TW201922721A - Chemical compounds - Google Patents

Abstract

The invention is directed to substituted benzimidazole derivatives. Specifically, the invention is directed to compounds according to Formula Ib: wherein R', R2', R3', R4', R5', R6', R7', and X1' are as defined herein; or a salt thereof including a pharmaceutically acceptable salt thereof. The compounds of the invention decrease MYC protein (c-MYC) in cells and/or inhibit p300/CBP histone acetyltransferase and can be useful in the treatment of cardiac hypertrophy, diabetes, obesity nonalcoholic fatty liver disease, HIV, polycystic kidney disease, inflammatory diseases, ankylosing spondylitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn's disease, multiple sclerosis, cancer and pre-cancerous syndromes, and diseases associated with dysregulation of Myc or inhibition of p300/CBP histone acetyltransferase. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of reducing MYC protein (c-MYC) in cells and inhibiting p300/CBP histone acetyltransferase activity, and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.

Description

   Chemical compound   

The present invention relates to substituted benzimidazole derivatives that reduce MYC protein (c-MYC) in cells and inhibit the p300 / CBP tissue protein acetamidine transferase. The present invention also relates to pharmaceutical compositions containing the compounds, methods of preparing the compounds, and use of the compounds (for example) in the treatment of cardiac hypertrophy, diabetes, obesity and non-alcoholic fatty liver disease, HIV, polycystic kidney disease, Methods for inflammatory diseases, joint adhesion spondylitis, psoriasis, psoriasis arthritis, rheumatoid arthritis, Crohn's disease, multiple sclerosis, cancer and precancerous syndromes.

The transcription factor Myc plays a role in regulating cell proliferation, cell cycle, cell growth, angiogenesis, apoptosis and tumor formation. Myc levels can be increased in tumors due to gene amplification, chromosomal rearrangements, increased expression or mutations (see, eg, Nesbit, et al. (1999) Oncogene 18: 3004-3016; Zeller, et al. (2001) J Biol. Chern. 276: 48285-48291; He, et al. (1998) Science 281: 1509-1512; McMahon, et al. (1998) Cel / 94: 363-374; Erisman, et al. (1985) Mol. Cell Biol. 5: 1969-1976; Rochlitz, et al. (1996). Oncology 53: 448-454). For example, increased levels of Myc have been found in breast and prostate cancers (Liao, et al. (2000) Endocrine-Related Cancer 7: 143-164; Jenkins, et al. (1997) Cancer Res. 57: 524-531).

When Myc acts as a cell cycle regulator, it promotes cell entry into the cell cycle (Trumpp, et al. (2001) Nature 414: 768-773; Holzel, et al. (2001) EMBO Reports 21: 1125-1132; Bouchard, et al. (2001) Genes Devel. 15: 2042-2047). Myc has been found to play a role in certain phases of the cell cycle, in which cell cycle genes (eg, cyclins and protein kinases) can be directly or indirectly regulated by Myc. Myc also regulates growth because it plays a role in regulating genes required for protein synthesis, such as genes encoding transcription factors and ribosomal proteins (Greasley, et al. (2000) Nucleic Acids Res. 28: 446-453); Zeller , et al. (2001) supra; Menssen, et al. (2002) Proc. Natl. Acad. Sci. USA 59: 6274-6279). Myc regulates apoptosis, which is damaged in cancer cells. Myc has been shown to regulate key apoptotic pathway proteins (Nesbit et al. (1998) Blood 92: 1003-1010).

Many diseases are associated with abnormal cellular messaging triggered by the aforementioned Myc-mediated events, including proliferative diseases (eg, cancer) and cardiovascular disease. Therefore, there is a need to identify Myc inhibitors that can be used as therapeutics and research tools.

The object of the present invention is to provide a novel compound that reduces MYC protein (c-MYC) in cells.

It is also an object of the present invention to provide a pharmaceutical composition comprising a pharmaceutical carrier and a compound useful in the method of the present invention.

The object of the present invention is also to provide a method for treating cancer and precancerous syndromes, which comprises administering such compounds that reduce MYC protein (c-MYC) in cells.

Tissue protein acetamidine transferase (HAT) catalyzes acetylation (transfer of acetamidine) on the epsilon-amine group of the target lysine side chain in the receptor tissue protein. Reversible acetylation of tissue proteins and other proteins is one of the most abundant post-translational modifications in eukaryotic cells and is the main mechanism of cellular regulation. HAT is classified into four main families based on primary sequence homology, common structural characteristics, and functional effects: Gcn5 / PCAF (generally controls non-inhibitory protein 5 and p300 and CBP-related factors); MYST (for basic members MOZ, Ybf2 / Sas3, Named Sas2 and Tip60); p300 / CBP (300kDa protein and CREB binding protein); and Rtt109 (regulator produced by Ty1 transposable gene 109).

Paralogs HATs p300 (KATB) and CBP (referred to as p300 / CBP) have 61% sequence identity and are retained in metazoan. In addition to the enzyme-catalyzed HAT domain, p300 / CBP has 30 multidomains, including three cysteine-histidine-rich domains (CH1, CH2, and CH3), KIX domain, bromine domain, and Steroid receptor co-activator interaction domain (SRC-1 interaction domain). P300 and CBP were originally discovered as binding partners of E1A adenovirus protein and cAMP-regulated enhancer binding protein (Yee and Branton, 1985, Virology 147: 142-153; Harlow et al., 1986, Mol. Cell BioI. 6 : 1579-1589; Chrivia et al., 1993, Nature 365: 855-859). P300 / CBP was later found to have endogenous HAT activity (Ogryzko et al., 1996, Cell 5 87: 953-959; Bannister and Kouzarides, 1996, Nature 384: 641-643). In addition to acetylating multiple lysines on all four core tissue proteins (H2A, H2B, H3, and H4), P300 / CBP has been shown to have mixed acetamyltransferase activity on> 70 substrates (Wang et al., 2008, Curr. Opin. Struct. BioI. 18: 741-747), including, for example, p53 (Gu et al., 1997, Cell 90: 595-606), MyoD (Polesskaya et al., 2002 , J. BioI. Chern. 275: 34359-64), STAT3 (Yuan et aI., 2005, Science 10 307: 269-73) and NFKB (Chen et aI., 2002, EMBO J. 21: 6539-48) . In addition to acting as an acetyltransferase, p300 also acts as a framework for transcription factors or a bridge that connects transcription factors to basic transcription mechanisms to activate transcription (Chan and Thangue, 2001, J. Cell Sci. 114: 2363-2373; Chen and Li, 2011, Epigenetics 6: 957-961). The P300 / CBP protein is involved in many cellular processes, including cell growth, proliferation, and differentiation (Chan and Thangue, supra).

Abnormal p300 / CBP activity or mutations are associated with various diseases. In prostate cancer (Heemers et al., 2008, Adv. Exp. Med. BioI. 617: 535-40; Isharwal et al., 2008, Prostate 68: 1097-104), liver cancer (Yokomizo et al., 2011, Cancer Lett. 310: 1407; Li et al., 2011, J. Transi. Med. 9: 5), and breast cancer (Fermento et al., 20 2010, Exp. Mol. Pathoi. 88: 256-64) To high p300 performance. Mutations in the p300 / CBP gene have been found in human tumors (Petrij et al., 1995, Nature 376: 348-51; Muraoka et al., 1996, Oncogene 12: 1565-69; Sobu10 et al., 1997, Proc. Nati. Acad. Sci. USA 94: 8732-37; Gayther et al., 2000, Nat. Genet. 24: 300-304). P300 missense mutations and truncations have been found in solid tumors and B-cell lymphomas, indicating their role as tumor suppressors (Iyer et aI., 2004, Oncogene 23: 4225-31; Pasqualucci et aI., 25 2011, nature 471: 189-95). Inhibition of p300 / CBP in cancer (Iyer et al., 2004, Proc. Nati. Acad. Sci. USA 101: 7386-7391; Stimson et al., 2005, Mol. Cancer Ther. 4: 1521-1532; Zheng et al. aI., 2004, Methods Enzymoi. 376: 188-199), heart disease (Davidson et aI., 2005, ChembioChem. 6: 162-170); diabetes (Davidson et aI., 2005, ChembioChem. 6: 162-170) ); Diabetes mellitus (Zhou et al., 2004, Nat. Med. 10: 633-637), and HIV (Varier and Kundu, 2006, Curro Pharm. Des. 12: 1975-1993) have therapeutic potential. Heterozygous germline mutations in CBP or p300 have also been described in Rubinstein-Taybi syndrome (a somatic and dominant disease characterized by mental retardation, skeletal abnormalities, and a high incidence of neoplasia) Medium (Petrij et al., 1995, Nature 376: 348-51; Petrij et al., 2000, Am. J. Med. Genet. 92: 47-52). P300 / CBP is also involved in the regulation of inflammatory mediators (Deng et al., 2004, Blood 103: 2135-42; Turner-Brannen et al., 2011, J. Immunol. 186: 7127-7135). P300 / CBP has also been linked to other diseases, such as fibrosis (Ghosh and Varga, 2007, J. Cell. Physiol. 213: 663-671), metabolic syndrome (Bricambert et aI., 2010, J. Clin. Invest. 120 : 4316-4331) and progressive neurodegenerative diseases such as Huntington Disease (Cong et al., 2005, Mol. Cell. Neurosci. 5 30: 12-23), Kennedy's disease ( Kennedy's disease) (Lieberman et aI., 2002, Hum. Mol. Genet. 11: 1967-76) and Alzheimer's disease (Francis et aI., 2007, Neurosci. Lett. 413: 137-140 ).

Additional disease states associated with increased or mutated p300 / CBP activity include: Thrombocytopenia (Kauppi, M .; Murphy, JM; de Graaf, CA; Hyland, CD; Greig, KT; Metcalf, D .; Hilton, AA; Nicola, NA; Kile, BT; Hilton, DJ; Alexander, WSBlood 2008, 112, 3148. Hilton, DJ; Kile, BT; Alexander, WSBlood 2009, 113, 5599); Cardiac hypertrophy (Gusterson, RJ; Jazrawi, E .; Adcock, IM; Latchman, DSJ Biol. Chem. 2003, 278, 6838); Diabetes (Zhou, XY; Shibusawa, N .; Naik, K .; Porras, D .; Temple, K .; Ou, H Kaihara, K .; Roe, MW; Brady, MJ; Wondisford, FENat.Med. 2004, 10,633); Obesity & non-alcoholic fatty liver disease (Bricambert, J .; Miranda, J .; Benhamed, F. Girard, J .; Postic, C .; Dentin, RJClin. Invest. 2010, 120, 4316). HIV treatment (Zou, W .; Wang, Z .; Liu, Y .; Fan, Y .; Zhou, BY; Yang, XF; He, JJGlia 2010, 58, 1640); polycystic kidney disease (Merrick D, Chapin H, Baggs JE, Yu Z, Somlo S, Sun Z, Hogenesch JB, Caplan MJ. Dev Cell. 2012 Jan 17; 22 (1): 197-210); and inflammatory diseases, including joint adhesion spondylitis , Psoriasis and psoriatic arthritis, rheumatoid arthritis, Crohn's disease, and multiple sclerosis (Hammitzsch A, Tallant C, Fedorov O, O'Mahony A, Brennan PE, Hay DA, Martinez FO, Al-Mossawi MH, de Wit J, Vecellio M, Kongs C, Wordsworth P, Müller S, Knapp S, Bowness P. Proc Natl Acad Sci US A. 2015 Aug 25; 112 (34): 10768-73).

The association of p300 / CBP activity in disease pathogenesis suggests the potential utility of p300 / CBP as a therapeutic target. However, identifying effective specific tissue protein acetamidine transferase inhibitors has been challenging (Cole, 2008, Nat. Chern. BioI. 4: 590-97). Recently, a selective p300 / CBP HAT inhibitor has been revealed (International Publication No. WO 2016/044770, and the International Publication Date is March 24, 2016).

Therefore, although progress has been made in the art, there remains a need in the art for improved compounds that reduce MYC protein (c-MYC) in cells and inhibit the p300 / CBP tissue protein acetamyltransferase. The present invention fulfills this need and provides other related advantages.

In one aspect, the invention relates to a substituted benzimidazole derivative, specifically a compound according to formula Ib: Wherein R ', R ^2' , R ^{3 '} , R ^4' , R ^{5 '} , R ^6' , R ^{7 '} , and X ^1' are as defined below; or a salt thereof, including a pharmaceutically acceptable salt.

The invention also relates to the discovery that compounds of formula (Ib) reduce MYC protein (c-MYC) in cells.

The invention also relates to the discovery of compounds of formula (Ib) for preventing the transcription and function of the c-MYC gene.

The present invention also relates to the compounds of formula (Ib) having activity as inhibitors of p300 / CBP tissue protein acetamyltransferase activity.

The invention also relates to a method for treating cancer and precancerous syndromes, which comprises administering an effective amount of a compound of formula (Ib) to a patient in need thereof.

The present invention also relates to a method for treating a disease state selected from the group consisting of cardiac hypertrophy, diabetes, obesity and non-alcoholic fatty liver disease, HIV, polycystic kidney disease, inflammatory diseases, joint adhesion spondylitis, psoriasis, psoriasis Arthritis, rheumatoid arthritis, Crohn's disease, and multiple sclerosis comprise administering an effective amount of a compound of formula (Ib) to a patient in need thereof.

In another aspect of the invention, there are provided novel methods and novel intermediates useful in the preparation of compounds of the invention.

The invention includes a pharmaceutical composition comprising a pharmaceutical carrier and a compound useful in the method of the invention.

The invention also relates to a compound of formula (Ib) or a pharmaceutically acceptable salt thereof for use in therapy.

The present invention also relates to a compound of formula (Ib) or a pharmaceutically acceptable salt thereof for use in the treatment of cancer and precancerous syndromes.

The invention also relates to the use of a compound of formula (Ib) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in the treatment of a disease selected from the following: cardiac hypertrophy, diabetes, obesity and non-alcoholic fatty liver disease , HIV, polycystic nephropathy, inflammatory diseases, joint adhesion spondylitis, psoriasis, psoriasis arthritis, rheumatoid arthritis, Crohn's disease, and multiple sclerosis.

The invention also relates to the use of a compound of formula (Ib) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in the treatment of cancer and precancerous syndromes.

The present invention also relates to a pharmaceutical composition as described above for use in therapy.

The invention also includes methods for co-administering a compound of the invention with other active ingredients.

The invention relates to novel compounds of formula (I): Where: R is C _1-6 alkyl, substituted with 1 to 3 substituents independently selected from: fluoro, pendant oxy, heteroaryl substituted with aryl, heterocyclyl, substituted with 1 to 4 Heterocyclyl substituted with a substituent independently selected from fluoro, chloro, bromo, heteroaryl, _C1-6 alkyl, and substituted with 1 to 5 substituents independently selected from C _1-6 alkyl: fluoro, chloro, bromo, iodo, pendant oxy, -CN, -OH and -NH ₂ , heteroaryl, substituted with 1 to 4 independently selected from the following the heteroaryl group substituents: fluoro, chloro, bromo, heteroaryl, C _1-6 alkyl, and with 1 to 5 substituents independently selected from the group consisting of substituted C _1-6 alkyl substituted with: Fluoro, chloro, bromo, iodo, pendant, -CN and -OH and -NH ₂ , C _1-6 alkoxy, C substituted with 1 to 9 substituents independently selected from _1-6 alkoxy: fluoro, chloro, pendant, -OH, -NH ₂ , -NHCH ₃ , and -N (CH3) 2, -O cycloalkyl, and independently through 1 to 4 -O cycloalkyl substituted with a substituent selected from the group consisting of fluoro, chloro, pendant, -OH, -NH ₂ , -NHCH ₃ , and -N (CH3) 2; X ¹ is selected from: CR ¹ And N, wherein R ¹ is selected from: hydrogen, fluoro, chloro, bromo, iodo, -OH, -CN, C _1-4 alkoxy, and is independently selected from 1 to 7 C _1-4 alkoxy substituted by substituents: fluoro, chloro, pendant, -OH, -NH ₂ , -NHCH ₃ , and -N (CH3) 2, C _1-6 alkyl, via 1 To C _1-6 alkyl substituted with 7 substituents independently selected from: fluoro, chloro, bromo, iodo, pendant oxy, -CN, -OH, -OC _1-5 alkyl, _{-COOH, -S (O) 2 H} , -S (O) 2 R x, wherein R ^x is selected from C _1-3 alkyl and substituted by 1 to 3 below, followed by C _1-3 alkyl: fluoro group , Heterocyclyl, and -NR ^a R ^b , wherein R ^a and R ^b are independently selected from: hydrogen, C _1-5 alkoxy, C substituted with 1 to 4 substituents independently selected from _1-5 alkoxy: fluoro, pendant, -OH, -OC _1-5 alkyl, cycloalkyl, -COOH, -NH ₂ , and -S (O) ₂ H, C _1-5 alkane Group, C _1-5 alkyl substituted with 1 to 4 substituents independently selected from: fluoro, pendant oxy, -OH, -OC _1-5 alkyl, cycloalkyl, -COOH,- _{NH 2, -S (O) 2} H, and -S (O) ₂ R ^x, wherein R ^x is selected from fluoro and C _1-3 alkyl substituted one to three times C _1-3 alkyl, cycloalkyl, and with 1 to 4 substituents independently selected from the group consisting of cycloalkyl substituents: fluoro, oxo, -OH, -O _1-5 alkyl, - COOH, and -NH ₂ , heteroaryl, and heteroaryl substituted with 1 to 4 substituents independently selected from fluoro, chloro, C _1-6 alkyl, and 1 to 5 independent C _1-6 alkyl substituted with a substituent selected from the group consisting of: fluoro, chloro, bromo, iodo, pendant, -CN, -OH, and -NH ₂ ; R ² , R ³ , and R ⁴ is independently selected from: hydrogen, fluoro, chloro, bromo, iodo, -OH boronic acid, 1,3,6,2-dioxazaborocane-4,8- Dione, -CN, -NR ^c R ^d , wherein R ^c and ^Rd are independently selected from: hydrogen, C _1-5 alkyl, C ₁ substituted with 1 to 4 substituents independently selected from _-5 alkyl: fluoro, pendant oxy, -OH, -OC _1-5 alkyl, cycloalkyl, -COOH, -NH ₂ , -S (O) ₂ H, and -S (O) ₂ R ^x, wherein R ^x is selected from fluoro and C _1-3 alkyl group substituted with 1 to 3 followed by C _1-3 alkyl, an aryl group, with 1 to 4 substituents independently selected from the group consisting of substituted aryl substituents Group: fluoro group, pendant oxygen group, -OH, -O _1-5 alkyl group, -COO H, and -NH ₂ , heteroaryl, heteroaryl substituted with 1 to 4 substituents independently selected from: fluoro, pendant oxy, -OH, -O _1-5 alkyl, -COOH , And -NH ₂ , a heterocyclic group, a heterocyclic group substituted with 1 to 4 substituents independently selected from the group consisting of a fluoro group, a pendant oxygen group, -OH, -O _1-5 alkyl group, -COOH, And -NH ₂ , cycloalkyl, and cycloalkyl substituted with 1 to 4 substituents independently selected from the group consisting of fluoro, pendant oxy, -OH, -O _1-5 alkyl, -COOH, and -NH _2, C _1-4 alkoxy, 1-7 substituents independently selected from the substituents of the C _1-4 alkoxy group: fluoro, chloro, oxo, -OH, - NH _2, -NHCH _3, and -N (CH3) 2, C _1-6 alkyl, 1-7 substituents independently selected from the group C _1-6 alkyl substituted with: fluoro, chloro, Bromo, iodo, pendant oxy, -CN, -OH, -OC _1-5 alkyl, heterocyclyl, -COOH, -S (O) ₂ H, -S (O) ₂ R ^x , where R ^x is selected from C _1-3 alkyl and fluorine, and -NR ^a R ^b substituted by 1 to 3 C _1-3 alkyl, followed, where R ^a and R ^b, are independently selected from: hydrogen, C _{1- 5} alkyl, with 1 to 4 substituents independently selected from the group consisting of substituted C _1-5 alkyl substituents : Fluoro, oxo, -OH, -OC _1-5 alkyl, _{cycloalkyl, -COOH, -NH 2, -S (} O) 2 H, and -S (0) ₂ R ^x, wherein R ^x is selected from fluoro and C _1-3 alkyl group substituted with 1 to 3 followed by C _1-3 alkyl, an aryl group, with 1 to 4 substituents independently selected from aryl of the following substituents: fluoro group , Pendant oxy, -OH, -O _1-5 alkyl, -COOH, and -NH ₂ , heteroalkyl, heteroalkyl substituted with 1 to 4 substituents independently selected from: fluoro, Pendant oxygen, -OH, -O _1-5 alkyl, -COOH, and -NH ₂ , heterocyclic ring, heteroalkyl substituted with 1 to 4 substituents independently selected from: fluoro, pendant oxygen , -OH, -O _1-5 alkyl, -COOH, and -NH ₂ , cycloalkyl, and cycloalkyl substituted with 1 to 4 substituents independently selected from: fluoro, pendant oxygen , -OH, -O _1-5 alkyl, -COOH, and -NH ₂ , aryl, aryl substituted with 1 to 4 substituents independently selected from fluoro, chloro, C _{1 -6} alkyl, and C _1-6 alkyl substituted with 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, pendant oxy, -CN, -OH, and -NH ₂ , cycloalkyl, separated by 1 to 4 Substituents selected from the group consisting of cycloalkyl substituents: fluoro, chloro, C _1-6 alkyl, and with 1 to 5 substituents independently selected from the group consisting of substituted C _1-6 alkyl substituents: fluoro , Chloro, bromo, iodo, pendant oxy, -CN, -OH, and -NH ₂ , heterocyclic ring, heterocyclic ring substituted with 1 to 4 substituents independently selected from: fluoro, chloro group, a C _1-6 alkyl group, and with 1 to 5 substituents independently selected from the group consisting of substituted C _1-6 alkyl substituents: fluoro, chloro, bromo, iodo, oxo, -CN , -OH and -NH ₂ , heteroaryl, and heteroaryl substituted with 1 to 4 substituents independently selected from: fluoro, chloro, C _1-6 alkyl, and 1 to 5 C _1-6 alkyl substituted independently by a substituent selected from the group consisting of fluoro, chloro, bromo, iodo, pendant oxy, -CN, -OH, and -NH ₂ , or R ¹ , R ² , R ³ and 2 adjacent members of R ⁴ together form a non-aromatic ring containing 3 to 6 member atoms independently selected from the group consisting of carbon, nitrogen, sulfur, oxygen, and boron to form an oxaboran Oxaborolyl, heterocyclyl, cycloalkyl, or heteroaryl, wherein the oxaborocyclopentadienyl Heterocyclyl, cycloalkyl, aryl, and heteroaryl are each optionally substituted with lines 1 to 3 substituents independently selected from the following substituents: fluoro, chloro, -OH, oxo, C _1-6 alkyl groups, and -NH _2; R ⁵ and R ⁶ are independently selected: C _1-4 alkyl, 1-6 substituents independently selected from the group C _1-4 alkyl substituted with: fluoro, Pendant oxy, -NH ₂ , C _1-4 alkoxy, and -OH, cycloalkyl, cycloalkyl substituted with 1 to 5 substituents independently selected from: fluoro, chloro,- OH, and C _1-6 alkyl, or R ⁵ and R ⁶ together with the nitrogen to which they are attached, and optionally 1 to 3 additional heteroatoms to form a heterocyclic group, which optionally passes 1 to five independently selected substituents: fluoro, chloro, C _1-6 alkyl, 1-9 substituents independently selected from the group C _1-6 alkyl substituents: fluoro group , Chloro, C _1-4 alkoxy, pendant oxy, -OH, -NH ₂ , -N (H) C _1-4 alkyl, -N (C _1-4 alkyl) ₂ , and -CN , C _1-4 alkoxy, 1 to 4 substituents independently selected from the group consisting of C _1-4 alkoxy substituents: fluoro, oxo, -OH, -COOH, -NH _2, and -CN, pendant oxygen, -N H ₂ , -N (H) C _1-4 alkyl, and -N (C _1-4 alkyl) ₂ ; and R ⁷ is selected from: hydrogen and fluoro, or one of R ⁵ and R ⁶ Together with R ⁷ and optionally 1 to 3 additional heteroatoms to form a heterocyclyl, optionally substituted with 1 to 5 substituents independently selected from the group consisting of fluoro, chloro, -OH , Pendant oxy, C _1-4 alkyl, C _1-4 alkoxy, and -NH ₂ ; or a pharmaceutically acceptable salt thereof.

For compounds of formula (I), X ¹ is suitably N. For a compound of formula (1), X ¹ is suitably CR ⁷ .

For compounds of formula (I), suitably R is C _1-2 alkyl substituted with: pyrazolyl, pyrazolyl substituted with C _1-3 alkyl, Oxazolyl, substituted with C _1-3 alkyl Azolyl, imidazolyl, imidazolyl substituted with C _1-3 alkyl, triazolyl, triazolyl substituted with C _1-3 alkyl, thiazolyl, thiazolyl substituted with C _1-3 alkyl, -O-cyclopentyl, C _1-6 alkoxy, fluoro substituted one to six times C _1-6 alkoxy, tetrahydrofuranyl, pyridinyl, substituted by bromo group of the substituted pyridinyl, pyrimidinyl, or Pyridyl.

For compounds of formula (I), R ¹ is suitably selected from: hydrogen, fluoro, chloro, bromo, -OH, -CN, -C (O) NHCH ₃ , -C (O) NHCH ₂ CH ₂ OH, -C (O) NHCH ₂ CH ₂ SO ₂ CH ₃ , -C (O) NHOCH ₃ , -C (O) NH ₂ , -C (O) OCH ₃ , -C (O) NHCH ₂ cyclopropyl , -C (O) NH cyclobutyl, optionally substituted with a hydroxyl group, -CH ₂ morpholinyl, -CH ₂ OH, -CH ₂ NHCH ₂ CF ₃ , -CH ₂ NHCH ₂ CH ₂ SO ₂ CH ₃ , -CH ₂ SO ₂ CH ₃ , -CH (OH) CF ₃ , -CH ₃ , -CF ₃ , -OCH ₃ , pyrazolyl, Oxazolyl, and substituted once or twice with methyl Azolyl, for compounds of formula (I), suitably R ² , R ³ , and R ⁴ are independently selected from: hydrogen, fluoro, chloro, bromo, -OH, boric acid, 1,3,6,2 -Dioxazepine-4,8-dione, -CN, -C (O) NHCH ₃ , -C (O) NHCH ₂ CH ₂ OH, -C (O) NHCH ₂ CH ₂ SO ₂ CH ₃ , -C (O) NHOCH ₃ , -C (O) NH ₂ , -C (O) OCH ₃ , -C (O) NHCH ₂ cyclopropyl, -C (O) NH cyclobutyl, depending on Substituted with a hydroxy group, -CH ₂ morpholinyl, -CH ₂ OH, -CH ₂ NHCH ₂ CF ₃ , -CH ₂ NHCH ₂ CH ₂ SO ₂ CH ₃ , -CH ₂ SO ₂ CH ₃ , -CH ( OH) CF ₃ , -CH ₃ , -CF ₃ , -OCH ₃ , -NHC (O) CH ₃ , -NH ₂ , -NHSO ₂ CH ₃ , morpholinylpyrazolyl, Oxazolyl, and substituted once or twice with methyl An oxazolyl group, or R ³ and R ⁴ together with the carbon atom to which they are attached to form an oxaborolyl, is optionally substituted with a hydroxyl group.

For compounds of formula (the I), suitably R ⁵ and R ⁶ are independently selected: C _1-3 alkyl, substituted by 1 to 3 fluoro groups, followed by C _1-3 alkyl and cyclopropyl, or R ⁵ and R ⁶ together with the nitrogen to which they are attached form: pyrrolidinyl, which is optionally substituted once or twice with: C _1-3 alkyl.

For compounds of formula (I), suitably R ⁷ is selected from: hydrogen and fluorine; or one of R ⁵ and R ⁶ together with R ⁷ and optionally an additional heteroatom to form: pyrrolidinyl , Or morpholinyl, each of them is optionally substituted 1 to 4 times with a C _1-3 alkyl group.

The invention relates to novel compounds of formula (Ib): Where: R 'is C _1-6 alkyl, substituted with 1 to 3 substituents independently selected from: fluoro, pendant oxy, heteroaryl substituted with aryl, heterocyclyl, substituted with 1 to 4 heterocyclic groups independently substituted with the following substituents: fluoro, chloro, bromo, pendant, -OH, heteroaryl, C _1-6 alkyl, and 1 to 5 independently C _1-6 alkyl substituted with a substituent selected from the group consisting of fluoro, chloro, bromo, iodo, pendant, -CN, -OH, and -NH ₂ , heteroaryl, 1 to 4 Heteroaryl substituted with independently selected from the group consisting of fluoro, chloro, bromo, -OH, heteroaryl, _C1-6 alkyl, and 1 to 5 independently selected from C _1-6 alkyl substituted with substituents: fluoro, chloro, bromo, iodo, pendant, -CN, -OH, and -NH ₂ , C _1-6 alkoxy, 1 to 9 C _1-6 alkoxy substituted with independently selected from the group consisting of fluoro, chloro, pendant, -OH, -NH ₂ , -NHCH ₃ , and -N (CH3) 2, -O ring Alkyl, and -O cycloalkyl substituted with 1 to 4 substituents independently selected from: fluoro, chloro, pendant oxy, -OH, -NH ₂ , -NHCH ₃ , and -N ( C H3) 2; X ^{1 '} is selected from CR ^1' and N, wherein R ^{1 '} is selected from: hydrogen, fluoro, chloro, bromo, iodo, -OH, -NH ₂ , -NHCH _{3 , -N (CH 3) 2,} -CN, C 1-4 alkoxy, 1-7 independently selected substituents of the C _1-4 alkoxy: fluoro, chloro, side _{alkoxy, -OH, -NH 2, -NHCH 3} , and -N (CH3) 2, C _1-6 alkyl, 1-7 substituents independently selected from the group C _1-6 alkyl substituents : Fluoro, chloro, bromo, iodo, pendant oxy, -CN, -OH, -OC _1-5 alkyl, heterocyclyl, -COOH, -S (O) ₂ H, -S (O ) ₂ R ^x, wherein R ^X is selected from fluorine and C _1-3 alkyl, heterocyclyl, and -NR ^a R ^b substituted by 1 to 3 C _1-3 alkyl, followed, where R ^a and R ^b are independently selected from: hydrogen, C _1-5 alkoxy, one to four substituents independently selected from the group C _1-5 alkoxy substituted with: fluoro, oxo, -OH, -OC _1-5 alkyl, cycloalkyl, cycloalkyl substituted by: -OH, -COOH, -NH ₂ , -S (O) ₂ H, and -S (O) ₂ CH ₃ , C _{1 -5} alkyl, one to four substituents independently selected from the group consisting of C _1-5 alkyl substituents: fluoro, oxo, -OH, -OC _1-5 alkyl Cycloalkyl, the cycloalkyl substituent of the _{following: -OH, -COOH, -NH 2,} -S (O) 2 H, and -S (O) ₂ R ^x, wherein R ^x is selected from C _1-3 Alkyl and C _1-3 alkyl substituted with fluoro groups 1 to 3 times, cycloalkyl, and cycloalkyl substituted with 1 to 4 substituents independently selected from the group consisting of fluoro, pendant oxygen, -OH, -O _1-5 alkyl, -COOH, and -NH ₂ , heteroaryl, and heteroaryl substituted with 1 to 4 substituents independently selected from: fluoro, chloro, C _1-6 alkyl, and C _1-6 alkyl substituted with 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, pendant oxy, -CN, -OH And -NH ₂ ; R ^{2 ′} , R ^{3 ′} , and R ^{4 ′} are independently selected from: hydrogen, fluoro, chloro, bromo, iodo, -OH boronic acid, 1,3,6,2-di Oxazaborocyclooctane-4,8-dione, -CN, -NR ^c R ^d , wherein R ^c and ^Rd are independently selected from: hydrogen, C _1-5 alkyl, via 1 to 4 C _1-5 alkyl substituted with substituents independently selected from: fluoro, pendant oxy, -OH, -OC _1-5 alkyl, cycloalkyl, -COOH, -NH ₂ , -N ( H) C _1-4 alkyl, -N (C _{1-4 alkyl) 2, -N (H) C} 1-4 alkyl (wherein the alkyl group via lines Group substituted with 1 to 3 times), N (C _1-4 alkyl) ₂ (wherein each alkyl group substituted with fluorine-based one to three _{times), - S (O) 2} H, and -S (O) ₂ R ^x, wherein R ^x is selected from fluoro and C _1-3 alkyl group substituted with 1 to 3 C _1-3 alkyl _{followed, -S (O) 2 H,} -S (O) 2 R x ', wherein R ^{x 'is} selected from fluoro and C _1-3 alkyl group substituted with 1 to 3 followed by C _1-3 alkyl, aryl, 1-4 substituents independently selected from the group consisting of a substituted aryl group: Fluoro, pendant oxy, -OH, -O _1-5 alkyl, -COOH, and -NH ₂ , heteroaryl, heteroaryl substituted with 1 to 4 substituents independently selected from: fluorine Group, pendant oxy group, -OH, -O _1-5 alkyl group, -COOH, and -NH ₂ , heterocyclic group, heterocyclic group substituted with 1 to 4 substituents independently selected from the following: fluoro group , Pendant oxy, -OH, -O _1-5 alkyl, -COOH, and -NH ₂ , cycloalkyl, and cycloalkyl substituted with 1 to 4 substituents independently selected from: fluoro , Pendant oxy, -OH, -O _1-5 alkyl, -COOH, and -NH ₂ , heterocyclyl, C _1-4 alkoxy, substituted with 1 to 7 substituents independently selected from C _1-4 alkoxy: fluoro, chloro, pendant, -OH, -NH ₂ , -NHCH ₃ , and -N (CH3) 2, C _1-6 alkyl, 1-7 substituents independently selected from the group C _1-6 alkyl substituents: fluoro, chloro, bromo, iodo, an oxygen side , -CN, -OH, -OC _1-5 alkyl, heterocyclyl, -COOH, -S (O) ₂ H, -S (O) ₂ R ^x , wherein R ^x is selected from C _1-3 Alkyl and C _1-3 alkyl substituted 1 to 3 times with fluoro, and -NR ^a R ^b , wherein R ^a and R ^b are independently selected from: hydrogen, C _1-5 alkyl, 1 to 3 C _1-5 alkyl substituted with 4 substituents independently selected from: fluoro, pendant oxy, -OH, -OC _1-5 alkyl, cycloalkyl, -COOH, -NH ₂ , -S (O) ₂ H, and -S (O) ₂ R ^x, wherein R ^x is selected from fluoro and C _1-3 alkyl group substituted with 1 to 3 followed by C _1-3 alkyl, aryl, 1 To 4 aryl groups independently substituted with substituents selected from: fluoro, pendant oxy, -OH, -O _1-5 alkyl, -COOH, and -NH ₂ , heteroalkyl, via 1 to 4 Heteroalkyl substituted independently with substituents selected from: fluoro, pendant oxy, -OH, -O _1-5 alkyl, -COOH, and -NH ₂ , heterocyclic, through 1 to 4 independent Heteroalkyl substituted with a substituent selected from the group consisting of fluoro, pendant oxy, -OH, -O _1-5 alkyl, -COOH, and- NH ₂ , cycloalkyl, and cycloalkyl substituted with 1 to 4 substituents independently selected from: fluoro, pendant oxy, -OH, -O _1-5 alkyl, -COOH, and- NH ₂ , aryl, aryl substituted with 1 to 4 substituents independently selected from fluoro, chloro, C _1-6 alkyl, and substituted with 1 to 5 independently selected from -Substituted C _1-6 alkyl: fluoro, chloro, bromo, iodo, pendant, -CN, -OH, and -NH ₂ , cycloalkyl, independently selected from 1 to 4 cycloalkyl of substituents: fluoro, chloro, C _1-6 alkyl, and with 1 to 5 substituents independently selected from the group consisting of substituted C _1-6 alkyl substituents: fluoro, chloro , Bromo, iodo, pendant oxy, -CN, -OH and -NH ₂ , heterocyclic ring, heterocyclic ring substituted with 1 to 4 substituents independently selected from: fluoro, chloro, C _{1 -6} alkyl, and C _1-6 alkyl substituted with 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, pendant oxy, -CN, -OH, and -NH _2, aryl, heteroaryl, and substituted with 1 to 4 substituents independently selected from the group consisting of a substituted heteroaryl group substituents: fluoro, chloro, C _1-6 alkyl, and 1-5 substituents independently selected from the group consisting of C _1-6 alkyl substituents: fluoro, chloro, bromo, iodo, oxo, -CN, -OH and -NH _2, or R ^{1 '} , R ^2' , R ^{3 '} , and R ^4' together form two non-aromatic rings containing 3 to 6 member atoms independently selected from the group consisting of carbon, nitrogen, sulfur, oxygen, and Boron to form an oxaborolyl, heterocyclyl, cycloalkyl, or heteroaryl, wherein the oxaborocyclopentadienyl, heterocyclyl, cycloalkyl, And heteroaryl are each optionally substituted with 1 to 3 substituents independently selected from the group consisting of fluoro, chloro, -OH, pendant oxy, C _1-6 alkyl, and -NH ₂ ; R ^{5 'and} R ^6' are independently selected: C _1-4 alkyl, 1-6 substituents independently selected from the group C _1-4 alkyl substituents: fluoro, oxo, -NH ₂ , C _1-4 alkoxy, and -OH, cycloalkyl, cycloalkyl substituted with 1 to 5 substituents independently selected from: fluoro, chloro, -OH, and C _{1- 6} alkyl, R ^{5 'and} R ^6' together with the nitrogen and optionally 1 to 3 additional hetero atoms, to form with their attached the heterocyclic group 1-5 independently selected substituents: fluoro, chloro, C _1-6 alkyl, 1-9 substituents independently selected from the group C _1-6 alkyl substituents: fluoro Alkyl, chloro, C _1-4 alkoxy, pendant oxy, -OH, -NH ₂ , -N (H) C _1-4 alkyl, -N (C _1-4 alkyl) ₂ , and- the CN, C _1-4 alkoxy, with 1 to 4 substituents independently selected from the group consisting of substituents of C _1-4 alkoxy: fluoro, oxo, -OH, -COOH, -NH _2, And -CN, pendant oxy, -NH ₂ , -N (H) C _1-4 alkyl, and -N (C _1-4 alkyl) ₂ , or one of R ^{5 '} and R ^6' R ^{7 '} together with optionally 1 to 3 additional heteroatoms to form a heterocyclyl, optionally substituted with 1 to 5 substituents independently selected from the group consisting of fluoro, chloro, -OH , Pendant oxy, C _1-4 alkyl, C _1-4 alkoxy, and -NH ₂ ; and R ^{7 ′} is selected from: hydrogen and fluoro, or one of R ^{5 ′} and R ^{6 ′} Together with R ^{7 ′} , and optionally 1 to 3 additional heteroatoms to form a heterocyclic group, optionally substituted with 1 to 5 substituents independently selected from the group consisting of fluoro, chloro,- OH, oxo, C _1-4 alkyl, C _1-4 alkoxy, -NH _2, and Or a pharmaceutically acceptable salt thereof.

For compound formula (Ib), X ^{1 ′} is suitably N. For compound formula (lb), X ^{1 ′} is suitably CR ^{7 ′} .

For compound formula (Ib), R ^' is suitably C _1-2 alkyl substituted with: phenyl substituted with pyrimidinyl, pyrazolyl, pyrazolyl substituted with C _1-3 alkyl, pyr _Pyridyl substituted with C _1-3 alkyl Base Phenyl _Ci, substituted with C _1-3 alkyl base, Oxazolyl, substituted with C _1-3 alkyl Azolyl, imidazolyl, imidazolyl substituted with C _1-3 alkyl, morpholinyl, morpholinyl substituted 1 or 2 times with C _1-3 alkyl, morpholin substituted with pendant oxy Base, two Alkyl, substituted by C _1-3 alkyl Alkyl, 4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine ; Triazolyl, triazolyl substituted with C _1-3 alkyl, thiazolyl, thiazolyl substituted with C _1-3 alkyl, -O cyclopentyl, C _1-6 alkoxy, fluoro substituted with 1-6 followed by C _1-6 alkoxy, hydroxy substituted C _1-6 alkoxy group of tetrahydrofuran, pyridinyl, substituted by bromo group of the substituted pyridinyl, pyrimidinyl, or pyridyl.

For compound formula (Ib), suitably R ^{2 ′} , R ^{3 ′} , and R ^{4 ′} are independently selected from: hydrogen, fluoro, chloro, bromo, —OH, boric acid, 1, 3, 6, 2 -Dioxazepine-4,8-dione, -CN, -C (O) NHCH ₃ , -C (O) NHCH ₂ CH ₃ , -C (O) NHCH ₂ CF ₂ H, -C (O) NHCH ₂ CH ₂ OH, -C (O) NHCH ₂ CH ₂ SO ₂ CH ₃ , -C (O) NHOCH ₃ , -C (O) NH ₂ , -C (O) OCH ₃ ,- C (O) NHCH ₂ cyclopropyl, -C (O) NH cyclobutyl, optionally substituted with a hydroxyl group, -CH ₂ morpholinyl, -CH ₂ OH, -CH ₂ NHCH ₂ CF ₃ , -CH ₂ NHCH ₂ CH ₂ SO ₂ CH ₃ , -CH ₂ SO ₂ CH ₃ , -CH (OH) CF ₃ , -CH ₃ , -CF ₃ , -OCH ₃ , methoxy-d ₃ , -NHC (O) CH ₃ , -NH ₂ , -NHSO ₂ CH ₃ , morpholinylpyrazolyl, Oxazolyl, and substituted once or twice with methyl An oxazolyl group, or R ^{3 ′} and R ^{4 ′,} together with the carbon atom to which they are attached to form an oxaborolyl, is optionally substituted with a hydroxyl group.

For compounds of formula (Ib), suitably R ^{5 'and} R ^6' are independently selected: C _1-3 alkyl, fluoro substituted with 1 to 3 followed by C _1-3 alkyl, and cyclopropyl, R ^{5b '} and R ^6b' together with the nitrogen to which they are attached to form: aziridinyl, pyrrolidinyl, each of which is optionally substituted once or twice as follows: C _1-3 alkyl or via fluorine 1 to 3 times of C _1-3 alkyl, or one of R ^{5b ′} and R ^{6b ′} together with R ^{7b ′} , and optionally an additional heteroatom to form: pyrrolidinyl, or Modinyl, each of them is optionally substituted 1 to 4 times with a C _1-3 alkyl group.

For compound formula (Ib), suitably R ^{7 ′} is selected from: hydrogen and fluorine; one of R ^{5 ′} and R ^{6 ′} together with R ^{7 ′} , and optionally an additional heteroatom to form: Pyrrolidinyl, or morpholinyl, each of them is optionally substituted 1 to 4 times with C _1-3 alkyl.

