HMOX1 inducers

Abstract

To provide heme oxygenase 1 (HMOX 1) inducers.SOLUTION: There are provided compounds represented by structural formula (I) as heme oxygenase 1 (HMOX 1) inducers (Formula I) and a method of controlling the activity or the amount, or both the activity and the amount, of heme-oxygenase 1 in a mammalian subject. A pharmaceutical composition is provided for use in methods of increasing the activity of or the amount of HMOX1 in a human subject, methods of activating transcription factor Nrf2 in a human subject, and methods of reducing the amount of ROS in a human subject, wherein the pharmaceutical composition comprises the compounds, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable diluent or carrier.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 833,031, filed April 12, 2019, and U.S. Provisional Patent Application No. 62 / 932,629, filed November 8, 2019. The entire teachings of the foregoing applications are incorporated herein by reference.

[0002] The present application relates to HMOX1 (heme oxygenase 1) inducers and methods of their use to regulate the activity or amount, or both the activity and amount, of heme oxygenase, for example, in a mammalian subject. [Background technology]

[0003] Oxidative stress represents an imbalance between the cellular production of reactive oxygen species (ROS) and the cellular response to ROS, such as the degradation of ROS species and the production of endogenous antioxidant molecules.

[0004] ROS respond to critical cell signaling requirements, but if produced in excess or left unchecked, they can have detrimental effects. Elevated intracellular ROS levels can damage components such as lipids, proteins, polysaccharides, and DNA. Prolonged oxidative stress is also associated with chronic diseases affecting nearly every major organ system. For example, prolonged oxidative stress has been implicated in the development or progression of pathologies such as neurodegenerative diseases, pulmonary disease, cardiovascular disease, renal disease, diabetes, inflammatory pain, and cancer. Therefore, strategies to mitigate oxidative stress are desirable in many therapeutic settings.

[0005] Under normal physiological conditions, ROS production is counteracted by a well-defined and conserved set of cellular pathways that respond to, limit, and repair ROS damage. This adaptive set of genes is called the Phase II system. They encode enzymes that not only directly degrade ROS but also increase the levels of endogenous antioxidant molecules in the cell, including glutathione and bilirubin.

[0006] Of the phase II enzyme systems, HMOX1, the human gene encoding the enzyme heme oxygenase 1, has been found to be a key component. The role of HMOX1 is to metabolize heme into bilirubin, carbon monoxide, and free iron through a two-step process. The first, rate-limiting step is the production of biliverdin and carbon monoxide from heme by HMOX1. The second step is the production of bilirubin from biliverdin by biliverdin reductase. Both bilirubin and carbon monoxide scavenge ROS and have been shown to have potent antioxidant and anti-inflammatory properties.

[0007] Agents that induce HMOX1 production have been shown to have beneficial activity in models of diabetes, cardiovascular disease, hypertension, and lung function. Heme, heavy metal ions (such as arsenite, cadmium, iron, lead, chromium, and mercury), and electrophiles (e.g., natural products such as sulforaphane and curcumin) can all induce HMOX1 production. The induction of HMOX1 and other phase II genes is controlled by numerous transcription factors that respond to heavy metals, heme, and electrophiles. The transcription factors Nrf2, Bach1, and small Maf proteins are particularly important in this process. For example, a common sequence called the antioxidant response element (ARE) is present in the promoter of each gene for phase II enzymes, and its expression is induced by the transcription factor Nrf2 (NF-E2-related factor 2).

[0008] HMOX1 is also induced as part of a general stress response to stimuli such as heat shock, oxidative stress, and cytokines such as interleukin-1 (IL-1), tumor necrosis factor, and interleukin-6 (IL-6). This stress response is considered beneficial in that it protects vulnerable cells from multiple insults.

[0009] It has been reported that HMOX1 can be induced by small molecules that bind to the transcription factor Bach1. It has been shown that heme binding to Bach1 reduces the DNA binding activity of Bach1 and induces gene transcription. See Ogawa K et al. EMBO J (2001) 20:2835-284 (Non-Patent Document 1). Furthermore, it has been reported that small molecules induce HMOX1 through binding to Bach1. See Attucks OC et al. PLOS ONE (2014) 9(7):e101044 (Non-Patent Document 2), WO2011 / 103018 (Patent Document 1), and WO2012 / 094580 (Patent Document 2).

[0010] Therefore, new HMOX1 inducers and / or Bach1 binders / inhibitors for the above therapeutic indications are needed. [Prior art documents] [Patent documents]

[0011] [Patent Document 1] WO2011 / 103018 [Patent Document 2] WO2012 / 094580 [Non-patent literature]

[0012] [Non-Patent Document 1] Ogawa K et al.EMBO J(2001)20:2835-284 [Non-patent document 2] Attucks OC et al.PLOS ONE(2014)9(7):e101044 Summary of the Invention

[0013] Applicants have discovered novel compounds that are effective HMOX1 inducers (see Examples 1-142). In particular, it has been demonstrated that certain compounds of the present invention effectively induce HMOX1 production (see Example 143). Certain compounds of the present invention also possess a combination of desirable properties, including potent HMOX1-inducing activity (see Example 143), significantly reduced hERG inhibition compared to certain comparative compounds (see Example 145), good solubility (see Example 144), and a strong effect on HMOX1 protein expression in vivo (see Example 151). Furthermore, Applicants have also discovered that the compounds disclosed herein bind to Bach1 (see Example 146).

[0014] In one embodiment, a compound of the following structural formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein the definition of each variable is provided below.

[0015] Pharmaceutical compositions of the compounds of the invention are also disclosed herein. Certain embodiments include a pharmaceutically acceptable carrier or diluent and one or more compounds of the invention or pharmaceutically acceptable salts thereof.

[0016] The compounds of formula (I) and pharmaceutically acceptable salts thereof are useful as agents that induce the production of and / or increase the activity of HMOX1, and therefore may be useful in treating a variety of chronic diseases that are at least in part related to oxidative stress, including, but not limited to, fibrotic diseases, neurodegenerative diseases, cardiovascular diseases, kidney diseases, inflammatory diseases, liver diseases, eye diseases, thyroid diseases, viral infections, osteoporosis, pregnancy disorders, endometriosis, diabetes, cancer, skin diseases, mitochondrial diseases, blood diseases, and muscle diseases.

[0017] Another embodiment of the present invention includes treating the above-mentioned diseases or conditions in a subject by administering to the subject an effective amount of one or more compounds of the present invention or pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising the disclosed compounds.

[0018] Also provided herein is the use of one or more compounds of the invention or pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising one or more compounds of the invention, for the preparation of a medicament for the treatment of the above-mentioned diseases or conditions.

[0019] In another embodiment, provided herein is a compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising one or more of the disclosed compounds, for use in the treatment of the above-mentioned diseases or conditions. [Brief explanation of the drawings]

[0020] [Figure 1A] Figures 1A and 1B are graphs showing the significant fold changes in gene-specific mRNA in HepG2 cells treated with the compound of Example 17 or the Nrf2 activator DMF. Figure 1A shows that the compound of Example 17 induces HMOX1 expression much more strongly than DMF. Figure 1B shows that the compound of Example 17 and DMF induce FTH1 expression with similar fold increases. [Figure 1B] See legend to Figure 1A. [Figure 2]1 is a graph showing that the compound of Example 17 inhibits microvascular congestion in Townes-SS sickle cell mice in a dose-responsive manner. Townes-SS mice were gavaged once daily for 8 days with vehicle or the compound of Example 17. After the final gavage, dorsal skinfold chambers were implanted into the mice, and 20-22 flowing venules were selected and mapped in the subcutaneous skin using an intravital microscope. The mice were then injected with panhematin (3.2 μmol heme / kg body weight) via the tail vein. One hour after injection, each venule was reexamined for microvascular congestion (no flow). Data are expressed as % congestion. Congestion values ​​are the mean + SD. Dunnett's one-way ANOVA with multiple comparisons to vehicle. ****P<0.0001 [Figure 3] 1 is a graph showing the percentage of F-cell increase in Townes-SS mice treated with the compound of Example 17. Heparinized whole blood was used to prepare blood smears for F-cell staining. Stained F-cells and total red blood cells were counted in four fields of blood smears. Mean = 77 red blood cells / field. F-cells are expressed as a percentage of total red blood cells. Values ​​are mean + SD. One-way ANOVA with multiple comparisons vs. Dunnett's vehicle. **p≦0.01, ***p≦0.001, ****p≦0.0001 [Figure 4] 1 is a graph showing glutathione (GSH) levels in primary human endothelial cells. Two-tailed unpaired t-test compared to DMSO ####p≦0.0001, one-way ANOVA with multiple comparisons compared to Dunnett's hemin (GSH graph) ****p≦0.0001 [Figure 5] Graph showing fold change in gene expression in primary human endothelial cells. ####p≦0.0001, Dunnett's one-way ANOVA with multiple comparisons to TNFα (VCAM graph)****p≦0.0001 DETAILED DESCRIPTION OF THE INVENTION

[0021] Detailed Description In response to elevated levels of reactive oxygen species (ROS), cells induce the expression of oxidative stress-responsive genes, such as genes encoding proteins that degrade ROS or increase the levels of endogenous antioxidant molecules in the cell. One such gene is HMOX1. The induction of HMOX1 and other oxidative stress-responsive gene expression is partially regulated by the transcription factor Nrf2. Under basal conditions, the adaptor protein Keap1 heterodimerizes with Nrf2, targeting Nrf2 for proteolysis and suppressing Nrf2-mediated transcription. Exposure of cells to chemical electrophiles or agents that increase ROS weakens the interaction between Keap1 and Nrf2, increasing intracellular Nrf2 levels, which in turn increases nuclear Nrf2 levels and induces oxidative stress-responsive genes. Nrf2 activity is also regulated by the transcriptional repressor Bach1, which blocks Nrf2 binding to the promoter regions of oxidative stress-responsive genes.

[0022] Therefore, to mitigate the effects of oxidative stress in cells, for example, in disease settings, it is desirable to identify compounds that promote the induction of oxidative stress-responsive gene expression, such as compounds that modulate the interaction between Nrf2 and Keap1 or the interaction between Bach1 and Maf recognition elements (MAREs) to increase the transcription of cytoprotective genes. However, it is also desirable that such compounds do not act as electrophiles or otherwise induce a stress response in cells.

[0023] Compounds of the Invention Disclosed herein are embodiments of compounds having the general structure of Formula (I):

[0024] In a first embodiment, the present invention provides a compound having the following structural formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A is a 5- to 7-membered monocyclic cycloalkyl, a 5- to 7-membered monocyclic heterocyclyl, a 5- to 6-membered heteroaryl, or phenyl; X is -S-, -O-, or -NR b - and When X is -S- and ring A is phenyl, R is selected from halo, -CN, -OH, -(C1-C4)alkyl, -(C1-C4)haloalkyl, -(C1-C4)hydroxyalkyl, -(C1-C4)alkoxy, -(C1-C4)haloalkoxy, and -NR a R a is a 3- to 7-membered monocyclic heterocyclyl optionally substituted with one or more groups selected from the group consisting of When X is -S- and ring A is a 5- to 7-membered monocyclic cycloalkyl, a 5- to 7-membered monocyclic heterocyclyl, or a 5- to 6-membered heteroaryl, or when X is -O- or -NR b -, R is -H, -(C1-C4) alkyl, or -(CH2) i The 3- to 7-membered monocyclic heterocyclyl is -(C1-C4) alkyl or 3- to 7-membered monocyclic heterocyclyl represented by R is halo, -CN, -OH, -(C1-C4) alkyl, -(C1-C4) haloalkyl, -(C1-C4) hydroxyalkyl, -(C1-C4) alkoxy, -(C1-C4) haloalkoxy, -SO2R a , and -NR a R a and optionally substituted with one or more groups selected from the group consisting of Each R1 is independently -H, halogen, -(CH2) k COOH, -(CH2) k CO(C1-C4) alkyl, -(CH2) k COO(C1-C4) alkyl, -(CH2) p C(=O)NR a R3, -CH(CF3)NR a R3, -C(=NOH)CF3, or -CH(CF3)OR3, and the (C1-C4) alkyl in the group represented by R1 is halo, -CN, -OH, -(C1-C4)hydroxyalkyl, -(C1-C4)alkoxy, -(C1-C4)haloalkoxy, and -NRa R a and optionally substituted with one or more groups selected from the group consisting of Each R2 is independently -H, halo, CN, -(C1-C4)alkyl, -OH, -(C1-C4)alkoxy, -COOH, -C(=O)(C1-C4)alkyl, -C(=O)O(C1-C4)alkyl, or -C(=O)NR a (C1-C4) alkyl, -NR a R a , 3-6 membered monocyclic cycloalkyl, -O(CH2) i a 3- to 7-membered monocyclic heterocyclyl, a 3- to 7-membered monocyclic heterocyclyl, or a 5- to 6-membered heteroaryl, and -(C1-C4)alkyl, -(C1-C4)alkoxy, heterocyclyl, or heteroaryl represented by R2 or in the group represented by R2 is selected from halo, -CN, -OH, -(C1-C4)alkyl, -(C1-C4)alkoxy, -(C1-C4)haloalkyl, -(C1-C4)hydroxyalkyl, -(C1-C4)haloalkoxy, and -NR a R a and optionally substituted with one or more groups selected from the group consisting of Each R3 is independently H, (C1-C4) alkyl, (C1-C4) alkoxy, -(CH2) p1 3-7 membered monocyclic heterocyclyl, -(CH2) p1 NH3-7 membered monocyclic heterocyclyl, 5-6 membered heteroaryl, -O(CH2) p2 NR a C(=O)(C1-C4) alkyl, -(CH2) p2 O(CH2) p2 O(C=O)(C1-C4) alkyl, or (CH2) p2 NR aC(═O)(C1-C4)alkyl, and alkyl, alkoxy, heteroaryl, or heterocyclyl represented by R3 or within a group represented by R3 is selected from halo, —CN, —OH, —(C1-C4)alkyl, —(C1-C4)haloalkyl, —(C1-C4)hydroxyalkyl, —(C1-C4)alkoxy, —(C1-C4)haloalkoxy, —(C1-C4)carboxyalkoxy, —S(O)2(C1-C4)alkyl, —(C1-C4)hydroxyalkoxy, and —NR a R a and optionally substituted with one or more groups selected from the group consisting of Each R a are independently —H or —(C1-C4)alkyl; Each R b are independently -H or -(C1-C4) alkyl, and R b The -(C1-C4) alkyl represented by the formula (I) may be substituted with one or more groups selected from halo, -CN, -OH, -(C3-C6)cycloalkyl, phenyl, 3- to 7-membered monocyclic heterocyclyl, and 5- or 6-membered heteroaryl; i is 0 or 1, k is 0, 1, 2, 3, or 4; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; p1 is 0, 1, 2, 3, or 4; p2 is 2, 3, or 4.

[0025] In a second embodiment, there is provided a compound according to the previous embodiment, wherein the compound has the following structural formula (II): [ka] or a pharmaceutically acceptable salt thereof, and the remainder of the variables are as defined in the first embodiment.

[0026] In a third embodiment, the present invention provides a compound according to the first embodiment, wherein the compound has structural formula (II'): [ka] or a pharmaceutically acceptable salt thereof, and the remainder of the variables are as defined in the first embodiment.

[0027] In a fourth embodiment, the present invention provides a compound according to the first or second embodiment, wherein the compound has structural formula (II-A): [ka] or a pharmaceutically acceptable salt thereof, and the remainder of the variables are as defined in the first embodiment.

[0028] In a fifth embodiment, the present invention provides a compound according to the first or second embodiment, wherein the compound has structural formula (II-B): [ka] or a pharmaceutically acceptable salt thereof, and the remainder of the variables are as defined in the first embodiment.

[0029] In a sixth embodiment, the present invention provides a compound according to the first or second embodiment, wherein the compound has structural formula (II-C): [ka] or a pharmaceutically acceptable salt thereof, and the remainder of the variables are as defined in the first embodiment.

[0030] In a seventh embodiment, the present invention provides a compound according to the first or third embodiment, wherein the compound has structural formula (II'-A): [ka] or a pharmaceutically acceptable salt thereof, and the remainder of the variables are as defined in the first embodiment.

[0031] In an eighth embodiment, the present invention provides a compound according to the sixth embodiment, or a pharmaceutically acceptable salt thereof, wherein R b is -H or -(C1-C4) alkyl, and R b The -(C1-C4) alkyl represented by the formula: is optionally substituted with one or more groups selected from halo, -CN, and -OH, and the remainder of the variables are as defined in the first embodiment. b is -H.

[0032] In a ninth embodiment, the present invention provides compounds according to the first, second, third, fifth, sixth, seventh, and eighth embodiments, or pharmaceutically acceptable salts thereof, wherein R is -(C1-C4)alkyl optionally substituted with -(C1-C4)alkoxy; or halo, -CN, -OH, -(C1-C4)alkyl, -(C1-C4)haloalkyl, -(C1-C4)hydroxyalkyl, -(C1-C4)alkoxy, -(C1-C4)haloalkoxy, and -NR a R a -(CH2) optionally substituted with one or more groups selected from the group consisting of i and 3-6 membered monocyclic heterocyclyl, and the remainder of the variables are as defined in the first or eighth embodiment.

[0033] In a tenth embodiment, the invention provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, or eighth embodiment, or a pharmaceutically acceptable salt thereof, wherein R is azetidinyl, azepanyl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl, each of which is optionally substituted with one or more groups selected from the group consisting of halo, —OH, —(C1-C4)alkyl, and —NH2, and the remainder of the variables are as defined in the first or eighth embodiment.

[0034] In an eleventh embodiment, the present invention provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment, or a pharmaceutically acceptable salt thereof, wherein R is —(CH) k COOH, optionally substituted with halo -(CH2) k CO(C1-C4) alkyl, -(CH2) p C(=O)NR a R3, -C(=NOH)CF3, or -CH(CF3)NR a R3, and the remainder of the variables are as defined in the first, eighth, ninth, or tenth embodiment.

[0035] In a twelfth embodiment, the present invention provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment, or a pharmaceutically acceptable salt thereof, wherein R2 is H; halogen; CN; -(C1-C4)alkyl optionally substituted with halo; -(C1-C4)alkoxy optionally substituted with halo, hydroxy, methoxy, or ethoxy; -C(=O)(C1-C4)alkyl; 3- to 4-membered monocyclic cycloalkyl; -O(CH2) i a 3- to 7-membered monocyclic heterocyclyl, a 3- to 7-membered monocyclic heterocyclyl, or a 5- to 6-membered heteroaryl, wherein the heterocyclyl or heteroaryl represented by R2 or within the group represented by R2 is optionally substituted with halo, hydroxy, or -(C1-C4)alkoxy, and the remainder of the variables are as defined in the first, eighth, ninth, tenth, or eleventh embodiment. In a preferred embodiment, R2 is H or -OCF3.

[0036] In a thirteenth embodiment, the present invention provides a compound according to the first, second, third, fifth, sixth, seventh, eighth, ninth, eleventh, or twelfth embodiment, or a pharmaceutically acceptable salt thereof, wherein R is -(C1-C4)alkyl optionally substituted with methoxy or -SO2CH3; -(CH2)tetrahydrofuranyl; -(CH2)oxetanyl optionally substituted with hydroxy; pyrrolidinyl; piperidinyl; or tetrahydropyranyl, wherein the pyrrolidinyl or piperidinyl is optionally substituted with -(C1-C4)alkyl, and the remainder of the variables are as defined in the first, eighth, ninth, tenth, eleventh, or twelfth embodiment. In a preferred embodiment, the pyrrolidinyl or piperidinyl is optionally substituted with -CH3.

[0037] In a fourteenth embodiment, the present invention provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiment, or a pharmaceutically acceptable salt thereof, wherein R1 is -COOH, -C(=O)CF3, -CH(CF3)(NH2), -C(=NOH)CF3, or -C(=O)NHR3, and the remainder of the variables are as defined in the first, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiment.

[0038] In a fifteenth embodiment, the present invention provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth embodiment, or a pharmaceutically acceptable salt thereof, wherein R3 is (C1-C4) alkyl, (C1-C4) alkoxy, (CH2) p1 3-6 membered monocyclic heterocyclyl, or (CH2) p2NHC(═O)(C1-C4)alkyl, and alkyl, alkoxy, or heterocyclyl represented by R3 or within a group represented by R3 is selected from halo, —OH, —(C1-C4)alkyl, —(C1-C4)haloalkyl, —(C1-C4)hydroxyalkyl, —(C1-C4)alkoxy, —(C1-C4)haloalkoxy, —S(O)2(C1-C4)alkyl, —(C1-C4)hydroxyalkoxy, and —NR a R a and the remainder of the variables are as defined in the first, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth embodiment.

[0039] In a sixteenth embodiment, the present invention provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, or fifteenth embodiment, or a pharmaceutically acceptable salt thereof, wherein R2 is H; halogen; CN; -(C1-C4)alkyl optionally substituted with halo; -(C1-C4)alkoxy optionally substituted with halo, hydroxy, methoxy, or ethoxy; -C(=O)(C1-C4)alkyl; cyclopropyl; O-tetrahydropyranyl; N-pyrrolidinyl; or thiazolyl, and the remainder of the variables are as defined in the first, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, or fifteenth embodiment.

[0040] In a seventeenth embodiment, the present invention provides a compound according to the fifth embodiment, wherein the compound has structural formula (III-B): [ka] or a pharmaceutically acceptable salt thereof, and the remainder of the variables are as defined in the first embodiment.

[0041] In an eighteenth embodiment, the present invention provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, or seventeenth embodiment, or a pharmaceutically acceptable salt thereof, wherein R1 is —COOH or —C(═O)NHR3, and R3 is —(C1-C4)alkyl, -hydroxy(C1-C4)alkyl, -methoxy(C1-C4)alkyl, -amino(C1-C4)alkyl, —(C1-C4)hydroxyalkoxy(C1-C4)alkyl, or —(CH2) p2 NHC(=O)(dimethylamino(C1-C4)alkyl), and the remainder of the variables are as defined in the first, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, or seventeenth embodiment.

[0042] In a nineteenth embodiment, the present invention provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, or eighteenth embodiment, or a pharmaceutically acceptable salt thereof, wherein R2 is H, halo, -(C1-C4)haloalkyl, -(C1-C4)haloalkoxy, -(C1-C4)alkoxy optionally substituted with methoxy, or -N-pyrrolidinyl, and the remainder of the variables are as defined in the first, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, or eighteenth embodiment. In a preferred embodiment, R2 is H, F, CF3, OCHF2, OCF3, OCH2CHOCH3, or -N-pyrrolidinyl.

[0043] In a twentieth embodiment, the present invention provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, or nineteenth embodiment, or a pharmaceutically acceptable salt thereof, wherein: R2 is H and R1 is OH, NH2, oxetanyl, or -C(=O)NH(C1-C4)alkyl optionally substituted with -(C1-C4)hydroxyalkoxy; or -C(=O)NH(CH2) p2 NHC(=O)(dimethylamino(C1-C4)alkyl), or R2 is F and R1 is —C(═O)NH(methoxy(C1-C4)alkyl), or R2 is -N-pyrrolidinyl and R1 is -C(=O)NH((C1-C4)hydroxyalkoxy(C1-C4)alkyl), or R2 is CF3, OCHF2, or OCF3 and R1 is -COOH; or R2 is OCH2CH2OCH3, and R1 is -C(=O)NH((C1-C4)hydroxyalkoxy(C1-C4)alkyl), -C(=O)NH(hydroxy(C1-C4)alkyl), -C(=O)NH(methoxy(C1-C4)alkyl), or -C(=O)NH(hydroxy(C1-C4)alkoxy); The remainder of the variables are as defined in the first, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, or nineteenth embodiment.

[0044] In a twenty-first embodiment, the present invention provides a compound according to the seventeenth embodiment, or a pharmaceutically acceptable salt thereof, wherein: R1 is —C(═O)NH(C1-C4)alkyl, optionally substituted with —OH, NH2, —(C1-C4)-alkoxy, or —(C1-C4)hydroxyalkoxy; R2 is H or OCH2CH2OCH3.

[0045] In a twenty-second embodiment, the present invention provides a compound according to the twenty-first embodiment, or a pharmaceutically acceptable salt thereof, wherein: R2 is H, The rest of the variables are as defined in the 21st embodiment.

[0046] In a twenty-third embodiment, the present invention provides a compound according to the twenty-second embodiment, or a pharmaceutically acceptable salt thereof, wherein: R1 is —C(═O)NH(C1-C4)alkyl substituted with —(C1-C4)hydroxyalkoxy; The rest of the variables are as defined in the 22nd embodiment.

[0047] In a twenty-fourth embodiment, the present invention provides a compound according to the twenty-first embodiment, or a pharmaceutically acceptable salt thereof, wherein: R1 is —C(═O)NH(C1-C4)alkyl substituted with —(C1-C4)alkoxy; R2 is OCH2CH2OCH3.

[0048] In one embodiment, the compound or a pharmaceutically acceptable salt thereof is selected from the compounds disclosed in the Examples and Table 1.

[0049] definition The term "pharmaceutically acceptable salt" refers to a pharmaceutical salt that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic reaction, within the scope of sound medical judgment, and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmacologically acceptable salts in J.Pharm.Sci., (1977), 66, 1-19.

[0050] The present teachings include pharmaceutically acceptable salts of the compounds disclosed herein. Compounds having a basic group can form pharmaceutically acceptable salts with pharmaceutically acceptable acids. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, and sulfuric acid) and salts of organic acids (e.g., acetic acid, benzenesulfonic acid, benzoic acid, methanesulfonic acid, methanesulfonic acid, and succinic acid). Compounds of the present teachings having an acidic group, such as a carboxylic acid, can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. Suitable pharmaceutically acceptable base salts include ammonium salts, alkali metal salts (e.g., sodium and potassium salts), and alkaline earth metal salts (e.g., magnesium and calcium salts).

[0051] The term "halo" as used herein means halogen and includes chloro, fluoro, bromo, and iodo.

[0052] The term "alkyl," used alone or as part of a larger moiety such as "alkoxy" or "haloalkyl," refers to a saturated aliphatic straight-chain or branched monovalent hydrocarbon group. Unless otherwise specified, an alkyl group typically has 1 to 5 carbon atoms, i.e., (C1-C5) alkyl. As used herein, a "(C1-C4) alkyl" group refers to a group having 1 to 4 carbon atoms in a linear or branched arrangement. Examples include methyl, ethyl, n-propyl, isopropyl, and the like.

[0053] The term "alkoxy" refers to an alkyl radical attached through an oxygen linking atom, represented by -O-alkyl. For example, "(C1-C4)alkoxy" includes methoxy, ethoxy, propoxy, and butoxy.

[0054] The terms "haloalkyl" and "haloalkoxy" mean alkyl or alkoxy, as the case may be, substituted with one or more halogen atoms.

[0055] The term "cycloalkyl" refers to a monocyclic saturated hydrocarbon ring system. Unless otherwise specified, cycloalkyl has 3 to 7 carbon atoms. For example, C3-C6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Unless otherwise specified, "cycloalkyl" has 3 to 6 carbon atoms.

[0056] The terms "heteroaryl," "heteroaromatic," "heteroaryl ring," "heteroaryl group," "heteroaromatic ring," or "heteroaromatic group," used alone or as part of a larger moiety, as in "heteroaralkyl" or "heteroarylalkoxy," refer to a monocyclic aromatic ring group having five or six ring atoms (i.e., "5-6 members") selected from carbon and at least one (typically 1 to 4, more typically 1 or 2) heteroatom (e.g., oxygen, nitrogen, or sulfur).

[0057] Examples of monocyclic heteroaryl groups are furanyl (e.g., 2-furanyl, 3-furanyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 2-oxadiazolyl, 5-oxadiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl), pyrrolyl (e.g., These include 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), triazolyl (e.g., 2-triazolyl, 5-triazolyl), tetrazolyl (e.g., tetrazolyl), thienyl (e.g., 2-thienyl, 3-thienyl), pyrimidinyl, pyridinyl and pyridazinyl.

[0058] The term "heterocyclyl" refers to a monocyclic non-aromatic ring radical containing 3 to 7 ring atoms (i.e., "3-7 members") selected from carbon atoms and 1 or 2 heteroatoms. Each heteroatom is independently selected from nitrogen, quaternary nitrogen, nitrogen oxide (e.g., NO); oxygen; and sulfur, including sulfoxide and sulfone. Representative heterocyclyl groups include morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrindinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like. A "substituted heterosilyl group" is substituted at any one or more substitutable ring atoms, which are hydrogen-bonded ring carbon or ring nitrogen atoms.

[0059] As used herein, many moieties (e.g., alkyl, alkylene, cycloalkyl, cycloalkylene, aryl, arylene, heteroaryl, heteroarylene, heterocyclyl, or heterocyclylene) are referred to as "substituted" or "optionally substituted." When a moiety is modified by one of these terms, unless otherwise specified, it means that any portion of the moiety known to those skilled in the art to be available for substitution can be substituted, which means that it contains one or more substituents. When multiple substituents are present, each substituent can be independently selected. Such means for substitution are well known in the art and / or taught by the present disclosure. An optional substituent can be any substituent suitable for binding to a moiety.

[0060] Suitable substituents are those that do not significantly adversely affect the ability of the compound to induce HMOX 1. If a suitable substituent is not specifically recited, exemplary substituents include, but are not limited to, (C1-C5) alkyl, (C1-C5) hydroxyalkyl, (C1-C5) haloalkyl, (C1-C5) alkoxy, (C1-C5) haloalkoxy, halogen, hydroxyl, -CN, -NH2, -NO2, -OR c1 , -NRa1 R b1 , -S(O) ii R a1 , -NR a1 S(O) ii R b1 , -S(O) ii NR a1 R b1 , -C(=O)OR a1 , -OC(=O)OR a1 , -C(=S)OR a1 , -O(C=S)R a1 , -C(=O)NR a1 R b1 , -NR a1 C(=O)R b1 , -C(=S)NR a1 R b1 , -NR a1 C(=S)R b1 , -NR a1 (C=O)OR b1 , -O(C=O)NR a1 R b1 , -NR a1 (C=S)OR b1 , -O(C=S)NR a1 R b1 , -NR a1 (C=O)NR a1 R b1 , -NR a1 (C=S)NR a1 R b1 , -C(=S)R a1 , -C(=O)R a1 , phenyl, or 5- to 6-membered heteroaryl. a1 and each R b1 is independently selected from —H and (C1-C5) alkyl, optionally substituted with hydroxyl or (C1-C3) alkoxy; R c1 is —H, (C1-C5)haloalkyl, or (C1-C5)alkyl, where the (C1-C5)alkyl is optionally substituted with hydroxyl or (C1-C3)alkoxy; and ii is 1 or 2.

[0061] Pharmaceutical Composition The compounds disclosed herein are HMOX1 inducers. The pharmaceutical compositions of the present invention comprise one or more HMOX1 inducers, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier or diluent.

[0062] "Pharmaceutically acceptable carrier" and "pharmaceutically acceptable diluent" refer to substances that aid in the formulation and / or administration of an active agent to a subject and / or its absorption by a subject, and can be included in the compositions of the present disclosure without causing significant adverse toxicological effects to the subject. Non-limiting examples of pharmaceutically acceptable carriers and / or diluents include water, NaCl, normal saline, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates such as lactose, amylose or starch, hydroxymethylcellulose, fatty acid esters, polyvinylpyrrolidine, coloring agents, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary substances such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents, and / or flavoring substances that do not adversely react with or interfere with the activity of the compounds provided herein. Those skilled in the art will recognize that other pharmaceutical excipients are suitable for use with the disclosed compounds.

[0063] Pharmaceutical compositions of the present invention optionally include one or more pharmaceutically acceptable carriers and / or diluents thereof, such as lactose, starch, cellulose, and dextrose. Other excipients may also be included, such as flavorings, sweeteners, and preservatives, such as methyl, ethyl, propyl, and butyl parabens. A more complete list of suitable excipients can be found in the Handbook of Pharmaceutical Excipients (5 thEd., Pharmaceutical Press (2005)). A person skilled in the art would know how to prepare suitable formulations for various types of administration routes. Conventional procedures and ingredients for selecting and preparing suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (2003-20th edition) and The United States Pharmacopeia: The National Formulary, published in 1999 (USP24 NF19). A carrier, diluent, and / or excipient is "acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical composition and not deleterious to the recipient thereof.

[0064] Treatment method In certain embodiments, the present invention provides a method for increasing the activity or amount of HMOX1 in a human subject, comprising administering to the human subject an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition thereof.

[0065] In certain embodiments, the present invention provides a method for activating the transcription factor Nrf2 in a human subject, comprising administering to the human subject an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition thereof.

[0066] In certain embodiments, the present invention provides a method for reducing the amount of ROS in a human subject, comprising administering to the human subject an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition thereof.

[0067] In certain embodiments, the present invention provides a method for using an effective amount of the compound of the present invention or its pharmaceutically acceptable salt, or an effective amount of its pharmaceutical composition.The compound of the present invention and its pharmaceutical composition can be used for various therapeutic purposes, including treating and / or alleviating a wide variety of diseases and disorders, including, for example, fibrotic disease, neurodegenerative disease, cardiovascular disease, kidney disease, inflammatory disease, liver disease, eye disease, thyroid disease, viral infection, osteoporosis, pregnancy disorder, endometriosis, diabetes, cancer, skin disease, mitochondrial disease, blood disease, and muscle disease.This method includes administering a pharmaceutically effective amount of one or more compounds of the present invention, their pharmaceutically acceptable salt, and / or their pharmaceutical composition to a subject in need thereof.

[0068] Compounds that increase the level or activity of HMOX1 are potentially useful for treating diseases or conditions that may be at least partially associated with oxidative stress, such as, but not limited to, fibrotic diseases, neurodegenerative diseases, cardiovascular diseases, kidney diseases, inflammatory diseases, liver diseases, eye diseases, thyroid diseases, viral infections, osteoporosis, pregnancy disorders, endometriosis, diabetes, cancer, skin diseases, mitochondrial diseases, blood diseases, and muscle diseases. As used herein, diseases or conditions associated with oxidative stress also include chronic effects (e.g., tissue damage, chronic inflammation) associated with persistent or long-term increases in oxidative stress resulting from the diseases or conditions described herein.

[0069] Fibrotic diseases associated with oxidative stress include, but are not limited to, pulmonary fibrotic diseases such as chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, and sarcoidosis; fibrotic diseases of the liver, including those caused by alcoholic cirrhosis, steatosis, cholestasis, drug side effects, and viral infections; and fibrotic diseases of the skin, including autoimmune diseases such as scleroderma and psoriasis.

[0070] Neurodegenerative diseases associated with oxidative stress include, but are not limited to, Friedreich's ataxia, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, cranial neurodegenerative diseases, and Charcot-Marie-Tooth syndrome.

[0071] Cardiovascular diseases associated with oxidative stress include, but are not limited to, hypertension, heart failure, hypercholesterolemia, atherosclerosis, arteriosclerosis, thrombosis, acute coronary thrombosis, deep vein thrombosis, peripheral vascular disease, congestive heart failure, acute coronary syndrome, failure of arterial fistula for dialysis, ischemia-reperfusion injury, primary pulmonary hypertension, primary pulmonary arterial hypertension, and secondary pulmonary arterial hypertension.

[0072] Kidney diseases associated with oxidative stress include, but are not limited to, acute kidney injury, polycystic kidney disease, Alport syndrome, diabetic nephropathy, glomerulonephritis, lupus nephritis, sickle cell nephropathy, and acute tubular necrosis.

[0073] Inflammatory diseases associated with oxidative stress include, but are not limited to, asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, inflammatory bowel syndrome, Crohn's disease, celiac disease, ulcerative colitis, chronic inflammatory bowel disease, scleroderma, dermatitis, systemic lupus erythematosus, esophagitis, vasculitis, pancreatitis, tendonitis, osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, and chronic inflammation of the brain.

[0074] Liver diseases associated with oxidative stress include, but are not limited to, drug-induced hepatotoxicity, non-alcoholic steatohepatitis, and hepatitis, such as hepatitis B and C infections.

[0075] Ocular diseases and conditions associated with oxidative stress include, but are not limited to, conjunctivitis, glaucoma, uveitis, wound healing (e.g., after surgery such as LASIK), ocular trauma, corneal transplants, Fuchs' endothelial corneal dystrophy, macular degeneration, cataracts, mild retinopathy, retinitis pigmentosa, diabetic retinopathy, and retinopathy of prematurity, as well as the inflammation and tissue damage associated with these diseases.

[0076] Thyroid diseases associated with oxidative stress include, but are not limited to, Graves' disease, follicular adenoma, and papillary and follicular carcinoma.

[0077] Lung diseases associated with oxidative stress include, but are not limited to, bronchitis, asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, pulmonary bronchitis, bronchiectasis, pulmonary edema, and emphysema.

[0078] Skin diseases associated with oxidative stress include, but are not limited to, dermatitis, scleroderma, and psoriasis.

[0079] Viral infections associated with oxidative stress include both viral replication and tissue damage (such as fibrosis) due to oxidative stress resulting from chronic viral infection, including but not limited to human immunodeficiency virus, hepatitis B, hepatitis C, and herpes viruses.

[0080] Diabetic conditions include, but are not limited to, type 1 diabetes, type 2 diabetes, gestational diabetes, prediabetes, hyperglycemia, and metabolic syndrome, as well as secondary conditions resulting from diabetic conditions (e.g., congestive heart failure and nephropathy).

[0081] Mitochondrial diseases associated with oxidative stress include, but are not limited to, mitochondrial myopathy, Leber's hereditary optic neuropathy (LHON), myoclonic epilepsy with ragged-red fibers (MERFF), mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) or Leigh's syndrome.

[0082] Hematological disorders associated with oxidative stress include, but are not limited to, Diamond-Blackfan anemia, myelodysplastic syndrome, sickle cell disease, and beta-thalassemia.

[0083] Muscle diseases associated with oxidative stress include, but are not limited to, Duchenne muscular dystrophy, limb-girdle muscular dystrophy, Becker muscular dystrophy, myotonic dystrophy, and rhabdomyolysis.

[0084] Cancers associated with oxidative stress include, but are not limited to, breast cancer, colorectal cancer, lung cancer, ovarian cancer, uterine cancer, prostate cancer, leukemia, lymphoma, brain cancer (including glioblastoma multiforme and neuroblastoma), head and neck cancer, pancreatic cancer, melanoma, hepatocellular carcinoma, renal cancer, and soft tissue sarcoma. In one embodiment, the cancer is breast cancer, colon cancer, or ovarian cancer. In one embodiment, the cancer is selected from leukemia, acute myeloid leukemia, chronic myeloid leukemia, breast cancer, brain cancer, colon cancer, colorectal cancer, head and neck cancer, hepatocellular carcinoma, lung adenocarcinoma, metastatic melanoma, pancreatic cancer, prostate cancer, ovarian cancer, and renal cancer. In one embodiment, the cancer is lung cancer, colon cancer, brain cancer, neuroblastoma, prostate cancer, melanoma, glioblastoma multiforme, or ovarian cancer. In another embodiment, the cancer is lung cancer, breast cancer, colon cancer, brain cancer, neuroblastoma, prostate cancer, melanoma, glioblastoma multiforme, or ovarian cancer. In yet another embodiment, the cancer is breast cancer, colon cancer, or lung cancer. In another embodiment, the cancer is breast cancer. In yet another embodiment, the cancer is basal subtype breast cancer or luminal B subtype breast cancer. In yet another embodiment, the cancer is basal subtype breast cancer. In yet another embodiment, the basal subtype breast cancer is ER (estrogen receptor), HER2, and PR (progesterone receptor) negative breast cancer. In yet another embodiment, the cancer is soft tissue cancer. "Soft tissue cancer" is an art-recognized term that encompasses tumors originating from any soft tissue of the body. Such soft tissues connect, support, or surround various structures and organs of the body, including, but not limited to, smooth muscle, skeletal muscle, tendon, fibrous tissue, adipose tissue, blood and lymphatic vessels, perivascular tissue, nerves, mesenchymal cells, and synovial tissue. Therefore, soft tissue cancer can be a cancer of adipose tissue, muscle tissue, nerve tissue, joint tissue, blood vessels, lymphatic vessels, and fibrous tissue. Soft tissue cancer can be benign or malignant. Generally, malignant soft tissue cancer is called sarcoma or soft tissue sarcoma.There are many types of soft tissue tumors, including lipoma, lipoblastoma, pheochromocytoma, liposarcoma, leiomyoma, leiomyosarcoma, rhabdomyoma, rhabdomyosarcoma, neurofibroma, schwannoma (neurilemmoma), neuroma, malignant schwannoma, neurofibrosarcoma, neurofibrosarcoma, neurogenic sarcoma, nodular tenosynovitis, synovial sarcoma, hemangioma, glomus tumor, hemangiopericytoma, hemangioendothelioma, angiosarcoma, Kaposi's sarcoma, lymphangioma, fibroma, fibroelastomatous tumor, superficial fibromatosis, fibrous histiocytoma, fibrosarcoma, fibromatosis, dermatofibrosarcoma protuberans (DFSP), malignant fibrous histiocytoma (MFH), myxoma, granular cell tumor, malignant mesenchymoma, alveolar soft part sarcoma, epithelioid sarcoma, clear cell sarcoma, and desmoplastic small cell tumor. In certain embodiments, the soft tissue cancer is a sarcoma selected from the group consisting of fibrosarcoma, gastrointestinal sarcoma, leiomyosarcoma, dedifferentiated liposarcoma, pleomorphic liposarcoma, malignant fibrous histiocytoma, round cell sarcoma, and synovial sarcoma.

[0085] Thus, the present invention provides a method of treatment comprising administering to a subject a compound of formula (I) or a pharmaceutically acceptable salt thereof to treat at least one of the above diseases or conditions.

[0086] A "subject" is a mammal, preferably a human, but may also be an animal in need of veterinary treatment, such as companion animals (e.g., dogs, cats, etc.), livestock (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.).

[0087] Administration method and dosage form The exact amount of compound administered to provide an "effective amount" to a subject depends on the mode of administration, the type and severity of the disease or condition, and the subject's characteristics, such as general health, age, sex, weight, and tolerance to drugs. Those skilled in the art will be able to determine appropriate dosages depending on these and other factors. When administered in combination with other therapeutic agents, for example, in combination with anti-cancer agents, the "effective amount" of any additional therapeutic agent will depend on the type of drug used. Suitable doses for approved therapeutic agents are known, and those skilled in the art can adjust dosages according to the subject's condition, the type of condition being treated, and the amount of the compound of the present invention used, for example, according to dosages reported in the literature and recommended in the Physician's Desk Reference (57th Ed., 2003).

[0088] The term "effective amount" means an amount that, when administered to a subject, produces beneficial or desired results, including clinical results, e.g., inhibits, suppresses, or reduces the symptoms of the condition being treated in the subject compared to a control. For example, a therapeutically effective amount can be provided in a unit dosage form (e.g., 0.1 mg to about 50 g per day, or 1 mg to about 5 grams per day, or 10 mg to 1 gram per day).

[0089] The terms "administer," "administering," "administration," and the like, as used herein, refer to methods that can be used to enable delivery of a composition to a desired site of biological effect. These methods include, but are not limited to, intra-articular (inside a joint site), intravenous, intramuscular, intratumor, intradermal, intraperitoneal, subcutaneous, oral, topical, intrathecal, inhalation, transdermal, rectal, and the like. Administration techniques that can be used with the agents and methods described herein can be found, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.

[0090] Furthermore, the disclosed HMOX1 inducers can be co-administered with other therapeutic agents. As used herein, the terms "co-administered," "administered in combination with," and their grammatical equivalents are meant to encompass the administration of two or more therapeutic agents to a single subject, where the agents are administered by the same or different routes of administration or at the same or different times. In some embodiments, one or more compounds described herein will be co-administered with other agents. These terms encompass the administration of two or more agents to a subject such that both agents and / or their metabolites are present in the subject at the same time. These include co-administration in separate compositions, administration at different times in separate compositions, and / or administration in a composition in which both agents are present. Thus, in some embodiments, the compounds described herein and other agents are administered in a single composition. In some embodiments, the compounds described herein and other agents are mixed in a composition.

[0091] Specific administration mode and dosage schedule will be selected by the attending physician, taking into consideration the details of the case (for example, subject, disease, involved pathology, specific treatment).Treatment can involve daily or multiple doses, or less than daily (such as once a week or once a month), for a period of several days to several months, or even several years.However, those skilled in the art will readily recognize appropriate and / or equivalent doses by looking at the doses of the approved compositions for treating disease using HMOX1 inducers disclosed for guidance.

