}-oxy)pyridine-2-carboxamide
470.6
702


 


1094b




N-methyl-4-({1-methyl-2-[(3-thien-3-ylphenyl)amino]-1H-benzimidazol-5-yl}oxy)-pyridine-2-carboxamide
456.5
702









General Preparation for Phenolic Benzimidazoles
3-Amino-4-methylaminophenol




Diamine 2 prepared as per Example 120b from nitroaniline 1.
EXAMPLE 1095
2-(3-Bromophenylamino)-1-methyl-1H-benzoimidazol-5-ol




Benzimidazole 2 was prepared as per Example 120b: LCMS m/z 318.1 (MH+), tR=2.07 min.
EXAMPLE 1096




LCMS m/z 332.1 (MH+), tR=2.22 min
EXAMPLE 1097




LCMS m/z 366.1 (MH+), tR=2.13 min
EXAMPLE 1098




LCMS m/z 340.2 (MH+), tR=2.39 min
EXAMPLE 1099
Preparation of Symmetrical bis-Benzimidazoles
Step 1: 4,4′-dimethylamino-3,3′-dinitro diphenyl ether




Diphenyl ether 2 was prepared using the method described in Example 120b: 1H NMR (300 MHz, CDCl3) δ 7.98 (br s, 2 H), 7.75 (d, J=3.0 Hz, 2 H), 7.29 (app d, J=3.0 Hz, 1 H), 6.87 (d, J=9.5 Hz, 2 H), 3.05 (d, J=5.2 Hz, 6 H).
Step 2: 4,4′-dimethylamino-3,3′-diamino diphenyl ether




Tetramine 2 was prepared as per Example 120b: 1H NMR (300 MHz, CDCl3) δ 6.59 (d, J=8.5 Hz, 2 H), 6.47 (dd, J=2.8, 8.5 Hz, 2 H), 6.41 (d, J=2.8 Hz, 2 H), 3.40 (br s, 4 H), 3.06 (br s, 2 H), 2.84 (d, J=5.5 Hz, 6 H).
EXAMPLE 1100
bis-5-[2-(3-Bromophenylamino)-1-methyl-1H-benzoimidazole]-ether




Prepared as per Example 120b: LCMS m/z 617.1 (MH+), tR=2.27 min
EXAMPLE 1101




Prepared as per Example 120b: LCMS m/z 573.4 (MH+), tR=2.78 min
EXAMPLE 1102




Prepared as per Example 120b: LCMS m/z 661.2 (MH+), tR=2.83 min
EXAMPLE 1103




Prepared as per Example 120b: LCMS m/z 545.4 (MH+), tR=2.73 min
EXAMPLE 1104




Prepared as per Example 120b: LCMS m/z 461.3 (MH+), tR=1.98 min
EXAMPLE 1105
Preparation of Benzo Derivatives
2-(N-Phthalimido)-4-fluoronitrobenzene




A suspension of 2,4 difluoronitrobenzene (15.9 g, 100 mmol) and postassium phthalimide (16.5 g, 100 mmol) was stirred in dry NMP (50 mL) for 3 d. The reaction solution was poured into MTBE and the resulting precipitate was collected by filtration. The solids were washed with MTBE (3×) and the mother liquor was extracted with MTBE (3×). The combined organic portions were washed with water (3×) and concentrated to furnish a yellow solid which was combined with the initial crop of precipitate. The combined crude solid was purified by recrystallization from hot toluene, and the crystals were washed with cold MTBE: 1H NMR (300 MHz, d6-DMSO) δ 8.31 (dd, J=5.2, 9.1 Hz, 1 H), 7.98 (m, 4 H), 7.69 (dd, J=2.8, 9.1 Hz, 1 H), 7.62 (ddd, J=1.7, 2.8, 7.7 Hz, 1 H).
EXAMPLE 1106
2-(N-Phthalimido)-4-phenoxynitrobenzene




2-(N-Phthalimido)-4-phenoxynitrobenzene 2 was prepared using a similar procedure employed in Example 120b.
EXAMPLE 1107
2-(N-Phthalimido)-4-phenoxyaniline




2-(N-Phthalimido)-4-phenoxyaniline 2 was obtained through the reduction of 2-(N-phthalimido)-4-phenoxynitrobenzene 1 as described in Example 120b.
EXAMPLE 1108
N-[2-(N-Phthalimido)-4-phenoxy-phenyl]-formamide