Included in the compounds of the invention and used in the methods of the invention are compounds of formula (II): Wherein: R ¹⁰ is C _1-4 alkyl, substituted with 1 to 3 substituents independently selected from the group consisting of pendant oxygen, phenyl substituted with pyrimidinyl, heterocyclyl, independently substituted with 1 to 4 Heterocyclyl substituted with a substituent selected from the group consisting of fluoro, chloro, bromo, heteroaryl, C _1-6 alkyl, and C ₁ substituted with 1 to 5 substituents independently selected from _-6 alkyl: fluoro, chloro, bromo, iodo, pendant, -CN, -OH, and -NH ₂ , heteroaryl, substituted with 1 to 4 substituents independently selected from the following heteroaryl group: fluoro, chloro, bromo, heteroaryl, C _1-6 alkyl, and with 1 to 5 substituents independently selected from the group consisting of substituted C _1-6 alkyl substituents: fluoro, chloro, bromo, iodo, oxo, -CN, -OH and -NH _2, C _1-6 alkoxy, 1-9 substituents independently selected from the group consisting of substituted C _1-6 Alkoxy: fluoro, chloro, pendant, -OH, -NH ₂ , -NHCH ₃ , and -N (CH3) 2, -O cycloalkyl, and independently selected from 1 to 4 -O-Cycloalkyl substituted with: fluoro, chloro, pendant oxy, -OH, -NH ₂ , -NHCH ₃ , and -N (CH3) 2; R ¹¹ is selected from: hydrogen, fluorine Group, chloro, bromo, iodo, -OH, -CN, C _1-4 alkoxy, 1-7 substituents independently selected from the group consisting of C _1-4 alkoxy substituents: fluoro group , Chloro, pendant oxy, -OH, -NH ₂ , -NHCH ₃ , and -N (CH3) 2, C _1-6 alkyl, C substituted with 1 to 7 substituents independently selected from _1-6 alkyl: fluoro, chloro, bromo, iodo, pendant oxy, -CN, -OH, -OC _1-5 alkyl, heterocyclyl, -COOH, -S (O) ₂ H ^{_{, -S (O) 2 R x1}} ( wherein R ^x1 is selected from fluoro and C _1-3 alkyl substituted with 1 to 3 followed by C _1-3 alkyl), and -NR ^a1 R ^b1, R ^a1 and wherein R ^b1 are independently selected from: hydrogen, C _1-5 alkoxy, C _1-5 alkyl, with 1 to 4 substituents independently selected from the group consisting of substituents of C _1-5 alkyl: fluoro, Pendant oxygen, -OH, -OC _1-5 alkyl, cycloalkyl, cycloalkyl substituted with -OH, -COOH, -NH ₂ , -S (O) ₂ H, and -S (O ) ₂ CH ₃ ; cycloalkyl, and cycloalkyl substituted with 1 to 4 substituents independently selected from: fluoro, pendant oxy, -OH, -O _1-5 alkyl, -COOH, and -NH _2; aryl, heteroaryl, and by 1-4 substituents independently selected from the group consisting of heteroaryl substituents: Group, chloro, C _1-6 alkyl, and with 1 to 5 substituents independently selected from the group consisting of substituted C _1-6 alkyl substituents: fluoro, chloro, bromo, iodo, oxo , -CN, -OH and -NH ₂ , R ¹² , R ¹³ , and R ¹⁴ are independently selected from: hydrogen, fluoro, chloro, bromo, iodo, -OH, boric acid, 1, 3, 6 , 2-dioxazepine-4,8-dione, -CN, -NR ^c1 R ^d1 , wherein R ^c1 and R ^d1 are independently selected from: hydrogen, C _1-5 alkyl, C _1-5 alkyl substituted with 1 to 4 substituents independently selected from: fluoro, pendant oxy, -OH, -OC _1-5 alkyl, cycloalkyl, -COOH, -NH ₂ , and -S (O) ₂ H, heterocyclyl, C _1-4 alkoxy, by 1-7 substituents independently selected from the substituents of the C _1-4 alkoxy group: fluoro, chloro , _{oxo, -OH, -NH 2, -NHCH 3} , and -N (CH3) 2, C _1-6 alkyl, substituted with 1-7 substituents independently selected from the group consisting of C _1-6 Alkyl: fluoro, chloro, bromo, iodo, pendant oxy, -CN, -OH, -OC _1-5 alkyl, heterocyclyl, -COOH, -S (O) ₂ H, -S (O) ₂ R ^x1 (wherein R ^x1 is selected from fluoro and C _1-3 alkyl substituted with 1 to 3 followed by C _1-3 alkyl), and - NR ^a1 R ^b1 , wherein R ^a1 and R ^b1 are independently selected from: hydrogen, C _1-5 alkoxy, C _1-5 alkyl, C substituted with 1 to 4 substituents independently selected from _1-5 alkyl: fluoro, pendant oxy, -OH, -OC _1-5 alkyl, cycloalkyl, -COOH, -NH ₂ , -S (O) ₂ H, and -S (O) ₂ R ^x1, wherein R ^x1 is selected from fluoro and C _1-3 alkyl substituted with 1 to 3 groups followed C _1-3 alkyl; cycloalkyl groups, and with 1 to 4 substituents independently selected from the group consisting of substituents Substituted cycloalkyl: fluoro, pendant oxy, -OH, -O _1-5 alkyl, -COOH, and -NH ₂ ; heteroaryl, and 1 to 3 substituents independently selected from the following the substituted heteroaryl groups: fluoro, chloro, C _1-6 alkyl, and with 1 to 5 substituents independently selected from the group consisting of substituted C _1-6 alkyl substituents: fluoro, chloro, bromo , Iodo, pendant oxy, -CN, -OH, and -NH ₂ , or 2 adjacent members of R ¹² , R ¹³ , and R ¹⁴ together form 3 to 6 member atoms independently selected from the following Non-aromatic rings: carbon, nitrogen, sulfur, oxygen, and boron to form an oxaborolyl, heterocyclyl, cycloalkyl, or heteroaryl group, wherein the oxaborolan ring Diene group, a heterocyclic group, cycloalkyl, aryl, and heteroaryl are each optionally substituted with lines 1 to 3 substituents independently selected from the following substituents: fluoro, chloro, -OH, oxo, C _C1-6 alkyl, and -NH _2; R ¹⁵ and R ¹⁶ are independently selected: C _1-4 alkyl, 1-6 substituents independently selected from the group C _1-4 alkyl substituted with : Fluoro, pendant oxy, -NH ₂ , C _1-4 alkoxy, and -OH, cycloalkyl, and cycloalkyl substituted with 1 to 5 substituents independently selected from the following: fluoro , Chloro, -OH, and C _1-6 alkyl, or R ¹⁵ and R ¹⁶ together with the nitrogen to which they are attached, and optionally 1 to 3 additional heteroatoms to form a heterocyclic group, which is with 1 to 5 substituents independently selected from the following substituents: fluoro, chloro, C _1-6 alkyl, 1-9 substituents independently selected from the group C _1-6 alkyl substituted with: Fluoro, chloro, C _1-4 alkoxy, pendant oxy, -OH, -NH ₂ , -N (H) C _1-4 alkyl, -N (C _1-4 alkyl) ₂ , and -CN, C _1-4 alkoxy, 1 to 4 substituents independently selected from the group consisting of C _1-4 alkoxy substituents: fluoro, oxo, -OH, -COOH, -NH ₂ , And -CN, lateral oxygen _{, -NH 2, -N (H)} C 1-4 alkyl, and -N (C _1-4 alkyl) _2; and R ¹⁷ is selected from: hydrogen and fluoro, or R ¹⁵ and R ¹⁶ in the One together with R ¹⁷ and optionally 1 to 3 additional heteroatoms to form a heterocyclic group, which are independently substituted optionally with 1 to 3 substituents: fluoro, chloro, -OH, Pendant oxygen, C _1-4 alkyl, C _1-4 alkoxy, and -NH ₂ ; or a pharmaceutically acceptable salt thereof.

For compounds of formula (II), suitably R ¹⁰ is C _1-2 alkyl substituted with: pyrazolyl, pyrazolyl substituted with C _1-3 alkyl, Oxazolyl, substituted with C _1-3 alkyl Azolyl, imidazolyl, imidazolyl substituted with C _1-3 alkyl, triazolyl, triazolyl substituted with C _1-3 alkyl, thiazolyl, thiazolyl substituted with C _1-3 alkyl, -O-cyclopentyl, C _1-6 alkoxy, fluoro substituted one to six times C _1-6 alkoxy, tetrahydrofuranyl, pyridinyl, substituted by bromo group of the substituted pyridinyl, pyrimidinyl, or Pyridyl.

For compounds of formula (II), suitably R ¹¹ , R ¹² , R ¹³ , and R ¹⁴ are independently selected from: hydrogen, fluoro, chloro, bromo, -OH, boric acid, 1, 3, 6, 2 -Dioxazepine-4,8-dione, -CN, -C (O) NHCH ₃ , -C (O) NHCH ₂ CH ₂ OH, -C (O) NHCH ₂ CH ₂ SO ₂ CH ₃ , -C (O) NHOCH ₃ , -C (O) NH ₂ , -C (O) OCH ₃ , -C (O) NHCH ₂ cyclopropyl, -C (O) NH cyclobutyl, depending on Substituted with a hydroxy group, -CH ₂ morpholinyl, -CH ₂ OH, -CH ₂ NHCH ₂ CF ₃ , -CH ₂ NHCH ₂ CH ₂ SO ₂ CH ₃ , -CH ₂ SO ₂ CH ₃ , -CH ( OH) CF ₃ , -CH ₃ , -CF ₃ , -OCH ₃ , pyrazolyl, Oxazolyl, and substituted once or twice with methyl An azole group, or R ¹³ and R ¹⁴ together with the carbon atom to which they are attached to form an oxaborolyl, is optionally substituted with a hydroxyl group.

For Formula (II) compound, suitably R ¹⁵ and R ¹⁶ are independently selected: C _1-3 alkyl, fluoro substituted with 1 to 3 followed by C _1-3 alkyl and cyclopropyl, or R ¹⁵ and R ¹⁶ together with the nitrogen to which they are attached form: pyrrolidinyl, which is optionally substituted once or twice with: C _1-3 alkyl.

For compounds of formula (II), suitably R ¹⁷ is selected from: hydrogen and fluorine; or one of R ¹⁵ and R ¹⁶ together with R ¹⁷ and optionally an additional heteroatom to form: pyrrolidinyl , Or morpholinyl, each of them is optionally substituted 1 to 4 times with a C _1-3 alkyl group.

Included in the compounds of the invention and used in the methods of the invention are compounds of formula (IIb): Wherein: R ^10b is C _1-4 alkyl, substituted with 1 to 3 substituents independently selected from the group consisting of pendant oxygen, phenyl substituted with pyrimidinyl, heterocyclyl, independently substituted with 1 to 4 Heterocyclyl substituted with a substituent selected from the group consisting of fluoro, chloro, bromo, pendant oxy, heteroaryl, C _1-6 alkyl, and 1 to 5 substituents independently selected from Substituted C _1-6 alkyl: fluoro, chloro, bromo, iodo, pendant oxy, -CN, -OH, and -NH ₂ , heteroaryl, independently selected from 1 to 4 substituted aryl of heteroaryl groups: fluoro, chloro, bromo, heteroaryl, C _1-6 alkyl, and with 1 to 5 substituents independently selected from the group consisting of substituents of C _1-6 alkyl : Fluoro, chloro, bromo, iodo, pendant, -CN, -OH, and -NH ₂ , C _1-6 alkoxy, substituted with 1 to 9 substituents independently selected from the following C _1-6 alkoxy: fluoro, chloro, pendant, -OH, -NH ₂ , -NHCH ₃ , and -N (CH3) 2, -O cycloalkyl, and through 1 to 4 independent substituents selected from the group consisting of -O-substituted cycloalkyl groups: fluoro, chloro, _{oxo, -OH, -NH 2, -NHCH 3} , and -N (CH3) 2; R ^11b selected from the group : Hydrogen, fluoro, chloro, bromo, _{iodo, -OH, -NH 2, -CN,} C 1-4 alkoxy, 1-7 substituents independently selected from the group consisting of a substituted C _{1 -4} alkoxy: fluoro, chloro, pendant, -OH, -NH ₂ , -NHCH ₃ , and -N (CH3) 2, C _1-6 alkyl, independently selected from 1 to 7 C _1-6 alkyl substituted with the following substituents: fluoro, chloro, bromo, iodo, pendant, -CN, -OH, -OC _1-5 alkyl, heterocyclyl, -COOH _{, -S (O) 2 H,} -S (O) 2 R x1 '( where R ^x1' is selected from fluoro and C _1-3 alkyl substituted with 1 to 3 followed by C _1-3 alkyl), and -NR ^{a1 '} R ^b1' , wherein R ^{a1 '} and R ^b1' are independently selected from: hydrogen, C _1-5 alkoxy, C _1-5 alkyl, independently selected from 1 to 4 C _1-5 alkyl substituted with substituents: fluoro, pendant oxy, -OH, -OC _1-5 alkyl, cycloalkyl, cycloalkyl substituted with: -OH, -COOH, -NH ₂ , -S (O) ₂ H, and -S (O) ₂ CH ₃ , cycloalkyl, and cycloalkyl substituted with 1 to 4 substituents independently selected from the group consisting of fluoro, pendant oxygen, -OH, -O _1-5 alkyl, -COOH, and -NH _2, aryl, heteroaryl, and with 1 to 4 substituents independently selected from the group consisting of take The heteroaryl group substituents: fluoro, chloro, C _1-6 alkyl, and with 1 to 5 substituents independently selected from the group consisting of substituted C _1-6 alkyl substituents: fluoro, chloro, bromo , Iodo, pendant oxy, -CN, -OH, and -NH ₂ ; R ^12b , R ^13b , and R ^14b are independently selected from: hydrogen, fluoro, chloro, bromo, iodo, -OH , Boric acid, 1,3,6,2-dioxazepine-octane-4,8-dione, -CN, -NR ^{c1 '} R ^d1' , wherein R ^{c1 '} and R ^d1' are independently selected from: hydrogen, C _1-5 alkyl, one to four substituents independently selected from the group consisting of C _1-5 alkyl substituents: fluoro, oxo, -OH, -OC _1-5 alkyl Group, cycloalkyl group, -COOH, -NH ₂ , -N (H) C _1-4 alkyl group, -N (H) C _1-4 alkyl group (where alkyl group is substituted by fluoro group 1 to 3 times) , And -S (O) ₂ H, -S (O) ₂ H, -S (O) ₂ C _1-3 alkyl, heterocyclyl, C _1-4 alkoxy, independently from 1 to 7 C _1-4 alkoxy substituted with a substituent selected from the group consisting of: fluoro, chloro, pendant, -OH, -NH ₂ , -NHCH ₃ , and -N (CH3) 2, C _1-6 alkane Group, C _1-6 alkyl substituted with 1 to 7 substituents independently selected from: fluoro, chloro, bromo, iodo, pendant oxy, -C N, -OH, -OC _1-5 alkyl, heterocyclyl, -COOH, -S (O) ₂ H, -S (O) ₂ R ^{x1 '} (where R ^x1' is selected from C _1-3 alkane And C _1-3 alkyl substituted by a fluoro group 1 to 3 times), and -NR ^{a1 '} R ^b1' , wherein R ^{a1 '} and R ^b1' are independently selected from: hydrogen, C _1-5 alkoxy group, C _1-5 alkyl, one to four substituents independently selected from the group consisting of C _1-5 alkyl substituents: fluoro, oxo, -OH, -OC _1-5 alkyl, cycloalkyl, Alkyl, -COOH, -NH ₂ , -S (O) ₂ H, and -S (O) ₂ R ^{x1 '} , where R ^x1' is selected from C _1-3 alkyl and substituted with 1 to 3 by a fluoro group Followed by C _1-3 alkyl; cycloalkyl, and cycloalkyl substituted with 1 to 4 substituents independently selected from: fluoro, pendant oxy, -OH, -O _1-5 alkyl , -COOH, and -NH ₂ , heteroaryl, and heteroaryl substituted with 1 to 3 substituents independently selected from: fluoro, chloro, C _1-6 alkyl, and 1 to 3 C _1-6 alkyl substituted with 5 substituents independently selected from the group consisting of fluoro, chloro, bromo, iodo, pendant oxy, -CN, -OH, and -NH ₂ , or R ^12b , R ^13b, and two adjacent members of R ^14b is formed containing 3-6 members independently selected from the group consisting of atoms with Aromatic ring: carbon, nitrogen, sulfur, oxygen, and boron to form an oxaborolyl, heterocyclyl, cycloalkyl, or heteroaryl group, wherein the oxaborolan Dienyl, heterocyclyl, cycloalkyl, and heteroaryl are each optionally substituted with 1 to 3 substituents independently selected from the group consisting of fluoro, chloro, -OH, pendant oxygen, C _C1-6 alkyl, and -NH _2; R ^15b and R ^16b are independently selected: C _1-4 alkyl, 1-6 substituents independently selected from the group consisting of substituted C _1-4 alkyl : Fluoro, pendant oxy, -NH ₂ , C _1-4 alkoxy, and -OH, cycloalkyl, and cycloalkyl substituted with 1 to 5 substituents independently selected from the following: fluoro , Chloro, -OH, and C _1-6 alkyl, R ^15b and R ^16b together with the nitrogen to which they are attached, and optionally 1 to 3 additional heteroatoms to form a heterocyclyl, as required substituted with 1-5 independently selected substituents: fluoro, chloro, C _1-6 alkyl, 1-9 substituents independently selected from the group C _1-6 alkyl substituted with : Fluoro, chloro, C _1-4 alkoxy, pendant oxy, -OH, -NH ₂ , -N (H) C _1-4 alkyl, -N (C _{1- 4} alkyl) _2, and -CN, C _1-4 alkoxy, with 1 to 4 substituents independently selected from the group consisting of the substituents C _1-4 alkoxy group: fluoro, oxo, -OH , -COOH, -NH ₂ , and -CN, pendant oxygen, -NH ₂ , -N (H) C _1-4 alkyl, and -N (C _1-4 alkyl) ₂ , or R ^15b and R One of ^16b , together with R ^17b , and optionally 1 to 3 additional heteroatoms to form a heterocyclic group, optionally substituted with 1 to 3 substituents independently selected from the group consisting of: fluoro, -OH, C _1-4 alkyl, and C _1-4 alkoxy; and R ^17b is selected from: hydrogen and fluoro, or one of R ^15b and R ^16b together with R ^17b , and optionally 1 to 3 additional heteroatoms to form a heterocyclyl, optionally substituted with 1 to 3 substituents independently selected from the group consisting of fluoro, -OH, C _1-4 alkyl, and C _{1- 4} alkoxy; or a pharmaceutically acceptable salt thereof.

For compounds of formula (IIb), suitably R ^10b is C _1-2 alkyl substituted with: phenyl substituted with pyrimidinyl, pyrazolyl, pyrazolyl substituted with C _1-3 alkyl, pyr _Pyridyl substituted with C _1-3 alkyl Base Phenyl _Ci, substituted with C _1-3 alkyl base, Oxazolyl, substituted with C _1-3 alkyl Azolyl, imidazolyl, imidazolyl substituted with C _1-3 alkyl, morpholinyl, morpholinyl substituted 1 or 2 times with C _1-3 alkyl, morpholin substituted with pendant oxy Base, two Alkyl, two substituted with C _1-3 alkyl Alkyl, 4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine ; Triazolyl, triazolyl substituted with C _1-3 alkyl, thiazolyl, thiazolyl substituted with C _1-3 alkyl, -O cyclopentyl, C _1-6 alkoxy, fluorine group substituted with 1-6 followed by C _1-6 alkoxy, hydroxy substituted C _1-6 alkoxy group of tetrahydrofuran, pyridinyl, substituted by bromo group of the substituted pyridinyl, pyrimidinyl, or pyridyl.

For compounds of formula (IIb), suitably R ^12b , R ^13b , and R ^14b are independently selected from: hydrogen, fluoro, chloro, bromo, -OH, boronic acid, 1,3,6,2-dioxy Azaborane-octane-4,8-dione, -CN, -C (O) NHCH ₃ , -C (O) NHCH ₂ CH ₃ , -C (O) NHCH ₂ CF ₂ H, -C ( O) NHCH ₂ CH ₂ OH, -C (O) NHCH ₂ CH ₂ SO ₂ CH ₃ , -C (O) NHOCH ₃ , -C (O) NH ₂ , -C (O) OCH ₃ , -C (O ) NHCH ₂ cyclopropyl, -C (O) NH cyclobutyl, optionally substituted with hydroxy, -CH ₂ morpholinyl, -CH ₂ OH, -CH ₂ NHCH ₂ CF ₃ , -CH ₂ NHCH ₂ CH ₂ SO ₂ CH ₃ , -CH ₂ SO ₂ CH ₃ , -CH (OH) CF ₃ , -CH ₃ , -CF ₃ , -OCH ₃ , methoxy-d ₃ , -NHC (O) CH ₃ , -NH ₂ , -NHSO ₂ CH ₃ , morpholinylpyrazolyl, Oxazolyl, and substituted once or twice with methyl An oxazolyl group, or R ^13b and R ^14b, together with the carbon atom to which they are attached to form an oxaborolyl, is optionally substituted with a hydroxyl group.

For formula (IIb) compound, suitably R ^15b and R ^16b are independently selected: C _1-3 alkyl, fluoro substituted with 1 to 3 followed by C _1-3 alkyl, and cyclopropyl, R ^15b And R ^16b together with the nitrogen to which they are attached to form: aziridinyl, pyrrolidinyl, each of which is optionally substituted once or twice as follows: C _1-3 alkyl or substituted with 1 to 5 3 times C _1-3 alkyl, or one of R ^15b and R ^16b together with R ^17b , and optionally an additional heteroatom to form: pyrrolidinyl, or morpholinyl, etc. Each is optionally substituted 1 to 4 times with a C _1-3 alkyl group.

For compounds of formula (IIb), suitably R ^17b is selected from: hydrogen and fluorine; or one of R ^15b and R ^16b together with R ^17b , and optionally one additional heteroatom to form: pyrrolidinyl , Or morpholinyl, each of them is optionally substituted 1 to 4 times with a C _1-3 alkyl group.

Included in the compounds of the invention and used in the methods of the invention are compounds of formula (IIa): Wherein: R ^10a is C _1-4 alkyl, substituted with 1 to 3 substituents independently selected from the group consisting of pendant oxygen, phenyl substituted with pyrimidinyl, heterocyclyl, independently substituted with 1 to 4 Heterocyclyl substituted with a substituent selected from the group consisting of fluoro, chloro, bromo, heteroaryl, C _1-6 alkyl, and C ₁ substituted with 1 to 5 substituents independently selected from _-6 alkyl: fluoro, chloro, bromo, iodo, pendant, -CN, -OH, and -NH ₂ , heteroaryl, substituted with 1 to 4 substituents independently selected from the following heteroaryl group: fluoro, chloro, bromo, heteroaryl, C _1-6 alkyl, and with 1 to 5 substituents independently selected from the group consisting of substituted C _1-6 alkyl substituents: fluoro, chloro, bromo, iodo, oxo, -CN, -OH and -NH _2, C _1-6 alkoxy, 1-9 substituents independently selected from the group consisting of substituted C _1-6 Alkoxy: fluoro, chloro, pendant, -OH, -NH ₂ , -NHCH ₃ , and -N (CH3) 2, -O cycloalkyl, and independently selected from 1 to 4 -O-Cycloalkyl substituted with: fluoro, chloro, pendant oxy, -OH, -NH ₂ , -NHCH ₃ , and -N (CH3) 2; R ^12a , R ^13a , and R ^{1 The 4a} system is independently selected from: hydrogen, fluoro, chloro, bromo, iodo, -OH, boric acid, 1,3,6,2-dioxazepine-4,8-dione , -CN, -NR ^c1a R ^d1a, wherein R ^c1a and R ^d1a are independently selected from: hydrogen, C _1-5 alkyl, one to four substituents independently selected from the group of C _1-5 substituted Alkyl: fluoro, pendant oxy, -OH, -OC _1-5 alkyl, cycloalkyl, -COOH, -NH ₂ , and -S (O) ₂ H, heterocyclyl, C _1-4 alkane Oxy, C _1-4 alkoxy substituted with 1 to 7 substituents independently selected from: fluoro, chloro, pendant oxy, -OH, -NH ₂ , -NHCH ₃ , and -N (CH3) 2, C _1-6 alkyl, 1-7 substituents independently selected from the group C _1-6 alkyl substituted with: fluoro, chloro, bromo, iodo, oxo, -CN, -OH, -OC _1-5 alkyl, heterocyclyl, -COOH, -S (O) ₂ H, -S (O) ₂ R ^x1a (where R ^x1a is selected from C _1-3 alkyl and fluorine substituted with 1 to 3 followed by C _1-3 alkyl), and -NR ^a1a R ^b1a, wherein R ^a1a and R ^b1a are independently selected from: hydrogen, C _1-5 alkoxy, C _1-5 Alkyl, C _1-5 alkyl substituted with 1 to 4 substituents independently selected from: fluoro, pendant oxy, -OH -OC _1-5 alkyl, cycloalkyl, -COOH, -NH ₂ , -S (O) ₂ H, and -S (O) ₂ R ^x1a , wherein R ^x1a is selected from C _1-3 alkyl And a C _1-3 alkyl group substituted 1 to 3 times with a fluoro group; a cycloalkyl group, and a cycloalkyl group substituted with 1 to 4 substituents independently selected from the group consisting of a fluoro group, a pendant oxygen group, and -OH , -O _1-5 alkyl, -COOH, and -NH ₂ ; heteroaryl, and heteroaryl substituted with 1 to 3 substituents independently selected from: fluoro, chloro, C _{1- 6} alkyl, and C _1-6 alkyl substituted with 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, pendant, -CN, -OH, and- NH ₂ , or two adjacent members of R ^12a , R ^13a , and R ^14a together form a non-aromatic ring containing 3 to 6 member atoms independently selected from the group consisting of carbon, nitrogen, sulfur, oxygen, and boron To form an oxaborolyl, heterocyclyl, cycloalkyl, or heteroaryl, wherein the oxaborolyl, heterocyclyl, cycloalkyl, and Heteroaryl groups are each optionally substituted with 1 to 3 substituents independently selected from the group consisting of fluoro, chloro, -OH, pendant oxy, C _1-6 alkyl, and -NH _2; R ^15a and R ^16a are independently selected: C _1-4 alkyl, 1-6 substituents independently selected from the group C _1-4 alkyl substituted with: fluoro, oxo , -NH ₂ , C _1-4 alkoxy, and -OH, or cycloalkyl, and a cycloalkyl substituted with 1 to 5 substituents independently selected from the group consisting of: fluoro, chloro, -OH , And C _1-6 alkyl, or the nitrogen to which R ^15a and R ^16a are attached to them, and optionally 1 to 3 additional heteroatoms to form a heterocyclic group, which is optionally passed through 1 to five independently selected substituents: fluoro, chloro, C _1-6 alkyl, substituted by the following 1-9 substituents independently selected from the group C _1-6 alkyl group: fluoro, Chloro, C _1-4 alkoxy, pendant oxy, -OH, -NH ₂ , -N (H) C _1-4 alkyl, -N (C _1-4 alkyl) ₂ , and -CN, C _1-4 alkoxy, 1 to 4 substituents independently selected from the group consisting of C _1-4 alkoxy substituents: fluoro, oxo, -OH, -COOH, -NH _2, and - CN, pendant oxy, -NH ₂ , -N (H) C _1-4 alkyl, and -N (C _1-4 alkyl) ₂ ; and R ^17a is selected from: hydrogen and fluoro, or R ^15a With one of R ^16a with R ^17a , and optionally 1 to 3 additional heteroatoms to form a heterocyclyl, optionally substituted with 1 to 3 substituents independently selected from: fluoro, chloro, -OH, pendant oxy, C _1-4 alkane Aryl, C _1-4 alkoxy, and -NH ₂ ; or a pharmaceutically acceptable salt thereof.

For compounds of formula (IIa), suitably R ^10a is C _1-2 alkyl substituted with: pyrazolyl, pyrazolyl substituted with C _1-3 alkyl, Oxazolyl, substituted with C _1-3 alkyl Azolyl, imidazolyl, imidazolyl substituted with C _1-3 alkyl, triazolyl, triazolyl substituted with C _1-3 alkyl, thiazolyl, thiazolyl substituted with C _1-3 alkyl, -O-cyclopentyl, C _1-6 alkoxy, fluoro substituted one to six times C _1-6 alkoxy, tetrahydrofuranyl, pyridinyl, substituted by bromo group of the substituted pyridinyl, pyrimidinyl, or Pyridyl.

For compounds of formula (IIa), suitably R ^12a , R ^13a , and R ^14a are independently selected from: hydrogen, fluoro, chloro, bromo, -OH, boric acid, 1,3,6,2-dioxo Azaborane-octane-4,8-dione, -CN, -C (O) NHCH ₃ , -C (O) NHCH ₂ CH ₂ OH, -C (O) NHCH ₂ CH ₂ SO ₂ CH ₃ , -C (O) NHOCH ₃ , -C (O) NH ₂ , -C (O) OCH ₃ , -C (O) NHCH ₂ cyclopropyl, -C (O) NH cyclobutyl, Hydroxyl substituted, -CH ₂ morpholinyl, -CH ₂ OH, -CH ₂ NHCH ₂ CF ₃ , -CH ₂ NHCH ₂ CH ₂ SO ₂ CH ₃ , -CH ₂ SO ₂ CH ₃ , -CH (OH) CF _{3, -CH 3, -CF 3,} -OCH 3, pyrazolyl, Oxazolyl, and substituted once or twice with methyl An oxazolyl group, or R ^13a and R ^14a, together with the carbon atom to which they are attached to form an oxaborolyl, is optionally substituted with a hydroxyl group.

For compounds of formula (Ha), suitably R ^15a and R ^16a are independently selected: C _1-3 alkyl, fluoro substituted with 1 to 3 followed by C _1-3 alkyl and cyclopropyl, or R ^15a and R ^16a together with the nitrogen to which they are attached form: pyrrolidinyl, which is optionally substituted once or twice with: C _1-3 alkyl.

For compounds of formula (IIa), suitably R ^17a is selected from: hydrogen and fluorine; or one of R ^15a and R ^16a together with R ^17a , and optionally an additional heteroatom, to form: pyrrolidinyl , Or morpholinyl, each of them is optionally substituted 1 to 4 times with a C _1-3 alkyl group.

Included in the compounds of the invention and used in the methods of the invention are compounds of formula (IIb '): Wherein: R ^{10b ′} is a C _1-4 alkyl group, which is substituted with 1 to 3 substituents independently selected from the group consisting of pendant oxygen, phenyl substituted with pyrimidinyl, heterocyclyl, substituted with 1 to 4 Heterocyclyl substituted with independently selected from the following: fluoro, chloro, bromo, pendant, heteroaryl, _C1-6 alkyl, and independently selected from 1 to 5 C _1-6 alkyl substituted by substituents: fluoro, chloro, bromo, iodo, pendant, -CN, -OH, and -NH ₂ , heteroaryl, independently selected from 1 to 4 Heteroaryl substituted with the following substituents: fluoro, chloro, bromo, heteroaryl, C _1-6 alkyl, and C _1-6 substituted with 1 to 5 substituents independently selected from Alkyl: fluoro, chloro, bromo, iodo, pendant, -CN, -OH, and -NH ₂ , C _1-6 alkoxy, 1 to 9 substituents independently selected from the following Substituted C _1-6 alkoxy: fluoro, chloro, pendant oxy, -OH, -NH ₂ , -NHCH ₃ , and -N (CH3) 2, -O cycloalkyl, and 1 to 4 -O cycloalkyl substituted with independently selected substituents: fluoro, chloro, pendant, -OH, -NH ₂ , -NHCH ₃ , and -N (CH3) 2; R ^{12b '} , R ^{13b '} , and R ^14b' are independently selected from: hydrogen, fluoro, chloro, bromo, iodo, -OH, boric acid, 1,3,6,2-dioxazepine ^Alkane -4,8-diketone, -CN, -NR ^c1b R ^d1b , wherein R ^c1b and R ^d1b are independently selected from: hydrogen, C _1-5 alkyl, independently selected from 1 to 4 via C _1-5 alkyl substituted with substituent: fluoro, pendant oxy, -OH, -OC _1-5 alkyl, cycloalkyl, -COOH, -NH ₂ , -N (H) C _1-4 alkane -N (H) C _1-4 alkyl (where alkyl is substituted 1 to 3 times with fluorine), and -S (O) ₂ H, -S (O) ₂ H, -S (O) ₂ C _1-3 alkyl, heterocyclyl, C _1-4 alkoxy, by 1-7 substituents independently selected from the group C _1-4 alkoxy substituted with: fluoro, chloro, oxo side _{group, -OH, -NH 2, -NHCH 3} , and -N (CH3) 2, C _1-6 alkyl, 1-7 substituents independently selected from the group C _1-6 alkyl substituted with: Fluoro, chloro, bromo, iodo, pendant oxy, -CN, -OH, -OC _1-5 alkyl, heterocyclyl, -COOH, -S (O) ₂ H, -S (O) ₂ R ^x1a (wherein R ^x1a selected from fluoro and C _1-3 alkyl substituted with 1 to 3 followed by C _1-3 alkyl), and -NR ^a1b R ^b1b, and wherein R ^a1b lines independently selected R ^b1b from Hydrogen, C _1-5 alkoxy, C _1-5 alkyl, with 1 to 4 substituents independently selected from the group consisting of substituents of C _1-5 alkyl: fluoro, oxo, -OH, - OC _1-5 alkyl, cycloalkyl, -COOH, -NH ₂ , -S (O) ₂ H, and -S (O) ₂ R ^x1b , where R ^x1b is selected from C _1-3 alkyl and via C _1-3 alkyl substituted with fluoro groups 1 to 3 times; cycloalkyl, and cycloalkyl substituted with 1 to 4 substituents independently selected from: fluoro, pendant oxy, -OH,- O _1-5 alkyl, -COOH, and -NH ₂ , heteroaryl, and heteroaryl substituted with 1 to 3 substituents independently selected from: fluoro, chloro, C _1-6 alkane And C _1-6 alkyl substituted with 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, pendant, -CN, -OH, and -NH ₂ , Or two adjacent members of R ^{12b ′} , R ^{13b ′} , and R ^{14b ′} together form a non-aromatic ring containing 3 to 6 member atoms independently selected from the group consisting of carbon, nitrogen, sulfur, oxygen, and Boron to form an oxaborolyl, heterocyclyl, cycloalkyl, or heteroaryl, wherein the oxaborocyclopentadienyl, heterocyclyl, cycloalkyl, And miscellaneous Each based group optionally substituted with 1 to 3 substituents independently selected from the following substituents: fluoro, chloro, -OH, oxo, C _1-6 alkyl, and -NH _2; R ^{15b 'and} R ^{16b 'are} independently selected: C _1-4 alkyl, 1-6 substituents independently selected from the group C _1-4 alkyl substituted with: fluoro, oxo, -NH _2, C _1-4 alkoxy, and -OH, cycloalkyl, and cycloalkyl substituted with 1 to 5 substituents independently selected from: fluoro, chloro, -OH, and C _1-6 alkane R ^{15b ′} and R ^{16b ′} together with the nitrogen to which they are attached, and optionally 1 to 3 additional heteroatoms to form a heterocyclic group, which are optionally selected from 1 to 5 independently following substituents: fluoro, chloro, C _1-6 alkyl, 1-9 substituents independently selected from the group C _1-6 alkyl substituents: fluoro, chloro, C _{1- 4} alkoxy, pendant oxy, -OH, -NH ₂ , -N (H) C _1-4 alkyl, -N (C _1-4 alkyl) ₂ , and -CN, C _1-4 alkoxy Group, a C _1-4 alkoxy group substituted with 1 to 4 substituents independently selected from a fluoro group, a pendant oxygen group, -OH, -COOH, -NH ₂ , and -CN, a pendant oxygen group, _{-NH 2, -N (H) C} 1-4 Group, and -N (C _1-4 alkyl) _2, or R ^{15b 'and} R ^16b' are one of the R ^{17b 'together,} and optionally 1 to 3 additional hetero atoms, to form a heterocyclic group , Which is substituted with 1 to 3 substituents independently selected from: fluoro, -OH, C _1-4 alkyl, and C _1-4 alkoxy; and R ^{17b '} is selected from: hydrogen and A fluoro group, or one of R ^{15b ′} and R ^{16b ′} together with R ^{17b ′} , and optionally 1 to 3 additional heteroatoms to form a heterocyclic group, which is independently selected from the following via 1 to 3 Substituted with: fluoro, -OH, C _1-4 alkyl, and C _1-4 alkoxy; or a pharmaceutically acceptable salt thereof.

For compounds of formula (IIb '), suitably R ^10b' is C _1-2 alkyl substituted with: phenyl substituted with pyrimidinyl, pyrazolyl, pyrazolyl substituted with C _1-3 alkyl, Pyridine _Pyridyl substituted with C _1-3 alkyl Base Phenyl _Ci, substituted with C _1-3 alkyl base, Oxazolyl, substituted with C _1-3 alkyl Azolyl, imidazolyl, imidazolyl substituted with C _1-3 alkyl, morpholinyl, morpholinyl substituted 1 or 2 times with C _1-3 alkyl, morpholin substituted with pendant oxy Base, two Alkyl, two substituted with C _1-3 alkyl Alkyl, 4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine ; Triazolyl, triazolyl substituted with C _1-3 alkyl, thiazolyl, thiazolyl substituted with C _1-3 alkyl, -O cyclopentyl, C _1-6 alkoxy, fluorine group substituted with 1-6 followed by C _1-6 alkoxy, hydroxy substituted C _1-6 alkoxy group of tetrahydrofuran, pyridinyl, substituted by bromo group of the substituted pyridinyl, pyrimidinyl, or pyridyl.

For compound formula (IIb '), suitably ^R12b' , ^{R13b '} , and ^R14b' are independently selected from: hydrogen, fluoro, chloro, bromo, -OH, boric acid, 1,3,6, 2-dioxaazepine-4,8-dione, -CN, -C (O) NHCH ₃ , -C (O) NHCH ₂ CH ₃ , -C (O) NHCH ₂ CF ₂ H , -C (O) NHCH ₂ CH ₂ OH, -C (O) NHCH ₂ CH ₂ SO ₂ CH ₃ , -C (O) NHOCH ₃ , -C (O) NH ₂ , -C (O) OCH ₃ , -C (O) NHCH ₂ cyclopropyl, -C (O) NH cyclobutyl, optionally substituted with a hydroxyl group, -CH ₂ morpholinyl, -CH ₂ OH, -CH ₂ NHCH ₂ CF ₃ ,- CH ₂ NHCH ₂ CH ₂ SO ₂ CH ₃ , -CH ₂ SO ₂ CH ₃ , -CH (OH) CF ₃ , -CH ₃ , -CF ₃ , -OCH ₃ , methoxy-d ₃ , -NHC (O ) CH ₃ , -NH ₂ , -NHSO ₂ CH ₃ , morpholinylpyrazolyl, Oxazolyl, and substituted once or twice with methyl An oxazolyl group, or R ^{13b ′} and R ^{14b ′} together with the carbon atom to which they are attached to form an oxaborolyl, is optionally substituted with a hydroxyl group.

For formula (IIb ') compound, suitably R ^15b' and R ^{16b 'are} independently selected: C _1-3 alkyl, fluoro substituted with 1 to 3 followed by C _1-3 alkyl, cyclopropyl and , R ^{15b ′} and R ^{16b ′} together with the nitrogen to which they are attached to form: aziridinyl, pyrrolidinyl, each of which is optionally substituted once or twice as follows: C _1-3 alkyl or via A fluoro group is substituted 1 to 3 times with a C _1-3 alkyl group, or one of R ^{15b ′} and R ^{16b ′} together with R ^{17b ′} , and optionally an additional heteroatom to form: pyrrolidinyl, Or morpholinyl, each of them is optionally substituted 1 to 4 times with a C _1-3 alkyl group.

For compound formula (IIb '), suitably R ^17b' is selected from: hydrogen and fluorine; or one of R ^{15b '} and R ^{16b '} together with R ^{17b '} , and optionally 1 additional heteroatom, to Formation: pyrrolidinyl, or morpholinyl, each of which is optionally substituted 1 to 4 times with a C _1-3 alkyl group.

Included in the compounds of the invention and used in the methods of the invention are compounds of formula (III): Where: R ²⁰ is C _1-2 alkyl substituted with: phenyl substituted with pyrimidinyl, pyrazolyl, pyrazolyl substituted with C _1-3 alkyl, Oxazolyl, substituted with C _1-3 alkyl Azolyl, imidazolyl, imidazolyl substituted with C _1-3 alkyl, triazolyl, triazolyl substituted with C _1-3 alkyl, thiazolyl, thiazolyl substituted with C _1-3 alkyl, -O-cyclopentyl, C _1-6 alkoxy, fluoro substituted one to six times C _1-6 alkoxy, tetrahydrofuranyl, pyridinyl, substituted by bromo group of the substituted pyridinyl, pyrimidinyl, or Pyridyl; R ²¹ is selected from: hydrogen, fluoro, chloro, bromo, -OH, -CN, -C (O) NHCH ₃ , -C (O) NHCH ₂ CH ₂ OH, -C (O) NHCH ₂ CH ₂ SO ₂ CH ₃ , -C (O) NHOCH ₃ , -C (O) NH ₂ , -C (O) OCH ₃ , -C (O) NHCH ₂ cyclopropyl, -C (O) NH Cyclobutyl, optionally substituted with hydroxy, -CH ₂ morpholinyl, -CH ₂ OH, -CH ₂ NHCH ₂ CF ₃ , -CH ₂ NHCH ₂ CH ₂ SO ₂ CH ₃ , -CH ₂ SO ₂ CH _{3, -CH (OH) CF 3} , -CH 3, -CF 3, -OCH 3, pyrazolyl, Oxazolyl, and substituted once or twice with methyl Zolyl, R ²² , R ²³ , and R ²⁴ are independently selected from: hydrogen, fluoro, chloro, bromo, -OH, boric acid, 1,3,6,2-dioxazepine Alkane-4,8-dione, -CN, -C (O) NHCH ₃ , -C (O) NHCH ₂ CH ₂ OH, -C (O) NHCH ₂ CH ₂ SO ₂ CH ₃ , -C (O) NHOCH ₃ , -C (O) NH ₂ , -C (O) OCH ₃ , -C (O) NHCH ₂ cyclopropyl, -C (O) NH cyclobutyl, optionally substituted with a hydroxyl group, -CH ₂ Morpholinyl, -CH ₂ OH, -CH ₂ NHCH ₂ CF ₃ , -CH ₂ NHCH ₂ CH ₂ SO ₂ CH ₃ , -CH ₂ SO ₂ CH ₃ , -CH (OH) CF ₃ , -CH ₃ , -CF ₃ , -OCH ₃ , -NHC (O) CH ₃ , -NH ₂ , -NHSO ₂ CH ₃ , morpholinylpyrazolyl, Oxazolyl, and substituted once or twice with methyl An oxazolyl group, or R ²³ and R ²⁴ together with the carbon atom to which they are attached to form an oxaborolyl, optionally substituted with a hydroxyl group; R ²⁵ and R ²⁶ are independently selected from : C _1-3 alkyl, fluoro substituted with 1 to 3 followed by C _1-3 alkyl and cyclopropyl, or R ²⁵ R ²⁶ are attached and the nitrogen and their together to form: pyrrolidinyl, It is optionally substituted once or twice with a C _1-3 alkyl group; and R ²⁷ is selected from: hydrogen and fluorine; or one of R ²⁵ and R ²⁶ together with R ²⁷ , and optionally 1 Extra heteroatoms to form: pyrrolidinyl, or morpholinyl, each of which is optionally substituted 1 to 4 times with C _1-3 alkyl; or a pharmaceutically acceptable salt thereof.