[0092] The compounds taught herein or corresponding pharmaceutical compositions can be administered to patients in various forms depending on the selected administration route, as will be understood by those skilled in the art.The compounds of the present teachings can be administered, for example, orally, parenterally, bucally, sublingually, nasally, rectally, by patch, pump, or transdermal administration, and the pharmaceutical compositions can be formulated accordingly.Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, intranasal, intrapulmonary, intrathecal, intrarectal, and topical administration modes.Parenteral administration can also be performed by continuous infusion over a selected period of time.

[0093] The pharmaceutical composition of the present invention is formulated to be compatible with its intended route of administration.In one embodiment, the composition is formulated according to routine procedures as a pharmaceutical composition suitable for intravenous, subcutaneous, intramuscular, oral, intranasal or topical administration to humans.In a preferred embodiment, the pharmaceutical composition is formulated for intravenous administration.

[0094] Typically, for oral therapeutic administration, the compounds of the present teachings can be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.

[0095] Typically, for parenteral administration, solutions of the compounds of the present teachings can be prepared in water, generally suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO, and mixtures thereof with or without alcohol, and oils. Under normal conditions of storage and use, these preparations contain preservatives to prevent the growth of microorganisms.

[0096] Typically, for injectable use, sterile aqueous solutions or dispersions and sterile powders of the compounds described herein are suitable for the extemporaneous preparation of sterile injectable solutions or dispersions.

[0097] Example Abbreviations used throughout this specification may be summarized below along with their specific meanings. ACN - acetonitrile; AcOH - acetic acid; AC2O - acetic anhydride; AlCl3 - aluminum chloride; anh.-anhydrous; Aq. - aqueous; BOC-tert-butyloxycarbonyl; bs - broad singlet; Conc.-concentration; ℃ - Celsius; CDI-carbonyldiimidazole; CH3MgBr - methylmagnesium bromide; CS2 - carbon disulfide; d-double; δ-delta; DCM - dichloromethane; DIPEA-N,N-diisopropylethylamine DMFA-N,N-dimethylformamide; DMSO - dimethyl sulfoxide; DMSO-D6 - deuterated dimethyl sulfoxide; D2O - deuterated water; DPPA-diphenylphosphoryl azide; EDC.HCl-1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; EtOH - ethanol; EtOAc - ethyl acetate; g - grams; h-time; 1 H - proton; H2 - hydrogen; HATU-N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide; HBTU-N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate; 1 HNMR - proton nuclear magnetic resonance; HNO3 - nitric acid; H2O - water; HCl - hydrochloric acid; Hz - Hertz; H2SO4 - sulfuric acid; J-coupling constant; K2CO3 - potassium carbonate; KOH - potassium hydroxide; K3PO4 - potassium phosphate; LC - liquid chromatography; LiOH.H2O - Lithium hydroxide monohydrate; M + - molecular ion; m-multiplet; M - mole; m-CPBA-meta-chloroperbenzoic acid; MeI-methyl iodide; MeOH - methanol; Mg - milligrams; min - minutes; MHz - megahertz (frequency); mL - milliliter; mM-mmol; mmol - mmol; MS-mass spectrometry; m / z - mass-to-charge ratio; N-normality; NaBH4 - sodium borohydride; NaH - sodium hydride; NaHCO3 - sodium bicarbonate; NaNO2 - sodium nitrite; NaNO3 - sodium nitrate; NaOEt - sodium ethoxide; NaOH - sodium hydroxide; NaOMe - sodium methoxide; NBS-N-Bromosuccinimide Pd / C - palladium on carbon; Pd(OAc)2 - palladium(II) acetate; POCl3 - phosphorus oxychloride; P2S5 - phosphorus pentasulfide; PtO2 - platinum dioxide; %-percentage; pH - Hydrogen ion potential; psi - pounds per square inch; Q-quartet; RT - room temperature; s-singlet; SOCl2-thionyl chloride; t-triplet; TBAF-tetra-n-butylammonium fluoride; TBDMSCl-tert-butyldimethylchlorosilane; TEA - triethylamine; TFA - trifluoroacetic acid; THF - tetrahydrofuran; TLC - Thin Layer Chromatography. [Example]

[0098] Examples 1h and 1i. Synthesis of 2-(benzo[d]oxazol-2-ylamino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid and 2-(benzo[d]oxazol-2-ylamino)-N-(2-methoxyethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide: [ka] Step-a: Synthesis of benzo[d]oxazole-2-thiol (1a) To a solution of 2-aminophenol (4.0 g, 36.7 mmol) in ethanol (80 mL) at RT, powdered potassium hydroxide (3.59 g, 64.2 mmol) and carbon disulfide (20 mL, 330.3 mmol) were added, and the reaction mixture was refluxed for 16 hours. The reaction mixture was concentrated, diluted with water (100 mL), and acidified with 1N HCl. The resulting solid was filtered and dried under vacuum to give the title compound (4.0 g, 72%). 1 H NMR (400MHz, DMSO-d6): δ13.85 (bs, 1H), 7.51-7.49 (m, 1H), 7.32-7.23 (m, 3H); LC-MS: m / z 152.0 (M+1) + .

[0099] Step-b: Synthesis of 2-(methylthio)benzo[d]oxazole (1b) To a solution of benzo[d]oxazole-2-thiol (3.0 g, 19.9 mmol) in acetonitrile (50 mL) was added potassium carbonate (3.01 g, 21.9 mmol) and methyl iodide (1.36 mL, 21.9 mmol) at 0 °C, and the reaction mixture was stirred at RT for 5 h. The reaction mixture was diluted with water (60 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give the product (2.5 g, 76%), which was used in the next step without further purification. 1 H NMR (400MHz, DMSO-d6): δ7.65-7.62(m, 2H), 7.34-7.30(m, 2H), 2.76(s, 3H); LC-MS: m / z 166.0(M+1) + .

[0100] Step-c: Synthesis of 2-(methylsulfonyl)benzo[d]oxazole (1c) To a solution of 2-(methylthio)benzo[d]oxazole (500 mg, 3.0 mmol) in DCM (20 mL) at 0 °C, meta-chloroperbenzoic acid (938 mg, 9.1 mmol) was added, and the reaction mixture was stirred at RT for 4 h. The reaction mixture was diluted with water (40 mL), and the aqueous layer was extracted with DCM (2 × 100 mL). The combined organic layers were washed with saturated sodium bicarbonate solution (6 × 150 mL), water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give the product, which was used immediately in the next step without further purification (300 mg). LC-MS: m / z 198.0 (M+1) + .

[0101] Step-d: Synthesis of ethyl 4-(methylamino)-3-nitrobenzoate (1d) To a solution of ethyl 4-chloro-3-nitrobenzoate (30.0 g, 131 mmol) in DMFA (100 mL) at RT was added methylamine (26.8 mL (40% aqueous solution, 262 mmol)) and the reaction mixture was stirred at 60 °C for 16 h. The reaction mixture was cooled to RT, diluted with cold water (1000 mL) and stirred at RT for 1 h. The resulting solid was filtered and dried under vacuum to give the product as a yellow solid (26.0 g, 89%). 1 H NMR (400MHz, DMSO-d6): δ8.62 (d, J=2.0Hz, 1H), 8.59 (bs, 1H), 7.99 (dd, J=2.0Hz, J=8.8Hz, 1H), 7. 07(d, J=8.8Hz, 1H), 4.29(q, J=6.8Hz, 2H), 3.01(d, J=5.2Hz, 3H), 1.31(t, J=6.8Hz, 3H);LC-MS:m / z 225.0(M+1) + .

[0102] Step-e: Synthesis of ethyl 3-amino-4-(methylamino)benzoate (1e) To a solution of ethyl 4-(methylamino)-3-nitrobenzoate (13.0 g, 58 mmol) in methanol (180 mL) was added a slurry of 10% Pd / C (1.3 g in 10 mL of ethanol) under a nitrogen atmosphere. The flask was placed on a Parr shaker under hydrogen pressure (60 psi) at room temperature for 5 hours. The reaction mixture was filtered through a bed of Celite and concentrated in vacuo to give the title compound (10.0 g, 88%). 1 H NMR (400MHz, DMSO-d6): δ7.23 (dd, J=1.6Hz, J=8.4Hz, 1H), 7.16 (d, J=1.6Hz, 1H), 6.39 (d, J=8.4Hz, 1H), 5.3 8-5.37(m, 1H), 4.66(s, 2H), 4.18(q, J=7.2Hz, 2H), 2.77(d, J=5.2Hz, 3H), 1.26(t, J=7.2Hz, 3H);LC-MS:m / z 195.1(M+1) + .

[0103] Step-f: Synthesis of ethyl 2-amino-1-methyl-1H-benzo[d]imidazole-5-carboxylate (1f) To a solution of ethyl 3-amino-4-(methylamino)benzoate (5.6 g, 28.8 mmol) in THF (23 mL) and water (56 mL) at RT, cyanogen bromide (3.7 g, 34.6 mmol) was added, and the reaction mixture was stirred at 50° C. for 16 h. The reaction mixture was cooled to RT, diluted with water (50 mL), and extracted with ethyl acetate (50 mL). The aqueous layer was basified with saturated sodium bicarbonate solution and extracted with EtOAc (2×250 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give the product, which was used in the next step without further purification (5.2 g, 82%). 1 H NMR (400MHz, DMSO-d6): δ7.70(d, J=1.2Hz, 1H), 7.59(dd, J=1.2Hz, J=8.4Hz, 1H), 7.20( d, J=8.4Hz, 1H), 6.64(s, 2H), 4.27(q, J=6.8Hz, 2H), 3.53(s, 3H), 1.32(t, J=6.8Hz, 3H).

[0104] Step-g: Synthesis of ethyl 2-(benzo[d]oxazol-2-ylamino)-1-methyl-1H-benzo[d]imidazole-5-carboxylate (1g) To a solution of ethyl 2-amino-1-methyl-1H-benzo[d]imidazole-5-carboxylate (150 mg, 0.68 mmol) in 1,4-dioxane (4 mL) at room temperature, sodium hydride (96 mg, 2.4 mmol) was added, and the reaction mixture was stirred for 15 minutes, followed by the addition of 2-(methylsulfonyl)benzo[d]oxazole (202 mg, 1.0 mmol). The reaction mixture was stirred at room temperature for 16 hours, concentrated, diluted with water (20 mL), and acidified (to approximately pH 6) with 1N HCl. The resulting solid was filtered, dried under vacuum, and purified by CombiFlash column chromatography using 100% DCM as the eluent to give the title compound (50 mg, 22%). 1 H NMR (400MHz, DMSO-d6): δ12.30(bs, 1H), 8.24(s, 1H), 7.88(d, J=8.4Hz, 1H), 7.53-7.43(m, 3H), 7.22(t, J LC-MS:m / z 337.0(M+1) + .

[0105] Step-h: Synthesis of 2-(benzo[d]oxazol-2-ylamino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid (1h) To a stirred solution of ethyl 2-(benzo[d]oxazol-2-ylamino)-1-methyl-1H-benzo[d]imidazole-5-carboxylate (50 mg, 0.15 mmol) in a solvent mixture of THF (1 mL), ethanol (1 mL), and water (0.5 mL) was added lithium hydroxide monohydrate (19 mg, 0.45 mmol). The reaction mixture was stirred at 60° C. for 16 hours. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was dissolved in water and acidified with 1N HCl to give a solid, which was filtered and dried under vacuum to give the title compound (35 mg, 76%).1 H NMR (400MHz, DMSO-d6): δ12.60(bs, 2H), 8.20(d, J=1.6Hz, 1H), 7.87(dd, J=1.6Hz, J=8.0Hz, 1H), 7.5 1-7.48(m, 2H), 7.44(d, J=7.2Hz, 1H), 7.23-7.20(m, 1H), 7.15-7.11(m, 1H), 3.64(s, 3H);LC-MS:m / z 308.6(M+1) + .

[0106] Step-i: Synthesis of 2-(benzo[d]oxazol-2-ylamino)-N-(2-methoxyethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide (1i) To a stirred solution of 2-(benzo[d]oxazol-2-ylamino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid (30 mg, 0.1 mmol) in DMFA (1.0 mL) at 0 °C, N-ethyldiisopropylamine (0.02 mL, 0.1 mmol) and diphenylphosphoryl azide (0.02 mL, 0.1 mmol) were added. The reaction mixture was stirred for 30 minutes, followed by the addition of 2-methoxyethylamine (8 mg, 0.1 mmol). The reaction mixture was then stirred at RT for 16 hours. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with cold water (15 mL) and stirred for 15 minutes. The resulting solid was filtered, washed with diethyl ether, and dried under vacuum to give the title compound as a white solid (22 mg, 53%). 1 H NMR (400MHz, DMSO-d6): δ12.2(bs, 1H), 8.45(t, J=4.9Hz, 1H), 8.08(s, 1H), 7.76(dd, J=1.5Hz, J=8.3Hz, 1H), 7.47(d, J=8. LC-MS: m / z 364.0(M-1).

[0107] Examples 2d and 2e. Synthesis of 1-(tetrahydro-2H-pyran-4-yl)-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid and N-(2-methoxyethyl)-1-(tetrahydro-2H-pyran-4-yl)-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide: [ka] Step-a: Synthesis of ethyl 3-nitro-4-((tetrahydro-2H-pyran-4-yl)amino)benzoate (2a) To a stirred solution of 4-chloro-3-nitrobenzoate (1.0 g, 4.4 mmol) in DMSO (10 mL) was added potassium carbonate (1.2 g, 8.7 mmol) and tetrahydro-2H-pyran-4-amine (0.53 g, 5.2 mmol) at RT. The reaction mixture was then heated to 70° C. and stirred for 16 hours, then cooled to RT. The reaction mixture was diluted with cold water, and the resulting solid was filtered and dried under vacuum to give the title compound (1.1 g, 86%). 1 H NMR (400MHz, DMSO-d6): δ8.62(d, J=2.0Hz, 1H), 8.23(d, J=7.8Hz, 1H), 7.97(dd, J=1.9Hz, J=8.8Hz, 1H), 7.29(d, J=9.3Hz, 1H), 4.29(q, J=7 .3Hz, 2H), 3.96-3.94(m, 1H), 3.90-3.83(m, 2H), 3.51-3.45(m, 2H), 1.96-1.93(m, 2H), 1.66-1.61(m, 2H), 1.31(t, J=7.3Hz, 3H);LC-MS:m / z 294.8(M+1) + .

[0108] Step-b: Synthesis of ethyl 3-amino-4-((tetrahydro-2H-pyran-4-yl)amino)benzoate (2b) The title compound was synthesized using the same procedure as followed for intermediate 1e using ethyl 3-nitro-4-((tetrahydro-2H-pyran-4-yl)amino)benzoate as starting material (yield: 100%). 1 H NMR (400MHz, DMSO-d6): δ7.19(d, J=8.0Hz, 1H), 7.17(s, 1H), 6.52(d, J=8.3Hz, 1H), 4.99(d, J=7.3Hz, 1H), 4.97(s, 2H), 4.18(q, J=7.3H) z, 2H), 3.89-3.87(m, 2H), 3.57-3.53(m, 1H), 3.45-3.40(m, 2H), 1.92-1.89(m, 2H), 1.48-1.38(m, 2H), 1.25(t, J=7.4Hz, 3H);LC-MS:m / z 264.8(M+1) + .

[0109] Step-c: Synthesis of ethyl 1-(tetrahydro-2H-pyran-4-yl)-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylate (2c) To a stirred solution of 2-amino-6-(trifluoromethoxy)benzothiazole (177 mg, 0.76 mmol) in DMFA (55 mL) was added 1,1'-thiocarbonyldiimidazole (270 mg, 1.5 mmol), and the solution was heated at 100°C for 4 h. The reaction mixture was cooled to RT. EDC.HCl (291 mg, 1.5 mmol) was added, and the reaction mixture was heated at 60°C for 10 min, followed by the addition of 3-amino-4-((tetrahydro-2H-pyran-4-yl)amino)benzoate (200 mg, 0.76 mmol). The reaction mixture was stirred at 100°C for 16 h. It was cooled to RT, diluted with water (50 mL), and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by Combiflash column chromatography using 100% DCM as eluent to give the title compound (120 mg, 31%). LC-MS: m / z 505.0 (M-1).

[0110] Step-d: Synthesis of 1-(tetrahydro-2H-pyran-4-yl)-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid (2d) The title compound was synthesized using the same procedure as that followed for intermediate 1h using ethyl 1-(tetrahydro-2H-pyran-4-yl)-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylate as starting material (yield: 53%). 1 H NMR (400MHz, DMSO-d6): δ12.91(bs, 1H), 12.57(bs, 1H), 8.24(s, 1H), 8.02-7.64(m, 4H), 7.37(s, 1H), 4. 96-4.94(m, 1H), 4.20-4.05(m, 2H), 3.59-3.52(m, 2H), 2.60-2.44(m, 2H), 1.79-1.76(m, 2H);LC-MS:m / z 477.0(M-1).

[0111] Step-e: Synthesis of N-(2-methoxyethyl)-1-(tetrahydro-2H-pyran-4-yl)-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide (2e) The title compound was synthesized using the same procedure as that followed for intermediate 1i using 1-(tetrahydro-2H-pyran-4-yl)-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid as the starting material (yield: 18%). 1H NMR (400MHz, DMSO-d6): δ8.25(t, J=5.4Hz, 1H), 7.90(d, J=1.5Hz, 1H), 7.71-7.64(m, 2H), 7.33(d, J=0.9Hz, 1H), 7.16-7.13(m, 1H), 6.87(d, J=8.8Hz) , 1H), 5.23-5.17(m, 1H), 4.11-4.10(m, 2H), 3.65(t, J=11.2Hz, 2H), 3.35- 3.32(m, 4H), 3.28(s, 3H), 2.66-2.60(m, 2H), 1.92-1.90(m, 2H);LC-MS:m / z 536.0(M+1) + .

[0112] Examples 3d and 3e. Synthesis of 1-(1-methylpiperidin-4-yl)-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid and N-(2-methoxyethyl)-1-(1-methylpiperidin-4-yl)-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide [ka] Step-a: Synthesis of ethyl 4-((1-methylpiperidin-4-yl)amino)-3-nitrobenzoate (3a) To a stirred solution of ethyl 4-chloro-3-nitrobenzoate (500 mg, 2.2 mmol) in DMFA (5 mL) was added 1-methylpiperidin-4-amine (0.30 mL, 2.6 mmol) and N-ethyldiisopropylamine (0.8 mL, 5.0 mmol). The reaction mixture was heated to 70° C. and stirring was continued at the same temperature for 16 hours. The reaction mixture was cooled to RT, diluted with water (50 mL), and extracted with EtOAc (2×100 mL). The combined organic layers were washed with water (50 mL), brine (30 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title compound (620 mg, 92%). 1H NMR (400MHz, DMSO-d6): δ8.62(s, 1H), 8.25(d, J=8.0Hz, 1H), 7.97(d, J=9.2Hz, 1H), 7.23(d, J=9.2Hz, 1H), 4.30(q, J=7.6Hz, 2H), 3.7 1(bs, 1H), 2.69-2.66(m, 2H), 2.18(s, 3H), 2.16-2.13(m, 2H), 1.96-1.93(m, 2H), 1.67-1.58(m, 2H), 1.33(t, J=7.6Hz, 3H);LC-MS:m / z 307.7(M+1) + .

[0113] Step-b: Synthesis of ethyl 3-amino-4-((1-methylpiperidin-4-yl)amino)benzoate (3b) The title compound was synthesized using the same procedure as followed for intermediate 1e using ethyl 4-((1-methylpiperidin-4-yl)amino)-3-nitrobenzoate as starting material and stirring for 2 hours (yield: 100%). 1 H NMR (400MHz, DMSO-d6): δ7.19-7.16(m, 2H), 6.47(d, J=8.4Hz, 1H), 4.96(d, J=7.2Hz, 1H), 4.78(bs, 2H), 4.18(q, J=7.2Hz, 2H), 3.37-3 .31(m, 1H), 2.86-2.83(m, 2H), 2.25(s, 3H), 2.19-2.13(m, 2H), 1.94-1.91(m, 2H), 1.54-1.45(m, 2H), 1.26(t, J=6.8Hz, 3H);LC-MS:m / z 278.2(M+1) + .

[0114] Step-c: Synthesis of ethyl 1-(1-methylpiperidin-4-yl)-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylate (3c) The title compound was synthesized using the same procedure as followed for intermediate 2c using ethyl 3-amino-4-((1-methylpiperidin-4-yl)amino)benzoate as starting material (yield: 15%). 1H NMR (400MHz, DMSO-d6): δ12.6(bs, 1H), 8.14(s, 1H), 7.91(s, 1H), 7.79(d, J=8.3 Hz, 1H), 7.62(d, J=8.3Hz, 1H), 7.55(s, 1H), 7.35(d, J=8.8Hz, 1H), 4.74-4.68(m 1H), 4.34(q, J=6.8Hz, 2H), 3.01-2.98(m, 2H), 2.67-2.56(m, 2H), 2.30(s, 3 LC-MS:m / z 520.1(M+1) + .

[0115] Step-d: Synthesis of 1-(1-methylpiperidin-4-yl)-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid (3d) The title compound was synthesized using the same procedure as that followed for intermediate 1h using ethyl 1-(1-methylpiperidin-4-yl)-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylate as starting material (yield: 56%). 1 H NMR (400MHz, DMSO-d6): δ12.40(bs, 1H), 8.12(s, 1H), 7.91(s, 1H), 7.78(d, J=8.3 Hz, 1H), 7.60(d, J=8.3Hz, 1H), 7.58(bs, 1H), 7.34(d, J=8.9Hz, 1H), 4.79-4.68(m 1H), 3.02-2.99(m, 2H), 2.57-2.54(m, 2H), 2.30(s, 3H), 2.21-2.15(m, 2H), 1.79-1.77(m, 2H);LC-MS:m / z 491.6(M+1) + .

[0116] Step-e: Synthesis of N-(2-methoxyethyl)-1-(1-methylpiperidin-4-yl)-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide (3e) The title compound was synthesized using the same procedure as followed for intermediate 1i using 1-(1-methylpiperidin-4-yl)-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid as starting material (yield: 40%); 1 H NMR (400MHz, DMSO-d6): δ12.40(bs, 1H), 8.44(s, 1H), 8.09(s, 1H), 7.91(s, 1H), 7.70-7.58(m, 3H), 7.35(d, J=6.8Hz, 1H), 4.75-4.65(m, LC-MS: m / z 549.2(M+1) + .

[0117] Examples 4d and 4e. Synthesis of 1-(1-methylpyrrolidin-3-yl)-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid and N-(2-methoxyethyl)-1-(1-methylpyrrolidin-3-yl)-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide: [ka] Step-a: Synthesis of ethyl 4-((1-methylpyrrolidin-3-yl)amino)-3-nitrobenzoate (4a) The title compound was synthesized using the same procedure as followed for intermediate 3a using ethyl 4-chloro-3-nitrobenzoate and 1-methylpyrrolidin-3-amine as starting materials (yield: 79%). 1H NMR (400MHz, DMSO-d6): δ8.62 (d, J=1.9Hz, 1H), 8.39 (d, J=6.8Hz, 1H), 7.98 (dd, J=2.0Hz, J=8.8Hz, 1H), 7.15 (d, J=9.3Hz, 1H), 4.32-4 .36(m, 3H), 2.80-2.75(m, 1H), 2.70-2.59(m, 2H), 2.42-2.30(m, 2H), 2.29(s, 3H), 1.73-1.65(m, 1H), 1.31(t, J=7.4Hz, 3H);LC-MS:m / z 294.1(M+1) + .

[0118] Step-b: Synthesis of ethyl 3-amino-4-((1-methylpyrrolidin-3-yl)amino)benzoate (4b) The title compound was synthesized using the same procedure as followed for intermediate 1e using ethyl 4-((1-methylpyrrolidin-3-yl)amino)-3-nitrobenzoate as starting material and stirring for 2 hours (yield: 78%). 1 H NMR (400MHz, DMSO-d6): δ7.19-7.15(m, 2H), 6.38(d, J=8.3Hz, 1H), 5.16(d, J=6.9Hz, 1H), 4.81(s, 2H), 4.18(q, J=7.3Hz, 2H), 3.95( bs, 1H), 2.74-2.70(m, 1H), 2.44-2.34(m, 2H), 2.28-2.22(m, 1H), 2.25(s, 3H), 1.67-1.63(m, 1H), 1.25(t, J=7.3Hz, 3H);LC-MS:m / z 264.1(M+1) + .

[0119] Step-c: Synthesis of ethyl 1-(1-methylpyrrolidin-3-yl)-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylate (4c) The title compound was synthesized using the same procedure as that followed for intermediate 2c, using ethyl 3-amino-4-((1-methylpyrrolidin-3-yl)amino)benzoate as the starting material. The obtained product was used in the next step without further purification. LC-MS: m / z 506.1 (M+1) + .

[0120] Step-d: Synthesis of 1-(1-methylpyrrolidin-3-yl)-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid (4d) The title compound was synthesized using the same procedure followed for intermediate 1h using ethyl 1-(1-methylpyrrolidin-3-yl)-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylate as starting material and THF, MeOH, and water (2:2:1) as solvent (yield: 13%). 1 H NMR (400MHz, DMSO-d6+D2O): δ8.03(s, 1H), 7.83(s, 1H), 7.78(d, J=8.3Hz, 1H), 7.59-7.54(m, 2H), 7.32(d, J=8.8Hz) , 1H), 5.50(bs, 1H), 3.86-3.75(m, 2H), 3.35(bs, 1H), 3.07-3.05(m, 1H), 2.91(s, 3H), 2.28-2.0(m, 2H);LC-MS:m / z 478.1(M+1) + .

[0121] Step-e: Synthesis of N-(2-methoxyethyl)-1-(1-methylpyrrolidin-3-yl)-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide (4e) The title compound was synthesized using the same procedure as followed for intermediate 1i using 1-(1-methylpyrrolidin-3-yl)-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid as starting material (yield: 30%);1 H NMR (400 MHz, DMSO-d6): δ 8.10 (bs, 1H), 8.04 (s, 1H), 7.85 (s, 1H), 7.76 (bs, 1H), 7.68 (d, J = 8.3 Hz, 1H), 7.62 (bs, 1H), 7.30 (d, J = 8.8 Hz, 1H), 5.50 (bs, 1H), 3.52-3.44 (m, 4H), 3.30 (s, 3H), 2.76-2.65 (m, 2H), 2.50 (s, 3H, merged with DMSO peak), 2.31-2.30 (m, 2H), 2.15-2.13 (m, 2H); LC-MS: m / z 535.0 (M+1) + .

[0122] Example 5. Synthesis of N-(2-methoxyethyl)-1-methyl-2-((4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide: [ka] Step-a: Synthesis of methyl 1-methyl-2-((4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylate (5a) To a stirred solution of 4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (216 mg, 1.4 mmol) in DMFA (5 mL) was added 1,1'-thiocarbonyldiimidazole (494 mg, 2.8 mmol), and the solution was heated at 100°C for 2 h. The reaction mixture was cooled to RT. EDC.HCl (533 mg, 2.8 mmol) was added, and the reaction mixture was heated at 60°C for 10 min, followed by the addition of methyl 3-amino-4-(methylamino)benzoate (250 mg, 1.4 mmol). The reaction mixture was stirred at 100°C for 16 h. It was cooled to RT, diluted with water (50 mL), and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by Combiflash column chromatography using 100% DCM as eluent to give the title compound (110 mg, 23%). 1H NMR (400 MHz, DMSO-d): δ 12.01 (bs, 1H), 7.97 (s, 1H), 7.73 (dd, J = 1.6 Hz, J = 8.4 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 3.84 (s, 3H), 3.61 (s, 3H), 2.50 (bs, 4H, merged with DMSO peak), 1.78 (bs, 4H); LC-MS: m / z 341.0 (M-1).

[0123] Step-b: Synthesis of 1-methyl-2-((4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid (5b) The title compound was synthesized using the same procedure as that followed for intermediate 1h using methyl 1-methyl-2-((4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylate as starting material and THF, MeOH and water (2:2:1) as solvent (yield: 83%); 1 H NMR (400 MHz, DMSO-d): δ 12.20 (bs, 2H), 7.95 (s, 1H), 7.73 (dd, J = 0.8 Hz, J = 8.4 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 3.61 (s, 3H), 2.50 (bs, 4H, merged with DMSO peak), 1.78 (bs, 4H); LC-MS: m / z 327.0 (M-1).

[0124] Step-c: Synthesis of N-(2-methoxyethyl)-1-methyl-2-((4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide (5c) The title compound was synthesized using the same procedure as that followed for compound 1i using 1-methyl-2-((4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid as starting material (yield: 30%); 1H NMR (400 MHz, DMSO-d): δ 12.0 (bs, 1H), 8.34 (bs, 1H), 7.95 (s, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 3.60 (s, 3H), 3.48-3.42 (m, 4H), 3.28 (s, 3H), 2.50 (bs, 4H, merged with DMSO peak), 1.78 (bs, 4H); LC-MS: m / z 384.0 (M-1).

[0125] Example 6. Synthesis of 2-((6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)-N-(2-(2-hydroxyethoxy)ethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide [ka] Step-a: Synthesis of ((4,4-dimethylcyclohex-1-en-1-yl)oxy)trimethylsilane To a solution of 4,4-dimethylcyclohexan-1-one (3.0 g, 23.8 mmol) in DCM (180 mL) at 0° C. was added triethylamine (9.95 mL, 71.42 mmol). The reaction mixture was stirred for 5 minutes, followed by the addition of trimethylsilyl trifluoromethanesulfonate (6.5 g, 29.28 mmol in 54 mL of DCM). The reaction mixture was stirred at 0° C. for 1.5 hours and then quenched with saturated sodium bicarbonate solution (30 mL) and water (100 mL). The organic layer was separated, washed with water (2×50 mL), brine solution (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title compound (3.8 g, 81%), which was used in the next step without further purification. 1 H NMR (400MHz, CDCl3): δ4.74(t, J=4.0Hz, 1H), 1.99-1.97(m, 2H), 1.80(d, J=2.0Hz, 2H), 1.39(t, J=6.8Hz, 2H), 1.16(s, 6H), 0.15(s, 9H).

[0126] Step-b: Synthesis of 6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine To a solution of ((4,4-dimethylcyclohex-1-en-1-yl)oxy)trimethylsilane (3.8 g, 19.16 mmol) in THF (40 mL) and water (40 mL) at RT, N-bromosuccinimide (4.09 g, 23.0 mmol) and sodium acetate (0.22 g, 2.7 mmol) were added. The reaction mixture was then stirred for 2 h. Thiourea (1.43 g, 18.8 mmol) was added, and the reaction mixture was heated at 80° C. with stirring for 6 h. It was then cooled to RT, and stirring was continued for 16 h. The reaction mixture was quenched with water (30 mL) and extracted with DCM (2×50 mL). The aqueous layer was basified with 2 M sodium hydroxide (pH 9) and stirred at RT for 2 h. The precipitated solid was filtered and dried under vacuum to give the title compound (1.3 g, 37%), which was used in the next step without further purification. 1 H NMR (400MHz, DMSO-d6): δ6.55(bs, 2H), 2.35(t, J=6.4Hz, 2H), 2.26(s, 2H), 1.46(t, J=6.0Hz, 2H), 0.95(s, 6H); LC-MS: m / z 183.1(M+1) + .

[0127] Step-c: Synthesis of ethyl 2-((6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylate To a stirred solution of 6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (809 mg, 4.44 mmol) in DMFA (10 mL) was added 1,1′-thiocarbonyldiimidazole (1.58 g, 8.88 mmol), and the solution was heated at 100° C. for 2 h. The reaction mixture was cooled to RT, and EDC.HCl (1.70 g, 8.88 mmol) was added. The reaction mixture was heated at 50° C. for 10 min, followed by the addition of ethyl 3-amino-4-(methylamino)benzoate (800 mg, 4.44 mmol). It was then heated at 100° C. for 16 h and cooled to RT. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by Combiflash column chromatography using 100% DCM as eluent to give the title compound (500 mg, 32%). 1 H NMR (400 MHz, DMSO-d6): δ 12.10 (bs, 1H), 7.98 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 4.30 (q, J = 7.2 Hz, 2H), 3.61 (s, 3H), 2.50 (2H, merged with DMSO peak), 2.33 (s, 2H), 1.56 (t, J = 6.0 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H), 1.00 (s, 6H); LC-MS: m / z 385.1 (M+1). + .

[0128] Step-d: Synthesis of 2-((6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid To a stirred solution of ethyl 2-((6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylate (500 mg, 1.30 mmol) in a mixture of THF (4 mL), ethanol (4 mL), and water (2 mL) was added lithium hydroxide monohydrate (136 mg, 3.25 mmol). The reaction mixture was heated at 80° C. for 16 h, then cooled to RT and concentrated under reduced pressure. The residue was dissolved in water and acidified with 1N HCl to give a solid, which was filtered and dried under vacuum to give the title compound (300 mg, 65%). 1 H NMR (400 MHz, DMSO-d): δ 8.00 (s, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 3.64 (s, 3H), 2.50 (2H, merged with DMSO peak), 2.38 (s, 2H), 1.58 (t, J = 6.0 Hz, 2H), 1.01 (s, 6H); LC-MS: m / z 357.1 (M+1). + .

[0129] Step-e: Synthesis of 2-((6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)-N-(2-(2-hydroxyethoxy)ethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide To a stirred solution of 2-((6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid (100 mg, 0.28 mmol) in DMFA (2 mL) at 0 °C, N-ethyldiisopropylamine (0.04 mL, 0.28 mmol) and HBTU (106 mg, 0.28 mmol) were added. The reaction mixture was stirred for 30 min, followed by the addition of 2-(2-aminoethoxy)ethan-1-ol (0.02 mL, 0.28 mmol), and stirring was continued at RT for 16 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with cold water (20 mL) and stirred for 15 min. The resulting solid was filtered and dried under vacuum. The residue was purified by Combiflash column chromatography using 2% MeOH in DCM as eluent to give the title compound (50 mg, 40%). 1 H NMR (400 MHz, DMSO-d6): δ 12.0 (bs, 1H), 8.34 (s, 1H), 7.95 (s, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 4.60 (bs, 1H), 3.60 (s, 3H), 3.56-3.42 (m, 8H), 2.50 (2H, merged with DMSO peak), 2.32 (m, 2H), 1.55 (t, J = 6.0 Hz, 2H), 1.00 (s, 6H); LC-MS: m / z 444.1 (M+1). + .

[0130] Example 7. Synthesis of N-(2-(2-hydroxyethoxy)ethyl)-1-methyl-2-((6-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide [ka] Step-a: Synthesis of trimethyl((4-methylcyclohex-1-en-1-yl)oxy)silane To a solution of 4-methylcyclohexan-1-one (2.0 g, 17.8 mmol) in DCM (50 mL) at 0° C., triethylamine (7.5 mL, 53.4 mmol) was added and stirred for 5 minutes, followed by the addition of trimethylsilyl trifluoromethanesulfonate (4.95 g, 22.3 mmol in 30 mL of DCM). The reaction mixture was stirred at 0° C. for 1.5 hours and then quenched with saturated sodium bicarbonate solution (20 mL) and water (100 mL). The organic layer was separated, washed with water (2×100 mL), brine solution (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title compound (3.4 g, 100%). 1 H NMR (400MHz, DMSO-d6): δ4.74-4.71(m, 1H), 2.66-2.49(m, 1H), 2.16-1.99(m, 2H), 1.89 -1.88(m, 1H), 1.62-1.57(m, 2H), 1.25-1.22(m, 1H), 0.89(d, J=2.4Hz, 3H), 0.27(s, 9H).

[0131] Step-b: Synthesis of 6-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine To a solution of trimethyl((4-methylcyclohex-1-en-1-yl)oxy)silane (3.3 g, 17.9 mmol) in THF (25 mL) and water (25 mL) at RT, N-bromosuccinimide (3.83 g, 21.5 mmol) and sodium acetate (0.20 g, 2.5 mmol) were added and stirred for 2 h. Thiourea (1.43 g, 18.8 mmol) was added and the reaction mixture was heated with stirring at 80° C. for 6 h. The reaction mixture was then cooled to RT and stirring was continued for 16 h. The reaction mixture was quenched with water (30 mL) and extracted with DCM (2×100 mL). The aqueous layer was basified with 2 M sodium hydroxide (pH 9) and extracted with DCM (3×100 mL). The combined organic layers were washed with brine solution (50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (1.9 g, 63%). 1H NMR (400MHz, DMSO-d6): δ6.55 (bs, 2H), 2.57-2.51 (m, 1H), 2.40-2.36 (m, 2H), 2.12- 2.05(m, 1H), 1.79-1.74(m, 2H), 1.35-1.34(m, 1H), 1.00(d, J=6.4Hz, 3H);LC-MS:m / z 169.2(M+1) + .

[0132] Step-c: Synthesis of ethyl 1-methyl-2-((6-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylate To a stirred solution of 6-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (400 mg, 2.38 mmol) in DMFA (10 mL) was added 1,1'-thiocarbonyldiimidazole (848 mg, 4.76 mmol) and the solution was heated at 100 °C for 2 h. The reaction mixture was cooled to RT and EDC.HCl (914 mg, 4.76 mmol) was added. The reaction mixture was heated at 50 °C for 10 min followed by addition of ethyl 3-amino-4-(methylamino)benzoate. To the resulting mixture was added ethyl acetate (462 mg, 2.38 mmol). The reaction mixture was stirred at 100° C. for 16 hours. It was cooled to RT, diluted with water (50 mL), and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by combiflash column chromatography using 100% DCM as the eluent to give the title compound (400 mg, 45%). 1H NMR (400MHz, DMSO-d6): δ12.03(bs, 1H), 7.98(s, 1H), 7.73(dd, J=1.0Hz, J=8.3Hz, 1H), 7.37(d, J=8.3Hz, 1H), 4.30(q, J=7.2Hz, 2H), 3.62(s, 3H), 2.67- 2.60 (m, 1H), 2.50 (2H, merged with DMSO peak), 2.18-2.11 (m, 1H), 1.87-1.84 (m, 2H) , 1.46-1.42(m, 1H), 1.34(t, J=7.1Hz, 3H), 1.05(d, J=6.3Hz, 3H);LC-MS:m / z 371.05(M+1) + .

[0133] Step-d: Synthesis of 1-methyl-2-((6-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid The title compound was synthesized using the same procedure as that followed for compound 1h using ethyl 1-methyl-2-((6-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylate as starting material (yield: 100%). 1 H NMR (400 MHz, DMSO-d6): δ 13.01 (bs, 1H), 12.83 (bs, 1H), 8.01 (s, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 3.67 (s, 3H), 2.67-2.66 (m, 1H), 2.52 (2H, merged with DMSO peak), 2.33-2.21 (m, 1H), 1.91-1.86 (m, 2H), 1.48-1.43 (m, 1H), 1.06 (d, J = 6.4 Hz, 3H); LC-MS: m / z 343.05 (M+1). + .

[0134] Step-e: Synthesis of N-(2-(2-hydroxyethoxy)ethyl)-1-methyl-2-((6-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed in step-e of Example 6 using 1-methyl-2-((6-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid and 2-(2-aminoethoxy)ethan-1-ol as starting materials (yield: 48%). 1 H NMR (400MHz, DMSO-d6): δ11.99(bs, 1H), 8.35(t, J=5.6Hz, 1H), 7.95(s, 1H), 7.64( d, J=8.0Hz, 1H), 7.32(d, J=8.4Hz, 1H), 4.62(t, J=5.0Hz, 1H), 3.61(s, 3H), 3.55-3 0.50 (m, 4H), 3.47-3.42 (m, 4H), 2.67-2.66 (m, 1H), 2.52 (2H, merged with DMSO peak), 2.17-2.16 (m, 1H), 1.90-1.88 (m, 2H), 1.45-1.40 (m, 1H), 1.05 (d, J = 6.4 Hz, 3H); LC-MS: m / z 430.10 (M+1) + .

[0135] Example 8. Synthesis of 2-((5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl)amino)-N-(2-methoxyethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide [ka] Step-a: Synthesis of 5,6-dihydro-4H-cyclopenta[d]thiazol-2-amine A mixture of cyclopentanone (1.0 g, 11.9 mmol), thiourea (1.8 g, 23.8 mmol), and iodine (3.0 g, 11.9 mmol) was stirred in a sealed tube at 110 °C for 12 h. The reaction mixture was cooled to RT, and hot water (30 mL) was added and stirred for 30 min. The reaction mixture was extracted with diethyl ether (2 × 20 mL), and the aqueous layer was basified with solid sodium bicarbonate (to approximately pH 8) and extracted with DCM (3 × 30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was purified by Combiflash chromatography using 10% methanol and 0.1% aqueous ammonia in DCM as the eluent to give the title compound (160 mg, 10%). 1 H NMR (400MHz, CDCl3): δ4.77 (bs, 2H), 2.79-2.74 (m, 2H), 2.68-2.64 (m, 2H), 2.41-2.34 (m, 2H); LC-MS: m / z 141.1 (M+1) + .

[0136] Step-b: Synthesis of ethyl 2-((5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylate The title compound was synthesized using the same procedure as that followed for compound 5a using ethyl 3-amino-4-(methylamino)benzoate and 5,6-dihydro-4H-cyclopenta[d]thiazol-2-amine as starting materials (yield: 23%). 1 H NMR (400MHz, DMSO-d6): δ12.0(bs, 1H), 8.05(s, 1H), 7.77(d, J=8.0Hz, 1H), 7.38(d, J=8.4Hz, 1H), 4.30 (q, J=6.8Hz, 2H), 3.56(s, 3H), 2.80-2.72(m, 4H), 2.36-2.33(m, 2H), 1.33(t, J=6.8Hz, 3H);LC-MS:m / z 343.0(M+1) + .

[0137] Step-c: Synthesis of 2-((5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid The title compound was synthesized using the same procedure as that followed for compound 1h using ethyl 2-((5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylate as starting material (yield: 55%). LC-MS: m / z 315.1 (M+1). + .

[0138] Step-d: Synthesis of 2-((5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl)amino)-N-(2-methoxyethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as followed for compound 1i using 2-((5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl)amino)-1-methyl-1H-benzo[d] as starting material (yield: 13%). 1 H NMR (400MHz, DMSO-d6): δ12.0(bs, 1H), 8.36(bs, 1H), 7.95(s, 1H), 7.67(d, J=7.6Hz, 1H), 7.33(d, J=8. LC-MS: m / z 372.0(M+1) + .

[0139] Example 9. Synthesis of N-(2-(2-hydroxyethoxy)ethyl)-1-methyl-2-((4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide hydrochloride [ka] Step-a: Synthesis of tert-butyl 2-amino-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate To a stirred solution of tert-butyl 4-oxopiperidine-1-carboxylate (3.0 g, 15.07 mmol) in THF (70 mL) at RT, pyrrolidone hydrobromide (7.47 g, 15.07 mmol) was added, and the reaction mixture was refluxed for 10 minutes. The reaction mixture was cooled to RT, the precipitated solid was removed by filtration, and the filtrate was concentrated. The resulting residue was dissolved in ethanol (80 mL), followed by the addition of thiourea (1.53 g, 20.14 mmol), and the reaction mixture was refluxed for 3 hours. The reaction mixture was cooled to RT and concentrated in vacuo. The residue was purified by Combiflash chromatography using 5% methanol in DCM as the eluent to give the title compound (450 mg, 12%). 1 H NMR (400MHz, DMSO-d6): δ6.80(s, 2H), 4.29(s, 2H), 3.56(t, J=5.6Hz, 2H), 2.43(bs, 2H), 1.41(s, 9H); LC-MS: m / z 256.2(M+1) + .

[0140] Step-b: Synthesis of tert-butyl 2-((5-(ethoxycarbonyl)-1-methyl-1H-benzo[d]imidazol-2-yl)amino)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate To a stirred solution of tert-butyl 2-amino-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (424 mg, 1.66 mmol) in DMFA (6 mL) was added 1,1′-thiocarbonyldiimidazole (593 mg, 3.33 mmol), and the solution was heated at 100° C. for 2 h. The reaction mixture was cooled to RT, and EDC HCl (639 mg, 3.33 mmol) was added. The reaction mixture was heated at 50° C. for 10 min, followed by the addition of ethyl 3-amino-4-(methylamino)benzoate (300 mg, 1.66 mmol). The reaction mixture was heated at 100° C. for 16 h. It was cooled to RT, diluted with water (50 mL), and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by Combiflash chromatography using 0.4% methanol in DCM as eluent to give the title compound (130 mg, 18%). 1 H NMR (400 MHz, DMSO-d6): δ 12.10 (bs, 1H), 8.03 (bs, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 4.39 (bs, 2H), 4.30 (q, J = 6.8 Hz, 2H), 3.67-3.59 (m, 5H), 2.50 (2H, merged with DMSO peak), 1.43 (s, 9H), 1.34 (t, J = 6.8 Hz, 3H); LC-MS: m / z 458.2 (M+1). + .