A mixture of formic acid (0.12 mL, 5.3 mmol) and acetic anhydride (0.24 mL, 2.5 mmol) was heated to 60° C. for 2 h. After allowing to cool to rt, a solution of aniline 1 (387 mg, 1.0 mmol) in dry THF (1 mL) was added and the reaction was maintained overnight. The reaction was concentrated and the resulting crude residue was directly used in the next step.
EXAMPLE 1109
N-Methyl-[2-(N-phthalimido)-4-phenoxy]-aniline




A solution of formamide 1 was treated with BH3-DMS solution (2.0 M in CH2Cl2, 0.5 mL, 1.0 mL) and the reaction was allowed to warm to rt overnight. The reaction was concentrated and the resulting residue was dissolved in EtOAc. The solution was partitioned with saturated aqueous NaHCO3 solution and the layers were separated. The aqueous phase was extracted with EtOAc (3×) and the combined organics phases were washed with brine, dried (MgSO4), adsorbed onto SiO2 and purified by flash chromatography (4:1 hexanes-EtOAc) to furnish 2 as a colorless residue.
EXAMPLE 1110
N1-Methyl-4-phenoxybenzene-1,2-diamine




Hydrazine monohydrate (0.13 mL, 2.7 mmol) was added to a solution of phthalimide 1 (134 mg, 0.39 mmol) in ethanol (4 mL). The reaction was maintained overnight at rt and then was filtered through Celite. The filter cake was rinse with EtOAc (3×) and the organic portions were combined and concentrated to give diamine 2 which was carried forward without further purification: LCMS m/z 215.1 (MH+), tR=1.77 min.
EXAMPLE 1111
Synthesis of (4-Bromophenyl)-(1-methyl-5-phenoxy-1H-benzoimidazol-2-yl)-amine




Benzimidazole 2 was prepared as per Example 120b: 1H NMR (300 MHz, CD3OD) δ 7.68 (app ddd, J=2.9, 4.9, 8.8 Hz, 2 H), 7.53 (app d, J=8.8 Hz, 1 H), 7.41 (app ddd, J=2.9, 4.9, 8.8 Hz, 2 H), 7.40 (app ddd, J=1.0, 2.0, 8.5 Hz, 2 h), 7.24 (app ddd, J=1.0, 2.0, 8.5 Hz, 1 H), 7.07 (app dd, J=2.2, 8.8 Hz, 1 H), 7.00 (app d, J=2.2 Hz, 1 H), 7.00 (app ddd, J=1.0, 2.0, 8.5 Hz, 2 H), 3.82 (s, 3 H); LCMS m/z 394.0 (MH+), tR=2.36 min.
EXAMPLE 1112




A solution of 1 in MeCN was treated with aqueous 1 N HCl and freeze dried. The resulting residue was purified by reverse-phase HPLC to provide vinyl chloride 2 as a TFA salt: LCMS m/z 434.2 (MH+), tR=2.48 min.
EXAMPLE 1113
4-[2-(3-Furan-3-yl-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyrindine-2-carboxylic acid methyl amide




A solution of Pd(OAc)2 (4.5 mg, 0.02 mmol) and triphenylphosphine (13.1 mg 0.05 mmol) in dry NMP (1 mL) was stirred at rt for 20 min. Aryl iodide 1 (100 mg, 0.2 mmol), 3-furyl boronic acid (45 mg, 0.4 mmol), and triethylamine (0.11 mL, 0.8 mmol) were added and the resulting solution was degassed and purged with Ar. The reaction was heated to 100° C. for 2 h; LCMS indicated no conversion. The reaction was allowed to cool to rt under Ar and Pd(dppf)Cl2CH2Cl2 and diisopropylethylamine (0.14 mL) were added. The reaction was heated to 100° C. and maintained overnight. The reaction was allowed to cool to rt and LCMS indicated complete conversion. The reaction was partitioned between saturated aqueous NaHCO3 solution and EtOAc and the resulting mixture filtered through Celite. The remaining solids were washed with water and EtOAc. The combined rinsings were partitioned and separated. The aqueous phase was extracted with EtOAc (3×) and the combined organic portions were washed with saturated aqueous Na2CO3, brine, dried (MgSO4), and concentrated. The crude residue was purified by reverse-phase HPLC to furnish 2 as a TFA salt: LCMS m/z 440.3 (MH+), tR=2.35 min.
EXAMPLE 1114