For compounds of formula (III), suitably R ²⁰ is a C _1-2 alkyl substituted with: pyrazolyl, a pyrazolyl substituted with C _1-3 alkyl, Azolyl, substituted with C _1-3 alkyl Azolyl, imidazolyl, imidazolyl substituted with C _1-3 alkyl, triazolyl, triazolyl substituted with C _1-3 alkyl, thiazolyl, thiazolyl substituted with C _1-3 alkyl, C _1-6 alkoxy, fluoro substituted one to six times C _1-6 alkoxy, tetrahydrofuranyl, pyridinyl, substituted by bromo group of pyridinyl, pyrimidinyl, or pyridyl substituted the.

For compounds of formula (III), suitably R ²¹ is selected from the group consisting of: hydrogen, fluoro, chloro, bromo, -OH, boric acid, 1,3,6,2-dioxazepine-4 , 8-diketone, -CN, -C (O) NHCH ₃ , -C (O) NHCH ₂ CH ₂ OH, -C (O) NHCH ₂ CH ₂ SO ₂ CH ₃ , -C (O) NHOCH ₃ , -C (O) NH ₂ , -C (O) OCH ₃ , -C (O) NHCH ₂ cyclopropyl, -C (O) NH cyclobutyl, optionally substituted with a hydroxyl group, -CH ₂ moforin Group, -CH ₂ OH, -CH ₂ NHCH ₂ CF ₃ , -CH ₂ NHCH ₂ CH ₂ SO ₂ CH ₃ , -CH ₂ SO ₂ CH ₃ , -CH (OH) CF ₃ , -CH ₃ , -CF ₃ , -OCH ₃ , pyrazolyl, Oxazolyl, and substituted once or twice with methyl An oxazolyl group, or R ²³ and R ²⁴ together with the carbon atom to which they are attached to form an oxaborolyl, is optionally substituted with a hydroxyl group.

For compounds of formula (III), suitably R ²² , R ²³ , and R ²⁴ are independently selected from: hydrogen, fluoro, chloro, bromo, -OH, boric acid, 1,3,6,2-dioxy Azaborane-octane-4,8-dione, -CN, -C (O) NHCH ₃ , -C (O) NHCH ₂ CH ₂ OH, -C (O) NHCH ₂ CH ₂ SO ₂ CH ₃ , -C (O) NHOCH ₃ , -C (O) NH ₂ , -C (O) OCH ₃ , -C (O) NHCH ₂ cyclopropyl, -C (O) NH cyclobutyl, Hydroxyl substituted, -CH ₂ morpholinyl, -CH ₂ OH, -CH ₂ NHCH ₂ CF ₃ , -CH ₂ NHCH ₂ CH ₂ SO ₂ CH ₃ , -CH ₂ SO ₂ CH ₃ , -CH (OH) CF _{3, -CH 3, -CF 3,} -OCH 3, -NHC (O) CH 3, -NH 2, -NHSO 2 CH 3, it Fulin Ji pyrazolyl, Oxazolyl, and substituted once or twice with methyl An oxazolyl group, or R ²³ and R ²⁴ together with the carbon atom to which they are attached to form an oxaborolyl, is optionally substituted with a hydroxyl group.

The compound of formula (III), suitably R ²⁵ and R ²⁶ are independently selected: C _1-3 alkyl, fluoro substituted with 1 to 3 followed by C _1-3 alkyl and cyclopropyl, or R ²⁵ and R ²⁶ together with the nitrogen to which they are attached form: pyrrolidinyl, which is optionally substituted once or twice with a C _1-3 alkyl group.

For compounds of formula (III), suitably R ²⁷ is selected from: hydrogen and fluorine; or one of R ²⁵ and R ²⁶ together with R ²⁷ and optionally an additional heteroatom to form: pyrrolidinyl , Or morpholinyl, each of them is optionally substituted 1 to 4 times with a C _1-3 alkyl group.

Included in the compounds of the present invention and used in the methods of the present invention are compounds of formula (IIIa): Wherein: R ^20a is C _1-2 alkyl substituted with: phenyl substituted with pyrimidinyl, pyrazolyl, pyrazolyl substituted with C _1-3 alkyl, Oxazolyl, substituted with C _1-3 alkyl Azolyl, imidazolyl, imidazolyl substituted with C _1-3 alkyl, triazolyl, triazolyl substituted with C _1-3 alkyl, thiazolyl, thiazolyl substituted with C _1-3 alkyl, -O-cyclopentyl, C _1-6 alkoxy, fluoro substituted one to six times C _1-6 alkoxy, tetrahydrofuranyl, pyridinyl, substituted by bromo group of the substituted pyridinyl, pyrimidinyl, or Pyridyl; R ^22a , R ^23a , and R ^24a are independently selected from: hydrogen, fluoro, chloro, bromo, -OH, boric acid, 1,3,6,2-dioxazepine Alkane-4,8-dione, -CN, -C (O) NHCH ₃ , -C (O) NHCH ₂ CH ₂ OH, -C (O) NHCH ₂ CH ₂ SO ₂ CH ₃ , -C (O) NHOCH ₃ , -C (O) NH ₂ , -C (O) OCH ₃ , -C (O) NHCH ₂ cyclopropyl, -C (O) NH cyclobutyl, optionally substituted with a hydroxyl group, -CH ₂ Morpholinyl, -CH ₂ OH, -CH ₂ NHCH ₂ CF ₃ , -CH ₂ NHCH ₂ CH ₂ SO ₂ CH ₃ , -CH ₂ SO ₂ CH ₃ , -CH (OH) CF ₃ , -CH ₃ , -CF ₃ , -OCH ₃ , -NHC (O) CH ₃ , -NH ₂ , -NHSO ₂ CH ₃ , morpholinylpyrazolyl, Oxazolyl, and substituted once or twice with methyl An oxazolyl group, or R ^23a and R ^24a together with the carbon atom to which they are attached to form an oxaborolyl, optionally substituted with a hydroxy group; R ^25a and R ^26a are independently selected from : C _1-3 alkyl, fluoro substituted with 1 to 3 followed by C _1-3 alkyl and cyclopropyl, or R ^25a and R ^26a together with the nitrogen to form their sum are attached together: pyrrolidinyl, It is optionally substituted by: C _1-3 alkyl once or twice; and R ^27a is selected from: hydrogen and fluorine; or one of R ^25a and R ^26a together with R ^27a , and optionally 1 Additional heteroatoms to form: pyrrolidinyl, or morpholinyl, each of which is optionally substituted 1 to 4 times with C _1-3 alkyl; or a pharmaceutically acceptable salt thereof.

For compound formula (IIIa), suitably R ^20a is C _1-2 alkyl substituted with: pyrazolyl, pyrazolyl substituted with C _1-3 alkyl, Oxazolyl, substituted with C _1-3 alkyl Azolyl, imidazolyl, imidazolyl substituted with C _1-3 alkyl, triazolyl, triazolyl substituted with C _1-3 alkyl, thiazolyl, thiazolyl substituted with C _1-3 alkyl, C _1-6 alkoxy, fluoro substituted one to six times C _1-6 alkoxy, tetrahydrofuranyl, pyridinyl, substituted by bromo group of pyridinyl, pyrimidinyl, or pyridyl substituted the.

For compound formula (IIIa), suitably R ^22a , R ^23a , and R ^24a are independently selected from: hydrogen, fluoro, chloro, bromo, -OH, boric acid, 1,3,6,2-dioxy Azaborane-octane-4,8-dione, -CN, -C (O) NHCH ₃ , -C (O) NHCH ₂ CH ₂ OH, -C (O) NHCH ₂ CH ₂ SO ₂ CH ₃ , -C (O) NHOCH ₃ , -C (O) NH ₂ , -C (O) OCH ₃ , -C (O) NHCH ₂ cyclopropyl, -C (O) NH cyclobutyl, Hydroxyl substituted, -CH ₂ morpholinyl, -CH ₂ OH, -CH ₂ NHCH ₂ CF ₃ , -CH ₂ NHCH ₂ CH ₂ SO ₂ CH ₃ , -CH ₂ SO ₂ CH ₃ , -CH (OH) CF _{3, -CH 3, -CF 3,} -OCH 3, -NHC (O) CH 3, -NH 2, -NHSO 2 CH 3, it Fulin Ji pyrazolyl, Oxazolyl, and substituted once or twice with methyl An oxazolyl group, or R ^23a and R ^24a, together with the carbon atom to which they are attached to form an oxaborolyl, is optionally substituted with a hydroxyl group.

For compounds of formula (Ilia), suitably R ^25a and R ^26a are independently selected: C _1-3 alkyl, fluoro substituted with 1 to 3 followed by C _1-3 alkyl and cyclopropyl, or R ^25a and R ^26a together with the nitrogen to which they are attached form: pyrrolidinyl, which is optionally substituted once or twice with: C _1-3 alkyl.

For compound formula (IIIa), suitably R ^27a is selected from: hydrogen and fluorine; or one of R ^25a and R ^26a together with R ^27a , and optionally an additional heteroatom to form: pyrrolidinyl , Or morpholinyl, each of them is optionally substituted 1 to 4 times with a C _1-3 alkyl group.

Included in the compounds of the invention and used in the methods of the invention are compounds of formula (IV): Where: R ²⁰ is C _1-2 alkyl substituted with: phenyl substituted with pyrimidinyl, pyrazolyl, pyrazolyl substituted with C _1-3 alkyl, Oxazolyl, substituted with C _1-3 alkyl Oxazolyl, imidazolyl, imidazolyl substituted with C _1-3 alkyl, morpholinyl, 1 or 2 times substituted with C _1-3 alkyl, morpholinyl, triazolyl, via C _1-3 the alkyl-substituted triazolyl, thiazolyl, substituted by the C _1-3 alkyl-thiazolyl, -O-cyclopentyl, C _1-6 alkoxy, fluoro substituted C _1-6 followed 1-6 Alkoxy, tetrahydrofuran, pyridyl, pyridyl substituted with bromo, or pyridyl substituted with pyrimidinyl; R ²¹ is selected from: hydrogen, fluoro, chloro, bromo, -OH, -CN,- C (O) NHCH ₃ , -C (O) NHCH ₂ CH ₂ OH, -C (O) NHCH ₂ CH ₂ SO ₂ CH ₃ , -C (O) NHOCH ₃ , -C (O) NH ₂ , -C (O) OCH ₃ , -C (O) NHCH ₂ cyclopropyl, -C (O) NH cyclobutyl, optionally substituted with a hydroxyl group, -CH ₂ morpholinyl, -CH ₂ OH, -CH ₂ NHCH ₂ CF ₃ , -CH ₂ NHCH ₂ CH ₂ SO ₂ CH ₃ , -CH ₂ SO ₂ CH ₃ , -CH (OH) CF ₃ , -CH ₃ , -CF ₃ , -OCH ₃ , pyrazolyl, Oxazolyl, and substituted once or twice with methyl Zolyl, R ²² , R ²³ , and R ²⁴ are independently selected from: hydrogen, fluoro, chloro, bromo, -OH, boric acid, 1,3,6,2-dioxazepine Alkan-4,8-dione, -CN, -C (O) NHCH ₃ , -C (O) NHCH ₂ CH ₃ , -C (O) NHCH ₂ CH ₂ OH, -C (O) NHCH ₂ CH ₂ SO ₂ CH ₃ , -C (O) NHOCH ₃ , -C (O) NH ₂ , -C (O) OCH ₃ , -C (O) NHCH ₂ cyclopropyl, -C (O) NH cyclobutyl, Substituted with a hydroxy group as necessary, -CH ₂ morpholinyl, -CH ₂ OH, -CH ₂ NHCH ₂ CF ₃ , -CH ₂ NHCH ₂ CH ₂ SO ₂ CH ₃ , -CH ₂ SO ₂ CH ₃ , -CH (OH) CF ₃ , -CH ₃ , -CF ₃ , -OCH ₃ , -NHC (O) CH ₃ , -NH ₂ , -NHSO ₂ CH ₃ , morpholinylpyrazolyl, Oxazolyl, and substituted once or twice with methyl An oxazolyl group, or R ²³ and R ²⁴ together with the carbon atom to which they are attached to form an oxaborolyl, optionally substituted with a hydroxyl group; R ²⁵ and R ²⁶ are independently selected from : C _1-3 alkyl, fluoro substituted with 1 to 3 followed by C _1-3 alkyl and cyclopropyl, or R ²⁵ and R ²⁶ together with the nitrogen of their attached together to form: a nitrogen Ta group, Pyrrolidinyl, each of which is optionally substituted: C _1-3 alkyl is substituted once or twice; and R ²⁷ is selected from: hydrogen and fluorine; or one of R ²⁵ and R ²⁶ and R ²⁷ Together, and optionally 1 additional heteroatom to form: pyrrolidinyl, or morpholinyl, each of which is optionally substituted 1 to 4 times with C _1-3 alkyl; or pharmaceutically acceptable Accepted salt.

For compound formula (IV), suitably R ²⁰ is a C _1-2 alkyl substituted with: pyrazolyl, a pyrazolyl substituted with C _1-3 alkyl, Oxazolyl, substituted with C _1-3 alkyl Oxazolyl, imidazolyl, imidazolyl substituted with C _1-3 alkyl, morpholinyl, 1 or 2 times substituted with C _1-3 alkyl, morpholinyl, triazolyl, via C _1-3 the alkyl-substituted triazolyl, thiazolyl, substituted by the C _1-3 alkyl thiazolyl, C _1-6 alkoxy, fluoro substituted one to six times a C _1-6 alkoxy group, tetrahydrofuran, Pyridyl, pyridyl substituted with bromo, or pyridyl substituted with pyrimidinyl.

For compound formula (IV), suitably R ²¹ is selected from: hydrogen, fluoro, chloro, bromo, -OH, boric acid, 1,3,6,2-dioxazepine-4 , 8-diketone, -CN, -C (O) NHCH ₃ , -C (O) NHCH ₂ CH ₂ OH, -C (O) NHCH ₂ CH ₂ SO ₂ CH ₃ , -C (O) NHOCH ₃ , -C (O) NH ₂ , -C (O) OCH ₃ , -C (O) NHCH ₂ cyclopropyl, -C (O) NH cyclobutyl, optionally substituted with a hydroxyl group, -CH ₂ morpholin Group, -CH ₂ OH, -CH ₂ NHCH ₂ CF ₃ , -CH ₂ NHCH ₂ CH ₂ SO ₂ CH ₃ , -CH ₂ SO ₂ CH ₃ , -CH (OH) CF ₃ , -CH ₃ , -CF ₃ , -OCH ₃ , pyrazolyl, Oxazolyl, and substituted once or twice with methyl An oxazolyl group, or R ²³ and R ²⁴ together with the carbon atom to which they are attached to form an oxaborolyl, is optionally substituted with a hydroxyl group.

For compound formula (IV), suitably R ²² , R ²³ , and R ²⁴ are independently selected from: hydrogen, fluoro, chloro, bromo, -OH, boric acid, 1,3,6,2-dioxy Azaborane-octane-4,8-dione, -CN, -C (O) NHCH ₃ , -C (O) NHCH ₂ CH ₃ , -C (O) NHCH ₂ CH ₂ OH, -C ( O) NHCH ₂ CH ₂ SO ₂ CH ₃ , -C (O) NHOCH ₃ , -C (O) NH ₂ , -C (O) OCH ₃ , -C (O) NHCH ₂ cyclopropyl, -C (O ) NH cyclobutyl, optionally substituted with hydroxy, -CH ₂ morpholinyl, -CH ₂ OH, -CH ₂ NHCH ₂ CF ₃ , -CH ₂ NHCH ₂ CH ₂ SO ₂ CH ₃ , -CH ₂ SO ₂ CH ₃ , -CH (OH) CF ₃ , -CH ₃ , -CF ₃ , -OCH ₃ , -NHC (O) CH ₃ , -NH ₂ , -NHSO ₂ CH ₃ , morpholinyl pyrazolyl, Oxazolyl, and substituted once or twice with methyl An oxazolyl group, or R ²³ and R ²⁴ together with the carbon atom to which they are attached to form an oxaborolyl, is optionally substituted with a hydroxyl group.

For compounds of formula (IV), suitably R ²⁵ and R ²⁶ are independently selected: C _1-3 alkyl, fluoro substituted with 1 to 3 followed by C _1-3 alkyl and cyclopropyl, or R ²⁵ and R ²⁶ together with the nitrogen to which they are attached to form: azepine, pyrrolidinyl, each of which is optionally substituted once or twice with: C _1-3 alkyl.

For compound formula (IV), suitably R ²⁷ is selected from: hydrogen and fluorine; or one of R ²⁵ and R ²⁶ together with R ²⁷ and optionally an additional heteroatom to form: pyrrolidinyl , Or morpholinyl, each of them is optionally substituted 1 to 4 times with a C _1-3 alkyl group.

Included in the compounds of the invention and used in the methods of the invention are compounds of formula (IVb): Where: R ^20b is C _1-2 alkyl substituted with: phenyl substituted with pyrimidinyl, pyrazolyl, pyrazolyl substituted with C _1-3 alkyl, pyr _Pyridyl substituted with C _1-3 alkyl Base Phenyl _Ci, substituted with C _1-3 alkyl base, Oxazolyl, substituted with C _1-3 alkyl Azolyl, imidazolyl, imidazolyl substituted with C _1-3 alkyl, morpholinyl, morpholinyl substituted 1 or 2 times with C _1-3 alkyl, morpholin substituted with pendant oxy Base, two Alkyl, substituted by C _1-3 alkyl Alkyl, 4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine ; Triazolyl, triazolyl substituted with C _1-3 alkyl, thiazolyl, thiazolyl substituted with C _1-3 alkyl, -O cyclopentyl, C _1-6 alkoxy, fluoro substituted with 1-6 followed by C _1-6 alkoxy, unsubstituted of substituted hydroxyl groups of C _1-6 alkoxy, tetrahydrofuranyl, pyridinyl, substituted by bromo group of pyridinyl, pyrimidinyl, or pyridinyl; R ^21b Is selected from: hydrogen, fluoro, chloro, bromo, -OH, -CN, -NH ₂ , -C (O) NHCH ₃ , -C (O) NHCH ₂ CH ₂ OH, -C (O) NHCH ₂ CH ₂ SO ₂ CH ₃ , -C (O) NHOCH ₃ , -C (O) NH ₂ , -C (O) OCH ₃ , -C (O) NHCH ₂ cyclopropyl, -C (O) NH ring Butyl, optionally substituted with hydroxy, -CH ₂ morpholinyl, -CH ₂ OH, -CH ₂ NHCH ₂ CF ₃ , -CH ₂ NHCH ₂ CH ₂ SO ₂ CH ₃ , -CH ₂ SO ₂ CH ₃ , -CH (OH) CF ₃ , -CH ₃ , -CF ₃ , -OCH ₃ , methoxy-d3, pyrazolyl, Oxazolyl, and substituted once or twice with methyl Oxazolyl; R ^22b , R ^23b , and R ^24b are independently selected from: hydrogen, fluoro, chloro, bromo, -OH, boric acid, 1,3,6,2-dioxazepine Alkane-4,8-dione, -CN, -C (O) NHCH ₃ , -C (O) NHCH ₂ CH ₃ , -C (O) NHCH ₂ CF ₂ H, -C (O) NHCH ₂ CH ₂ OH, -C (O) NHCH ₂ CH ₂ SO ₂ CH ₃ , -C (O) NHOCH ₃ , -C (O) NH ₂ , -C (O) OCH ₃ , -C (O) NHCH ₂ cyclopropyl , -C (O) NH cyclobutyl, optionally substituted with a hydroxyl group, -CH ₂ morpholinyl, -CH ₂ OH, -CH ₂ NHCH ₂ CF ₃ , -CH ₂ NHCH ₂ CH ₂ SO ₂ CH ₃ , -CH ₂ SO ₂ CH ₃ , -CH (OH) CF ₃ , -CH ₃ , -CF ₃ , -OCH ₃ , methoxy -d ₃ , -NHC (O) CH ₃ , -NH ₂ , -NHSO ₂ CH ₃ , morpholinyl pyrazolyl, Oxazolyl, and substituted once or twice with methyl Oxazolyl, or R ^23b and R ^24b together with the carbon atom to which they are attached to form oxaborolyl, optionally substituted with a hydroxyl group; R ^25b and R ^26b are independently selected from : C _1-3 alkyl, fluoro substituted with 1 to 3 followed by C _1-3 alkyl, and cyclopropyl, R ^25b and R ^26b together with the nitrogen of their attached together to form: a nitrogen Ta, pyrrolyl piperidinyl, their respective lines or two optionally substituted by one of the following: C _1-3 alkyl or fluorine substituted with 1 to 3 followed by C _1-3 alkyl, or R ^25b and R ^26b one of Together with R ^27b , and optionally an additional heteroatom to form: pyrrolidinyl, or morpholinyl, each of which is optionally substituted with C _1-3 alkyl groups 1 to 4 times; and R ^27b is selected from: hydrogen and fluorine; or one of R ^25b and R ^26b together with R ^27b , and optionally an additional heteroatom to form: pyrrolidinyl, or morpholinyl, etc. Each is optionally substituted 1 to 4 times with a C _1-3 alkyl group; or a pharmaceutically acceptable salt thereof.

For compounds of formula (IVb), suitably R ^20b is C _1-2 alkyl substituted with: phenyl substituted with pyrimidinyl, pyrazolyl, pyrazolyl substituted with C _1-3 alkyl, pyr _Pyridyl substituted with C _1-3 alkyl Base Phenyl _Ci, substituted with C _1-3 alkyl base, Oxazolyl, substituted with C _1-3 alkyl Azolyl, imidazolyl, imidazolyl substituted with C _1-3 alkyl, morpholinyl, morpholinyl substituted 1 or 2 times with C _1-3 alkyl, morpholin substituted with pendant oxy Base, two Alkyl, substituted by C _1-3 alkyl Alkyl, 4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine ; Triazolyl, triazolyl substituted with C _1-3 alkyl, thiazolyl, thiazolyl substituted with C _1-3 alkyl, -O cyclopentyl, C _1-6 alkoxy, fluorine group substituted with 1-6 followed by C _1-6 alkoxy, hydroxy substituted C _1-6 alkoxy group of tetrahydrofuran, pyridinyl, substituted by bromo group of the substituted pyridinyl, pyrimidinyl, or pyridyl.

For compounds of formula (IVb), suitably R ^21b is selected from: hydrogen, fluoro, chloro, bromo, -OH, -CN, -NH ₂ , -C (O) NHCH ₃ , -C (O) NHCH ₂ CH ₂ OH, -C (O) NHCH ₂ CH ₂ SO ₂ CH ₃ , -C (O) NHOCH ₃ , -C (O) NH ₂ , -C (O) OCH ₃ , -C (O) NHCH ₂ Cyclopropyl, -C (O) NH cyclobutyl, optionally substituted with hydroxy, -CH ₂ morpholinyl, -CH ₂ OH, -CH ₂ NHCH ₂ CF ₃ , -CH ₂ NHCH ₂ CH ₂ SO ₂ CH ₃ , -CH ₂ SO ₂ CH ₃ , -CH (OH) CF ₃ , -CH ₃ , -CF ₃ , -OCH ₃ , methoxy-d3, pyrazolyl, Oxazolyl, and substituted once or twice with methyl Azolyl, for compounds of formula (IVb), suitably R ^22b , R ^23b , and R ^24b are independently selected from: hydrogen, fluoro, chloro, bromo, -OH, boric acid, 1,3,6,2 -Dioxazepine-4,8-dione, -CN, -C (O) NHCH ₃ , -C (O) NHCH ₂ CH ₃ , -C (O) NHCH ₂ CF ₂ H, -C (O) NHCH ₂ CH ₂ OH, -C (O) NHCH ₂ CH ₂ SO ₂ CH ₃ , -C (O) NHOCH ₃ , -C (O) NH ₂ , -C (O) OCH ₃ ,- C (O) NHCH ₂ cyclopropyl, -C (O) NH cyclobutyl, optionally substituted with a hydroxyl group, -CH ₂ morpholinyl, -CH ₂ OH, -CH ₂ NHCH ₂ CF ₃ , -CH ₂ NHCH ₂ CH ₂ SO ₂ CH ₃ , -CH ₂ SO ₂ CH ₃ , -CH (OH) CF ₃ , -CH ₃ , -CF ₃ , -OCH ₃ , methoxy-d ₃ , -NHC (O) CH ₃ , -NH ₂ , -NHSO ₂ CH ₃ , morpholinylpyrazolyl, Oxazolyl, and substituted once or twice with methyl An oxazolyl group, or R ^23b and R ^24b, together with the carbon atom to which they are attached to form an oxaborolyl, is optionally substituted with a hydroxyl group.

For formula (IVb) compound, suitably R ^25b and R ^26b are independently selected: C _1-3 alkyl, fluoro substituted with 1 to 3 followed by C _1-3 alkyl, and cyclopropyl, R ^25b And R ^26b together with the nitrogen to which they are attached to form: aziridinyl, pyrrolidinyl, each of which is optionally substituted once or twice with the following: C _1-3 alkyl or 1 to 2 substituted with fluoro 3 times C _1-3 alkyl, or one of R ^25b and R ^26b together with R ^27b , and optionally an additional heteroatom to form: pyrrolidinyl, or morpholinyl, etc. Each is optionally substituted 1 to 4 times with a C _1-3 alkyl group. For compounds of formula (IVb), suitably R ^27b is selected from: hydrogen and fluorine; or one of R ^25b and R ^26b together with R ^27b , and optionally one additional heteroatom to form: pyrrolidinyl , Or morpholinyl, each of them is optionally substituted 1 to 4 times with a C _1-3 alkyl group.

Included in the compounds of the invention and used in the methods of the invention are compounds of formula (IVa): Wherein: R ^20a is C _1-2 alkyl substituted with: phenyl substituted with pyrimidinyl, pyrazolyl, pyrazolyl substituted with C _1-3 alkyl, Oxazolyl, substituted with C _1-3 alkyl Oxazolyl, imidazolyl, imidazolyl substituted with C _1-3 alkyl, morpholinyl, 1 or 2 times substituted with C _1-3 alkyl, morpholinyl, triazolyl, via C _1-3 the alkyl-substituted triazolyl, thiazolyl, substituted by the C _1-3 alkyl-thiazolyl, -O-cyclopentyl, C _1-6 alkoxy, fluoro substituted C _1-6 followed 1-6 Alkoxy, tetrahydrofuran, pyridyl, pyridyl substituted with bromoyl, or pyridyl substituted with pyrimidinyl; R ^22a , R ^23a , and R ^24a are independently selected from: hydrogen, fluoro, chloro, bromo , -OH, boric acid, 1,3,6,2-dioxazepine-4,8-diketone, -CN, -C (O) NHCH ₃ , -C (O) NHCH ₂ CH ₃ , -C (O) NHCH ₂ CH ₂ OH, -C (O) NHCH ₂ CH ₂ SO ₂ CH ₃ , -C (O) NHOCH ₃ , -C (O) NH ₂ , -C (O) OCH ₃ , -C (O) NHCH ₂ cyclopropyl, -C (O) NH cyclobutyl, optionally substituted with a hydroxyl group, -CH ₂ morpholinyl, -CH ₂ OH, -CH ₂ NHCH ₂ CF ₃ , -CH ₂ NHCH ₂ CH ₂ SO ₂ CH ₃ , -CH ₂ SO ₂ CH ₃ , -CH (OH) CF ₃ , -CH ₃ , -CF ₃ , -OCH ₃ , -NHC (O) CH ₃ ,- NH ₂ , -NHSO ₂ CH ₃ , morpholinylpyrazolyl, Oxazolyl, and substituted once or twice with methyl An oxazolyl group, or R ^23a and R ^24a together with the carbon atom to which they are attached to form an oxaborolyl, optionally substituted with a hydroxy group; R ^25a and R ^26a are independently selected from : C _1-3 alkyl, fluoro substituted with 1 to 3 followed by C _1-3 alkyl and cyclopropyl, or R ^25a and R ^26a together with the nitrogen of their attached together to form: a nitrogen Ta group, Pyrrolidinyl, each of which is optionally substituted once or twice with a C _1-3 alkyl group; and R ^27a is selected from: hydrogen and fluorine; or one of R ^25a and R ^26a together with R ^27a , And optionally an additional heteroatom to form: pyrrolidinyl, or morpholinyl, each of which is optionally substituted with C _1-3 alkyl groups 1 to 4 times; or pharmaceutically acceptable salt.

For compounds of formula (IVa), suitably R ^20a is C _{1-2 in which} alkyl is substituted with: pyrazolyl, pyrazolyl substituted with C _1-3 alkyl, Oxazolyl, substituted with C _1-3 alkyl Oxazolyl, imidazolyl, imidazolyl substituted with C _1-3 alkyl, morpholinyl, 1 or 2 times substituted with C _1-3 alkyl, morpholinyl, triazolyl, via C _1-3 the alkyl-substituted triazolyl, thiazolyl, substituted by the C _1-3 alkyl thiazolyl, C _1-6 alkoxy, fluoro substituted one to six times a C _1-6 alkoxy group, tetrahydrofuran, Pyridyl, pyridyl substituted with bromo, or pyridyl substituted with pyrimidinyl.

For compounds of formula (IVa), suitably R ^22a , R ^23a , and R ^24a are independently selected from: hydrogen, fluoro, chloro, bromo, -OH, boric acid, 1,3,6,2-dioxy Azaborane-octane-4,8-dione, -CN, -C (O) NHCH ₃ , -C (O) NHCH ₂ CH ₃ , -C (O) NHCH ₂ CH ₂ OH, -C ( O) NHCH ₂ CH ₂ SO ₂ CH ₃ , -C (O) NHOCH ₃ , -C (O) NH ₂ , -C (O) OCH ₃ , -C (O) NHCH ₂ cyclopropyl, -C (O ) NH cyclobutyl, optionally substituted with hydroxy, -CH ₂ morpholinyl, -CH ₂ OH, -CH ₂ NHCH ₂ CF ₃ , -CH ₂ NHCH ₂ CH ₂ SO ₂ CH ₃ , -CH ₂ SO ₂ CH ₃ , -CH (OH) CF ₃ , -CH ₃ , -CF ₃ , -OCH ₃ , -NHC (O) CH ₃ , -NH ₂ , -NHSO ₂ CH ₃ , morpholinylpyrazolyl, Oxazolyl, and substituted once or twice with methyl An oxazolyl group, or R ^23a and R ^24a, together with the carbon atom to which they are attached to form an oxaborolyl, is optionally substituted with a hydroxyl group.

For formula (IVa) compound, suitably R ^25a and R ^26a are independently selected: C _1-3 alkyl, fluoro substituted with 1 to 3 followed by C _1-3 alkyl and cyclopropyl, or R ^25a and R ^26a together with the nitrogen to which they are attached to form: azepine, or pyrrolidinyl, each of which is optionally substituted once or twice with: C _1-3 alkyl. For compounds of formula (IVa), suitably R ^27a is selected from: hydrogen and fluorine; or one of R ^25a and R ^26a together with R ^27a , and optionally one additional heteroatom to form: pyrrolidinyl , Or morpholinyl, each of them is optionally substituted 1 to 4 times with a C _1-3 alkyl group.

Included in the compounds of the invention and used in the methods of the invention are compounds of formula (IVb '): Wherein: R ^{20b ′} is a C _1-2 alkyl group substituted with: phenyl substituted with pyrimidinyl, pyrazolyl, pyrazolyl substituted with C _1-3 alkyl, pyr _Pyridyl substituted with C _1-3 alkyl Base Phenyl _Ci, substituted with C _1-3 alkyl base, Oxazolyl, substituted with C _1-3 alkyl Azolyl, imidazolyl, imidazolyl substituted with C _1-3 alkyl, morpholinyl, morpholinyl substituted 1 or 2 times with C _1-3 alkyl, morpholin substituted with pendant oxy Base, two Alkyl, substituted by C _1-3 alkyl Alkyl, 4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine ; Triazolyl, triazolyl substituted with C _1-3 alkyl, thiazolyl, thiazolyl substituted with C _1-3 alkyl, -O cyclopentyl, C _1-6 alkoxy, fluoro substituted with 1-6 followed by C _1-6 alkoxy, unsubstituted of substituted hydroxyl groups of C _1-6 alkoxy, tetrahydrofuranyl, pyridinyl, substituted by bromo group of pyridinyl, pyrimidinyl, or pyridinyl; R ^{22b '} , R ^23b' , and R ^{24b '} are independently selected from: hydrogen, fluoro, chloro, bromo, -OH, boric acid, 1,3,6,2-dioxazepine- 4,8-dione, -CN, -C (O) NHCH ₃ , -C (O) NHCH ₂ CH ₃ , -C (O) NHCH ₂ CF ₂ H, -C (O) NHCH ₂ CH ₂ OH, -C (O) NHCH ₂ CH ₂ SO ₂ CH ₃ , -C (O) NHOCH ₃ , -C (O) NH ₂ , -C (O) OCH ₃ , -C (O) NHCH ₂ cyclopropyl,- C (O) NH cyclobutyl, optionally substituted with hydroxy, -CH ₂ morpholinyl, -CH ₂ OH, -CH ₂ NHCH ₂ CF ₃ , -CH ₂ NHCH ₂ CH ₂ SO ₂ CH ₃ ,- CH ₂ SO ₂ CH ₃ , -CH (OH) CF ₃ , -CH ₃ , -CF ₃ , -OCH ₃ , methoxy -d ₃ , -NHC (O) CH ₃ , -NH ₂ , -NHSO ₂ CH ₃ , morpholinyl pyrazolyl, Oxazolyl, and substituted once or twice with methyl An oxazolyl group, or R ^{23b '} and R ^24b' together with the carbon atom to which they are attached to form an oxaborolyl, optionally substituted with a hydroxyl group; R ^{25b '} and R ^26b' are is independently selected from: C _1-3 alkyl, fluoro substituted with 1 to 3 followed by C _1-3 alkyl, and cyclopropyl, R ^{25b 'and} R ^26b' are connected to the nitrogen to form, together with their : Da nitrogen group, pyrrolidinyl, their respective lines of the following optionally substituted with one or two substituted: C _1-3 alkyl or fluorine substituted with 1 to 3 followed by C _1-3 alkyl, or R ^{25b One of '} and R ^26b' together with R ^{27b '} , and optionally one additional heteroatom to form: pyrrolidinyl, or morpholinyl, each of them is optionally passed C _1-3 Alkyl substitution 1 to 4 times; and R ^{27b '} is selected from: hydrogen and fluorine; or one of R ^25b' and R ^{26b '} together with R ^27b' , and optionally one additional heteroatom to form : Pyrrolidinyl, or morpholinyl, each of which is optionally substituted with C _1-3 alkyl groups 1 to 4 times; or a pharmaceutically acceptable salt thereof.

For compounds of formula (IVb '), suitably R ^20b' is C _1-2 alkyl substituted with: phenyl substituted with pyrimidinyl, pyrazolyl, pyrazolyl substituted with C _1-3 alkyl, Pyridine _Pyridyl substituted with C _1-3 alkyl Base Phenyl _Ci, substituted with C _1-3 alkyl base, Oxazolyl, substituted with C _1-3 alkyl Azolyl, imidazolyl, imidazolyl substituted with C _1-3 alkyl, morpholinyl, morpholinyl substituted 1 or 2 times with C _1-3 alkyl, morpholin substituted with pendant oxy Base, two Alkyl, substituted by C _1-3 alkyl Alkyl, 4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine ; Triazolyl, triazolyl substituted with C _1-3 alkyl, thiazolyl, thiazolyl substituted with C _1-3 alkyl, -O cyclopentyl, C _1-6 alkoxy, fluoro C1-6 alkoxy substituted 1 to 6 times, C1-6 alkoxy substituted with hydroxy, tetrahydrofuran, pyridyl, pyridyl substituted with bromoyl, or pyridyl substituted with pyrimidinyl.

For compounds of formula (IVb '), suitably R ^22b' , R ^{23b '} , and R ^24b' are independently selected from: hydrogen, fluoro, chloro, bromo, -OH, boric acid, 1,3,6, 2-dioxaazepine-4,8-dione, -CN, -C (O) NHCH ₃ , -C (O) NHCH ₂ CH ₃ , -C (O) NHCH ₂ CF ₂ H , -C (O) NHCH ₂ CH ₂ OH, -C (O) NHCH ₂ CH ₂ SO ₂ CH ₃ , -C (O) NHOCH ₃ , -C (O) NH ₂ , -C (O) OCH ₃ , -C (O) NHCH ₂ cyclopropyl, -C (O) NH cyclobutyl, optionally substituted with a hydroxyl group, -CH ₂ morpholinyl, -CH ₂ OH, -CH ₂ NHCH ₂ CF ₃ ,- CH ₂ NHCH ₂ CH ₂ SO ₂ CH ₃ , -CH ₂ SO ₂ CH ₃ , -CH (OH) CF ₃ , -CH ₃ , -CF ₃ , -OCH ₃ , methoxy-d ₃ , -NHC (O ) CH ₃ , -NH ₂ , -NHSO ₂ CH ₃ , morpholinylpyrazolyl, Oxazolyl, and substituted once or twice with methyl An oxazolyl group, or R ^{23b ′} and R ^{24b ′,} together with the carbon atom to which they are attached to form an oxaborolyl, is optionally substituted with a hydroxyl group.

For formula (IVb ') compound, suitably R ^25b' and R ^{26b 'are} independently selected: C _1-3 alkyl, fluoro substituted with 1 to 3 followed by C _1-3 alkyl, cyclopropyl and , R ^{25b ′} and R ^{26b ′} together with the nitrogen to which they are attached to form: aziridinyl, pyrrolidinyl, each of which is optionally substituted once or twice with the following: C _1-3 alkyl or via A fluoro group is substituted 1 to 3 times with a C _1-3 alkyl group, or one of R ^{25b ′} and R ^{26b ′} together with R ^{27b ′} , and optionally an additional heteroatom to form: pyrrolidinyl, Or morpholinyl, each of them is optionally substituted 1 to 4 times with a C _1-3 alkyl group.

For compounds of formula (IVb '), suitably R ^27b' is selected from: hydrogen and fluorine; or one of R ^{25b '} and R ^{26b '} together with R ^{27b '} , and optionally one additional heteroatom, to Formation: pyrrolidinyl, or morpholinyl, each of which is optionally substituted 1 to 4 times with a C _1-3 alkyl group.