[0141] Step-c: Synthesis of 2-((5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid The title compound was synthesized using the same procedure as that followed for compound 1h, using tert-butyl 2-((5-(ethoxycarbonyl)-1-methyl-1H-benzo[d]imidazol-2-yl)amino)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate as the starting material and THF, methanol, water (2:2:1) as the solvent. (Yield: 70%) 1 H NMR (400MHz, DMSO-d6): δ12.50(bs, 1H), 8.00(s, 1H), 7.78(d, J=8.4Hz, 1H), 7.40(d, J=8.4Hz, 1 LC-MS:m / z 430.1(M+1) + .

[0142] Step-d: Synthesis of tert-butyl 2-((5-((2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)ethyl)carbamoyl)-1-methyl-1H-benzo[d]imidazol-2-yl)amino)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate The title compound was synthesized using the same procedure as in step-e of Example 6 using 2-((5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid and 2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)ethan-1-amine as starting materials (yield: 40%). LC-MS: m / z 631.2 (M+1) + .

[0143] Step-e: Synthesis of N-(2-(2-hydroxyethoxy)ethyl)-1-methyl-2-((4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide hydrochloride To a stirred solution of tert-butyl 2-((5-((2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)ethyl)carbamoyl)-1-methyl-1H-benzo[d]imidazol-2-yl)amino)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (50 mg, 0.08 mmol) in 1,4-dioxane (0.8 mL) at 0° C. was added 4 M HCl in 1,4-dioxane (0.3 mL) and stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was triturated with diethyl ether and the solvent was decanted. The resulting solid was dried under vacuum to give the title compound (12 mg, 33%). 1 H NMR (400MHz, CD3OD): δ8.01(s, 1H), 7.87(d, J=8.0Hz, 1H), 7.55(d, J=8.4Hz, 1H) , 4.35(s, 2H), 3.74(s, 3H), 3.71-3.53(m, 10H), 3.05(t, J=6.0Hz, 2H);LC-MS:m / z 417.1(M+1) + .

[0144] Example 10. Synthesis of 2-((5-acetyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)amino)-N-(2-(2-hydroxyethoxy)ethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide [ka] Step-a: Synthesis of 1-methyl-2-((4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid trifluoroacetate To a stirred solution of 2-((5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid (170 mg, 0.39 mmol) in DCM (5 mL) at 0° C. was added TFA (0.1 mL, 1.19 mmol) and stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was triturated with diethyl ether and the solvent was decanted. The residue was dried under vacuum to give the title compound (180 mg, 100%). 1 H NMR (400MHz, DMSO-d6): δ9.22(s, 2H), 8.04(s, 1H), 7.81(dd, J=1.6Hz, J=8.4Hz, 1H), 7.4 2(d, J=8.4Hz, 1H), 4.23(s, 2H), 3.60(s, 3H), 3.48-3.46(m, 2H), 2.89(bs, 2H);LC-MS:m / z 330.1(M+1) + .

[0145] Step-b: Synthesis of 2-((5-acetyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid To a stirred solution of 1-methyl-2-((4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid trifluoroacetate (180 mg, 0.55 mmol) in pyridine (2 mL) at 0° C., acetic anhydride (0.06 mL, 0.6 mmol) was added and stirred at RT for 16 h. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with 1N HCl (30 mL), water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate, concentrated in vacuo, and the resulting residue was triturated with diethyl ether and the solvent was decanted. The resulting solid was dried under vacuum to give the title compound (70 mg, 46%). LC-MS: m / z 372.1 (M+1) + .

[0146] Step-c: Synthesis of 2-((5-acetyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)amino)-N-(2-(2-hydroxyethoxy)ethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed in step-e of Example 6 using 2-((5-acetyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid and 2-(2-aminoethoxy)ethan-1-ol as starting materials (yield: 29%). 1 H NMR (400MHz, DMSO-d6): δ12.0(bs, 1H), 8.38(s, 1H), 7.96(d, J=3.6Hz, 1H), 7.67(d, J=7.6Hz, 1H), 7.35(d, J=8.4Hz) , 1H), 4.62-4.49(m, 3H), 3.78-3.73(m, 2H), 3.60-3.41(m, 10H), 3.30(2H, merged with DMSO water peak), 2.09(s, 3H); LC-MS: m / z 459.1(M+1) + .

[0147] Example 11. Synthesis of 2-((6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-yl)amino)-N-(2-methoxyethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide [ka] Step-a: Synthesis of methyl 2-((6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylate The title compound was synthesized using the same procedure as that followed for compound 5a, using methyl 3-amino-4-(methylamino)benzoate and 6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-amine as starting materials and stirring for 16 hours (yield: 20%). 1H NMR (400 MHz, DMSO-d): δ 12.20 (bs, 1H), 8.02 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 4.58 (s, 2H), 3.93 (t, J = 5.6 Hz, 2H), 3.84 (s, 3H), 3.60 (s, 3H), 2.50 (2H, merged with DMSO peak); LC-MS: m / z 343.0 (M-1).

[0148] Step-b: Synthesis of 2-((6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid The title compound was synthesized using the same procedure as that followed for compound 1h, using methyl 2-((6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylate as the starting material and THF, methanol, and water (2:2:1) as the solvent (yield: 52%). δ 12.40 (bs, 2H), 7.98 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 4.58 (s, 2H), 3.92 (t, J = 4.8 Hz, 2H), 3.59 (s, 3H), 2.50 (2H, merged with DMSO peak); LC-MS: m / z 330.7 (M+1). + .

[0149] Step-c: Synthesis of 2-((6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-yl)amino)-N-(2-methoxyethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed for compound 1i, using 2-((6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid and 2-methoxyethylamine as starting materials. The crude product was purified by Combiflash chromatography using 1.2% methanol in DCM as the eluent (yield: 34%). 1H NMR (400 MHz, DMSO-d6): δ 12.20 (bs, 1H), 8.40 (bs, 1H), 7.96 (s, 1H), 7.66 (bs, 1H), 7.35 (d, J = 8.4 Hz, 1H), 4.58 (bs, 2H), 3.93 (s, 2H), 3.58 (s, 3H), 3.48-3.42 (m, 4H), 3.27 (s, 3H), 2.50 (2H, merged with DMSO peak); LC-MS: m / z 387.6 (M+1) + .

[0150] Example 12. Synthesis of 2-((1H-benzo[d]imidazol-2-yl)amino)-N-(2-methoxyethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide: [ka] Step-a: Synthesis of N-(1H-benzo[d]imidazol-2-yl)-1H-imidazole-1-carbothioamide To a solution of 1H-benzo[d]imidazol-2-amine (1.0 g, 7.5 mmol) in acetonitrile (10 mL) at RT, 1,1'-thiocarbonyldiimidazole (1.34 g, 7.5 mmol) was added and stirred at RT for 16 h. The reaction mixture was filtered and the resulting solid was dried under vacuum to give the title compound (1.1 g, 60%). 1 H NMR (400MHz, DMSO-d6): δ13.18(bs, 2H), 8.55(s, 1H), 7.93(d, J=1.2Hz, 1H), 7.63-7.59(m, 2H), 7.36-7.32(m, 2H), 6.99(d, J=1.2Hz, 1H).

[0151] Step-b: Synthesis of methyl 2-((1H-benzo[d]imidazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylate To a stirred solution of N-(1H-benzo[d]imidazol-2-yl)-1H-imidazole-1-carbothioamide (188 mg, 0.77 mmol) in DMFA (5 mL) was added EDC.HCl (297 mg, 1.5 mmol) and heated to 60° C. for 10 min. The reaction mixture was cooled to RT, followed by the addition of methyl 3-amino-4-(methylamino)benzoate (150 mg, 0.77 mmol) and heating at 100° C. for 16 h. The reaction mixture was cooled to RT, diluted with water (30 mL), and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by CombiFlash column chromatography using 2% methanol in DCM as the eluent to give the title compound (40 mg, 16%). 1 H NMR (400MHz, DMSO-d6): δ12.12(bs, 2H), 8.05(d, J=1.6Hz, 1H), 7.73(dd, J=1.6Hz, J=8 .4Hz, 1H), 7.37-7.34(m, 3H), 7.12-7.08(m, 2H), 3.85(s, 3H), 3.65(s, 3H);LC-MS:m / z 322.0(M+1) + .

[0152] Step-c: Synthesis of 2-((1H-benzo[d]imidazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid The title compound was synthesized using the same procedure as that followed for intermediate 1h using methyl 2-((1H-benzo[d]imidazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylate as starting material and methanol, THF, and water as solvents (yield: 92%). 1 H NMR (400MHz, DMSO-d6): δ13.0 (bs, 3H), 7.92 (s, 1H), 7.89 (d, J=1.6Hz, 1H), 7.60 (d, J=8.4Hz, 1H), 7.45-7.41(m, 2H), 7.29-7.26(m, 2H), 3.68(s, 3H);LC-MS:m / z 308.1(M+1) + .

[0153] Step-d: Synthesis of 2-((1H-benzo[d]imidazol-2-yl)amino)-N-(2-methoxyethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed for compound 1i using 2-((1H-benzo[d]imidazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid as the starting material (yield: 14%). 1 H NMR (400MHz, DMSO-d6): δ12.10(bs, 2H), 8.33(t, J=4.8Hz, 1H), 7.98(d, J=0.8Hz, 1H), 7.62(dd, J=1.2Hz, J LC-MS: m / z 365.0(M+1) + .

[0154] Examples 13 and 14. Synthesis of 1-methyl-2-((5-(trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid and N-(2-methoxyethyl)-1-methyl-2-((5-(trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide: [ka] Step-a: Synthesis of 4-(trifluoromethoxy)benzene-1,2-diamine To a solution of methyl 2-nitro-5-(trifluoromethoxy)aniline (2.0 g, 9.0 mmol) in methanol (40 mL) was added 10% Pd / C (1.0 g) under a nitrogen atmosphere. The reaction mixture was then stirred under hydrogen gas for 16 hours. The reaction mixture was filtered through a bed of Celite and concentrated in vacuo to give the title compound (1.6 g, 93%). 1H NMR (400MHz, DMSO-d6): δ6.48 (d, J=8.0Hz, 1H), 6.45 (d, J=1.6Hz, 1H), 6.29 (dd, J=2.0Hz, J=8.0Hz, 1H), 4.80 (s, 2H), 4.58 (s, 2H); LC-MS: m / z 193.0(M+1) + .

[0155] Step-b: Synthesis of ethyl 2-(1H-imidazole-1-carbothioamido)-1-methyl-1H-benzo[d]imidazole-5-carboxylate To a solution of ethyl 2-amino-1-methyl-1H-benzo[d]imidazole-5-carboxylate (500 mg, 2.28 mmol) in acetonitrile (10 mL) at RT, 1,1'-thiocarbonyldiimidazole (529 mg, 2.97 mmol) was added and the reaction mixture was stirred at 60°C for 16 h. It was cooled to RT and stirred for 30 min. The resulting solid was filtered and dried under vacuum to give the title compound (500 mg, 66%). 1 H NMR (400MHz, DMSO-d6): δ13.40(bs, 1H), 8.68(s, 1H), 8.40(d, J=1.2Hz, 1H), 8.03(s, 1H), 7.99(dd, J=1.2Hz, J=8. 4Hz, 1H), 7.75(d, J=8.4Hz, 1H), 7.01(s, 1H), 4.35(q, J=7.2Hz, 2H), 3.79(s, 3H), 1.36(t, J=7.2Hz, 3H);LC-MS:m / z 328.2(M-1).

[0156] Step-c: Synthesis of ethyl 1-methyl-2-((5-(trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylate The title compound was synthesized using the same procedure as in step b of Example 12, using ethyl 2-(1H-imidazole-1-carbothioamido)-1-methyl-1H-benzo[d]imidazole-5-carboxylate and 4-(trifluoromethoxy)benzene-1,2-diamine as starting materials (yield: 27%). 1H NMR-VT (400MHz, DMSO-d6):δ 12.0(bs, 2H), 8.09(s, 1H), 7.77(d, J=8.4Hz, 1H), 7.35(d, J=8.4Hz, 2H), 7.28(s, 1H), 7. 0(d, J=8.4Hz, 1H), 4.35(q, J=6.8Hz, 2H), 3.63(s, 3H), 1.35(t, J=6.8Hz, 3H);LC-MS:m / z 420.0(M+1) + .

[0157] Step-d: Synthesis of 1-methyl-2-((5-(trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid The title compound was synthesized using the same procedure as that followed for intermediate 1h using ethyl 1-methyl-2-((5-(trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylate (yield: 77%). 1 H NMR (400MHz, DMSO-d6): δ12.60(bs, 3H), 8.05(d, J=1.6Hz, 1H), 7.82(dd, J=1.6Hz, J=8.4Hz, 1H), 7.45(d, J LC-MS:m / z 392.0(M+1) + .

[0158] Step-e: Synthesis of N-(2-methoxyethyl)-1-methyl-2-((5-(trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed for compound 1i using 1-methyl-2-((5-(trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid as the starting material (yield: 43%). 1H NMR (400MHz, DMSO-d6): δ12.20(bs, 2H), 8.37(bs, 1H), 8.0(d, J=1.2Hz, 1H), 7.68(dd, J=1.2Hz, J=8.4Hz, 1H), 7. 36(d, J=8.4Hz, 2H), 7.30(s, 1H), 7.01(d, J=8.4Hz, 1H), 3.63(s, 3H), 3.59-3.43(m, 4H), 3.29(s, 3H);LC-MS:m / z 449.0(M+1) + .

[0159] Example 15. Synthesis of 1-methyl-2-((1-methyl-5-(trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid [ka] Step-a: Synthesis of N-methyl-2-nitro-4-(trifluoromethoxy)aniline To a stirred solution of 2-nitro-4-(trifluoromethoxy)aniline (2.0 mg, 9.0 mmol) in DMFA (20 mL) at 0° C., sodium hydride (60% dispersion in mineral oil) (0.4 g, 10.0 mmol) was added, and the reaction mixture was stirred for 10 minutes. Methyl iodide (0.56 mL, 9.0 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by Combiflash chromatography using 5% ethyl acetate in hexane as the eluent to give the title compound (1.8 g, 85%). 1 H NMR (400MHz, DMSO-d6): δ8.28(d, J=4.0Hz, 1H), 8.00(d, J=2.4Hz, 1H), 7.61(dd, LC-MS:m / z 237.0(M+1) + .

[0160] Step-b:N 1 Synthesis of 1,2-methyl-4-(trifluoromethoxy)benzene-1,2-diamine The title compound was synthesized using the same procedure as followed for compound 1e, using N-methyl-2-nitro-4-(trifluoromethoxy)aniline as starting material and stirring for 6 hours (yield: 92%). 1 H NMR (400MHz, DMSO-d6): δ6.44(s, 1H), 6.42(d, J=10.4Hz, 1H), 6.33(d, J=8.4Hz, 1H), 4.84(bs, 2H), 2.70(s, 3H); LC-MS: m / z 207.0(M+1) + .

[0161] Step-c: Synthesis of ethyl 1-methyl-2-((1-methyl-5-(trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylate The title compound was synthesized using the same procedure as in step b of Example 12, using ethyl 2-(1H-imidazole-1-carbothioamido)-1-methyl-1H-benzo[d]imidazole-5-carboxylate and N1-methyl-4-(trifluoromethoxy)benzene-1,2-diamine as starting materials (yield: 37%). LC-MS: m / z 434.2 (M+1). + .

[0162] Step-d: Synthesis of 1-methyl-2-((1-methyl-5-(trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid The title compound was synthesized using the same procedure as that followed for compound 1h using ethyl 1-methyl-2-((1-methyl-5-(trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylate as starting material (yield: 53%). 1H NMR (400MHz, DMSO-d6): δ12.5(bs, 2H), 8.10(d, J=1.2Hz, 1H), 7.79(dd, J=1.6Hz, J=8.4Hz, 1H ), 7.44(s, 1H), 7.41-7.37(m, 2H), 7.08(d, J=8.8Hz, 1H), 3.70(s, 3H), 3.68(s, 3H);LC-MS:m / z 406.1(M+1) + .

[0163] Example 16. Synthesis of 2-(benzo[d]oxazol-2-ylamino)-N-(2-hydroxyethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide [ka] To a stirred solution of 2-(benzo[d]oxazol-2-ylamino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid (50 mg, 0.16 mmol) in DMFA (1.0 mL) at 0 °C, N-ethyldiisopropylamine (0.03 mL, 0.16 mmol) and HBTU (62 mg, 0.16 mmol) were added. The reaction mixture was stirred for 30 min, followed by the addition of 2-aminoethan-1-ol (10 mg, 0.16 mmol), and stirring was continued at RT for 16 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with cold water (20 mL) and stirred for 15 min. The resulting solid was filtered, washed with diethyl ether, and dried under vacuum to give the title compound as a white solid (25 mg, 44%). 1 H NMR (400MHz, DMSO-d6): δ12.30(bs, 1H), 8.36(t, J=5.4Hz, 1H), 8.08(d, J=0.9Hz, 1H), 7.78-7.76(m, 1H), 7.48(d, J=8.3Hz, 2H), 7.43(d, J LC-MS: m / z 352.2(M+1) + .

[0164] Example 17. Synthesis of 2-(benzo[d]oxazol-2-ylamino)-N-(2-(2-hydroxyethoxy)ethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide [ka] Step-a: Synthesis of ethyl 4-(methylamino)-3-nitrobenzoate To a solution of ethyl 4-chloro-3-nitrobenzoate (30.0 g, 131 mmol) in DMFA (100 mL) at RT, methylamine (26.8 mL (40% aqueous solution), 262 mmol) was added and the reaction mixture was stirred at 60° C. for 16 h. The reaction mixture was cooled to RT, diluted with cold water (1000 mL), and stirred for 1 h. The resulting solid was filtered and dried under vacuum to give the product as a yellow solid (28.0 g, 96%). 1 H NMR (400MHz, DMSO-d6): δ8.62 (d, J=2.0Hz, 1H), 8.59 (bs, 1H), 7.99 (dd, J=2.0Hz, J=8.8Hz, 1H), 7. 07(d, J=8.8Hz, 1H), 4.29(q, J=6.8Hz, 2H), 3.01(d, J=5.2Hz, 3H), 1.31(t, J=6.8Hz, 3H);LC-MS:m / z 225.0(M+1) + .

[0165] Step-b: Synthesis of ethyl 3-amino-4-(methylamino)benzoate To a solution of ethyl 4-(methylamino)-3-nitrobenzoate (27.0 g, 120 mmol) in methanol (300 mL) was added a slurry of 10% Pd / C (2.8 g in 15 mL of ethanol) under a nitrogen atmosphere. The flask was placed on a Parr shaker under hydrogen (60 psi) at room temperature for 3 hours. The reaction mixture was filtered through a bed of celite and concentrated in vacuo to give the title compound (19.0 g, 82%). 1H NMR (400MHz, DMSO-d6): δ7.23(dd, J=1.6Hz, J=8.4Hz 1H), 7.16(d, J=1.6Hz, 1H), 6.39(d, J=8.4Hz, 1H), 5.38-5.37(m, 1H), 4.66(s, 2H) ), 4.18(q, J=7.2Hz, 2H), 2.77(d, J=5.2Hz, 3H), 1.26(t, J=7.2Hz, 3H);LC-MS:m / z 195.1(M+1) + .

[0166] Step-c: Synthesis of ethyl 2-amino-1-methyl-1H-benzo[d]imidazole-5-carboxylate To a solution of ethyl 3-amino-4-(methylamino)benzoate (17.0 g, 87.6 mmol) in THF (68 mL) and water (170 mL) at RT, cyanogen bromide (11.13 g, 105.2 mmol) was added and the reaction mixture was stirred at 60° C. for 16 h. The reaction mixture was cooled to RT and basified with saturated sodium bicarbonate solution. The resulting solid was filtered and dried under vacuum to give the title compound, which was used in the next step without further purification (18.0 g, 94%). 1 H NMR (400MHz, DMSO-d6): δ7.70(d, J=1.2Hz, 1H), 7.59(dd, J=1.2Hz, J=8.4Hz, 1H), 7.20(d, J=8 .4Hz, 1H), 6.64(s, 2H), 4.27(q, J=6.8Hz, 2H), 3.53(s, 3H), 1.32(t, J=6.8Hz, 3H);LC-MS:m / z 220.1(M+1) + .

[0167] Step-d: Synthesis of ethyl 2-(benzo[d]oxazol-2-ylamino)-1-methyl-1H-benzo[d]imidazole-5-carboxylate To a solution of ethyl 2-amino-1-methyl-1H-benzo[d]imidazole-5-carboxylate (4.0 g, 18.3 mmol) in 1,4-dioxane (40 mL) at 0 °C, sodium hydride (60% dispersion in mineral oil) (1.09 g, 27.4 mmol) was added portionwise and stirred for 10 min. 2-Chlorobenzo[d]oxazole (2.79 g, 18.3 mmol) was added to the reaction mixture and stirred at RT for 16 h. The reaction mixture was poured into cold water (100 mL) and stirred at RT for 5–10 min. The resulting solid was filtered, dried under vacuum, and purified by CombiFlash column chromatography using 100% DCM as eluent to give the title compound (4.0 g, 60%). 1 H NMR (400MHz, DMSO-d6): δ12.30(bs, 1H), 8.24(s, 1H), 7.88(d, J=8.4Hz, 1H), 7.53-7.43(m, 3H), 7.22(t, J LC-MS:m / z 337.0(M+1) + .

[0168] Step-e: Synthesis of 2-(benzo[d]oxazol-2-ylamino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid To a stirred solution of ethyl 2-(benzo[d]oxazol-2-ylamino)-1-methyl-1H-benzo[d]imidazole-5-carboxylate (4.0 g, 11.90 mmol) in a solvent mixture of THF (20 mL), ethanol (20 mL), and water (10 mL) was added lithium hydroxide monohydrate (1.25 g, 29.76 mmol). The reaction mixture was heated at 60° C. with stirring for 16 hours. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was dissolved in water (60 mL) and acidified with 1N HCl to give a solid, which was filtered and dried under vacuum to give the title compound (3.4 g, 93%). 1H NMR (400MHz, DMSO-d6): δ12.60(bs, 2H), 8.20(d, J=1.6Hz, 1H), 7.87(dd, J=1.6Hz, J=8.0Hz, 1H), 7.5 1-7.48(m, 2H), 7.44(d, J=7.2Hz, 1H), 7.23-7.20(m, 1H), 7.15-7.11(m, 1H), 3.64(s, 3H);LC-MS:m / z 309.1(M+1) + .

[0169] Step-f: Synthesis of 2-(benzo[d]oxazol-2-ylamino)-N-(2-(2-hydroxyethoxy)ethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide To a stirred solution of 2-(benzo[d]oxazol-2-ylamino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid (3.0 g, 9.74 mmol) in DMFA (30 mL) at 0 °C, N-ethyldiisopropylamine (4.36 mL, 24.25 mmol) and HBTU (4.06 g, 10.71 mmol) were added. The reaction mixture was stirred for 30 min, followed by the addition of 2-(2-aminoethoxy)ethan-1-ol (1.02 g, 9.74 mmol), and stirring was continued at RT for 16 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with cold water (300 mL) and stirred for 30 min. The resulting solid was filtered, dried under vacuum, and purified by CombiFlash column chromatography using 5% methanol in DCM as the eluent to give the title compound (2.9 g, 75%) as a white solid. 1 H NMR (400MHz, DMSO-d6): δ12.20(bs, 1H), 8.43(t, J=5.3Hz, 1H), 8.07(s, 1H), 7.76(d, J=8.4Hz, 1H), 7.48(d, J=7.9Hz, 2H), 7 .43(d, J=7.8Hz, 1H), 7.21(t, J=7.3Hz, 1H), 7.11(t, J=7.3Hz, 1H), 4.60(bs, 1H), 3.63(s, 3H), 3.57-3.42(m, 8H); LC-MS: m / z 396.2(M+1) + .

[0170] Example 18. Synthesis of N-(2-aminoethyl)-2-(benzo[d]oxazol-2-ylamino)-1-methyl-1H-benzo[d]imidazole-5-carboxamide hydrochloride [ka] Step-a: Synthesis of tert-butyl (2-(2-(benzo[d]oxazol-2-ylamino)-1-methyl-1H-benzo[d]imidazole-5-carboxamido)ethyl)carbamate The title compound was synthesized using the same procedure as followed in step-e of Example 6 using 2-(benzo[d]oxazol-2-ylamino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid and tert-butyl(2-aminoethyl)carbamate as starting materials (yield: 51%); 1 H NMR (400MHz, DMSO-d6): δ12.20(bs, 1H), 8.41(t, J=5.1Hz, 1H), 8.08(s, 1H), 7.75(d, J=8.3Hz, 1H), 7.48(d, J=8.4Hz, 2H), 7.43(d, J=7.8Hz, 1H), 7.2 3-7.19(m, 1H), 7.14-7.09(m, 1H), 6.92(d, J=5.4Hz, 1H), 3.64(s, 3H), 3.3 4-3.33 (m, 2H, merged with DMSO water peak), 3.15-3.10 (m, 2H), 1.38 (s, 9H); LC-MS: m / z 451.55(M+1) + .

[0171] Step-b: Synthesis of N-(2-aminoethyl)-2-(benzo[d]oxazol-2-ylamino)-1-methyl-1H-benzo[d]imidazole-5-carboxamide hydrochloride To a 0° C. solution of tert-butyl (2-(2-(benzo[d]oxazol-2-ylamino)-1-methyl-1H-benzo[d]imidazole-5-carboxamido)ethyl)carbamate (50 mg, 0.11 mmol) in THF (2 mL) was added 4 N HCl in 1,4-dioxane (0.5 mL) and the reaction mixture was stirred at RT for 3 h. The reaction mixture was concentrated on a rotary evaporator and stirred in diethyl ether (10 mL). The resulting solid was filtered and dried under vacuum to give the title compound (35 mg, 81%). 1 H NMR (400MHz, DMSO-d6): δ12.40(bs, 1H), 8.70(s, 1H), 8.13(s, 1H), 7.96(bs, 3H), 7.86(d, J=8.3Hz, 1H), 7.56(d, J=8.3Hz, 1H), 7.4 8(d, J=7.9Hz, 2H), 7.25(t, J=7.6Hz, 1H), 7.17(t, J=7.8Hz, 1H), 3.67(s, 3H), 3.55(q, J=5.7Hz, 2H), 3.03-2.99(m, 2H);LC-MS:m / z 351.10(M+1) + .

[0172] Example 19. Synthesis of 2-(benzo[d]oxazol-2-ylamino)-N-(2-(2-(dimethylamino)acetamido)ethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide [ka] Step-a: Synthesis of tert-butyl (2-(2-(dimethylamino)acetamido)ethyl)carbamate To a stirred solution of dimethylglycine (1.0 g, 9.71 mmol) in DMFA (10 mL) at 0 °C, N-ethyldiisopropylamine (1.69 mL, 9.71 mmol) and HBTU (3.68 g, 9.71 mmol) were added. The reaction mixture was stirred for 30 min, followed by the addition of tert-butyl (2-aminoethyl)carbamate (1.55 g, 9.71 mmol). The reaction mixture was stirred at RT for 16 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with cold water (50 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with water (3 × 30 mL), brine solution (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting solid was stirred in diethyl ether (20 mL) for 5 min, filtered, and dried in vacuo to give the title compound (600 mg, 25%). 1 H NMR (400MHz, DMSO-d6): δ7.77(t, J=5.6Hz, 1H), 6.83(t, J=5.2Hz, 1H), 3.11(q, J=6 .2Hz, 2H), 2.99(q, J=6.1Hz, 2H), 2.82(s, 2H), 2.18(s, 6H), 1.37(s, 9H);LC-MS:m / z 246.15(M+1) + .

[0173] Step-b: Synthesis of N-(2-aminoethyl)-2-(dimethylamino)acetamide trifluoroacetate To a solution of tert-butyl (2-(2-(dimethylamino)acetamido)ethyl)carbamate (600 mg, 2.45 mmol) in DCM (15 mL) at 0° C., TFA (0.56 mL, 7.34 mmol) was added and the reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated on a rotary evaporator and dried under vacuum to give the title compound (600 mg, 100%). 1 H NMR (400MHz, DMSO-d6): δ9.75 (bs, 1H), 8.75 (t, J=5.6Hz, 1H), 7.90 (bs, 2H), 3. 88(s, 2H), 3.38(q, J=6.2Hz, 2H), 2.91(q, J=5.9Hz, 2H), 2.82(s, 6H);LC-MS:m / z 146.20(M+1) + .

[0174] Step-c: Synthesis of 2-(benzo[d]oxazol-2-ylamino)-N-(2-(2-(dimethylamino)acetamido)ethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide To a stirred solution of 2-(benzo[d]oxazol-2-ylamino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid (100 mg, 0.32 mmol) in DMFA (4 mL) at 0 °C, N-ethyldiisopropylamine (0.17 mL, 0.97 mmol) and HBTU (123 mg, 0.32 mmol) were added. The reaction mixture was stirred for 30 min, followed by the addition of N-(2-aminoethyl)-2-(dimethylamino)acetamide trifluoroacetate (145 mg, 0.39 mmol). The reaction mixture was then stirred at RT for 16 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with cold water (15 mL). The resulting solid was filtered, washed with diethyl ether, and dried under vacuum to give the title compound as a white solid (40 mg, 28%). 1 H NMR (400MHz, DMSO-d6): δ12.20(bs, 1H), 8.44(t, J=4.9Hz, 1H), 8.07(s, 1H), 7.92(bs, 1H), 7.74(d, J=7.8Hz, 1H), 7.49-7.47(m, 2H), 7.43(d, J=7.8Hz, 1H), 7.21 (t, J=7.6Hz, 1H), 7.12 (t, J=7.6Hz, 1H), 3.63 (s, 3H), 3.37 (t, J=5.2Hz, 2H), 3.35 (2H, merged with DMSO water peak), 2.86 (s, 2H), 2.19 (s, 6H); LC-MS: m / z 436.0(M+1) + .

[0175] Example 20. Synthesis of 2-(benzo[d]oxazol-2-ylamino)-1-methyl-N-(2-morpholinoethyl)-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed for compound 1i, using 2-morpholinoethan-1-amine and 2-(benzo[d]oxazol-2-ylamino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid as starting materials. 1 H NMR (400MHz, DMSO-d6): δ12.21(bs, 1H), 8.33(s, 1H), 8.06(s, 1H), 7.73(d, J=8.4Hz, 1H), 7.48(d, J=8.4Hz, 1H), 7.43(d, J=8.0Hz, 2H), 7.21(t, J= 7.2Hz, 1H), 7.11(t, J=8.0Hz, 1H), 3.63(s, 3H), 3.58(t, J=3.6Hz, 4H), 3.41(q, J=6.4Hz, 2H), 3.30(2H, merged with DMSO water peak), 2.43(bs, 4H); LC-MS: m / z 421.2(M+1) + .

[0176] Example 21. Synthesis of 2-(benzo[d]oxazol-2-ylamino)-N-(2-(dimethylamino)ethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed for compound 1i, using N,N-dimethylethane-1,2-diamine and 2-(benzo[d]oxazol-2-ylamino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid as starting materials. 1 H NMR (400MHz, DMSO-d6): δ12.21(bs, 1H), 8.29(t, J=5.2Hz, 1H), 8.07(s, 1H), 7.74(d, J=8.4Hz, 1H), 7.48-7.42(m, 3H), 7 .21(t, J=7.6Hz, 1H), 7.11(t, J=8.0Hz, 1H), 3.63(s, 3H), 3.39-3.35(m, 2H), 2.50-2.42(m, 2H), 2.19(s, 6H);LC-MS:m / z 379.2(M+1) + .

[0177] Example 22. Synthesis of 2-(benzo[d]oxazol-2-ylamino)-N-(2-((4,5-dihydro-1H-imidazol-2-yl)amino)ethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide N as starting material 1 The title compound was synthesized using the same procedure as that followed for compound 1i using -(4,5-dihydro-1H-imidazol-2-yl)ethane-1,2-diamine and 2-(benzo[d]oxazol-2-ylamino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid. 1 H NMR (400MHz, DMSO-d6): δ12.30(bs, 2H), 8.52(bs, 1H), 8.20(bs, 1H), 8.09(s, 1H), 7.75(d, J=8.4Hz, 1H), 7.52-7.43(m, 3H) ), 7.21(t, J=7.2Hz, 1H), 7.12(t, J=8.0Hz, 1H), 3.64(s, 3H), 3.59(s, 2H), 3.45-3.43(m, 2H), 3.36-3.34(m, 4H);LC-MS:m / z 417.05(M-1) - .

[0178] Example 23. Synthesis of 2-(benzo[d]oxazol-2-ylamino)-N-(2-hydroxypropyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed for compound 1i, using 1-aminopropan-2-ol and 2-(benzo[d]oxazol-2-ylamino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid as starting materials. 1H NMR (400MHz, DMSO-d6): δ12.30(bs, 1H), 8.36(t, J=5.6Hz, 1H), 8.19(d, J=1.2Hz, 1H), 7.78(dd, J=1.2Hz, J=8.4Hz, 1H), 7.52-7.36(m, 3H), 7.2 1-7.19(m, 1H), 7.14-7.09(m, 1H), 4.87-4.78(m, 1H), 3.81(q, J=6.0Hz, 1H), 3.64(s, 3H), 3.24-3.20(m, 2H), 1.14(d, J=6.8Hz, 3H);LC-MS:m / z 366.2(M+1) + .

[0179] Example 24. Synthesis of 2-(benzo[d]oxazol-2-ylamino)-N-(2,3-dihydroxypropyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed for compound 1i, using 3-aminopropane-1,2-diol and 2-(benzo[d]oxazol-2-ylamino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid as starting materials. 1 H NMR (400MHz, DMSO-d6): δ12.30(bs, 1H), 8.31(t, J=5.2Hz, 1H), 8.08(s, 1H), 7.77(dd, J=1.6Hz, J=8.4Hz, 1H), 7.49-7.42(m, 3H), 7.21(t , J=8.0Hz, 1H), 7.11(t, J=7.2Hz, 1H), 4.82(d, J=4.4Hz, 1H), 4.58(bs, 1H), 3.64(s, 3H), 3.45-3.37(m, 3H), 3.26-3.19(m, 2H);LC-MS:m / z 382.1(M+1) + .

[0180] Example 25. Synthesis of 2-(benzo[d]oxazol-2-ylamino)-N-(2-(2-hydroxypropoxy)ethyl)-1,6-dimethyl-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed for compound 1i, using 1-(2-aminoethoxy)propan-2-ol and 2-(benzo[d]oxazol-2-ylamino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid as starting materials. 1 H NMR (400MHz, DMSO-d6): δ12.30(bs, 1H), 8.42(t, J=5.2Hz, 1H), 8.07(s, 1H), 7. 75(dd, J=1.2Hz, J=8.4Hz, 1H), 7.49-7.42(m, 3H), 7.21(t, J=7.6Hz, 1H), 7.11( t, J=8.0Hz, 1H), 4.57(bs, 1H), 3.75(q, J=5.6Hz, 1H), 3.63(s, 3H), 3.57-3.54( LC-MS:m / z 410.2(M+1) + .

[0181] Example 26. Synthesis of 2-(benzo[d]oxazol-2-ylamino)-N-((3-hydroxyoxetan-3-yl)methyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide Synthesized using the same procedure as followed for compound 1i using 3-(aminomethyl)oxetan-3-ol and 2-(benzo[d]oxazol-2-ylamino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid as starting materials. 1 H NMR (400MHz, DMSO-d6): δ12.30(bs, 1H), 8.55(t, J=5.2Hz, 1H), 8.10(d, J=1.2Hz, 1H), 7.79(dd, J=1.6Hz, J=8.4Hz, 1H), 7.51-7.42(m, 3H), 7.21( t, J=7.6Hz, 1H), 7.14(t, J=7.6Hz, 1H), 5.90(s, 1H), 4.52(d, J=6.8Hz, 2H), 4.41(d, J=6.4Hz, 2H), 3.64(s, 3H), 3.59(d, J=6.0Hz, 2H);LC-MS:m / z 394.2(M+1) + .

[0182] Example 27. Synthesis of 2-(benzo[d]oxazol-2-ylamino)-N-(2-(2-hydroxy-2-methylpropoxy)ethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed for compound 1i, using 1-(2-aminoethoxy)-2-methylpropan-2-ol and 2-(benzo[d]oxazol-2-ylamino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid as starting materials. 1 H NMR (400MHz, DMSO-d6): δ12.30(bs, 1H), 8.43(t, J=5.2Hz, 1H), 8.07(d, J=1.2 Hz, 1H), 7.75(dd, J=2.4Hz, J=8.4Hz, 1H), 7.49-7.42(m, 3H), 7.21(dd, J=1.2H z, J=7.6Hz, 1H), 7.12(dd, J=1.2Hz, J=7.6Hz, 1H), 4.34(bs, 1H), 3.63(s, 3H), 3.57(t, J=6.4Hz, 2H), 3.47-3.43(m, 2H), 3.20(s, 2H), 1.09(s, 6H);LC-MS:m / z 424.2(M+1) + .

[0183] Example 28. Synthesis of 2-(benzo[d]oxazol-2-ylamino)-1-methyl-N-(2-(pyrrolidin-1-yl)ethyl)-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed for compound 1i, using 2-(pyrrolidin-1-yl)ethan-1-amine and 2-(benzo[d]oxazol-2-ylamino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid as starting materials. 1H NMR (400 MHz, DMSO-d6): δ 12.24 (bs, 1H), 8.38 (t, J = 5.6 Hz, 1H), 8.07 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.49-7.42 (m, 3H), 7.21 (t, J = 6.8 Hz, 1H), 7.11 (t, J = 7.2 Hz, 1H), 3.69 (s, 3H), 3.48-3.37 (m, 2H), 2.64-2.57 (m, 2H), 2.50 (4H, merged with DMSO peak), 1.66 (bs, 4H); LC-MS: m / z 405.2 (M+1) + .

[0184] Example 29. Synthesis of 2-(2-(2-(benzo[d]oxazol-2-ylamino)-1-methyl-1H-benzo[d]imidazole-5-carboxamido)ethoxy)acetic acid [ka] Step-a: Synthesis of ethyl 2-(2-((tert-butoxycarbonyl)amino)ethoxy)acetate To a solution of tert-butyl (2-hydroxyethyl)carbamate (1.0 g, 6.21 mmol) in THF (10 mL) at 0° C., sodium hydride (60% dispersion in mineral oil) (397 mg, 9.93 mmol) was added portionwise, followed by potassium iodide (164 mg, 0.99 mmol) and ethyl bromoacetate (2.07 g, 12.42 mmol). The reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with cold water (60 mL) and extracted with ethyl acetate (3×60 mL). The combined organic layers were washed with water (30 mL), brine solution (30 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by CombiFlash column chromatography using 1% methanol in dichloromethane as the eluent to give the title compound (1.0 g, 65%). 1H NMR (400MHz, DMSO-d6): δ6.74(bs, 1H), 4.14-4.08(m, 4H), 3.45(t, J=5.6Hz, 2H), 3.08(q, J=6.2Hz, 2H), 1.37(s, 9H), 1.19(t, J=6.8Hz, 3H); LC-MS: m / z 148.1(M-Boc) + .

[0185] Step-b: Synthesis of ethyl 2-(2-aminoethoxy)acetate trifluoroacetate To a stirred solution of ethyl 2-(2-((tert-butoxycarbonyl)amino)ethoxy)acetate (1.0 g, 4.05 mmol) in DCM (5 mL) at RT, trifluoroacetic acid (1 mL) was added and stirred at RT for 5 h. The reaction mixture was concentrated under reduced pressure to give the title compound (1.1 g, 100%), which was used in the next step without further purification. 1 H NMR (400MHz, DMSO-d6): δ7.88(bs, 3H), 4.17(s, 2H), 4.14(q, J=6.8Hz, 2H), 3.68(t, J=5.0Hz, 2H), 3.01(q, J=5.2Hz, 2H), 1.21(t, J=7.0Hz, 3H); LC-MS: m / z 148.2(M+1) + .

[0186] Step-c: Synthesis of ethyl 2-(2-(2-(benzo[d]oxazol-2-ylamino)-1-methyl-1H-benzo[d]imidazole-5-carboxamido)ethoxy)acetate To a stirred solution of 2-(benzo[d]oxazol-2-ylamino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid (150 mg, 0.48 mmol) in DMFA (2 mL) at 0 °C, N-ethyldiisopropylamine (0.26 mL, 1.46 mmol) and HBTU (184 mg, 0.48 mmol) were added. The reaction mixture was stirred for 30 min, followed by the addition of ethyl 2-(2-aminoethoxy)acetate trifluoroacetate (129 mg, 0.53 mmol). The reaction mixture was stirred at RT for 16 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with cold water (6 mL) and stirred for 5 min. The precipitated solid was filtered and dried under vacuum to give the title compound (125 mg, 59%). 1 H NMR (400MHz, DMSO-d6): δ12.3(bs, 1H), 8.46(bs, 1H), 8.08(s, 1H), 7.76(d, J=8.4Hz, 1H), 7.49-7.47(m, 2H), 7.43(d, J=7.6Hz, 1H), 7.21(t, J=8 .0Hz, 1H), 7.14(t, J=7.6Hz, 1H), 4.15(s, 2H), 4.12(q, J=7.0Hz, 2H), 3.65-3.62(m, 5H), 3.47(q, J=5.8Hz, 2H), 1.19(t, J=7.0Hz, 3H);LC-MS:m / z 438.1(M+1) + .

[0187] Step-d: Synthesis of 2-(2-(2-(benzo[d]oxazol-2-ylamino)-1-methyl-1H-benzo[d]imidazole-5-carboxamido)ethoxy)acetic acid To ethyl 2-(2-(2-(benzo[d]oxazol-2-ylamino)-1-methyl-1H-benzo[d]imidazole-5-carboxamido)ethoxy)acetate (110 mg, 0.25 mmol) in a solvent mixture of THF (1 mL), ethanol (1 mL), and water (0.5 mL) was added lithium hydroxide monohydrate (26 mg, 0.63 mmol). The reaction mixture was stirred at RT for 3 h. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (5 mL) and acidified with 1 N HCl to give a solid, which was filtered and dried under vacuum to give the title compound (80 mg, 78%).1 H NMR (400MHz, DMSO-d6): δ12.60(bs, 1H), 8.47(s, 1H), 8.08(s, 1H), 7.77(d, J=8.4Hz, 1H), 7.50-7.43(m, 3H) , 7.22(t, J=7.6Hz, 1H), 7.13(t, J=7.2Hz, 1H), 4.06(s, 2H), 3.64(bs, 5H), 3.45(q, J=5.2Hz, 2H);LC-MS:m / z 410.4(M+1) + .

[0188] Example 30. 2-(2-(2-(benzo[d]oxazol-2-ylamino)-1-methyl-1H-benzo[d]imidazole-5-carboxamido)ethoxy)ethyl DL-valinate hydrochloride [ka] Step-a: Synthesis of (tert-butoxycarbonyl)-DL-valine To a stirred solution of DL-valine (2.0 g, 17.07 mmol) in THF (25 mL) and water (20 mL) at RT, sodium hydroxide (0.82 g, 20.5 mmol) and di-tert-butyl dicarbonate (4.09 g, 18.77 mmol) were added, and the reaction mixture was stirred for 16 h. The mixture was cooled to 0 °C, acidified with 1 N HCl, and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine solution (30 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product (1.8 g) was used in the next step without further purification.

[0189] Step-b: Synthesis of 2-(2-(2-(benzo[d]oxazol-2-ylamino)-1-methyl-1H-benzo[d]imidazole-5-carboxamido)ethoxy)ethyl(tert-butoxycarbonyl)-DL-valinate To a stirred solution of 2-(benzo[d]oxazol-2-ylamino)-N-(2-(2-hydroxyethoxy)ethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide (70 mg, 0.18 mmol) and (tert-butoxycarbonyl)-DL-valine (42 mg, 0.19 mmol) in DMFA (5 mL) at 0 °C, N-ethyldiisopropylamine (0.04 mL, 0.21 mmol) and HATU (80 mg, 0.21 mmol) were added. The reaction mixture was stirred at RT for 16 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with cold water (20 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with water (20 mL), brine solution (20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by Combiflash column chromatography using 4.1% methanol in dichloromethane as the eluent to give the title compound (40 mg, 38%). LC-MS: m / z 595.7 (M+1) + .