Prepared as per Example 120b.
EXAMPLE 1115




Prepared as per Example 120b.
EXAMPLE 1116
Raf/Mek Filtration Assay
Buffers
Assay buffer: 50 mM Tris, pH 7.5, 15 mM MgCl2, 0.1 mM EDTA, 1 mM DTT
Wash buffer: 25 mM Hepes, pH 7.4, 50 mM sodium pyrophosphate, 500 mM NaCl
Stop reagent: 30 mM EDTA










Materials
















Raf, active:
Upstate Biotech #14–352


Mek, inactive:
Upstate Biotech #14–205


33P-ATP:
NEN Perkin Elmer #NEG 602 h


96 well assay plates:
Falcon U-bottom polypropylene



plates #35–1190


Filter apparatus:
Millipore #MAVM 096 OR


96 well filtration plates:
Millipore Immobilon 1 #MAIP NOB


Scintillation fluid:
Wallac OptiPhase “SuperMix” #1200–439









Assay Conditions

Raf approximately 120 pM
Mek approximately 60 nM
33P-ATP 100 nM
Reaction time 45–60 minutes at room temperature
Assay Protocol
Raf and Mek were combined at 2× final concentrations in assay buffer (50 mM Tris, pH 7.5, 15 mM MgCl2. 0.1 mM EDTA and 1 mM DTT) and dispensed 15 μl per well in polypropylene assay plates (Falcon U-bottom polypropylene 96 well assay plates #35-1190. Background levels are determined in wells containing Mek and DMSO without Raf.
To the Raf/Mek containing wells was added 3 μl of 10× of a raf kinase inhibitor test compound diluted in 100% DMSO. The raf kinase activity reaction was started by the addition of 12 μl per well of 2.5×33P-ATP diluted in assay buffer. After 45–60 minutes, the reactions were stopped with the addition of 70 μl of stop reagent (30 mM EDTA). Filtration plates were pre-wetted for 5 min with 70% ethanol, and then rinsed by filtration with wash buffer. Samples (90 μl) from the reaction wells were then transferred to the filtration plates. The filtration plates were washed 6× with wash buffer using Millipore filtration apparatus. The plates were dried and 100 μl per well of scintillation fluid (Wallac OptiPhase “SuperMix” #1200-439) was added. The CPM is then determined using a Wallac Microbeta 1450 reader.
EXAMPLE 1117
ASSAY 2: Biotinylated Raf Screen
In Vitro Raf Screen
The activity of various isoforms of Raf serine/threonine kinases can be measured by providing ATP, MEK substrate, and assaying the transfer of phosphate moiety to the MEK residue. Recombinant isoforms of Raf were obtained by purification from sf9 insect cells infected with a human Raf recombinant baculovirus expression vector. Recombinant kinase inactive MEK was expressed in E. coli and labeled with Biotin post purification. For each assay, test compounds were serially diluted in DMSO then mixed with Raf (0.50 nM) and kinase inactive biotin-MEK (50 nM) in reaction buffer plus ATP (1 uM). Reactions were subsequently incubated for 2 hours at room temperature and stopped by the addition of 0.5 M EDTA. Stopped reaction mixture was transferred to a neutradavin-coated plate (Pierce) and incubated for 1 hour. Phosphorylated product was measured with the DELFIA time-resolved fluorescence system (Wallac), using a rabbit anti-p-MEK (Cell Signaling) as the primary antibody and europium labeled anti-rabbit as the secondary antibody. Time resolved fluorescence was read on a Wallac 1232 DELFIA fluorometer. The concentration of each compound for 50% inhibition (IC50) was calculated by non-linear regression using XL Fit data analysis software.
Using the procedures of Examples 1116 or 1117, the compounds of Examples 1–1094 were shown to have a raf kinase inhibitory activity at an IC50 of less than 5 μM.
While the preferred embodiment of the invention has been illustrated and described, it will be appreciated that various changes can be made therein without departing from the spirit and scope of the invention.