Included in compounds of formula (Ib): N, N-diethyl-5- (1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d ] Imidazol-2-yl) pyridin-2-amine; 5- (1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazol-2-yl ) -N, N-dipropylpyridine-2-amine; N-ethyl-5- (1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [ d) imidazol-2-yl) -N-propylpyridin-2-amine; 1-((1-ethyl-1H-pyrazol-3-yl) methyl) -2- (6- (2-methyl Pyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole; N-ethyl-5- (1-((1-ethyl-1H-pyrazol-3-yl) (Methyl) -1H-benzo [d] imidazol-2-yl) -N-isopropylpyridin-2-amine; 2- (6- (diethylamino) pyridin-3-yl) -1- ( (1-ethyl-1H-pyrazol-3-yl) methyl) -N-methyl-1H-benzo [d] imidazole-5-carboxamide; (S) -1-((1-ethyl -1H-pyrazol-3-yl) methyl) -N-methyl-2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d ] Imidazole-5-carboxamide; 2- (6-((2S, 5R) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl -1H-pyrazol-3-yl) methyl) -N-methyl-1H-benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5S) -2,5- Dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -N-formyl -1H-benzo [d] imidazole-5-carboxamide; 2- (6- (cyclopropyl (ethyl) amino) pyridin-3-yl) -1-((1-ethyl-1H -Pyrazol-3-yl) methyl) -N-methyl-1H-benzo [d] imidazole-5-carboxamide; 2- (6- (diethylamino) -5-fluoropyridine-3 -Yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -N-methyl-1H-benzo [d] imidazole-5-carboxamide; (S)- 1-((1-ethyl-1H-pyrazol-3-yl) methyl) -2- (5-fluoro-6- (2-methylpyrrolidin-1-yl) pyridin-3-yl)- N-methyl-1H-benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) -5-fluoro Pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -N-methyl-1H-benzo [d] imidazole-5-carboxamide; 2 -(6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) (Methyl) -N- (2-hydroxyethyl) -1H-benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidine -1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide; ( S) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H -Benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5R) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1 -((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide; 5- (4-chloro-1-((1-ethyl 1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine; N, N-diethyl- 5- (1-((1-ethyl-1H-pyraol) -3-yl) methyl) -4-methyl-1H-benzo [d] imidazol-2-yl) pyridine-2- Amine; 4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H- Pyrazol-3-yl) methyl) -1H-benzo [d] imidazole; 5- (7-chloro-1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H -Benzo [d] imidazol-2-yl) -N, N-diethylpyridine-2-amine; 5-bromo-2- (6-((2S, 5S) -2,5-dimethylpyrrole Pyridin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole; (2- (6- ((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl)- 1H-benzo [d] imidazol-5yl) boronic acid; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- ( (1-ethyl-1H-pyrazol-3-yl) methyl) -5- (1H-pyrazol-3-yl) -1H-benzo [d] imidazole; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -5- (1H -Pyrazol-4-yl) -1 H-benzo [d] imidazole; 5- (4,5-dichloro-1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole- 2-yl) -N, N-diethylpyridin-2-amine; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -5-fluoro-1H-benzo [d] imidazole; N, N-diethyl-5- (1- ( (1-ethyl-1H-pyrazol-3-yl) methyl) -5-methoxy-1H-benzo [d] imidazol-2-yl) pyridin-2-amine; N, N-diethyl -5- (1-((1-ethyl-1H-pyrazol-3-yl) methyl) -6-methyl-1H-benzo [d] imidazol-2-yl) pyridin-2-amine ; 2- (6- (diethylamino) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole- 7-carbonitrile; 2- (6- (diethylamino) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [ d) imidazole-5-carbonitrile; 2- (6- (diethylamino) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H -Benzo [d] imidazole-4-carbonitrile; 2- (6- (diethylamino) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl Yl) -1H-benzo [d] imidazole-4-carboxamide; N, N-diethyl-5- (1-((1-ethyl-1H-pyrazol-3-yl) methyl) -5-methyl-1H-benzo [d] imidazol-2-yl) pyridin-2-amine; 5- (5-chloro-1-((1-ethyl-1H-pyrazol-3-yl) ) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine; N, N-diethyl-5- (1-((1-ethyl- 1H-pyrazol-3-yl) methyl) -7-methyl-1H-benzo [d] imidazol-2-yl) pyridin-2-amine; N, N-diethyl-5- (1- ((1-ethyl-1H-pyrazol-3-yl) methyl) -4-methoxy-1H-benzo [d] imidazol-2-yl) pyridin-2-amine; 2- (6- ((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl)- 4- (trifluoromethyl) -1H-benzo [d] imidazole; (2- (6- (diethylamino) pyridin-3-yl) -1-((1-ethyl-1H-pyrazole -3-yl) methyl) -1H-benzo [d] imidazol-5-yl) boronic acid; (S) -1- (2- (tertiary butoxy) ethyl) -2- (6- ( 2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole; 1- (2- (tertiary butoxy) ethyl) -2- (6-(( 2S, 5R) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole; 1- (2- (tertiary butoxy) ethyl) 2- (6- (diethylamino) pyridin-3-yl) -1H-benzo [d] imidazole-5-carboxylic acid methyl ester; 1- (2- (tertiary butoxy) ethyl)- 2- (6- (diethylamino) pyridin-3-yl) -1H-benzo [d] imidazole-5-carboxamide; 1- (2- (tertiary butoxy) ethyl) -N -(Cyclopropylmethyl) -2- (6- (diethylamino) pyridin-3-yl) -1H-benzene [d] Imidazole-5-carboxamide; 1- (2- (tertiary butoxy) ethyl) -2- (6- (diethylamino) pyridin-3-yl) -N- (2- Hydroxyethyl) -1H-benzo [d] imidazole-5-carboxamide; 5- (1- (2- (tertiary butoxy) ethyl) -4-chloro-1H-benzo [d] Imidazol-2-yl) -N, N-diethylpyridin-2-amine; 5- (1- (2- (tertiary butoxy) ethyl) -4- (trifluoromethyl) -1H- Benzo [d] imidazol-2-yl) -N, N-diethylpyridine-2-amine; 5- (5-bromo-1- (2- (tertiary butoxy) ethyl) -1H- Benzo [d] imidazol-2-yl) -N, N-diethylpyridine-2-amine; (1- (2- (tertiary butoxy) ethyl) -2- (6- (diethyl Amine) pyridin-3-yl) -1H-benzo [d] imidazol-5-yl) boronic acid; 5- (1- (2- (tertiary butoxy) ethyl) -5- (1H-pyridine Azol-3-yl) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine; 5- (1- (2- (tertiary butoxy) ethyl ) -5-fluoro-1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine; 5- (1- (2- (tertiary butoxy) ethyl) ) -4-fluoro-1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine; 1- (2- (tertiary butoxy) ethyl)- 2- (6- (diethylamino) pyridin-3-yl) -1H-benzo [d] imidazole-4-carbonitrile; 1- (2- (tertiary butoxy) ethyl) -2- (6- (Diethylamino) pyridin-3-yl) -1H-benzo [d] imidazole-4-methyl Amine; N, N-diethyl-5- (1- (2-isopropoxyethyl) -1H-benzo [d] imidazol-2-yl) pyridin-2-amine; 5- (4- Chloro-1- (2-isopropoxyethyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine; 2- (6- (diethyl Amine) pyridin-3-yl) -1- (2-isopropoxyethyl) -1H-benzo [d] imidazole-5-carboxamide; (S) -1- (2-isopropoxy Ethyl) -2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-5-carboxamide; (S) -1- (2-isopropoxyethyl) -2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-5-carboxamide; 4-chloro-2- (6- (diethylamino) pyridin-3-yl) -1- (2-isopropoxyethyl) -1H-benzo [d] imidazole-5-carboxamide; 5- (4-chloro-1- (2-isopropoxyethyl) -5- (morpholinylmethyl) -1H-benzo [d] imidazol-2-yl) -N, N-di Ethylpyridine-2-amine; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl ) -1H-benzo [d] imidazole; 2- (6-((2S, 5R) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2- (Ethoxyethyl) -1H-benzo [d] imidazole; (S) -1- (2-ethoxyethyl) -2- (6- (2-methylpyrrolidin-1-yl) pyridine -3-yl) -1H-benzo [d] imidazole; 1- (2-ethoxyethyl ) -2- (1-ethyl-2,2-dimethyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1H-benzo [d] Imidazole; 7- (1- (2-ethoxyethyl) -1H-benzo [d] imidazol-2-yl) -4-ethyl-3-methyl-3,4-dihydro-2H- Pyrido [3,2-b] [1,4] ; 5- (1- (2-ethoxyethyl) -1H-benzo [d] imidazol-2-yl) -N-ethyl-N- (2,2,2-trifluoroethyl) pyridine -2-amine; 5- (4-chloro-1- (2-ethoxyethyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridine-2-amine ; (2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -4-methyl -1H-benzo [d] imidazol-5-yl) boronic acid; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl)- 3- (2-ethoxyethyl) -3H- [1,2] oxaborolo [4 ', 3': 3,4] benzo [1,2-d ] Imidazole-6 (8H) -alcohol; 4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- ( 2-ethoxyethyl) -1H-benzo [d] imidazole; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -5-fluoro-1H-benzo [d] imidazole; 5- (5-bromo-4-chloro-1- (2-ethoxyethyl) -1H -Benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine; (4-chloro-2- (6- (diethylamino) pyridin-3-yl) -1 -(2-ethoxyethyl) -1H-benzo [d] imidazol-5-yl) boronic acid; 5-bromo-4-chloro-2- (6-((2S, 5S) -2,5- Dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] imidazole; (4-chloro-2- ( 6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] imidazole -5-yl) boronic acid; 5- (5-bromo-4-chloro-1- (2-ethoxyethyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethyl Methyl-3-fluoropyridine-2-amine; (4-chloro-2- (6- (diethylamino) -5-fluoropyridin-3-yl) -1- (2-ethoxyethyl)- 1H-benzo [d] imidazol-5-yl) boronic acid; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -4- (trifluoromethyl) -1H-benzo [d] imidazole; 5- (5-bromo-1- (2-ethoxyethyl) -1H-benzene Benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine; (2- (6- (diethylamino) pyridin-3-yl) -1- (2-ethoxy Ethyl) -1H-benzo [d] imidazol-5-yl) boronic acid; (S)-(1- (2-ethoxyethyl) -2- (6- (2-methylpyrrolidine- 1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-5-yl) boronic acid; 5-bromo-2- (6-((2S, 5S) -2,5-dimethylpyrrole Pyridin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] imidazole; (2- (6-((2S, 5S) -2,5 -Dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] imidazol-5-yl) boronic acid; 2- (6- ((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl ) -5,6-difluoro-1H-benzo [d] imidazole; (S) -1- (2-ethoxyethyl) -4-fluoro-2- (6- (2-methylpyrrole) Pyridin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridine- 3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] imidazole-5-carboxylic acid methyl ester; 2- (6-((2S, 5S) -2,5-dimethyl Pyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -N-methyl-1H-benzo [d] imidazole-5-carboxamide; (S) -1- (2-ethoxyethyl) -6-fluoro-2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole; 5- (3- (2-ethoxyethyl) -3H-imidazo [4,5-b] pyridin-2-yl) -N, N-diethylpyridin-2-amine; 2- (6 -((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3- (2-ethoxyethyl) -N-methyl-3H-imidazo [4,5-b] pyridine-6-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3- (2-ethoxyethyl) -7-methyl-3H-imidazo [4,5-b] pyridine; (2- (6- (diethylamino) pyridin-3-yl) -3- ( 2-ethoxyethyl) -3H-imidazo [4,5-b] pyridin-6-yl) boronic acid; (2- (6-((2S, 5S) -2,5-dimethylpyrrole -1-yl) pyridin-3-yl) -3- (2-ethoxyethyl) -3H-imidazo [4,5-b] pyridine -6-yl) boronic acid; (2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3- (2-ethoxyethyl ) -7-methyl-3H-imidazo [4,5-b] pyridin-6-yl) boronic acid; 5- (4-chloro-1- (2-propoxyethyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridine-2-amine; 5- (4-chloro-1- (2- (cyclopentyloxy) ethyl) -1H-benzo [ d] imidazol-2-yl) -N, N-diethylpyridine-2-amine; 5-bromo-4-chloro-1- (2- (2,2-difluoroethoxy) ethyl)- 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole; (4-chloro-1- ( 2- (2,2-difluoroethoxy) ethyl) -2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl)- 1H-benzo [d] imidazol-5-yl) boronic acid; 4-chloro-1- (2- (2,2-difluoroethoxy) ethyl) -2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole; N, N-diethyl-5- (1-((2-ethyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-2-yl) pyridin-2-amine; 4-ethyl-7- (1-((2-ethyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-2-yl) -3-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1, 4] ; 4-ethyl-7- (1-((2-ethyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-2-yl) -3,3-dimethyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] ; 2-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-1-yl ) Methyl) -4-ethyl Azole; 4-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-1- (Methyl) methyl) -2-ethyl Azole; 2- (4-ethyl-3-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] -7-yl) -1-((2-ethyl Azole-4-yl) methyl) -N-methyl-1H-benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrole Pyridin-1-yl) pyridin-3-yl) -1-((2-ethyl Azole-4-yl) methyl) -N-methyl-1H-benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrole Pyridin-1-yl) pyridin-3-yl) -1-((2-ethyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-5-carboxamide; (2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1- Yl) pyridin-3-yl) -1-((2-ethyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-5-yl) metanol; N-((2- (6-((2S, 5S) -2,5-dimethyl Pyrrolidin-1-yl) pyridin-3-yl) -1-((2-ethyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-5-yl) methyl) -2,2,2-trifluoroethylamine; (S) -1-((1-methyl -1H-pyrazol-3-yl) methyl) -2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole; N, N -Diethyl-5- (1-((2-ethyl-1H-imidazol-4-yl) methyl) -1H-benzo [d] imidazol-2-yl) pyridin-2-amine; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((2-ethyl-1H-imidazol-4-yl) methyl ) -1H-benzo [d] imidazole; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((4- Ethyl-1H-imidazol-2-yl) methyl) -1H-benzo [d] imidazole; N, N-diethyl-5- (1-((3-ethyl-1H-1,2, 4-triazol-5-yl) methyl) -1H-benzo [d] imidazol-2-yl) pyridin-2-amine; N, N-diethyl-5- (1-((2-ethyl Ylthiazol-4-yl) methyl) -1H-benzo [d] imidazol-2-yl) pyridin-2-amine; N, N-diethyl-5- (1- ( Azol-2-ylmethyl) -1H-benzo [d] imidazol-2-yl) pyridin-2-amine; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidine- 1-yl) pyridin-3-yl) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole; 2- (6-((2S , 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -N-methyl-1-((1-methyl-1H-pyrazol-3-yl) methyl ) -1H-benzo [d] imidazole-5-carboxamide; 2- (4-ethyl-3,3-dimethyl-3,4-dihydro-2H-pyrido [3,2-b ] [1,4] -7-yl) -N-methyl-1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-methyl-1H-pyrazol-3-yl) methyl Yl) -1H-benzo [d] imidazole-5-carboxamide; 2- (4-ethyl-3,3-dimethyl-3,4-dihydro-2H-pyrido [3,2- b] [1,4] -7-yl) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazol-5-carboxamide; 2- (1-ethyl -2,2-dimethyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-5-yl) -N-methyl-1-((1-methyl-1H- Pyrazol-3-yl) methyl) -1H-benzo [d] imidazol-5-carboxamide; 2- (1-ethyl-2,2-dimethyl-2,3-dihydro-1H -Pyrrolo [2,3-b] pyridin-5-yl) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5- Formamidine; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -N-methyl-1-((2-methyl Azole-4-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl ) Pyridin-3-yl) -4-fluoro-N-methyl-1-((2-methyl Azole-4-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl ) Pyridin-3-yl) -4-fluoro-1-((2-methyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-5-carboxamide; 5-bromo-2- (6-((2S, 5S) -2,5-dimethylpyrrolidine -1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -4-fluoro-1H-benzo [d] imidazole; 2- (6-((2S, 5S) -2 , 5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -4-fluoro-N-methyl-1H-benzo [d] imidazole- 5-formamidine; (2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl ) -1H-benzo [d] imidazol-5-yl) methanol; 2- (6- (diethylamino) pyridin-3-yl) -N-methyl-3-((1-methyl-1H -Pyrazol-3-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-carboxamide; 2- (6-((2S, 5S) -2,5-dimethyl Pyrrolidin-1-yl) pyridin-3-yl) -N-methyl-3-((1-methyl-1H-pyrazol-3-yl) methyl) -3H-imidazo [4,5- b) pyridine-6-formamidine; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3-((1-methyl -1H-pyrazol-3-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-carboxamide; 2- (1-ethyl-2,2-dimethyl- 2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-5-yl) -N-methyl-3-((1-methyl-1H-pyrazol-3-yl) methyl ) -3H-imidazo [4,5-b] pyridine-6-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) Pyridin-3-yl) -1-((3-ethyl-1H-1,2,4-triazol-5-yl) methyl) -1H-benzo [d] imidazole; 4-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -5-((methylsulfonyl) methyl) -1H-benzo (d ] Imidazol-1-yl) methyl) -2-ethyl Azole; 2- (4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxy (Ethyl) -1H-benzo [d] imidazol-5-yl) -6-methyl-1,3,6,2-dioxazepine-4,8-dione; 1- (2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((2-ethyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-5-yl) -2,2,2-trifluoroethanol; N- (2- (6-((2S, 5S) -2 , 5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] imidazol-5-yl) acetamidinium; R) -2- (4-ethyl-3-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] -7-yl) -N-methyl-3-((2-methyl Azole-4-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidine -1-yl) pyridin-3-yl) -N-methyl-3-((2-methyl Azole-4-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-carboxamide; (4-chloro-2- (6-((2S, 5S) -2,5- Dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((2-methyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-5-yl) boronic acid; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl ) Pyridin-3-yl) -1- (2-ethoxyethyl) -N-((1r, 3S) -3-hydroxycyclobutyl) -1H-benzo [d] imidazole-5-carboxamidine Amine; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -N-methyl Oxy-1H-benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -N- (2-hydroxyethyl) -1H-benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5S)- 2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -N- (2- (methylsulfonyl) ethyl) -1H- Benzo [d] imidazole-5-carboxamide; N-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl)- 1- (2-ethoxyethyl) -1H-benzo [d] imidazol-5-yl) methyl) -2- (methylsulfonyl) ethylamine; 4-((2- (6- ( (2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] imidazole-5- (Yl) methyl) morpholin; (4-chloro-1- (2-ethoxyethyl) -2- (4-ethyl-3,3-dimethyl-3,4-dihydro-2H -Pyrido [3,2-b] [1,4] -7-yl) -1H-benzo [d] imidazol-5-yl) boronic acid; 5- (1- (2-ethoxyethyl) -1H-benzo [d] imidazol-2-yl)- N, N-diethylpyridine-2-amine; 5- (1- (2-ethoxyethyl) -7-methoxy-1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridine-2-amine; N, N-diethyl-5- (1-((2-methyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-2-yl) pyridin-2-amine; 2- (6-((2S, 5S) -2,5-dimethylpyrrole -1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] imidazol-5-amine; N- (2- (6-((2S, 5S ) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] imidazol-5-yl) methanesulfonate Amidoamine; 4- (2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3-((1-methyl-1H- Pyrazol-3-yl) methyl) -3H-imidazo [4,5-b] pyridin-6-yl) morpholin; (R) -2- (4-ethyl-3-methyl-3 , 4-dihydro-2H-pyrido [3,2-b] [1,4] -7-yl) -N-methyl-3-((1-methyl-1H-pyrazol-3-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-formamidine Amine; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((2-methyl Azole-4-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl ) Pyridin-3-yl) -3-((2-methyl Azole-4-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-carboxamide; 2- (4-ethyl-3,3-dimethyl-3,4-di Hydrogen-2H-pyrido [3,2-b] [1,4] -7-yl) -N-methyl-3-((1-methyl-1H-pyrazol-3-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-formamidine Amine; (4-chloro-2- (4-ethyl-3,3-dimethyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] -7-yl) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazol-5-yl) boronic acid; (4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((2-ethyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-5-yl) boronic acid; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl ) Pyridin-3-yl) -4-fluoro-N-methyl-1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5- Formamidine; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-1-((1-methyl- 1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidine- 1-yl) pyridin-3-yl) -3-((2-methyl-1H-imidazol-4-yl) methyl) -3H-imidazo [4,5-b] pyridine; 2- (6- ((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -6-fluoro-3-((1-methyl-1H-pyrazol-3-yl) (Methyl) -3H-imidazo [4,5-b] pyridine; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl)- 3-((1-methyl-1H-pyrazol-3-yl) methyl) -3H-imidazo [4,5-b] pyridine; 2- (6- (diethylamino) pyridine-3- Yl) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide; 2- (6- (diethylamino) ) Pyridin-3-yl) -N-methyl-1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide; N, N-diethyl-5- (1-((tetrahydrofuran-2-yl) methyl) -1H-benzo [d] imidazol-2-yl) pyridin-2-amine (S) -N, N-diethyl-5- (1-((tetrahydrofuran-2-yl) methyl) -1H-benzo [d] imidazol-2-yl) pyridin-2-amine; N, N-diethyl-5- (1- (3- (pyrimidin-5-yl) benzyl) -1H-benzo [d] imidazol-2-yl) pyridin-2-amine; 2- (6- (Diethylamino) pyridin-3-yl) -N-methyl-1- (3- (pyrimidin-5-yl) benzyl) -1H-benzo [d] imidazole-5-carboxamide; (S) -2-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-7-methoxy -1H-benzo [d] imidazol-1-yl) methyl) morpholin; (S) -2-((2- (6-((2S, 5S) -2,5-dimethylpyrrole -1-yl) pyridin-3-yl) -4-fluoro-7-methoxy-1H-benzo [d] imidazol-1-yl) methyl) -4-methylmorpholin; (S) -2-((4-fluoro-7-methoxy-2- (6-((S) -2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] Imidazol-1-yl) methyl) morpholin; (S) -2-((2- (6-((2S, 4S) -2,4-dimethylazepine-1-yl) pyridine-3 -Yl) -4-fluoro-7-methoxy-1H-benzo [d] imidazol-1-yl) methyl) morpholin; 2- (6-((2S, 5S) -2,5- Dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1-((((S) -4-methylmorpholin-2-yl) methyl) -1H-benzene Benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy -N-methyl-1-(((S) -4-methylmorpholin-2-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide; 2- (6- ((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -N-ethyl-7-methoxy-1-((((S) -morpholin 2-yl) methyl) -1H-benzo [d] imidazol-5-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) Pyridine-3-yl) -N-ethyl-7-methoxy-1-((((S) -4-methylmorpholin-2-yl) methyl) -1H-benzo [d] imidazole 5-formamidine; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-1-(((S ) -Morpholin-2-yl) methyl) -1H-benzo [d] imidazol-7-ol; (S) -2-((4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-1-yl) methyl) morpholin; (S) -2-(( 4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-1-yl) (Methyl) -4-methylmorpholin; (S) -2-((7-methoxy-2- (6-((S) -2-methylpyrrolidin-1-yl) pyridine-3 -Yl) -1H-benzo [d] imidazol-1-yl) methyl); (S) -2-((2- (6-((2S, 5S) -2,5-dimethylpyrrole -1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [d] imidazol-1-yl) methyl) morpholin; (2S, 6S) -2-((2- (6-((2S, 5S) -2,5-dimethyl Pyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [d] imidazol-1-yl) methyl) -6-methylmorpholine; (2S, 6S) -2-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [d ] Imidazol-1-yl) methyl) -4,6-dimethylmorpholin; 1-((((2S, 6S) -4,6-dimethylmorpholin-2-yl) methyl) -2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-N-methyl-1H-benzo [ d) imidazol-5-carboxamide; 1-(((2S, 6S) -4,6-dimethylmorpholin-2-yl) methyl) -2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [d] imidazole-5-carboxamide; (S) -2- ( (2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-fluoro-1H-benzo [d] imidazol-1-yl ) Methyl) morpholin; (S) -2-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7 -Fluoro-1H-benzo [d] imidazol-1-yl) methyl) -4-methylmorpholine; (S) -2-((4-chloro-2- (6-((S)- 2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-1-yl) methyl) morpholin; 2- (6-((2S, 5S)- 2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -N-ethyl-3-((1-methyl-1H-pyrazol-3-yl) methyl) -3H- Zolo [4,5-b] pyridine-6-carboxamide; N- (2,2-difluoroethyl) -2- (6-((2S, 5S) -2,5-dimethylpyrrole Pyridin-1-yl) pyridin-3-yl) -3-((1-methyl-1H-pyrazol-3-yl) methyl) -3H-imidazo [4,5-b] pyridine-6- Formamidine; 1-(((R) -1,4-di Alk-2-yl) methyl) -2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7- (methoxy- d3) -1H-benzo [d] imidazole; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7- (methoxy -D3) -1- (pyridine 2-ylmethyl) -1H-benzo [d] imidazole; N-ethyl-7-methoxy-1-((((S) -4-methylmorpholin-2-yl) methyl ) -2- (6-((S) -2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-5-carboxamide; 1- (2- Ethoxyethyl) -2- (6- (ethyl (2,2,2-trifluoroethyl) amino) pyridin-3-yl) -7-methoxy-1H-benzo [d] Imidazole-5-carboxamide; 1- (2-ethoxyethyl) -2- (6- (ethyl (2,2,2-trifluoroethyl) amino) pyridin-3-yl)- 7-methoxy-N-methyl-1H-benzo [d] imidazole-5-carboxamide; 1- (2-ethoxyethyl) -2- (6- (ethyl (2,2 , 2-trifluoroethyl) amino) pyridin-3-yl) -7-hydroxy-1H-benzo [d] imidazole-5-carboxamide; 1- (2-ethoxyethyl) -2 -(6- (ethyl (2,2,2-trifluoroethyl) amino) pyridin-3-yl) -7-hydroxy-N-methyl-1H-benzo [d] imidazole-5-methyl Fluorenamine; N, N-diethyl-5- (5-methoxy-1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole 2-yl) pyridine-2-amine; 2- (6- (diethylamino) pyridin-3-yl) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazol-5-ol; 4- (2- (2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridine-3- ) -4-fluoro-7-methoxy-1H-benzo [d] imidazol-1-yl) ethyl) piperyl -2-one; 4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-(((S)- Morpholin-2-yl) methyl) -1H-benzo [d] imidazol-7-ol; (R) -6-((2- (6-((2S, 5S) -2,5-di Methylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [d] imidazol-1-yl) methyl) morpholin-3-one; 2-(( 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [d] imidazole-1- (Methyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine ; (R) -7-methoxy-1-((1-methyl-1H-pyrazol-3-yl) methyl) -2- (6- (2- (trifluoromethyl) pyrrolidine- 1-yl) pyridin-3-yl) -1H-benzo [d] imidazole; (R) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -2- (6 -(2- (trifluoromethyl) pyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-7-ol; 2- (6-((2S, 5S) -2 , 5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -N-ethyl-4-fluoro-7-methoxy-1-(((S) -morpholin-2-yl ) Methyl) -1H-benzo [d] imidazole-5-carboxamide; N-ethyl-4-fluoro-7-methoxy-1-(((S) -4-methylmorpholin 2-yl) methyl) -2- (6-((S) -2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-5-carboxamidine Amine; 1-(((R) -1,4-di Alk-2-yl) methyl) -2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -N-methyl-1H- Benzo [d] imidazole-5-carboxamide; 4- (2- (4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridine -3-yl) -1H-benzo [d] imidazol-1-yl) ethyl) piper -2-one; N-ethyl-4-fluoro-7-methoxy-2- (6-((S) -2-methylpyrrolidin-1-yl) pyridin-3-yl) -1- ((((S) -morpholin-2-yl) methyl) -1H-benzo [d] imidazol-5-carboxamide; 3-((2- (6-((2S, 5S) -2 , 5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [d] imidazol-1-yl) methyl) morpholin; (R)- 7-methoxy-N-methyl-1-((1-methyl-1H-pyrazol-3-yl) methyl) -2- (6- (2- (trifluoromethyl) pyrrolidine- 1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-5-carboxamide; (S) -2- (6- (4,4-difluoro-2-methylpyrrolidine- 1-yl) pyridin-3-yl) -7-methoxy-1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole; 2- (6-((2S, 4S) -4-fluoro-2-methylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1-((1-methyl-1H-pyridine Azole-3-yl) methyl) -1H-benzo [d] imidazole; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl ) -7-methoxy-1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole; 4- (2- (2- (6- ( ((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [d] imidazol-1-yl) ethyl) Morpholine; 2- (2- (2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H -benzene [d] Imidazol-1-yl) ethoxy) eth-1-ol; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl ) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazol-7-amine; 4-fluoro-7-methoxy-1- ( ((S) -4-methylmorpholin-2-yl) methyl) -2- (6-((S) -2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H -Benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro -7-methoxy-1- (2-morpholinylethyl) -1H-benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5S) -2,5 -Dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-7-methoxy-N-methyl-1- (2-morpholinylethyl) -1H-benzo [d] Imidazole-5-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-7- Methoxy-1-(((S) -4-methylmorpholin-2-yl) methyl) -1H-benzo [d] imidazol-5-carboxamide; and N, N-diethyl 5- (1-((6- (pyrimidin-5-yl) pyridin-2-yl) methyl) -1H-benzo [d] imidazol-2-yl) pyridin-2-amine; or a pharmaceutical thereof Acceptable salt.

Included in compounds of formula (I) are: N, N-diethyl-5- (1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d ] Imidazol-2-yl) pyridin-2-amine; 5- (1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazol-2-yl ) -N, N-dipropylpyridine-2-amine; N-ethyl-5- (1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [ d) imidazol-2-yl) -N-propylpyridin-2-amine; 1-((1-ethyl-1H-pyrazol-3-yl) methyl) -2- (6- (2-methyl Pyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole; N-ethyl-5- (1-((1-ethyl-1H-pyrazol-3-yl) (Methyl) -1H-benzo [d] imidazol-2-yl) -N-isopropylpyridin-2-amine; 2- (6- (diethylamino) pyridin-3-yl) -1- ( (1-ethyl-1H-pyrazol-3-yl) methyl) -N-methyl-1H-benzo [d] imidazole-5-carboxamide; (S) -1-((1-ethyl -1H-pyrazol-3-yl) methyl) -N-methyl-2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d ] Imidazole-5-carboxamide; 2- (6-((2S, 5R) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl -1H-pyrazol-3-yl) methyl) -N-methyl-1H-benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5S) -2,5- Dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -N-formyl -1H-benzo [d] imidazole-5-carboxamide; 2- (6- (cyclopropyl (ethyl) amino) pyridin-3-yl) -1-((1-ethyl-1H -Pyrazol-3-yl) methyl) -N-methyl-1H-benzo [d] imidazole-5-carboxamide; 2- (6- (diethylamino) -5-fluoropyridine-3 -Yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -N-methyl-1H-benzo [d] imidazole-5-carboxamide; (S)- 1-((1-ethyl-1H-pyrazol-3-yl) methyl) -2- (5-fluoro-6- (2-methylpyrrolidin-1-yl) pyridin-3-yl)- N-methyl-1H-benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) -5-fluoro Pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -N-methyl-1H-benzo [d] imidazole-5-carboxamide; 2 -(6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) (Methyl) -N- (2-hydroxyethyl) -1H-benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidine -1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide; ( S) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H -Benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5R) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- ((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide; 5- (4-chloro-1-((1-ethyl -1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine; N, N-diethyl-5 -(1-((1-ethyl-1H-pyraol-3-yl) methyl) -4-methyl-1H-benzo [d] imidazol-2-yl) pyridin-2-amine ; 4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyridine Azole-3-yl) methyl) -1H-benzo [d] imidazole; 5- (7-chloro-1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H- Benzo [d] imidazol-2-yl) -N, N-diethylpyridine-2-amine; 5-bromo-2- (6-((2S, 5S) -2,5-dimethylpyrrolidine -1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole; (2- (6- ( (2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H -Benzo [d] imidazol-5-yl) boronic acid; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- ( (1-ethyl-1H-pyrazol-3-yl) methyl) -5- (1H-pyrazol-3-yl) -1H-benzo [d] imidazole; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -5- (1H -Pyrazol-4-yl)- 1H-benzo [d] imidazole; 5- (4,5-dichloro-1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole- 2-yl) -N, N-diethylpyridin-2-amine; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -5-fluoro-1H-benzo [d] imidazole; N, N-diethyl-5- (1- ( (1-ethyl-1H-pyrazol-3-yl) methyl) -5-methoxy-1H-benzo [d] imidazol-2-yl) pyridin-2-amine; N, N-diethyl -5- (1-((1-ethyl-1H-pyrazol-3-yl) methyl) -6-methyl-1H-benzo [d] imidazol-2-yl) pyridin-2-amine ; 2- (6- (diethylamino) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole- 7-carbonitrile; 2- (6- (diethylamino) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [ d) imidazole-5-carbonitrile; 2- (6- (diethylamino) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H -Benzo [d] imidazole-4-carbonitrile; 2- (6- (diethylamino) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl Yl) -1H-benzo [d] imidazole-4-carboxamide; N, N-diethyl-5- (1-((1-ethyl-1H-pyrazol-3-yl) methyl) -5-methyl-1H-benzo [d] imidazol-2-yl) pyridin-2-amine; 5- (5-chloro-1-((1-ethyl-1H-pyrazol-3-yl) (Methyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine; N, N-diethyl-5- (1-((1-ethyl -1H-pyrazol-3-yl) methyl) -7-methyl-1H-benzo [d] imidazol-2-yl) pyridin-2-amine; N, N-diethyl-5- (1 -((1-ethyl-1H-pyrazol-3-yl) methyl) -4-methoxy-1H-benzo [d] imidazol-2-yl) pyridin-2-amine; 2- (6 -((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -4- (trifluoromethyl) -1H-benzo [d] imidazole; (2- (6- (diethylamino) pyridin-3-yl) -1-((1-ethyl-1H-pyridine Azole-3-yl) methyl) -1H-benzo [d] imidazol-5-yl) boronic acid; (S) -1- (2- (tertiary butoxy) ethyl) -2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole; 1- (2- (tertiary butoxy) ethyl) -2- (6- ( (2S, 5R) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole; methyl 1- (2- (tertiary butoxy) Ethyl) -2- (6- (diethylamino) pyridin-3-yl) -1H-benzo [d] imidazole-5-formate; 1- (2- (tertiary butoxy) ethyl ) -2- (6- (diethylamino) pyridin-3-yl) -1H-benzo [d] imidazole-5-carboxamide; 1- (2- (tertiary butoxy) ethyl ) -N- (cyclopropylmethyl) -2- (6- (diethylamino) pyridin-3-yl) -1H- Benzo [d] imidazole-5-carboxamide; 1- (2- (tertiary butoxy) ethyl) -2- (6- (diethylamino) pyridin-3-yl) -N- ( 2-hydroxyethyl) -1H-benzo [d] imidazole-5-carboxamide; 5- (1- (2- (tertiary butoxy) ethyl) -4-chloro-1H-benzo [ d] imidazol-2-yl) -N, N-diethylpyridine-2-amine; 5- (1- (2- (tertiary butoxy) ethyl) -4- (trifluoromethyl)- 1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine; 5- (5-bromo-1- (2- (tertiary butoxy) ethyl)- 1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine; (1- (2- (tertiary butoxy) ethyl) -2- (6- ( Diethylamino) pyridin-3-yl) -1H-benzo [d] imidazol-5-yl) boronic acid; 5- (1- (2- (tertiary butoxy) ethyl) -5- (1H -Pyrazol-3-yl) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine; 5- (1- (2- (tertiary butoxy) ) Ethyl) -5-fluoro-1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine; 5- (1- (2- (tertiary butoxy ) Ethyl) -4-fluoro-1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine; 1- (2- (tertiary butoxy) ethyl ) -2- (6- (diethylamino) pyridin-3-yl) -1H-benzo [d] imidazole-4-carbonitrile; 1- (2- (tertiary butoxy) ethyl)- 2- (6- (diethylamino) pyridin-3-yl) -1H-benzo [d] imidazole-4 -Formamidine; N, N-diethyl-5- (1- (2-isopropoxyethyl) -1H-benzo [d] imidazol-2-yl) pyridin-2-amine; 5- (4-chloro-1- (2-isopropoxyethyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine; 2- (6- (Diethylamino) pyridin-3-yl) -1- (2-isopropoxyethyl) -1H-benzo [d] imidazole-5-carboxamide; (S) -1- (2- Isopropoxyethyl) -2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-5-carboxamide; (S) -1- (2-isopropoxyethyl) -2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-5-methyl Fluorenamine; 4-chloro-2- (6- (diethylamino) pyridin-3-yl) -1- (2-isopropoxyethyl) -1H-benzo [d] imidazole-5-methyl Fluorenamine; 5- (4-chloro-1- (2-isopropoxyethyl) -5- (morpholinylmethyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethyl (Oxyethyl) -1H-benzo [d] imidazole; 2- (6-((2S, 5R) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] imidazole; (S) -1- (2-ethoxyethyl) -2- (6- (2-methylpyrrolidine-1- Yl) pyridin-3-yl) -1H-benzo [d] imidazole; 1- (2-ethoxy ) -2- (1-ethyl-2,2-dimethyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1H-benzo [d ] Imidazole; 7- (1- (2-ethoxyethyl) -1H-benzo [d] imidazol-2-yl) -4-ethyl-3-methyl-3,4-dihydro-2H -Pyrido [3,2-b] [1,4] ; 5- (1- (2-ethoxyethyl) -1H-benzo [d] imidazol-2-yl) -N-ethyl-N- (2,2,2-trifluoroethyl) pyridine -2-amine; 5- (4-chloro-1- (2-ethoxyethyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridine-2-amine ; (2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -4-methyl -1H-benzo [d] imidazol-5-yl) boronic acid; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl)- 3- (2-ethoxyethyl) -3H- [1,2] oxaborolo [4 ', 3': 3,4] benzo [1,2-d ] Imidazole-6 (8H) -alcohol; 4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- ( 2-ethoxyethyl) -1H-benzo [d] imidazole; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -5-fluoro-1H-benzo [d] imidazole; 5- (5-bromo-4-chloro-1- (2-ethoxyethyl) -1H -Benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine; (4-chloro-2- (6- (diethylamino) pyridin-3-yl) -1 -(2-ethoxyethyl) -1H-benzo [d] imidazol-5-yl) boronic acid; 5-bromo-4-chloro-2- (6-((2S, 5S) -2,5- Dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] imidazole; (4-chloro-2- ( 6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] imidazole -5-yl) boronic acid; 5- (5-bromo-4-chloro-1- (2-ethoxyethyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethyl Methyl-3-fluoropyridine-2-amine; (4-chloro-2- (6- (diethylamino) -5-fluoropyridin-3-yl) -1- (2-ethoxyethyl)- 1H-benzo [d] imidazol-5-yl) boronic acid; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -4- (trifluoromethyl) -1H-benzo [d] imidazole; 5- (5-bromo-1- (2-ethoxyethyl) -1H-benzene Benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine; (2- (6- (diethylamino) pyridin-3-yl) -1- (2-ethoxy Ethyl) -1H-benzo [d] imidazol-5-yl) boronic acid; (S)-(1- (2-ethoxyethyl) -2- (6- (2-methylpyrrolidine- 1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-5-yl) boronic acid; 5-bromo-2- (6-((2S, 5S) -2,5-dimethylpyrrole Pyridin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] imidazole; (2- (6-((2S, 5S) -2,5 -Dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] imidazol-5-yl) boronic acid; 2- (6- ((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl ) -5,6-difluoro-1H-benzo [d] imidazole; (S) -1- (2-ethoxyethyl) -4-fluoro-2- (6- (2-methylpyrrole) Pyridin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridine- 3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] imidazole-5-carboxylic acid methyl ester; 2- (6-((2S, 5S) -2,5-dimethyl Pyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -N-methyl-1H-benzo [d] imidazole-5-carboxamide; (S) -1- (2-ethoxyethyl) -6-fluoro-2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole; 5- (3- (2-ethoxyethyl) -3H-imidazo [4,5-b] pyridin-2-yl) -N, N-diethylpyridin-2-amine; 2- (6 -((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3- (2-ethoxyethyl) -N-methyl-3H-imidazo [4,5-b] pyridine-6-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3- (2-ethoxyethyl) -7-methyl-3H-imidazo [4,5-b] pyridine; (2- (6- (diethylamino) pyridin-3-yl) -3- ( 2-ethoxyethyl) -3H-imidazo [4,5-b] pyridin-6-yl) boronic acid; (2- (6-((2S, 5S) -2,5-dimethylpyrrole -1-yl) pyridin-3-yl) -3- (2-ethoxyethyl) -3H-imidazo [4,5-b] pyridine- 6-yl) boronic acid; (2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3- (2-ethoxyethyl ) -7-methyl-3H-imidazo [4,5-b] pyridin-6-yl) boronic acid; 5- (4-chloro-1- (2-propoxyethyl) -1H-benzo [ d] imidazol-2-yl) -N, N-diethylpyridine-2-amine; 5- (4-chloro-1- (2- (cyclopentyloxy) ethyl) -1H-benzo [d ] Imidazol-2-yl) -N, N-diethylpyridine-2-amine; 5-bromo-4-chloro-1- (2- (2,2-difluoroethoxy) ethyl) -2 -(6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole; (4-chloro-1- (2 -(2,2-difluoroethoxy) ethyl) -2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H -Benzo [d] imidazol-5-yl) boronic acid; 4-chloro-1- (2- (2,2-difluoroethoxy) ethyl) -2- (6-((2S, 5S)- 2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole; N, N-diethyl-5- (1-((2-ethyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-2-yl) pyridin-2-amine; 4-ethyl-7- (1-((2-ethyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-2-yl) -3-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1, 4] ; 4-ethyl-7- (1-((2-ethyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-2-yl) -3,3-dimethyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] ; 2-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-1-yl ) Methyl) -4-ethyl Azole; 4-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-1- (Methyl) methyl) -2-ethyl Azole; 2- (4-ethyl-3-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] -7-yl) -1-((2-ethyl Azole-4-yl) methyl) -N-methyl-1H-benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrole Pyridin-1-yl) pyridin-3-yl) -1-((2-ethyl Azole-4-yl) methyl) -N-methyl-1H-benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrole Pyridin-1-yl) pyridin-3-yl) -1-((2-ethyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-5-carboxamide; (2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1- Yl) pyridin-3-yl) -1-((2-ethyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-5-yl) metanol; N-((2- (6-((2S, 5S) -2,5-dimethyl Pyrrolidin-1-yl) pyridin-3-yl) -1-((2-ethyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-5-yl) methyl) -2,2,2-trifluoroethylamine; (S) -1-((1-methyl -1H-pyrazol-3-yl) methyl) -2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole; N, N -Diethyl-5- (1-((2-ethyl-1H-imidazol-4-yl) methyl) -1H-benzo [d] imidazol-2-yl) pyridin-2-amine; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((2-ethyl-1H-imidazol-4-yl) methyl ) -1H-benzo [d] imidazole; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((4- Ethyl-1H-imidazol-2-yl) methyl) -1H-benzo [d] imidazole; N, N-diethyl-5- (1-((3-ethyl-1H-1,2, 4-triazol-5-yl) methyl) -1H-benzo [d] imidazol-2-yl) pyridin-2-amine; N, N-diethyl-5- (1-((2-ethyl Thiazol-4-yl) methyl) -1H-benzo [d] imidazol-2-yl) pyridin-2-amine; N, N-diethyl-5- (1- ( Azol-2-ylmethyl) -1H-benzo [d] imidazol-2-yl) pyridin-2-amine; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidine- 1-yl) pyridin-3-yl) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole; 2- (6-((2S , 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -N-methyl-1-((1-methyl-1H-pyrazol-3-yl) methyl ) -1H-benzo [d] imidazole-5-carboxamide; 2- (4-ethyl-3,3-dimethyl-3,4-dihydro-2H-pyrido [3,2-b ] [1,4] -7-yl) -N-methyl-1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-methyl-1H-pyrazol-3-yl) methyl Yl) -1H-benzo [d] imidazole-5-carboxamide; 2- (4-ethyl-3,3-dimethyl-3,4-dihydro-2H-pyrido [3,2- b] [1,4] -7-yl) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazol-5-carboxamide; 2- (1-ethyl -2,2-dimethyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-5-yl) -N-methyl-1-((1-methyl-1H- Pyrazol-3-yl) methyl) -1H-benzo [d] imidazol-5-carboxamide; 2- (1-ethyl-2,2-dimethyl-2,3-dihydro-1H -Pyrrolo [2,3-b] pyridin-5-yl) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5- Formamidine; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -N-methyl-1-((2-methyl Azole-4-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl ) Pyridin-3-yl) -4-fluoro-N-methyl-1-((2-methyl Azole-4-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl ) Pyridin-3-yl) -4-fluoro-1-((2-methyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-5-carboxamide; 5-bromo-2- (6-((2S, 5S) -2,5-dimethylpyrrolidine -1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -4-fluoro-1H-benzo [d] imidazole; 2- (6-((2S, 5S) -2 , 5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -4-fluoro-N-methyl-1H-benzo [d] imidazole- 5-formamidine; (2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl ) -1H-benzo [d] imidazol-5-yl) methanol; 2- (6- (diethylamino) pyridin-3-yl) -N-methyl-3-((1-methyl-1H -Pyrazol-3-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-carboxamide; 2- (6-((2S, 5S) -2,5-dimethyl Pyrrolidin-1-yl) pyridin-3-yl) -N-methyl-3-((1-methyl-1H-pyrazol-3-yl) methyl) -3H-imidazo [4,5- b) pyridine-6-formamidine; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3-((1-methyl -1H-pyrazol-3-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-carboxamide; 2- (1-ethyl-2,2-dimethyl- 2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-5-yl) -N-methyl-3-((1-methyl-1H-pyrazol-3-yl) methyl ) -3H-imidazo [4,5-b] pyridine-6-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) Pyridin-3-yl) -1-((3-ethyl-1H-1,2,4-triazol-5-yl) methyl) -1H-benzo [d] imidazole; 4-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -5-((methylsulfonyl) methyl) -1H-benzo (d ] Imidazol-1-yl) methyl) -2-ethyl Azole; 2- (4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxy (Ethyl) -1H-benzo [d] imidazol-5-yl) -6-methyl-1,3,6,2-dioxazepine-4,8-dione; 1- (2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((2-ethyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-5-yl) -2,2,2-trifluoroethanol; N- (2- (6-((2S, 5S) -2 , 5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] imidazol-5-yl) acetamidinium; R) -2- (4-ethyl-3-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] -7-yl) -N-methyl-3-((2-methyl Azole-4-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidine -1-yl) pyridin-3-yl) -N-methyl-3-((2-methyl Azole-4-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-carboxamide; (4-chloro-2- (6-((2S, 5S) -2,5- Dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((2-methyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-5-yl) boronic acid; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl ) Pyridin-3-yl) -1- (2-ethoxyethyl) -N-((1r, 3S) -3-hydroxycyclobutyl) -1H-benzo [d] imidazole-5-carboxamidine Amine; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -N-methyl Oxy-1H-benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -N- (2-hydroxyethyl) -1H-benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5S)- 2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -N- (2- (methylsulfonyl) ethyl) -1H- Benzo [d] imidazole-5-carboxamide; N-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl)- 1- (2-ethoxyethyl) -1H-benzo [d] imidazol-5-yl) methyl) -2- (methylsulfonyl) ethylamine; 4-((2- (6- ( (2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] imidazole-5- (Yl) methyl) morpholin; (4-chloro-1- (2-ethoxyethyl) -2- (4-ethyl-3,3-dimethyl-3,4-dihydro-2H -Pyrido [3,2-b] [1,4] -7-yl) -1H-benzo [d] imidazol-5-yl) boronic acid; 5- (1- (2-ethoxyethyl) -1H-benzo [d] imidazol-2-yl)- N, N-diethylpyridine-2-amine; 5- (1- (2-ethoxyethyl) -7-methoxy-1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine; 5- (1-((6-bromopyridin-2-yl) methyl) -1H-benzo [d] imidazol-2-yl) -N, N-di Ethylpyridine-2-amine; N, N-diethyl-5- (1-((6- (pyrimidin-5-yl) pyridin-2-yl) methyl) -1H-benzo [d] imidazole -2-yl) pyridine-2-amine; N, N-diethyl-5- (1-((2-methyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-2-yl) pyridin-2-amine; 2- (6-((2S, 5S) -2,5-dimethylpyrrole -1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] imidazol-5-amine; N- (2- (6-((2S, 5S ) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] imidazol-5-yl) methanesulfonate Amidoamine; 4- (2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3-((1-methyl-1H- Pyrazol-3-yl) methyl) -3H-imidazo [4,5-b] pyridin-6-yl) morpholin; (R) -2- (4-ethyl-3-methyl-3 , 4-dihydro-2H-pyrido [3,2-b] [1,4] -7-yl) -N-methyl-3-((1-methyl-1H-pyrazol-3-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-formamidine Amine; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((2-methyl Azole-4-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl ) Pyridin-3-yl) -3-((2-methyl Azole-4-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-carboxamide; 2- (4-ethyl-3,3-dimethyl-3,4-di Hydrogen-2H-pyrido [3,2-b] [1,4] -7-yl) -N-methyl-3-((1-methyl-1H-pyrazol-3-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-formamidine Amine; (4-chloro-2- (4-ethyl-3,3-dimethyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] -7-yl) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazol-5-yl) boronic acid; (4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((2-ethyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-5-yl) boronic acid; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl ) Pyridin-3-yl) -4-fluoro-N-methyl-1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5- Formamidine; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-1-((1-methyl- 1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidine- 1-yl) pyridin-3-yl) -3-((2-methyl-1H-imidazol-4-yl) methyl) -3H-imidazo [4,5-b] pyridine; 2- (6- ((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -6-fluoro-3-((1-methyl-1H-pyrazol-3-yl) (Methyl) -3H-imidazo [4,5-b] pyridine; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl)- 3-((1-methyl-1H-pyrazol-3-yl) methyl) -3H-imidazo [4,5-b] pyridine; 2- (6- (diethylamino) pyridine-3- Yl) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide; 2- (6- (diethylamino) ) Pyridin-3-yl) -N-methyl-1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide; N, N-diethyl-5- (1-((tetrahydrofuran-2-yl) methyl) -1H-benzo [d] imidazol-2-yl) pyridin-2-amine (S) -N, N-diethyl-5- (1-((tetrahydrofuran-2-yl) methyl) -1H-benzo [d] imidazol-2-yl) pyridin-2-amine; N, N-diethyl-5- (1- (3- (pyrimidin-5-yl) benzyl) -1H-benzo [d] imidazol-2-yl) pyridin-2-amine; 2- (6- (Diethylamino) pyridin-3-yl) -N-methyl-1- (3- (pyrimidin-5-yl) benzyl) -1H-benzo [d] imidazole-5-carboxamide; (S) -2-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-7-methoxy -1H-benzo [d] imidazol-1-yl) methyl) morpholin; (S) -2-((2- (6-((2S, 5S) -2,5-dimethylpyrrole -1-yl) pyridin-3-yl) -4-fluoro-7-methoxy-1H-benzo [d] imidazol-1-yl) methyl) -4-methylmorpholin; (S) -2-((4-fluoro-7-methoxy-2- (6-((S) -2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] Imidazol-1-yl) methyl) morpholin; (S) -2-((2- (6-((2S, 4S) -2,4-dimethylazepine-1-yl) pyridine-3 -Yl) -4-fluoro-7-methoxy-1H-benzo [d] imidazol-1-yl) methyl) morpholin; 2- (6-((2S, 5S) -2,5- Dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1-((((S) -4-methylmorpholin-2-yl) methyl) -1H-benzene Benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy -N-methyl-1-(((S) -4-methylmorpholin-2-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide; 2- (6- ((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -N-ethyl-7-methoxy-1-((((S) -morpholin 2-yl) methyl) -1H-benzo [d] imidazol-5-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) Pyridine-3-yl) -N-ethyl-7-methoxy-1-((((S) -4-methylmorpholin-2-yl) methyl) -1H-benzo [d] imidazole 5-formamidine; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-1-(((S ) -Morpholin-2-yl) methyl) -1H-benzo [d] imidazol-7-ol; (S) -2-((4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-1-yl) methyl) morpholin; (S) -2-(( 4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-1-yl) (Methyl) -4-methylmorpholin; (S) -2-((7-methoxy-2- (6-((S) -2-methylpyrrolidin-1-yl) pyridine-3 -Yl) -1H-benzo [d] imidazol-1-yl) methyl); (S) -2-((2- (6-((2S, 5S) -2,5-dimethylpyrrole -1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [d] imidazol-1-yl) methyl) morpholin; (2S, 6S) -2-((2- (6-((2S, 5S) -2,5-dimethyl Pyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [d] imidazol-1-yl) methyl) -6-methylmorpholine; (2S, 6S) -2-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [d ] Imidazol-1-yl) methyl) -4,6-dimethylmorpholin; 1-((((2S, 6S) -4,6-dimethylmorpholin-2-yl) methyl ) -2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-N-methyl-1H-benzo (d) Imidazole-5-carboxamide; 1-((((2S, 6S) -4,6-dimethylmorpholin-2-yl) methyl) -2- (6-((2S, 5S ) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [d] imidazol-5-carboxamide; (S) -2- ((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-fluoro-1H-benzo [d] imidazole-1- (Methyl) methyl) morpholin; (S) -2-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl)- 7-fluoro-1H-benzo [d] imidazol-1-yl) methyl) -4-methylmorpholin; and (S) -2-((4-chloro-2- (6-((S ) -2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-1-yl) methyl) morpholin; or a pharmaceutically acceptable salt thereof.