[0190] Step-c: Synthesis of 2-(2-(2-(benzo[d]oxazol-2-ylamino)-1-methyl-1H-benzo[d]imidazole-5-carboxamido)ethoxy)ethyl DL-valinate hydrochloride To a stirred solution of 2-(2-(2-(benzo[d]oxazol-2-ylamino)-1-methyl-1H-benzo[d]imidazole-5-carboxamido)ethoxy)ethyl(tert-butoxycarbonyl)-DL-valinate (40 mg, 0.07 mmol) in 1,4-dioxane (5 mL) at 10° C. was added 4 N HCl in 1,4-dioxane (0.03 mL, 0.13 mmol) and the reaction mixture was stirred at RT for 16 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure and lyophilized for 18 h to afford the title compound as the hydrochloride salt (19 mg, 53%). 1H NMR (400MHz, DMSO-d6): δ12.50(s, 1H), 8.52(bs, 1H), 8.40(bs, 3H), 8.09(s, 1H), 7.80(d, J=8. 4Hz, 1H), 7.54(d, J=7.6Hz, 1H), 7.48(d, J=7.6Hz, 2H), 7.25(t, J=7.2Hz, 1H), 7.17(t, J=8.0Hz, 1H), 4.43-4.40(m, 2H), 4.28-4.25(m, 2H), 3.95(bs, 1H), 3.70-3.67(s, 3H), 3.61-3.57(m, 2H) , 3.45-3.44(m, 2H), 2.15-2.11(m, 1H), 0.97(d, J=6.8Hz, 3H), 0.92(d, J=6.8Hz, 3H);LC-MS:m / z 495.1(M+1) + .

[0191] Examples 31 and 32. Synthesis of 1-methyl-2-((6-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid and N-(2-methoxyethyl)-1-methyl-2-((6-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide [ka] Step-a: Synthesis of 2-nitro-5-(trifluoromethyl)phenol To a solution of 3-(trifluoromethyl)phenol (5.0 g, 30.86 mmol) in acetic acid (50 mL) was added dropwise 60% aqueous nitric acid solution (3.5 mL) at 0 °C. The mixture was then stirred at this temperature for 1.5 h, and stirring was continued at RT for 16 h. The mixture was poured into ice water (80 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine solution (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by combiflash column chromatography using 5% ethyl acetate in hexane as the eluent to give the title compound (1.0 g, 16%). 1H NMR (400MHz, DMSO-d6): δ11.75 (bs, 1H), 8.06 (d, J=8.3Hz, 1H), 7.41 (d, J=1.4Hz, 1H), 7.32 (dd, J=1.4Hz, J=8.3Hz, 1H); LC-MS: m / z 206.0 (M-1) - .

[0192] Step-b: Synthesis of 2-amino-5-(trifluoromethyl)phenol To a solution of 2-nitro-5-(trifluoromethyl)phenol (1.0 g, 4.83 mmol) in methanol (15 mL) was added 10% Pd / C (100 mg) under a nitrogen atmosphere. The reaction mixture was stirred under a hydrogen balloon for 16 hours. The reaction mixture was filtered through a celite bed, and the filtrate was concentrated in vacuo to give the title compound (850 mg, 99%). 1 H NMR (400MHz, DMSO-d6): δ9.58(bs, 1H), 6.88(s, 1H), 6.86(s, 1H), 6.66(d, J=7.8Hz, 1H), 5.18(s, 2H); LC-MS: m / z178.0(M+1) + .

[0193] Step-c: Synthesis of 6-(trifluoromethyl)benzo[d]oxazole-2-thiol To a solution of 2-amino-5-(trifluoromethyl)phenol (850 mg, 4.8 mmol) in ethanol (10 mL) at room temperature was added potassium ethyl xanthate (1.69 g, 10.56 mmol), and the reaction mixture was refluxed for 16 hours. The reaction mixture was concentrated in vacuo, diluted with cold water (50 mL), and acidified with 1N HCl. The resulting solid was filtered and dried in vacuo to give the title compound (1.0 g, 95%). 1 H NMR (400MHz, DMSO-d6): δ14.2 (bs, 1H), 7.98 (s, 1H), 7.66 (d, J=8.4Hz, 1H), 7.41 (d, J=7.8Hz, 1H); LC-MS: m / z 217.9 (M-1) - .

[0194] Step-d: Synthesis of 2-chloro-6-(trifluoromethyl)benzo[d]oxazole To a solution of 6-(trifluoromethyl)benzo[d]oxazole-2-thiol (500 mg, 2.28 mmol) in thionyl chloride (4 mL) at RT, dimethylformamide (catalytic amount) was added and the reaction mixture was refluxed for 3 h. The reaction mixture was concentrated, diluted with cold water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine solution (20 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (290 mg, 57%). 1 H NMR (400MHz, DMSO-d6): δ8.31 (s, 1H), 7.97 (d, J=8.3Hz, 1H), 7.80 (d, J=8.3Hz, 1H).

[0195] Step-e: Synthesis of ethyl 1-methyl-2-((6-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylate To a solution of ethyl 2-amino-1-methyl-1H-benzo[d]imidazole-5-carboxylate (240 mg, 1.09 mmol) in 1,4-dioxane (8 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil) (109 mg, 2.74 mmol), followed by 2-chloro-6-(trifluoromethyl)benzo[d]oxazole (290 mg, 1.31 mmol). The reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated, diluted with cold water (15 mL), and stirred at RT for 30 min. The resulting solid was filtered, dried under vacuum, and purified by CombiFlash column chromatography using 100% DCM as the eluent to give the title compound (150 mg, 34%). 1 H NMR (400MHz, DMSO-d6): δ12.40(bs, 1H), 8.25(d, J=1.5Hz, 1H), 7.89(dd, J=1.5Hz, J=8.3Hz, 1H), 7. 83(s, 1H), 7.61-7.51(m, 3H), 4.33(q, J=6.9Hz, 2H), 3.66(s, 3H), 1.36(t, J=6.9Hz, 3H);LC-MS:m / z 405.30(M+1)+ .

[0196] Step-f: Synthesis of 1-methyl-2-((6-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid (Example 31) To a stirred solution of ethyl 1-methyl-2-((6-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylate (80 mg, 0.20 mmol) in a solvent mixture of THF (0.5 mL), ethanol (0.5 mL), and water (0.25 mL) was added lithium hydroxide monohydrate (20 mg, 0.50 mmol). The reaction mixture was heated at 60° C. for 16 h. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was dissolved in water and acidified with 1N HCl to give a solid, which was filtered and dried under vacuum to give the title compound (55 mg, 81%). 1 H NMR (400MHz, DMSO-d6): δ12.80(bs, 1H), 12.40(bs, 1H), 8.22(s, 1H), 7.89(d, J=8.3Hz, 1H), 7.84(s, 1H), 7.63-7.53(m, 3H), 3.67(s, 3H); LC-MS: m / z 377.05(M+1) + .

[0197] Step-g: Synthesis of N-(2-methoxyethyl)-1-methyl-2-((6-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide (Example 32) To a stirred solution of 1-methyl-2-((6-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid (50 mg, 0.13 mmol) in DMFA (1.5 mL) at 0° C. was added N-ethyldiisopropylamine (0.02 mL, 0.13 mmol) and diphenylphosphoryl azide (0.02 mL, 0.13 mmol). The reaction mixture was stirred for 30 min, followed by the addition of 2-methoxyethylamine (0.01 mL, 0.13 mmol), and the reaction mixture was then stirred at RT for 16 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with cold water (15 mL) and stirred for 15 min. The resulting solid was filtered, washed with diethyl ether, and dried under vacuum to give the title compound (28 mg, 49%). 1 H NMR (400MHz, DMSO-d6): δ12.40(bs, 1H), 8.48(s, 1H), 8.10(s, 1H), 7.83(s, 1H), 7.79(d, LC-MS:m / z 434.1(M+1) + .

[0198] Example 33. Synthesis of N-(2-hydroxyethyl)-1-methyl-2-((6-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide [ka] The title compound was synthesized using the same procedure as that followed in step-e of Example 6 using 1-methyl-2-((6-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid as starting material (yield: 34%). 1H NMR (400MHz, DMSO-d6): δ12.40(bs, 1H), 8.39(t, J=5.3Hz, 1H), 8.10(s, 1H), 7.82(s, 1H), 7.80(d, J=8.3Hz, 1H), 7.61-7.51(m, 3H), 4.72(t, J=5.2Hz, 1H), 3.67(s, 3H), 3.54-3.51(m, 2H), 3.37-3.34(m, 2H);LC-MS:m / z 420.0(M+1) + .

[0199] Example 34. Synthesis of N-(2-(2-hydroxyethoxy)ethyl)-1-methyl-2-((6-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide [ka] The title compound was synthesized using the same procedure as that followed in step-e of Example 6 using 1-methyl-2-((6-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid and 2-(2-aminoethoxy)ethan-1-ol as starting materials (yield: 50%). 1 H NMR (400MHz, DMSO-d6): δ12.40(bs, 1H), 8.46(bs, 1H), 8.10(s, 1H), 7.83(s, 1H), 7.79(d, LC-MS:m / z 464.20(M+1) + .

[0200] Example 35. Synthesis of N-(2-hydroxypropyl)-1-methyl-2-((6-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed for compound 1i, using 1-aminopropan-2-ol and 1-methyl-2-((6-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid as starting materials. 1 H NMR (400MHz, DMSO-d6): δ12.30(bs, 1H), 8.35(t, J=1.2Hz, 1H), 8.10(d, J=1.2Hz, 1H), 7.82-7.79(m, 2H), 7.61-7.51 (m, 3H), 4.76(d, J=4.0Hz, 1H), 3.84-3.80(m, 1H), 3.67(s, 3H), 3.26-3.21(m, 2H), 1.09(d, J=6.4Hz, 3H);LC-MS:m / z 434.2(M+1) + .

[0201] Example 36. Synthesis of 1-methyl-N-(2-(pyrrolidin-1-yl)ethyl)-2-((6-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed for compound 1i, using 2-(pyrrolidin-1-yl)ethan-1-amine and 1-methyl-2-((6-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid as starting materials. 1 H NMR (400 MHz, DMSO-d6): δ 12.30 (bs, 1H), 8.39 (t, J = 5.2 Hz, 1H), 8.09 (s, 1H), 7.82 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.61-7.51 (m, 3H), 3.66 (s, 3H), 3.43-3.38 (m, 2H), 2.61 (t, J = 7.2 Hz, 2H), 2.5 (m, merged with 4H DMSO peak), 1.69 (bs, 4H); LC-MS: m / z 473.1 (M+1) + .

[0202] Example 37. Synthesis of 1-methyl-N-(2-(piperidin-1-yl)ethyl)-2-((6-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed for compound 1i, using 2-(piperidin-1-yl)ethan-1-amine and 1-methyl-2-((6-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid as starting materials. 1 H NMR (400MHz, DMSO-d6): δ12.30(bs, 1H), 8.32(t, J=5.6Hz, 1H), 8.07(s, 1H), 7.82(s, 1H), 7.75(d, J=8.0Hz , 1H), 7.61-7.51(m, 3H), 3.66(s, 3H), 3.41-3.36(m, 2H), 2.43-2.32(m, 6H), 1.53-1.38(m, 6H);LC-MS:m / z 487.15(M+1) + .

[0203] Example 38. Synthesis of N-(2-(2-hydroxypropoxy)ethyl)-1-methyl-2-((6-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed for compound 1i, using 1-(2-aminoethoxy)propan-2-ol and 1-methyl-2-((6-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid as starting materials. 1H NMR (400MHz, DMSO-d6): δ12.30(bs, 1H), 8.46(t, J=5.6Hz, 1H), 8.09(s, 1H), 7.83(s, 1H), 7.78(d, J=8.8Hz, 1H), 7.62-7.52(m, 3H), 4.58(d, J= LC-MS: m / z 478.2(M+1) + .

[0204] Example 39. Synthesis of N-(2,3-dihydroxypropyl)-1-methyl-2-((6-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide Synthesized using the same procedure as followed for compound 1i using 3-aminopropane-1,2-diol and 1-methyl-2-((6-(trifluoromethyl)benzo[d]oxazol-2-yl)amino-1H-benzo[d]imidazole-5-carboxylic acid as starting materials. 1 H NMR (400MHz, DMSO-d6): δ12.40(bs, 1H), 8.39(t, J=5.2Hz, 1H), 8.10(s, 1H), 7.84(s, 1H), 7.80(d, J=8.4Hz, 1H), 7.62-7.53(m, 3 LC-MS: m / z 450.15(M+1) + .

[0205] Example 40. Synthesis of N-(2-(2-(dimethylamino)acetamido)ethyl)-1-methyl-2-((6-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed in step-c of Example 19 using N-(2-aminoethyl)-2-(dimethylamino)acetamide trifluoroacetate and 1-methyl-2-((6-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid as starting materials. 1 H NMR (400MHz, DMSO-d6): δ12.30(bs, 1H), 8.47(bs, 1H), 8.09(s, 1H), 7.92(bs, 1H), 7.83(s, 1H), 7.76(d , J=8.4Hz, 1H), 7.61-7.52(m, 3H), 3.66(s, 3H), 3.38-3.35(m, 4H), 2.86(s, 2H), 2.19(s, 6H);LC-MS:m / z 504.2(M+1) + .

[0206] Example 41. Synthesis of 2-(2-(1-methyl-2-((6-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamido)ethoxy)acetic acid [ka] Step-a: Synthesis of ethyl 2-(2-(1-methyl-2-((6-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamido)ethoxy)acetate The title compound was synthesized using the same procedure as in step-c of Example 29, using 1-methyl-2-((6-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid and 2-(2-aminoethoxy)acetate trifluoroacetate as starting materials (yield: 65%). 1H NMR (400MHz, DMSO-d6): δ12.38(bs, 1H), 8.49(bs, 1H), 8.10(s, 1H), 7.82(s, 1H), 7.79(d, J=8.8Hz, 1H), 7. 61-7.52(m, 3H), 4.15-4.09(m, 4H), 3.66-3.62(m, 5H), 3.48-3.46(m, 2H), 1.19(t, J=7.0Hz, 3H);LC-MS:m / z 506.1(M+1) + .

[0207] Step-b: Synthesis of 2-(2-(1-methyl-2-((6-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide)ethoxy)acetic acid The title compound was synthesized using the same procedure as followed for step-d of Example 29 using ethyl 2-(2-(1-methyl-2-((6-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamido)ethoxy)acetate as starting material (yield: 75%). 1 H NMR (400MHz, DMSO-d6): δ12.70(bs, 1H), 12.30(bs, 1H), 8.49(bs, 1H), 8.10(s, 1H), 7.82-7. 78(m, 2H), 7.61-7.51(m, 3H), 4.06(s, 2H), 3.66-3.62(m, 5H), 3.48-3.41(m, 2H);LC-MS:m / z 478.2(M+1) + .

[0208] Example 42. Synthesis of N-(2-(2-hydroxy-2-methylpropoxy)ethyl)-1-methyl-2-((6-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed for compound 1i, using 1-(2-aminoethoxy)-2-methylpropan-2-ol and 1-methyl-2-((6-(trifluoromethyl)benzo[d]oxazol)-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid as starting materials. 1 H NMR (400MHz, DMSO-d6): δ12.40(bs, 1H), 8.83(s, 1H), 8.08(s, 1H), 7.81(s, 1H), 7.77(d, J=8.4Hz, 1H), 7.58-7.5 2(m, 3H), 4.32(bs, 1H), 3.66(s, 3H), 3.58-3.56(m, 2H), 3.46-3.44(m, 2H), 3.21(s, 2H), 1.08(s, 6H);LC-MS:m / z 492.1(M+1) + .

[0209] Example 43. Synthesis of N-(2-(2-hydroxyethoxy)ethyl)-1-methyl-2-((5-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide [ka] Step-a: Synthesis of 2-nitro-4-(trifluoromethyl)phenol To a solution of 1-chloro-2-nitro-4-(trifluoromethyl)benzene (10.0 g, 44.3 mmol) in DMSO (100 mL) at RT was added sodium hydroxide (4.44 g, 110.7 mmol), and the mixture was stirred at 60° C. for 16 h. The reaction mixture was cooled to RT, diluted with water (250 mL), and extracted with EtOAc (200 mL). The aqueous layer was acidified to approximately pH 1 with 3 N HCl and extracted with EtOAc (2×250 mL), and the organic layer was washed with brine solution (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title compound (7.0 g, 81%). 1H NMR (400MHz, DMSO-d6): δ11.99 (bs, 1H), 8.22 (d, J=1.6Hz, 1H), 7.88 (dd, J=2.0Hz, J=8.8Hz, 1H), 7.30 (d, J=8.8Hz, 1H).

[0210] Step-b: Synthesis of 2-amino-4-(trifluoromethyl)phenol To a solution of 2-nitro-4-(trifluoromethyl)phenol (5.0 g, 24.15 mmol) in methanol (50 mL) was added 10% Pd / C (2.5 g) under a nitrogen atmosphere. The reaction mixture was stirred under a hydrogen balloon for 16 hours. The reaction mixture was filtered through a celite bed, and the filtrate was concentrated in vacuo to give the title compound (3.0 g, 70%). 1 H NMR (400MHz, DMSO-d6): δ9.85 (bs, 1H), 6.87 (d, J=2.0Hz, 1H), 6.77-6.70 (m, 2H), 5.0 (bs, 2H); LC-MS: m / z 178.1 (M+1) + .

[0211] Step-c: Synthesis of 5-(trifluoromethyl)benzo[d]oxazole-2-thiol To a solution of 2-amino-4-(trifluoromethyl)phenol (3.0 g, 16.9 mmol) in ethanol (45 mL) at room temperature was added potassium ethyl xanthate (6.78 g, 42.4 mmol), and the reaction mixture was refluxed for 16 hours. The reaction mixture was concentrated in vacuo, diluted with cold water (100 mL), and acidified with 3N HCl. The precipitated solid was filtered and dried in vacuo to give the title compound (3.0 g, 81%). 1 H NMR (400MHz, DMSO-d6): δ14.2 (bs, 1H), 7.72 (d, J=8.4Hz, 1H), 7.64 (d, J=8.4Hz, 1H), 7.51 (s, 1H); LC-MS: m / z 220.0 (M+1) + .

[0212] Step-d: Synthesis of 2-chloro-5-(trifluoromethyl)benzo[d]oxazole To a solution of 5-(trifluoromethyl)benzo[d]oxazole-2-thiol (2.0 g, 9.1 mmol) in thionyl chloride (10 mL) at RT, N,N-dimethylformamide (catalytic amount) was added and the reaction mixture was refluxed for 1 h. The reaction mixture was concentrated, diluted with cold water (60 mL), and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine solution (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title compound (1.3 g, 65%). 1 H NMR (400MHz, DMSO-d6): δ8.23 (s, 1H), 8.02 (d, J=8.8Hz, 1H), 7.85 (d, J=8.8Hz, 1H).

[0213] Step-e: Synthesis of ethyl 1-methyl-2-((5-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylate To a solution of ethyl 2-amino-1-methyl-1H-benzo[d]imidazole-5-carboxylate (200 mg, 0.91 mmol) in 1,4-dioxane (10 mL) at 0 °C was added sodium hydride (60% dispersion in mineral oil) (91 mg, 2.27 mmol) and stirred for 15 minutes. Subsequently, 2-chloro-5-(trifluoromethyl)benzo[d]oxazole (222 mg, 1.0 mmol) was added and stirring was continued at RT for 16 hours. The reaction mixture was concentrated, diluted with cold water (50 mL), acidified with 3N HCl, and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with water (30 mL), brine solution (30 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by CombiFlash column chromatography using 100% dichloromethane as the eluent to give the title compound (150 mg, 40%). 1H NMR (400MHz, DMSO-d6): δ12.41(bs, 1H), 8.25(s, 1H), 7.90(dd, J=1.2Hz, J=8.4Hz, 1H), 7.67-7.64(m, 2H), 7.5 7(d, J=8.4Hz, 1H), 7.49(d, J=8.4Hz, 1H), 4.33(q, J=7.2Hz, 2H), 3.66(s, 3H), 1.35(t, J=7.2Hz, 3H);LC-MS:m / z 405.00(M+1) + .

[0214] Step-f: Synthesis of 1-methyl-2-((5-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid To a stirred solution of ethyl 1-methyl-2-((5-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylate (150 mg, 0.37 mmol) in a solvent mixture of THF (2 mL), methanol (2 mL), and water (2 mL) was added lithium hydroxide monohydrate (78 mg, 1.85 mmol). The reaction mixture was stirred at 50° C. for 16 h. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was dissolved in water (30 mL), acidified to about pH 2 with 3 N HCl, and stirred for 1 h. The precipitated solid was filtered and dried under vacuum to give the title compound (140 mg, 100%). 1 H NMR (400MHz, DMSO-d6): δ12.85(bs, 1H), 12.40(bs, 1H), 8.18(s, 1H), 7.87(d, J=8.4Hz, 1H), 7.67( s, 1H), 7.63(d, J=8.4Hz, 1H), 7.52(d, J=8.4Hz, 1H), 7.46(d, J=8.0Hz, 1H), 3.64(s, 3H);LC-MS:m / z 377.1(M+1) + .

[0215] Step-g: Synthesis of N-(2-(2-hydroxyethoxy)ethyl)-1-methyl-2-((5-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide To a stirred solution of 1-methyl-2-((5-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid (80 mg, 0.21 mmol) in DMFA (5 mL) at 0° C. was added N-ethyldiisopropylamine (0.04 mL, 0.21 mmol) and HBTU (81 mg, 0.21 mmol). The reaction mixture was stirred for 15 minutes, followed by the addition of 2-(2-aminoethoxy)ethan-1-ol (22 mg, 0.21 mmol). The reaction mixture was then stirred at RT for 16 hours. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with cold water (30 mL) and stirred for 1 hour. The precipitated solid was filtered and dried under vacuum. The solid was stirred in diethyl ether (15 mL), filtered, and dried under vacuum to give the title compound (80 mg, 85%). 1 H NMR (400MHz, DMSO-d6): δ12.33(bs, 1H), 8.46(t, J=5.4Hz, 1H), 8.09(d, J=1.2Hz, 1H), 7.78(dd, J=1.6Hz, J=8.4Hz, 1H), 7.68(s, 1H), 7.64(d, J=8.4Hz, 1H), 7.52(d, J=8.0Hz, 1H), 7.48(d, J=8.4Hz, 1H), 4.60(t, J=5.2Hz, 1H), 3.66(s, 3H), 3.58-3.43(m, 8H); LC-MS: m / z 464.2(M+1) + .

[0216] Examples 44 and 45. Synthesis of 1-methyl-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid, and synthesis of N-(2-methoxyethyl)-1-methyl-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide: [ka] Step-a: Synthesis of 2-nitro-5-(trifluoromethoxy)phenol To a solution of 3-(trifluoromethoxy)phenol (1 g, 5.6 mmol) in acetic acid (10 mL) was added dropwise 60% aqueous nitric acid solution (1 mL) at 10-15 °C. The mixture was stirred at this temperature for 1.5 h and continued to stir at RT for 16 h. The mixture was poured into ice water (20 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with brine solution (25 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by Combiflash chromatography using 5% EtOAc in hexane as the eluent to give the title compound (300 mg, 24%). 1 H NMR (400MHz, CDCl3): δ10.73(s, 1H), 8.18(d, J=9.6Hz, 1H), 6.99(s, 1H), 6.83(d, J=9.2Hz, 1H); LC-MS: m / z 222.0(M-1).

[0217] Step-b: Synthesis of 2-amino-5-(trifluoromethoxy)phenol To a solution of 2-nitro-5-(trifluoromethoxy)phenol (300 mg, 1.35 mmol) in methanol (6 mL) was added 10% Pd / C (60 mg) under a nitrogen atmosphere. The reaction mixture was stirred under hydrogen gas for 5 hours. The reaction mixture was filtered through a bed of Celite and concentrated in vacuo to give the title compound (250 mg, 96%). 1 H NMR (400MHz, DMSO-d6): δ 9.60 (s, 1H), 6.59-6.57 (m, 2H), 6.53-6.50 (m, 1H), 4.68 (bs, 2H); LC-MS: m / z 194.0 (M+1) + .

[0218] Step-c: Synthesis of 6-(trifluoromethoxy)benzo[d]oxazole-2-thiol To a solution of 2-amino-5-(trifluoromethoxy)phenol (250 mg, 1.3 mmol) in ethanol (5 mL) at RT, powdered potassium hydroxide (127 mg, 2.3 mmol) and carbon disulfide (1 mL, 17.0 mmol) were added. The reaction mixture was refluxed for 6 h. After cooling to RT, the mixture was concentrated in vacuo. The residue was diluted with cold water (100 mL) and acidified with 1N HCl. The resulting solid was filtered and dried under vacuum to give the title compound (200 mg, 66%). 1 H NMR (400MHz, DMSO-d6): δ14.10 (bs, 1H), 7.73 (s, 1H), 7.32 (s, 2H); LC-MS: m / z 235.9 (M+1) + .

[0219] Step-d: Synthesis of 2-(methylthio)-6-(trifluoromethoxy)benzo[d]oxazole The title compound was synthesized using the same procedure as followed for compound 1b, using 6-(trifluoromethoxy)benzo[d]oxazole-2-thiol as starting material and stirring at RT for 16 h (yield: 94%). 1 H NMR (400MHz, DMSO-d6): δ7.85 (d, J=1.6Hz, 1H), 7.73 (d, J=8.0Hz, 1H), 7.37-7.34 (m, 1H), 2.77 (s, 3H); LC-MS: m / z 250.1 (M+1) + .

[0220] Step-e: Synthesis of 2-(methylsulfonyl)-6-(trifluoromethoxy)benzo[d]oxazole The title compound was synthesized using the same procedure as followed for compound 1c, using 2-(methylthio)-6-(trifluoromethoxy)benzo[d]oxazole as starting material and stirring at RT for 6 h (yield: 94%). 1 H NMR (400MHz, DMSO-d6): δ8.22(s, 1H), 8.15(d, J=8.8Hz, 1H), 7.62(d, J=8.8Hz, 1H), 3.67(s, 3H).

[0221] Step-f: Synthesis of ethyl 1-methyl-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylate To a solution of ethyl 2-amino-1-methyl-1H-benzo[d]imidazole-5-carboxylate (100 mg, 0.46 mmol) in 1,4-dioxane (2 mL) at room temperature, sodium hydride (60% dispersion in mineral oil) (64 mg, 1.6 mmol) was added, followed by 2-(methylsulfonyl)-6-(trifluoromethoxy)benzo[d]oxazole (167 mg, 0.6 mmol). The reaction mixture was stirred at room temperature for 16 hours. It was then concentrated, diluted with cold water (15 mL), and acidified with 1N HCl. The resulting solid was filtered, dried under vacuum, and purified by CombiFlash column chromatography using 100% DCM as the eluent to give the title compound (30 mg, 16%). 1 H NMR (400MHz, DMSO-d6): δ12.40(bs, 1H), 8.24(s, 1H), 7.89(dd, J=1.6Hz, J=8.4Hz, 1H), 7.58-7.50( LC-MS:m / z 421.0(M+1) + .

[0222] Step-g: Synthesis of 1-methyl-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid The title compound was synthesized using the same procedure as that followed for compound 1h using ethyl 1-methyl-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylate as starting material (yield: 72%). 1H NMR (400MHz, DMSO-d6): δ12.80(bs, 1H), 12.30(bs, 1H), 8.20(s, 1H), 7.88(d, J=8.4Hz, 1H), 7.58(s, 1H), 7.52(d, J=8.8Hz, 2H), 7.22(d, J=8.0Hz, 1H), 3.65(s, 3H);LC-MS:m / z 393.0(M+1) + .

[0223] Step-h: Synthesis of N-(2-methoxyethyl)-1-methyl-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed for compound 1i using 1-methyl-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid as the starting material (yield: 23%). 1 H NMR (400MHz, DMSO-d6): δ12.30(bs, 1H), 8.47(t, J=5.2Hz, 1H), 8.08(s, 1H), 7.78(d, J=8.4Hz, 1H), 7.57( s, 1H), 7.52-7.49(m, 2H), 7.21(d, J=8.4Hz, 1H), 3.64(s, 3H), 3.48-3.44(m, 4H), 3.28(s, 3H);LC-MS:m / z 450.0(M+1) + .

[0224] Example 46. Synthesis of 1-methyl-N-(1H-pyrazol-4-yl)-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed for compound 1i, using 1H-pyrazol-4-amine and 1-methyl-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid as starting materials. 1H NMR (400MHz, DMSO-d6): δ12.65(bs, 1H), 12.30(bs, 1H), 10.40(s, 1H), 8.17(d, J=1.2Hz, 1H), 8.02(bs, 1H), 7. 89(dd, J=1.2Hz, J=8.4Hz, 1H), 7.69(bs, 1H), 7.58-7.49(m, 3H), 7.21(d, J=8.4Hz, 1H), 3.67(s, 3H);LC-MS:m / z 458.0(M+1) + .

[0225] Example 47. Synthesis of N-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)-1-methyl-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed for compound 1i, using 2-amino-2-(hydroxymethyl)propane-1,3-diol and 1-methyl-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid as starting materials. 1 H NMR (400MHz, DMSO-d6): δ12.30(bs, 1H), 8.05(s, 1H), 7.43(d, J=8.4Hz, 1H), 7.57(s, 1H), 7.50(d, J= LC-MS:m / z 496.3(M+1) + .

[0226] Example 48. Synthesis of N-(1,3-dihydroxypropan-2-yl)-1-methyl-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide Synthesized using the same procedure as followed for compound 1i using 2-amino-propane-1,3-diol and 1-methyl-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid as starting materials. 1 H NMR (400MHz, DMSO-d6): δ12.30(bs, 1H), 8.09(s, 1H), 7.88(d, J=7.6Hz, 1H), 7.81(d, J=8.4Hz, 1H), 7.57(d, J=1.2Hz, 1H), 7.51(d, J= LC-MS:m / z 466.0(M+1) + .

[0227] Example 49. Synthesis of N-(2-(2-(dimethylamino)acetamido)ethyl)-1-methyl-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using N-(2-aminoethyl)-2-(dimethylamino)acetamide trifluoroacetate and 1-methyl-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid as starting materials using the same procedure as followed in step-c of Example 19. 1 H NMR (400MHz, DMSO-d6): δ12.0(bs, 1H), 8.45(t, J=4.4Hz, 1H), 8.07(s, 1H), 7.91(t, J=5.6Hz, 1H), 7.75(d, J=8.4Hz, 1H), 7.56(s, 1H), 7.50( d, J=8.4Hz, 2H), 7.21(d, J=8.0Hz, 1H), 3.64(s, 3H), 3.36(t, J=5.6Hz, 2H), 3.30(2H, merged with DMSO water peak), 2.85(s, 2H), 2.18(s, 6H); LC-MS: m / z 520.5(M+1) + .

[0228] Example 50. Synthesis of 1-methyl-N-(1-methyl-1H-pyrazol-4-yl)-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed for compound 1i using 1-methyl-1H-pyrazol-4-amine and 1-methyl-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid as starting materials. 1 H NMR (400MHz, DMSO-d6): δ12.30(bs, 1H), 10.40(s, 1H), 8.17(s, 1H), 8.03(s, 1H), 7.88(d, J LC-MS:m / z 472.0(M+1) + .

[0229] Example 51. Synthesis of 1-methyl-N-(oxetan-3-yl)-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed for compound 1i using oxetan-3-amine and 1-methyl-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid as starting materials. 1 H NMR (400MHz, DMSO-d6): δ12.30(bs, 1H), 9.07(d, J=6.0Hz, 1H), 8.10(s, 1H), 7.85(d, J=8.4Hz, 1H), 7.57(s, 1H), 7.52(t, J= LC-MS:m / z 448.0(M+1)+ .

[0230] Example 52. Synthesis of N-((3-hydroxyoxetan-3-yl)methyl)-1-methyl-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed for compound 1i, using 3-(aminomethyl)oxetan-3-ol and 1-methyl-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid as starting materials. 1 H NMR (400MHz, DMSO-d6): δ12.30(bs, 1H), 8.54(t, J=6.0Hz, 1H), 8.10(d, J=1.2Hz, 1H), 7.80(dd, J=1.2Hz, J=8.8Hz, 1H), 7.57(d, J=1.6Hz, 1H), 7.53-7 .49(m, 2H), 7.21(dd, J=1.6Hz, J=8.8Hz, 1H), 5.88(s, 1H), 4.52(d, J=6.4Hz , 2H), 4.41(d, J=6.4Hz, 2H), 3.65(s, 3H), 3.59(d, J=6.0Hz, 2H);LC-MS:m / z 478.2(M+1) + .

[0231] Example 53. Synthesis of N-(2-hydroxyethyl)-1-methyl-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed for compound 1i, using 2-aminoethan-1-ol and 1-methyl-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid as starting materials. 1H NMR (400MHz, DMSO-d6): δ12.30(bs, 1H), 8.38(t, J=5.2Hz, 1H), 8.09(d, J=1.2Hz, 1H), 7.78(dd, J=1.6Hz, J=8.8Hz, 1H), 7.57(s, 1H) , 7.52-7.49(m, 2H), 7.22(d, J=8.0Hz, 1H), 4.72(t, J=5.2Hz, 1H), 3.64(s, 3H), 3.54(q, J=6.0Hz, 2H), 3.37-3.30(m, 2H);LC-MS:m / z 436.0(M+1) + .

[0232] Example 54. Synthesis of 1-methyl-N-(2-(methylsulfonyl)ethyl)-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed for compound 1i, using 2-(methylsulfonyl)ethan-1-amine hydrochloride and 1-methyl-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid as starting materials. 1 H NMR (400MHz, DMSO-d6): δ12.30(bs, 1H), 8.68(t, J=5.2Hz, 1H), 8.09(d, J=1.6Hz, 1H), 7.76(dd, J=1.6Hz, J=8.4Hz, 1H), 7.57(s , 1H), 7.53-7.50(m, 2H), 7.27-7.20(m, 1H), 3.70(q, J=6.0Hz, 2H), 3.65(s, 3H), 3.40(t, J=6.8Hz, 2H), 3.05(s, 3H);LC-MS:m / z 497.9(M+1) + .

[0233] Examples 55 and 56. Synthesis of 2-((6-(2-methoxyethoxy)benzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid and 2-((6-(2-methoxyethoxy)benzo[d]oxazol-2-yl)amino)-N-(2-methoxyethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide [ka] Step-a: Synthesis of 5-(2-methoxyethoxy)-2-nitrophenol To stirred 2-methoxyethan-1-ol (50 mL) at 0° C. was added sodium metal (2.29 g, 95.46 mmol), and the reaction mixture was stirred at RT for 30 minutes, followed by the addition of 5-fluoro-2-nitrophenol (5.0 g, 31.82 mmol). The reaction mixture was heated to 100° C. for 16 hours. Upon completion of the reaction (monitored by TLC), the reaction mixture was cooled to 0° C., diluted with cold water (200 mL), and acidified with 1N HCl. The resulting solid was filtered and dried under vacuum to give the title compound as a yellow solid (4.0 g, 59%). 1 H NMR (400MHz, DMSO-d6): δ10.93(s, 1H), 7.96(d, J=9.3Hz, 1H), 6.64-6.58(m, 2H), 4.19-4.17(m, 2H), 3.67-3.65(m, 2H), 3.30(s, 3H).

[0234] Step-b: Synthesis of 2-amino-5-(2-methoxyethoxy)phenol The title compound was synthesized using the same procedure as that followed for compound 1e using 5-(2-methoxyethoxy)-2-nitrophenol as starting material (yield: 96%). LC-MS: m / z 184.1 (M+1) + .

[0235] Step-c: Synthesis of 6-(2-methoxyethoxy)benzo[d]oxazole-2-thiol The title compound was synthesized using the same procedure as followed in step-c of Example 32 using 2-amino-5-(2-methoxyethoxy)phenol as starting material (yield: 76%). 1 H NMR (400MHz, DMSO-d6): δ13.78(s, 1H), 7.29(d, J=2.4Hz, 1H), 7.19(d, J=8.8Hz, 1H), 6.96 (dd, J=2.4Hz, J=8.8Hz, 1H), 4.18-4.16(m, 2H), 3.73-3.71(m, 2H), 3.36(s, 3H);LC-MS:m / z 226.0(M+1) + .

[0236] Step-d: Synthesis of 2-chloro-6-(2-methoxyethoxy)benzo[d]oxazole The title compound was synthesized using the same procedure as that followed in step-d of Example 32, using 6-(2-methoxyethoxy)benzo[d]oxazole-2-thiol as starting material and stirred for 2 hours (yield: 69%). LC-MS: m / z 228.05 (M+1). + .

[0237] Step-e: Synthesis of ethyl 2-((6-(2-methoxyethoxy)benzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylate The title compound was synthesized using the same procedure as followed in step-e of compound example 32 using ethyl 2-amino-1-methyl-1H-benzo[d]imidazole-5-carboxylate and 2-chloro-6-(2-methoxyethoxy)benzo[d]oxazole as starting materials (yield: 24%); 1H NMR (400MHz, DMSO-d6): δ12.20(bs, 1H), 8.21(d, J=1.5Hz, 1H), 7.86(dd, J=1.5Hz , J=8.3Hz, 1H), 7.49(d, J=8.3Hz, 1H), 7.35(d, J=8.8Hz, 1H), 7.14(d, J=2.4Hz, 1H ), 6.83(dd, J=2.4Hz, J=8.8Hz, 1H), 4.33(q, J=7.2Hz, 2H), 4.12(t, J=4.6Hz, 2H), 3.67(t, J=4.6Hz, 2H), 3.62(s, 3H), 3.32(s, 3H), 1.35(t, J=7.1Hz, 3H);LC-MS:m / z 411.0(M+1) + .

[0238] Step-f: Synthesis of 2-((6-(2-methoxyethoxy)benzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid The title compound was synthesized using the same procedure as that followed for compound 1h using ethyl 2-((6-(2-methoxyethoxy)benzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylate as starting material (yield: 77%); 1 H NMR (400MHz, DMSO-d6): δ12.15(bs, 2H), 8.17(d, J=1.5Hz, 1H), 7.85(dd, J=2.0Hz, J=8.8Hz, 1H), 7.47(d, J=8.3Hz, 1H), 7.36(d, J=8.3Hz, 1H) ), 7.13(d, J=2.4Hz, 1H), 6.82(dd, J=2.4Hz, J=8.3Hz, 1H), 4.12(t, J=4.6Hz, 2H), 3.67(t, J=4.6Hz, 2H), 3.62(s, 3H), 3.32(s, 3H);LC-MS:m / z 383.0(M+1) + .

[0239] Step-g: Synthesis of 2-((6-(2-methoxyethoxy)benzo[d]oxazol-2-yl)amino)-N-(2-methoxyethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed for compound 1i using 2-((6-(2-methoxyethoxy)benzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid as starting material (yield: 29%); 1 H NMR (400MHz, DMSO-d6): δ12.15(bs, 1H), 8.44(t, J=5.4Hz, 1H), 8.05(d, J=1.5Hz, 1H), 7.75(dd, J=1.4Hz, J=8.3Hz, 1H), 7.45(d, J=8.3Hz, 1H), 7.35(d, J=8.3Hz, 1H) , 7.13(d, J=2.4Hz, 1H), 6.82(dd, J=2.4Hz, J=8.3Hz, 1H), 4.12-4.10(m, 2H), 3.68- 3.66(m, 2H), 3.62(s, 3H), 3.49-3.43(m, 4H), 3.32(s, 3H), 3.28(s, 3H);LC-MS:m / z 440.60(M+1) + .

[0240] Example 57. Synthesis of N-(2-hydroxyethyl)-2-((6-(2-methoxyethoxy)benzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxamide [ka] The title compound was synthesized using the same procedure as that followed in step-e of Example 6 using 2-((6-(2-methoxyethoxy)benzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid as starting material (yield: 27%). 1H-NMR (400MHz, DMSO-d6): δ12.16(bs, 1H), 8.35(t, J=5.4Hz, 1H), 8.05(d, J=1.0Hz, 1H), 7.75(d d, J=1.5Hz, J=8.3Hz, 1H), 7.45(d, J=8.3Hz, 1H), 7.35(d, J=8.8Hz, 1H), 7.12(d, J=2.4Hz, 1H), 6.81(dd, J=2.5Hz, J=8.4Hz, 1H), 4.72(bs, 1H), 4.11(t, J=4.6Hz, 2H), 3.67(t, J=4.6 Hz, 2H), 3.61(s, 3H), 3.53(t, J=5.3Hz, 2H), 3.35(t, J=6.0Hz, 2H), 3.32(s, 3H);LC-MS:m / z 426.45(M+1) + .

[0241] Example 58. Synthesis of N-(2-(2-hydroxyethoxy)ethyl)-2-((6-(2-methoxyethoxy)benzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxamide [ka] Synthesized using the same procedure as followed in step-e of example 6 using 2-((6-(2-methoxyethoxy)benzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid and 2-(2-aminoethoxy)ethan-1-ol as starting materials (yield: 61%). 1 H NMR (400MHz, DMSO-d6): δ12.15(bs, 1H), 8.41(t, J=5.4Hz, 1H), 8.05(d, J=0.9Hz, 1H ), 7.74(dd, J=1.5Hz, J=8.3Hz, 1H), 7.45(d, J=8.3Hz, 1H), 7.35(d, J=8.8Hz, 1H), 7.1 2(d, J=1.9Hz, 1H), 6.82(dd, J=2.4Hz, J=8.8Hz, 1H), 4.60(bs, 1H), 4.13(t, J=4.6Hz , 2H), 3.67(t, J=4.6Hz, 2H), 3.62(s, 3H), 3.57-3.42(m, 8H), 3.32(s, 3H);LC-MS:m / z 470.25(M+1)+ .

[0242] Examples 59 and 60. Synthesis of 2-((6-isopropylbenzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid and 2-((6-isopropylbenzo[d]oxazol-2-yl)amino)-N-(2-methoxyethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide [ka] Step-a: Synthesis of 5-isopropyl-2-nitrophenol To a solution of 3-isopropylphenol (2.0 g, 14.7 mmol) in DCM (30 mL) and 3 M sulfuric acid (25 mL) was added sodium nitrite (1.37 g, 16.18 mmol) and sodium nitrite (10 mg, 0.14 mmol) at RT. The mixture was then stirred for 24 hours. The mixture was poured into ice water (100 mL) and extracted with DCM (2 × 50 mL). The combined organic layers were washed with brine solution (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by Combiflash chromatography using 5% ethyl acetate in hexane as the eluent to give the title compound (500 mg, 19%). 1 H NMR (400MHz, DMSO-d6): δ10.76(s, 1H), 7.86(d, J=8.8Hz, 1H), 6.98(d, J=1.5Hz, 1H), 6.89(dd, J=1.5Hz, J=8.3Hz, 1H), 2.92-2.89(m, 1H), 1.19(d, J=6.9Hz, 6H);LC-MS:m / z 180.0(M-1).

[0243] Step-b: Synthesis of 2-amino-5-isopropylphenol The title compound was synthesized using the same procedure as followed for compound 1e using 5-isopropyl-2-nitrophenol as starting material (yield: 86%). 1H NMR (400MHz, DMSO-d6): δ8.88(bs, 1H), 6.50(dd, J=1.9Hz, J=10.7Hz, 1H), 6.41(d, J=2.0Hz, 1H), 6.39(d, J=2.0Hz, 1H), 4.25(s, 2H), 2.68-2.61(m, 1H), 1.10(d, J=6.8Hz, 6H);LC-MS:m / z 152.15(M+1) + .

[0244] Step-c: Synthesis of 6-isopropylbenzo[d]oxazole-2-thiol The title compound was synthesized using the same procedure as followed in step-c of Example 32 using 2-amino-5-isopropylphenol as starting material (yield: 68%). 1 H NMR (400MHz, DMSO-d6): δ13.74(s, 1H), 7.41(s, 1H), 7.20-7.13(m, 2H), 3.0-2.93(m, 1H), 1.21(d, J=6.9Hz, 6H); LC-MS: m / z 194.15(M+1) + .

[0245] Step-d: Synthesis of 2-chloro-6-isopropylbenzo[d]oxazole The title compound was synthesized using the same procedure as followed in step-d of example 32 using 6-isopropylbenzo[d]oxazole-2-thiol as starting material and stirred for 2 hours (yield: 85%). 1 H NMR (400MHz, DMSO-d6): δ7.17(s, 1H), 7.02-6.97(m, 2H), 2.96-2.86(m, 1H), 1.19(d, J=6.8Hz, 6H); LC-MS: m / z 196.0(M+1) + .

[0246] Step-e: Synthesis of ethyl 2-((6-isopropylbenzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylate The title compound was synthesized using the same procedure as that followed in step-e of Example 32 using ethyl 2-amino-1-methyl-1H-benzo[d]imidazole-5-carboxylate and 2-chloro-6-isopropylbenzo[d]oxazole as starting materials (yield: 77%). 1 H NMR (400MHz, DMSO-d6): δ12.15(bs, 1H), 8.22(d, J=1.0Hz, 1H), 7.86(dd, J=1.0Hz, J=8.3Hz, 1H), 7.50(d, J=8.3Hz, 1H), 7.38(d, J=8.3Hz, 1H), 7. 33(s, 1H), 7.11(d, J=7.8Hz, 1H), 4.33(q, J=7.0Hz, 2H), 3.63(s, 3H), 3.01-2.95(m, 1H), 1.35(t, J=7.0Hz, 3H), 1.25(d, J=6.8Hz, 6H);LC-MS:m / z 379.1(M+1) + .