## Claims

1. A compound of the formula (I):



wherein, X1 and X2 are ═N— or —NR4—, provided that if X1 is —NR4—, then X2 is ═N—, or if X2 is —NR4—, then X1 is ═N—;
Y is O or S;
A1 is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl, heteroarylaryl, heteroarylheteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, biarylalkyl, or heteroarylarylalkyl;
A2 is substituted or unsubstituted heteroaryl;
R1 is O or H, and R2 is NR5 R6 or hydroxyl; or R1 is taken together with R2 to form a substituted or unsubstituted heterocycloalkyl or heteroaryl group; wherein, the dashed line represents a single or double bond, provided that





represents a double bond when R1 is O and




represents a single bond when R1 is H;
R3 is hydrogen, halogen, loweralkyl, or loweralkoxy;
R4 is hydrogen, hydroxyl, alkylamino, dialkylamino or alkyl;
R5 and R6 are independently selected from hydrogen, and substituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl; or R5 and R6 are taken together to form substituted or unsubstituted heterocyclo or heteroaryl; and
the pharmaceutically acceptable salts, esters and prodrugs thereof.

2. A compound of claim 1 wherein X1 is NR4.

3. A compound of claim 2 wherein R4 is hydrogen.

4. A compound of claim 2 wherein R4 is methyl.

5. A compound of claim 1 wherein Y is O.

6. A compound of claim 1 wherein A1 is selected from the group consisting of substituted or unsubstituted phenyl, pyridyl, pyrimidinyl, phenylalkyl, pyridylalkyl, pyrimidinylalkyl, heterocyclylcarbonylphenyl, heterocyclylphenyl, heterocyclylalkylphenyl, chlorophenyl, fluorophenyl, bromophenyl, iodophenyl, dihalophenyl, nitrophenyl, 4-bromophenyl, 4-chlorophenyl, alkylbenzoate, alkoxyphenyl, dialkoxyphenyl, dialkylphenyl, trialkylphenyl, thiophene, thiophene-2-carboxylate, alkylthiophenyl, trifluoromethylphenyl, acetylphenyl, sulfamoylphenyl, biphenyl, cyclohexylphenyl, phenyloxyphenyl, dialkylaminophenyl, alkylbromophenyl, alkylchlorophenyl, alkylflourophenyl, triflouromethylchlorophenyl, triflouromethylbromophenyl, indenyl, 2,3-dihydroindenyl, tetralinyl, trifluorophenyl, (trifluoromethyl)thiophenyl, alkoxybiphenyl, morpholinyl, N-piperazinyl, N-morpholinylalkyl, piperazinylalkyl, cyclohexylalkyl, indolyl, 2,3-dihydroindolyl, 1-aceytl-2,3-dihydroindolyl, cycloheptyl, bicyclo[2.2.1]hept-2-yl, hydroxyphenyl, hydroxyalkylphenyl, pyrrolidinyl, pyrrolidin-1-yl, pyrrolidin-1-ylalkyl, 4-amino(imino)methylphenyl, isoxazolyl, indazolyl, adamantyl, bicyclohexyl, quinuclidinyl, imidazolyl, benzimidazolyl, imidazolylphenyl, phenylimidazolyl, pthalamido, napthyl, benzophenone, anilinyl, anisolyl, quinolinyl, quinolinonyl, phenylsulfonyl, phenylalkylsulfonyl, 9H-flouren-1-yl, piperidin-1-yl, piperidin-1-ylalkyl, cyclopropyl, cyclopropylalkyl, pyrimidin-5-ylphenyl, quinolidinylphenyl, furanyl, furanylphenyl, N-methylpiperidin-4-yl, pyrrolidin-4-ylpyridinyl, 4-diazepan-1-yl, hydroxypyrrolidn-1-yl, dialkylaminopyrrolidin-1-yl, 1,4′-bipiperidin-1′-yl, and (1,4′-bipiperidin-1′-ylcarbonyl)phenyl.

7. A compound of claim 1 wherein A2 is substituted or unsubstituted pyridyl.

8. A compound of claim 1 wherein R1 is O and




represents a double bond.

9. A compound of claim 1 wherein R2 is NR5R6, R5 is hydrogen and R6 is selected from hydrogen, and substituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl.

10. A compound of claim 1 wherein R1 is taken together with R2 to form a substituted or unsubstituted heterocycloalkyl or heteroaryl group.