Those skilled in the art will appreciate that salts, including pharmaceutically acceptable salts, of compounds of formula (Ib) can be prepared. In fact, in certain embodiments of the invention, the salts (including pharmaceutically acceptable salts) of the compounds according to formula (Ib) may be superior to the respective free or non-salt compounds. The invention therefore further relates to the salts of the compounds according to formula (Ib), including pharmaceutically acceptable salts.

Salts (including pharmaceutically acceptable salts) of the compounds of the present invention can be easily prepared by those skilled in the art.

Generally, the salts of the present invention are pharmaceutically acceptable salts. A salt included within the term "pharmaceutically acceptable salt" refers to a non-toxic salt of a compound of the invention.

Representative pharmaceutically acceptable acid addition salts include, but are not limited to, 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonic acid Salt (besylate), benzoate, bisulfate, hydrogen tartrate, butyrate, calcium edetate, camphor salt, camphor sulfonate (camphor sulfonate (camsylate)), decanoate (decanoate), hexanoate (hexanoate), octanoate (octanoate), cinnamate, citrate, cyclohexylamine Sulfonate, digluconate, 2,5-dihydroxybenzoate, disuccinate, dodecyl sulfate (estolate), edetate (ethylenediamine tetra Acetate), estolate (laurate sulfate), ethane-1,2-disulfonate (edisylate), ethanesulfonate (esylate )), Formate, fumarate, galactarate (mucate), cholic acid (2,5-dihydroxybenzoate), glucoheptane Glucoheptonate (gluceptate), glucose Glucate, glucuronide, glutamate, glutarate, glyceryl phosphate, glycolate, hexyl resorcinol, hippurate, hydrabamine (N, N ' -Bis (dehydrorosinyl) -ethylenediamine), hydrobromide, hydrochloride, hydroiodate, hydroxynaphthoate, isobutyrate, lactate, lactate, laurate, Malate, maleate, malonate, mandelate, methanesulfonate (mesylate), methyl sulfate, mucate, naphthalene-1, 5-disulfonate (napadisylate), naphthalene-2-sulfonate (napsylate), nicotinate, nitrate, oleate, palmitate, P-Aminobenzenesulfonate, p-Aminosalicylate, pamoate (embonate), pantothenate, pectate, persulfate, phenylacetate , Phenylethyl barbiturate, phosphate, polygalacturonate, propionate, p-toluenesulfonate (tosylate), pyroglutamate, pyruvate, Salicylate, Sebacate, Stearate, Hypoacetate, Succinate , Sulfamate, sulfate, tanninate, tartrate, teoclate (8-chlorotheophylate), thiocyanate, triethyliodine, undecanoate, Undecylenate and valerate.

Representative pharmaceutically acceptable base addition salts include, but are not limited to, aluminum, 2-amino-2- (hydroxymethyl) -1,3-propanediol (TRIS, tromethamine), refined Amino acid, benethamine (N-phenylmethylphenylethylamine), benzathine (N, N'-diphenylmethylethylenediamine), bis- (2-hydroxyethyl) Amine, bismuth, calcium, chloroprocaine, choline, clemizole (1-p-chlorobenzyl-2-pyrrolidin-1'-ylmethylbenzimidazole), cyclohexylamine, Diphenylmethylethylenediamine, diethylamine, diethyltriamine, dimethylamine, dimethylethanolamine, dopamine, ethanolamine, ethylenediamine, L-histidine, iron, isoquinoline, lepidine (lepidine), lithium, lysine, magnesium, meglumine (N-methylglucamine), piperazine , Piperidinyl, potassium, procaine, quinine, quinoline, sodium, strontium, tert-butylamine, and zinc.

Compounds according to formula Ib can contain one or more asymmetric centers (also known as palmar centers) and can therefore exist as individual mirror isomers, non-mirro isomers or other stereoisomeric forms or as mixtures thereof . Equivalent palm centers (such as palm carbon atoms) may be present in a substituent such as an alkyl group. If the stereochemistry of the palm centers is not specified to exist in the compound of Formula Ib or in any of the chemical structures shown herein, the structure is intended to encompass all individual stereoisomers and all mixtures thereof. Thus, a compound according to formula Ib containing one or more pairs of palm centers can be racemic mixtures, enantiomerically or non-enantiomerically enriched mixtures, or purely enantiomerically or non-enantiomerically. Individual stereoisomers are used.

Compounds according to formula (Ib) and their pharmaceutically acceptable salts may contain isotopically labeled compounds, which are the same as the compounds of formula (Ib) and later, but in practice one or more atomic systems are Atomic weight or mass number is different from the atomic weight or mass number usually found in nature. Examples of such isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O , ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ³⁶ Cl, ¹²³ I and ¹²⁵ I.

Isotopically labeled compounds, such as those in which radioisotopes such as ³ H or ¹⁴ C are incorporated, can be used for drug and / or matrix tissue distribution analysis. Europium (i.e. ³ H) and carbon-14 (i.e. ¹⁴ C) isotopes are particularly preferred due to their easy preparation and easy detection. ^{The 11} C and ¹⁸ F isotopes are particularly useful for PET (positron emission tomography), and the ¹²⁵ I isotope is particularly useful for SPECT (single photon computer tomography), both of which are used for brain imaging. In addition, replacement with heavier isotopes such as deuterium (i.e., ² H) may provide certain therapeutic advantages due to higher metabolic stability, such as increased half-life in the body or reduced dose requirements, and is therefore better in some cases of. Isotopically labeled compounds can generally be prepared by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents. Suitably, the deuterated substituent used herein is methoxy-d3.

Compounds according to formula (Ib) may also contain double bonds or other centers of geometric asymmetry. Where the stereochemistry of the geometrically asymmetric center present in formula (Ib) or any of the chemical structures shown herein is not specified, the structure is intended to include trans (E) geometric isomers, cis (Z) Geometric isomers, and all their mixtures. Likewise, all tautomeric forms are also included in formula (Ib), regardless of whether these tautomers exist in equilibrium or predominantly in one form.

The compounds of the invention may exist in solid or liquid form. In solid form, the compounds of the invention can exist in a continuous solid state ranging from completely amorphous to fully crystalline. The term 'amorphous' refers to a state in which a material lacks a long-range order at the molecular level and assumes physical properties of a solid or liquid depending on the temperature. Generally, these materials do not produce a distinct X-ray diffraction pattern, and although they exhibit a solid nature, they are more formally described as liquids. Once heated, a change in solid-to-liquid properties characterized by a change in state occurs, usually a second order ('glass transition'). The term 'crystalline' refers to a solid phase in which a material has a regularly ordered internal structure at the molecular level and produces a unique X-ray diffraction pattern with defined peaks. These materials also exhibit liquid properties when fully heated, but the change from solid to liquid is characterized by a phase change, usually a first order ('melting point').

The compounds of the present invention may have the ability to crystallize in more than one form, which is referred to as a feature of polymorphism ("polymorph"). Polymorphism can usually occur in response to changes in temperature or pressure, or both, and can also result from differences in the crystallization process. Polymorphs can be distinguished by various physical characteristics known in the art, such as X-ray diffraction patterns, solubility, and melting points.

Compounds of formula (Ib) can exist in solvated and unsolvated forms. As used herein, the term "solvate" refers to a complex of variable stoichiometry formed by a solute (in the present invention, a compound or salt of formula (Ib)) and a solvent. For the purposes of the present invention, these solvents must not interfere with the biological activity of the solute. The skilled artisan will understand that, as far as crystalline compounds are concerned, pharmaceutically acceptable solvates can be formed, in which solvent molecules are incorporated into the crystal lattice during crystallization. The incorporated solvent molecules can be water molecules or non-aqueous (such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and ethyl acetate) molecules. Crystal lattices incorporating water molecules are often referred to as "hydrates." Hydrates include stoichiometric hydrates and compositions containing variable amounts of water.

It should also be noted that compounds of formula (Ib) can form tautomers. &Quot; Tautomers " refers to compounds that have interchangeable forms of the structure of a particular compound and that have shifted hydrogen atom and electron shifts. Therefore, the two structures can be balanced by moving π electrons and atoms (usually H). For example, enols and ketones are tautomers because they are rapidly converted to each other by treatment with an acid or a base. It is understood that all tautomers and mixtures of tautomers of the compounds of the invention are included within the scope of the compounds of the invention.

Although the aspects of each variable have generally been listed separately above for each variable, the present invention includes those in which many or each aspect in formula (Ib) is selected from each of the aspects listed above. Compound. Accordingly, the invention is intended to include all combinations of aspects of each variable.

definition

It should be understood that unless the context otherwise requires, the following definitions apply to each of the above formulas and all instances of these terms.

"Alkyl", and derivatives thereof, refers to a hydrocarbon chain having a specified number of "carbon atoms". For example, C ₁ -C ₆ alkyl refers to an alkyl group having 1 to 6 carbon atoms. The alkyl group may be a saturated or unsaturated straight or branched chain. Representative branched alkyl groups have one, two or three branches. Alkyl includes, but is not limited to: methyl, methylene, ethyl, ethylene, propyl (n-propyl and isopropyl), butyl, butyl (n-butyl, isobutyl, and tributyl) Butyl), pentyl and hexyl.

"Alkoxy" refers to -O-alkyl, where "alkyl" is as defined herein. For example, C ₁ -C ₄ alkoxy refers to an alkoxy group having 1 to 4 carbon member atoms. Examples of such groups include, but are not limited to: methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tertiary butoxy.

"Aryl" refers to an aromatic hydrocarbon ring system. Aryl is a monocyclic, fused bicyclic, and fused tricyclic ring system having a total of 5 to 14 ring member atoms, at least one of which is aromatic and each ring in the system contains 3 to 7 member atoms, such as Phenyl, naphthalene and tetrahydronaphthalene. Suitably aryl is phenyl.

"Cycloalkyl" refers to a saturated or unsaturated, non-aromatic hydrocarbon ring having the specified number of member atoms. Cycloalkyl is a monocyclic or bicyclic system. For example, C ₃ -C ₇ cycloalkyl refers to a cycloalkyl group having 3 to 7 member atoms. Examples of cycloalkyl as used herein include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl. Suitably the cycloalkyl is cyclopropyl.

" Halo " refers to the halogen groups fluoro, chloro, bromo, and iodo.

"Heteroaryl" means a monocyclic aromatic 5- to 8-membered ring containing 1 to 7 ring member carbon atoms and 1 to 4 ring member heteroatoms. The prerequisite is that when the number of carbon atoms is 3, Family rings contain at least two heteroatoms. Heteroaryl groups containing more than one heteroatom may contain different heteroatoms. Heteroaryl groups include: pyrrolyl, pyrazolyl, imidazolyl, Oxazolyl, iso Oxazolyl, triazolyl, thiazolyl, isothiazolyl, furyl, furoxanyl, thienyl, triazolyl, pyridyl, pyrimidinyl, Base Base, three Base, four base. Suitably, "heteroaryl" includes: pyrazolyl, Oxazolyl, triazolyl, thiazolyl, pyridyl, and pyrimidinyl.

"Heterocyclyl" means a saturated or unsaturated, non-aromatic ring containing 4 to 12 member atoms, of which 1 to 11 are carbon atoms and 1 to 6 are heteroatoms. A heterocycloalkyl group containing more than one heteroatom may contain different heteroatoms. The heterocycloalkyl group may be a monocyclic ring system or a monocyclic ring fused with an aryl ring or a heteroaryl ring having 3 to 6 member atoms. In some specific examples, the heterocyclyl is saturated. In other specific examples, the heterocyclyl is unsaturated but not aromatic. Heterocyclyls include pyrrolidinyl, tetrahydrofuryl, dihydrofuryl, piperanyl, tetrahydropiperanyl, dihydropiperanyl, tetrahydrothienyl, pyrazolyl, Oxazidinyl, propylene oxide, thiazolidinyl, piperidinyl, homopiperidinyl, piperidinyl Base, morpholinyl, thioformyl, 1,3-dioxolyl, 1,3-dioxoyl Alkyl, 1,4-di Alkyl, 1,3-oxathialanyl, 1,3-oxathianyl, 1,3-dithianyl, 1,3- Oxazidin-2-one, hexahydro-1H-acyl, 4,5,6,7-tetrahydro-1H-benzimidazolyl, piperidinyl, 1,2,3,6-tetrahydro-pyridine And acridine.

Suitably "heterocyclyl" includes: pyrrolidinyl and morpholinyl.

Suitably "heterocyclyl" includes: two Alkyl, 4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine "Hetero atom" refers to a nitrogen-based, sulfur or oxygen atom.

"Pharmaceutically acceptable" means compounds which, within the scope of sound medical judgment, are suitable for contact with human and animal tissues without excessive toxicity, irritation or other problems or complications, commensurate with a reasonable benefit / risk ratio , Materials, compositions, and dosage forms.

As used herein, the notations and conventions used in these methods, procedures, and examples are consistent with those used in contemporary scientific literature, such as the Journal of the American Chemical Society or the Journal of Biological Chemistry . Standard single-letter or three-letter abbreviations are generally used to designate amino acid residues and are assumed to be in the L-configuration unless otherwise noted. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. In particular, the following abbreviations can be used in the examples and throughout the specification: Ac (ethenyl); Ac ₂ O (acetic anhydride); ACN (acetonitrile); AIBN (azobis (isobutyronitrile)); ATP (adenosine) Triphosphate); double pinacol borate (4,4,4 ', 4', 5,5,5 ', 5'-octamethyl-2,2'-bis-1,3,2- Dioxaborane); BSA (bovine serum albumin); BINAP (2,2'-bis (diphenylphosphino) -1,1'-binaphalene); BMS (borane-dimethylsulfide Complex); Bn (benzyl); Boc (tertiary butoxycarbonyl); Boc ₂ O (di-tertiary butyl dicarbonate)); BOP (benzotriazol-1-yl-oxy-gin- (Dimethylamino) -fluorene hexafluorophosphate); C18 (refers to the 18-carbon alkyl group on silicon in the HPLC solid phase); CH ₃ CN (acetonitrile); Cy (cyclohexyl); CAN (nitric acid) Cerium ammonium); Cbz (benzyloxycarbonyl); CSI (chlorosulfonyl isocyanate); DABCO (1,4-diazabicyclo [2.2.2] octane); DAST (diethylamino) Sulfur trifluoride); DBU (1,8-diazabicyclo [5.4.0] undec-7-ene); DCC (dicyclohexylcarbodiimide); DCE (1,2-dichloroethyl) Alkane); DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone); DCM (dichloromethane); DIEA (Hünig's base, diisopropylethylamine, N- Ethyl-N- (1-methylethyl) -2- Amine); DIPEA (Hünig's base, diisopropylethylamine, N-ethyl-N- (1-methylethyl) -2-propylamine); DMAP (4-dimethylaminopyridine); DME ( 1,2-dimethoxyethane); DMF (N, N-dimethylformamide); DMSO (dimethylsulfinium); DPPA (diphenylphosphonium azide); EDC (N -(3-dimethylaminopropyl) -N'ethylcarbodiimide); EDTA (ethylenediaminetetraacetic acid); EtOAc (ethyl acetate); EtOH (ethanol); Et ₂ O (ether); HEPES (4- (2-hydroxyethyl) -1-piperate Ethanesulfonic acid); HATU O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethylurenium hexafluorophosphate HOAt (1-hydroxy-7 -Azabenzotriazole); HOBt (1-hydroxybenzotriazole); HOAc (acetic acid); HPLC (high pressure liquid chromatography); HMDS (hexamethyldisilazide); Hunig's base (N, N-diisopropylethylamine); IPA (isopropanol); indoline (2,3-dihydro-1H-indole); KHMDS (potassium hexamethyldisilazide); LAH (lithium aluminum hydride); LDA (lithium diisopropylamide); LHMDS (lithium hexamethyldisilazide) MeOH (methanol); MTBE (methyl tertiary butyl ether); mCPBA (m-- Chloroperoxybenzoic acid); NaHMDS (sodium hexamethyldisilazide); NBS (N-bromosuccinimide); PE (petroleum ether); Pd ₂ (dba) ₃ ((dibenzylideneacetone) ) Dipalladium (0)); Pd (dppf) Cl ₂ ([1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II)); PyBOP (benzotriazol-1-yl -Oxytripyrrolidinyl hexafluorophosphate phosphonium salt); PyBrOP (bromotripyrrolidinyl hexafluorophosphate phosphonium salt); RPHPLC (reverse phase high pressure liquid chromatography); RuPhos (2-dicyclohexylphosphine) -2 ', 6'-isopropoxy-biphenyl); the SFC (supercritical fluid chromatography) SGC (silica gel chromatography); T3P ^® ( Alkyl phosphonic acid anhydride); TEA (triethylamine); TEMPO (2,2,6,6- tetramethylpiperidine 1-oxyl, radical); TFA (trifluoroacetic acid); and THF (tetrahydrofuran)

All references to ether refer to diethyl ether and brine refers to a saturated aqueous solution of NaCl.

Compound preparation

Compounds according to formula (Ib) are prepared using conventional organic synthesis methods. Appropriate synthetic pathways are described below with the following general reaction schemes. All starting materials are commercially available or can be easily prepared from commercially available starting materials by those skilled in the art.

Those skilled in the art will appreciate that if the substituents described herein are incompatible with the synthetic methods described herein, the substituents may be protected with a suitable protecting group that is stable to the reaction conditions. This protecting group can be removed at a suitable point in the reaction sequence to provide the desired intermediate or target compound. Appropriate protecting groups and methods of protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples can be found in T. Greene and P. Wuts, Protecting Groups in Organic Synthesis (4th ed. ), John Wiley and Sons, NY (2006). In some cases, the substituents are specifically selected to be reactive under the reaction conditions used. In these cases, the reaction conditions convert the selected substituent into another substituent, which can be used as an intermediate compound or as a desired substituent in the target compound.

As shown in Scheme 1, intermediate 3 can be synthesized using techniques well known in the art. For example, Intermediate 1 (which is commercially available or can be easily obtained by established methods) and an appropriate primary amine provide Intermediate 3 under reaction conditions well known in the art. Alternatively, the intermediate 3 can be prepared from the intermediate 2 which is commercially available or can be easily obtained by a predetermined method. Alkylation of intermediate 2 with a suitable electrophile under appropriate S _N 2 reaction conditions provides intermediate 3 . The final product 6 can be synthesized from intermediate 3 using techniques well known in the art. Reduction of the nitro group to the corresponding aniline provides intermediate 4 which can then be reacted with aldehyde 5 under oxidizing conditions to provide the desired product 6. Alternatively, the final product 6 can be obtained directly in one step from the nitro intermediate 3 and the aldehyde intermediate 5 in the presence of a suitable reagent such as sodium disulfonate in a suitable solvent such as EtOH or DMSO mixed with water at high temperature preparation.

An alternative method of preparing the final product 6 is illustrated in Scheme 2. Diphenylamine 7 is commercially available or can be synthesized using techniques well known in the art. The reaction of intermediate 7 with aldehyde 5 using a suitable reagent such as sodium metabisulfite in a suitable solvent such as DMF at a suitable temperature (from about 80 to 100 ° C) provides intermediate 8 . Alkylation of intermediate 8 with a suitable electrophile under appropriate S _N 2 reaction conditions provides the final product 3 .

Skilled artisans will understand that if further manipulation of the functionality present in the substituent is necessary, it can be performed at different stages during the synthesis of the final product 6. The synthesis of selected aminopyridine 5 used in the examples is highlighted in the flow chart below.

Scheme 3 illustrates the synthesis of 5-F and 5-H 6-aminopyridine 5 from an intermediate 9 that is commercially available or can be synthesized using techniques well known in the art. Intermediate 9 is neutralized with a suitable amine in a suitable solvent (such as DMSO) and a suitable base (such as K ₂ CO ₃ or N, N-diisopropylethylamine) The reaction provided an intermediate 5 .

Commercially available aminopyridine 5 can be tritiated with trimethylacetamidine chloride to provide an intermediate 12 by techniques well known in the art. Intermediate 12 is reacted with a suitable vinyl boron species (such as shown in Scheme 4) using a palladium catalyst (such as Pd ₂ (dba) ₃ , (t-Bu) ₃ PHBF ₄ and a suitable base ( Such as K ₃ PO ₄ ), in a suitable solvent such as 1,4-di Suzuki coupling at high temperatures (approximately 85 to 90 ° C) provides intermediate 13 . The reaction of the intermediate 13 with an aqueous HCl solution at a high temperature (about 110 ° C) provides the intermediate 14 . Ethylation of intermediate 14 using reductive amination conditions well known in the art using acetaldehyde and a suitable reducing agent such as NaBH (OAc) ₃ provides the corresponding vinylated intermediate 15 . Bromination of intermediate 15 and NBS using conditions well known in the art provides a bromo-based intermediate 16 , which can then be converted to the desired intermediate 5a. The reaction of intermediate 16 with n-BuLi is then quenched with DMF to provide the desired aminopyridine 5a .

Intermediate 18 is commercially available or can be prepared from a commercially available intermediate 17 by a bromination reaction using techniques well known in the art such as the brominating agent NBS in a suitable solvent such as DMF. The reaction of intermediate 18 with methylmagnesium bromide in the presence of ZrCl ₄ in a suitable solvent such as 2-MeTHF at a suitable temperature (about -15 ° C to room temperature) provides intermediate 19 . Ethylation of intermediate 19 with a suitable ethylating agent (such as iodoethane) using a suitable base (such as NaH) in a suitable solvent (such as DMF) provides the ethylated intermediate 20 . Conversion of the bromo-based intermediate 20 to the desired aldehyde 5b can be accomplished according to a scheme similar to the aforementioned synthesis of 5a .

Racemic intermediate 5c can be prepared as described in Scheme 6. Treatment of intermediate 18 with MeMgBr followed by NaHB (OAc) ₃ provides intermediate 21 . Ethylation of intermediate 21 with a suitable ethylating agent such as iodoethane using a suitable base such as NaH in a suitable solvent such as DMF provides ethylated intermediate 22 . Conversion of the bromo-based intermediate 22 to the racemic aldehyde 5c can be accomplished according to a scheme similar to the aforementioned synthesis of 5a and 5b .

Alternatively, optically pure ( R ) -5c can be prepared as described in Scheme 7. Intermediate 24 can be easily prepared from commercially available starting materials 23 and ( R ) -2-aminopropan-1-ol by techniques well known in the art. Palladium-catalyzed cyclization provides an intermediate 25, which can then be converted to an aldehyde by the aforementioned method.

Instructions

Compounds according to Formula Ib and their pharmaceutically acceptable salts reduce MYC protein (c-MYC) in cells and inhibit p300 / CBP tissue protein acetamyltransferase.

These compounds may be useful in the treatment of conditions where underlying pathologies are attributable to, but not limited to, Myc disorders, such as cancer and precancerous syndromes.

The compounds according to formula Ib and their pharmaceutically acceptable salts are inhibitors of p300 / CBP tissue protein acetamidine transferase activity. These compounds may be useful in treating conditions where the underlying pathology is attributable to, but not limited to, p300 / CBP tissue protein acetyltransferase activity disorders, such as cancer, precancerous syndrome, thrombocytopenia, cardiac hypertrophy, Diabetes, obesity and non-alcoholic fatty liver disease, HIV, polycystic kidney disease, inflammatory diseases, joint adhesion spondylitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn's disease, and multiple sclerosis disease.

Suitably, the present invention relates to a method for treating breast cancer (including inflammatory breast cancer, ductal cancer, and lobular cancer).

Suitably the invention relates to a method for treating colorectal cancer.

Suitably the invention relates to a method for treating pancreatic cancer, including insulinoma, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, and glucagonoma.

Suitably the invention relates to a method for treating skin cancers, including melanoma and metastatic melanoma.

Suitably the invention relates to a method for treating lung cancer (including small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma, adenocarcinoma and large cell carcinoma).

Suitably the invention relates to a method of treating a cancer selected from the group consisting of: brain cancer (glioma), glioblastoma, astrocytoma, pleomorphic glioblastoma, Bannayan- Zonana's syndrome, Cowden's disease, Lhermitte-Duclos disease, Wilm's tumor, Ewing's sarcoma, rhabdomyosarcoma, ependymal tumor, neurotubular cell tumor, head and neck cancer, kidney cancer, liver cancer, melanoma, ovarian cancer, pancreas Cancer, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate cancer, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid cancer, lymphocytic T cell leukemia, chronic Myeloid leukemia, chronic lymphocytic leukemia, hairy cell leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic neutrophilic leukemia, acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, external Membrane cell leukemia, multiple myeloma, megakaryoblastic leukemia, multiple myeloma, acute megakaryoblastic leukemia, anterior pulp Cell leukemia, red blood cell leukemia, malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoblast T cell lymphoma, Burkitt's lymphoma, follicular lymphoma, neuroblastoma, Bladder cancer, urinary epithelial cancer, vulvar cancer, cervical cancer, endometrial cancer, kidney cancer, mesothelioma, esophageal cancer, salivary adenocarcinoma, hepatocellular carcinoma, gastric cancer, nasopharyngeal cancer, cheek cancer, oral cancer, GIST ( Gastrointestinal stromal tumors) and testicular cancer.

Suitably, the present invention relates to a method for treating a precancerous syndrome in mammals (including humans), wherein the precancerous syndrome is selected from the group consisting of cervical intraepithelial neoplasia, unidentified single gamma globulin (MGUS), and myelodysplasia. Symptoms, aplastic anemia, cervical lesions, skin moles (pre-melanoma), prostate intraepithelial neoplasm (intratubular) neoplasia (PIN), ductal carcinoma in situ (DCIS), colon polyps and severe hepatitis or sclerosis .

Suitably the invention relates to the treatment of additional diseases associated with inhibition of the p300 / CBP tissue protein acetamyltransferase (for example: type 1 diabetes, Alzheimer's disease, stroke, Parkinson's disease, Huntington's dance Disease, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular disease, atherosclerosis, and arrhythmia).

c-MYC inhibition has been shown to eliminate angiogenesis involved in the treatment of eye diseases. Nature Reviews Drug Discovery 4 , 711-712 (September 2005). Suitably the invention relates to a method for treating eye diseases / angiogenesis. In a specific example of the method according to the invention, the pathological changes of the eye disease including vascular leakage may be: edema or neovascularization of any occlusive or inflammatory retinal vascular disease, such as redness of the iris, neovascular glaucoma, wings Pterygium, vascularized glaucoma filter vesicles, conjunctival papilloma; choroidal neovascularization such as neovascular senile macular degeneration (AMD), myopia, anterior uveitis, trauma, or idiopathic; Macular edema, such as macular edema after surgery, uveitis secondary to macular edema, including retinal and / or choroidal inflammation, diabetic secondary macular edema, and retinal vascular occlusive disease (i.e. branch and central retinal vein occlusion ) Secondary macular edema; retinal neovascularization due to diabetes, such as retinal vein occlusion, uveitis, ocular hemorrhagic syndrome from carotid artery disease, occlusion of the eye or retinal artery, sickle cell retinopathy, other diseases Bloody or occlusive neovascular retinopathy, retinopathy of prematurity, or Iles's Disease (Eale's Disease); and genetic diseases such as VonHippel-Lindau syndrome.

In some specific examples, neovascular macular degeneration is wet macular degeneration. In other specific examples, neovascular age-related macular degeneration is dry age-related macular degeneration and the patient is characterized by an increased risk of developing wet age-related macular degeneration.

The method of treatment of the present invention comprises administering an effective amount of a compound according to Formula Ib or a pharmaceutically acceptable salt thereof to a patient in need thereof.

The invention also provides a compound according to formula Ib or a pharmaceutically acceptable salt thereof for use in medicine, particularly for cancer treatment. Thus, in another aspect, the invention relates to the use of a compound according to Formula Ib or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a condition characterized by a Myc disorder, such as cancer.

The method of treatment of the present invention comprises administering an effective amount of a compound according to formula (Ib) or a pharmaceutically acceptable salt thereof to a patient in need thereof.

The term "treatment" and its derivatives, as used herein, means: (1) improving one or more biological manifestations of a condition, or (2) interfering with (a) one or more of the biological cascades that cause or are responsible for the condition A little bit, or (b) one or more biological manifestations of the condition, (3) alleviating one or more symptoms or effects associated with the condition, or (4) alleviating the condition or one or more biological manifestations of the condition progress.

The term "treatment" and its derivatives refer to therapeutic treatment. Therapeutic treatment is suitable for reducing symptoms or treating early symptoms of the disease or their progression.

Skilled artisans will understand that "prevention" is not an absolute term. In medicine, "prevention" is understood to mean the prophylactic administration of a drug to substantially reduce the likelihood or severity of its condition or its biological manifestations, or to delay the onset of that condition or its biological manifestations.

Prophylactic treatment is appropriate when the subject has, for example, a strong family history of cancer or is otherwise considered to have a high risk of developing cancer, or when the subject has been exposed to carcinogens.

As used herein, the term "effective amount" and its derivatives mean the amount of a drug or agent that will elicit a biological or medical response from, for example, a tissue, system, animal or human sought by a researcher or clinician. Furthermore, the term "therapeutically effective amount" and its derivatives mean those that result in the treatment, healing, or improvement of a disease, disorder, or side effect, or decrease the rate of progression of the disease or disorder compared to a counterpart who does not receive the amount. Any amount. The term also includes within its scope amounts effective to enhance normal physiological functions.

As used herein, "patient" or "subject" refers to a human or other animal. The patient or subject is suitably a human.

The compound of Formula Ib or a pharmaceutically acceptable salt thereof can be administered by any suitable route of administration, including systemic administration. Systemic administration includes oral administration and parenteral administration. And parenteral administration refers to parenteral, transdermal, or inhalation routes, and usually by injection or infusion. Parenteral administration includes intravenous, intramuscular, intraperitoneal injection, and subcutaneous injection or infusion.

The compound of Formula Ib or a pharmaceutically acceptable salt thereof can be administered once or in accordance with a dosing schedule in which multiple doses are administered at different time intervals over a given period of time. For example, the dose may be administered one, two, three or four times per day. The dose can be administered until the desired therapeutic effect is achieved or maintained indefinitely. The appropriate dosing regimen for the compounds of the present invention depends on the pharmacokinetic properties of the compounds, such as absorption, distribution, and half-life, which can be determined by the skilled artisan. In addition, the appropriate dosing regimen of the compounds of the present invention (including the period of administration of the regimen) depends on the condition to be treated, the severity of the condition to be treated, the age and physical condition of the patient to be treated, and the Medical history, nature of concurrent treatment, desired treatment effect, and other factors within the knowledge and experience of skilled technicians. Those skilled in the art will further understand that appropriate dosing regimens may need to be adjusted based on individual patient response to dosing regimens or individual patient needs to change over time.

Typical daily dosages may vary depending on the particular route of administration chosen. Typical doses for oral administration range from 1 mg to 1000 mg per person per dose. The preferred dose is 1-500 mg per person or twice daily (BID).

In addition, the compound of Formula Ib or a pharmaceutically acceptable salt thereof may be administered as a prodrug. As used herein, a "prodrug" of a compound of the invention is a functional derivative of the compound that, when administered to a patient, finally releases the compound of the invention in vivo. Administration of a prodrug of a compound of the present invention allows one skilled in the art to perform one or more of the following: (a) altering the onset of the compound in vivo; (b) altering the period of action of the compound in vivo; (c) altering the compound Delivery or distribution in vivo; (d) altering the solubility of the compound in vivo; and (e) overcoming side effects or other difficulties encountered by the compound. When a -COOH or -OH group is present, a pharmaceutically acceptable ester such as methyl, ethyl, etc. for -COOH, or acetate maleate, etc. for -OH, and the like can be used. Esters for improving solubility or hydrolysis characteristics are known in the art.

The compound of formula (Ib) or a pharmaceutically acceptable salt thereof can be co-administered with at least one other active agent known to be useful for treating cancer or precancerous syndrome.

The term "co-administered" as used herein means the simultaneous administration or c-MYC inhibitory compounds and other active agents or agents known to be useful in the treatment of cancer (including chemotherapy and radiation therapy), or as described herein, in any Ways of separate administration in order. The term other active agent or agents, etc., as used herein, includes any compound or therapeutic agent known or proven to have beneficial properties when administered to a patient in need of cancer treatment. Preferably, if they are not administered at the same time, the compounds are administered within a time close to each other. Furthermore, it does not matter whether the compounds are administered in the same dosage form, for example, one compound may be administered by injection and another compound may be administered orally.

Examples of other active agents, active agents, and the like (antitumor agents) used in combination or in combination with the combination of the present invention are shown below. This list is non-limiting. Additional antitumor agents are contemplated for use with compounds of the invention.

Generally, in the treatment of cancer of the present invention, any antitumor agent that is active in the sensitive tumor to be treated can be co-administered. Examples of these agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (eds.), 6th Edition (February 15, 2001), Lippincott Williams and Wilkins Publishers. A person of ordinary skill can judge the available combination of drugs based on the specific characteristics of the drug and the cancer involved. Typical antitumor agents useful in the present invention include, but are not limited to: anti-microtubule agents such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustard gas, oxazacyclic Oxazaphosphorine, alkyl sulfonates, nitrosourea, and triazene; antibiotics such as anthracyclins, actinomycins, and bleomycins; topological isomerism Enzyme II inhibitors such as epipodophyllotoxin; antimetabolites such as purine and pyrimidine analogs and antifolate compounds; topoisomerase I inhibitors such as camptothecin; hormones and hormone analogs; messaging pathway inhibitors Non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeutics; pro-apoptotic agents; cell cycle messaging inhibitors; proteasome inhibitors; and cancer metabolism inhibitors.

Examples of other active ingredients or ingredients (antitumor agents) used in combination or co-administration with the compound of the present invention are chemotherapeutic agents.

Anti-microtubule agents or anti-mitotic agents are period-specific agents that are effective against the microtubules of tumor cells during the M-phase or mitotic phase of the cell cycle. Examples of anti-microtubule agents include, but are not limited to, diterpenes and vinca alkaloids.

Diterpenes derived from natural sources are phase-specific anticancer agents that operate in the G2 / M phase of the cell cycle. Xianxin diterpenes stabilize the microtubule β-tubulin subunits by binding to this protein. The breakdown of proteins appears to be inhibited by mitosis and subsequent cell death. The breakdown of the protein appears to prevent it from being inhibited by mitosis, followed by cell death. Examples of diterpenes include, but are not limited to, paclitaxel and its analog docetaxel.

Paclitaxel (with 5β, 20-epoxy-1,2α, 4,7β, 10β, 13α-hexa-hydroxy violet with (2R, 3S) -N-benzylidene-3-phenylisoserine) Cedar-11-ene-9-one 4,10-diacetic acid 2-benzoate 13-ester) is a natural diterpene product isolated from Taxus brevifolia and is commercially available as an injectable Solution TAXOL®. It is a member of the taxane family of terpenes. It was first isolated by Wani et al. In 1971 (J. Am. Chem, Soc., 93: 2325.1971). Wani et al. Used chemical and X-ray crystallography to express their structural properties. One mechanism of its activity is the ability of paclitaxel to bind to microtubules, thereby inhibiting the growth of cancer cells. Schiff et al., Proc. Natl, Acad, Sci. USA, 77: 1561-1565 (1980); Schiff et al., Nature, 277: 665-667 (1979); Kumar, J. Biol, Chem, 256: 10435-10441 (1981). For a discussion of the synthesis and anticancer activity of some paclitaxel derivatives, see: DGIKingston et al. , Studies in Organic Chemistry vol.26, entitled "New trends in Natural Products Chemistry 1986", Attaur-Rahman, PWLe Quesne, Eds. (Elsevier Amsterdam, 1986) pp 219-235.