[0247] Step-f: Synthesis of 2-((6-isopropylbenzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid The title compound was synthesized using the same procedure as that followed for compound 1h, using ethyl 2-((6-isopropylbenzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylate as starting material and stirring at 60°C for 5 hours (yield: 92%). 1 H NMR (400MHz, DMSO-d6): δ12.20(bs, 2H), 8.18(s, 1H), 7.86(d, J=8.3Hz, 1H), 7.49(d, J=8.3Hz, 1H), 7.39(d, J=7 .8Hz, 1H), 7.33(s, 1H), 7.10(d, J=7.8Hz, 1H), 3.63(s, 3H), 2.98-2.97(m, 1H), 1.25(d, J=6.8Hz, 6H);LC-MS:m / z 351.20(M+1) + .

[0248] Step-g: Synthesis of 2-((6-isopropylbenzo[d]oxazol-2-yl)amino)-N-(2-methoxyethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed for compound 1i using 2-((6-isopropylbenzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid as the starting material (yield: 69%). 1 H NMR (400MHz, DMSO-d6): δ12.15(bs, 1H), 8.44(s, 1H), 8.07(s, 1H), 7.75(d, J=8.3Hz, 1H), 7.46(d, J=8.3Hz, 1H), 7.37(d, J=8.3Hz, 1H) , 7.32(s, 1H), 7.09(d, J=7.8Hz, 1H), 3.63(s, 3H), 3.48-3.44(m, 4H), 3.28(s, 3H), 2.98-2.97(m, 1H), 1.25(d, J=6.8Hz, 6H);LC-MS:m / z 408.0(M+1) + .

[0249] Example 61. Synthesis of N-(2-hydroxyethyl)-2-((6-isopropylbenzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxamide. The title compound was synthesized using the same procedure as followed in step-e of Example 6 using 2-((6-isopropylbenzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid and 2-aminoethan-1-ol as starting materials. 1H NMR (400MHz, DMSO-d6): δ12.50(bs, 1H), 8.43(bs, 1H), 8.08(s, 1H), 7.82(d, J=8.0Hz, 1H), 7.55(d, J=8.2Hz, 1H), 7.38-7.36(m, 2H), 7.16(d, J=8.0Hz, 1H), 3.67(s, 3H), 3.54(d, J=5.6Hz, 2H), 3.36(q, J=6.0Hz, 2H), 3.02-2.99(m, 1H), 1.25(d, J=7.2Hz, 6H);LC-MS:m / z 394.0(M+1) + .

[0250] Example 62. Synthesis of 2-((6-(difluoromethoxy)benzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid [ka] Step-a: Synthesis of 2-(benzyloxy)-4-fluoro-1-nitrobenzene To a stirred solution of 5-fluoro-2-nitrophenol (10 g, 63.7 mmol) in DMFA (100 mL) at RT, potassium carbonate (10.54 g, 76.43 mmol) and benzyl bromide (7.56 mL, 63.7 mmol) were added. The reaction mixture was then stirred at RT for 16 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (300 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with cold water (2 × 200 mL), brine solution (100 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by combiflash column chromatography using 5% EtOAc in hexane as the eluent to give the title compound (12.0 g, 76%). 1 H NMR (400MHz, DMSO-d6): δ8.04 (dd, J=5.8Hz, J=9.3Hz, 1H), 7.48-7.34 (m, 6H), 7.02-6.97 (m, 1H), 5.33 (s, 2H).

[0251] Step-b: Synthesis of 3-(benzyloxy)-4-nitrophenol To a stirred solution of KOH (7.93 g, 141.7 mmol) in water (70 mL) at RT, 2-(benzyloxy)-4-fluoro-1-nitrobenzene (7.0 g, 28.3 mmol) was added, and the reaction mixture was stirred at 100° C. for 30 h. The reaction mixture was cooled to RT, diluted with water (100 mL), acidified with 3 N HCl, and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine solution (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by combiflash column chromatography using 20% ​​EtOAc in hexane as the eluent to give the title compound (2.0 g, 29%). 1 H NMR (400MHz, DMSO-d6): δ10.88(s, 1H), 7.90(d, J=8.8Hz, 1H), 7.47(t, J=7.4Hz, 2H), 7.41-7.39(m, 2H) ), 7.36-7.32(m, 1H), 6.69(d, J=2.0Hz, 1H), 6.49(dd, J=2.4Hz, J=9.3Hz, 1H), 5.25(s, 2H);LC-MS:m / z 244.0(M-1).

[0252] Step-c: Synthesis of 2-(benzyloxy)-4-(difluoromethoxy)-1-nitrobenzene To a stirred solution of 3-(benzyloxy)-4-nitrophenol (1.1 g, 4.49 mmol) in acetonitrile (6 mL) at 0° C. was added potassium hydroxide (5.02 g, 89.79 mmol) and diethyl (bromodifluoromethyl)phosphonate (1.58 mL, 8.98 mmol) in water (6 mL). The reaction mixture was stirred at RT for 1 h and diluted with water (100 mL). The reaction mixture was extracted with ethyl acetate (3×60 mL). The combined organic layers were washed with brine solution (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by combiflash column chromatography using 10% EtOAc in hexane as the eluent to give the title compound (1.2 g, 91%). 1H NMR (400MHz, DMSO-d6): δ8.04 (d, J=9.3Hz, 1H), 7.64-7.27 (m, 6H), 7.26 (d, J=2.5Hz, 1H), 6.93 (dd, J=2.5Hz, J=8.8Hz, 1H), 5.34 (s, 2H).

[0253] Step-d: Synthesis of 2-amino-5-(difluoromethoxy)phenol To a solution of 2-(benzyloxy)-4-(difluoromethoxy)-1-nitrobenzene (1.2 g, 4.07 mmol) in methanol (20 mL) was added 10% Pd / C (300 mg) under a nitrogen atmosphere. The reaction mixture was stirred under a hydrogen balloon for 16 hours. The reaction mixture was filtered through a celite bed and concentrated in vacuo to give the title compound (600 mg, 84%). LC-MS: m / z 176.0 (M+1) + .

[0254] Step-e: Synthesis of 6-(difluoromethoxy)benzo[d]oxazole-2-thiol The title compound was synthesized using the same procedure as followed in step-c of Example 32 using 2-amino-5-(difluoromethoxy)phenol as starting material (yield: 81%). 1 H NMR (400MHz, DMSO-d6): δ13.96(bs, 1H), 7.49(d, J=2.0Hz, 1H), 7.26(d, J=8.3Hz, 1H), 7.21(t, J=73.2Hz, 1H), 7.13(dd, J=2.4Hz, J=8.8Hz, 1H); LC-MS: m / z 218.0(M+1) + .

[0255] Step-f: Synthesis of 2-chloro-6-(difluoromethoxy)benzo[d]oxazole The title compound was synthesized using the same procedure as followed in step-d of example 32 using 6-(difluoromethoxy)benzo[d]oxazole-2-thiol as starting material and stirred for 2 hours (yield: 82%). 1H NMR (400MHz, DMSO-d6): δ7.80 (d, J=8.8Hz, 1H), 7.74 (d, J=2.5Hz, 1H), 7.29-7.27 (m, 2H).

[0256] Step-g: Synthesis of ethyl 2-((6-(difluoromethoxy)benzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylate The title compound was synthesized using the same procedure as that followed in step-e of Example 32 using ethyl 2-amino-1-methyl-1H-benzo[d]imidazole-5-carboxylate and 2-chloro-6-(difluoromethoxy)benzo[d]oxazole as starting materials (yield: 27%). 1 H NMR (400MHz, DMSO-d6): δ12.20(bs, 1H), 8.23(d, J=1.0Hz, 1H), 7.88(dd, J=1.5Hz, J=8.4Hz, 1H), 7.53(d, J=8.3Hz, 1H), 7.46(d, J=8 .3Hz, 1H), 7.38-7.37(m, 1H), 7.19(s, 1H), 7.07-7.00(m, 1H), 4.33(q, J=7.0Hz, 2H), 3.64(s, 3H), 1.35(t, J=7.1Hz, 3H);LC-MS:m / z 403.0(M+1) + .

[0257] Step-h: Synthesis of 2-((6-(difluoromethoxy)benzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid The title compound was synthesized using the same procedure as that followed for compound 1h using ethyl 2-((6-(difluoromethoxy)benzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylate as starting material (yield: 93%). 1H NMR (400MHz, DMSO-d6): δ12.80(bs, 1H), 12.40(bs, 1H), 8.19(d, J=1.0Hz, 1H), 7.87(dd , J=1.4Hz, J=8.3Hz, 1H), 7.52-7.46(m, 2H), 7.38-7.00(m, 3H), 3.64(s, 3H);LC-MS:m / z 375.0(M+1) + .

[0258] Example 63. Synthesis of 2-((6-(difluoromethoxy)benzo[d]oxazol-2-yl)amino)-N-(2-methoxyethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed for compound 1i, using 2-((6-(difluoromethoxy)benzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid and 2-methoxyethan-1-amine as starting materials. 1 H NMR (400MHz, DMSO-d6): δ12.25(bs, 1H), 8.45(t, J=5.2Hz, 1H), 8.07(s, 1H), 7.77(d, J=8.4Hz, 1H), 7.49-7.45 (m, 2H), 7.37(s, 1H), 7.18(s, 1H), 7.06-7.00(m, 1H), 3.63(s, 3H), 3.48-3.44(m, 4H), 3.28(s, 3H);LC-MS:m / z 432.0(M+1) + .

[0259] Example 64. Synthesis of 2-((6-(difluoromethoxy)benzo[d]oxazol-2-yl)amino)-N-(2-hydroxyethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed in step-e of Example 6 using 2-((6-(difluoromethoxy)benzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid and 2-aminoethan-1-ol as starting materials. 1H NMR (400MHz, DMSO-d6): δ12.30(bs, 1H), 8.38(t, J=5.6Hz, 1H), 8.08(s, 1H), 7.78(d, J=8.4Hz, 1H), 7.50(d, J=8.4Hz) , 1H), 7.46(d, J=8.4Hz, 1H), 7.38-7.00(m, 3H), 3.64(s, 3H), 3.53(t, J=6.4Hz, 2H), 3.35(q, J=6.0Hz, 2H);LC-MS:m / z 418.0(M+1) + .

[0260] Example 65. Synthesis of N-(2-methoxyethyl)-1-methyl-2-((5-methylbenzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide [ka] Step-a: Synthesis of 2-amino-4-methylphenol To a solution of 4-methyl-2-nitrophenol (1.75 g, 11.4 mmol) in methanol (15 mL) was added a slurry of 10% Pd / C (500 mg in 5 mL of methanol) under a nitrogen atmosphere. The reaction mixture was then stirred under a hydrogen gas balloon for 16 hours. The reaction mixture was filtered through a bed of Celite and concentrated in vacuo to give the title compound (1.3 g, 93%). 1 H NMR (400MHz, DMSO-d6): δ8.62(bs, 1H), 6.49(d, J=8.0Hz, 1H), 6.38(s, 1H), 6.17(d, J=8.0Hz, 1H), 4.36(bs, 2H), 2.07(s, 3H); LC-MS: m / z 124.2(M+1) + .

[0261] Step-b: Synthesis of 5-methylbenzo[d]oxazole-2-thiol To a solution of 2-amino-4-methylphenol (1.3 g, 10.5 mmol) in ethanol (15 mL) at room temperature was added potassium ethyl xanthate (3.7 g, 22.2 mmol), and the reaction mixture was refluxed for 16 hours. The reaction mixture was concentrated in vacuo, diluted with cold water (30 mL), and acidified with 1N HCl. The resulting solid was filtered and dried in vacuo to give the title compound (1.3 g, 75%). 1 H NMR (400MHz, DMSO-d6): δ13.78(s, 1H), 7.37(d, J=8.0Hz, 1H), 7.07-7.05(m, 2H), 2.36(s, 3H); LC-MS: m / z 166.1(M+1) + .

[0262] Step-c: Synthesis of 5-methyl-2-(methylthio)benzo[d]oxazole To a solution of 5-methylbenzo[d]oxazole-2-thiol (1.3 g, 7.9 mmol) in acetonitrile (15 mL) at 0° C., potassium carbonate (1.3 g, 9.4 mmol) and methyl iodide (0.53 mL, 8.7 mmol) were added, and the reaction mixture was stirred at RT for 3 hours. The reaction mixture was concentrated in vacuo, diluted with water (30 mL), and acidified with 1N HCl. The resulting solid was filtered and dried in vacuo to give the title compound (1.4 g, 99%). 1 H NMR (400MHz, DMSO-d6): δ7.50 (d, J=8.0Hz, 1H), 7.43 (s, 1H), 7.11 (d, J=8.4Hz, 1H), 2.74 (s, 3H), 2.40 (s, 3H); LC-MS: m / z 180.1 (M+1) + .

[0263] Step-d: Synthesis of 5-methyl-2-(methylsulfonyl)benzo[d]oxazole To a solution of 5-methyl-2-(methylthio)benzo[d]oxazole (350 mg, 1.95 mmol) in DCM (10 mL) at 0 °C, metachloroperbenzoic acid (2.14 g, 6.8 mmol) was added, and the reaction mixture was stirred at RT for 3 h. The reaction mixture was diluted with DCM (100 mL), washed with saturated sodium bicarbonate solution (2 × 30 mL), aqueous 1 N sodium hydroxide (30 mL), water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give the product (340 mg), which was used immediately in the next step without further purification. 1 H NMR (400MHz, DMSO-d6): δ7.84-7.79(m, 2H), 7.49(d, J=8.4Hz, 1H), 3.65(s, 3H), 2.48(s, 3H).

[0264] Step-e: Synthesis of 4-chloro-3-nitrobenzoyl chloride To a solution of 4-chloro-3-nitrobenzoic acid (15.0 g, 74.6 mmol) in DCM (150 mL) at 10° C., thionyl chloride (15.9 mL, 223.8 mmol) and DMFA (1 mL) were added, and the reaction mixture was refluxed for 4 h. The reaction mixture was concentrated in vacuo to give the product, which was used immediately in the next step without further purification (15.0 g).

[0265] Step-f: Synthesis of 4-chloro-N-(2-methoxyethyl)-3-nitrobenzamide To a solution of 2-methoxyethan-1-amine (5.1 g, 68.2 mmol) in DCM (60 mL) at 0° C., triethylamine (20 mL, 138.6 mmol) was added and stirred for 10 minutes. A solution of 4-chloro-3-nitrobenzoyl chloride (15.0 g, 68.2 mmol) in DCM (50 mL) was then added to the reaction mixture, and the contents were stirred at RT for 16 hours. The reaction mixture was diluted with DCM (150 mL) and water (100 mL). The organic layer was separated, washed with water (150 mL), brine (100 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title compound (18.5 g, 100%). 1H NMR (400MHz, DMSO-d6): δ8.88(bs, 1H), 8.51(d, J=2.0Hz, 1H), 8.14(dd, J=2.0Hz, J=8.4Hz, 1H), 7.90(d, J=8.4Hz, 1H), 3.49-3.42(m, 4H), 3.30(s, 3H).

[0266] Step-g: Synthesis of N-(2-methoxyethyl)-4-(methylamino)-3-nitrobenzamide To a solution of 4-chloro-N-(2-methoxyethyl)-3-nitrobenzamide (18.0 g, 69.8 mmol) in DMFA (180 mL) at 0° C. was added DIPEA (12.5 mL, 69.8 mmol) and 2 M methylamine in THF (70 mL, 139.3 mmol). The reaction mixture was stirred at 70° C. for 24 hours. The reaction mixture was cooled to RT, diluted with water (200 mL), and extracted with EtOAc (2×250 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give the product, which was used in the next step without further purification (17.0 g, 96%). 1 H NMR (400MHz, DMSO-d6): δ8.65 (d, J=2.0Hz, 1H), 8.54 (t, J=5.2Hz, 1H), 8.42 (d, J=4.8Hz, 1H), 8.02 (dd, J=1. LC-MS: m / z 254.1(M+1) + .

[0267] Step-h: Synthesis of 3-amino-N-(2-methoxyethyl)-4-(methylamino)benzamide To a solution of N-(2-methoxyethyl)-4-(methylamino)-3-nitrobenzamide (6.0 g, 23.7 mmol) in methanol (100 mL) was added a slurry of 10% Pd / C (1.2 g in 20 mL of ethanol) under a nitrogen atmosphere. The reaction mixture was stirred under a hydrogen gas balloon for 16 hours. The reaction mixture was filtered through a bed of Celite and concentrated in vacuo to give the title compound (4.0 g, 75%). 1 H NMR (400MHz, DMSO-d6): δ7.88 (t, J=5.2Hz, 1H), 7.11-7.06 (m, 2H), 6.34 (d, J=8.0Hz, 1H), 5 .07(bs, 1H), 4.54(bs, 2H), 3.42-3.34(m, 4H) 3.27(s, 3H), 2.75(d, J=2.8Hz, 3H);LC-MS:m / z 224.2(M+1) + .

[0268] Step-i: Synthesis of 2-amino-N-(2-methoxyethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide To a solution of 3-amino-N-(2-methoxyethyl)-4-(methylamino)benzamide (2.0 g, 8.92 mmol) in THF (10 mL) and water (20 mL) at RT, cyanogen bromide (1.04 g, 9.82 mmol) was added, and the reaction mixture was stirred at 50°C to 60°C for 16 h. The reaction mixture was cooled to RT, basified with saturated sodium bicarbonate solution, and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give the crude product, which was purified by Combiflash chromatography using 5% methanol in DCM as the eluent to give the title compound (1.3 g, 59%). 1 H NMR (400MHz, DMSO-d6): δ8.26(bs, 1H), 7.66(s, 1H), 7.48(d, J=7.6Hz, 1H), 7.14(d, J=8.0Hz, 1H), 6.52(bs, 2H), 3.51(s, 3H), 3.45-3.41(m, 4H), 3.26(s, 3H);LC-MS:m / z 249.2(M+1) + .

[0269] Step-j: Synthesis of N-(2-methoxyethyl)-1-methyl-2-((5-methylbenzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide To a solution of 2-amino-N-(2-methoxyethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide (300 mg, 1.2 mmol) in 1,4-dioxane (5 mL) at 10° C., sodium hydride (60% dispersion in mineral oil) (96 mg, 2.4 mmol) was added and stirred for 10 minutes, followed by the addition of 5-methyl-2-(methylsulfonyl)benzo[d]oxazole (306 mg, 1.45 mmol), which was stirred at RT for 16 hours. The reaction mixture was quenched with cold water (20 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give the crude product, which was purified by Combiflash chromatography using 2% methanol in DCM as the eluent to give the title compound (6 mg, 1%). 1 H NMR (400MHz, DMSO-d6): δ12.2(bs, 1H), 8.45(t, J=5.2Hz, 1H), 8.08(d, J=1.6Hz, 1H), 7.76(dd, J=1.2Hz, J=8.0Hz, 1H), 7.47(d, J=8.4H) z, 1H), 7.30(d, J=8.4Hz, 1H), 7.26(s, 1H), 6.93(d, J=7.6Hz, 1H), 3.62(s, 3H), 3.50-3.42(m, 4H), 3.29(s, 3H), 2.49(s, 3H);LC-MS:m / z 380.2(M+1) + .

[0270] Examples 66 and 67. Synthesis of 2-((5-fluorobenzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid and 2-((5-fluorobenzo[d]oxazol-2-yl)amino)-N-(2-methoxyethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide [ka] Step-a: Synthesis of 2-amino-4-fluorophenol The title compound was synthesized using the same procedure as followed for step b of Example 32 using 4-fluoro-2-nitrophenol as starting material (yield: 91%). 1 H NMR (400MHz, DMSO-d6): δ8.88(bs, 1H), 6.56-6.53(m, 1H), 6.35(dd, J=2.0Hz, J=10.4Hz, 1H), 6.13-6.08(m, 1H), 4.78(bs, 2H); LC-MS: m / z 128.1(M+1) + .

[0271] Step-b: Synthesis of 5-fluorobenzo[d]oxazole-2-thiol The title compound was synthesized using the same procedure as followed in step-c of Example 32 using 2-amino-4-fluorophenol as starting material (yield: 86%). 1 H NMR (400MHz, DMSO-d6): δ14.01 (bs, 1H), 7.55-7.51 (m, 1H), 7.15-7.08 (m, 2H); LC-MS: m / z 170.0 (M+1) + .

[0272] Step-c: Synthesis of 5-fluoro-2-(methylthio)benzo[d]oxazole The title compound was synthesized using the same procedure as followed for compound 1b using 5-fluorobenzo[d]oxazole-2-thiol as starting material (stirring for 16 h) (yield: 92%). 1 H NMR (400MHz, DMSO-d6): δ7.69-7.65(m, 1H), 7.53(dd, J=2.4Hz, J=8.8Hz, 1H), 7.19-7.11(m, 1H), 2.76(s, 3H); LC-MS: m / z 184.1(M+1) + .

[0273] Step-d: Synthesis of 5-fluoro-2-(methylsulfonyl)benzo[d]oxazole The title compound was synthesized using the same procedure as followed for compound 1c using 5-fluoro-2-(methylthio)benzo[d]oxazole as starting material (stirring for 4 h) (yield: 99%). 1 H NMR (400MHz, DMSO-d6): δ8.05-8.01(m, 1H), 7.94(dd, J=2.4Hz, J=8.0Hz, 1H), 7.57-7.54(m, 1H), 3.67(s, 3H); LC-MS: m / z 216.0(M+1) + .

[0274] Step-e: Synthesis of 2-((5-fluorobenzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylate The title compound was synthesized using the same procedure as that followed for compound 1g using ethyl 2-amino-1-methyl-1H-benzo[d]imidazole-5-carboxylate and 5-fluoro-2-(methylsulfonyl)benzo[d]oxazole as starting materials (yield: 26%). 1 H NMR (400MHz, DMSO-d6): δ12.34(bs, 1H), 8.23(s, 1H), 7.88(dd, J=1.6Hz, J=8.4Hz, 1H), 7.49(d, J=8.0Hz, 1H), 7.46-7.42(m, 1 LC-MS:m / z 355.2(M+1) + .

[0275] Step-f: Synthesis of 2-((5-fluorobenzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid The title compound was synthesized using the same procedure as that followed for compound 1h using ethyl 2-((5-fluorobenzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylate as starting material (yield: 58%). 1H NMR (400MHz, DMSO-d6): δ12.8(bs, 1H), 12.3(bs, 1H), 8.19(s, 1H), 7.87(d, J=8.4Hz, 1H), 7.51(d, J=8.8 Hz, 1H), 7.45-7.42(m, 1H), 7.24(dd, J=2.4Hz, J=8.8Hz, 1H), 6.96-6.91(m, 1H), 3.64(s, 3H);LC-MS:m / z 327.2(M+1) + .

[0276] Step-g: Synthesis of 2-((5-fluorobenzo[d]oxazol-2-yl)amino)-N-(2-methoxyethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed for compound 1i using 2-((5-fluorobenzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid and 2-methoxyethylamine as starting materials (yield: 62%). 1 H NMR (400MHz, DMSO-d6): δ12.2(bs, 1H), 8.20(s, 1H), 8.06(s, 1H), 7.76(d, J=8.4Hz, 1H), 7.44(d, J=8.4Hz, 1H), 7.40 -7.37(m, 1H), 7.20(d, J=8.8Hz, 1H), 6.89(t, J=10.0Hz, 1H), 3.63(s, 3H), 3.50-3.45(m, 4H), 3.09(s, 3H);LC-MS:m / z 384.2(M+1) + .

[0277] Examples 68 and 69. Synthesis of 2-((6-fluorobenzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid and 2-((6-fluorobenzo[d]oxazol-2-yl)amino)-N-(2-methoxyethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide [ka] Step-a: Synthesis of 2-amino-5-fluorophenol The title compound was synthesized using the same procedure as followed in step b of Example 32 using 5-fluoro-2-nitrophenol as starting material (yield: 92%). 1 H NMR (400MHz, DMSO-d6): δ9.5 (bs, 1H), 6.54-6.51 (m, 1H), 6.46 (dd, J=2.8Hz, J=10.0Hz, 1H), 6.37-6.32 (m, 1H); LC-MS: m / z 128.2 (M+1) + .

[0278] Step-b: Synthesis of 6-fluorobenzo[d]oxazole-2-thiol The title compound was synthesized using the same procedure as followed in step-c of Example 32 using 2-amino-5-fluorophenol as starting material (yield: 89%). 1 H NMR (400MHz, DMSO-d6): δ13.94(bs, 1H), 7.57(dd, J=2.0Hz, J=8.4Hz, 1H), 7.25-7.22(m, 1H), 7.19-7.14(m, 1H); LC-MS: m / z 170.0(M+1) + .

[0279] Step-c: Synthesis of 6-fluoro-2-(methylthio)benzo[d]oxazole The title compound was synthesized using the same procedure as followed for compound 1b, using 6-fluorobenzo[d]oxazole-2-thiol as starting material (stirring for 5 hours) (yield: 99%). 1 H NMR (400MHz, DMSO-d6): δ7.67-7.63(m, 2H), 7.24-7.18(m, 1H), 2.75(s, 3H); LC-MS: m / z 184.0(M+1) + .

[0280] Step-d: Synthesis of 6-fluoro-2-(methylsulfonyl)benzo[d]oxazole The title compound was synthesized using the same procedure as followed for compound 1c using 6-fluoro-2-(methylthio)benzo[d]oxazole as starting material (stirring for 4 hours) (yield: 95%). 1 H NMR (400MHz, DMSO-d6): δ8.08-8.02(m, 1H), 8.01-7.99(m, 1H), 7.56-7.46(m, 1H), 3.67(s, 3H).

[0281] Step-e: Synthesis of ethyl 2-((6-fluorobenzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylate The title compound was synthesized using the same procedure as that followed for compound 1g using ethyl 2-amino-1-methyl-1H-benzo[d]imidazole-5-carboxylate and 6-fluoro-2-(methylsulfonyl)benzo[d]oxazole as starting materials (yield: 28%). 1 H NMR (400MHz, DMSO-d6): δ12.3(bs, 1H), 8.23(d, J=1.6Hz, 1H), 7.88(dd, J=2.0Hz, J=8.4Hz, 1H), 7.52(d, J=8.4Hz , 1H), 7.45-7.41(m, 2H), 7.10-7.04(m, 1H), 4.33(q, J=6.8Hz, 2H), 3.64(s, 3H), 1.35(t, J=7.2Hz, 3H);LC-MS:m / z 355.1(M+1) + .

[0282] Step-f: Synthesis of 2-((6-fluorobenzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid To a stirred solution of ethyl 2-((6-fluorobenzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylate (45 mg, 0.13 mmol) in a solvent mixture of THF (1 mL), ethanol (1 mL), and water (0.5 mL) was added lithium hydroxide monohydrate (10 mg, 0.25 mmol). The reaction mixture was heated at 60° C. with stirring for 16 h. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was dissolved in water (15 mL) and acidified with 1N HCl to give a solid, which was filtered and dried under vacuum to give the title compound (30 mg, 72%). 1 H NMR (400MHz, DMSO-d6): δ12.8(bs, 1H), 12.3(bs, 1H) 8.19(d, J=1.6Hz, 1H), 7.87(dd, J=1.6Hz, J= LC-MS: m / z 327.05(M+1) + .

[0283] Step-g: Synthesis of 2-((6-fluorobenzo[d]oxazol-2-yl)amino)-N-(2-methoxyethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide To a stirred solution of 2-((6-fluorobenzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid (30 mg, 0.09 mmol) in DMFA (2 mL) at 0 °C, N-ethyldiisopropylamine (0.03 mL, 0.18 mmol) and diphenylphosphoryl azide (0.02 mL, 0.09 mmol) were added. The reaction mixture was stirred for 30 min, followed by the addition of 2-methoxyethylamine (6 mg, 0.09 mmol), and the reaction mixture was then stirred at RT for 16 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with cold water (6 mL) and stirred for 15 min. The resulting solid was filtered, washed with diethyl ether, and dried under vacuum to give the title compound as a white solid (20 mg, 58%). 1H NMR (400MHz, DMSO-d6): δ12.2(bs, 1H), 8.45(t, J=5.2Hz, 1H), 8.07(d, J=1.2Hz, 1H), 7.75(dd, J=1.6Hz, J= LC-MS: m / z 384.1(M+1) + .

[0284] Examples 70 and 71. Synthesis of 6-fluoro-1-methyl-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid and 6-fluoro-N-(2-methoxyethyl)-1-methyl-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide [ka] Step-a: Synthesis of methyl 2-amino-6-fluoro-1-methyl-1H-benzo[d]imidazole-5-carboxylate The title compound was synthesized using the same procedure as that followed for compound 1f, using methyl 5-amino-2-fluoro-4-(methylamino)benzoate as the starting material and heating at 60° C. for 16 hours (yield: 89%); 1 H NMR (400MHz, DMSO-d6): δ7.54 (d, J=6.4Hz, 1H), 7.16 (d, J=11.6Hz, 1H), 6.69 (bs, 2H), 3.80 (s, 3H), 3.51 (s, 3H); LC-MS: m / z 224.1 (M+1) + .

[0285] Step-b: Synthesis of methyl 6-fluoro-1-methyl-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylate The title compound was synthesized using the same procedure as that followed for compound 1g using methyl 2-amino-6-fluoro-1-methyl-1H-benzo[d]imidazole-5-carboxylate and 2-(methylsulfonyl)-6-(trifluoromethoxy)benzo[d]oxazole as starting materials (yield: 18%). 1 H NMR (400MHz, DMSO-d6): δ12.3 (bs, 1H), 8.10 (d, J=6.0Hz, 1H), 7.95-7.51 (m, 3H), 7.22 (d, J=8.4Hz, 1H), 3.87 (s, 3H), 3.61 (s, 3H); LC-MS: m / z 425.1(M+1) + .

[0286] Step-c: Synthesis of 6-fluoro-1-methyl-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid The title compound was synthesized using the same procedure as that followed for compound 1h, using methyl 6-fluoro-1-methyl-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylate as starting material and THF, methanol and water (2:2:1) as solvent (yield: 66%); 1 H NMR (400MHz, DMSO-d6): δ13.0(bs, 1H), 12.3(bs, 1H), 8.08(d, J=6.0Hz, 1H), 7 .59(s, 1H), 7.53-7.49(m, 2H), 7.22(d, J=7.2Hz, 1H), 3.61(s, 3H);LC-MS:m / z 411.1(M+1) + .

[0287] Step-d: Synthesis of 6-fluoro-N-(2-methoxyethyl)-1-methyl-2-((6-(trifluoromethoxy)-benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed for compound 1i using 6-fluoro-1-methyl-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid and 2-methoxyethylamine as starting materials (yield: 48%); 1 H NMR (400MHz, DMSO-d6): δ12.3(bs, 1H), 8.18(d, J=4.0Hz, 1H), 7.86(d, J=6.4Hz, 1H), 7.58(s, 1H), 7.52-7.49(m, 2H), 7.21(d, J=9.2Hz, 1H), 3.61(s, 3H), 3.47-3.44(m, 4H), 3.29(s, 3H);LC-MS:m / z 468.1(M+1) + .

[0288] Example 72. Synthesis of 2-(benzo[d]oxazol-2-ylamino)-6-fluoro-N-(2-(2-hydroxyethoxy)ethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide [ka] Step-a: Synthesis of methyl 2-(benzo[d]oxazol-2-ylamino)-6-fluoro-1-methyl-1H-benzo[d]imidazole-5-carboxylate The title compound was synthesized using the same procedure as that followed for step e of Example 32 using methyl 2-amino-6-fluoro-1-methyl-1H-benzo[d]imidazole-5-carboxylate and 2-chlorobenzo[d]oxazole as starting materials (yield: 66%). 1 H NMR (400MHz, DMSO-d6): δ12.25 (bs, 1H), 8.09 (d, J=6.0Hz, 1H), 7.55-7.44 (m, 3 LC-MS:m / z 341.0(M+1) + .

[0289] Step-b: Synthesis of 2-(benzo[d]oxazol-2-ylamino)-6-fluoro-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid The title compound was synthesized using the same procedure as that followed for compound 1h, using methyl 2-(benzo[d]oxazol-2-ylamino)-6-fluoro-1-methyl-1H-benzo[d]imidazole-5-carboxylate as starting material and methanol, THF and water (2:2:1) as solvent (yield: 75%); 1 H NMR (400MHz, DMSO-d6): δ12.80 (bs, 2H), 8.07 (d, J=6.8Hz, 1H), 7.50-7.44 (m, 3H), 7.22 (t, J=6.8Hz, 1H), 7.15-7.11 (m, 1H), 3.60 (s, 3H); LC-MS: m / z 327.0(M+1) + .

[0290] Step-c: Synthesis of 2-(benzo[d]oxazol-2-ylamino)-6-fluoro-N-(2-(2-hydroxyethoxy)ethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as in step-e of Example 6, using 2-(benzo[d]oxazol-2-ylamino)-6-fluoro-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid and 2-(2-aminoethoxy)ethan-1-ol as starting materials (yield: 49%). 1 H NMR (400MHz, DMSO-d6): δ12.20(bs, 1H), 8.15(bs, 1H), 7.86(d, J=6.4Hz, 1H), 7.50-7.47(m, 2H), 7.43(d, J=8.0Hz, 1H) ), 7.23-7.19(m, 1H), 7.14-7.10(m, 1H), 4.60(bs, 1H), 3.60(s, 3H), 3.57-3.51(m, 4H), 3.48-3.31(m, 4H);LC-MS:m / z 414.05(M+1) + .

[0291] Example 73. Synthesis of 2-((5-fluoro-1H-benzo[d]imidazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid [ka] Step-a: Synthesis of ethyl 2-(1H-imidazole-1-carbothioamido)-1-methyl-1H-benzo[d]imidazole-5-carboxylate To a solution of ethyl 2-amino-1-methyl-1H-benzo[d]imidazole-5-carboxylate (1.0 g, 4.5 mmol) in acetonitrile (20 mL) at RT, 1,1'-thiocarbonyldiimidazole (1.06 g, 5.9 mmol) was added and stirred at 60 °C for 16 h. The reaction mixture was cooled to RT and stirred for 30 min. The resulting solid was filtered and dried under vacuum to give the title compound, which was used in the next step without further purification (1.1 g, 73%). 1 H NMR (400MHz, DMSO-d6): δ13.4(bs, 1H), 8.68(s, 1H), 8.41(d, J=1.6Hz, 1H), 8.03(s, 1H), 7.99(dd, J=1.2Hz, J=8. 8Hz, 1H), 7.75(d, J=8.4Hz, 1H), 7.01(d, J=1.2Hz, 1H), 4.35(q, J=7.2Hz, 2H), 3.79(s, 3H), 1.36(t, J=6.8Hz, 3H).

[0292] Step-b: Synthesis of ethyl 2-((5-fluoro-1H-benzo[d]imidazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylate To a stirred solution of ethyl 2-(1H-imidazole-1-carbothioamido)-1-methyl-1H-benzo[d]imidazole-5-carboxylate (900 mg, 2.74 mmol) in DMFA (15 mL) was added EDC HCl (1.05 g, 5.47 mmol) and heated to 60° C. for 10 min. The reaction mixture was cooled to RT, followed by the addition of 4-fluorobenzene-1,2-diamine (345 mg, 2.74 mmol) and heating at 100° C. for 16 h. The reaction mixture was cooled to RT, diluted with water (30 mL), and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue which was purified by Combiflash chromatography using 0.5% methanol in DCM as the eluent to give the title compound (200 mg, 21%); LC-MS: m / z 354.2 (M+1). + .

[0293] Step-c: Synthesis of 2-((5-fluoro-1H-benzo[d]imidazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid To ethyl 2-((5-fluoro-1H-benzo[d]imidazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylate (200 mg, 0.57 mmol) in a solvent mixture of THF (5 mL), methanol (5 mL), and water (5 mL) was added lithium hydroxide monohydrate (119 mg, 2.83 mmol). The reaction mixture was heated at 60° C. with stirring for 16 hours. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was dissolved in water (15 mL) and acidified with 1N HCl to give a solid, which was filtered and dried under vacuum to give the title compound (150 mg, 81%). 1 H NMR (400MHz, DMSO-d6): δ12.2 (bs, 2H), 8.04 (s, 1H), 7.75 (d, J=8.0Hz, 1H), 7.32- 7.26(m, 2H), 7.13(d, J=8.4Hz, 1H), 6.88(t, J=8.0Hz, 1H), 3.62(s, 3H);LC-MS:m / z 326.05(M+1) + .

[0294] Example 74. Synthesis of 1-(2-(dimethylamino)ethyl)-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid [ka] Step-a: Synthesis of ethyl 4-((2-(dimethylamino)ethyl)amino)-3-nitrobenzoate To a RT solution of ethyl 4-chloro-3-nitrobenzoate (5.0 g, 21.8 mmol) in DMFA (40 mL) was added DIPEA (9.5 mL, 54.4 mmol) and N 1 ,N 1 -dimethylethane-1,2-diamine (2.87 g, 32.7 mmol) was added and the reaction mixture was stirred at 60° C. for 16 hours. The reaction mixture was cooled to RT, diluted with cold water (250 mL), and stirred for 10 minutes. The precipitated solid was filtered and dried under vacuum to give the title compound (4.8 g, 92%). 1 H NMR (400MHz, DMSO-d6): δ8.65(t, J=4.4Hz, 1H), 8.62(d, J=2.0Hz, 1H), 7.79(dd, J=2.0Hz, J=8.8Hz, 1H), 7.13(d, J LC-MS: m / z 282.2(M+1) + .

[0295] Step-b: Synthesis of ethyl 3-amino-4-((2-(dimethylamino)ethyl)amino)benzoate The title compound was synthesized using the same procedure as that followed for compound 1e, using ethyl 4-((2-(dimethylamino)ethyl)amino)-3-nitrobenzoate as the starting material and stirring for 16 hours. (Yield: 67%); 1H NMR (400MHz, DMSO-d6): δ7.23 (dd, J=2.0Hz, J=8.0Hz, 1H), 7.18 (d, J=2.0Hz, 1H), 6.45 (d, J=8.4Hz, 1H), 5.09 (bs, 1H), 4 .68(s, 2H), 4.18(q, J=6.8Hz, 2H), 3.19-3.15(m, 2H), 2.49-2.46(m, 2H), 2.18(s, 6H), 1.26(t, J=6.8Hz, 3H);LC-MS:m / z 252.2(M+1) + .

[0296] Step-c: Synthesis of ethyl 2-amino-1-(2-(dimethylamino)ethyl)-1H-benzo[d]imidazole-5-carboxylate The title compound was synthesized using the same procedure as followed for compound 1f, using ethyl 3-amino-4-((2-(dimethylamino)ethyl)amino)benzoate as starting material and heating to 60° C. for 16 hours. (Yield: 26%); LC-MS: m / z 277.2 (M+1). + .

[0297] Step-d: Synthesis of ethyl 1-(2-(dimethylamino)ethyl)-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylate The title compound was synthesized using the same procedure as that followed for compound 1g using ethyl 2-amino-1-(2-(dimethylamino)ethyl)-1H-benzo[d]imidazole-5-carboxylate and 2-(methylsulfonyl)-6-(trifluoromethoxy)benzo[d]oxazole as starting materials (yield: 26%). 1H NMR (400MHz, DMSO-d6): δ12.4(bs, 1H), 8.25(d, J=1.2Hz, 1H), 7.87(dd, J=1.2Hz, J=8.4Hz, 1H), 7.59-7.57(m, 2H), 7.51(d, J LC-MS:m / z 478.1(M+1) + .

[0298] Step-e: Synthesis of 1-(2-(dimethylamino)ethyl)-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid The title compound was synthesized using the same procedure as that followed for compound 1h using ethyl 1-(2-(dimethylamino)ethyl)-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylate as starting material (yield: 18%). 1 H NMR (400MHz, DMSO-d6): δ12.8(bs, 1H), 12.3(bs, 1H), 8.20(d, J=1.6Hz, 1H), 7.86(dd, J=1.6Hz, J=8.4Hz, 1H) , 7.59-7.51(m, 3H), 7.21(d, J=8.4Hz, 1H), 4.27(t, J=6.4Hz, 2H), 2.79-2.66(m, 2H), 2.21(s, 6H);LC-MS:m / z 450.1(M+1) + .

[0299] Examples 75 and 76. Synthesis of 1-(2-methoxyethyl)-2-((5-(trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid and N,1-bis(2-methoxyethyl)-2-((5-(trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide [ka] Step-a: Synthesis of ethyl 4-((2-methoxyethyl)amino)-3-nitrobenzoate To a solution of ethyl 4-chloro-3-nitrobenzoate (10 g, 43.7 mmol) in DMSO (100 mL) at RT, 2-methoxyethan-1-amine (7.5 mL, 87.3 mmol) was added and the reaction mixture was stirred at 60° C. for 16 h. The reaction mixture was cooled to RT, diluted with cold water (250 mL), and stirred for 1 h. The precipitated solid was filtered and dried under vacuum to give the title compound (12 g, 100%). 1 H NMR (400MHz, DMSO-d6): δ8.61(d, J=2.4Hz, 1H), 8.54(s, 1H), 7.97(dd, J=1.6Hz, J=8.8Hz, 1H), 7.18( d, J=9.2Hz, 1H), 4.29(q, J=6.8Hz, 2H), 3.60(bs, 4H), 3.31(s, 3H), 1.31(t, J=6.8Hz, 3H);LC-MS:m / z 269.1(M+1) + .

[0300] Step-b: Synthesis of ethyl 3-amino-4-((2-methoxyethyl)amino)benzoate The title compound was synthesized using the same procedure as followed for compound 1e using ethyl 4-((2-methoxyethyl)amino)-3-nitrobenzoate as starting material (yield: 75%). 1 H NMR (400MHz, DMSO-d6): δ7.22-7.17(m, 2H), 6.46(d, J=8.4Hz, 1H), 5.20(t, J=7.6Hz, 1H), 4.74(bs, 2 LC-MS:m / z 239.1(M+1) + .

[0301] Step-c: Synthesis of ethyl 2-amino-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylate The title compound was synthesized using the same procedure as followed for compound 1f, using ethyl 3-amino-4-((2-methoxyethyl)amino)benzoate as starting material and heating to 60° C. for 16 hours. (Yield: 73%); LC-MS: m / z 264.1 (M+1). + .

[0302] Step-d: Synthesis of ethyl 2-(1H-imidazole-1-carbothioamido)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylate The title compound was synthesized using the same procedure as that followed for compound 12a using ethyl 2-amino-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylate and 1,1′-thiocarbonyldiimidazole as starting materials (yield: 60%). 1 H NMR (400MHz, DMSO-d6): δ13.5(bs, 1H), 8.66(s, 1H), 8.42(s, 1H), 8.01-7.97(m, 2H), 7.78(d, J=8.8Hz, 1H), 7.01 (s, 1H), 4.54(t, J=4.8Hz, 2H), 4.35(q, J=7.2Hz, 2H), 3.74(t, J=4.8Hz, 2H), 3.20(s, 3H), 1.35(t, J=7.2Hz, 3H).

[0303] Step-e: Synthesis of ethyl 1-(2-methoxyethyl)-2-((5-(trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylate The title compound was synthesized using the same procedure as followed for compound 12b using ethyl 2-(1H-imidazole-1-carbothioamido)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylate and 4-(trifluoromethoxy)benzene-1,2-diamine as starting materials (yield: 38%); LC-MS: m / z 464.0 (M+1). + .

[0304] Step-f: Synthesis of 1-(2-methoxyethyl)-2-((5-(trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid The title compound was synthesized using the same procedure as that followed for compound 1h, using ethyl 1-(2-methoxyethyl)-2-((5-(trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylate as the starting material and THF, methanol, and water as the solvents. (Yield: 65%) 1 H NMR (400MHz, DMSO-d6): δ12.3(bs, 3H), 8.08(d, J=1.2Hz, 1H), 7.74(dd, J=1.6Hz, J=8.4Hz, 1H), 7.41(d, J=8.4Hz, 1 LC-MS:m / z 436.0(M+1) + .