11. A compound of claim 1 wherein R3 is loweralkoxy.

12. A compound of claim 11 wherein R3 is methoxy.

13. A compound of claim 1 wherein R4 is loweralkyl.

14. A compound of claim 13 wherein R4 is methyl.

15. The compound of claim 1 wherein R1 is O, R2 is NR5R6, R5 is H, and R6 is methyl.

16. A compound of the formula (II):



wherein and Y is O or S;
A1 is substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl, heteroarylaryl, heteroarylheteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, biarylalkyl, or heteroarylarylalkyl;
A2 is substituted or unsubstituted heteroaryl;
R1 is O and R2 is NR5 R6; or R1 is taken together with R2 to form a substituted or unsubstituted heterocycloalkyl or heteroaryl group; wherein, the dashed line represents a single or double bond, provided that R1 is O,





represents a double bond;
R3 is hydrogen, halogen, loweralkyl, or loweralkoxy;
R4 is hydrogen or loweralkyl;
R5 and R6 are independently selected from hydrogen, and substituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl; or R5 and R6 are taken together to form substituted or unsubstituted heterocyclo or heteroaryl; and
the pharmaceutically acceptable salts, esters, and prodrugs thereof.

17. A compound of claim 16 wherein R4 is hydrogen.

18. A compound of claim 16 wherein R4 is methyl.

19. A compound of claim 16 wherein Y is O.

20. A compound of claim 16 wherein A1 is selected from the group consisting of substituted or unsubstituted phenyl, pyridyl, pyrimidinyl, phenylalkyl, pyridylalkyl, pyrimidinylalkyl, heterocyclylcarbonylphenyl, heterocyclylphenyl, heterocyclylalkylphenyl, chlorophenyl, fluorophenyl, bromophenyl, iodophenyl, dihalophenyl, nitrophenyl, 4-bromophenyl, 4-chlorophenyl, alkylbenzoate, alkoxyphenyl, dialkoxyphenyl, dialkylphenyl, trialkylphenyl, thiophene, thiophene-2-carboxylate, alkylthiophenyl, trifluoromethylphenyl, acetylphenyl, sulfamoylphenyl, biphenyl, cyclohexylphenyl, phenyloxyphenyl, dialkylaminophenyl, alkylbromophenyl, alkylchlorophenyl, alkylflourophenyl, triflouromethylchlorophenyl, triflouromethylbromophenyl indenyl, 2,3-dihydroindenyl, tetralinyl, trifluorophenyl, (trifluoromethyl)thiophenyl, alkoxybiphenyl, morpholinyl, N-piperazinyl, N-morpholinylalkyl, piperazinylalkyl, cyclohexylalkyl, indolyl, 2,3-dihydroindolyl, 1-aceytl-2,3-dihydroindolyl, cycloheptyl, bicyclo[2.2.1-]hept-2-yl, hydroxyphenyl, hydroxyalkylphenyl, pyrrolidinyl, pyrrolidin-1-yl, pyrrolidin-1-ylalkyl, 4-amino(imino)methylphenyl, isoxazolyl, indazolyl, adamantyl, bicyclohexyl, quinuclidinyl, imidazolyl, benzimidazolyl, imidazolylphenyl, phenylimidazolyl, pthalamido, napthyl, benzophenone, anilinyl, anisolyl, quinolinyl, quinolinonyl, phenylsulfonyl, phenylalkylsulfonyl, 9H-flouren-1-yl, piperidin-1-yl, piperidin-1-ylalkyl, cyclopropyl, cyclopropylalkyl, pyrimidin-5-ylphenyl, quinolidinylphenyl, furanyl, furanylphenyl, N-methylpiperidin-4-yl, pyrrolidin-4-ylpyridinyl, 4-diazepan-1-yl, hydroxypyrrolidn-1-yl, dialkylaminopyrrolidin-1-yl, 1,4′-bipiperidin-1′-yl, and (1,4′-bipiperidin-1′-ylcarbonyl)phenyl.

21. A compound of claim 16 wherein A2 is substituted or unsubstituted pyridyl.

22. A compound of claim 16 wherein R2 is NR5R6, R5 is hydrogen and R6 is selected from hydrogen, and substituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl.

23. A compound of claim 16 wherein R1 is taken together with R2 to form a substituted or unsubstituted heterocycloalkyl or heteroaryl group.