Paclitaxel has been approved for clinical use in the United States for the treatment of refractory ovarian cancer (Markman et al., Yale Journal of Biology and Medicine, 64: 583, 1991; McGuire et al., Ann.lntem, Med., 111: 273, 1989) and for the treatment of breast cancer (Holmes et al., J. Nat. Cancer Inst., 83: 1797, 1991). It is a potential treatment for skin tumors (Einzig et.al., Proc. Am. Soc. Clin. Oncol., 20:46) and head and neck cancer (Forastire et.al., Sem. Oncol., 20:56, 1990). Drug candidate. This compound also shows the possibility of treating polycystic kidney disease (Woo.et.al., Nature, 368: 750.1994), lung cancer and malaria. Treatment of patients with paclitaxel leads to myelosuppression (multicellular lineage, Ignoff, RJet.al, Cancer Chemotherapy Pocket Guide, 1998), which is related to the period of dose above the threshold concentration (50nM) (Kearns, CMet.al., Seminars in Oncology, 3 (6) p. 16-23, 1995).

Docetaxel (with 5β-20-epoxy-1,2α, 4,7β, 10β, 13α-hexahydroxytaxe-11-ene-9-one 4-ethyl ester 2-benzoate three (2R, 3S) -N-carboxy-3-phenylisoserine acid, N-tertiary butyl ester, 13-ester) of a hydrate is an injectable solution commercially available as TAXOTERE®. Docetaxel is suitable for the treatment of breast cancer. Docetaxel is a semi-synthetic derivative of paclitaxel q.v., which is prepared using 10-deacetyl-baccatin III, a natural precursor extracted from the needles of the European Yew tree. The dose-limiting toxicity of docetaxel is neutropenia.

Vinca alkaloids are period specific antitumor agents derived from periwinkle plants. Vinca alkaloids work in the M phase (mitosis) of the cell cycle by specifically binding to microtubules. Therefore, the bound tubulin molecules cannot aggregate into microtubules. Xianxin mitosis was stopped in the middle and cell death followed. Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine, and vinorelbine.

Vinblastine (vincaleukoblastine sulfate) is commercially available as an injection solution of VELBAN®. Although it has possible applicability as a second-line treatment for various solid tumors, it is mainly applicable to the treatment of testicular cancer and various lymphomas (including Hodgkin's disease); and lymphatic and histiocytic lymphoma. Myelosuppression is a dose limiting side effect of vinblastine.

Vincristine (vincaleukoblastine, 22-keto-) is commercially available as an injection solution of ONCOVIN®. Vincristine is suitable for the treatment of acute leukemia and its use has also been found in treatment protocols for Hodgkin's and non-Hodgkin's malignant lymphoma. Hair loss and neurological effects are the most common side effects of vincristine and occur with a lower degree of bone marrow suppression and gastrointestinal mucositis effects.

Vinorelbine (3 ', 4'-Didehydro-4'-deoxy-C'-norvincaleukoblastine) (R- (R *, R *)-2,3-dihydroxysuccinic acid (1: 2) (Salt)]) The commercially available injection solution of vinorelbine tartrate (NAVELBINE®) is a semi-synthetic vinca alkaloid. Vinorelbine is suitable for the treatment of various solid tumors in a single dose or in combination with other chemotherapeutic agents such as cisplatin, especially non-small cell lung cancer, advanced breast cancer and hormone-refractory prostate cancer. Myelosuppression is Changchun Ribin is the most common dose limiting side effect.

Platinum coordination complexes are non-phase specific anticancer agents that interact with DNA. The platinum complex enters tumor cells, undergoes water and effects, and forms intrastrand and interstrand cross-links with DNA, causing harmful biological effects on the tumor. Examples of platinum coordination complexes include, but are not limited to, cisplatin and carboplatin.

Cisplatin (cis-diaminodichloroplatinum) is commercially available as an injection solution of PLATINOL®. Cisplatin is mainly used for the treatment of metastatic testicular cancer, ovarian cancer and advanced bladder cancer. The main dose-limiting side effects of cisplatin are renal toxicity (which can be controlled by hydration and diuresis) and ototoxicity.

Carboplatin (platinum, diamino [1,1-cyclobutane-dicarboxylate (2-)-O, O ']) is commercially available as an injection solution of ARAPLATIN®. Carboplatin is mainly used for first and second line treatment of advanced ovarian cancer. Myelosuppression is the dose-limiting toxicity of carboplatin.

Alkylating agents are non-stage anticancer specific drugs and strong electrophiles. In general, alkylating agents form covalent bonds to DNA by alkylating through the electrophilic portions of the DNA molecule, such as phosphate, amine, thiol, hydroxyl, carboxyl, and imidazolyl. This alkylation disrupts nucleic acid function and causes cell death. Examples of alkylating agents include, but are not limited to, nitrogen mustards, such as cyclophosphamide, melphalan, and chlorambucil; alkylsulfonates, such as busulfan ; Nitrosourea, such as carmustine; and triazene, such as dacarbazine.

Cyclophosphamide (2- [bis (2-chloroethyl) amino] tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide monohydrate) is CYTOXAN® is a commercially available injection or lozenge. Cyclophosphamide is suitable for the treatment of malignant lymphoma, multiple myeloma and leukemia in a single dose or in combination with other chemotherapeutic agents. Hair loss, nausea, nausea and leukocytopenia are the most common dose limiting side effects of cyclophosphamide.

Melphalan (4- [bis (2-chloroethyl) amino] -L-phenylalanine) is an injection or lozenge commercially available as ALKERAN®. Melphalan is suitable for the relief therapy of multiple myeloma and unresectable ovarian epithelial cancer. Myelosuppression is the most common dose limiting side effect of melphalan.

Phenylbutyric acid mustard (4- [bis (2-chloroethyl) amino] phenylbutyric acid) is commercially available as LEUKERAN® lozenges. Phenylbutyrate must be used for chronic lymphocytic leukemia and malignant lymphomas such as lymphosarcoma, giant follicular lymphoma, and relief therapy for Hodgkin's disease. The most common dose limiting side effect of chlorambucil is myelosuppression. Myelosuppression is the most common dose limiting side effect of chlorambucil.

Busulfan (1,4-butanediol dimesylate) is commercially available as MYLERAN® lozenge. Busulfan is suitable for the relief therapy of chronic myelogenous leukemia. Myelosuppression is the most common dose limiting side effect of busulfan.

Carmustine (1,3- [bis (2-chloroethyl) -1-nitrosourea] is commercially available as a single bottle of BiCNU® lyophilized material. Carmustine is suitable for use as a single dose or with other The combination of agents is used in brain tumors, multiple myeloma, Hodgkin's disease, and non-Hodgkin's lymphoma to reduce therapies. Delayed bone marrow suppression is the most common dose-limiting side effect of carmustine.

Dacabaren (5- (3,3-dimethyl-1-triazenyl) -imidazole-4-carboxamide) is commercially available as a single bottle of DTIC-Dome® material. Dakabaren is suitable for the treatment of metastatic malignant melanoma and in combination with other agents for second-line treatment of Hodgkin's disease. Nausea, vomiting and anorexia are the most common dose limiting side effects of dacarbabaren.

Antibiotic antineoplastic agents are non-phase specific agents that bind or insert DNA. Generally, this effect results in the breaking of stable DNA complexes or strands, which disrupts the normal function of the nucleic acid, leading to cell death. Examples of antibiotic antineoplastic agents include, but are not limited to, actinomycin (such as dactinomycin), anthracyclines (such as daunorubicin, and doxorubicin); and bleomycin (bleomycin).

Dactinomycin (also known as actinomycin D) is commercially available as an injection form of COSMEGEN®. Dactinomycin is suitable for the treatment of Wilm's tumor and rhabdomyosarcoma. Nausea, vomiting and anorexia are the most common dose limiting side effects of dactinomycin.

Daunorubicin ((8S-cis-)-8-acetamido-10-[(3-amino-2,3,6-trideoxy-α-L-lyxo) -hexapiperan Glycosyl (hexopyranosyl) oxy) -7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-thickened tetrabenzodione hydrochloride) Liposome injection form sold as DAUNOXOME® or injectable CERUBIDINE®. Daunorubicin is suitable for the induction of remission in the treatment of acute non-lymphatic blood cancer and end-stage HIV-associated Kaposi's sarcoma. Myelosuppression is the most common dose limiting side effect of daunorubicin.

Doxorubicin ((8S, 10S) -10-((3-amino-2,3,6-trideoxy-α-L-lyxo) -hexopyranosyl) oxygen Methyl] -8-ethanolamyl-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-dense tetrabenzodione hydrochloride) commercially available It is an injection form of RUBEX® or ADRIAMYCIN RDF®. Doxorubicin is mainly used for the treatment of acute lymphoblastic leukemia and acute myelogenous leukemia, but it is also a useful component in the treatment of some solid tumors and lymphomas. Myelosuppression is the most common dose limiting side effect of doxorubicin.

Bleomycin (a mixture of cytotoxin glycopeptide antibiotics isolated from Streptomyces verticillus strains) is commercially available as BLENOXANE®. Bleomycin is suitable for the relief therapy of squamous cell carcinoma, lymphoma and testicular cancer in a single dose or in combination with other agents. Lung and skin toxicity are the most common dose limiting side effects of bleomycin.

Topoisomerase II inhibitors include, but are not limited to, epipodophyllotoxin.

Epipodophyllotoxin is a phase-specific antitumor agent derived from the Mandela plant. Epipodophyllotoxin usually affects cells in the S and G2 phases of the cell cycle by breaking up DNA strands by forming a ternary complex with topoisomerase II and DNA. Strand rupture accumulates, followed by cell death. Examples of epipodophyllotoxins include, but are not limited to, etoposide and teniposide.

Etoposide (4'-desmethyl-epipodophyllotoxin 9 [4,6-0- (R) -ethylene-β-D-grape piperanoside]) is commercially available as an injection solution of VePESID® or Capsules are commonly referred to as VP-16. Etoposide is suitable for the treatment of testicular cancer and non-small cell lung cancer in a single dose or in combination with other chemotherapeutic agents. Myelosuppression is the most common side effect of etoposide. Leukopenia is often more severe than thrombocytopenia.

Teniposide, 4'-desmethyl-epipodophyllotoxin 9 [4,6-0- (R) -thiophene subunit (thenylidene) -β-D-grapepiside), commercially available as VUMON® The injection solution is commonly referred to as VM-26. Teniposide is suitable for the treatment of acute childhood acute leukemia in a single dose or in combination with other chemotherapeutic agents. Myelosuppression is the most common dose-limiting side effect of teniposide. Teniposide induces both leukopenia and thrombocytopenia.

An antimetabolite tumor agent is a phase-specific antitumor agent that acts in the S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting and limiting DNA synthesis by purine or pyrimidine base synthesis. Therefore, S phase cannot proceed and subsequent cell death. Examples of antimetabolite antitumor agents include, but are not limited to, fluorouracil, methotrexate, cytarabine, mercaptopurine, thioguanine, and gemcitabine.

5-Fluorouracil (5-fluoro-2,4- (1H, 3H) pyrimidinedione) is commercially available as fluorouracil. Administration of 5-fluorouracil results in inhibition of thymidylate synthesis and is also incorporated into both RNA and DNA. The result is usually cell death. 5-Fluorouracil is suitable for treating breast cancer, colon cancer, rectal cancer, gastric cancer, and pancreatic cancer in a single dose or in combination with other chemotherapeutic agents. Myelosuppression and mucositis are dose-limiting side effects of 5-fluorouracil. Other fluoropyrimidine analogs include 5-fluorodeoxyuridine (floxuridine) and 5-fluorodeoxyuridine monophosphate.

Cytarabine (4-amino-1-β-D-furan arabinosyl-2 (1H) -pyrimidone) is commercially available as CYTOSAR-U® and is commonly known as Ara-C. Xianxin cytarabine exhibits cell-phase specificity in the S-phase by inhibiting DNA strand lengthening by incorporating a growing DNA strand at the end of cytarabine. Cytarabine is suitable for the treatment of acute leukemia in a single dose or in combination with other chemotherapeutic agents. Other cytidine analogs include 5-azacytidine and 2 ', 2'-difluorodeoxycytidine (gemcitabine). Cytarabine induces leukopenia, thrombocytopenia, and mucositis.

Thiopurine (1,7-dihydro-6H-purine-6-thione monohydrate) is commercially available as PURINETHOL®. Thiopurines are cell-phase specific at the S-phase by inhibiting DNA synthesis by mechanisms that have not yet been clarified. Thiopurine is suitable for the treatment of acute leukemia in a single dose or in combination with other chemotherapeutic agents. Myelosuppression and gastrointestinal mucositis are expected side effects of high-dose thiopurine. A useful thiopurine analog is azathioprin.

Thioguanine (2-amino-1,7-dihydro-6H-purine-6-thione) is commercially available as TABLOID®. The thioguanine system exhibits cell-phase specificity in the S-phase by inhibiting DNA synthesis through mechanisms that have not yet been clarified. Thioguanine is suitable for the treatment of acute leukemia in a single dose or in combination with other chemotherapeutic agents. Myelosuppression (including leukopenia, thrombocytopenia, and anemia) is the most common dose limiting side effect of thioguanine administration. However, gastrointestinal side effects occur and can be dose limiting. Other purine analogs include pentostatin, erythrohydroxynonyl adenine, fludarabine phosphate, and cladribine.

Gemcitabine (2'-deoxy-2 ', 2'-difluorocytidine monohydrochloride (β-isomer)) is commercially available as GEMZAR®. Gemcitabine exhibits cell-phase specificity in the S-phase and blocks cell processes by crossing the G1 / S boundary. Gemcitabine is suitable for combination with cisplatin for the treatment of locally advanced non-small cell lung cancer, and for the treatment of locally advanced pancreatic cancer alone. Myelosuppression (including leukopenia, thrombocytopenia, and anemia) is the most common dose-limiting side effect of gemcitabine administration.

Methotrexate (N- [4 [[((2,4-diamino-6-pyridinyl) methyl] methylamino] benzylidene] -L-glutamic acid) is commercially available as amine methylamine Triopterin sodium. Methotrexate is specifically expressed in the S-phase by inhibiting DNA synthesis, repair, and / or replication by inhibiting the dyhydrofolic acid reductase required for the synthesis of purine nucleotides and thymidine. Cell-phase effect. Methotrexate is suitable for the treatment of choriocarcinoma, meningeal leukemia, non-Hodgkin's lymphoma, and breast, head, neck, ovarian and bladder cancers in a single dose or in combination with other chemotherapeutic agents. Myelosuppression (leukopenia, thrombocytopenia, and anemia) and mucositis are expected side effects of methotrexate administration.

Camptothecin (including camptothecin and camptothecin derivatives) is useful or developed as a topoisomerase I inhibitor. The cytotoxic activity of Xianxin camptothecin is related to its topoisomerase I inhibitory activity. Examples of camptothecin include, but are not limited to, irinotecan, topotecan, and 7- (4-methylpiperidin) described below (Methylene-methylene) -10,11-ethylenedioxy-20-camptothecin in various optical forms.

Irinotecan HCl ((4S) -4,11-diethyl-4-hydroxy-9-[(4-piperidinopiperidinyl) carbonyloxy] -1H-piperano [3 ', 4' , 6,7] indino [1,2-b] quinoline-3,14 (4H, 12H) -dione hydrochloride) is commercially available as an injection solution CAMPTOSAR®.

Irinotecan is a derivative of camptothecin, which, along with its active metabolite SN-38, binds to the topoisomerase I-DAN complex. Xianxin, due to the irreparable double-strand break caused by the interaction of topoisomerase I: DNA: irinotecan or SN-38 ternary complex with replication enzymes, resulting in cytotoxicity. Irinotecan is suitable for the treatment of metastatic cancer of the large intestine or rectum. The dose-limiting side effects of irinotecan HCl are myelosuppression (including neutropenia) and GI effects (including diarrhea).

Topotecan HCl ((S) -10-[(dimethylamino) methyl] -4-ethyl-4,9-dihydroxy-1H-piperano [3 ', 4', 6,7 ] Indino [1,2-b] quinoline-3,14- (4H, 12H) -dione monohydrochloride)) is commercially available as an injection solution HYCAMTIN®. Topotecan is a camptothecin derivative that binds to Topoisomerase I-DNA complex and prevents reconnection of single strand breaks caused by Topoisomerase I in response to twisted strands of DNA molecules . Topotecan is suitable for second-line treatment of ovarian and small cell lung cancer metastatic cancer. The dose-limiting side effect of Topotecan HCl is bone marrow suppression, mainly neutropenia.

Also of interest are the camptothecin derivatives of the following formula A, including the racemic mixture (R, S) type and the mirror image isomers of R and S: Known chemical name is "7- (4-methylpiperazine -Methylene) -10,11-ethylenedioxy-20 (R, S) -camptothecin (racemic mixture) or "7- (4-methylpiperidine -Methylene) -10,11-ethylenedioxy-20 (R) -camptothecin (R mirror image isomer) or "7- (4-methylpiper -Methylene) -10,11-ethylenedioxy-20 (S) -camptothecin (S mirror image isomer). This compound and related compounds, including manufacturing methods, are described in U.S. Patent Nos. 6,063,923; 5,342,947; 5,559,235; 5,491,237 and U.S. Patent Application No. 08 / 977,217, filed on November 24, 1997.

Hormones and hormone analogs are useful compounds for treating cancers in which there is a relationship between hormones and cancer growth and / or lack of growth. Examples of hormones and hormone analogs that can be used in cancer treatment include, but are not limited to, adrenal corticosteroids such as prednisone and prednisolone that can be used to treat children with malignant lymphoma and acute leukemia; Aminoglutethimide and other aromatase inhibitors, such as anastrozole, letrazole, and voclodazole, that can be used to treat adrenocortical cancer and hormone-dependent breast cancer with estrogen receptors (vorazole) and exemestane; progestins that can be used to treat hormone-dependent breast and endometrial cancers, such as megestrol acetate; females that can treat prostate cancer and benign prostatic hypertrophy Hormones, androgens and anti-androgens such as flutamide, nilutamide, bicalutamide, cyproterone acetate, and 5α-reductase, such as finasteride ( finasteride and dutasteride; anti-estrogens that can be used to treat hormone-dependent breast cancer and other susceptible cancers, such as tamoxifen, toremifene , Raloxifene, droloxifene, iodoxyfene, and selective estrogen receptor modulators (SERM), such as those described in U.S. Patent Nos. 5,681,835, 5,877,219, and 6,207,716 The author; and gonadotropin-releasing hormone (GnRH) and its analogs that stimulate the release of luteinizing hormone (LH) and / or follicle-stimulating hormone (FSH) to treat prostate cancer, such as LHRH agonists and antagonists, such as Goserelin acetate and luprolide.

Messaging pathway inhibitors are inhibitors that block or inhibit chemical processes that provoke intracellular changes. As used herein, this change is cell proliferation or differentiation. Messaging inhibitors useful in the present invention include receptor tyrosine kinases, non-receptor tyrosine kinases, SH2 / SH3 domain blockers, serine / threonine kinases, phospholipids inositol-3 kinase, Inositol messaging and inhibitor of Ras oncogene.

Several protein tyrosine kinases catalyze the phosphorylation of specific tyrosine hydrazone residues in various proteins involved in the regulation of cell growth. These protein tyrosine kinases can be broadly classified as receptor or non-receptor kinases.

Receptor tyrosine kinases are transmembrane proteins with extracellular ligand binding domains, transmembrane domains, and tyrosine kinase domains. Receptor tyrosine kinases are involved in the regulation of cell growth and are commonly referred to as growth factor receptors. For example, many of these kinases have been shown to cause uncontrolled cell growth due to improper or uncontrolled activation of overexpression or mutation (ie, abnormal kinase growth factor receptor activity). Therefore, the abnormal activity of these kinases is related to malignant tissue growth. Therefore, inhibitors of these kinases can provide cancer treatment methods. Growth factor receptors include, for example, epidermal growth factor receptor (EGFr), platelet-derived growth factor receptor (PDGFr), erbB2, erbB4, vascular endothelial growth factor receptor (VEGFr), immunoglobulin-like and epidermal growth factor Homologous domain (TIE-2) tyrosine kinase, insulin growth factor-I (IGFI) receptor, macrophage colony-stimulating factor (cfms), BTK, ckit, cmet, fibroblast growth factor (FGF ) Receptor, Trk receptor (TrkA, TrkB, and TrkC), ephrin (eph) receptor and RET proto-oncogene. Many inhibitors of growth receptors are under development and include ligand antagonists, antibodies, tyrosine kinase inhibitors, and antisense oligonucleotides. Growth factor receptors and agents that inhibit the function of growth factor receptors are described, for example, in Kath, John C., Exp. Opin. Ther. Patents (2000) 10 (6): 803-818; Shawver et al DDT Vol 2, No .2 February 1997; and Lofts, FJet al, "Growth factor receptors as targets", New Molecular Targets for Cancer Chemotherapy, ed. Workman, Paul and Kerr, David, CRC press 1994, London.

Suitably, the pharmaceutically active compound of the present invention can be combined with a VEGFR inhibitor (suitably 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl) methylamino] -2-pyrimidine [Amino] amino] -2-methylbenzenesulfonamide, or a pharmaceutically acceptable salt thereof, suitably a hydrochloride salt, is used in combination, which is disclosed and claimed in International Application No. PCT / US01 / 49367 (The international application date is December 19, 2001), the international publication number WO02 / 059110, and the international publication date are August 1, 2002, the entire disclosure thereof is hereby incorporated by reference, and it is the Compound. 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl) methylamino] -2-pyrimidinyl] amino] -2-methylbenzenesulfonamide can be as international Prepared as described in application number PCT / US01 / 49367.

Suitably 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl) methylamino] -2-pyrimidinyl] amino] -2-methylbenzenesulfonamide It is a type of monohydrochloride. This salt form can be prepared by those skilled in the art from the international application number PCT / US01 / 49367 (the international application date is December 19, 2001).

5-[[4-[(2,3-dimethyl-2H-indazol-6-yl) methylamino] -2-pyrimidinyl] amino] -2-methylbenzenesulfonamide is commercially available as monohydrochloride and the generic name, pazopanib (pazopanib) and known for Votrient ^® tradename.

Pazopanib involves the treatment of cancer and eye diseases / angiogenesis. Suitably the invention relates to the treatment of cancer and ocular diseases / angiogenesis (appropriately age-related macular degeneration), the method comprising administering a compound of formula (Ib) alone or in combination with pazopanib.

Tyrosine kinases that are not growth factor receptor kinases are called non-receptor tyrosine kinases. Non-receptor tyrosine kinases (which are targets or potential targets for anticancer drugs) that can be used in the present invention include cSrc, Lck, Fyn, Yes, Jak, cAbl, FAK (point adhesion kinase), blue Brutons tyrosine kinase and Bcr-Abl. Such non-receptor kinases and agents that inhibit the function of non-receptor tyrosine kinases are described in Sinh, S. and Corey, SJ, (1999) Journal of Hematotherapy and Stem Cell Research 8 (5): 465-80; and Bolen, JB, Brugge, JS, (1997) Annual review of Immunology. 15: 371-404.

SH2 / SH3 domain blockers are those that disrupt SH2 in various enzymes or adaptors (including SH3 domain-binding drug. The SH2 / SH3 domain as a target for anticancer drugs is discussed in Smithgall, T.E. (1995), Journal of Pharmacological and Toxicological Methods, 34 (3) 125-32.

Inhibitors of serine / threonine kinase include MAP kinase cascade blockers, which include Raf kinase (rafk), mitogen or extracellular regulatory kinase (MEK), and extracellular regulatory kinase (ERK). Blocking agents; and blockers of protein kinase C family members, including blocking agents of PKC (α, β, γ, ε, μ, λ, ι, ζ). IkB kinase family (IKKa, IKKb), PKB family kinase, members of akt kinase family, PDK1 and TGF β receptor kinase. These serine / threonine kinases and their inhibitors are described in Yamamoto, T., Taya, S., Kaibuchi, K., (1999), Journal of Biochemistry. 126 (5) 799-803; Brodt, P, Samani, A., and Navab, R. (2000), Biochemical Pharmacology, 60.1101-1107; Massague, J., Weis-Garcia, F. (1996) Cancer Surveys. 27: 41-64; Philip, PA, and Harris, AL (1995), Cancer Treatment and Research. 78: 3-27, Lakekey, K. et al Bioorganic and Medicinal Chemistry Letters, (10), 2000, 223-226; US Patent No. 6,268,391; Pearce, LR et al. Nature Reviews Molecular Cell Biology (2010) 11, 9-22. and Martinez-Iacaci, L., et al, Int. J. Cancer (2000), 88 (1), 44-52.

Suitably, the pharmaceutically active compound of the present invention is used in combination with a MEK inhibitor. Suitably, N- {3- [3-cyclopropyl-5- (2-fluoro-4-iodo-phenylamino) -6,8-dimethyl-2,4,7-trisoxy -3,4,6,7-tetrahydro-2H-pyrido [4,3-d] pyrimidin-1-yl] phenyl} acetamide, or a pharmaceutically acceptable salt or solvate thereof, as appropriate It is a dimethyl sulfene solvate, which is disclosed and claimed in the international application number PCT / JP2005 / 011082, the international application date is June 10, 2005; the international publication number WO 2005/121142, and the international publication date is 2005 On December 22, the entire disclosure is hereby incorporated by reference. N- {3- [3-cyclopropyl-5- (2-fluoro-4-iodo-phenylamino) -6,8-dimethyl-2,4,7-trioxo-3, 4,6,7-tetrahydro-2H-pyrido [4,3-d] pyrimidin-1-yl] phenyl} acetamidin may be as disclosed in US Patent Publication No. US 2006/0014768 (published on January 19, 2006 , Whose entire disclosure is hereby incorporated by reference).

Suitably, the pharmaceutically active compound of the present invention is used in combination with a B-Raf inhibitor. Suitably, N- {3- [5- (2-Amino-4-pyrimidinyl) -2- (1,1-dimethylethyl) -1,3-thiazol-4-yl] -2- Fluorophenyl} -2,6-difluorobenzenesulfonamide, or a pharmaceutically acceptable salt thereof, is disclosed and claimed in International Application No. PCT / US2009 / 042682, the international application date is May 4, 2009 , Whose entire disclosure is hereby incorporated by reference. N- {3- [5- (2-Amino-4-pyrimidinyl) -2- (1,1-dimethylethyl) -1,3-thiazol-4-yl] -2-fluorophenyl } -2,6-difluorobenzenesulfonamide can be prepared as described in International Application No. PCT / US2009 / 042682.

Suitably, the pharmaceutically active compound of the present invention is used in combination with an Akt inhibitor. Suitably, N-{(1S) -2-amino-1-[(3,4-difluorophenyl) methyl] ethyl} -5-chloro-4- (4-chloro-1-methyl -1H-pyrazol-5-yl) -2-furanmethanamine or a pharmaceutically acceptable salt thereof, which is disclosed and claimed in International Application No. PCT / US2008 / 053269, with an international filing date of February 2008 7th; International Publication No. WO 2008/098104 and the International Publication Date is August 14, 2008, the entire disclosure of which is hereby incorporated by reference. N-{(1S) -2-amino-1-[(3,4-difluorophenyl) methyl] ethyl} -5-chloro-4- (4-chloro-1-methyl-1H- Pyrazol-5-yl) -2-furamidine is the compound of Example 224 and can be prepared as described in International Application No. PCT / US2008 / 053269.

Suitably, the pharmaceutically active compound of the present invention is used in combination with an Akt inhibitor. Suitably, N -{(1 S ) -2-amino-1-[(3-fluorophenyl) methyl] ethyl} -5-chloro-4- (4-chloro-1-methyl-1 H -pyrazol-5-yl) -2-thienolamide, or a pharmaceutically acceptable salt thereof, is disclosed and claimed in International Application No. PCT / US2008 / 053269, with an international filing date of February 7, 2008 Day; International Publication No. WO 2008/098104 and the International Publication Date is August 14, 2008, the entire disclosure of which is hereby incorporated by reference. N -{(1S) -2-amino-1-[(3-fluorophenyl) methyl] ethyl} -5-chloro-4- (4-chloro-1-methyl-1 H -pyrazole (-5-yl) -2-thienolamide is the compound of Example 96 and can be prepared as described in International Application No. PCT / US2008 / 053269. Suitably, N -{(1 S ) -2-amino-1-[(3-fluorophenyl) methyl] ethyl} -5-chloro-4- (4-chloro-1-methyl-1 H -pyrazol-5-yl) -2-thienformamide is in the form of the hydrochloride salt. The salt form can be prepared by those skilled in the art from the international application number PCT / US2010 / 022323 with an international application date of January 28, 2010.

Inhibitors of members of the phospholipid inositol-3 kinase family, including blockers of PI3-kinase, ATM, DNA-PK and Ku, can also be used in the present invention. These kinases are discussed in Abraham, RT (1996), Current Opinion in Immunology. 8 (3) 412-8; Canman, CE, Lim, DS (1998), Oncogene 17 (25) 3301-3308; Jackson, SP ( 1997), International Journal of Biochemistry and Cell Biology. 29 (7): 935-8; and Zhong, H. et al, Cancer res, (2000) 60 (6), 1541-1545.

Also of interest in the present invention are inositol messaging inhibitors such as phospholipase C blockers and inositol analogs. Such signal inhibitors are described in Powis, G., and Kozikowski A., (1994) New Molecular Targets for Cancer Chemotherapy ed., Paul Workman and David Kerr, CRC press 1994, London.

Another group of pathway inhibitors are inhibitors of Ras oncogenes. These inhibitors include inhibitors of farnesyl transferase, geranyl-geranyl transferase and CAAX protease, as well as antisense oligonucleotides, ribonucleases and immunotherapy. These inhibitors have been shown to block ras activation in cells containing wild-type mutant ras, and thus can act as antiproliferative agents. Suppression of Ras oncogenes is discussed in Scharovsky, OG, Rozados, VR, Gervasoni, SIMatar, P. (2000), Journal of Biomedical Science. 7 (4) 292-8; Ashby, MN (1998), Current Opinion in Lipidology .9 (2) 99-102; and BioChim. Biophys. Acta, (19899) 1423 (3): 19-30.

As mentioned above, antibody antagonists that bind to receptor kinase ligands can also act as messaging inhibitors. This group of signaling pathway inhibitors includes the use of humanized antibodies for the extracellular ligand binding domains of receptor tyrosine kinases. For example, Imclone C225 EGFR-specific antibodies (see Green, MCet al, Monoclonal Therapy for Solid Tumors, Cancer Treat. Rev., (2000), 26 (4), 269-286); Herceptin ® erbB2 antibodies (see Tyrosine Kinase Signalling in Breast cancer: erbB Family Receptor Tyrosine Kniases, Breast cancer Res., 2000, 2 (3), 176-183); and 2CB VEGFR2 specific antibodies (see Brekken, RAet al, Selective Inhibition of VEGFR2 Activity by a monoclonal Anti-VEGF antibody blocks tumor growth in mice, Cancer Res. (2000) 60, 5117-5124).

Non-receptor kinase angiogenesis inhibitors can also be used in the present invention. Inhibitors of angiogenesis related to VEGFR and TIE2 are discussed above with regard to messaging inhibitors (both receptors are receptor tyrosine kinases). Angiogenesis is generally related to erbB2 / EGFR messaging inhibitors, as inhibitors of erbB2 and EGFR have been shown to inhibit angiogenesis, mainly VEGF manifestations. Therefore, non-receptor tyrosine kinase inhibitors can be used in combination with the compounds of the present invention. For example, anti-VEGF antibodies, which cannot recognize VEGFR (receptor tyrosine kinase), but can bind to ligands; small molecule inhibitors of integrin (α _v β ₃ ) that can inhibit angiogenesis; endostatin (endostatin) and angiostatin (non-RTK) have also proven useful in combination with the disclosed compounds. (See Bruns CJ et al (2000), Cancer Res., 60: 2926-2935; Schreiber AB, Winkler ME, and Derynck R. (1986), Science, 232: 1250-1253; YenL et al. (2000), Oncogene 19: 3460-3469).

Agents used in immunotherapy regimens can also be used in combination with compounds of formula (Ib). There are many immune strategies that generate an immune response. These strategies are generally in the field of tumor vaccination. The combined inhibition of the signaling pathway using small molecule inhibitors can greatly enhance the efficacy of the immunological method. For a discussion of the erbB2 / EGFR immunization / tumor vaccine approach, see Reilly RT et al. (2000), Cancer Res. 60: 3569-3576; and Chen Y, Hu D, Eling DJ, Robbins J, and Kipps TJ. (1998 ), Cancer Res. 58: 1965-1971.

Agents used in pro-apoptotic protocols (eg, bcl-2 antisense oligonucleotides) can also be used in combination with the present invention. Members of the Bcl-2 family of proteins block apoptosis. Bcl-2 up-regulation is therefore related to chemical resistance. Studies have shown that epidermal growth factor (EGF) stimulates anti-apoptotic members of the bcl-2 family (ie, mcl-1). Therefore, strategies designed to down-regulate the performance of bcl-2 in tumors have demonstrated clinical benefit and have now entered phase II / III trials (ie, Genta's G3139 bcl-2 antisense oligonucleotide). These pro-apoptotic strategies using antisense oligonucleotide strategies for bcl-2 are discussed in Water JS et al. (2000), J. Clin. Oncol. 18: 1812-1823; and Kitada S et al. (1994), Antisense Res. Dev. 4: 71-79.

Cell cycle messaging inhibitors inhibit molecules involved in controlling the cell cycle. A family of protein kinases called cyclin-dependent kinases (CDK) and their interactions with a family of proteins called cyclins control progress through the eukaryotic cell cycle. Coordination activation and inactivation of different cyclin / CDK complexes are required for normal progression through the cell cycle. Several inhibitors of cell cycle messaging are under development. For example, cyclin-dependent kinases (including CDK2, CDK4, and CDK6) and their inhibitors are described, for example, in Rosania et al, Exp. Opin. Ther. Patents (2000) 10 (2): 215-230. In addition, p21WAF1 / CIP1 is described as a potent and versatile inhibitor of cyclin-dependent kinase (Cdk) (Ball et al., Progress in Cell Cycle Res., 3 : 125 (1997)). Compounds known to cause p21WAF1 / CIP1 expression have been implicated in the inhibition of cell proliferation and have tumor suppressive activity (Richon et al., Proc. Nat Acad. Sci. USA 97 (18): 10014-10019 (2000)) and can be included as Cell cycle messaging inhibitor. Tissue protein deacetylase (HDAC) inhibitors are involved in the transcriptional activation of p21WAF1 / CIP (Vigushin et al., Anticancer Drugs, 13 (1): 1-13 (Jan 2002)) and are suitable for combination use herein Cell cycle messaging inhibitor.

Examples of these HDAC inhibitors include:

1. Vorinostat, including its pharmaceutically acceptable salts. Marks et al., Nature Biotechnology 25, 84 to 90 (2007); Stenger, Community Oncology 4, 384-386 (2007).

Vorinostat has the following chemical structure and name: N -hydroxy- N' -phenyl-octanediamine

2. Romidepsin, including its pharmaceutically acceptable salts.

Vinodhkumar et al., Biomedicine and Pharmacotherapy 62 (2008) 85-93.

Romidepsin has the following chemical structure and name: (1S, 4S, 7Z, 10S, 16E, 21R) -7-ethylene-4,21-bis (prop-2-yl) -2-oxa-12,13-dithia-5,8, 20,23-Tetraazabicyclo [8.7.6] Eicosan-16-ene-3,6,9,19,22-pentanone.

3. Panobinostat, including its pharmaceutically acceptable salts. Drugs of the Future 32 (4): 315-322 (2007).

Papistast, has the following chemical structure and name: (2 E ) -N -hydroxy-3- [4-({[2- (2-methyl-1 H -indol-3-yl) ethyl] amino} methyl) phenyl] acrylamide

4. Valproic acid, including its pharmaceutically acceptable salts. Gottlicher, et al., EMBO J. 20 (24): 6969-6978 (2001).

Valproic acid has the following chemical structure and name: 2-propylvaleric acid

5. Mocetinostat (MGCD0103), including its pharmaceutically acceptable salts. Balasubramanian et al., Cancer Letters 280: 211-221 (2009).

Mossetinolt has the following chemical structure and name: N- (2-aminophenyl) -4-[[(4-pyridin-3-ylpyrimidin-2-yl) amino] methyl] benzidine

Other examples of these HDAC inhibitors are included in the European Journal of Medicinal Chemistry 45, (2010) 2095-2116, in particular the compounds of Table 3 which are shown below.

Proteasome inhibitors are drugs that block the action of proteasomes, and cellular complexes that break down proteins, such as p53 protein. Several proteasome inhibitors have been marketed or are being studied for cancer treatment. Proteasome inhibitors suitable for use in combination herein include:

1. Bortezomib (Velcade®), including its pharmaceutically acceptable salts. Adams J, Kauffman M (2004), Cancer Invest 22 (2): 304-11.

Bortezomib has the following chemical structure and name.

[(1 R ) -3-methyl-1-({(2 S ) -3-phenyl-2-[(pyridine 2-ylcarbonyl) amino] propanyl} amino) butyl] boronic acid

2. Disulfiram, including its pharmaceutically acceptable salts. Bouma et al. (1998). J. Antimicrob. Chemother. 42 (6): 817-20.

Disulfiram has the following chemical structure and name.

1,1 ', 1 ", 1'''-[Disulfanediylbis (Carbothiothionyl nitrogen (nitrile))] tetraethane

3. Epigallocatechin gallate (EGCG), including its pharmaceutically acceptable salts. Williamson et al., (December 2006), The Journal of Allergy and Clinical Immunology 118 (6): 1369-74.

Epigallocatechin gallate has the following chemical structure and name.

[(2R, 3R) -5,7-dihydroxy-2- (3,4,5-trihydroxyphenyl) dihydrobenzopiperan-3-yl] 3,4,5-trihydroxybenzoic acid ester

4. Salinosporamide A, including its pharmaceutically acceptable salts. Feling et at., (2003), Angew. Chem. Int. Ed. Engl. 42 (3): 355-7.

Halosporin A has the following chemical structure and name.

(4R, 5S) -4- (2-chloroethyl) -1-((1S) -cyclohex-2-enyl (hydroxy) methyl) -5-methyl-6-oxa-2-nitro Heterobicyclo 3.2.0 heptane-3,7-dione

5. Carfilzomib, including its pharmaceutically acceptable salts. Kuhn DJ, et al, Blood, 2007, 110: 3281-3290.

Carfilzomib has the following chemical structure and name.

(S) -4-methyl-N-((S) -1-(((S) -4-methyl-1-((R) -2-methyloxiran-2-yl)- 1-oxopentyl-2-yl) amino) -1-oxo-3-phenylprop-2-yl) -2-((S) -2- (2-morpholinylacetamidinyl) ) -4-phenylbutyramido) pentamidine

70 kilodalton heat shock proteins (Hsp70s) and 90 kilodalton heat shock proteins (Hsp90s) are a group of ubiquitous heat shock proteins. Hsp70s and Hsp90s are overexpressed in some cancer types. Several Hsp70s and Hsp90s inhibitors are being studied for the treatment of cancer. Hsp70s and Hsp90s inhibitors suitable for use in combination herein include:

1.17-AAG (Geldanamycin), including its pharmaceutically acceptable salts. Jia W et al. Blood. 2003 Sep 1; 102 (5): 1824-32.

17-AAG (geldanamycin) has the following chemical structure and name.

17- (allylamino) -17-desmethoxygeldanamycin

2. Radicicol, including its pharmaceutically acceptable salts. (Lee et al., Mol Cell Endocrinol. 2002, 188, 47-54)

Rhizoptin has the following chemical structure and name.

(1aR, 2Z, 4E, 14R, 15aR) -8-chloro-9,11-dihydroxy-14-methyl-15,15a-dihydro-1aH-benzo [c] epoxyvinyl [2,3 -k] [1] oxetane-6,12 (7H, 14H) -dione

Inhibitors of Cancer Metabolism-Many tumor cells show metabolic effects that are significantly different from normal tissues. For example, the rate of glycolysis (the metabolic process of converting glucose to pyruvate) is increased, and the pyruvate produced is reduced to lactate, instead of being further oxidized in the mitochondria via the tricarboxylic acid (TCA) cycle. This effect often occurs even under aerobic conditions and is called the Warburg effect.

Lactate dehydrogenase A (LDH-A), an isoform of lactate dehydrogenase expressed in muscle cells, plays a key role in tumor cell metabolism. It is reduced by pyruvate to lactic acid, and then It is exported outside the cell. This enzyme has been shown to be upregulated in many tumor types. The altered glucose metabolism described in the Warburg effect is crucial for the growth and proliferation of cancer cells, and the use of RNA-i to knock out LDH-A has been shown to lead to a reduction in cell proliferation and tumor growth in xenograft models.

D.A.Tennant.et.al., Nature Reviews, 2010, 267.

P. Leder, et.al., Cancer Cell, 2006, 9,425.

High levels of fatty acid synthase (FAS) have been found in precancerous lesions. The pharmacological inhibition of FAS affects the expression of key oncogenes involved in both cancer development and maintenance.

Alli et al. Oncogene (2005) 24, 39-46. Doi: 10.1038

Cancer metabolic inhibitors (including inhibitors of LDH-A and inhibitors of fatty acid biosynthesis (or FAS inhibitors)) are suitable for use in combination with the compounds of the present invention.

In a specific example, the claimed cancer treatment method comprises co-administration of a compound of formula (Ib) and / or a pharmaceutically acceptable salt thereof and at least one antitumor agent, such as those selected from the group consisting of: Antimicrotubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormone analogs, and pathway inhibitors And non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeutics; pro-apoptotic agents; cell cycle messaging inhibitors; proteasome inhibitors; and cancer metabolism inhibitors.

In a specific example, compounds of formula (Ib) are used as chemical sensitizers to enhance tumor cell killing.

In a specific example, the compound of formula (Ib) is used in combination as a chemical sensitizer to enhance tumor cell killing.

In a specific example, the compound of formula (Ib) is used in combination with a protein kinase R (PKR) -like ER kinase PERK active compound (PERK inhibitor).

Suitably, the compound of formula (Ib) and a pharmaceutically acceptable salt thereof may be used with at least one known to treat or reduce neurodegenerative diseases / injuries such as Alzheimer's disease, spinal injury, traumatic brain injury, Ischemic stroke, stroke, diabetes, Parkinson's disease, Huntington's disease, Kouja's disease, and related Prion disease, progressive supranuclear palsy, amyotrophic lateral sclerosis, myocardial infarction, Cardiovascular disease, inflammation, fibrosis, chronic and acute liver disease, chronic and acute lung disease, chronic and acute kidney disease, chronic traumatic encephalopathy (CTE), neurodegenerative disease, dementia, traumatic brain injury, cognitive impairment, atherosclerosis Sclerosis, eye disease, arrhythmia, and severity of organ transplantation and transplantation of organs for transplantation) are co-administered with other active agents of inhibitors of PERK kinase (EIF2K3).

"Chemotherapeutic" or "chemotherapeutic agent" is used in its ordinary meaning and refers to a chemical composition or compound that has antitumor properties or the ability to inhibit cell growth or proliferation.

In addition, the compounds described herein can be used with conventional immunotherapeutics (including, but not limited to) immune enhancers (e.g., BCG, levamisole, interleukin-2, alpha-interferon, etc. Etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody-Cage Calicheamicin conjugate, anti-CD22 monoclonal antibody-Pseudomonas exotoxin conjugate, etc.), and radioimmunotherapy (e.g., conjugated to ¹¹¹ In, ⁹⁰ Y, or ¹³¹ I Anti-CD20 monoclonal antibodies, etc.)) co-administered.