[0305] Step-g: Synthesis of N,1-bis(2-methoxyethyl)-2-((5-(trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed for compound 1i using 1-(2-methoxyethyl)-2-((5-(trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid and 2-methoxyethylamine as starting materials (yield: 2%). 1H NMR (400MHz, DMSO-d6): δ12.23(bs, 1H), 8.26-8.23(m, 1H), 7.58-7.53(m, 1H), 7.43-7.38(m, 1H), 7.30-6 .37(m, 5H), 4.50-4.48(m, 2H), 3.86-3.80(m, 2H), 3.32(s, 3H), 3.27-3.25(m, 4H), 3.16(s, 3H);LC-MS:m / z 493.1(M+1) + .

[0306] Examples 77 and 78. Synthesis of 1-(2-methoxyethyl)-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid and N,1-bis(2-methoxyethyl)-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide [ka] Step-a: Synthesis of 1-(2-methoxyethyl)-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid To a solution of ethyl 2-amino-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylate (200 mg, 0.76 mmol) in 1,4-dioxane (10 mL) at 0° C., sodium hydride (60% dispersion in mineral oil) (107 mg, 2.66 mmol) was added and stirred for 10 minutes. 2-Chloro-6-(trifluoromethoxy)benzo[d]oxazole (270 mg, 1.14 mmol) was added to the reaction mixture, which was stirred at 90° C. for 16 hours. The reaction mixture was cooled to room temperature. The solvent was evaporated, and the residue was diluted with cold water (20 mL) and acidified with 1N HCl. The reaction mixture was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by Combiflash chromatography using 2% methanol in DCM as eluent to give the title compound (70 mg, 21%). 1 H NMR (400MHz, DMSO-d6): δ12.8(bs, 1H), 12.3(bs, 1H), 8.20(d, J=1.6Hz, 1H), 7.86(dd, J=1.2Hz, J=8.0Hz, 1H), 7.58-7.52(m, 3H), 7.22(d, J=7.2Hz, 1H), 4.36(t, J=4.8Hz, 2H), 3.74(t, J=5.6Hz, 2H), 3.24(s, 3H);LC-MS:m / z 437.05(M+1) + .

[0307] Step-b: Synthesis of N,1-bis(2-methoxyethyl)-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed for compound 1i using 1-(2-methoxyethyl)-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid and 2-methoxyethylamine as starting materials (yield: 2%). 1H NMR (400MHz, DMSO-d6): δ12.30(bs, 1H), 8.45(bs, 1H), 8.08(s, 1H), 7.75(d, J=8.4Hz, 1H), 7.56(s, 1H), 7.53-7.50(m, 2H), 7.21(d, J=8.4Hz, 1H), 4.35(t, J=4.8Hz, 2H), 3.73(t, J=5.2Hz, 2H), 3.48-3.43(m, 4H), 3.28(s, 3H), 3.24(s, 3H); LC-MS: m / z 494.15(M+1) + .

[0308] Examples 79 and 80. Synthesis of 1-(tetrahydro-2H-pyran-4-yl)-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid and N-(2-methoxyethyl)-1-(tetrahydro-2H-pyran-4-yl)-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide [ka] Step-a: Synthesis of ethyl 2-amino-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazole-5-carboxylate The title compound was synthesized using the same procedure as that followed for compound 1f, using ethyl 3-amino-4-((tetrahydro-2H-pyran-4-yl)amino)benzoate as the starting material and heating to 60° C. (Yield: 92%); 1 H NMR (400MHz, DMSO-d6): δ7.71(s, 1H), 7.55(dd, J=1.6Hz, J=8.4Hz, 1H), 7.41(d, J=8.0Hz, 1H), 6.65(bs, 2H), 4.50-4.48(m, 1H), 4.28(q , J=7.2Hz, 2H), 4.05-4.01(m, 2H), 3.47(t, J=11.2Hz, 2H), 2.36-2.32(m, 2H), 1.72(d, J=10.4Hz, 2H), 1.31(t, J=6.8Hz, 3H);LC-MS:m / z 290.1(M+1)+ .

[0309] Step-b: Synthesis of ethyl 1-(tetrahydro-2H-pyran-4-yl)-2-((6-(trifluoromethoxy)-benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylate To a solution of ethyl 2-amino-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazole-5-carboxylate (100 mg, 0.35 mmol) in 1,4-dioxane (2 mL) at RT, sodium hydride (60% dispersion in mineral oil) (34 mg, 0.86 mmol) was added and stirred for 10 min. 2-Chloro-6-(trifluoromethoxy)benzo[d]oxazole (99 g, 0.41 mmol) was added to the reaction mixture and stirred at RT for 16 h. The reaction mixture was concentrated, diluted with cold water (30 mL), and stirred at RT for 5–10 min. The resulting solid was filtered, dried under vacuum, and purified by Combiflash chromatography using 100% DCM as eluent to give the title compound (60 mg, 35%). 1 H NMR (400MHz, DMSO-d6): δ12.40(bs, 1H), 8.29(d, J=1.6Hz, 1H), 7.86(dd, J=1.2Hz, J=8.0 Hz, 1H), 7.74(d, J=8.4Hz, 1H), 7.58(d, J=1.6Hz, 1H), 7.52(d, J=8.4Hz, 1H), 7.21(dd, J=1 .6Hz, J=8.8Hz, 1H), 4.97-4.93(m, 1H), 4.33(q, J=7.6Hz, 2H), 4.07-4.03(m, 2H), 3.56(t, LC-MS:m / z 491.1(M+1) + .

[0310] Step-e: Synthesis of 1-(tetrahydro-2H-pyran-4-yl)-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid The title compound was synthesized using the same procedure as that followed for compound 1h using ethyl 1-(tetrahydro-2H-pyran-4-yl)-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylate as starting material (yield: 71%). 1 H NMR (400MHz, DMSO-d6): δ12.8(bs, 1H), 12.50(bs, 1H), 8.24(d, J=1.6Hz, 1H), 7.86 (dd, J=1.2Hz, J=8.8Hz, 1H), 7.71(d, J=8.0Hz, 1H), 7.58(d, J=1.2Hz, 1H), 7.53(d, J=8.8Hz, 1H), 7.22(d, J=10.4Hz, 1H), 5.01-4.92(m, 1H), 4.05(dd, J=4.0Hz, J=11. 2Hz, 2H), 3.58-3.53(m, 2H), 2.67-2.57(m, 2H), 1.78(d, J=10.0Hz, 2H);LC-MS:m / z 463.1(M+1) + .

[0311] Step-f: Synthesis of N-(2-methoxyethyl)-1-(tetrahydro-2H-pyran-4-yl)-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed for compound 1i using 1-(tetrahydro-2H-pyran-4-yl)-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid and 2-methoxyethylamine as starting materials (yield: 76%); 1H NMR (400MHz, DMSO-d6): δ12.3(bs, 1H), 8.48(t, J=5.2Hz, 1H), 8.13(d, J=1.2Hz, 1H), 7 .76(dd, J=1.6Hz, J=8.8Hz, 1H), 7.68(d, J=8.0Hz, 1H), 7.57(s, 1H), 7.52(d, J=8.4Hz, 1H), 7.21(d, J=8.8Hz, 1H), 4.98-4.92(m, 1H), 4.07-4.04(m, 2H), 3.56(t, J=1.2Hz, 2H) ), 3.49-3.44(m, 4H), 3.28(s, 3H), 2.67-2.58(m, 2H), 1.78(d, J=9.6Hz, 2H);LC-MS:m / z 520.2(M+1) + .

[0312] Example 81. Synthesis of N-(2-methoxyethyl)-1-(tetrahydro-2H-pyran-4-yl)-2-((5-(trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide [ka] Step-a: Synthesis of ethyl 2-(1H-imidazole-1-carbothioamido)-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazole-5-carboxylate The title compound was synthesized using the same procedure as that followed for compound 12a using ethyl 2-amino-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazole-5-carboxylate and 1,1′-thiocarbonyldiimidazole as starting materials (yield: 72%). 1H NMR (400MHz, DMSO-d6): δ13.50(bs, 1H), 8.64(s, 1H), 8.43(s, 1H), 7.98(d, J=4.4Hz, 1H), 7.96-7.94(m, 1H), 7.09(s, 1H), 6.72(bs, 1H), 5. 05-5.00(m, 1H), 4.36-4.26(m, 2H), 4.06-4.02(m, 2H), 3.60(t, J=11.6Hz, 2H), 2.54-2.50(m, 2H), 1.86(d, J=9.6Hz, 2H), 1.37-1.33(m, 3H).

[0313] Step-b: Ethyl 1-(tetrahydro-2H-pyran-4-yl)-2-((5-(trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylate The title compound was synthesized using the same procedure as that followed for compound 12b using ethyl 2-(1H-imidazole-1-carbothioamido)-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazole-5-carboxylate and 4-(trifluoromethoxy)benzene-1,2-diamine as starting materials (yield: 46%); 1 H NMR (400MHz, DMSO-d6): δ12.3(bs, 1H), 8.12(d, J=6.4Hz, 1H), 7.95(s, 1H), 7.74(dd, J =2.0Hz, J=8.4Hz, 1H), 7.57(d, J=8.4Hz, 1H), 7.37-7.32(m, 2H), 7.06(dd, J=1.6Hz, J= 8.4Hz, 1H), 4.97-4.90(m, 1H), 4.32(q, J=6.8Hz, 2H), 4.08-4.05(m, 2H), 3.51(t, J=11 .6Hz, 2H), 2.67-2.55(m, 2H), 1.75(d, J=9.6Hz, 2H), 1.07(t, J=8.4Hz, 3H);LC-MS:m / z 490.0(M+1) + .

[0314] Step-c: Synthesis of 1-(tetrahydro-2H-pyran-4-yl)-2-((5-(trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid The title compound was synthesized using the same procedure as that followed for compound 1h using ethyl 1-(tetrahydro-2H-pyran-4-yl)-2-((5-(trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylate as starting material (yield: 55%); 1 H NMR (400MHz, DMSO-d6): δ12.7(bs, 3H), 8.04(s, 1H), 7.80(d, J=8.4Hz, 1H), 7.65(d, J=8.8Hz, 1H), 7.42-7.35(m, 2H), 7.12( d, J=8.0Hz, 1H), 4.93(bs, 1H), 4.08-4.05(m, 2H), 3.54-3.48(m, 2H), 2.61-2.58(m, 2H), 1.77(d, J=10.0Hz, 2H);LC-MS:m / z 462.15(M+1) + .

[0315] Step-d: Synthesis of N-(2-methoxyethyl)-1-(tetrahydro-2H-pyran-4-yl)-2-((5-(trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed for compound 1i using 1-(tetrahydro-2H-pyran-4-yl)-2-((5-(trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid and 2-methoxyethylamine as starting materials (yield: 42%). 1H NMR (400MHz, DMSO-d6): δ12.2(bs, 2H), 8.37(t, J=5.6Hz, 1H), 8.02(d, J=1.6Hz, 1H), 7.64(dd, J=1.2Hz, J=8.0Hz, 1H), 7.52(d, J=8.8Hz, 1H), 7.53-7.3 0(m, 2H), 7.03(d, J=8.0Hz, 1H), 4.98-4.89(m, 1H), 4.08-4.05(m, 2H), 3.51 -3.43(m, 6H), 3.28(s, 3H), 2.67-2.58(m, 2H), 1.75-1.73(m, 2H);LC-MS:m / z 519.1(M+1) + .

[0316] Examples 82 and 83. Synthesis of 2-((5-chloro-1H-benzo[d]imidazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid and 2-((5-5-chloro-1H-benzo[d]imidazol-2-yl)amino)-N-(2-methoxyethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide [ka] Step-a: Synthesis of ethyl 2-((5-chloro-1H-benzo[d]imidazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylate The title compound was synthesized using the same procedure as that followed for compound 12b using ethyl 2-(1H-imidazole-1-carbothioamido)-1-methyl-1H-benzo[d]imidazole-5-carboxylate and 4-chlorobenzene-1,2-diamine as starting materials (yield: 24%). 1 H NMR (400MHz, DMSO-d6): δ12.2 (bs, 2H), 8.10 (s, 1H), 7.76 (d, J=8.4Hz, 1H), 7.40-7.29 (m, 3H), 7.0 9(dd, J=1.2Hz, J=8.4Hz, 1H), 4.31(q, J=6.8Hz, 2H), 3.64(s, 3H), 1.35(t, J=6.8Hz, 3H);LC-MS:m / z 370.05(M+1) + .

[0317] Step-b: Synthesis of 2-((5-chloro-1H-benzo[d]imidazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid The title compound was synthesized using the same procedure as that followed for compound 1h using ethyl 2-((5-chloro-1H-benzo[d]imidazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylate as starting material (yield: 84%); 1 H NMR (400MHz, DMSO-d6): δ12.3(bs, 3H), 8.07(s, 1H), 7.76(d, J=8.0Hz, 1H), 7.37-7.29(m, 3H), 7.07(d, J=7.6Hz, 1H), 3.63(s, 3H); LC-MS: m / z 342.0(M+1) + .

[0318] Step-c: Synthesis of 2-((5-chloro-1H-benzo[d]imidazol-2-yl)amino)-N-(2-methoxyethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed for compound 1i using 2-((5-chloro-1H-benzo[d]imidazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid and 2-methoxyethylamine as starting materials (yield: 49%). 1 H NMR (400MHz, DMSO-d6): δ12.2(bs, 2H), 8.36(s, 1H), 7.99(s, 1H), 7.66(d, J=7.2Hz, 1H), 7.35(d, J=8.4H) z, 1H), 7.30-7.28(m, 2H), 7.06(d, J=8.4Hz, 1H), 3.62(s, 3H), 3.48-3.43(m, 4H), 3.17(s, 3H);LC-MS:m / z 399.1(M+1) + .

[0319] Examples 84 and 85. Synthesis of 1-ethyl-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid and 1-ethyl-N-(2-methoxyethyl)-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide [ka] Step-a: Synthesis of ethyl 4-(ethylamino)-3-nitrobenzoate To a solution of ethyl 4-chloro-3-nitrobenzoate (4.0 g, 17.5 mmol) in DMFA (100 mL) at RT, ethylamine (2.24 mL (70% aqueous solution), 34.9 mmol) was added and the reaction mixture was stirred at 60° C. for 16 h. The reaction mixture was cooled to RT, diluted with cold water (200 mL), and stirred for 15 min. The precipitated solid was filtered and dried under vacuum to give the title product (3.0 g, 63%). 1 H NMR (400MHz, DMSO-d6): δ8.62(d, J=2.0Hz, 1H), 8.51(t, J=5.2Hz, 1H), 7.97(dd, J=2.0Hz, J=9.2Hz, 1H), 7.14(d, LC-MS: m / z 239.0(M+1) + .

[0320] Step-b: Synthesis of ethyl 3-amino-4-(ethylamino)benzoate The title compound was synthesized using the same procedure as followed for compound 1e using ethyl 4-(ethylamino)-3-nitrobenzoate as starting material (yield: 79%), and the crude compound was used in the next step without purification.

[0321] Step-c: Synthesis of ethyl 2-amino-1-ethyl-1H-benzo[d]imidazole-5-carboxylate The title compound was synthesized using the same procedure as followed for compound 1f using ethyl 3-amino-4-(ethylamino)benzoate as starting material (yield: 74%). 1 H NMR (400MHz, DMSO-d6): δ7.70(s, 1H), 7.58(dd, J=1.6Hz, J=8.4Hz, 1H), 7.23(d, J=8.4Hz, 1H), 6.66(bs, 2 LC-MS:m / z 234.1(M+1) + .

[0322] Step-d: Synthesis of ethyl 1-ethyl-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylate The title compound was synthesized using the same procedure as that followed for compound 1g, using ethyl 2-amino-1-ethyl-1H-benzo[d]imidazole-5-carboxylate and 2-chloro-6-(trifluoromethoxy)benzo[d]oxazole as starting materials (yield: 54%); 1 H NMR (400MHz, DMSO-d6): δ12.3(bs, 1H), 8.25(d, J=1.6Hz, 1H), 7.88(dd, J=2.0Hz, J=8.8Hz, 1H), 7.60-7.57(m, 2H), 7.51(d, LC-MS:m / z 435.05(M+1) + .

[0323] Step-e: Synthesis of 1-ethyl-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid The title compound was synthesized using the same procedure as that followed for compound 1h using ethyl 1-ethyl-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylate as starting material (yield: 75%). 1 H NMR (400MHz, DMSO-d6): δ12.8(bs, 1H), 12.3(bs, 1H), 8.21(s, 1H), 7.88(d, J=8.0Hz, 1H), 7.58-7.57(m, 2 H), 7.52(d, J=8.4Hz, 1H), 7.20(d, J=9.6Hz, 1H), 4.22(q, J=7.6Hz, 2H), 1.33(t, J=6.8Hz, 3H);LC-MS:m / z 407.0(M+1) + .

[0324] Step-f: Synthesis of 1-ethyl-N-(2-methoxyethyl)-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed for compound 1i using 1-ethyl-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid and 2-methoxyethylamine as starting materials (yield: 58%). 1 H NMR (400MHz, DMSO-d6): δ12.3(bs, 1H), 8.46(s, 1H), 8.09(s, 1H), 7.77(d, J=8.4Hz, 1H), 7.56-7.50(m, 3H), 7 .21(d, J=8.0Hz, 1H), 4.22(q, J=7.6Hz, 2H), 3.48-3.44(m, 4H), 3.28(s, 3H), 1.32(t, J=7.6Hz, 3H);LC-MS:m / z 464.1(M+1) + .

[0325] Example 86. Synthesis of 1-ethyl-N-(2-hydroxyethyl)-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide [ka] To a stirred solution of 1-ethyl-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid (60 mg, 0.14 mmol) in DMFA (1 mL) at 0 °C, N-ethyldiisopropylamine (0.02 mL, 0.14 mmol) and HBTU (52 mg, 0.14 mmol) were added. The reaction mixture was stirred for 30 min, followed by the addition of 2-aminoethan-1-ol (8 mg, 0.14 mmol), and stirring was continued at RT for 16 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with cold water (15 mL) and stirred for 15 min. The resulting solid was filtered, washed with diethyl ether, and dried under vacuum to give the title compound as a white solid (20 mg, 30%). 1 H NMR (400MHz, DMSO-d6): δ12.3(bs, 1H), 8.37(t, J=4.8Hz, 1H), 8.09(s, 1H), 7.78(d, J=8.4Hz, 1H), 7.56-7.49(m, 3H), 7.21(d, J=8. 0Hz, 1H), 4.72(t, J=5.6Hz, 1H), 4.22(q, J=7.2Hz, 2H), 3.53(q, J=5.2Hz, 2H), 3.39-3.37(m, 2H), 1.32(t, J=8.0Hz, 3H);LC-MS:m / z 450.1(M+1) + .

[0326] Examples 87 and 88. Synthesis of 1-((tetrahydrofuran-3-yl)methyl)-2-((6-(trifluoromethoxy)-benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid and N-(2-methoxyethyl)-1-((tetrahydrofuran-3-yl)methyl)-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide [ka] Step-a: Synthesis of ethyl 3-nitro-4-(((tetrahydrofuran-3-yl)methyl)amino)benzoate To a solution of ethyl 4-chloro-3-nitrobenzoate (2.0 g, 8.7 mmol) in THF (40 mL) at RT, DIPEA (4.6 mL, 26.1 mmol) and (tetrahydrofuran-3-yl)methanamine (1.06 g, 10.5 mmol) were added, and the reaction mixture was then stirred at 60° C. for 16 hours. The reaction mixture was cooled to RT, diluted with cold water (200 mL), and stirred for 1 hour. The precipitated solid was filtered and dried under vacuum to give the title compound (2.4 g, 94%). 1 H NMR (400MHz, DMSO-d6): δ8.62-8.59(m, 2H), 7.97(dd, J=2.0Hz, J=9.2Hz, 1H) , 7.20(d, J=8.8Hz, 1H), 4.29(q, J=7.6Hz, 2H), 3.82-3.77(m, 1H), 3.73-3.69( m, 1H), 3.66-3.60(m, 1H), 3.53-3.50(m, 1H), 3.45-3.40(m, 2H), 2.67-2.58(m , 1H), 2.03-1.95(m, 1H), 1.69-1.63(m, 1H), 1.31(t, J=7.2Hz, 3H);LC-MS:m / z 295.0(M+1) + .

[0327] Step-b: Synthesis of ethyl 3-amino-4-(((tetrahydrofuran-3-yl)methyl)amino)benzoate The title compound was synthesized using the same procedure as followed for compound 1e using ethyl 3-nitro-4-(((tetrahydrofuran-3-yl)methyl)amino)benzoate as starting material (yield: 86%). 1H NMR (400MHz, DMSO-d6): δ7.20 (dd, J=2.0Hz, J=8.0Hz, 1H), 7.16 (d, J=2.0Hz, 1H), 6.46(d, J=8.0Hz, 1H), 5.26(bs, 1H), 4.75(s, 2H), 4.18(q, J=7.2Hz, 2H), 3.77-3. 73(m, 2H), 3.64-3.62(m, 1H), 3.49-3.47(m, 1H), 3.07(t, J=6.4Hz, 2H), 2.50-2.4 9(m, 1H), 2.11-1.98(m, 1H), 1.63-1.48(m, 1H), 1.26(t, J=7.2Hz, 3H);LC-MS:m / z 265.1(M+1) + .

[0328] Step-c: Synthesis of ethyl 2-amino-1-((tetrahydrofuran-3-yl)methyl)-1H-benzo[d]imidazole-5-carboxylate The title compound was synthesized using the same procedure as followed for compound 1f using ethyl 3-amino-4-(((tetrahydrofuran-3-yl)methyl)amino)benzoate as starting material (yield: 79%). 1 H NMR (400MHz, DMSO-d6): δ7.70(s, 1H), 7.58(dd, J=1.6Hz, J=8.4Hz, 1H), 7.27(d, J=8.4Hz, 1H), 6.71(s, 2H), 4.27(q, J=6.8Hz, 2H), 4.03(d, J=8.0Hz, 2H) ), 3.78-3.71(m, 1H), 3.63-3.59(m, 2H), 3.48-3.41(m, 1H), 2.72-2.68(m, 1 LC-MS:m / z 290.1(M+1) + .

[0329] Step-d: Synthesis of ethyl 1-((tetrahydrofuran-3-yl)methyl)-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylate The title compound was synthesized using the same procedure as that followed in step-e of Example 32 using ethyl 2-amino-1-ethyl-1H-benzo[d]imidazole-5-carboxylate and 2-chloro-6-(trifluoromethoxy)benzo[d]oxazole as starting materials (yield: 44%). 1 H NMR (400MHz, DMSO-d6): δ12.4(bs, 1H), 8.26(d, J=1.6Hz, 1H), 7.88(dd, J=1.6Hz, J=8. 4Hz, 1H), 7.63(d, J=8.4Hz, 1H), 7.59(s, 1H), 7.52(d, J=8.4Hz, 1H), 7.22(d, J=7.6Hz, 1 H), 4.33(q, J=7.2Hz, 2H), 4.20-4.18(m, 2H), 3.88-3.86(m, 1H), 3.70-3.56(m, 3H), 3.8 0-3.78(m, 1H), 1.94-1.91(m, 1H), 1.73-1.71(m, 1H), 1.35(t, J=7.2Hz, 3H);LC-MS:m / z 491.15(M+1) + .

[0330] Step-e: Synthesis of 1-((tetrahydrofuran-3-yl)methyl)-2-((6-(trifluoromethoxy)-benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid The title compound was synthesized using the same procedure as followed for compound 1h using ethyl 1-((tetrahydrofuran-3-yl)methyl)-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino-1H-benzo[d]imidazole-5-carboxylate as starting material. Yield: 76%). 1H NMR (400MHz, DMSO-d6): δ12.8(bs, 1H), 12.3(bs, 1H), 8.21(s, 1H), 7.87(d, J=8.0Hz, 1H), 7.62-7.58(m, 2H), 7.53(d, J=8.8Hz, 1H), 7.21(d, J LC-MS: m / z 463.1(M+1) + .

[0331] Step-f: Synthesis of N-(2-methoxyethyl)-1-((tetrahydrofuran-3-yl)methyl)-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed for compound 1i using 1-((tetrahydrofuran-3-yl)methyl)-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid and 2-methoxyethylamine as starting materials (yield: 18%). 1 H NMR (400MHz, DMSO-d6): δ12.3(bs, 1H), 8.47(s, 1H), 8.09(s, 1H), 7.77(d, J=7.6Hz, 1H), 7.60-7.50(m, 3H), 7.21(d, J=8.0Hz, 1H) , 4.18(bs, 2H), 3.87(bs, 1H), 3.67-3.57(m, 3H), 3.47(bs, 4H), 3.28(s, 3H), 2.88(bs, 1H), 1.92(bs, 1H), 1.73(bs, 1H);LC-MS:m / z 520.15(M+1) + .

[0332] Examples 89 and 90. Synthesis of 1-(2-(methylsulfonyl)ethyl)-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid and N-(2-methoxyethyl)-1-(2-(methylsulfonyl)ethyl)-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide [ka] Step-a: Synthesis of ethyl 4-((2-(methylsulfonyl)ethyl)amino)-3-nitrobenzoate The title compound was synthesized using the same procedure as that followed for compound 3a, using ethyl 4-chloro-3-nitrobenzoate and 2-(methylsulfonyl)ethan-1-amine hydrochloride as starting materials and heating to 60° C. (Yield: 89%); 1 H NMR (400MHz, DMSO-d6): δ8.69(t, J=6.0Hz, 1H), 8.63(d, J=2.0Hz, 1H), 8.02(dd, J=2.0Hz, J=8.8Hz, 1H), 7.20(d, J=9.2Hz) , 1H), 4.30(q, J=6.8Hz, 2H), 3.89(q, J=5.6Hz, 2H), 3.52(t, J=6.8Hz, 2H), 3.08(s, 3H), 1.30(t, J=6.8Hz, 3H);LC-MS:m / z 317.0(M+1) + .

[0333] Step-b: Synthesis of ethyl 3-amino-4-((2-(methylsulfonyl)ethyl)amino)benzoate The title compound was synthesized using the same procedure as followed for compound 1e using ethyl 4-((2-(methylsulfonyl)ethyl)amino)-3-nitrobenzoate as starting material (yield: 86%). 1H NMR (400MHz, DMSO-d6): δ7.24-7.20(m, 2H), 6.52(d, J=8.4Hz, 1H), 5.45(t, J=5.2Hz, 1H), 4.72(s, 2H), 4.19( q, J=7.2Hz, 2H), 3.58(q, J=6.4Hz, 2H), 3.38(t, J=6.8Hz, 2H), 3.03(s, 3H), 1.26(t, J=6.8Hz, 3H);LC-MS:m / z 287.0(M+1) + .

[0334] Step-c: Synthesis of ethyl 2-amino-1-(2-(methylsulfonyl)ethyl)-1H-benzo[d]imidazole-5-carboxylate The title compound was synthesized using the same procedure as followed for compound 1f using ethyl 3-amino-4-((2-(methylsulfonyl)ethyl)amino)benzoate as starting material (yield: 86%). 1 H NMR (400MHz, DMSO-d6): δ7.71 (d, J=1.2Hz, 1H), 7.61 (dd, J=1.6Hz, J=8.4Hz, 1H), 7.28 (d, J=8.4Hz, 1H), 6.75 (s, 2H), 4.47-4.40(m, 2H), 4.30(q, J=7.6Hz, 2H), 3.55(t, J=6.8Hz, 2H), 3.03(s, 3H), 1.31(t, J=6.8Hz, 3H).

[0335] Step-d: Synthesis of ethyl 1-(2-(methylsulfonyl)ethyl)-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylate The title compound was synthesized using the same procedure as that followed for compound 1g, using ethyl 2-amino-1-(2-(methylsulfonyl)ethyl)-1H-benzo[d]imidazole-5-carboxylate and 2-chloro-6-(trifluoromethoxy)benzo[d]oxazole as starting materials (yield: 24%); 1H NMR (400MHz, DMSO-d6): δ13.4(bs, 1H), 8.25(d, J=1.6Hz, 1H), 7.89(dd, J=1.2Hz, J=8.0Hz, 1H), 7.63-7.61(m, 2H), 7.54(d, J=8.8Hz, 1H) , 7.56-7.51(m, 1H), 4.61(t, J=6.8Hz, 2H), 4.34(q, J=7.2Hz, 2H), 3.73(d), J=6.8Hz, 2H), 3.14(s, 3H), 1.35(t, J=7.6Hz, 3H);LC-MS:m / z 513.05(M+1) + .

[0336] Step-e: Synthesis of 1-(2-(methylsulfonyl)ethyl)-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid The title compound was synthesized using the same procedure as that followed for compound 1h using ethyl 1-(2-(methylsulfonyl)ethyl)-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylate as starting material (yield: 17%); 1 H NMR (400MHz, DMSO-d6): δ12.8(bs, 1H), 12.4(bs, 1H), 8.20(d, J=1.2Hz, 1H), 7.88(dd, J=1.2Hz, J=8.0Hz, 1H), 7.61-7.59( LC-MS:m / z 484.9(M+1) + .

[0337] Step-f: Synthesis of N-(2-methoxyethyl)-1-(2-(methylsulfonyl)ethyl)-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed for compound 1i using 1-(2-(methylsulfonyl)ethyl)-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid and 2-methoxyethylamine as starting materials (yield: 32%). 1 H NMR (400MHz, DMSO-d6): δ12.30(bs, 1H), 8.48(t, J=5.2Hz, 1H), 8.08(s, 1H), 7.77(d, J=8.4Hz, 1H), 7.67-7.54(m, 3H), 7.21(d , J=9.6Hz, 1H), 4.60(t, J=6.8Hz, 2H), 3.74(t, J=10.8 Confirm coupling constant Hz, 2H), 3.48-3.44(m, 4H), 3.28(s, 3H), 3.14(s, 3H); LC-MS: m / z 542.0(M+1) + .

[0338] Example 91. Synthesis of 2-((6-bromobenzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid [ka] Step-a: Synthesis of 2-amino-5-bromophenol To a solution of 5-bromo-2-nitrophenol (4.0 g, 18.35 mmol) in ethanol (60 mL) at RT, add SnCl 2· 2H2O (20.6 g, 91.74 mmol) was added and the reaction mixture was refluxed for 4 hours. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was diluted with water (20 mL), basified with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with water (50 mL), brine (30 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title compound (2.4 g, 70%). 1H NMR (400MHz, DMSO-d6): δ9.44(bs, 1H), 6.75(d, J=2.4Hz, 1H), 6.67(dd, J=2.0Hz, J=8.4Hz, 1H), 6.51(d, J=8.4Hz, 1H), 4.65(bs, 2H); LC-MS: m / z 190.0(M+1) + .

[0339] Step-b: Synthesis of 6-bromobenzo[d]oxazole-2-thiol The title compound was synthesized using the same procedure as followed in step-c of Example 32 using 2-amino-5-bromophenol as starting material (yield: 98%). 1 H NMR (400MHz, DMSO-d6): δ14.0(bs, 1H), 7.84(d, J=1.6Hz, 1H), 7.47(dd, J=1.6Hz, J=8.4Hz, 1H), 7.18(d, J=8.4Hz, 1H); LC-MS: m / z 227.9(M-1) - .

[0340] Step-c: Synthesis of 6-bromo-2-chlorobenzo[d]oxazole To a solution of 6-bromobenzo[d]oxazole-2-thiol (2.89 g, 12.56 mmol) in thionyl chloride (20 mL) at room temperature was added N,N-dimethylformamide (0.2 mL), and the reaction mixture was refluxed for 3 hours. The reaction mixture was concentrated, diluted with cold water (50 mL), and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (50 mL), brine solution (40 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title compound (2.8 g, 96%). 1 H NMR (400MHz, DMSO-d6): δ8.14 (s, 1H), 7.72 (d, J=8.8Hz, 1H), 7.62 (dd, J=2.0Hz, J=8.8Hz, 1H).

[0341] Step-d: Synthesis of ethyl 2-((6-bromobenzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylate The title compound was synthesized using the same procedure as that followed for step e of Example 32 using ethyl 2-amino-1-methyl-1H-benzo[d]imidazole-5-carboxylate and 6-bromo-2-chlorobenzo[d]oxazole as starting materials (yield: 20%). 1 H NMR (400MHz, DMSO-d6): δ11.56(bs, 1H), 8.23(d, J=1.6Hz, 1H), 7.88(dd, J=1.6Hz, J=8.4Hz, 1H), 7.72(d, J=1.6Hz, 1H), 7.54(d, J=8.8Hz, 1H), 7.38-7.36(m, 2H), 4.33(q, J=7.2Hz, 2H), 3.64(s, 3H), 1.35(t, J=7.2Hz, 3H);LC-MS:m / z 416.9(M+1) + .

[0342] Step-e: Synthesis of 2-((6-bromobenzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid The title compound was synthesized using the same procedure as that followed for compound 1h using ethyl 2-((6-bromobenzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylate as starting material (yield: 75%). 1 H NMR (400MHz, DMSO-d6): δ12.8(bs, 1H), 12.3(bs, 1H), 8.19(s, 1H), 7.87(d, J=8.4Hz, 1H) , 7.71(d, J=1.6Hz, 1H), 7.51(d, J=8.8Hz, 1H), 7.42-7.35(m, 2H), 3.64(s, 3H);LC-MS:m / z 388.9(M+1) + .

[0343] Example 92. Synthesis of N-(2-hydroxyethyl)-2-((6-methoxybenzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxamide [ka] Step-a: Synthesis of 5-methoxy-2-nitrophenol To a stirred suspension of sodium methoxide (0.86 g, 18.35 mmol) in methanol (50 mL) at RT, a solution of 5-fluoro-2-nitrophenol (3.0 g, 19.1 mmol) in methanol (40 mL) was added via syringe, and the reaction mixture was heated at 60° C. for 40 hours. The reaction mixture was cooled to RT, quenched with cold water (50 mL), acidified with 1N HCl, and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by Combiflash chromatography using 3% ethyl acetate in hexane as the eluent to give the title compound (2.0 g, 62%). 1 H NMR (400MHz, DMSO-d6): δ10.94(s, 1H), 7.97(d, J=9.6Hz, 1H), 6.63(d, J=2.4Hz, 1H), 6.59(dd, J=3.0Hz, J=9.2Hz, 1H), 3.83(s, 3H); LC-MS: m / z 167.95(M-1) - .

[0344] Step-b: Synthesis of 2-amino-5-methoxyphenol The title compound was synthesized using the same procedure as followed for compound 1e using 5-methoxy-2-nitrophenol as starting material (yield: 96%). 1 H NMR (400MHz, DMSO-d6): δ8.8(bs, 1H), 6.49(d, J=8.4Hz, 1H), 6.30(d, J=2.1Hz, 1H), 6.18-6.14(m, 1H), 3.58(s, 3H); LC-MS: m / z 140.15(M+1) + .

[0345] Step-c: Synthesis of 6-methoxybenzo[d]oxazole-2-thiol The title compound was synthesized using the same procedure as followed in step-c of Example 32 using 2-amino-5-methoxyphenol as starting material (yield: 72%). 1H NMR (400MHz, DMSO-d6): δ13.7(s, 1H), 7.21(d, J=2.4Hz, 1H), 7.13(d, J=8.4Hz, 1H), 6.88(dd, J=2.0Hz, J=8.4Hz, 1H), 3.77(s, 3H); LC-MS: m / z 182.0(M+1) + .

[0346] Step-d: Synthesis of 2-chloro-6-methoxybenzo[d]oxazole The title compound was synthesized using the same procedure as that followed in step-d of Example 32, using 6-methoxybenzo[d]oxazole-2-thiol as starting material and stirred for 2 hours (yield: 91%). LC-MS: m / z 184.0 (M+1) + .

[0347] Step-e: Synthesis of ethyl 2-((6-methoxybenzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylate The title compound was synthesized using the same procedure as that followed in step-e of Example 32 using ethyl 2-amino-1-methyl-1H-benzo[d]imidazole-5-carboxylate and 2-chloro-6-methoxybenzo[d]oxazole as starting materials (yield: 18%). 1 H NMR (400MHz, DMSO-d6): δ12.3(bs, 1H), 8.21(d, J=1.4Hz, 1H), 7.87(dd, J=1.2Hz, J=8.4Hz, 1H), 7.50(d, J=8.0Hz, 1H), 7.36(d, J=8.4Hz, 1H) , 7.13(d, J=2.0Hz, 1H), 6.83(dd, J=2.4Hz, J=8.4Hz, 1H), 4.33(q, J=6.8Hz, 2H), 3.82(s, 3H), 3.62(s, 3H), 1.35(t, J=7.2Hz, 3H);LC-MS:m / z 367.0(M+1) + .

[0348] Step-f: Synthesis of 2-((6-methoxybenzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid The title compound was synthesized using the same procedure as that followed for compound 1h using ethyl 2-((6-methoxybenzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylate as starting material (yield: 79%). 1 H NMR (400MHz, DMSO-d6): δ12.5(bs, 2H), 8.17(s, 1H), 7.85(dd, J=1.6Hz, J=8.4Hz, 1H), 7.47(d, J=8.4Hz, 1H), 7.3 7(d, J=8.8Hz, 1H), 7.12(d, J=2.0Hz, 1H), 6.82(dd, J=2.4Hz, J=8.8Hz, 1H), 3.79(s, 3H), 3.62(s, 3H);LC-MS:m / z 339.0(M+1) + .

[0349] Step-g: Synthesis of N-(2-hydroxyethyl)-2-((6-methoxybenzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed in step-e of Example 6 using 2-((6-methoxybenzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylate and 2-aminoethan-1-ol as starting materials (yield: 59%). 1 H NMR (400MHz, DMSO-d6): δ12.18(bs, 1H), 8.35(t, J=5.2Hz, 1H), 8.05(d, J=1.2 Hz, 1H), 7.75(dd, J=1.6Hz, J=8.4Hz, 1H), 7.45(d, J=8.4Hz, 1H), 7.35(d, J=8.4 Hz, 1H), 7.11(d, J=2.4Hz, 1H), 6.81(dd, J=2.4Hz, J=8.8Hz, 1H), 4.72(bs, 1H), 3.78(s, 3H), 3.61(s, 3H), 3.53(t, J=6.0Hz, 2H), 3.35-3.30(m, 2H);LC-MS:m / z 382.0(M+1) + .

[0350] Examples 93 and 94. Synthesis of 1-((3-hydroxyoxetan-3-yl)methyl)-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid and 1-((3-hydroxyoxetan-3-yl)methyl)-N-(2-methoxyethyl)-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide [ka] Step-a: Synthesis of 3-(nitromethyl)oxetan-3-ol To a solution of oxetan-3-one (10.0 g, 138.9 mmol) in nitromethane (25 mL) at 0° C., triethylamine (5 mL, 347.2 mmol) was added, and the reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by Combi-Flash column chromatography using 40% ethyl acetate in hexane as the eluent to give the title compound (14.0 g, 77%) as a pale yellow liquid. 1 H NMR (400MHz, CDCl3): δ4.82 (s, 2H), 4.71 (d, J=8.0Hz, 2H), 4.61 (d, J=8.0Hz, 2H), 3.53 (s, 1H).

[0351] Step-b: Synthesis of 3-(aminomethyl)oxetan-3-ol To a solution of 3-(nitromethyl)oxetan-3-ol (5.0 g, 37.6 mmol) in methanol (80 mL) was added a slurry of 10% Pd / C (2.0 g in 20 mL methanol) under a nitrogen atmosphere. The reaction mixture was then stirred under a hydrogen gas balloon for 3 hours. The reaction mixture was filtered through a bed of celite and concentrated in vacuo to give the title compound (3.8 g, 98%). LC-MS: m / z 104.2 (M+1) + .

[0352] Step-c: Synthesis of ethyl 4-(((3-hydroxyoxetan-3-yl)methyl)amino)-3-nitrobenzoate The title compound was synthesized using the same procedure as followed for compound 3a, using ethyl 4-chloro-3-nitrobenzoate and 3-(aminomethyl)oxetan-3-ol as starting materials and heating to 60° C. (yield: 54%). 1 H NMR (400MHz, DMSO-d6): δ8.62(d, J=1.6Hz, 1H), 8.53(bs, 1H), 7.99(dd, J=2.0Hz, J=9.2Hz, 1H), 7.29(d, J=9.2Hz, 1H), 6.35(s, 1 LC-MS:m / z 297.1(M+1) + .

[0353] Step-d: Synthesis of ethyl 3-amino-4-(((3-hydroxyoxetan-3-yl)methyl)amino)benzoate The title compound was synthesized using the same procedure as followed for compound 1e using 4-(((3-hydroxyoxetan-3-yl)methyl)amino)-3-nitrobenzoate as starting material (yield: 95%). 1 H NMR (400MHz, DMSO-d6): δ7.23-7.20(m, 2H), 6.57(d, J=8.4Hz, 1H), 5.96(bs, 1H), 5.04(bs, 1H), 4.75(s , 2H), 4.46-4.43(m, 4H), 4.19(q, J=7.2Hz, 2H), 3.40(d, J=5.6Hz, 2H), 1.26(t, J=6.8Hz, 3H);LC-MS:m / z 267.1(M+1) + .

[0354] Step-e: Synthesis of ethyl 2-amino-1-((3-hydroxyoxetan-3-yl)methyl)-1H-benzo[d]imidazole-5-carboxylate The title compound was synthesized using the same procedure as followed for compound 1f using ethyl 3-amino-4-(((3-hydroxyoxetan-3-yl)methyl)amino)benzoate as starting material (yield: 70%). 1 H NMR (400MHz, DMSO-d6): δ7.72(s, 1H), 7.59(dd, J=1.6Hz, J=8.0Hz, 1H), 7.35(d, J=8.0Hz, 1H), 6.56(s, 2H), 6.45(s, 1 LC-MS:m / z 292.1(M+1) + .

[0355] Step-f: Synthesis of ethyl 1-((3-hydroxyoxetan-3-yl)methyl)-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylate The title compound was synthesized using the same procedure as in step-e of Example 32 using ethyl 2-amino-1-((3-hydroxyoxetan-3-yl)methyl)-1H-benzo[d]imidazole-5-carboxylate and 2-chloro-6-(trifluoromethoxy)benzo[d]oxazole as starting materials (yield: 18%). 1 H NMR (400MHz, DMSO-d6): δ12.4(bs, 1H), 8.24(d, J=1.6Hz, 1H), 7.85(dd, J=1.6Hz, J=8.4Hz, 1H), 7.60-7.58(m, 2H), 7.53(d, J=8.4Hz, 1H), 7.23(dd, J= 1.2Hz, J=8.8Hz, 1H), 6.18(s, 1H), 4.79(d, J=6.8Hz, 2H), 4.50(bs, 2H), 4.4 6(d, J=6.8Hz, 2H), 4.33(q, J=6.8Hz, 2H), 1.35(t, J=7.6Hz, 3H);LC-MS:m / z 493.0(M+1) + .

[0356] Step-g: Synthesis of 1-((3-hydroxyoxetan-3-yl)methyl)-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid The title compound was synthesized using the same procedure as that followed for compound 1h using ethyl 1-((3-hydroxyoxetan-3-yl)methyl)-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylate as starting material (yield: 49%). 1 H NMR (400MHz, DMSO-d6): δ12.8(bs, 1H), 12.3(bs, 1H), 8.19(d, J=1.2Hz, 1H), 7.84(dd, J=1.2Hz, J=8.0Hz, 1H), 7.60-7.52( LC-MS: m / z 465.1(M+1) + .

[0357] Step-h: Synthesis of 1-((3-hydroxyoxetan-3-yl)methyl)-N-(2-methoxyethyl)-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed for compound 1i, using 1-((3-hydroxyoxetan-3-yl)methyl)-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid and 2-methoxyethylamine as starting materials. The crude product was purified by Combiflash chromatography using 2% methanol in DCM as the eluent to give the title compound (yield: 28%). 1H NMR (400MHz, DMSO-d6): δ12.3(bs, 1H), 8.43(t, J=5.2Hz, 1H), 8.07(s, 1H), 7.73(d, J=8.8Hz, 1H), 7.58(s, 1H), 7.55-7.51(m, 2H), 7.2 1(d, J=8.4Hz, 1H), 6.17(s, 1H), 4.79(d, J=6.8Hz, 2H), 4.50(s, 2H), 4.46(d, J=6.4Hz, 2H), 3.49-3.43(m, 4H), 3.28(s, 3H); LC-MS: m / z 522.0(M+1) + .