24. A compound of claim 16 wherein R1 is O, R2 is NR5R6, R5 is H, and R6 is methyl.

25. A compound of claim 16 wherein R3 is loweralkoxy.

26. A compound of claim 25 wherein R3 is methoxy.

27. A compound of claim 16 wherein R4 is loweralkyl.

28. A compound of claim 27 wherein R4 is methyl.

29. A compound of the formula (III):



wherein X is NR4;
A1 is substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl, heteroarylaryl, heteroarylheteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, biarylalkyl, or heteroarylarylalkyl;
A2 is substituted or unsubstituted heteroaryl;
R1 is O and R2 is NR5 R6; or R1 is taken together with R2 to form a substituted or unsubstituted heterocycloalkyl or heteroaryl group; wherein, the dashed line represents a single or double bond, provided that when R1 is O,





represents a double bond;
R3 is hydrogen, halogen, loweralkyl, or loweralkoxy;
R4 is hydrogen or loweralkyl;
R5 and R6 are independently selected from hydrogen, and substituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl; or R5 and R6 are taken together to form substituted or unsubstituted heterocyclo or heteroaryl; and
the pharmaceutically acceptable salts, esters and prodrugs thereof.

30. A compound of claim 29 wherein R4 is hydrogen.

31. A compound of claim 29 wherein R4 is methyl.

32. A compound of claim 29 wherein A1 is selected from the group consisting of substituted or unsubstituted phenyl, pyridyl, pyrimidinyl, phenylalkyl, pyridylalkyl, pyrimidinylalkyl, heterocyclylcarbonylphenyl, heterocyclylphenyl, heterocyclylalkylphenyl, chlorophenyl, fluorophenyl, bromophenyl, iodophenyl, dihalophenyl, nitrophenyl, 4-bromophenyl, 4-chlorophenyl, alkylbenzoate, alkoxyphenyl, dialkoxyphenyl, dialkylphenyl, trialkylphenyl, thiophene, thiophene-2-carboxylate, alkylthiophenyl, trifluoromethylphenyl, acetylphenyl, sulfamoylphenyl, biphenyl, cyclohexylphenyl, phenyloxyphenyl, dialkylaminophenyl, alkylbromophenyl, alkylchlorophenyl, alkylflourophenyl, triflouromethylchlorophenyl, triflouromethylbromophenyl indenyl, 2,3-dihydroindenyl, tetralinyl, trifluorophenyl, (trifluoromethyl)thiophenyl, alkoxybiphenyl, morpholinyl, N-piperazinyl, N-morpholinylalkyl, piperazinylalkyl, cyclohexylalkyl, indolyl, 2,3-dihydroindolyl, 1-aceytl-2,3-dihydroindolyl, cycloheptyl, bicyclo[2.2.1]hept-2-yl, hydroxyphenyl, hydroxyalkylphenyl, pyrrolidinyl, pyrrolidin-1-yl, pyrrolidin-1-ylalkyl, 4-amino(imino)methylphenyl, isoxazolyl, indazolyl, adamantyl, bicyclohexyl, quinuclidinyl, imidazolyl, benzimidazolyl, imidazolylphenyl, phenylimidazolyl, pthalamido, napthyl, benzophenone, anilinyl, anisolyl, quinolinyl, quinolinonyl, phenylsulfonyl, phenylalkylsulfonyl, 9H-flouren-1-yl, piperidin-1-yl, piperidin-1-ylalkyl, cyclopropyl, cyclopropylalkyl, pyrimidin-5-ylphenyl, quinolidinylphenyl, furanyl, furanylphenyl, N-methylpiperidin-4-yl, pyrrolidin-4-ylpyridinyl, 4-diazepan-1-yl, hydroxypyrrolidn-1-yl, dialkylaminopyrrolidin-1-yl, 1,4′-bipiperidin-1′-yl, and (1,4′-bipiperidin-1′-ylcarbonyl)phenyl.

33. A compound of claim 29 wherein A2 is substituted or unsubstituted pyridyl.

34. A compound of claim 29 wherein R2 is NR5R6, R5 is hydrogen and R6 is selected from hydrogen, and substituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl.

35. A compound of claim 29 wherein R1 is taken together with R2 to form a substituted or unsubstituted heterocycloalkyl or heteroaryl group.