In another specific example, the compounds described herein can be used with conventional radiotherapeutics (including, but not limited to) radionuclides such as ⁴⁷ Sc, ⁶⁴ C, ⁶⁷ C, ⁸⁹ Sr, ⁸⁶ Y, ⁸⁷ Y, and ²¹² Bi ) Co-administered, optionally coupled with antibodies against tumor antigens.

Additional examples of other active ingredients or ingredients (antitumor agents) that can be used in combination or co-administration with the ATF4 pathway inhibitory compound of the present invention are anti-PD-L1 agents.

Anti-PD-L1 antibodies and methods of making them are known in the art.

Such antibodies to PD-L1 may be multiple or single strains and / or recombinant and / or humanized antibodies.

Exemplary PD-L1 antibody systems are disclosed in: U.S. Patent No. 8,217,149; 12 / 633,339; U.S. Patent No. 8,383,796; 13 / 091,936; U.S. Patent No. 8,552,154; 13 / 120,406; U.S. Publication No. 20110280877; 13/068337; U.S. Publication No. 20130309250; 13/892671; WO2013019906; WO2013079174; U.S. Application No. 13 / 511,538 (filed on August 7, 2012), which is the U.S. country of International Application No. PCT / US10 / 58007 (filed in 2010) Phase; and US Application No. 13 / 478,511 (filed on May 23, 2012).

Additional exemplary antibodies to PD-L1 (also known as CD274 or B7-H1) and methods of use are disclosed in U.S. Patent No. 7,943,743; US20130034559, WO2014055897, U.S. Patent No. 8,168,179; and U.S. Patent No. 7,595,048. PD-L1 antibodies are being developed as immunomodulators for the treatment of cancer.

In a specific example, the antibody to PD-L1 is the antibody disclosed in US Patent No. 8,217,149. In another specific example, the anti-PD-L1 antibody comprises the CDRs of the antibodies disclosed in U.S. Patent No. 8,217,149.

In another specific example, the antibody to PD-L1 is the antibody disclosed in US Application No. 13 / 511,538. In another specific example, the anti-PD-L1 antibody comprises the CDRs of the antibodies disclosed in US Application No. 13 / 511,538.

In another specific example, the antibody to PD-L1 is the antibody disclosed in application number 13 / 478,511. In another specific example, the anti-PD-L1 antibody comprises the CDRs of the antibodies disclosed in US Application No. 13 / 478,511.

In a specific example, the anti-PD-L1 antibody is BMS-936559 (MDX-1105). In another specific example, the anti-PD-L1 antibody is MPDL3280A (RG7446). In another specific example, the anti-PD-L1 antibody is MEDI4736.

Additional examples of other active ingredients or ingredients (antitumor agents) that can be used in combination or co-administration with the ATF4 pathway inhibitory compound of the present invention are PD-1 antagonists.

"PD-1 antagonist" means blocking the binding of PD-L1 expressed on cancer cells to PD-1 expressed on immune cells (T cells, B cells or NKT cells), and preferably also blocks Any chemical compound or biomolecule that binds PD-L2 on cancer cells to PD-1 on immune cells. Alternative names or synonyms for PD-1 and its ligands include: PDCD1, PD1, CD279, and SLEB2 for PD-1; PDCD1L1, PDL1, B7H1, B7-4, CD274, and B7- for PD-L1 H; and PDCD1L2, PDL2, B7-DC, Btdc and CD273 for PD-L2. In any specific example of the aspect or specific example of the present invention in which a human individual is to be treated, a PD-1 antagonist blocks the binding of human PD-L1 to human PD-1, and preferably blocks human PD-L1 and The combination of both PD-L2 and human PD-1. The human PD-1 amino acid sequence can be found at the NCBI site number: NP_005009. Human PD-L1 and PD-L2 amino acid sequences can be found in NCBI site numbers: NP_054862 and NP_079515, respectively.

A PD-1 antagonist useful in any of the aspects of the invention includes a monoclonal antibody (mAb), or an antigen-binding fragment thereof, which specifically binds to PD-1 or PD-L1 and is preferably specific Sexually binds to human PD-1 or human PD-L1. The mAb may be a human antibody, a humanized antibody, or a chimeric antibody, and may include a human constant region. In some specific examples, the human constant region is selected from the group consisting of IgG1, IgG2, IgG3, and IgG4 constant regions, and in a preferred embodiment, the human constant region is an IgG1 or IgG4 constant region. In some specific examples, the antigen-binding fragment is selected from the group consisting of Fab, Fab'-SH, F (ab ') 2, scFv, and Fv fragments.

Examples of mAb that incorporate human PD-1 and can be used in various aspects and specific examples of the present invention are described in US7488802, US7521051, US8008449, US8354509, US8168757, WO2004 / 004771, WO2004 / 072286, WO2004 / 056875, and US2011 / 0271358.

In any of the aspects and specific examples of the present invention, specific anti-human PD-1 mAbs that can be used as PD-1 antagonists include: MK-3475 (with WHO Drug Information, Vol. 27, No. 2 , humanized IgG4 mAb with the structure described in pages 161-162 (2013) and containing the heavy and light chain amino acid sequences shown in Figure 6), nivolumab (with WHO Drug Information, Vol. 27, No. 1, pages 68-69 (2013), human IgG4 mAb having the structure shown in FIG. 7 and containing the heavy and light chain amino acid sequences shown in FIG. 7); humanized antibody h409A11 , H409A16 and h409A17 (which are described in WO2008 / 156712) and AMP-514 (developed by MedImmune).

Other PD-1 antagonists that can be used in any aspect and embodiment of the invention include immunoadhesins that specifically bind to PD-1, and preferably specifically to human PD-1, for example: containing constant regions (such as immune Globulin molecule Fc region) fusion protein of extracellular or PD-1 binding portion of PD-L1 or PD-L2. Examples of immunoadhesion molecules that specifically bind to PD-1 are described in WO2010 / 027827 and WO2011 / 066342. Specific fusion proteins of PD-1 antagonists useful in the methods, medicaments, and uses of the present invention include AMP-224 (also known as B7-DCIg), which is a PD-L2-FC fusion protein and binds to human PD -1.

Other examples of mAbs that bind to human PD-L1 and are useful in the methods, medicaments and uses of the invention are described in WO2013 / 019906, WO2010 / 077634 A1 and US8383796. In the method, medicament and use of the present invention, specific anti-human PD-L1 mAbs used as PD-1 antagonists include MPDL3280A, BMS-936559, MEDI4736, and MSB0010718C.

KEYTRUDA / pembrolizumab is an anti-PD-1 antibody sold by Merck to treat lung cancer. The amino acid sequence and use method of paimumab is disclosed in US Patent No. 8,168,757.

Opdivo / nivolumab is a fully human monoclonal antibody with immunopotentiating activity sold by Bristol Myers Squibb, which is directed against the negative immunomodulatory human cell surface receptor PD-1 (programmed death-1 or Stylized cell death-1 / PCD-1). Nivolumab binds to PD-1 (Ig superfamily transmembrane protein) and blocks PD-1 activation through its ligands PD-L1 and PD-L2, leading to T cells and cell-mediated immune responses Activation against tumor cells or pathogens. Activated PD-1 negatively regulates T cell activity and effector function by inhibiting P13k / Akt pathway activation. Other names for nivolumab include: BMS-936558, MDX-1106, and ONO-4538. The amino acid sequence of nivolumab and methods of use and manufacture are disclosed in US Patent No. US 8,008,449.

Additional examples of other active ingredients or ingredients (antitumor agents) that can be used in combination or co-administration with the ATF4 pathway inhibitory compound of the present invention are immunomodulators.

"Immune modulator" as used herein refers to any substance that affects the immune system, including monoclonal antibodies. The ICOS binding protein of the present invention can be considered as an immunomodulator. Immunomodulators can be used as antitumor agents for the treatment of cancer. For example, immunomodulators include, but are not limited to, anti-CTLA-4 antibodies (such as ipilimumab (YERVOY)) and anti-PD-1 antibodies (Opdivo / navumab and Keytruda / Pim MAb). Other immunomodulators include, but are not limited to, OX-40 antibody, PD-L1 antibody, LAG3 antibody, TIM-3 antibody, 41BB antibody, and GITR antibody.

Yervoy is a fully human CTLA-4 antibody sold by Bristol Myers Squibb. The protein structure of ipleizumab and methods for its use are described in US Patent Nos. 6,984,720 and 7,605,238.

Composition

The pharmaceutically active compound within the scope of the present invention can be used to reduce MYC protein (c-MYC) in cells and inhibit p300 / CBP tissue protein acetamyltransferase in mammals (especially humans) in need.

The present invention therefore provides a method for treating cancer, arthritis and other conditions requiring a reduction in c-MYC content; a method for inhibiting p300 / CBP tissue protein acetamyltransferase, comprising administering an effective amount of a compound of formula (Ib) Pharmaceutically acceptable salt. The compounds of formula (Ib) also provide a method for treating the above-mentioned disease states, as they have been shown to have the ability to reduce the MYC protein (c-MYC) in cells and inhibit the p300 / CBP tissue protein acetamyltransferase. Drugs can be administered to patients in need by any conventional route of administration, including (but not limited to) intravenous, intramuscular, oral, subcutaneous, intradermal, and parenteral.

The pharmaceutically active compound of the present invention is incorporated into a convenient dosage form such as a capsule, lozenge, or injectable preparation. Use solid or liquid pharmaceutical carriers. Solid carriers include starch, lactose, calcium sulfate dihydrate, white clay, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, and stearic acid. Liquid carriers include syrup, peanut oil, olive oil, saline and water. Likewise, the carrier or diluent may include any extended release substance, such as glyceryl monostearate or glyceryl distearate, alone or with wax. The amount of solid carrier can vary widely, but is preferably about 25 mg to about 1 g per dosage unit. When a liquid carrier is used, the preparation will be in the form of a syrup, an elixir, an emulsion, a soft gelatin capsule, a sterile injectable liquid such as an ampoule, or an aqueous or non-aqueous liquid suspension.

When referring to pharmaceutical compositions, the terms carrier and excipient are used interchangeably herein.

The terms "disease" and "disease state" as used herein are considered to refer to the same condition. These terms are used interchangeably herein.

The pharmaceutical composition is manufactured according to the customary techniques of medical chemists. The tablet form includes mixing, granulating and, when needed, compacting, or mixing, filling and dissolving these ingredients if necessary to produce the desired oral or Parenteral products.

The dosage of the pharmaceutically active compound of the present invention in a pharmaceutical dosage unit as described above should be an effective amount, preferably an active compound selected from the range of 0.001-100 mg / kg, preferably 0.001-50 mg / kg. When treating human patients in need of reducing c-MYC content and / or inhibiting p300 / CBP tissue protein acetamidine transferase activity, the chosen dose is preferably administered orally or parenterally 1-6 times a day. Preferred parenteral administration includes topical, rectal, transdermal or by injection or continuous infusion. Oral dosage units for human administration preferably contain from 0.05 to 3500 mg of the active compound. It is preferred to use lower doses for oral administration. However, for patient safety and convenience, high-dose parenteral administration can also be used.

Those skilled in the art can easily determine the optimal dosage and will vary with the particular inhibitor used, the concentration of the formulation, the mode of administration, and the progress of the disease situation. Additional factors depending on the particular patient to be treated will result in a need to adjust the dosage, including patient age, weight, diet, and timing of administration.

The method of the present invention for inducing p300 / CBP tissue protein acetamyltransferase inhibitory activity in mammals (including humans) comprises administering an effective amount of p300 / CBP tissue protein acetamyltransferase inhibitory amount to a pharmaceutical active compound of the present invention. For those who need this activity.

The method of the present invention for reducing the c-MYC content of cells in mammals, including humans, comprises administering an effective c-MYC reduced amount of the pharmaceutically active compound of the present invention to a subject in need of the activity.

The present invention also provides the use of a compound of formula (Ib) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for reducing MYC protein (c-MYC) in cells.

The invention also provides the use of a compound of formula (Ib) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use as a p300 / CBP tissue protein acetamidine transferase inhibitor.

The invention also provides the use of a compound of formula (Ib) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in therapy.

The invention also provides the use of a compound of formula (Ib) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating cancer.

The present invention also provides a pharmaceutical composition for reducing the c-Myc protein content of cells, which comprises a compound of formula (Ib) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The present invention also provides a pharmaceutical composition for use as a p300 / CBP tissue protein acetamyltransferase inhibitor, which comprises a compound of formula (Ib) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The present invention also provides a pharmaceutical composition for treating cancer, comprising a compound of formula (Ib) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In addition, the pharmaceutically active compound of the present invention can be co-administered with other active ingredients such as other compounds known for treating cancer, or compounds known to have an effect when used in combination with a compound that reduces c-MYC protein in cells.

In addition, the pharmaceutically active compound of the present invention may be combined with other active ingredients such as other compounds known to treat cancer, or compounds known to have an effect when used in combination with a p300 / CBP tissue protein acetamidine transferase inhibitor. ) Co-investment.

The invention also provides novel methods and novel intermediates that can be used to prepare the compounds of the invention.

The present invention also provides a pharmaceutical composition comprising 0.5 to 1,000 mg of a compound of formula (Ib) or a pharmaceutically acceptable salt thereof and 0.5 to 1,000 mg of a pharmaceutically acceptable excipient.

Without further detailed description, it is believed that those skilled in the art using the foregoing description can make the best use of the present invention. Accordingly, the following examples are to be construed as illustrative only and do not limit the scope of the invention in any way.

Examples

The following examples illustrate the invention. These examples are not intended to limit the scope of the invention, but to provide guidance to a skilled artisan in the preparation and use of the compounds, compositions and methods of the invention. Although specific specific examples of the invention have been described, those skilled in the art will understand that various changes and modifications can be made without departing from the spirit and scope of the invention.

Intermediate 1

6- (diethylamino) nicotinaldehyde

Diethylamine (8.43 mL, 81 mmol) and K ₂ CO ₃ (11.16 g, 81 mmol) were added to 6-bromonicotinaldehyde (10.01 g, 53.8 mmol) in DMSO (5 mL), and the reaction mixture was maintained at 60 Heated overnight at ° C. The reaction was quenched with water (30 mL) and extracted with EtOAc (4 X 30 mL). The organic extracts were combined and washed with brine, dried (MgSO _4), filtered, and concentrated. Purification by flash chromatography on SiO ₂ (gradient from 0 to 25% EtOAc / hexane) provided 6- (diethylamino) nicotinaldehyde (7.99 g) as a pale yellow solid. LC-MS (ES) m / z = 179 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.14 (t, J = 7.1Hz, 6H), 3.59 (q, J = 6.9Hz, 4H), 6.73 (d, J = 9.1Hz, 1H), 7.84 (dd, J = 9.1, 2.3 Hz, 1H), 8.56 (d, J = 2.3 Hz, 1H), 9.70 (s, 1H).

Intermediate 2

(S) -6- (2-methylpyrrolidin-1-yl) nicotinaldehyde

6-Bromonicotinaldehyde (1.552 g, 8.35 mmol), (S) -2-methylpyrrolidine (1.067 g, 13.5 mmol), and K ₂ CO ₃ (1.732 g, 13 mmol) in DMSO (40 mL) The mixture was heated at 80 ° C for 16 hours. The reaction was poured into water and _extracted with CH ₂ Cl. The organic extracts were washed with water, dried over MgSO _4, filtered, and concentrated. The resulting residue was purified via silica gel chromatography (0% to 50% (3: 1 EtOAc: EtOH) / hexane) to provide (S) -6- (2-methylpyrrolidin-1-yl as an oil ) Nicotinaldehyde (1.26 g). LC-MS (ES) m / z = 191 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 9.75 (s, 1H), 8.55 (d, J = 2.0Hz, 1H), 7.89 (dd, J = 2.3, 8.9Hz, 1H), 6.42 (d, J = 9.1Hz, 1H), 4.31 (br.s., 1H), 3.34-3.79 (m, 2H), 1.99-2.32 (m, 3H), 1.80 (dd, J = 4.1, 5.8Hz, 1H), 1.27 ( d, J = 6.3 Hz, 3H).

Intermediate 3

6-((2S, 5R) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde

6-Bromonicotinaldehyde (2.91 g, 15.64 mmol), (2R, 5S) -2,5-dimethylpyrrolidin hydrochloride (3.18 g, 23.47 mmol), and N, N-diisopropyl A mixture of ethylamine (9.56 mL, 54.8 mmol) in DMSO (15 mL) was stirred at 60 ° C overnight. The reaction was quenched with water (100 mL), and the resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with brine (30 mL), dried over Na ₂ SO _4, filtered, and concentrated. The remaining residue was purified by silica chromatography (0-20%, EtOAc / hexanes) to provide the desired product (1.68 g) as a yellow solid. LC-MS (ES) m / z = 205 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 9.71 (s, 1H), 8.58 (d, J = 2.3Hz, 1H), 7.84 (dd, J = 2.4, 9.0Hz, 1H), 6.63 (d, J = 9.1Hz, 1H), 4.00-4.33 (m, 2H), 2.00-2.18 (m, 2H), 1.68-1.84 (m, 2H), 1.29 (d, J = 6.3Hz, 6H).

Intermediate 3a

6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde

K ₂ CO ₃ (17.29 g, 125 mmol), triethylamine (16.10 mL, 115 mmol), and (2S, 5S) -2,5-dimethylpyrrolidine hydrochloride (13.71 g, 101 mmol) were added to 6-fluoronicotinaldehyde (12.04 g, 96 mmol) in DMSO (150 mL), and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with water (100 mL) and extracted with EtOAc (4 x 30 mL). The organic extracts were combined and washed with brine, dried over MgSO _4, filtered, and concentrated. Purification by chromatography on SiO ₂ (gradient of 0 to 40% EtOAc / hexane) provided 6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl as a yellow solid ) Nicotinaldehyde (12.2 g). LC-MS (ES) m / z = 205 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.07-1.21 (m, 6H), 1.65 (br.s., 2H), 2.23 (br.s., 2H), 4.14-4.43 (m, 2H) , 6.61 (d, J = 9.1 Hz, 1H), 7.82 (dd, J = 9.1, 2.3 Hz, 1H), 8.57 (d, J = 2.3 Hz, 1H), 9.70 (s, 1H).

Intermediate 4

6- (cyclopropyl (ethyl) amino) nicotinaldehyde

N-ethylcyclopropylamine (299 mg, 3.52 mmol) and K ₂ CO ₃ (574 mg, 4.16 mmol) were added to 6-fluoronicotinaldehyde (400 mg, 3.20 mmol) in DMSO (2 mL), and the reaction mixture was Heated at 60 ° C overnight. The reaction was quenched with water and the resulting solid was filtered. The filtrate was extracted with EtOAc (4 X 10 mL). The organic extracts were combined and washed with brine, dried (MgSO _4), filtered, and concentrated. Purification by flash chromatography on SiO ₂ (Condition: 2 minutes at 100% hexane, then 2 minutes at 100% CH ₂ Cl ₂ , followed by a gradient from 0 to 8% CH ₃ OH / CH ₂ Cl ₂ ) Provide 6- (cyclopropyl (ethyl) amino) nicotinaldehyde (450 mg) as a yellow oil. LC-MS (ES) m / z = 191 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 0.69 (dd, J = 3.9, 2.15 Hz, 2H), 0.94-1.01 (m, 2H), 1.11 (t, J = 7.0 Hz, 3H), 2.65- 2.73 (m, 1H), 3.70-3.81 (m, 2H), 7.08 (d, J = 8.9Hz, 1H), 7.88-7.97 (m, 1H), 8.62 (d, J = 2.0Hz, 1H), 9.76 (s, 1H).

Intermediate 5

6- (diethylamino) -5-fluoronicotinaldehyde

DMSO (2 mL), diethylamine (0.169 mL, 1.630 mmol), and K ₂ CO ₃ (225 mg, 1.630 mmol) were added to 6-chloro-5-fluoronicotinaldehyde (200 mg, 1.254 mmol), and the reaction The mixture was heated under microwave conditions at 80 ° C for 2 hours. The reaction was then quenched with water (5 mL) and extracted with EtOAc (4 X 5 mL). The organic extracts were combined and washed with brine, dried (MgSO _4), filtered, and concentrated. Purification by flash chromatography on SiO ₂ (gradient from 0 to 30% EtOAc / hexanes) provided 6- (diethylamino) -5-fluoronicotinaldehyde (225 mg) as a yellow oil. LC-MS (ES) m / z = 197 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.19 (t, J = 7.1Hz, 6H), 3.62 (qd, J = 7.0, 1.9Hz, 4H), 7.66 (dd, J = 15.0, 1.8Hz, 1H), 8.46 (t, J = 2.0Hz, 1H), 9.76 (d, J = 2.5Hz, 1H).

Intermediate 6

(S) -5-Fluoro-6- (2-methylpyrrolidin-1-yl) nicotinaldehyde

(S) -2-methylpyrrolidine (173 mg, 2.037 mmol) and K ₂ CO ₃ (282 mg, 2.037 mmol) were added to 6-chloro-5-fluoronicotinaldehyde (250 mg, 1.567 mmol), and the reaction mixture was stirred at 60 ° C overnight. The reaction was quenched with water (5 mL) and extracted with EtOAc (4 X 5 mL). The organic extracts were combined and washed with brine, dried (MgSO _4), filtered, and concentrated. Purification by flash chromatography on SiO ₂ (gradient from 0 to 30% EtOAc / hexane) provided (S) -5-fluoro-6- (2-methylpyrrolidin-1-yl as a yellow oil ) Nicotinaldehyde (50 mg). LC-MS (ES) m / z = 209 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.20 (d, J = 6.3Hz, 3H), 1.69 (dd, J = 5.2, 2.9Hz, 1H), 1.88-1.98 (m, 1H), 1.98- 2.08 (m, 2H), 3.59-3.69 (m, 1H), 3.83 (m, 1H), 4.42-4.51 (m, 1H), 7.65 (dd, J = 14.5, 1.8Hz, 1H), 8.46 (t, J = 1.9 Hz, 1H), 9.76 (d, J = 2.8 Hz, 1H).

Intermediate 7

6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) -5-fluoronicotinaldehyde

(2S, 5S) -2,5-dimethylpyrrolidine, hydrochloride (276 mg, 2.037 mmol), triethylamine (0.437 mL, 3.13 mmol), and K ₂ CO ₃ (282 mg, 2.037 mmol) were added. To 6-chloro-5-fluoronicotinaldehyde (250 mg, 1.567 mmol) in DMSO (5 mL), and the reaction mixture was stirred at 60 ° C overnight. The reaction was quenched with water (5 mL) and then extracted with EtOAc (4 X 5 mL). The organic extracts were combined and washed with brine, dried (MgSO _4), filtered, and concentrated. Purification by flash chromatography on SiO ₂ (gradient from 0 to 30% EtOAc / hexanes) provided 6-((2S, 5S) -2,5-dimethylpyrrolidine-1- as a yellow oil ) -5-fluoronicotinaldehyde (190 mg). LC-MS (ES) m / z = 223 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 1.12 (d, J = 6.1 Hz, 6H). 1.64 (d, J = 5.8Hz, 2H), 2.14-2.27 (m, 2H), 4.55 (br.s, 2H), 7.68 (dd, J = 14.5, 1.8Hz, 1H), 8.49 (t, J = 2.0Hz, 1H), 9.77 (d, J = 2.5Hz, 1H).

Intermediate 8

N- (3-bromopyridin-2-yl) trimethylacetamide

Trimethylacetamidine chloride (19.20 mL, 156 mmol) was quickly added to 3-bromo-2-aminopyridine (22.50 g, 130 mmol) and N, N-diisopropyl in 500 mL RBF over a period of 5 minutes. Ethylamine (34.1mL, 195mmol) in 1,4-diamine The mixture was stirred in alkane (200 mL), and the reaction mixture was heated in a heating group at 40 ° C for 1 hour. The mixture was diluted with water (200 mL) and extracted with EtOAc (600 mL). The organic extract was concentrated and washed with saturated NaHCO (80mL) ₃ solution (120 mL) and brine, dried over Na ₂ SO _4, filtered and in vacuo. The resulting light brown solid residue (33.38 g) was triturated with methyltributyl ether (100 mL), and the resulting suspension was filtered. The filter cake was washed with methyltributyl ether (40 mL) and dried under room vacuum for 1 hour at room temperature to provide the title compound (27.34 g) as an off-white powder solid. LC-MS m / z = 257,259 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.24 (s, 9H), 7.27 (dd, J = 7.9, 4.6Hz, 1H) 8.14 (dd, J = 8.0, 1.7Hz, 1H), 8.45 (dd , J = 4.6, 1.5Hz, 1H), 9.75 (s, 1H). The mother liquor was adsorbed on silica and purified by silica chromatography (0% to 100% EtOAc / hexane) to provide another 2.96 g of the title compound as an off-white solid.

Intermediate 9

N- (N- (3- (2-methylprop-1-en-1-yl) pyridin-2-yl) trimethylacetamide

N- (3-Bromopyridin-2-yl) trimethylacetamide (30.0 g, 117 mmol) in a 1 L 3-neck RBF equipped with a temperature control probe, a mechanical overhead stirrer, and a radiator condenser , 4,4,5,5-tetramethyl-2- (2-methylprop-1-en-1-yl) -1,3,2-dioxaborolane (25.5g, 140mmol ), K ₃ PO ₄ (61.9 g, 292 mmol) and Pd ₂ (dba) ₃ (5.34 g, 5.83 mmol) The mixture dioxane (300 mL) and water (100 mL) was stirred at room temperature in the evacuated and flushed with N ₂ and back (repeated 3x). (T-Bu) ₃ PHBF ₄ (3.39 g, 11.67 mmol, 0.1 equivalent) was added to the mixture in one portion and the resulting mixture was evacuated and flushed with N ₂ (repeated 4x), and exposed to a positive nitrogen atmosphere ( Bubbling). The reaction mixture was then heated to 87-88 ° C in a heating mantle at gentle reflux for 24 hours. The mixture was cooled to room temperature, diluted with water (200 mL) and then filtered through celite. The filter cake was washed with EtOAc (700 mL total). The organic layers of the combined filtrates were separated, and the aqueous layer was extracted with EtOAc (200 mL). The combined dried organic extracts were Na ₂ SO _4, filtered, and concentrated in vacuo. The resulting thick brown slurry (49 g) was dissolved in CH ₂ Cl ₂ and adsorbed on silica (divided into three equal portions). (Each) Purification by silica gel chromatography (0% to 100% EtOAc / hexane) provided two crops of the desired product. The first batch (27 g of yellow thick oil) contained pinacol-type impurities. The second batch was the pure title compound (9.5 g) as a pale yellow, viscous oil that turned into a waxy solid upon aging at room temperature. LC-MS m / z = 233 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.20 (s, 9H), 1.64 (d, J = 1.3Hz, 3H), 1.82 (d, J = 1.5Hz, 3H), 6.03 (s, 1H) , 7.27 (dd, J = 7.6, 4.8 Hz, 1H), 7.63 (dd, J = 7.6, 1.3 Hz, 1H), 8.30 (dd, J = 4.8, 1.5 Hz, 1H), 9.45 (s, 1H).

Intermediate 10

2,2-dimethyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridine

Add N- (3- (2-methylprop-1-en-1-yl) pyridin-2-yl) trimethylacetamide (theoretical 117 mmol, 1 equivalent, containing pinacol-type impurities) and 6N The mixture of HCl (150 mL) was stirred in 500 mL RBF equipped with a magnetic stirrer and a radiator condenser, and heated under gentle reflux at 110 ° C for 16 hours in the heating block insert. LC-MS showed that the mixture was mostly a 3- (2-methylprop-1-en-1-yl) pyridin-2-amine intermediate. An additional 6N HCl (100 mL) was added to the mixture, and the mixture was heated at 120 ° C for another 20 hours. The mixture was cooled in an ice bath, was added portionwise followed by NH ₄ OH (120mL) until the final pH reached 10, and solid precipitated out of solution. The resulting frozen suspension was filtered, and the filter cake was washed with water (3 x 15 mL). The filter cake was aspirated at room temperature under room vacuum for 8 hours, and then dried under high vacuum at room temperature over P ₂ O _{5 for} 60 hours to provide the title compound (12.17 g) as a light brown powdery solid. LC-MS m / z = 149 [M + H]. ¹ H NMR (400MHz, CD ₃ OD): δ 1.33 (s, 6H), 2.85 (s, 2H), 6.49 (dd, J = 7.1, 5.6Hz, 1H), 7.28 (dq, J = 7.0, 1.4Hz , 1H), 7.64 (d, J = 4.8Hz, 1H).

Intermediate 11

1-ethyl-2,2-dimethyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridine

Acetaldehyde (3.73 mL, 66.1 mmol) was added in one portion to 2,2-dimethyl-2,3-dihydro- in a 500 mL 3-neck RBF equipped with a magnetic stirrer and a temperature probe at room temperature. A stirred mixture of 1H-pyrrolo [2,3-b] pyridine (1.96 g, 13.22 mmol) and acetic acid (1.51 mL, 26.4 mmol) in CH ₃ OH (60 mL) was followed by the addition of NaBH ( OAc) ₃ (8.41 g, 39.7 mmol). Each addition of hydride involves the addition of 5 equivalents of acetaldehyde, followed by the addition of 3 equivalents of NaBH (OAc) _{3 in} portions. The mixture was stirred at room temperature for 20 minutes, and then additional hydride addition was started. After the hydride was added, the mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo to give a white solid residue, which was dissolved in water (100 mL). The pH was adjusted by adding a 5N NaOH solution (140 mL). The resulting aqueous mixture was extracted with CH ₂ Cl ₂ are in the 10% CH ₃ OH and extracted (250mL). An intermediate emulsion layer was observed. The mixture was filtered through celite, and the resulting filtrate was phase separated. The aqueous layer was extracted with in the _{10% CH 3 OH CH 2 Cl} 2 (5 x 125mL). The combined organic extracts were dried over Na ₂ SO _4, filtered and concentrated in vacuo. The resulting yellow gel-like oil was dissolved in CH ₂ Cl ₂ and adsorbed on silica. Purification by silica gel chromatography (0% to 60% EtOAc / hexane) provided the title compound (1.48 g) as a pale yellow oil. LC-MS m / z = 177 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.22 (t, J = 7.1Hz, 3H), 1.30 (s, 6H), 2.84 (s, 2H), 3.25-3.37 (m, 2H), 6.40 (dd , J = 6.8, 5.6 Hz, 1H), 7.20 (dq, J = 6.8, 1.4 Hz, 1H), 7.66 (dd, J = 5.5, 0.9 Hz, 1H).

Intermediate 12

5-bromo-1-ethyl-2,2-dimethyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridine

Add NBS (1.781g, 10.01mmol) to 1-ethyl-2,2-dimethyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridine (1.47g, 8.34mmol) The mixture was in DMF (5 mL), and the reaction mixture was heated in a heating block at 50 ° C. for 4 hours. The cooled mixture was diluted with water (15 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were concentrated in vacuo and lysed by silica chromatography with a gradient from 0 to 30% EtOAc / hexane. The resulting crude oil was purified to provide 5-bromo-1-ethyl-2,2-dimethyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridine (1.45 g) as a light brown oil. ), Which partially crystallized after standing. LC-MS (ES) m / z = 255,257 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 7.89-7.85 (m, 1H), 7.20-7.16 (m, 1H), 3.28 (q, J = 7.1Hz, 2H), 2.80 (s, 2H), 1.29 ( s, 6H), 1.24 (t, J = 7.1 Hz, 3H).

Intermediate 13

1-ethyl-2,2-dimethyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridine-5-carboxaldehyde

5-Bromo-1-ethyl-2,2-dimethyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridine (1.7 g, 6.66 mmol) was dissolved in THF (15 mL) The resulting solution was cooled to -78 ° C in a dry ice / acetone bath for 10 minutes. Then, n-butyllithium (3.20 mL, 8.00 mmol) was added dropwise at -78 ° C, and the reaction was stirred at -78 ° C for 1 hour. DMF (1.032 mL, 13.33 mmol) was then added dropwise, the cooling bath was removed, and the reaction mixture was warmed to room temperature over 1 hour. During this time, the reaction changed from pale yellow to red-orange. The reaction was then saturated with aqueous NH ₄ Cl was quenched, and the resulting mixture was extracted with EtOAc. Dried combined organic extracts were washed with brine, Na ₂ SO _4, filtered, and concentrated. The resulting crude brown oil was purified by silica gel chromatography with a gradient from 0 to 70% EtOAc / CH ₂ Cl ₂ to provide 1-ethyl-2,2-dimethyl-2,3-dihydro-1H -Pyrrolo [2,3-b] pyridine-5-carboxaldehyde (0.641 g) as a yellow solid after drying under high vacuum. LC-MS (ES) m / z = 205 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 9.67 (s, 1H), 8.27 (d, J = 1.8Hz, 1H), 7.58 (q, J = 1.8Hz, 1H), 3.45 (q, J = 7.1Hz , 2H), 2.88 (d, J = 1.0 Hz, 2H), 1.36 (s, 6H), 1.29 (t, J = 7.1 Hz, 3H).

Intermediate 14

7-bromo-2H-pyrido [3,2-b] [1,4] -3 (4H) -one

NBS (74.7 g, 420 mmol) was added as a whole to 2H-pyrido [3,2-b] [1,4] in DMF (360 mL) at 20 ° C. -3 (4H) -one (45.0 g, 300 mmol), and the resulting light brown suspension was heated at 50 ° C for 20 hours. The mixture was cooled to 25 ° C and the contents were poured into stirred water (1 L) in a 3 L flask equipped with an overhead mechanical stirrer. The resulting aqueous suspension was stirred at room temperature for 30 minutes and then filtered. The yellow filter cake was washed with a 10% Na ₂ S ₂ O ₃ solution (100 mL) followed by water (2 x 100 mL). The filter cake was aspirated overnight at room temperature under vacuum in a room. The solid was washed with Et ₂ O (100 mL), sucked at room temperature under room vacuum for 18 hours, and then dried under high vacuum at 50 ° C. for 72 hours to provide the title compound (65.30 as a light tan powdery solid g). LC-MS (ES) m / z = 229,231 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 4.68 (s, 2H), 7.66 (d, J = 2.0 Hz, 1 H), 8.02 (d, J = 2.0 Hz, 1 H), 11.44 (br.s. , 1H).

Intermediate 15

7-bromo-3,3-dimethyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4]

The starting material 7-bromo-2H-pyrido [3,2-b] [1,4] -3 (4H) -one (15.0 g, 65.5 mmol) was added to a 1 L glass reactor equipped with an overhead mechanical stirrer, followed by addition of 2-MeTHF (330 mL), and the resulting mixture was capped and purged with nitrogen (positive N ₂ Pressure bubbling). The resulting suspension was stirred at -15 ° C for 20 minutes, and then ZrCl ₄ (15.26 g, 65.5 mmol) fine powder was added in one portion. After the suspension was stirred at -15 ° C under nitrogen for 20 minutes, a magnesium bromide solution (3.4M in THF, 116 mL, 393 mmol) was added via a syringe during a total of 120 minutes to keep the internal temperature at -10 ° C. The reaction mixture was stirred at -15 ° C for another 20 minutes, and then it was slowly heated to 25 ° C over 1 hour, and held at 25 ° C for 2 hours. The reaction was cooled back to 0 ° C and then slowly treated with a saturated aqueous NH ₄ Cl solution (200 mL) to keep the internal temperature below 15 ° C. The mixture was then stirred at 20 ° C for 20 minutes. EtOAc (200 mL) was added to this mixture, which became a biphasic mixture of liquid and gel-like solid. Diatomaceous earth (150 mL) was added, and the resulting mixture was filtered through diatomaceous earth (100 mL), and the filter cake was washed with EtOAc. Add more diatomaceous earth to help filter. A total of 450 mL of diatomaceous earth was used throughout, and a total of 550 mL of EtOAc was used in the wash. The filtrate was phase separated, and the aqueous layer was extracted with EtOAc (200 mL). The combined organic extracts were dried over Na ₂ SO _4, filtered, and concentrated to provide a dark brown viscous oil / foam residue (17g) in vacuo. This residue was redissolved in CH ₂ Cl ₂ and adsorbed onto Silica. Purification by silica gel chromatography (0% to 40% EtOAc / hexane) provided the title compound (5.42 g) as a pale yellow powdery solid. LC-MS (ES) m / z = 243,245 [M + H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 1.27 (s, 6H), 3.84 (s, 2H), 7.16 (d, J = 2.0 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H).

Intermediate 16

7-bromo-4-ethyl-3,3-dimethyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4]

NaH (60% in mineral oil, 2.00 g, 49.9 mmol) was added portionwise to 7-bromo-3,3-dimethyl-3 in 250 mL RBF and stirred at room temperature over 5 minutes 4-dihydro-2H-pyrido [3,2-b] [1,4] (8.09 g, 33.3 mmol) as a mixture in DMF (60 mL). The mixture was stirred at room temperature under nitrogen for 20 minutes, and then cooled to 5 ° C (ice bath). Iodoethane (3.23 mL, 39.9 mmol) was then added dropwise / in portions over a period of 20 minutes. After the addition was complete, the ice bath was removed and the reaction mixture was stirred under N ₂ at ambient temperature for 1 hour. The mixture was cooled in an ice bath, and saturated aqueous NH ₄ Cl (20 mL) was added, followed by water (100 mL) and EtOAc (120 mL). The mixture was shaken and the phases were separated, and the aqueous phase was extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with brine (3 x 40mL), dried over Na ₂ SO _4, filtered, and concentrated in vacuo to give a pale brown viscous oil 10g. This material was dissolved in CH ₂ Cl ₂ and adsorbed on silica. Purification by silica gel chromatography (0% to 25% EtOAc / hexane) provided the title compound (7.96 g) as a white solid. LC-MS m / z = 271,273 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.13 (t, J = 6.8Hz, 3H), 1.23 (s, 6H), 3.42-3.54 (m, 2H), 3.87 (s, 2H), 7.17 ( d, J = 2.3 Hz, 1H), 7.76 (d, J = 2.3 Hz, 1H).

Intermediate 17

4-ethyl-3,3-dimethyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] -7-formaldehyde

N-BuLi (2.4M, 0.979mL, 2.350mmol) in hexane was added dropwise to 7-bromo-4-ethyl-3,3-dimethyl-3,4 at -78 ° C under a nitrogen atmosphere. -Dihydro-2H-pyrido [3,2-b] [1,4] (531 mg, 1.958 mmol) in THF (6 mL), and the resulting mixture was stirred at -78 ° C for 1 hour. Then DMF (0.303 mL, 3.92 mmol) was added, and the reaction mixture was stirred at -78 ° C for 1 hour. The mixture was warmed to room temperature and treated with aqueous NH ₄ Cl (5ml) and quenched. Water (100 ml) was then added and the resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated. The resulting residue was purified by silica gel chromatography (1:20 EtOAc: hexanes) to give the desired product (340 mg) as a yellow solid. LC-MS (ES) m / z = 221 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 9.75 (s, 1H), 8.21 (s, 1H), 7.34 (s, 1H), 3.85 (s, 2H), 3.69 (q, J = 7.0Hz, 2H) , 1.35 (s, 6H), 1.29 (t, J = 7.0 Hz, 3H).

Intermediate 18

7-bromo-3-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4]

Methyl magnesium bromide (1.562 g, 13.10 mmol) was added to 7-bromo-2H-pyrido [3,2-b] [1,4] at 0 ° C. A stirred solution of -3 (4H) -one (1.0 g, 4.37 mmol) in THF (25 mL), and the resulting mixture was stirred at room temperature for 2 hours. Then NaBH (OAc) ₃ (2.78 g, 13.10 mmol) was added, and the reaction mixture was stirred at room temperature for 12 hours. The reaction was quenched by the addition of NH ₄ Cl (aq. ₅ mL), and the mixture was concentrated under vacuum. The residue was poured into water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over anhydrous Na ₂ SO _4, and concentrated. The resulting crude product was purified by silica gel chromatography (1: 3 EtOAc: hexanes) to give 7-bromo-3-methyl-3,4-dihydro-2H-pyrido [3,2 as an off-white solid. -b] [1,4] (500 mg, 2.074 mmol). LC-MS (ES) m / z = 229,231 [M + H] ⁺ .

Intermediate 19

7-bromo-4-ethyl-3-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4]

Add NaH (60%, 0.733 g, 18.33 mmol) to 7-bromo-3-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] (2.1 g, 9.17 mmol) in DMF (30 mL), and the mixture was stirred for 10 minutes. Then iodoethane (5.72 g, 36.7 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated. The resulting residue was purified by silica gel chromatography (eluted with 1:10 EtOAc / hexanes) to give the desired product (1.66 g) as a yellow solid. LC-MS (ES) m / z = 256,259 [M + H] ⁺ .

Intermediate 20

4-ethyl-3-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] -7-formaldehyde

N-BuLi (2.4M, 3.23mL, 7.75 mmol) in hexane was added dropwise to 7-bromo-4-ethyl-3-methyl-3,4-dihydrogen at -78 ° C under a nitrogen atmosphere. -2H-pyrido [3,2-b] [1,4] (1.66 g, 6.46 mmol) in THF (20 mL), and the resulting mixture was stirred at -78 ° C for 1 hour. Then DMF (1.0 mL, 12.9 mmol) was added, and the reaction was stirred at -78 ° C for 1 hour. The mixture was warmed to room temperature and ₄ Cl aq NH (5mL) and quenched. Water (100 mL) was added and the mixture was extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated. The resulting residue was purified by silica gel chromatography (eluted with 1:20 EtOAc / hexanes) to give the desired product (1 g) as a yellow solid. LC-MS (ES) m / z = 207 [M + H] ⁺ .

Intermediate 21

(R) -2-((3-Bromopyridin-2-yl) amino) propan-1-ol

References: Tetrahedron Lett. 2010 , 51, 3886.

Using a microwave reactor, a solution of 3-bromo-2-chloropyridine (3.0 g, 15.59 mmol) and (R) -2-aminopropan-1-ol (2.93 g, 39.0 mmol) in pyridine (10 mL) was placed in Irradiate at 180 ° C for 2 hours. The reaction mixture was poured into saturated aqueous NaHCO ₃ (30mL) and the mixture CH ₂ Cl ₂ (20mL) of. The phases were separated and the aqueous layer was further extracted with CH ₂ Cl ₂ (2 x 25 mL). The combined organic extracts were dried over Na ₂ SO ₄ and then concentrated under reduced pressure. The resulting dark brown oil was purified by flash chromatography on silica with a gradient of 0 to 60% EtOAc / hexanes to provide (R) -2-((3-bromopyridin-2-yl) as a yellow oil ) Amino) propan-1-ol (2.76 g). LC-MS (ES) m / z = 231,233 [M + H] ⁺¹ H NMR (400MHz, CDCl ₃ ): δ 7.99 (dd, J = 1.5,5.1Hz, 1H), 7.64 (dd, J = 1.5, 7.6Hz, 1H), 6.49 (dd, J = 4.9, 7.7Hz, 1H), 5.08 (d, J = 3.8Hz, 1H), 4.64 (br.s., 1H), 4.23-4.15 (m, 1H) , 3.78 (dd, J = 2.9, 10.8 Hz, 1H), 3.63 (dd, J = 7.4, 10.9 Hz, 1H), 1.31 (d, J = 6.6 Hz, 3H).