[0358] Example 95. Synthesis of N-(2-hydroxyethyl)-1-((3-hydroxyoxetan-3-yl)methyl)-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide [ka] The title compound was synthesized using the same procedure as followed in step-e of Example 6 using 1-((3-hydroxyoxetan-3-yl)methyl)-2-((6-(trifluoromethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid and 2-aminoethan-1-ol as starting materials. The crude product was purified by Combiflash chromatography using 3% methanol in DCM as eluent to give the title compound (yield: 15%). 1H NMR (400MHz, DMSO-d6): δ12.3(bs, 1H), 8.35(t, J=5.6Hz, 1H), 8.07(d, J=1.2Hz, 1 H), 7.73(dd, J=1.6Hz, J=8.4Hz, 1H), 7.58(s, 1H), 7.58-7.51(m, 2H), 7.22(dd, J= 1.2Hz, J=10.0Hz, 1H), 6.17(s, 1H), 4.80(d, J=6.8Hz, 2H), 4.71(t, J=5.2Hz, 1H), 4.51(s, 2H), 4.46(d, J=6.4Hz, 2H), 3.55-3.51(m, 2H), 3.37-27(m, 2H);LC-MS:m / z 508.45(M+1) + .

[0359] Examples 96 and 97. Synthesis of 2-((6-chlorobenzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid and 2-((6-chlorobenzo[d]oxazol-2-yl)amino)-N-(2-hydroxyethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide [ka] Step-a: Synthesis of 6-chlorobenzo[d]oxazole-2-thiol The title compound was synthesized using the same procedure as followed in step-c of Example 32 using 2-amino-5-chlorophenol as starting material (yield: 69%). 1 H NMR (400MHz, DMSO-d6): δ14.0(bs, 1H), 7.73(d, J=2.0Hz, 1H), 7.35(dd, J=1.6Hz, J=8.0Hz, 1H), 7.23(d, J=8.8Hz, 1H); LC-MS: m / z 184.0(M-1) - .

[0360] Step-b: Synthesis of 2,6-dichlorobenzo[d]oxazole The title compound was synthesized using the same procedure as followed in step-d of Example 32 using 6-chlorobenzo[d]oxazole-2-thiol as starting material (yield: 69%).1 H NMR (400MHz, DMSO-d6): δ8.01 (d, J=1.6Hz, 1H), 7.77 (d, J=8.4Hz, 1H), 7.51 (dd, J=2.0Hz, J=8.4Hz, 1H).

[0361] Step-c: Synthesis of ethyl 2-((6-chlorobenzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylate The title compound was synthesized using the same procedure as followed in step-e of Example 32 using ethyl 2-amino-1-methyl-1H-benzo[d]imidazole-5-carboxylate and 2,6-dichlorobenzo[d]oxazole as starting materials (yield: 24%); 1 H NMR (400MHz, DMSO-d6): δ12.3(bs, 1H), 8.23(d, J=1.6Hz, 1H), 7.88(d, J=8.0Hz, 1H), 7.60(d, J=2.0Hz, 1H), 7.53(d, J=8.4Hz, 1H ), 7.44(d, J=8.0Hz, 1H), 7.25(dd, J=2.0Hz, J=8.0Hz, 1H), 4.33(q, J=7.2Hz, 2H), 3.64(s, 3H), 1.35(t, J=7.2Hz, 3H);LC-MS:m / z 369.0(M-1) - .

[0362] Step-d: Synthesis of 2-((6-chlorobenzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid The title compound was synthesized using the same procedure as that followed for compound 1h using ethyl 2-((6-chlorobenzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylate as starting material (yield: 81%). 1H NMR (400MHz, DMSO-d6): δ12.8(bs, 1H), 12.3(bs, 1H), 8.19(d, J=1.2Hz, 1H), 7.87(dd, J=1.6Hz, J=8.4Hz, 1H), 7.59(d , J=2.0Hz, 1H), 7.51(d, J=8.4Hz, 1H), 7.45(d, J=8.4Hz, 1H), 7.24(dd, J=2.0Hz, J=8.4Hz, 1H), 3.64(s, 3H);LC-MS:m / z 342.9(M+1) + .

[0363] Step-e: Synthesis of 2-((6-chlorobenzo[d]oxazol-2-yl)amino)-N-(2-hydroxyethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as followed in step-e of Example 6 using 2-((6-chlorobenzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid and 2-aminoethan-1-ol as starting materials (yield: 53%); 1 H NMR (400MHz, DMSO-d6): δ12.3(bs, 1H), 8.37(t, J=5.6Hz, 1H), 8.08(s, 1H), 7.78(d, J=8.4Hz, 1H), 7.58(d, J=2.0Hz, 1H), 7.49(d, J=8.8Hz, 1H) , 7.44(d, J=8.4Hz, 1H), 7.24(dd, J=2.0Hz, J=8.4Hz, 1H), 4.72(t, J=5.2Hz, 1H), 3.64(s, 3H), 3.55-3.51(m, 2H), 3.37-3.33(m, 2H);LC-MS:m / z 386.1(M+1) + .

[0364] Examples 98 and 99. Synthesis of 1-methyl-2-((6-(2,2,2-trifluoroethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid and N-(2-methoxyethyl)-1-methyl-2-((6-(2,2,2-trifluoroethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide [ka] Step-a: Synthesis of 2-(benzyloxy)-4-fluoro-1-nitrobenzene To a stirred solution of 5-fluoro-2-nitrophenol (8.0 g, 50.9 mmol) in DMFA (80 mL) at 0 °C, potassium carbonate (14.0 g, 101.8 mmol) and benzyl bromide (5.4 mL, 45.8 mmol) were added, and the reaction mixture was stirred at RT for 16 hours. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (2 × 200 mL). The combined organic layers were washed with water (2 × 200 mL), brine (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by Combiflash chromatography using 10% ethyl acetate in hexane as the eluent to give the title compound (8.0 g, 64%). 1 H NMR (400MHz, DMSO-d6): δ8.06-8.02(m, 1H), 7.47-7.36(m, 6H), 7.05-6.95(m, 1H), 5.33(s, 2H).

[0365] Step-b: Synthesis of 2-(benzyloxy)-1-nitro-4-(2,2,2-trifluoroethoxy)benzene To a solution of trifluoroethanol (0.23 mL, 3.24 mmol) in THF (10 mL) at 0° C., sodium hydride (60% dispersion in mineral oil) (194 mg, 4.86 mmol) was added portionwise and stirred for 1 h. Then, a solution of 2-(benzyloxy)-4-fluoro-1-nitrobenzene (400 mg, 1.62 mmol) was added to the reaction mixture and stirred at RT for 2 h. The reaction mixture was concentrated and diluted with cold water (20 mL). The precipitated solid was filtered and dried under vacuum to give the title compound (350 mg, 66%). 1 H NMR (400MHz, DMSO-d6): δ8.01(d, J=9.2Hz, 1H), 7.48-7.33(m, 5H), 7.11(d, J=2 .8Hz, 1H), 6.82(dd, J=2.4Hz, J=8.8Hz, 1H), 5.32(s, 2H), 4.94(q, J=8.8Hz, 2H).

[0366] Step-c: Synthesis of 2-amino-5-(2,2,2-trifluoroethoxy)phenol To a solution of 2-(benzyloxy)-1-nitro-4-(2,2,2-trifluoroethoxy)benzene (350 mg, 1.07 mmol) in methanol (10 mL) was added 10% Pd / C (50 mg) under a nitrogen atmosphere. The reaction mixture was stirred under a hydrogen gas balloon for 16 hours. The reaction mixture was filtered through a celite bed and concentrated in vacuo to give the title compound (210 mg, 95%). 1 H NMR (400MHz, DMSO-d6): δ6.51 (d, J=8.8Hz, 1H), 6.38 (d, J=2.4Hz, 1H), 6.28 (dd, J=2.8Hz, J=8.8Hz, 1H), 4.48 (q, J=8.8Hz, 2H); LC-MS: m / z 208.0 (M+1) + .

[0367] Step-d: Synthesis of 6-(2,2,2-trifluoroethoxy)benzo[d]oxazole-2-thiol The title compound was synthesized using the same procedure as followed in step-c of Example 32 using 2-amino-5-(2,2,2-trifluoroethoxy)phenol as starting material (yield: 79%).1 H NMR (400MHz, DMSO-d6): δ13.8(bs, 1H), 7.38(d, J=2.4Hz, 1H), 7.18(d, J=8.8Hz, 1H), 7.01(dd, J=2.4Hz, J=8.8Hz, 1H), 4.79(q, J=8.8Hz, 2H); LC-MS: m / z 250.0(M+1) + .

[0368] Step-e: Synthesis of 2-chloro-6-(2,2,2-trifluoroethoxy)benzo[d]oxazole The title compound was synthesized using the same procedure as that followed in step-d of Example 32, using 6-(2,2,2-trifluoroethoxy)benzo[d]oxazole-2-thiol as the starting material and stirring for 2 hours. (Yield: 87%) 1 H NMR (400MHz, DMSO-d6): δ7.69 (d, J=8.8Hz, 1H), 7.60 (d, J=2.4Hz, 1H), 6.15 (dd, J=2.4Hz, J=8.8Hz, 1H), 4.85 (q, J=8.8Hz, 2H).

[0369] Step-f: Synthesis of ethyl 1-methyl-2-((6-(2,2,2-trifluoroethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylate The title compound was synthesized using the same procedure as followed in step-e of Example 32 using ethyl 2-amino-1-methyl-1H-benzo[d]imidazole-5-carboxylate and 2-chloro-6-(2,2,2-trifluoroethoxy)benzo[d]oxazole) as starting materials (yield: 21%). 1H NMR (400MHz, DMSO-d6): δ12.3(bs, 1H), 8.22(d, J=1.6Hz, 1H), 7.88(dd, J=1.2Hz, J=8.0Hz, 1H), 7.51(d, J=8.4Hz, 1H), 7.39(d, J=8.4Hz, 1H), 7.2 9(d, J=2.4Hz, 1H), 6.94(dd, J=2.4Hz, J=8.4Hz, 1H), 4.77(q, J=8.8Hz, 2H), 4.33(q, J=7.2Hz, 2H), 3.63(s, 3H), 1.35(t, J=7.2Hz, 3H);LC-MS:m / z 435.35(M+1) + .

[0370] Step-g: Synthesis of 1-methyl-2-((6-(2,2,2-trifluoroethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid The title compound was synthesized using the same procedure as that followed for compound 1h using ethyl 1-methyl-2-((6-(2,2,2-trifluoroethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylate as starting material (yield: 62%); 1 H NMR (400MHz, DMSO-d6): δ12.5(bs, 2H), 8.18(d, J=1.2Hz, 1H), 7.86(dd, J=1.6Hz, J=8.4Hz, 1H), 7.48(d, J=8.8Hz, 1H), 7.4 0(d, J=8.8Hz, 1H), 7.29(d, J=2.4Hz, 1H), 6.93(dd, J=2.4Hz, J=8.8Hz, 1H), 4.77(q, J=9.2Hz, 2H), 3.62(s, 3H);LC-MS:m / z 407.0(M+1) + .

[0371] Step-h: Synthesis of N-(2-methoxyethyl)-1-methyl-2-((6-(2,2,2-trifluoroethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed for compound 1i using 1-methyl-2-((6-(2,2,2-trifluoroethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid and 2-methoxyethylamine as starting materials (yield: 70%); 1 H NMR (400MHz, DMSO-d6): δ12.2(bs, 1H), 8.4(t, J=5.6Hz, 1H), 8.06(s, 1H), 7.75(d, J=8.0Hz, 1H), 7.46(d, J=8.0Hz, 1H), 7.39(d, J=8.0Hz, 1 H), 7.28(d, J=1.6Hz, 1H), 6.93(dd, J=2.4Hz, J=8.4Hz, 1H), 4.77(q, J=8.8Hz, 2H), 3.62(s, 3H), 3.48-3.43(m, 4H), 3.28(s, 3H);LC-MS:m / z 464.0(M+1) + .

[0372] Example 100. Synthesis of N-(2-hydroxyethyl)-1-methyl-2-((6-(2,2,2-trifluoroethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide [ka] The title compound was synthesized using the same procedure as in step-e of Example 6 using 1-methyl-2-((6-(2,2,2-trifluoroethoxy)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid and 2-aminoethan-1-ol as starting materials (yield: 63%). 1H NMR (400MHz, DMSO-d6): δ12.5(bs, 1H), 8.42(t, J=5.2Hz, 1H), 8.07(s, 1H), 7.81(d, J=8.4Hz, 1H), 7.53(d, J=8.4Hz, 1H), 7.40(d, J=8.8Hz, 1H), 7. 32(d, J=2.4Hz, 1H), 6.98(dd, J=2.4Hz, J=8.8Hz, 1H), 4.80(q, J=8.8Hz, 2H), 3.66(s, 3H), 3.54(t, J=6.4Hz, 2H), 3.36(q, J=6.0Hz, 2H);LC-MS:m / z 450.0(M+1) + .

[0373] Examples 101 and 102. Synthesis of 2-((6-(2-hydroxyethoxy)benzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid and 2-((6-(2-hydroxyethoxy)benzo[d]oxazol-2-yl)amino)-N-(2-methoxyethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide [ka] Step-a: Synthesis of 3-(benzyloxy)-4-nitrophenol To a stirred suspension of 2-(benzyloxy)-4-fluoro-1-nitrobenzene (4.0 g, 16.2 mmol) in water (70 mL) at RT, potassium hydroxide (4.53 g, 80.9 mmol) was added, and the reaction mixture was stirred at 100° C. for 30 h. The reaction mixture was cooled to RT, diluted with water (50 mL), acidified with 1 N HCl, and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give a residue that was purified by Combiflash chromatography using 20% ​​ethyl acetate in hexane as the eluent to give the title compound (1.5 g, 38%). 1H NMR (400MHz, DMSO-d6): δ10.88(s, 1H), 7.90(d, J=8.8Hz, 1H), 7.49-7.47(m, 2H), 7.43-7.40(m, 2H), 7.35(d, J=6.8Hz, 1H), 6.69(d, J=2.4Hz, 1H), 6.49(dd, J=2.4Hz, J=9.2Hz, 1H), 5.25(s, 2H).

[0374] Step-b: Synthesis of (2-(3-(benzyloxy)-4-nitrophenoxy)ethoxy)(tert-butyl)dimethylsilane To a stirred solution of 3-(benzyloxy)-4-nitrophenol (1.5 g, 6.1 mmol) in DMFA (15 mL) at RT in a sealed tube was added potassium carbonate (2.1 g, 15.3 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (1.75 g, 7.3 mmol) and heated at 130° C. for 4 h. The reaction mixture was cooled to RT, diluted with water (50 mL), and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water (2×500 mL), brine (30 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give a residue that was purified by Combiflash chromatography using 5% ethyl acetate in hexanes as the eluent to give the title compound (8.0 g, 64%). 1 H NMR (400MHz, DMSO-d6): δ7.96(d, J=8.8Hz, 1H), 7.49-7.47(m, 2H), 7.43-7.39(m, 2H), 7.36-7.34(m, 1H), 6.89(d, J=2.4Hz, 1H), 6.67(dd, J=2.4Hz, J=9.2Hz, 1H), 5.32(s, 2H), 4.17(t, J=4.4Hz, 2H), 3.92(t, J=4.8Hz, 2H), 0.86(s, 9H), 0.02(s, 6H).

[0375] Step-c: Synthesis of 2-amino-5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)phenol The title compound was synthesized using the same procedure as followed for compound 1e using (2-(3-(benzyloxy)-4-nitrophenoxy)ethoxy)(tert-butyl)dimethylsilane as starting material (yield: 87%). 1 H NMR (400MHz, DMSO-d6): δ6.47(d, J=8.0Hz, 1H), 6.30(d, J=2.8Hz, 1H), 6.15(dd, J=2.4Hz, J=8.4Hz, 1H), 3.84-3.80(m, 4H), 0.87(s, 9H), 0.02(s, 6H);LC-MS:m / z 284.1(M+1) + .

[0376] Step-d: Synthesis of 6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)benzo[d]oxazole-2-thiol The title compound was synthesized using the same procedure as in step c of Example 32 using 2-amino-5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)phenol as the starting material (yield: 77%). The crude compound was used in the next step without analytical data.

[0377] Step-e: Synthesis of 6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-(methylthio)benzo[d]oxazole The title compound was synthesized using the same procedure as that followed for compound 1b, using 6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)benzo[d]oxazole-2-thiol as the starting material and stirring for 16 hours. (Yield: 80%); 1 H NMR (400MHz, DMSO-d6): δ7.50 (d, J=8.8Hz, 1H), 7.28 (d, J=2.4Hz, 1H), 6.91 (dd, J=2.8Hz, J=8.8Hz, 1H), 4.06(t, J=4.4Hz, 2H), 3.92(t, J=5.2Hz, 2H), 2.27(s, 3H), 0.86(s, 9H), 0.2(s, 6H);LC-MS:m / z 340.0(M+1) + .

[0378] Step-f: Synthesis of 6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-(methylsulfonyl)-benzo[d]oxazole The title compound was synthesized using the same procedure as followed for compound 1c, using 6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-(methylthio)benzo[d]oxazole as starting material and stirring for 4 hours (yield: 100%). 1 H NMR (400MHz, DMSO-d6): δ7.90-7.89(m, 1H), 7.55(d, J=8.0Hz, 1H), 6.99-6.97(m, 1H) , 4.10(t, J=4.8Hz, 2H), 3.95(t, J=5.2Hz, 2H), 3.62(s, 3H), 0.85(s, 9H), 0.2(s, 6H).

[0379] Step-g: Synthesis of ethyl 2-((6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)benzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylate The title compound was synthesized using the same procedure as that followed for compound 1g using ethyl 2-amino-1-methyl-1H-benzo[d]imidazole-5-carboxylate and 6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-(methylsulfonyl)benzo[d]oxazole as starting materials (yield: 17%); 1 H NMR (400MHz, DMSO-d6): δ12.2(bs, 1H), 8.21(d, J=1.6Hz, 1H), 7.86(dd, J=1.6Hz, J =8.4Hz, 1H), 7.49(d, J=8.0Hz, 1H), 7.35(d, J=8.4Hz, 1H), 7.12(d, J=2.4Hz, 1H), 6 .81(dd, J=1.6Hz, J=8.0Hz, 1H), 4.32(q, J=7.6Hz, 2H), 4.06-4.04(m, 2H), 3.94-3. 92(m, 2H), 3.62(s, 3H), 1.35(t, J=6.8Hz, 3H), 0.88(s, 9H), 0.2(s, 6H);LC-MS:m / z 511.1(M+1) + .

[0380] Step-h: Synthesis of 2-((6-(2-hydroxyethoxy)benzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid To a stirred solution of ethyl 2-((6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)benzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylate (80 mg, 0.15 mmol) in a solvent mixture of THF (2 mL), ethanol (2 mL), and water (1 mL) was added lithium hydroxide monohydrate (32 mg, 0.78 mmol). The reaction mixture was heated at 60° C. with stirring for 16 h. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was dissolved in water (20 mL) and acidified with 1 N HCl. The resulting solid was filtered and dried under vacuum to give the title compound (50 mg, 87%). 1 H NMR (400MHz, DMSO-d6): δ12.8(bs, 1H), 12.3(bs, 1H), 8.16(d, J=1.6Hz, 1H), 7.85(dd, J=1.6Hz, J=8.4Hz, 1H), 7.46(d, J=8.4Hz, 1H), 7.36(d, J=8. 4Hz, 1H), 7.12(d, J=2.4Hz, 1H), 6.82(dd, J=2.4Hz, J=8.4Hz, 1H), 4.85(bs, 1H), 4.01(t, J=4.8Hz, 2H), 3.75-3.73(m, 2H), 3.66(s, 3H);LC-MS:m / z 369.0(M+1) + .

[0381] Step-i: Synthesis of 2-((6-(2-hydroxyethoxy)benzo[d]oxazol-2-yl)amino)-N-(2-methoxyethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed for compound 1i, using 2-((6-(2-hydroxyethoxy)benzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid and 2-methoxyethylamine as starting materials. The crude product was purified by Combiflash chromatography using 4% methanol in DCM as the eluent (yield: 17%). 1 H NMR (400MHz, DMSO-d6): δ12.2(bs, 1H), 8.43(t, J=5.2Hz, 1H), 8.05(d, J=1.2Hz, 1H) , 7.75(dd, J=1.6Hz, J=8.4Hz, 1H), 7.45(d, J=8.8Hz, 1H), 7.35(d, J=8.4Hz, 1H), 7.1 2(d, J=2.4Hz, 1H), 6.82(dd, J=2.8Hz, J=8.8Hz, 1H), 4.11(t, J=4.4Hz, 2H), 3.66(t, LC-MS:m / z 426.4(M+1) + .

[0382] Example 103. Synthesis of 2-((6-(2-hydroxyethoxy)benzo[d]oxazol-2-yl)amino)-N-(2-hydroxyethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide [ka] The title compound was synthesized using the same procedure as followed in step-e of Example 6 using 2-((6-(2-hydroxyethoxy)benzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid and 2-aminoethan-1-ol as starting materials. The crude product was purified by Combiflash chromatography using 6% methanol in DCM as eluent to give the title compound (yield: 18%). 1H NMR (400MHz, DMSO-d6): δ12.05(bs, 1H), 8.35(t, J=5.2Hz, 1H), 8.05(s, 1H), 7.75(d, J= 8.0Hz, 1H), 7.45(d, J=8.4Hz, 1H), 7.35(d, J=8.4Hz, 1H), 7.11(d, J=2.4Hz, 1H), 6.82(d d, J=2.8Hz, J=8.8Hz, 1H), 4.85(bs, 1H), 4.72(t, J=4.8Hz, 1H), 4.01(t, J=4.8Hz, 2H), 3 .72(q, J=4.4Hz, 2H), 3.61(s, 3H), 3.53(q, J=5.6Hz, 2H), 3.37-3.33(m, 2H);LC-MS:m / z 412.0(M+1) + .

[0383] Example 104. Synthesis of 2-((6-(2-hydroxyethoxy)benzo[d]oxazol-2-yl)amino)-N-(2-(2-hydroxyethoxy)ethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide [ka] The title compound was synthesized using the same procedure as followed in step-e of Example 6 using 2-((6-(2-hydroxyethoxy)benzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid and 2-(2-aminoethoxy)ethan-1-ol as starting materials. The crude product was purified by Combiflash chromatography using 10% methanol in DCM as eluent to give the title compound (yield: 18%). 1H NMR (400MHz, DMSO-d6): δ12.05(bs, 1H), 8.41(bs, 1H), 8.04(s, 1H), 7.74(d, J=8.4Hz, 1H), 7.45(d, J=8.4Hz, 1H), 7.35(d, J=8.8Hz, 1H), 7 .11(s, 1H), 6.82(d, J=6.8Hz, 1H), 4.61(bs, 2H), 4.01(t, J=4.4Hz, 2H), 3.72(t, J=4.8Hz, 2H), 3.66(s, 3H), 3.57-3.43(m, 8H);LC-MS:m / z 456.3(M+1) + .

[0384] Example 105. Synthesis of N-(2-aminoethyl)-2-((6-(2-hydroxyethoxy)benzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxamide hydrochloride [ka] Step-a: Synthesis of tert-butyl (2-(2-((6-(2-hydroxyethoxy)benzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxamido)ethyl)carbamate To a stirred solution of 2-((6-(2-hydroxyethoxy)benzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid (100 mg, 0.27 mmol) in DMFA (2 mL) at 0° C. was added N-ethyldiisopropylamine (0.09 mL, 0.54 mmol) and HBTU (102 mg, 0.27 mmol). The reaction mixture was stirred for 30 min, followed by the addition of tert-butyl (2-aminoethyl)carbamate (48 mg, 0.30 mmol), and stirring was continued at RT for 16 h. Upon completion of the reaction, the reaction mixture was diluted with water (15 mL) and stirred for 15 min. The resulting solid was filtered and dried under vacuum to give the crude product, which was purified by Combiflash chromatography using 3% methanol in DCM as the eluent to give the title compound (70 mg, 50%). 1H NMR (400MHz, DMSO-d6): δ12.20(bs, 1H), 8.39(bs, 1H), 8.05(s, 1H), 7.73(d, J=8.4Hz, 1H), 7.45(d, J=8.4Hz, 1H), 7.35(d, J=8.0Hz, 1H), 7.11(d, J=2.0Hz, 1H), 6.91(bs, 1H) , 6.82(dd, J=2.0Hz, J=8.4Hz, 1H), 4.85(bs, 1H), 4.01(t, J=4.8Hz, 2H), 3.72(bs, 2H), 3.61 (s, 3H), 3.30 (2H, merged with DMSO water peak), 3.12 (d, J=6.0Hz, 2H), 1.38 (s, 9H); LC-MS: m / z 511.3(M+1) + .

[0385] Step-b: Synthesis of N-(2-aminoethyl)-2-((6-(2-hydroxyethoxy)benzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxamide hydrochloride To a stirred solution of tert-butyl (2-(2-((6-(2-hydroxyethoxy)benzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxamido)ethyl)carbamate (70 mg, 0.14 mmol) in 1,4-dioxane (3 mL) at 0° C. was added 4 M HCl in 1,4-dioxane (1 mL) and stirred at RT for 3 h. The reaction mixture was concentrated under reduced pressure, the residue was triturated with diethyl ether, and the solvent was decanted. The resulting solid was dried in vacuo to give the title compound (35 mg, 57%). 1 H NMR (400MHz, DMSO-d6): δ12.5(bs, 1H), 8.78(s, 1H), 8.12-8.07(m, 4H), 7.90(d, J=8.0Hz, 1H), 7.56(d, J=8.4Hz, 1H), 7.36(d, J=8.4Hz, 1 LC-MS:m / z 411.2(M+1) + .

[0386] Example 106. Synthesis of N-(2-((4,5-dihydro-1H-imidazol-2-yl)amino)ethyl)-2-((6-(2-hydroxyethoxy)benzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxamide [ka] The title compound was synthesized using the same procedure as that followed in step-e of Example 6 using 2-((6-(2-hydroxyethoxy)benzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid and N1-(4,5-dihydro-1H-imidazol-2-yl)ethane-1,2-diamine as starting materials (yield: 58%). 1 H NMR (400MHz, DMSO-d6): δ8.73(bs, 1H), 8.49(s, 1H), 8.05(s, 1H), 7.75(d, J=8 .4Hz, 1H), 7.41(d, J=8.0Hz, 1H), 7.31(d, J=8.4Hz, 1H), 7.08(d, J=2.0Hz, 1H), 6.79(dd, J=1.6Hz, J=8.0Hz, 1H), 4.86(bs, 1H), 4.00(t, J=4.8Hz, 2H), 3.72(b s, 2H), 3.60-3.55 (m, 7H), 3.43 (bs, 2H), 3.30 (2H, merged with DMSO water peak); LC-MS: m / z 479.2(M+1) + .

[0387] Examples 107 and 108. Synthesis of 2-((5-fluoro-6-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid and 2-((5-fluoro-6-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-N-(2-hydroxyethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide [ka] Step-a: Synthesis of 4-fluoro-2-nitro-5-(trifluoromethyl)phenol To a solution of 4-fluoro-3-(trifluoromethyl)phenol (1 g, 5.6 mmol) in acetic acid (20 mL) was added dropwise 60% aqueous nitric acid solution (3 mL) in acetic acid (5 mL) at 10-15 °C. The reaction mixture was stirred at RT for 2 h. The mixture was then poured into ice-water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with water (2 × 50 mL), brine solution (30 mL), dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by Combiflash chromatography using 5% EtOAc in hexane as the eluent to give the title compound (700 mg, 22%). 1 H NMR (400MHz, DMSO-d6): δ11.71 (bs, 1H), 8.14 (d, J=10.4Hz, 1H), 7.44 (d, J=5.6Hz, 1H); LC-MS: m / z 224.0 (M-1) - .

[0388] Step-b: Synthesis of 2-amino-4-fluoro-5-(trifluoromethyl)phenol The title compound was synthesized using the same procedure as followed for compound 1e using 4-fluoro-2-nitro-5-(trifluoromethyl)phenol as starting material (yield: 82%). 1 H NMR (400MHz, DMSO-d6): δ9.54 (s, 1H), 6.78 (d, J=7.2Hz, 1H), 6.48 (d, J=13.2Hz, 1H), 5.5 (bs, 2H).

[0389] Step-c: Synthesis of 5-fluoro-6-(trifluoromethyl)benzo[d]oxazole-2-thiol The title compound was synthesized using the same procedure as followed in step-c of Example 32 using 2-amino-4-fluoro-5-(trifluoromethyl)phenol as starting material (yield: 82%). 1H NMR (400MHz, DMSO-d6): δ14.4 (bs, 1H), 8.10 (d, J=5.6Hz, 1H), 7.43 (d, J=9.6Hz, 1H); LC-MS: m / z 236.0 (M-1) - .

[0390] Step-d: Synthesis of 2-chloro-5-fluoro-6-(trifluoromethyl)benzo[d]oxazole The title compound was synthesized using the same procedure as followed in step-d of Example 32, using 5-fluoro-6-(trifluoromethyl)benzo[d]oxazole-2-thiol as starting material and stirring for 2 hours (yield: 99%). 1 H NMR (400MHz, DMSO-d6): δ7.74 (d, J=6.0Hz, 1H), 7.30 (d, J=10.0Hz, 1H).

[0391] Step-e: Synthesis of ethyl 2-((5-fluoro-6-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylate The title compound was synthesized using the same procedure as that followed in step-e of Example 32 using ethyl 2-amino-1-methyl-1H-benzo[d]imidazole-5-carboxylate and 2-chloro-5-fluoro-6-(trifluoromethyl)benzo[d]oxazole as starting materials (yield: 52%). 1 H NMR (400MHz, DMSO-d6): δ12.43(bs, 1H), 8.22(d, J=1.6Hz, 1H), 7.88(dd, J=1.6Hz, J=8.4Hz, 1H), 7.83(d, J=6.0Hz, 1H) ), 7.75(d, J=8.4Hz, 1H), 7.41(d, J=11.2Hz, 1H), 4.33(q, J=7.2Hz, 2H), 3.66(s, 3H), 1.35(t, J=7.2Hz, 3H);LC-MS:m / z 423.0(M+1) + .

[0392] Step-f: Synthesis of 2-((5-fluoro-6-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid The title compound was synthesized using the same procedure as that followed for compound 1h using ethyl 2-((5-fluoro-6-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylate as starting material (yield: 86%). 1 H NMR (400MHz, DMSO-d6): δ12.4(bs, 2H), 8.20(s, 1H), 7.89(d, J=8.4Hz, 1H), 7.84(d, LC-MS:m / z 395.1(M+1) + .

[0393] Step-g: Synthesis of 2-((5-fluoro-6-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-N-(2-hydroxyethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as in step-e of Example 6, using 2-((5-fluoro-6-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid and 2-aminoethan-1-ol as starting materials (yield: 72%). 1 H NMR (400MHz, DMSO-d6): δ12.35(bs, 1H), 8.40(bs, 1H), 8.09(s, 1H), 7.84-7.79(m, 2H), 7.54(d, J=8.4Hz, 1 LC-MS:m / z 438.0(M+1) + .

[0394] Example 109. Synthesis of N-(2-methoxyethyl)-1-methyl-2-(oxazolo[5,4-b]pyridin-2-ylamino)-1H-benzo[d]imidazole-5-carboxamide [ka] Step-a: Synthesis of 3-aminopyridin-2-ol The title compound was synthesized using the same procedure as followed for compound 1e using 3-nitropyridin-2-ol as starting material (yield: 85%). 1 H NMR (400MHz, DMSO-d6): δ11.3(bs, 1H), 6.59(dd, J=2.0Hz, J=6.8Hz, 1H), 6.43(dd, J=2.4Hz, J=6.8Hz, 1H), 5.98(t, J=6.0Hz, 1H), 4.97(bs, 2H); LC-MS: m / z 111.25(M+1) + .

[0395] Step-b: Synthesis of oxazolo[5,4-b]pyridine-2-thiol To a solution of 3-aminopyridin-2-ol (500 mg, 4.5 mmol) in THF (15 mL) at RT, thiophosgene (0.41 mL, 5.4 mmol) was added slowly over a period of 15 minutes and stirred at RT for 16 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (9 mL) and concentrated. The aqueous layer was basified with 10 N sodium hydroxide solution (5 mL) and extracted with ethyl acetate (2 × 30 mL). The aqueous layer was acidified with 1 N HCl and extracted with ethyl acetate (2 × 100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue that was purified by Combiflash chromatography using 2% methanol in DCM as the eluent to give the title compound (200 mg, 29%). LC-MS: m / z 153.15 (M+1) + .

[0396] Step-c: Synthesis of 2-chlorooxazolo[5,4-b]pyridine To a solution of oxazolo[5,4-b]pyridine-2-thiol (200 mg, 1.31 mmol) in thionyl chloride (5 mL) at room temperature was added N,N-dimethylformamide (1 drop) and the reaction mixture was refluxed for 2 h. The reaction mixture was concentrated under reduced pressure and the crude compound (220 mg) was used in the next step without further purification. 1 H NMR (400MHz, DMSO-d6): δ8.40 (dd, J=1.6Hz, J=4.8Hz, 1H), 8.26 (dd, J=1.2Hz, J=7.6Hz, 1H), 7.56-7.53 (m, 1H); LC-MS: m / z 155.1 (M+1) + .

[0397] Step-d: Synthesis of ethyl 1-methyl-2-(oxazolo[5,4-b]pyridin-2-ylamino)-1H-benzo[d]imidazole-5-carboxylate The title compound was synthesized using the same procedure as that followed in step-e of Example 32 using ethyl 2-amino-1-methyl-1H-benzo[d]imidazole-5-carboxylate and 2-chlorooxazolo[5,4-b]pyridine as starting materials (yield: 20%). 1 H NMR (400MHz, DMSO-d6): δ8.24(s, 1H), 8.02(d, J=5.2Hz, 1H), 7.89(dd, J=1.6Hz, J=8.8Hz, 1H), 7.79(d, J=7.2Hz, 1 LC-MS:m / z 338.15(M+1) + .

[0398] Step-e: Synthesis of 1-methyl-2-(oxazolo[5,4-b]pyridin-2-ylamino)-1H-benzo[d]imidazole-5-carboxylic acid The title compound was synthesized using the same procedure as that followed for compound 1h using ethyl 1-methyl-2-(oxazolo[5,4-b]pyridin-2-ylamino)-1H-benzo[d]imidazole-5-carboxylate as starting material (yield: 54%). 1 H NMR (400MHz, DMSO-d6): δ12.8(bs, 1H), 12.4(bs, 1H), 8.20(s, 1H), 8.01(d, J=5.2Hz, 1H), 7.89(d, J= LC-MS:m / z 310.1(M+1) + .

[0399] Step-f: Synthesis of N-(2-methoxyethyl)-1-methyl-2-(oxazolo[5,4-b]pyridin-2-ylamino)-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed for compound 1i using 1-methyl-2-(oxazolo[5,4-b]pyridin-2-ylamino)-1H-benzo[d]imidazole-5-carboxylic acid and 2-methoxyethylamine as starting materials (yield: 38%). 1 H NMR (400MHz, DMSO-d6): δ12.38(bs, 1H), 8.47(s, 1H), 8.09(s, 1H), 8.0(d, J=3.6Hz, 1H), 7.79-7.77(m, 2H), 7.52(d, J=8.4Hz, 1H), 7.27-7.24(m, 1H), 3.66(s, 3H), 3.48-3.44(m, 4H), 3.28(s, 3H);LC-MS:m / z 367.2(M+1) + .

[0400] Example 110. Synthesis of N-(2-hydroxyethyl)-1-methyl-2-(oxazolo[5,4-b]pyridin-2-ylamino)-1H-benzo[d]imidazole-5-carboxamide [ka] The title compound was synthesized using the same procedure as in step-e of Example 6, using 1-methyl-2-(oxazolo[5,4-b]pyridin-2-ylamino)-1H-benzo[d]imidazole-5 carboxylic acid and 2-aminoethan-1-ol as starting materials (yield: 51%). 1 H NMR (400MHz, DMSO-d6): δ12.3(bs, 1H), 8.38(bs, 1H), 8.09(s, 1H), 8.01(d, J=4.4Hz, 1H), 7.80-7.76(m, 2H), 7.52( d, J=8.4Hz, 1H), 7.25(t, J=6.8Hz, 1H), 4.72(bs, 1H), 3.66(s, 3H), 3.53(bs, 2H), 3.35(q, J=6.0Hz, 2H);LC-MS:m / z 353.0(M+1) + .

[0401] Examples 111 and 112. Synthesis of 1-methyl-2-(oxazolo[4,5-b]pyridin-2-ylamino)-1H-benzo[d]imidazole-5-carboxylic acid and N-(2-methoxyethyl)-1-methyl-2-(oxazolo[4,5-b]pyridin-2-ylamino)-1H-benzo[d]imidazole-5-carboxamide [ka] Step-a: Synthesis of oxazolo[4,5-b]pyridine-2-thiol To a solution of 2-aminopyridin-3-ol (2.2 g, 20 mmol) in ethanol (40 mL) at room temperature was added potassium hydroxide (1.68 g, 30 mmol) and carbon disulfide (15 mL). The reaction mixture was refluxed for 12 h, then cooled to room temperature, diluted with water (75 mL), and neutralized with glacial acetic acid. A solid precipitated, which was filtered and dried under vacuum to give the title compound (1.8 g, 59%). 1 H NMR (400MHz, DMSO-d6): δ14.5(s, 1H), 8.23(dd, J=1.2Hz, J=5.2Hz, 1H), 7.88(dd, J=1.6Hz, J=8.4Hz, 1H), 7.29-7.26(m, 1H); LC-MS: m / z 153.1(M+1) + .

[0402] Step-b: Synthesis of 2-chlorooxazolo[4,5-b]pyridine The title compound was synthesized using the same procedure as that followed in step d of Example 32, using oxazolo[4,5-b]pyridine-2-thiol as the starting material and heating for 2 h (yield: 100%); 1 H NMR (400MHz, DMSO-d6): δ8.01 (dd, J=1.6Hz, J=5.6Hz, 1H), 7.61 (dd, J=1.2Hz, J=8.0Hz, 1H), 7.10-7.06 (m, 1H); LC-MS: m / z 155.01 (M+1) + .

[0403] Step-c: Synthesis of ethyl 1-methyl-2-(oxazolo[4,5-b]pyridin-2-ylamino)-1H-benzo[d]imidazole-5-carboxylate The title compound was synthesized using the same procedure as that followed in step-e of Example 32 using ethyl 2-amino-1-methyl-1H-benzo[d]imidazole-5-carboxylate and 2-chlorooxazolo[4,5-b]pyridine as starting materials (yield: 32%). 1 H NMR (400MHz, DMSO-d6): δ7.98(s, 1H), 7.94(d, J=4.4Hz, 1H), 7.62(d, J=9.2Hz, 1H), 7.36(d, J=7.2Hz, 1H) , 7.21-7.18(m, 1H), 6.77-6.74(m, 1H), 4.32-4.26(m, 2H), 3.57(s, 3H), 1.38(t, J=6.8Hz, 3H);LC-MS:m / z 338.15(M+1) + .

[0404] Step-d: Synthesis of 1-methyl-2-(oxazolo[4,5-b]pyridin-2-ylamino)-1H-benzo[d]imidazole-5-carboxylic acid The title compound was synthesized using the same procedure as that followed for compound 1h using ethyl 1-methyl-2-(oxazolo[4,5-b]pyridin-2-ylamino)-1H-benzo[d]imidazole-5-carboxylate as starting material (yield: 73%). 1 H NMR (400MHz, DMSO-d6): δ12.83(bs, 1H), 12.44(bs, 1H), 8.26-8.23(m, 2H), 7.89(d, J=8.4Hz, 1H), 7.78(d, J=7.6Hz, 1H), 7.75(d, J=8.4Hz, 1H), 7.12-7.09(m, 1H), 3.72(s, 3H);LC-MS:m / z 310.15(M+1) + .

[0405] Step-e: Synthesis of N-(2-methoxyethyl)-1-methyl-2-(oxazolo[4,5-b]pyridin-2-ylamino)-1H-benzo[d]imidazole-5-carboxamide Synthesized using the same procedure as followed for compound 1i using 1-methyl-2-(oxazolo[4,5-b]pyridin-2-ylamino)-1H-benzo[d]imidazole-5-carboxylic acid and 2-methoxyethylamine as starting materials (yield: 53%). 1 H NMR (400MHz, DMSO-d6): δ12.4(bs, 1H), 8.48(bs, 1H), 8.23(d, J=4.4Hz, 1H), 8.13(s, 1H), 7.79-7.75(s , 2H), 7.53(d, J=8.4Hz, 1H), 7.11-7.08(m, 1H), 3.67(s, 3H), 3.48-3.44(m, 4H), 3.29(s, 3H);LC-MS:m / z 367.2(M+1) + .

[0406] Example 113. Synthesis of N-(2-hydroxyethyl)-1-methyl-2-((5-(trifluoromethyl)oxazolo[5,4-b]pyridin-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide [ka] Step-a: Synthesis of 3-nitro-6-(trifluoromethyl)pyridin-2-ol To a solution of 2-nitroacetamide (5.0 g, 47.8 mmol) in ethanol (25 mL) at RT was added ethyl (E)-5,5,5-trifluoro-4-oxopent-2-enoate (11.24 g, 57.3 mmol) and 25% sodium ethoxide in ethanol (25.9 mL, 95.3 mmol). The reaction mixture was stirred at 90° C. for 2 hours. The reaction mixture was cooled to RT, diluted with water (50 mL), acidified with 1N HCl, and extracted with EtOAc (2×150 mL). The combined organic layers were washed with brine solution (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give a residue that was purified by Combiflash chromatography using 50% EtOAc in hexane as the eluent to give the title compound (1.5 g). 1 H NMR (400MHz, DMSO-d6): δ8.58 (d, J=8.4Hz, 1H), 7.84 (bs, 1H), 7.51 (d, J=7.6Hz, 1H).

[0407] Step-b: Synthesis of 3-amino-6-(trifluoromethyl)pyridin-2-ol The title compound was synthesized using the same procedure as followed for compound 1e using 3-nitro-6-(trifluoromethyl)pyridin-2-ol as starting material (yield: 82%). 1 H NMR (400MHz, DMSO-d6): δ11.7 (bs, 1H), 6.88 (bs, 1H), 6.69 (bs, 1H), 5.60 (s, 2H); LC-MS: m / z 179.1 (M+1) + .

[0408] Step-c: Synthesis of 5-(trifluoromethyl)oxazolo[5,4-b]pyridine-2-thiol The title compound was synthesized using the same procedure as followed in step-b of Example 109 using 3-amino-6-(trifluoromethyl)pyridin-2-ol as starting material (yield: 65%). 1H NMR (400MHz, DMSO-d6): δ7.81-7.75 (m, 2H); LC-MS: m / z 219.0 (M-1).

[0409] Step-d: Synthesis of 2-chloro-5-(trifluoromethyl)oxazolo[5,4-b]pyridine The title compound was synthesized using the same procedure as that followed for step-d of Example 32 using 5-(trifluoromethyl)oxazolo[5,4-b]pyridine-2-thiol as the starting material (yield: 74%). The crude compound was used in the next step without further purification.

[0410] Step-e: Synthesis of ethyl 1-methyl-2-((5-(trifluoromethyl)oxazolo[5,4-b]pyridin-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylate The title compound was synthesized using the same procedure as in step-e of Example 32 using ethyl 2-amino-1-methyl-1H-benzo[d]imidazole-5-carboxylate and 2-chloro-5-(trifluoromethyl)oxazolo[5,4-b]pyridine as starting materials (yield: 43%). 1 H NMR (400MHz, DMSO-d6): δ12.5(bs, 1H), 8.27(s, 1H), 7.93-7.89(m, 2H), 7.75(d, J=12.4Hz, 1H) ), 7.62(d, J=8.4Hz, 1H), 4.34(q, J=6.8Hz, 2H), 3.71(s, 3H), 1.35(t, J=7.2Hz, 3H);LC-MS:m / z 406.1(M+1) + .

[0411] Step-f: Synthesis of 1-methyl-2-((5-(trifluoromethyl)oxazolo[5,4-b]pyridin-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid The title compound was synthesized using the same procedure as that followed for compound 1h using ethyl 1-methyl-2-((5-(trifluoromethyl)oxazolo[5,4-b]pyridin-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylate as starting material (yield: 75%); 1 H NMR (400MHz, DMSO-d6): δ8.20(bs, 1H), 7.74-7.70(m, 2H), 7.55(d, J=6.8Hz, 1H), 7.09(d, J=8.4Hz, 1H), 3.62(s, 3H); LC-MS: m / z 378.1(M+1) + .

[0412] Step-g: Synthesis of N-(2-hydroxyethyl)-1-methyl-2-((5-(trifluoromethyl)oxazolo[5,4-b]pyridin-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as followed in step-e of Example 6 using 1-methyl-2-((5-(trifluoromethyl)oxazolo[5,4-b]pyridin-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid and 2-aminoethan-1-ol as starting materials (yield: 28%); 1 H NMR (400MHz, DMSO-d6): δ8.22(bs, 1H), 7.78(bs, 1H), 7.60(d, J=8.0Hz, 1H), 7.51(bs, 1H), 7.31(d, J=8 .4Hz, 2H), 4.70(t, J=5.2Hz, 1H), 3.67(s, 3H), 3.50(q, J=5.2Hz, 2H), 3.36(q, J=6.0Hz, 2H);LC-MS:m / z 421.1(M+1) + .