36. A compound of claim 29 wherein R3 is loweralkoxy.

37. A compound of claim 36 wherein R3 is methoxy.

38. A compound of claim 29 wherein R4 is loweralkyl.

39. A compound of claim 38 wherein R4 is methyl.

40. A compound of claim 29 wherein R1 is O, R2 is NR5R6, R5 is H, and R6 is methyl.

41. A compound of the formula (IV):



wherein X is NR4;
Y is O or S;
A1 is substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl, heteroarylaryl, heteroarylheteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, biarylalkyl, or heteroarylarylalkyl;
R1 is O and R2 is NR5 R6; or R1 is taken together with R2 to form a substituted or unsubstituted heterocycloalkyl or heteroaryl group; wherein, the dashed line represents a single or double bond, provided that when R1 is O,





represents a double bond;
R3 is hydrogen, halogen, loweralkyl, or loweralkoxy;
R4 is hydrogen or loweralkyl;
R5 and R6 are independently selected from hydrogen, and substituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl; or R5 and R6 are taken together to form substituted or unsubstituted heterocyclo or heteroaryl; and
the pharmaceutically acceptable salts, esters and prodrugs thereof.

42. A compound of claim 41 wherein R4 is hydrogen.

43. A compound of claim 41 wherein R4 is methyl.

44. A compound of claim 41 wherein Y is O.

45. A compound of claim 41 wherein A1 is selected from the group consisting of substituted or unsubstituted phenyl, pyridyl, pyrimidinyl, phenylalkyl, pyridylalkyl, pyrimidinylalkyl, heterocyclylcarbonylphenyl, heterocyclylphenyl, heterocyclylalkylphenyl, chlorophenyl, fluorophenyl, bromophenyl, iodophenyl, dihalophenyl, nitrophenyl, 4-bromophenyl, 4-chlorophenyl, alkylbenzoate, alkoxyphenyl, dialkoxyphenyl, dialkylphenyl, trialkylphenyl, thiophene, thiophene-2-carboxylate, alkylthiophenyl, trifluoromethylphenyl, acetylphenyl, sulfamoylphenyl, biphenyl, cyclohexylphenyl, phenyloxyphenyl, dialkylaminophenyl, alkylbromophenyl, alkylchlorophenyl, alkylflourophenyl, triflouromethylchlorophenyl, triflouromethylbromophenyl indenyl, 2,3-dihydroindenyl, tetralinyl, trifluorophenyl, (trifluoromethyl)thiophenyl, alkoxybiphenyl, morpholinyl, N-piperazinyl, N-morpholinylalkyl, piperazinylalkyl, cyclohexylalkyl, indolyl, 2,3-dihydroindolyl, 1-aceytl-2,3-dihydroindolyl, cycloheptyl, bicyclo[2.2.1]hept-2-yl, hydroxyphenyl, hydroxyalkylphenyl, pyrrolidinyl, pyrrolidin-1-yl, pyrrolidin-1-ylalkyl, 4-amino(imino)methylphenyl, isoxazolyl, indazolyl, adamantyl, bicyclohexyl, quinuclidinyl, imidazolyl, benzimidazolyl, imidazolylphenyl, phenylimidazolyl, pthalamido, napthyl, benzophenone, anilinyl, anisolyl, quinolinyl, quinolinonyl, phenylsulfonyl, phenylalkylsulfonyl, 9H-flouren-1-yl, piperidin-1-yl, piperidin-1-ylalkyl, cyclopropyl, cyclopropylalkyl, pyrimidin-5-ylphenyl, quinolidinylphenyl, furanyl, furanylphenyl, N-methylpiperidin-4-yl, pyrrolidin-4-ylpyridinyl, 4-diazepan-1-yl, hydroxypyrrolidn-1-yl, dialkylaminopyrrolidin-1-yl, 1,4′-bipiperidin-1′-yl, and (1,4′-bipiperidin-1′-ylcarbonyl)phenyl.

46. A compound of claim 41 wherein R2 is NR5R6, R5 is hydrogen and R6 is selected from hydrogen, and substituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl.

47. A compound of claim 41 wherein R1 is taken together with R2 to form a substituted or unsubstituted heterocycloalkyl or heteroaryl group.

48. A compound of claim 41 wherein R3 is loweralkoxy.

49. A compound of claim 48 wherein R3 is methoxy.

50. A compound of claim 44 wherein R4 is loweralkyl.

51. A compound of claim 50 wherein R4 is methyl.

52. A compound of claim 41 wherein R1 is O, R2 is NR5R6, R5 is H, and R6 is methyl.

53. A compound of the formula (V):



wherein X is NR4;
A1 is substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl, heteroarylaryl, heteroarylheteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, biarylalkyl, or heteroarylarylalkyl;
R1 is O and R2 is NR5 R6; or R1 is taken together with R2 to form a substituted or unsubstituted heterocycloalkyl or heteroaryl group; wherein, the dashed line represents a single or double bond, provided that when R1is O,





represents a double bond;
R3 is hydrogen, halogen, loweralkyl, or loweralkoxy;
R4 is hydrogen or loweralkyl;
R5 and R6 are independently selected from hydrogen, and substituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl; or R5 and R6 are taken together to form substituted or unsubstituted heterocyclo or heteroaryl; and
the pharmaceutically acceptable salts, esters and prodrugs thereof.