[0413] Example 114. Synthesis of N-(2-(2-hydroxyethoxy)ethyl)-1-methyl-2-(thiazolo[4,5-b]pyrazin-2-ylamino)-1H-benzo[d]imidazole-5-carboxamide [ka] Step-a: Synthesis of 114a To a stirred solution of pyrazin-2-amine (2.0 mg, 21.0 mmol) in 1,4-dioxane (20 mL) at room temperature, O-ethylcarbonyl isothiocyanatidate (3.03 g, 23.1 mmol) was added and stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo. Ethyl acetate was added to the residue, and the precipitated solid was filtered and dried in vacuo to give the title compound (2.0 g, 42%). 1 H NMR (400MHz, DMSO-d6): δ12.07(s, 1H), 11.76(s, 1H), 9.67(s, 1H), 8.50(s, 2H), 4.24(q, J=7.2Hz, 2H), 1.27(t, J=7.2Hz, 3H); LC-MS: m / z 227.0(M+1) + .

[0414] Step-b: Synthesis of ethyl thiazolo[4,5-b]pyrazin-2-ylcarbamate To a stirred solution of 114a (1.8 g, 7.96 mmol) in 1,4-dioxane (9 mL) was added 6 M HCl (18 mL) and stirred for 4 h at 50° C. The reaction mixture was cooled to RT and the resulting solid was filtered and dried under vacuum to give the title compound (1.5 g, 84%). 1 H NMR (400MHz, DMSO-d6): δ12.60(bs, 1H), 8.58(d, J=3.2Hz, 1H), 8.44(d, J=2.4Hz, 1H), 4.29(q, J=6.8Hz, 2H), 1.30(t, J=7.6Hz, 3H); LC-MS: m / z 225.0(M+1) + .

[0415] Step-c: Synthesis of thiazolo[4,5-b]pyrazin-2-amine To a solution of ethyl thiazolo[4,5-b]pyrazin-2-ylcarbamate (500 mg, 2.23 mmol) in water (5 mL) was added sodium hydroxide (267 mg, 6.69 mmol) and heated at 120° C. for 16 h. The reaction mixture was cooled to RT and acidified with 1N HCl. The resulting solid was filtered and dried under vacuum to give the title compound (300 mg, 88%). 1H NMR (400MHz, DMSO-d6): δ8.42(s, 2H), 8.23(d, J=2.8Hz, 1H), 8.03(d, J=2.8Hz, 1H); LC-MS: m / z 153.1(M+1) + .

[0416] Step-d: Synthesis of ethyl 1-methyl-2-(thiazolo[4,5-b]pyrazin-2-ylamino)-1H-benzo[d]imidazole-5-carboxylate The title compound was synthesized using the same procedure as that followed for compound 2c using ethyl 3-amino-4-(methylamino)benzoate and thiazolo[4,5-b]pyrazin-2-amine as starting materials (yield: 9%). 1 H NMR (400MHz, DMSO-d6): δ12.63(bs, 1H), 8.44(d, J=2.4Hz, 1H), 8.33(s, 1H), 8.23(d, J=2.8Hz, 1H), 7.91(dd, J=1 .2Hz, J=8.4Hz, 1H), 7.60(d, J=8.4Hz, 1H), 4.33(q, J=7.2Hz, 2H), 3.67(s, 3H), 1.35(d, J=7.2Hz, 3H);LC-MS:m / z 355.0(M+1) + .

[0417] Step-e: Synthesis of 1-methyl-2-(thiazolo[4,5-b]pyrazin-2-ylamino)-1H-benzo[d]imidazole-5-carboxylic acid To a stirred solution of ethyl 1-methyl-2-(thiazolo[4,5-b]pyrazin-2-ylamino)-1H-benzo[d]imidazole-5-carboxylate (60 mg, 0.17 mmol) in a solvent mixture of THF (1 mL), ethanol (1 mL), and water (0.5 mL) was added lithium hydroxide monohydrate (35 mg, 0.85 mmol). The reaction mixture was stirred at 60° C. for 16 h. The reaction mixture was cooled to RT and concentrated under reduced pressure. The crude material was used directly in the next step (40 mg). LC-MS: m / z 326.95 (M+1) + .

[0418] Step-f: Synthesis of N-(2-(2-hydroxyethoxy)ethyl)-1-methyl-2-(thiazolo[4,5-b]pyrazin-2-ylamino)-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as in step-e of Example 6, using 1-methyl-2-(thiazolo[4,5-b]pyrazin-2-ylamino)-1H-benzo[d]imidazole-5-carboxylic acid and 2-(2-aminoethoxy)ethan-1-ol as starting materials (yield: 59%). 1 H NMR (400MHz, DMSO-d6): δ12.60(bs, 1H), 8.46-8.41(m, 2H), 8.20-8.14(m, 2H), 7.78( s, 1H), 7.56(s, 1H), 4.60(t, J=4.8Hz, 1H), 3.70(s, 3H), 3.59-3.43(m, 8H);LC-MS:m / z 414.05(M+1) + .

[0419] Examples 115 and 116. Synthesis of 2-((6-cyclopropylbenzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid and 2-((6-cyclopropylbenzo[d]]oxazol-2-yl)amino)-N-(2-methoxyethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide [ka] Step-a: Synthesis of 5-cyclopropyl-2-nitrophenol To a stirred solution of 5-bromo-2-nitrophenol (2.0 g, 9.17 mmol) and cyclopropylboronic acid (1.02 g, 11.92 mmol) in toluene (40 mL) was added potassium phosphate (6.81 g, 32.1 mmol), tricyclohexylphosphine (0.25 g, 0.91 mmol), and water (2 mL). The reaction mixture was purged with nitrogen gas for 10 minutes, and then palladium diacetate (0.1 g, 0.45 mmol) was added to the reaction mixture, which was heated at 100 °C for 16 hours. The reaction mixture was cooled to room temperature, filtered through a bed of Celite, and washed with ethyl acetate (150 mL). The organic layer was washed with brine solution (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give a residue that was purified by Combiflash chromatography using 100% hexane as the eluent to give the title compound (0.9 g, 55%). 1 H NMR (400MHz, DMSO-d6): δ10.72(bs, 1H), 7.82(d, J=8.8Hz, 1H), 6.82(d, J=2.0Hz, 1H), 6. 68(dd, J=2.0Hz, J=8.8Hz, 1H), 1.99-1.94(m, 1H), 1.08-1.03(m, 2H), 0.78-0.74(m, 2H).

[0420] Step-b: Synthesis of 2-amino-5-cyclopropylphenol To a solution of 5-cyclopropyl-2-nitrophenol (1.75 g, 11.4 mmol) in ethanol (4 mL) and THF (4 mL) was added PtO (12 mg). The reaction mixture was stirred under a hydrogen gas balloon for 4 hours. It was filtered through a celite bed and concentrated in vacuo to give the title compound (250 mg, 100%). 1 H NMR (400MHz, DMSO-d6): δ8.99 (bs, 1H), 6.61-6.59 (m, 1H), 6.45 (d, J=2.0Hz, 1H), 6.43 -6.34(m, 1H), 5.35(bs, 2H), 1.74-1.65(m, 1H), 0.80-0.75(m, 2H), 0.48-0.44(m, 2H).

[0421] Step-c: Synthesis of 6-cyclopropylbenzo[d]oxazole-2-thiol The title compound was synthesized using the same procedure as followed in step-c of Example 32 using 2-amino-5-cyclopropylphenol as starting material (yield: 90%). 1 H NMR (400MHz, DMSO-d6): δ13.72(bs, 1H), 7.22(s, 1H), 7.11-7.04(m, 2H), 2.02-1.98(m, 1H), 0.98-0.94(m, 2H), 0.71-0.67(m, 2H); LC-MS: m / z 190.05(M-1).

[0422] Step-d: Synthesis of 2-chloro-6-cyclopropylbenzo[d]oxazole The title compound was synthesized using the same procedure as followed for step-d of Example 32 using 6-cyclopropylbenzo[d]oxazole-2-thiol as starting material (yield: 98%). 1 H NMR (400MHz, DMSO-d6): δ7.59(d, J=8.0Hz, 1H), 7.46(s, 1H), 7.18(d, J=8.4Hz, 1H), 2.09-2.01(m, 1H), 1.02-0.99(m, 2H), 0.75-0.74(m, 2H); LC-MS: m / z 194.0(M+1) + .

[0423] Step-e: Synthesis of ethyl 2-((6-cyclopropylbenzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylate The title compound was synthesized using the same procedure as that followed in step-e of Example 32 using ethyl 2-amino-1-methyl-1H-benzo[d]imidazole-5-carboxylate and 2-chloro-6-cyclopropylbenzo[d]oxazole as starting materials (yield: 27%). 1H NMR (400MHz, DMSO-d6): δ12.3(bs, 1H), 8.22(s, 1H), 7.87(d, J=8.4Hz, 1H), 7.50(d, J=8.4Hz, 1H), 7.33(d, J=8.4Hz, 1H), 7.15(s, 1H), 6.9 7(d. 377.2(M+1) + .

[0424] Step-f: Synthesis of 2-((6-cyclopropylbenzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid The title compound was synthesized using the same procedure as that followed for compound 1h using ethyl 2-((6-cyclopropylbenzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylate as starting material (yield: 81%). 1 H NMR (400MHz, DMSO-d6): δ13.5-11.2(bs, 2H), 8.18(s, 1H), 7.91(d, J=8.4Hz, 1H), 7.58(d, J=8.4Hz, 1H), 7.34(d, J=8.4Hz, 1H), 7.22(s, 1H), 7.04(d, J=8.4Hz, 1H), 3.67(s, 3H), 2.06-2.02(m, 1H), 1.00-0.95(m, 2H), 0.72-0.68(m, 2H);LC-MS:m / z 349.0(M+1) + .

[0425] Step-g: Synthesis of 2-((6-cyclopropylbenzo[d]oxazol-2-yl)amino)-N-(2-methoxyethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed for compound 1i using 2-((6-cyclopropylbenzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid and 2-methoxyethylamine as starting materials (yield: 46%); 1 H NMR (400MHz, DMSO-d6): δ12.2(bs, 1H), 8.44(t, J=5.2Hz, 1H), 8.06(d, J=1.6H) z, 1H), 7.75(d, J=8.4Hz, 1H), 7.46(d, J=8.4Hz, 1H), 7.33(d, J=8.0Hz, 1H), 7.1 4(s, 1H), 6.96(dd, J=1.6Hz, J=8.4Hz, 1H), 3.62(s, 3H), 3.48-3.43(m, 4H), 3. 28(s, 3H), 2.02-1.98(m, 1H), 0.96-0.92(m, 2H), 0.70-0.66(m, 2H);LC-MS:m / z 406.2(M+1) + .

[0426] Example 117. Synthesis of N-(2-(2-hydroxyethoxy)ethyl)-1-methyl-2-((7-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide [ka] Step-a: Synthesis of 2-nitro-6-(trifluoromethyl)phenol To 3 M sulfuric acid (25 mL) stirred at RT, sodium nitrite (1.73 g, 20.37 mmol) and sodium nitrite (100 mg) were added, followed by a solution of 2-(trifluoromethyl)phenol (3.0 g, 18.52 mmol) in DCM (40 mL) and stirred for 16 h. The mixture was poured into ice water (50 mL) and extracted with DCM (2 × 100 mL). The combined organic layers were washed with water (50 mL), brine solution (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by Combiflash chromatography using 5% ethyl acetate in hexane as the eluent to give the title compound (1.3 g, 40%). 1H NMR (400MHz, DMSO-d6): δ11.34(bs, 1H), 8.27(dd, J=1.6Hz, J=8.4Hz, 1H), 8.00(dd, J=1.2Hz, J=7.6Hz, 1H), 7.21-7.17(m, 1H).

[0427] Step-b: Synthesis of 2-amino-6-(trifluoromethyl)phenol The title compound was synthesized using the same procedure as followed for compound 1e, using 2-nitro-6-(trifluoromethyl)phenol as starting material and stirring for 4 hours (yield: 90%). 1 H NMR (400MHz, DMSO-d6): δ6.88-6.84 (m, 1H), 6.75-6.70 (m, 2H), 6.50 (bs, 2H); LC-MS: m / z 178.05 (M+1) + .

[0428] Step-c: Synthesis of 7-(trifluoromethyl)benzo[d]oxazole-2(3H)-thione The title compound was synthesized using the same procedure as followed in step-c of Example 32 using 2-amino-6-(trifluoromethyl)phenol as starting material (yield: 65%). 1 H NMR (400MHz, DMSO-d6): δ14.28 (bs, 1H), 7.59-7.53 (m, 2H), 7.49-7.45 (m, 1H); LC-MS: m / z 218.1 (M-1) - .

[0429] Step-d: Synthesis of 2-chloro-7-(trifluoromethyl)benzo[d]oxazole The title compound was synthesized using the same procedure as followed in step-d of Example 32, using 7-(trifluoromethyl)benzo[d]oxazole-2(3H)-thione as starting material and stirring for 2 hours (yield: 84%). 1 H NMR (400MHz, DMSO-d6): δ8.11 (d, J=8.0Hz, 1H), 7.84 (d, J=7.6Hz, 1H), 7.64 (t, J=7.2Hz, 1H).

[0430] Step-e: Synthesis of ethyl 1-methyl-2-((7-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylate The title compound was synthesized using the same procedure as that followed in step-e of Example 32 using ethyl 2-amino-1-methyl-1H-benzo[d]imidazole-5-carboxylate and 2-chloro-7-(trifluoromethyl)benzo[d]oxazole as starting materials (yield: 36%). 1 H NMR (400MHz, DMSO-d6): δ12.41(s, 1H), 8.26(d, J=1.6Hz, 1H), 7.90(dd, J=1.6Hz, J=8.4Hz, 1H), 7.75(d, J=6.4Hz, 1 LC-MS:m / z 405.0(M+1) + .

[0431] Step-f: Synthesis of 1-methyl-2-((7-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid The title compound was synthesized using the same procedure as that followed for compound 1h using ethyl 1-methyl-2-((7-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole as starting material (yield: 75%). 1 H NMR (400MHz, DMSO-d6): δ12.83(bs, 1H), 12.40(bs, 1H), 8.22(d, J=1.6Hz, 1H), 7.89(dd, J=1.2Hz, J= LC-MS:m / z 377.0(M+1) + .

[0432] Step-g: Synthesis of N-(2-(2-hydroxyethoxy)ethyl)-1-methyl-2-((7-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed in step-e of Example 6 using 1-methyl-2-((7-(trifluoromethyl)benzo[d]oxazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxylic acid and 2-(2-aminoethoxy)ethan-1-ol as starting materials (yield: 61%). 1 H NMR (400MHz, DMSO-d6): δ12.30(bs, 1H), 8.46(t, J=5.2Hz, 1H), 8.10(d, J=1.2Hz, 1H), 7.80-7.73(m, 2 LC-MS:m / z 464.1(M+1) + .

[0433] Example 118. Synthesis of N-(2-(2-hydroxyethoxy)ethyl)-2-((1-methyl-1H-benzo[d]imidazol-2-yl)amino)benzo[d]oxazole-5-carboxamide [ka] Step-a: Synthesis of N-methyl-2-nitroaniline To a solution of 1-fluoro-2-nitrobenzene (1.0 g, 7.08 mmol) in DMFA (3 mL) at RT, methylamine (1 mL, 40% aqueous solution, 35.4 mmol) was added and the reaction mixture was stirred at 60° C. for 16 h. The reaction mixture was cooled to RT, diluted with cold water (50 mL), and stirred for 2 h. The resulting solid was filtered and dried under vacuum to give the product as a yellow solid (700 mg, 75%). 1H NMR (400MHz, DMSO-d6): δ8.14 (bs, 1H), 8.06 (dd, J=1.2Hz, J=8.8Hz, 1H), 7.57-7.53 (m, 1H), 6.98(d, J=8.8Hz, 1H), 6.69-6.66(m, 1H), 2.96(d, J=4.8Hz, 3H);LC-MS:m / z 153.0(M+1) + .

[0434] Step-b:N 1 Synthesis of methylbenzene-1,2-diamine The title compound was synthesized using the same procedure as followed for compound 1e using N-methyl-2-nitroaniline as starting material (yield: 98%). 1 H NMR (400MHz, DMSO-d6): δ6.52-6.48(m, 2H), 6.41-6.34(m, 2H), 4.45(bs, 2H), 2.68(s, 3H); LC-MS: m / z 123.2(M+1) + .

[0435] Step-c: Synthesis of 1-methyl-1H-benzo[d]imidazol-2-amine N as starting material 1- The title compound was synthesized using the same procedure as followed for compound 1f using methylbenzene-1,2-diamine (yield: 83%). 1 H NMR (400MHz, DMSO-d6): δ7.11-7.09(m, 2H), 6.94-6.87(m, 2H), 6.37(s, 2H), 3.78(s, 3H).

[0436] Step-d: Synthesis of ethyl 2-((1-methyl-1H-benzo[d]imidazol-2-yl)amino)benzo[d]oxazole-5-carboxylate The title compound was synthesized using the same procedure as that followed in step-e of Example 32 using 1-methyl-1H-benzo[d]imidazol-2-amine and ethyl 2-chlorobenzo[d]oxazole-5-carboxylate as starting materials (yield: 31%). 1H NMR (400MHz, DMSO-d6): δ12.20(bs, 1H), 7.99(d, J=1.6Hz, 1H), 7.76-7.74(m, 1H), 7.64-7.62(m, 1H), 7.52(d, J=8.0 Hz, 1H), 7.45-7.43(m, 1H), 7.26-7.23(m, 2H), 4.32(q, J=7.6Hz, 2H), 3.63(s, 3H), 1.35(t, J=6.8Hz, 3H);LC-MS:m / z 336.95(M+1) + .

[0437] Step-e: Synthesis of 2-((1-methyl-1H-benzo[d]imidazol-2-yl)amino)benzo[d]oxazole-5-carboxylic acid The title compound was synthesized using the same procedure as that followed for compound 1h using ethyl 2-((1-methyl-1H-benzo[d]imidazol-2-yl)amino)benzo[d]oxazole-5-carboxylate as the starting material (yield: 78%). 1 H NMR (400MHz, DMSO-d6): δ12.80(bs, 1H), 12.22(bs, 1H), 7.98(d, J=1.6Hz, 1H), 7.76(dd, J=2.0Hz, J=8.4Hz, 1H), 7.67-7.63(m, 1H), 7.52(d, J=8.4Hz, 1H), 7.47-7.45(m, 1H), 7.28-7.21(m, 2H), 3.68(s, 3H);LC-MS:m / z 309.1(M+1) + .

[0438] Step-f: Synthesis of N-(2-(2-hydroxyethoxy)ethyl)-2-((1-methyl-1H-benzo[d]imidazol-2-yl)amino)benzo[d]oxazole-5-carboxamide The title compound was synthesized using the same procedure as that followed in step-e of Example 6, using 2-((1-methyl-1H-benzo[d]imidazol-2-yl)amino)benzo[d]oxazole-5-carboxylic acid and 2-(2-aminoethoxy)ethan-1-ol as starting materials. The crude product was purified by Combiflash chromatography using 9% methanol in DCM as the eluent (yield: 64%). 1 H NMR (400MHz, DMSO-d6): δ12.30(bs, 1H), 8.48(t, J=5.2Hz, 1H), 7.92(s, 1H), 7.65-7.62( LC-MS:m / z 396.2(M+1) + .

[0439] Example 119. Synthesis of 2-(benzo[d]oxazol-2-ylamino)-N-(2-methoxyethoxy)-1-methyl-1H-benzo[d]imidazole-5-carboxamide [ka] Step-a: Synthesis of 2-(2-methoxyethoxy)isoindoline-1,3-dione To a stirred solution of N-hydroxyphthalimide (4.6 g, 28.2 mmol) in DMFA (15 mL) at RT, triethylamine (8.0 mL, 56.4 mmol) and 1-bromo-2-methoxyethane (4.0 mL, 42.3 mmol) were added. The reaction mixture was then stirred at 60° C. for 16 hours. Upon completion of the reaction (monitored by TLC), the reaction mixture was cooled to RT, diluted with cold water (100 mL), and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with cold water (2×200 mL), brine solution (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title compound (2.8 g, 45%). 1H NMR (400MHz, DMSO-d6): δ7.86(s, 4H), 4.26(t, J=4.4Hz, 2H), 3.65-3.63(m, 2H), 3.25(s, 3H); LC-MS: m / z 222.20(M+1) + .

[0440] Step-b: Synthesis of O-(2-methoxyethyl)hydroxylamine To a stirred solution of 2-(2-methoxyethoxy)isoindoline-1,3-dione (2.8 g, 12.6 mmol) in methanol (75 mL) at RT, hydrazine hydrate (0.95 g, 19.0 mmol) was added and refluxed for 4 h. The reaction mixture was then cooled to RT, filtered, and the filtrate was concentrated. The resulting residue was stirred in diethyl ether (30 mL) and filtered. The filtrate was concentrated in vacuo to give the title compound (550 mg, 48%). 1 H NMR (400MHz, DMSO-d6): δ5.50(s, 2H), 3.84-3.82(m, 2H), 3.58-3.56(m, 2H), 3.39(s, 3H).

[0441] Step-c: Synthesis of 2-(benzo[d]oxazol-2-ylamino)-N-(2-methoxyethoxy)-1-methyl-1H-benzo[d]imidazole-5-carboxamide The title compound was synthesized using the same procedure as that followed for compound 1i using 2-(benzo[d]oxazol-2-ylamino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid and O-(2-methoxyethyl)hydroxylamine as starting materials (yield: 20%). 1 H NMR (400MHz, DMSO-d6): δ12.28(s, 1H), 11.73(s, 1H), 8.01(s, 1H), 7.64(d, J=8.3Hz, 1H), 7.48(d, J=7.8Hz, 2H), 7.44(d, J=7.8Hz, 1 LC-MS:m / z 382.0(M+1)+ .

[0442] Example 120. Synthesis of 2-(benzo[d]oxazol-2-ylamino)-N-(2-hydroxypropoxy)-1-methyl-1H-benzo[d]imidazole-5-carboxamide [ka] Step-a: Synthesis of 2-(2-hydroxypropoxy)isoindoline-1,3-dione To a stirred solution of 2-hydroxyisoindoline-1,3-dione (5.0 g, 30.65 mmol) and 2-methyloxirane (4.1 mL, 61.3 mmol) in toluene (50 mL) at RT, DIPEA (0.6 mL, 3.1 mmol) and tetrabutylammonium bromide (0.99 g, 3.1 mmol) were added. The reaction mixture was then refluxed for 5 hours. The mixture was cooled to RT, concentrated under reduced pressure, and extracted with EtOAc (2 × 100 mL) and water (50 mL). The combined organic layers were washed with water (30 mL), brine solution (30 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by CombiFlash column chromatography using 100% dichloromethane as the eluent to give the title compound (4.0 g, 59%). 1 H NMR (400MHz, DMSO-d6): δ7.85(s, 4H), 4.80(d, J=4.8Hz, 1H), 4.03-4.00(m, 1H), 3.96-3.93(m, 2H), 1.14(d, J=6.0Hz, 3H); LC-MS: m / z 222.1(M+1) + .

[0443] Step-b: Synthesis of 1-(aminooxy)propan-2-ol hydrochloride A solution of 2-(2-hydroxypropoxy)isoindoline-1,3-dione (2.0 g, 9.0 mmol) in 6N aqueous hydrochloric acid (15 mL) was stirred at room temperature for 16 hours. The solids precipitated in the reaction mixture were removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound as a hydrochloride salt (1.0 g). The crude compound was used in the next step without further purification.

[0444] Step-c: Synthesis of 2-(benzo[d]oxazol-2-ylamino)-N-(2-hydroxypropoxy)-1-methyl-1H-benzo[d]imidazole-5-carboxamide To a stirred solution of 2-(benzo[d]oxazol-2-ylamino)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid (100 mg, 0.32 mmol) in DMFA (5 mL) at 0 °C, N-ethyldiisopropylamine (0.06 mL, 0.32 mmol) and HBTU (122 mg, 0.32 mmol) were added. The reaction mixture was stirred for 30 min, followed by the addition of 1-(aminooxy)propan-2-ol hydrochloride (41 mg, 0.32 mmol), and stirring was continued at RT for 16 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with cold water (20 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with water (30 mL), brine solution (30 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (35 mg, 28%). TIFF2024178242000080.tif43128 1 H NMR (400MHz, DMSO-d6): δ12.30(bs, 1H), 11.7(bs, 1H), 8.01(d, J=1.2Hz, 1H), 7.63(dd, J=1.2Hz, J=8.0Hz, 1H), 7.48(d, J=8.8Hz, 2H), 7.43(d, J=7.6Hz) , 1H), 7.21(t, J=7.6Hz, 1H), 7.12(t, J=7.6Hz, 1H), 4.90(bs, 1H), 3.92-3.8 9(m, 1H), 3.78-3.74(m, 2H), 3.63(s, 3H), 1.10(d, J=6.4Hz, 3H);LC-MS:m / z 382.05(M+1) + .

[0445] Example 121. Synthesis of 2-(benzo[d]oxazol-2-ylamino)-N-(2-(2-(dimethylamino)acetamido)ethoxy)-1-methyl-1H-benzo[d]imidazole-5-carboxamide [ka] Step-a: Synthesis of tert-butyl (2-((1,3-dioxoisoindolin-2-yl)oxy)ethyl)carbamate To a stirred solution of 2-hydroxyisoindoline-1,3-dione (5.0 g, 30.67 mmol) in THF (150 mL) at 0 °C, tert-butyl (2-hydroxyethyl)carbamate (4.93 g, 30.67 mmol) and triphenylphosphine (8.03 g, 30.67 mmol) were added. The reaction mixture was stirred for 10 minutes, followed by the addition of diisopropyl azo...

Claims

1. Structural formula (I): 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, Ring A is a 5- to 7-membered monocyclic cycloalkyl, a 5- to 7-membered monocyclic heterocyclyl, a 5- to 6-membered heteroaryl, or phenyl; X is -S-, -O-, or -NR ｂ - and When X is -S- and ring A is phenyl, R is halo, -CN, -OH, -(C １ ~C ４ ) alkyl, -(C １ ~C ４ ) haloalkyl, -(C １ ~C ４ ) hydroxyalkyl, -(C １ ~C ４ ) alkoxy, -(C １ ~C ４ ) haloalkoxy, and -NR ａ R ａ is a 3- to 7-membered monocyclic heterocyclyl optionally substituted with one or more groups selected from the group consisting of When X is -S- and ring A is a 5- to 7-membered monocyclic cycloalkyl, a 5- to 7-membered monocyclic heterocyclyl, or a 5- to 6-membered heteroaryl, or when X is -O- or -NR ｂ -, R is -H, -(C １ ~C ４ ) alkyl, or -(CH ２ ) ｉ is a 3- to 7-membered monocyclic heterocyclyl, １ ~C ４ ) alkyl or 3- to 7-membered monocyclic heterocyclyl is halo, —CN, —OH, —(C １ ~C ４ ) alkyl, -(C １ ~C ４ ) haloalkyl, -(C １ ~C ４ ) hydroxyalkyl, -(C １ ~C ４ ) alkoxy, -(C １ ~C ４ ) haloalkoxy, —SO ２ R ａ and -NR ａ R ａ and optionally substituted with one or more groups selected from the group consisting of Each R １ are independently -H, halogen, -(CH ２ ) ｋ COOH, -(CH ２ ) ｋ CO (C １ ~C ４ ) alkyl, -(CH ２ ) ｋ COO (C １ ~C ４ ) alkyl, -(CH ２ ) ｐ C(=O)NR ａ R ３ , -CH(CF ３ ) N.R. ａ R ３ , -C(=NOH)CF ３ or -CH(CF ３ ) OR ３ and R １ The above (C １ ~C ４ ) Alkyl is halo, -CN, -OH, -(C １ ~C ４ ) hydroxyalkyl, -(C １ ~C ４ ) alkoxy, -(C １ ~C ４ ) haloalkoxy, and -NR ａ R ａ and optionally substituted with one or more groups selected from the group consisting of Each R ２ are independently -H, halo, CN, -(C １ ~C ４ ) alkyl, —OH, —(C １ ~C ４ ) alkoxy, -COOH, -C(=O)(C １ ~C ４ ) alkyl, -C(=O)O(C １ ~C ４ ) alkyl, —C(═O)NR ａ (C １ ~C ４ ) alkyl, -NR ａ R ａ , 3-6 membered monocyclic cycloalkyl, —O(CH ２ ) ｉ 3- to 7-membered monocyclic heterocyclyl, 3- to 7-membered monocyclic heterocyclyl, or 5- to 6-membered heteroaryl; R ２ or R ２ The -(C １ ~C ４ ) alkyl, -(C １ ~C ４ ) alkoxy, heterocyclyl or heteroaryl is halo, —CN, —OH, —(C １ ~C ４ ) alkyl, -(C １ ~C ４ ) alkoxy, -(C １ ~C ４ ) haloalkyl, -(C １ ~C ４ ) hydroxyalkyl, -(C １ ~C ４ ) haloalkoxy, and -NR ａ R ａ and optionally substituted with one or more groups selected from the group consisting of Each R ３ are independently H, (C １ ~C ４ ) alkyl, (C １ ~C ４ ) alkoxy, -(CH ２ ) ｐ１ 3- to 7-membered monocyclic heterocyclyl, -(CH ２ ) ｐ１ NH3-7 membered monocyclic heterocyclyl, 5-6 membered heteroaryl, -O(CH ２ ) ｐ２ N.R. ａ C(=O)(C １ ~C ４ ) alkyl, -(CH ２ ) ｐ２ O (CH ２ ) ｐ２ O(C=O)(C １ ~C ４ ) alkyl, or (CH ２ ) ｐ２ N.R. ａ C(=O)(C １ ~C ４ ) alkyl, R ３ or R ３ The alkyl, alkoxy, heteroaryl, or heterocyclyl in the group represented by the formula: １ ~C ４ ) alkyl, -(C １ ~C ４ ) haloalkyl, -(C １ ~C ４ ) alkoxy, -(C １ ~C ４ ) hydroxyalkyl, -(C １ ~C ４ ) haloalkoxy, -(C １ ~C ４ ) carboxyalkoxy, -S(O) ２ (C １ ~C ４ ) alkyl, -(C １ ~C ４ ) hydroxyalkoxy, and -NR ａ R ａ and optionally substituted with one or more groups selected from the group consisting of Each R ａ are independently -H or -(C １ ~C ４ ) alkyl; Each R ｂ are independently -H or -(C １ ~C ４ ) alkyl, R ｂ The -(C １ ~C ４ ) Alkyl is halo, -CN, -OH, -(C ３ ~C ６ ) optionally substituted with one or more groups selected from cycloalkyl, phenyl, 3- to 7-membered monocyclic heterocyclyl, and 5- to 6-membered heteroaryl; i is 0 or 1; k is 0, 1, 2, 3, or 4; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; p １ is 0, 1, 2, 3, or 4, p ２ is 2, 3, or 4; The compound, or a pharma- ceutically acceptable salt thereof.

2. Structural formula (II): 【Chemistry 2】 2. The compound of claim 1, represented by:

3. Structural formula (II'): 【Chemistry 3】 2. The compound of claim 1, represented by:

4. Structural formula (II-A): 【Chemistry 4】 3. The compound of claim 1 or 2, represented by:

5. Structural formula (II-B): 【Chemistry 5】 3. The compound of claim 1 or 2, represented by:

6. Structural formula (II-C): 【Chemistry 6】 3. The compound of claim 1 or 2, represented by:

7. Structural formula (II'-A): 【Chemistry 7】 4. The compound of claim 1 or 3, represented by:

8. R ｂ is -H or -(C １ ~C ４ ) alkyl, R ｂ The -(C １ ~C ４ 7. The compound of claim 6, or a pharma- ceutically acceptable salt thereof, wherein: -alkyl is optionally substituted with one or more groups selected from halo, -CN, and -OH.

9. R is -(C １ ~C ４ ) optionally substituted with alkoxy -(C １ ~C ４ ) alkyl; or halo, —CN, —OH, —(C １ ~C ４ ) alkyl, -(C １ ~C ４ ) haloalkyl, -(C １ ~C ４ ) hydroxyalkyl, -(C １ ~C ４ ) alkoxy, -(C １ ~C ４ ) haloalkoxy, and -NR ａ R ａ -(CH ２ ) ｉ The compound according to any one of claims 1 to 3 or 5 to 8, which is a 3- to 6-membered monocyclic heterocyclyl, or a pharma- ceutically acceptable salt thereof.

10. R is azetidinyl, azepanyl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl, each of which is selected from the group consisting of halo, —OH, —(C １ ~C ４ ) alkyl, and -NH ２ The compound according to any one of claims 1 to 8, or a pharma- ceutically acceptable salt thereof, optionally substituted with one or more groups selected from the group consisting of:

11. R １ But -(CH ２ ) ｋ COOH, -(CH ２ ) ｋ CO (C １ ~C ４ ) alkyl, -(CH ２ ) ｐ C(=O)NR ａ R ３ , -C(=NOH)CF ３ or -CH(CF ３ ) N.R. ａ R ３ 11. The compound according to any one of claims 1 to 10, which is: or a pharma- ceutically acceptable salt thereof.

12. R ２ is optionally substituted with H; halogen; CN; halo -(C １ ~C ４ ) alkyl; optionally substituted with halo, hydroxy, methoxy, or ethoxy -(C １ ~C ４ ) alkoxy; -C(=O)(C １ ~C ４ ) alkyl; 3-4 membered monocyclic cycloalkyl; —O(CH ２ ) ｉ 3- to 7-membered monocyclic heterocyclyl, 3- to 7-membered monocyclic heterocyclyl, or 5- to 6-membered heteroaryl; R ２ or R ２ The heterocyclyl or heteroaryl in the group represented by １ ~C ４ 12. The compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, which is optionally substituted with alkoxy.

13. R is methoxy or -SO ２ CH ３ may be substituted with -(C １ ~C ４ ) alkyl; -(CH ２ ) tetrahydrofuranyl; -(CH ２ ) oxetanyl; pyrrolidinyl; piperidinyl; or tetrahydropyranyl, wherein the pyrrolidinyl or piperidinyl is -(C １ ~C ４ 13. The compound according to any one of claims 1 to 3, 5 to 9, 11, or 12, or a pharma- ceutically acceptable salt thereof, optionally substituted with alkyl.

14. R １ is -COOH, -C(=O)CF ３ , -CH(CF ３ ) (NH ２ ), -C(=NOH)CF ３ or -C(=O)NHR ３ 14. The compound according to any one of claims 1 to 13, which is: or a pharma- ceutically acceptable salt thereof.

15. R ３ However, (C １ ~C ４ ) alkyl, (C １ ~C ４ ) alkoxy, (CH ２ ) ｐ１ 3-6 membered monocyclic heterocyclyl, or (CH ２ ) ｐ２ NHC(=O)(C １ ~C ４ ) alkyl, R ３ or R ３ The alkyl, alkoxy, or heterocyclyl in the group represented by the formula: １ ~C ４ ) alkyl, -(C １ ~C ４ ) haloalkyl, -(C １ ~C ４ ) hydroxyalkyl, -(C １ ~C ４ ) alkoxy, -(C １ ~C ４ ) haloalkoxy, -S(O) ２ (C １ ~C ４ ) alkyl, -(C １ ~C ４ ) hydroxyalkoxy, and -NR ａ R ａ The compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, optionally substituted with one or more groups selected from the group consisting of:

16. R ２ is optionally substituted with H; halogen; CN; halo -(C １ ~C ４ ) alkyl; optionally substituted with halo, hydroxy, methoxy, or ethoxy -(C １ ~C ４ ) alkoxy; -C(=O)(C １ ~C ４ 16. The compound of any one of claims 1 to 15, which is aryl, aryl, cyclopropyl, O-tetrahydropyranyl, N-pyrrolidinyl, or thiazolyl, or a pharma- ceutically acceptable salt thereof.

17. Structural formula (III-B): 【Chemistry 8】 6. The compound of claim 5, represented by:

18. R １ is -COOH or -C(=O)NHR ３ and R ３ But -(C １ ~C ４ ) alkyl, -hydroxy(C １ ~C ４ ) alkyl, -methoxy (C １ ~C ４ ) alkyl, -amino (C １ ~C ４ ) alkyl, -(C １ ~C ４ ) Hydroxyalkoxy (C １ ~C ４ ) alkyl, or -(CH ２ ) ｐ２ NHC(=O)(dimethylamino(C １ ~C ４ ) alkyl; 18. The compound according to any one of claims 1 to 17, or a pharma- ceutically acceptable salt thereof.

19. R ２ H, halo, -(C １ ~C ４ ) haloalkyl, -(C １ ~C ４ ) optionally substituted with haloalkoxy, methoxy -(C １ ~C ４ 20. The compound of claim 1, wherein N-(N-phenyl)-1,N-phenyl-2,N-phenyl-3,N-phenyl-4,N-phenyl-5,N-phenyl-6,N-phenyl-7,N-phenyl-8,N-phenyl-9,N-phenyl-10,N-phenyl-11,N-phenyl-12,N-phenyl-13,N-phenyl-14,N-phenyl-15,N-phenyl-16,N-phenyl-17,N

20. R ２ But H, F, CF ３ , O.C.H.F. ２ , O.C.F. ３ , O.C.H. ２ CH ２ OCH ３ 20. The compound of claim 1, which is -N-pyrrolidinyl, or a pharma- ceutically acceptable salt thereof.

21. R ２ is H, and R １ But -OH, NH ２ , oxetanyl, or -(C １ ~C ４ ) optionally substituted with hydroxyalkoxy -C(=O)NH(C １ ~C ４ ) alkyl, or -C(=O)NH(CH ２ ) ｐ２ NHC(=O)(dimethylamino(C １ ~C ４ ) alkyl), or R ２ is F and R １ -C(=O)NH(Methoxy(C １ ~C ４ ) alkyl), or R ２ is -N-pyrrolidinyl, R １ is -C(=O)NH((C １ ~C ４ ) Hydroxyalkoxy (C １ ~C ４ ) alkyl) or R ２ is CF ３ , O.C.H.F. ２ , or O.C.F. ３ and R １ is —COOH, or R ２ OCH ２ CH ２ OCH ３ and R １ is -C(=O)NH((C １ ~C ４ ) Hydroxyalkoxy (C １ ~C ４ ) alkyl), -C(=O)NH(hydroxy(C １ ~C ４ ) alkyl), -C(=O)NH(methoxy(C １ ~C ４ ) alkyl), or -C(=O)NH (hydroxy(C １ ~C ４ ) alkoxy; 21. The compound according to any one of claims 1 to 20, or a pharma- ceutically acceptable salt thereof.

22. R １ But -OH, NH ２ , -(C １ ~C ４ )-alkoxy, or -(C １ ~C ４ ) optionally substituted with hydroxyalkoxy; １ ~C ４ ) alkyl; R ２ is H, or OCH ２ CH ２ OCH ３ That is, 18. The compound of claim 17, or a pharma- ceutically acceptable salt thereof.

23. R ２ is H, or a pharma- ceutically acceptable salt thereof.

24. R １ But -(C １ ~C ４ ) hydroxyalkoxy-substituted —C(═O)NH(C １ ~C ４ 24. The compound of claim 23, or a pharma- ceutically acceptable salt thereof, wherein: R is 1 or 2; and R is 3 or 4.

25. 25. The compound of claim 24 which is 2-(benzo[d]oxazol-2-ylamino)-N-(2-(2-hydroxyethoxy)ethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide, or a pharma- ceutically acceptable salt thereof.

26. R １ But -(C １ ~C ４ ) alkoxy-substituted —C(═O)NH(C １ ~C ４ ) alkyl; R ２ OCH ２ CH ２ OCH ３ That is, 23. The compound of claim 22, or a pharma- ceutically acceptable salt thereof.

27. 27. The compound of claim 26, which is 2-((6-(2-methoxyethoxy)benzo[d]oxazol-2-yl)amino)-N-(2-methoxyethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide or a pharma- ceutically acceptable salt thereof.

28. 【Chemical 9】 2. The compound of claim 1, wherein:

29. A pharmaceutical composition comprising a pharma- ceutically acceptable carrier or diluent and a compound according to any one of claims 1 to 28, or a pharma- ceutically acceptable salt thereof.

30. A method for increasing the activity or amount of HMOX-1 in a human subject, comprising administering to the human subject an effective amount of a compound according to any one of claims 1 to 28 or a pharma- ceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition according to claim 29.

31. A method for activating the transcription factor Nrf2 in a human subject, comprising administering to the human subject an effective amount of a compound described in any one of claims 1 to 28 or a pharma- ceutically acceptable salt thereof, or an effective amount of the pharmaceutical composition described in claim 29.

32. A method of reducing the amount of ROS in a human subject, comprising administering to the human subject an effective amount of a compound according to any one of claims 1 to 28 or a pharma- ceutically acceptable salt thereof, or an effective amount of the pharmaceutical composition according to claim 29.

33. A method of treating a disease, disorder, or condition comprising administering to a human subject an effective amount of a compound according to any one of claims 1 to 28 or a pharma- ceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition according to claim 29, wherein the disease, disorder, or condition is (i) a fibrotic disease, including pulmonary fibrotic diseases, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, sarcoidosis, alcoholic cirrhosis, steatosis, cholestasis, fibrotic diseases of the liver, including those caused by drug side effects and viral infections, fibrotic diseases of the skin, scleroderma, or psoriasis; (ii) neurodegenerative diseases, including Friedreich's ataxia, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, cranial neurodegenerative diseases, or Charcot-Marie-Tooth syndrome; (iii) cardiovascular diseases, including hypertension, hypercholesterolemia, atherosclerosis, arteriosclerosis, thrombosis, acute coronary thrombosis, deep vein thrombosis, peripheral vascular disease, congestive heart failure, acute coronary syndrome, failure of arterial fistula for dialysis, ischemia-reperfusion injury, primary pulmonary hypertension, primary pulmonary arterial hypertension, or secondary pulmonary arterial hypertension; (iv) acute kidney injury, multiple sclerosis, or pulmonary vascular disease, including acute kidney injury, multiple sclerosis ... (v) inflammatory diseases, including asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, inflammatory bowel syndrome, Crohn's disease, celiac disease, ulcerative colitis, chronic inflammatory bowel disease, scleroderma, dermatitis, systemic lupus erythematosus, esophagitis, vasculitis, pancreatitis, tendonitis, osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, or chronic inflammation of the brain; (vi) liver diseases, including drug-induced hepatotoxicity, nonalcoholic steatohepatitis, hepatitis B infection, or hepatitis C infection; (vii) conjunctival (viii) eye diseases, including glaucoma, uveitis, eye injuries, eye trauma, corneal grafts, Fuchs endothelial corneal dystrophy, macular degeneration, cataracts, mild retinopathy, retinitis pigmentosa, diabetic retinopathy, and retinopathy of prematurity; (viii) thyroid diseases, including Graves' disease, follicular adenoma, or papillary and follicular carcinoma; (ix) viral infections, including infections from human immunodeficiency virus, hepatitis B, hepatitis C, or herpes viruses; (x) osteoporosis; (xi) pregnancy disorders; (xii) endometriosis; (xiii) type 1 diabetes, type 2 diabetes, gestational diabetes, prediabetes, hyperglycemia;(xiv) diabetes, including metabolic syndrome or secondary conditions resulting from a diabetic condition, (xv) cancer, (xv) skin disease, including dermatitis, scleroderma, or psoriasis, (xvi) mitochondrial disease, such as mitochondrial myopathy, Leber's hereditary optic neuropathy (LHON), myoclonus epilepsy with ragged red fibers (MERFF), mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) or Leigh's syndrome, (xvii) blood disease, such as Diamond-Blackfan anemia, myelodysplastic syndrome, sickle cell disease, and beta thalassemia, or (xviii) muscle disease, such as Duchenne muscular dystrophy, limb-girdle muscular dystrophy, Becker muscular dystrophy, myotonic dystrophy, and rhabdomyolysis.

34. A compound according to any one of claims 1 to 28 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 29, for the treatment of a disease, disorder, or condition according to claim 33 in a human subject, comprising administering to said subject in need thereof.

35. Use of a compound according to any one of claims 1 to 28 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 29, for the manufacture of a medicament for the treatment of a disease, disorder, or condition according to claim 33 in a human subject, comprising administering to said subject in need thereof.

36. Use of a compound according to any one of claims 1 to 28 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 29, for the treatment of a disease, disorder, or condition according to claim 33 in a human subject, comprising administering to said subject in need thereof.

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