54. A compound of claim 53 wherein R4 is hydrogen.

55. A compound of claim 53 wherein R4 is methyl.

56. A compound of claim 53 wherein A1 is selected from the group consisting of substituted or unsubstituted phenyl, pyridyl, pyrimidinyl, phenylalkyl, pyridylalkyl, pyrimidinylalkyl, heterocyclylcarbonylphenyl, heterocyclylphenyl, heterocyclylalkylphenyl, chlorophenyl, fluorophenyl, bromophenyl, iodophenyl, dihalophenyl, nitrophenyl, 4-bromophenyl, 4-chlorophenyl, alkylbenzoate, alkoxyphenyl, dialkoxyphenyl, dialkylphenyl, trialkylphenyl, thiophene, thiophene-2-carboxylate, alkylthiophenyl, trifluoromethylphenyl, acetylphenyl, sulfamoylphenyl, biphenyl, cyclohexylphenyl, phenyloxyphenyl, dialkylaminophenyl, alkylbromophenyl, alkylchlorophenyl, alkylflourophenyl, triflouromethylchlorophenyl, triflouromethylbromophenyl indenyl, 2,3-dihydroindenyl, tetralinyl, trifluorophenyl, (trifluoromethyl)thiophenyl, alkoxybiphenyl, morpholinyl, N-piperazinyl, N-morpholinylalkyl, piperazinylalkyl, cyclohexylalkyl, indolyl, 2,3-dihydroindolyl, 1-aceytl-2,3-dihydroindolyl, cycloheptyl, bicyclo [2.2.1]hept-2-yl, hydroxyphenyl, hydroxyalkylphenyl, pyrrolidinyl, pyrrolidin-1-yl, pyrrolidin-1-ylalkyl, 4-amino(imino)methylphenyl, isoxazolyl, indazolyl, adamantyl, bicyclohexyl, quinuclidinyl, imidazolyl, benzimidazolyl, imidazolylphenyl, phenylimidazolyl, pthalamido, napthyl, benzophenone, anilinyl, anisolyl, quinolinyl, quinolinonyl, phenylsulfonyl, phenylalkylsulfonyl, 9H-flouren-1-yl, piperidin-1-yl, piperidin-1-ylalkyl, cyclopropyl, cyclopropylalkyl, pyrimidin-5-ylphenyl, quinolidinylphenyl, furanyl, furanylphenyl, N-methylpiperidin-4-yl, pyrrolidin-4-ylpyridinyl, 4-diazepan-1-yl, hydroxypyrrolidn-1-yl, dialkylaminopyrrolidin-1-yl, 1,4′-bipiperidin-1′-yl, and (1,4′-bipiperidin-1′-ylcarbonyl)phenyl.

57. A compound of claim 53 wherein R2 is NR5R6, R5 is hydrogen and R6 is selected from hydrogen, and substituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl.

58. A compound of claim 53 wherein R1 is taken together with R2 to form a substituted or unsubstituted heterocycloalkyl or heteroaryl group.

59. A compound of claim 53 wherein R3 is loweralkoxy.

60. A compound of claim 59 wherein R3 is methoxy.

61. A compound of claim 53 wherein R4 is loweralkyl.

62. A compound of claim 61 wherein R4 is methyl.

63. A compound of claim 53 wherein R1 is O, R2 is NR5R6, R5 is H, and R6 is methyl.

64. A composition comprising an amount of a compound of claim 1, 16, 29, 41, or 53 effective to inhibit Raf activity in a human or animal subject when administered thereto, together with a pharmaceutically acceptable carrier.

65. A composition of claim 64 which further comprises at least one additional agent for the treatment of cancer.

66. A composition of claim 65 in which the at least one additional agent for the treatment of cancer is selected from irinotecan, topotecan, gemeitabine, 5-fluorouracil, leucovorin carboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide, vinca alkaloids, imatinib, anthracyclines, rituximab and trastuzumab.