Intermediate 22

(R) -3-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4]

References: Tetrahedron Lett, 2010 , 51, 3886

A 250 mL round bottom flask was charged with Pd (OAc) ₂ (0.597 g, 2.66 mmol), 2- (di-tertiary butylphosphino) biphenyl (1.270 g, 4.25 mmol), and Cs ₂ CO ₃ (26.0 g, 80 mmol ). The flask was evacuated, backfilled with argon, and a rubber septum was fitted. (R) -2-((3-Bromopyridin-2-yl) amino) propan-1-ol (12.29 g, 53.2 mmol) and toluene (150 mL) were added, and the flask was preheated and heated at 100 ° C After 48 hours in the group. The reaction was cooled to room temperature, diluted with Et ₂ O (150mL), and then filtered through a pad of diatomaceous earth. The filtrate was concentrated in vacuo, and the resulting residue was purified by silica chromatography using a gradient of 20 to 80% EtOAc / hexanes to provide (R) -3-methyl-3,4- as a yellow-brown oil. Dihydro-2H-pyrido [3,2-b] [1,4] (1.57g). LC-MS (ES) m / z = 151 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 7.54 (dd, J = 1.5, 4.8 Hz, 1H), 7.16 (s, 1H), 6.85 (dd, J = 1.4, 7.7 Hz, 1H), 6.39 (dd, J = 5.1, 7.6 Hz, 1H), 4.02 (d, J = 8.4Hz, 1H), 3.62-3.50 (m, 2H), 1.11 (d, J = 6.1Hz, 3H).

Intermediate 23

(R) -4-ethyl-3-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4]

NaH (0.399 g, 9.99 mmol, 60% dispersion in mineral oil) was added to (R) -3-methyl-3,4-dihydro-2H-pyrido [3, 2-b] [1,4] (1.5 g, 9.99 mmol) in ice-cooled solution in DMF (20 mL), and the resulting mixture was stirred at 0 ° C for 1 hour. Then, iodoethane (0.888 mL, 10.99 mmol) was added dropwise, and the reaction mixture was allowed to warm to room temperature. After 15 hours, the mixture was poured into water and extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed successively with brine, water, dried with Na ₂ SO _4, and concentrated in vacuo. The crude product was purified by silica gel chromatography with a gradient of 0 to 30% EtOAc / hexanes to provide (R) -4-ethyl-3-methyl-3,4-dihydro-2H as a white solid -Pyrido [3,2-b] [1,4] (1.08g). LC-MS (ES) m / z = 179 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 7.78 (dd, J = 1.5, 5.1 Hz, 1H), 6.92 (dd, J = 1.5, 7.6 Hz, 1H), 6.48 (dd, J = 5.1, 7.6 Hz, 1H), 4.07-3.95 (m, 3H), 3.70-3.62 (m, 1H), 3.32 (dd, J = 7.1, 14.2Hz, 1H), 1.28 (d, J = 6.6Hz, 3H), 1.21 (t , J = 7.1Hz, 3H).

Intermediate 24

(R) -7-bromo-4-ethyl-3-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4]

Add NBS (1.078 g, 6.06 mmol) to (R) -4-ethyl-3-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] (1.08 g, 6.06 mmol) in DMF (20 mL), and the reaction mixture was heated at 75 ° C for 2 hours. The reaction was cooled to room temperature and then poured into water (100 mL) and stirred. The resulting mixture was extracted with CH ₂ Cl ₂ , and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The crude residue was purified by silica gel chromatography with a gradient from 0 to 50% EtOAc / hexanes to provide (R) -7-bromo-4-ethyl-3-methyl-3,4 as a yellow solid -Dihydro-2H-pyrido [3,2-b] [1,4] (1.09g). LC-MS (ES) m / z = 257,259 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 7.79 (d, J = 2.0Hz, 1H), 7.05 (d, J = 2.0Hz, 1H), 4.01 (d, J = 2.8Hz, 2H), 3.94 (qd , J = 7.1, 14.2Hz, 1H), 3.68-3.60 (m, 1H), 3.29 (qd, J = 6.9, 14.1Hz, 1H), 1.26 (d, J = 6.3Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H).

Intermediate 25

(R) -4-ethyl-3-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] -7-formaldehyde

Add (R) -7-bromo-4-ethyl-3-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] (1.4 g, 5.44 mmol) in THF (10 mL) was cooled to -78 ° C in a dry ice / acetone bath for 10 minutes. Next, n-butyllithium (2.396 mL, 5.99 mmol) was added dropwise at -78 ° C, and the reaction mixture was stirred at -78 ° C for 1 hour. Then DMF (0.843 mL, 10.89 mmol) was added dropwise, the cooling bath was removed, and the reaction mixture was allowed to warm to room temperature over 1 hour. During this time, the reaction changed from pale yellow to red-orange. Then with saturated aqueous NH ₄ Cl and the reaction was quenched, and the resulting mixture was extracted with EtOAc. Dried combined organic extracts were washed with brine, Na ₂ SO _4, filtered, and concentrated. The crude brown oil was purified by silica gel chromatography with a gradient from 0 to 50% EtOAc / DCM to provide (R) -4-ethyl-3-methyl-3,4-dihydro-2H-pyrido [ 3,2-b] [1,4] -7-formaldehyde (0.75 g, 3.64 mmol, 66.8% yield), as a yellow solid after drying under high vacuum. [R] _D = +27.9 (c = 1.00, CHCl ₃ ). LC-MS (ES) m / z = 207 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 9.74 (s, 1H), 8.18 (d, J = 2.0Hz, 1H), 7.33 (d, J = 2.0Hz, 1H), 4.14-4.03 (m, 2H) , 4.01-3.95 (m, 1H), 3.77-3.68 (m, 1H), 3.41 (qd, J = 7.0, 13.9Hz, 1H), 1.33 (d, J = 6.6Hz, 3H), 1.25 (t, J = 7.1Hz, 3H).

Intermediate 26

1-ethyl-1H-pyrazole-3-carbonitrile

A solution of 1H-pyrazole-3-carbonitrile (6.92 g, 74.3 mmol) in THF (25 mL) was added dropwise to cooled sodium hydride (60% in oil, 3.87 g, 97 mmol) in an ice bath. The mixture was in THF (50 mL), and then the reaction mixture was stirred at room temperature for 1 hour. Then iodoethane (3.22 mL, 39.8 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with water (30 mL) and extracted with EtOAc (3 × 30 mL). The organic extracts were combined and washed with brine, dried (MgSO _4), filtered, and concentrated. Purification by flash chromatography on SiO ₂ (gradient from 0 to 30% EtOAc / hexane) provided 1-ethyl-1H-pyrazole-3-carbonitrile (5.66 g) as a clear oil. LC-MS (ES) m / z = 122 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.39 (t, J = 7.4Hz, 3H), 4.25 (q, J = 7.4Hz, 2H), 6.96 (d, J = 2.3Hz, 1H), 8.05 (d, J = 2.5Hz, 1H).

Intermediate 27

(1-ethyl-1H-pyrazol-3-yl) methylamine

LiAlH ₄ (51.4 mL, 103 mmol, 2M in THF) was slowly added to 1-ethyl-1H-pyrazole-3-carbonitrile (5.66 g, 46.7 mmol) in Et ₂ cooled in an ice bath. O (150 mL) and the reaction mixture was stirred at room temperature overnight. The reaction was then cooled in an ice bath and treated sequentially with water (4 mL), 15% NaOH solution (4 mL), and water (12 mL) [Note: H ₂ evolution]. The resulting mixture was stirred for 15 minutes and then filtered. The filtrate was dried over MgSO ₄ and concentrated to provide a clear oil of (1-ethyl--1H- pyrazol-3-yl) methanamine (4.60g). LC-MS (ES) m / z = 126 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.33 (t, J = 7.4Hz, 3H), 1.61 (br.s., 2H), 3.61 (s, 2H), 4.00-4.08 (m, 2H) , 6.13 (s, 1H), 7.58 (s, 1H).

Intermediate 28

N-((1-ethyl-1H-pyrazol-3-yl) methyl) -2-nitroaniline

(1-ethyl-1H-pyrazol-3-yl) methylamine (444 mg, 3.54 mmol) and K ₂ CO ₃ (490 mg, 3.54 mmol) were added to 1-fluoro-2-nitrobenzene (500 mg, 3.54 mmol) ) In DMF (15 mL), and the reaction mixture was stirred at 35 ° C for 18 hours. The reaction was quenched with water (30 mL) and extracted with EtOAc (3x). The extracts were dried (Na ₂ SO ₄₎ and concentrated. The resulting residue was purified using column chromatography (silica gel, 0 to 60% EtOAc / hexanes) to give the desired product (670 mg) as a light brown oil. LC-MS (ES) m / z = 247 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 1.55 (t, J = 7.4Hz, 3H), 4.22 (q, J = 7.4Hz, 2H), 4.58 (d, J = 5.1Hz, 2H) 6.26 (d, J = 2.3Hz, 1H), 6.71 (ddd, J = 8.5, 7.0, 1.3Hz, 1H), 7.01 (dd, J = 8.7, 0.9Hz, 1H), 7.41 (d, J = 2.3Hz, 1H), 7.47 (ddd, J = 8.6,7.1, 1.5Hz, 1H), 8.23 (dd, J = 8.6,1.5Hz, 1H), 8.49 (br.s., 1H).

Example 1

N, N-diethyl-5- (1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazol-2-yl) pyridine-2- amine

N-((1-ethyl-1H-pyrazol-3-yl) methyl) -2-nitroaniline (180 mg, 0.731 mmol), 6- (diethylamino) nicotinaldehyde (130 mg, 0.731 mmol ), Sodium bisulfite (452mg, 85%, 1.864mmol), ethanol (4.5mL), and water (3.00mL) were added to a 20-mL microwave tube, and the reaction mixture was heated at 135 ° C for 20 minutes under microwave conditions. . The reaction mixture was then concentrated and the resulting residue was treated with CH ₃ OH and filtered. The filtrate was concentrated and the resulting residue was purified using silica gel chromatography (0 to 100% EtOAc / heptane and then 0 to 50% (3: 1 EtOAc: EtOH) / heptane) to give the desired product (101 mg) After lyophilization, it turned into a light brown solid. LC-MS (ES) m / z = 375 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.24 (t, J = 7.0Hz, 6H), 1.43 (t, J = 7.2Hz, 3H), 3.62 (q, J = 7.1Hz, 4H), 4.16 ( q, J = 7.3Hz, 2H), 5.47 (s, 2H), 6.06 (d, J = 2.3Hz, 1H), 6.71-6.81 (m, 1H), 7.25-7.33 (m, 2H), 7.45-7.53 (m, 1H), 7.58 (d, J = 2.3 Hz, 1H), 7.65-7.73 (m, 1H), 7.93 (dd, J = 9.1, 2.5 Hz, H) 8.48-8.55 (m, 1H).

Intermediate 29

6- (dipropylamino) nicotinaldehyde

Dipropylamine (0.331 mL, 2.419 mmol) and K ₂ CO ₃ (267 mg, 1.935 mmol) were added to 6-bromonicotinaldehyde (300 mg, 1.613 mmol) in DMSO (1.5 mL), and the reaction mixture was maintained at 60 Heated overnight at ° C. The reaction was quenched with water (5 mL), and then extracted with EtOAc (4 x 3 mL). The organic extracts were combined and washed with brine, dried (MgSO _4), filtered, and concentrated. Purification by flash chromatography on SiO ₂ (gradient: 0 to 20% EtOAc / hexanes) provided 6- (dipropylamino) nicotinaldehyde (300 mg) as a clear oil. LC-MS (ES) m / z = 207 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 0.89 (t, J = 7.4Hz, 6H), 1.52-1.65 (m, 4H), 3.50 (t, J = 7.4Hz, 4H), 6.74 (d, J = 9.1 Hz, 1H), 7.82 (dd, J = 9.1, 2.3 Hz, 1H), 8.55 (d, J = 2.0 Hz, 1H), 9.69 (s, 1H).

Example 2

5- (1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazol-2-yl) -N, N-dipropylpyridine-2- amine

6- (Dipropylamino) nicotinaldehyde (47.7 mg, 0.231 mmol), followed by potassium monohydroxide (Oxone) (92 mg, 0.150 mmol) was added to N1- in DMF (2 mL) and water (2.000 mL) ((1-ethyl-1H-pyrazol-3-yl) methyl) benzene-1,2-diamine (50 mg, 0.231 mmol), and the reaction mixture was stirred at room temperature for 0.5 hours. The reaction was quenched with aqueous saturated NH ₄ Cl and extracted with EtOAc (3 x 20mL). The organic extracts were then combined and washed with brine, dried (MgSO _4), filtered, and concentrated. Purification by chromatography on SiO ₂ (gradient: 0 to 75% EtOAc / hexane) provided 5- (1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H -Benzo [d] imidazol-2-yl) -N, N-dipropylpyridin-2-amine (54 mg) as a white solid after freeze-drying. LC-MS (ES) m / z = 403 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 0.91 (t, J = 7.4Hz, 6H), 1.33 (t, J = 7.2Hz, 3H), 1.54-1.65 (m, 4H), 3.43-3.51 ( m, 4H), 4.08 (q, J = 7.4Hz, 2H), 5.40 (s, 2H), 6.07 (d, J = 2.0Hz, 1H), 6.74 (d, J = 9.1Hz, 1H), 7.17- 7.22 (m, 2H), 7.48-7.53 (m, 1H), 7.61-7.66 (m, 1H), 7.68 (d, J = 2.4Hz, 1H), 8.00 (dd, J = 9.0, 2.4Hz, 1H) , 8.56 (d, J = 2.0 Hz, 1H).

Intermediate 30

6- (ethyl (propyl) amino) nicotinaldehyde

N-ethylpropan-1-amine (211 mg, 2.419 mmol), and K ₂ CO ₃ (267 mg, 1.935 mmol) were added to 6-bromonicotinaldehyde (300 mg, 1.613 mmol) in DMSO (1.5 mL) The reaction mixture was heated at 60 ° C overnight. The reaction was then quenched with (5 mL) water and extracted with EtOAc (4 x 3 mL). The organic extracts were combined and washed with brine, dried (MgSO _4), filtered, and concentrated. Purification by flash chromatography on SiO ₂ (gradient: 0 to 30% EtOAc / hexane) provided 6- (ethyl (propyl) amino) nicotinaldehyde (195 mg) as a clear oil. LC-MS (ES) m / z = 193 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 0.90 (t, J = 7.4Hz, 3H), 1.13 (t, J = 7.1Hz, 3H), 1.52-1.65 (m, 2H), 3.49 (t, J = 7.4 Hz, 2H), 3.60 (q, J = 7.0 Hz, 2H), 6.74 (d, J = 9.1 Hz, 1H), 7.83 (dd, J = 9.1, 2.3 Hz, 1H), 8.56 (d, J = 2.0Hz, 1H), 9.70 (s, 1H).

Example 3

N-ethyl-5- (1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazol-2-yl) -N-propylpyridine- 2-amine

Add 6- (ethyl (propyl) amino) nicotinaldehyde (41.8 mg, 0.217 mmol) followed by potassium monohydroxide (Oxone) (87 mg, 0.141 mmol) to DMF (2 mL) and water (2.000 mL) N1-((1-ethyl-1H-pyrazol-3-yl) methyl) benzene-1,2-diamine (47 mg, 0.217 mmol), and the reaction mixture was stirred at room temperature for 0.5 hours. The reaction was quenched with saturated aqueous NH ₄ Cl was quenched and extracted with EtOAc (3 x 20mL). The organic extracts were combined and washed with brine, dried (MgSO _4), filtered, and concentrated. The resulting material was diluted with DMSO (1.5 mL) and purified by reverse-phase HPLC (two injections: 30 to 60% CH ₃ CN / 0.1% NH ₄ OH in H ₂ O). The product portions were combined, concentrated, and then freeze-dried. The resulting amber was dissolved in CH ₂ Cl ₂ and purified by chromatography on SiO ₂ (gradient: 0 to 75% EtOAc / hexane) to provide N-ethyl-5- (1-((1- Ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazol-2-yl) -N-propylpyridin-2-amine (42mg, 0.108mmol), after lyophilization White solid. LC-MS (ES) m / z = 389 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 0.92 (t, J = 7.4Hz, 3H), 1.10-1.18 (m, 3H), 1.30-1.36 (m, 3H), 1.54-1.67 (m, 2H ), 3.42-3.50 (m, 2H), 3.57 (q, J = 7.1Hz, 2H), 4.08 (q, J = 7.2Hz, 2H), 5.40 (s, 2H), 6.08 (d, J = 2.3Hz , 1H), 6.74 (d, J = 9.1Hz, 1H), 7.16-7.24 (m, 2H), 7.47-7.53 (m, 1H), 7.61-7.66 (m, 1H), 7.68 (d, J = 2.0 Hz, 1H), 8.01 (dd, J = 9.0, 2.4 Hz, 1H), 8.57 (d, J = 2.3 Hz, 1H).

Intermediate 31

6- (2-methylpyrrolidin-1-yl) nicotinaldehyde (34.3 mg, 0.180 mmol)

Add 2-methylpyrrolidine (0.198 mL, 1.935 mmol) and K ₂ CO ₃ (267 mg, 1.935 mmol) to 6-bromonicotinaldehyde (300 mg, 1.613 mmol) in DMSO (5 mL), and react The mixture was heated under microwave conditions at 100 ° C for 1 hour. The reaction was quenched with water (5 mL) and extracted with EtOAc (4 x 3 mL). The organic extracts were then combined and washed with brine, dried (MgSO _4), filtered, and concentrated. Purification by chromatography on SiO ₂ (gradient: 0 to 40% EtOAc / hexane) provided 6- (2-methylpyrrolidin-1-yl) nicotinaldehyde (271 mg) as a clear oil. LC-MS (ES) m / z = 191 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.15-1.22 (m, 3H), 1.71 (d, J = 3.0Hz, 1H), 1.94-2.12 (m, 3H), 3.39 (br.s., 1H), 3.59 (br.s., 1H), 4.29 (br.s., 1H), 6.59 (d, J = 8.9Hz, 1H), 7.84 (dd, J = 9.0, 2.4Hz, 1H), 8.57 (d, J = 2.3Hz, 1H), 9.71 (s, 1H).

Example 4

1-((1-ethyl-1H-pyrazol-3-yl) methyl) -2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] Imidazole

6- (2-methylpyrrolidin-1-yl) nicotinaldehyde (34.3 mg, 0.180 mmol) followed by oxone (72.1 mg, 0.117 mmol) was added to DMF (2 mL) and water ( N1-((1-ethyl-1H-pyrazol-3-yl) methyl) benzene-1,2-diamine (39 mg, 0.180 mmol) in 2 mL), and the reaction mixture was stirred at room temperature for 0.5 hour. The reaction was quenched with aqueous NH ₄ Cl and washed with saturated NaHCO ₃ solution was adjusted to slightly basic pH. The resulting mixture was extracted with EtOAc (3 x 20mL), and then the organic extracts were combined and washed with brine, dried (MgSO _4), filtered, and concentrated. Purification by chromatography on SiO ₂ (gradient: 0 to 8% CH ₃ OH / CH ₂ Cl ₂ ) provides 1-((1-ethyl-1H-pyrazol-3-yl) methyl)- 2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole (30 mg) was freeze-dried to a white solid. LC-MS (ES) m / z = 387 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.19 (d, J = 6.1Hz, 3H), 1.33 (t, J = 7.4Hz, 3H), 1.67-1.74 (m, 1H), 1.93-2.12 ( m, 3H), 3.29-3.38 (m, 1H), 3.51-3.60 (m, 1H), 4.08 (q, J = 7.2Hz, 2H), 4.22 (t, J = 6.0Hz, 1H), 5.40 (s , 2H), 6.08 (d, J = 2.3Hz, 1H), 6.60 (d, J = 8.6Hz, 1H), 7.16-7.23 (m, 2H), 7.49-7.54 (m, 1H), 7.61-7.66 ( m, 1H), 7.68 (d, J = 2.3Hz, 1H), 8.03 (dd, J = 8.9, 2.3Hz, 1H), 8.59 (d, J = 1.8Hz, 1H).

Intermediate 32

6- (ethyl (isopropyl) amino) nicotinaldehyde

N-ethylpropan-2-amine (0.293 mL, 2.419 mmol) and K ₂ CO ₃ (334 mg, 2.419 mmol) were added to 6-bromonicotinaldehyde (300 mg, 1.613 mmol) in DMSO (1.5 mL). And the reaction mixture was heated under microwave conditions at 100 ° C for 1 hour. The reaction was then quenched with water (5 mL) and extracted with EtOAc (4 x 3 mL). The organic extracts were combined and washed with brine, dried (MgSO _4), filtered, and concentrated. Purification by chromatography on SiO ₂ (gradient: 0 to 20% EtOAc / hexane) provided 6- (ethyl (isopropyl) amino) nicotinaldehyde (220 mg) as a clear oil. LC-MS (ES) m / z = 193 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.12-1.22 (m, 9H), 3.47 (q, J = 6.8Hz, 2H), 4.82-5.05 (m, 1H), 6.74 (d, J = 9.1 Hz, 1H), 7.84 (dd, J = 9.1, 2.3 Hz, 1H), 8.58 (d, J = 2.0 Hz, 1H), 9.71 (s, 1H).

Example 5

N-ethyl-5- (1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazol-2-yl) -N-isopropylpyridine -2-amine

6- (ethyl (isopropyl) amino) nicotinaldehyde (40.0 mg, 0.208 mmol) followed by oxone (83 mg, 0.135 mmol) was added to DMF (2 mL) and water (2 mL) N1-((1-ethyl-1H-pyrazol-3-yl) methyl) benzene-1,2-diamine (45 mg, 0.208 mmol), and the reaction mixture was stirred at room temperature for 0.5 hours. The reaction was quenched with saturated aqueous NH ₄ Cl was quenched and extracted with EtOAc (3 x 20mL). The organic extracts were combined and washed with brine, dried (MgSO _4), filtered, and concentrated. The resulting material was diluted with DMSO (1.5 mL) and purified by reverse-phase HPLC (two injections: 30 to 60% CH ₃ CN / 0.1% NH ₄ OH in H ₂ O). The product portions were combined, concentrated, and lyophilized. The resulting amber oil was dissolved in CH ₂ Cl ₂ and purified over SiO ₂ by chromatography (gradient: 0 to 75% EtOAc / hexane) to provide N-ethyl-5- (1-((1 -Ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazol-2-yl) -N-isopropylpyridin-2-amine (35mg), yellow after freeze-drying Oily. LC-MS (ES) m / z = 389 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.14-1.21 (m, 9H), 1.33 (t, J = 7.4Hz, 3H), 3.44 (q, J = 6.8Hz, 2H), 4.08 (q, J = 7.4 Hz, 2H), 4.84-4.93 (m, 1H), 5.41 (s, 2H), 6.09 (d, J = 2.3Hz, 1H), 6.74 (d, J = 8.9Hz, 1H), 7.17- 7.23 (m, 2H), 7.48-7.54 (m, 1H), 7.61-7.66 (m, 1H), 7.68 (d, J = 2.3Hz, 1H), 8.03 (dd, J = 9.0, 2.4Hz, 1H) , 8.59 (d, J = 2.0 Hz, 1H).

Intermediate 33

4-(((1-ethyl-1H-pyrazol-3-yl) methyl) amino) -N-methyl-3-nitrobenzamide

Add 4-fluoro-N-methyl-3-nitrobenzamide (1.583 g, 7.99 mmol) and K ₂ CO ₃ (638 mg, 4.62 mmol) to (1-ethyl) in DMF (15 mL). -1H-pyrazol-3-yl) methylamine (1 g, 7.99 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with water (40 mL) and a solid formed. The resulting mixture was stirred at room temperature for 30 minutes and then filtered. Trituration of the filtered solid from Et ₂ O provided 4-(((1-ethyl-1H-pyrazol-3-yl) methyl) amino) -N-methyl-3-nitrobenzyl as a yellow solid Lamine (1.76 g). LC-MS (ES) m / z = 304 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.36 (t, J = 7.2Hz, 3H), 2.76 (d, J = 4.6Hz, 3H), 4.11 (q, J = 7.27Hz, 2H), 4.58 (d, J = 5.6Hz, 2H), 6.19 (d, J = 2.3Hz, 1H), 7.16 (d, J = 9.1Hz, 1H), 7.69 (d, J = 2.3Hz, 1H), 7.93-7.98 (m, 1H), 8.46 (d, J = 4.6 Hz, 1H), 8.64 (d, J = 2.0 Hz, 1H), 8.79 (t, J = 5.5 Hz, 1H).

Intermediate 34

3-amino-4-(((1-ethyl-1H-pyrazol-3-yl) methyl) amino) -N-methylbenzidine

NiCl ₂ ‧6H ₂ O (3.46 g, 14.51 mmol) followed by sodium borohydride (1.098 g, 29.0 mmol) was added in small portions to 4-(((1-ethyl-1H -Pyrazol-3-yl) methyl) amino) -N-methyl-3-nitrobenzamide (1.76 g, 5.80 mmol) in CH ₃ OH (100 mL) and the reaction mixture Stir at room temperature for 30 minutes. The reaction was then diluted with concentrated NH ₄ OH (40mL) and extracted with _{CH 2 Cl 2 (4 x 50mL} ). The organic extracts were combined and washed with brine, dried (MgSO _4), filtered, and concentrated. Trituration from EtOAc and hexane provided 3-amino-4-(((1-ethyl-1H-pyrazol-3-yl) methyl) amino) -N-methylbenzylamine ( 1.20g). LC-MS (ES) m / z = 274 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.35 (t, J = 7.4Hz, 3H), 2.70 (d, J = 4.3Hz, 3H), 4.03-4.13 (m, 2H), 4.24 (d, J = 5.8 Hz, 2H), 4.65 (s, 2H), 5.31 (t, J = 5.6 Hz, 1H), 6.14 (d, J = 2.0 Hz, 1H), 6.47 (d, J = 8.4 Hz, 1H) , 7.00 (dd, J = 8.2,1.9Hz, 1H), 7.07 (d, J = 2.0Hz, 1H), 7.63 (d, J = 2.3Hz, 1H), 7.87 (d, J = 4.8Hz, 1H) .

Example 6

2- (6- (diethylamino) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -N-methyl-1H-benzo [ d) imidazol-5-carboxamide

Add 6- (diethylamino) nicotinaldehyde (195 mg, 1.094 mmol) followed by oxone (437 mg, 0.711 mmol) to the 3-amine group in DMF (10 mL) and water (10 mL) 4-(((1-ethyl-1H-pyrazol-3-yl) methyl) amino) -N-methylbenzidine (299 mg, 1.094 mmol), and the reaction mixture was at room temperature Stir for 0.5 hours. The reaction was quenched with saturated aqueous NH ₄ Cl (2 mL), and then saturated aqueous NaHCO ₃ (3 mL) was added. The resulting mixture was extracted with EtOAc (3 x 20mL), and the organic extracts were combined and washed with brine, dried (MgSO _4), filtered, and concentrated. Purification by chromatography on SiO ₂ (gradient of 0 to 8% CH ₃ OH in CH ₂ Cl ₂ ) provided 2- (6- (diethylamino) pyridin-3-yl) -1- ((1-ethyl-1H-pyrazol-3-yl) methyl) -N-methyl-1H-benzo [d] imidazole-5-carboxamide (348mg), lyophilized to a light brown solid . LC-MS (ES) m / z = 432 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 1.13-1.17 (m, 6H), 1.32 (t, J = 7.2Hz, 3H), 2.81 (d, J = 4.3Hz, 3H), 3.57 (q , J = 7.0Hz, 4H), 4.05 (q, J = 16.3Hz, 2H), 5.44 (s, 2H), 6.10 (d, J = 2.3Hz, 1H), 6.75 (d, J = 8.6Hz, 1H ), 7.56 (d, J = 8.4Hz, 1H), 7.69 (d, J = 2.3Hz, 1H), 7.71-7.75 (m, 1H), 8.03 (dd, J = 9.1, 2.5Hz, 1H), 8.15 (d, J = 1.0Hz, 1H), 8.41 (d, J = 4.6Hz, 1H), 8.58 (d, J = 1.8Hz, 1H).

Example 7

(S) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -N-methyl-2- (6- (2-methylpyrrolidin-1-yl) pyridine- 3-yl) -1H-benzo [d] imidazole-5-carboxamide

(S) -6- (2-methylpyrrolidin-1-yl) nicotinaldehyde (34.8 mg, 0.183 mmol) followed by oxone (73.1 mg, 0.119 mmol) was added to DMF (2 mL ) And 3-amino-4-(((1-ethyl-1H-pyrazol-3-yl) methyl) amino) -N-methylbenzylamine (50 mg, 0.183 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. The reaction was followed with aqueous saturated NaHCO ₄ Cl saturated NH ₃ (5mL) solution was quenched, and the resulting aqueous mixture was extracted with EtOAc (3 x 20mL). The organic extracts were combined and washed with brine, dried (MgSO _4), filtered, and concentrated. Purification by flash chromatography on SiO ₂ (Condition: 100% hexane in 2 minutes, then 100% CH ₂ Cl ₂ in 2 minutes, then gradient from 0 to 8% CH ₃ OH / CH ₂ Cl ₂ ) Provides off-white oil. CH ₃ CN (3 mL) was then added, and the resulting precipitate was filtered to provide (S) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -N-formaldehyde as a white solid. 2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-5-carboxamide (51 mg). LC-MS (ES) m / z = 444 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.20 (d, J = 6.08 Hz, 3H), 1.32 (t, J = 7.4 Hz, 3H), 1.71 (br.s., 1H), 1.94-2.10 (m, 4H), 2.81 (d, J = 4.3Hz, 3H), 3.56 (dd, J = 10.3,7.5Hz, 1H), 4.07 (q, J = 7.2Hz, 2H), 4.23 (t, J = 6.1Hz, 1H), 5.43 (s, 2H), 6.09 (d, J = 2.3Hz, 1H), 6.61 (d, J = 8.9Hz, 1H), 7.56 (d, J = 8.4Hz, 1H), 7.68 (d, J = 2.3Hz, 1H), 7.73 (dd, J = 8.5, 1.7Hz, 1H), 8.03 (dd, J = 8.9, 2.3Hz, 1H), 8.15 (d, J = 1.3Hz, 1H) , 8.41 (d, J = 4.3 Hz, 1H), 8.59 (d, J = 2.3 Hz, 1H).

Example 8

2- (6-((2S, 5R) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl ) Methyl) -N-methyl-1H-benzo [d] imidazole-5-carboxamide

6-((2S, 5R) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (39.6 mg, 0.194 mmol) followed by oxone (77 mg, 0.126 mmol) was added to 3-Amino-4-(((1-ethyl-1H-pyrazol-3-yl) methyl) amino) -N-methylbenzidine in DMF (2mL) and water (1mL) Amine (53 mg, 0.194 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. The reaction was quenched with saturated aqueous NH ₄ Cl solution followed by saturated aqueous NaHCO ₃ solution (5 mL), and the resulting aqueous mixture was extracted with EtOAc (3 x 20 mL). The organic extracts were combined and washed with brine, dried (MgSO _4), filtered, and concentrated. Purification by flash chromatography on SiO ₂ (Condition: 2 minutes at 100% hexane, then 2 minutes at 100% CH ₂ Cl ₂ , followed by a gradient from 0 to 10% CH ₃ OH / CH ₂ Cl ₂ ) Provide a clear oil, freeze-dried to provide 2- (6-((2S, 5R) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- as a white solid ((1-ethyl-1H-pyrazol-3-yl) methyl) -N-methyl-1H-benzo [d] imidazole-5-carboxamide (63 mg). LC-MS (ES) m / z = 458 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.26-1.35 (m, 9H), 1.70-1.80 (m, 2H), 2.02-2.13 (m, 2H), 2.81 (d, J = 4.3Hz, 3H ), 4.02-4.16 (m, 4H), 5.44 (s, 2H), 6.10 (d, J = 2.3Hz, 1H), 6.64 (d, J = 8.9Hz, 1H), 7.56 (d, J = 8.6Hz , 1H), 7.69 (d, J = 2.28Hz, 1H), 7.73 (dd, J = 8.4,1.5Hz, 1H), 8.03 (dd, J = 8.9,2.5Hz, 1H), 8.15 (d, J = 1.3Hz, 1H), 8.37-8.44 (m, 1H), 8.59 (s, 1H).

Example 9

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl ) Methyl) -N-methyl-1H-benzo [d] imidazole-5-carboxamide

Add potassium oxone (123 mg, 0.200 mmol) to 3-amino-4-(((1-ethyl-1H-pyrazol-3-yl) methyl) amino) -N-formyl Benzamidine (84mg, 0.307mmol) and 6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (69.1mg, 0.338mmol) in DMF (3mL) And water (3 mL), and the reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with saturated aqueous NH ₄ Cl (8mL), and treated with NH ₄ OH (10mL) the pH was adjusted to ~ 10. The product was extracted with CH ₂ Cl ₂ (3 x 25 mL). The combined organic layers were washed with brine (3 mL), dried over Na ₂ SO ₄ , filtered, and concentrated. The remaining residue was dissolved in CH ₃ OH (1.25mL). Some solids did not dissolve and more precipitate formed in the sample. The sample was diluted with DMSO (1.2 mL) and water (5 mL), and the solid was collected via filtration, and then dried under high vacuum overnight to provide 2- (6-((2S, 5S) -2,5- Dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -N-methyl-1H-benzo [d ] Imidazole-5-carboxamide (65 mg). LC-MS (ES) m / z = 458 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.59 (d, J = 2.0 Hz, 1 H), 8.42 (d, J = 4.6 Hz, 1 H), 8.15 (d, J = 1.3 Hz, 1 H), 8.01 (dd, J = 2.4,9.0Hz, 1H), 7.73 (dd, J = 1.52,8.62Hz, 1H), 7.69 (d, J = 2.3Hz, 1H), 7.56 (d, J = 8.4Hz, 1H) , 6.63 (d, J = 8.6Hz, 1H), 6.10 (d, J = 2.3Hz, 1H), 5.44 (s, 2H), 4.13-4.39 (m, 2H), 4.07 (q, J = 7.4Hz, 2H), 2.81 (d, J = 4.6Hz, 3H), 2.24 (br.s., 2H), 1.65 (d, J = 5.3Hz, 2H), 1.32 (t, J = 7.4Hz, 3H), 1.15 (d, J = 6.1Hz, 6H).

Example 10

2- (6- (cyclopropyl (ethyl) amino) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -N-methyl- 1H-benzo [d] imidazole-5-carboxamide

Add 6- (cyclopropyl (ethyl) amino) nicotinaldehyde (34.8 mg, 0.183 mmol) and water (2 mL) followed by potassium oxone (73.1 mg, 0.119 mmol) to DMF (2 mL 3-amino-4-(((1-ethyl-1H-pyrazol-3-yl) methyl) amino) -N-methylbenzidine (50 mg, 0.183 mmol), and The reaction mixture was stirred at room temperature for 30 minutes. The reaction was quenched with saturated aqueous NH ₄ Cl solution followed by saturated aqueous NaHCO ₃ solution (5 mL), and the resulting aqueous mixture was extracted with EtOAc (3 x 20 mL). The organic extracts were combined and washed with brine, dried (MgSO _4), filtered, and concentrated. Purification by flash chromatography on SiO ₂ (Condition: 2 minutes at 100% hexane, then 2 minutes at 100% CH ₂ Cl ₂ , followed by a gradient from 0 to 8% CH ₃ OH / CH ₂ Cl ₂ ) Freeze-dried to provide 2- (6- (cyclopropyl (ethyl) amino) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl as a white solid ) -N-methyl-1H-benzo [d] imidazole-5-carboxamide (65 mg). LC-MS (ES) m / z = 444 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 0.63-0.69 (m, 2H), 0.93-0.99 (m, 2H), 1.11 (t, J = 7.0Hz, 3H), 1.31 (t, J = 7.4 Hz, 3H), 2.63 (dt, J = 6.9, 3.3 Hz, 1H), 2.81 (d, J = 4.3 Hz, 3H), 3.73 (q, J = 7.0 Hz, 2H), 4.07 (q, J = 7.3 Hz, 2H), 5.44 (s, 2H), 6.10 (d, J = 2.3 Hz, 1H), 7.11 (d, J = 8.9 Hz, 1H), 7.58 (d, J = 8.6 Hz, 1H), 7.68 ( d, J = 2.0Hz, 1H), 7.74 (dd, J = 8.6, 1.5Hz, 1H), 8.10 (dd, J = 9.0, 2.4Hz, 1H), 8.16 (d, J = 1.3Hz, 1H), 8.42 (d, J = 4.6 Hz, 1H), 8.63 (d, J = 2.5 Hz, 1H).

Example 11

2- (6- (diethylamino) -5-fluoropyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -N-methyl-1H -Benzo [d] imidazole-5-carboxamide

Add 6- (diethylamino) -5-fluoronicotinaldehyde (35.9 mg, 0.183 mmol) and water (2 mL) followed by oxone (73.1 mg, 0.119 mmol) to DMF (2 mL) 3-amino-4-(((1-ethyl-1H-pyrazol-3-yl) methyl) amino) -N-methylbenzidine (50 mg, 0.183 mmol), and The reaction mixture was stirred at room temperature for 30 minutes. The reaction was quenched with saturated aqueous NH ₄ Cl solution followed by saturated aqueous NaHCO ₃ solution (5 mL), and the resulting aqueous mixture was extracted with EtOAc (3 x 20 mL). The organic extracts were combined and washed with brine, dried (MgSO _4), filtered, and concentrated. Purification by flash chromatography on SiO ₂ (conditions: 100% hexane for 2 minutes, then 100% CH2Cl _{2 for} 2 minutes, then gradient from 0 to 8% CH ₃ OH / CH ₂ Cl ₂ ) 2- (6- (diethylamino) -5-fluoropyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -N-formaldehyde as a white solid 1H-benzo [d] imidazole-5-carboxamide (64 mg). LC-MS (ES) m / z = 450 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.20 (t, J = 7.0Hz, 6H), 1.28-1.34 (m, 3H), 2.81 (d, J = 4.3Hz, 3H), 3.54-3.63 ( m, 4H), 4.07 (q, J = 7.4Hz, 2H), 5.47 (s, 2H), 6.15 (d, J = 2.3Hz, 1H), 7.64 (d, J = 8.6Hz, 1H), 7.69 ( d, J = 2.3Hz, 1H), 7.77 (dd, J = 8.6, 1.52Hz, 1H), 8.05 (dd, J = 15.6, 1.9Hz, 1H), 8.17 (d, J = 1.3Hz, 1H), 8.40-8.45 (m, 1H), 8.46 (t, J = 1.9Hz, 1H).

Example 12

(S) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -2- (5-fluoro-6- (2-methylpyrrolidin-1-yl) pyridine-3 -Yl) -N-methyl-1H-benzo [d] imidazole-5-carboxamide

Combine (S) -5-fluoro-6- (2-methylpyrrolidin-1-yl) nicotinaldehyde (34.3 mg, 0.165 mmol) and water (2 mL) followed by potassium oxone (65.8 mg, 0.107 mmol) added to 3-amino-4-(((1-ethyl-1H-pyrazol-3-yl) methyl) amino) -N-methylbenzidine in DMF (2 mL) Amine (45 mg, 0.165 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. The reaction was quenched with saturated aqueous NH ₄ Cl solution followed by saturated aqueous NaHCO ₃ solution (5 mL), and the resulting aqueous mixture was extracted with EtOAc (3 x 20 mL). The organic extracts were combined and washed with brine, dried (MgSO _4), filtered, and concentrated. Purification by flash chromatography on SiO ₂ (purification procedure was performed twice; conditions: 2 minutes at 100% hexane, then 2 minutes at 100% CH ₂ Cl ₂ , followed by a gradient from 0 to 10% CH ₃ OH / CH ₂ Cl ₂ ) (S) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -2- (5-fluoro-6- (2-methyl Pyrrolidin-1-yl) pyridin-3-yl) -N-methyl-1H-benzo [d] imidazole-5-carboxamide (45 mg). LC-MS (ES) m / z = 462 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.19-1.22 (d, 3H), 1.31 (t, J = 7.2Hz, 3H), 1.64-1.72 (m, 1H), 1.86-2.11 (m, 3H ), 2.81 (d, J = 4.6 Hz, 3H), 3.53-3.63 (m, 1H), 3.79 (m, 1H), 4.07 (q, J = 7.1 Hz, 2H), 4.41 (br.s., 1H ), 5.46 (s, 2H), 6.15 (d, J = 2.3Hz, 1H), 7.62 (s, 1H), 7.69 (s, 1H), 7.76 (dd, J = 8.6, 1.52Hz, 1H), 8.03 (dd, J = 15.0, 1.8Hz, 1H), 8.16 (d, J = 1.3Hz, 1H), 8.40-8.48 (m, 2H).

Example 13

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) -5-fluoropyridin-3-yl) -1-((1-ethyl-1H-pyrazole -3-yl) methyl) -N-methyl-1H-benzo [d] imidazole-5-carboxamide

Combine 6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) -5-fluoronicotinaldehyde (40.7 mg, 0.183 mmol) and water (2 mL) followed by potassium monosulfate (oxone ) (73.1 mg, 0.119 mmol) was added to 3-amino-4-(((1-ethyl-1H-pyrazol-3-yl) methyl) amino) -N- in DMF (2 mL) Toluidine (50 mg, 0.183 mmol), and the reaction was stirred at room temperature for 30 minutes. The reaction was quenched with saturated aqueous NH ₄ Cl solution followed by saturated aqueous NaHCO ₃ solution (5 mL), and the resulting aqueous mixture was extracted with EtOAc (3 x 20 mL). The organic extracts were combined and washed with brine, dried (MgSO _4), filtered, and concentrated. Purification by flash chromatography on SiO ₂ (Condition: 100% hexane in 2 minutes, then 100% CH ₂ Cl ₂ in 2 minutes, then gradient from 0 to 8% CH ₃ OH / CH ₂ Cl ₂ ) Provides 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) -5-fluoropyridin-3-yl) -1-((1-ethyl -1H-pyrazol-3-yl) methyl) -N-methyl-1H-benzo [d] imidazole-5-carboxamide (70 mg). LC-MS (ES) m / z = 476 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.12 (d, J = 6.3Hz, 6H), 1.31 (t, J = 7.2Hz, 3H), 1.63 (d, J = 5.6Hz, 2H), 2.18 -2.25 (m, 2H), 2.81 (d, J = 4.5Hz, 3H), 4.07 (q, J = 7.4Hz, 2H), 4.46-4.56 (m, 2H), 5.48 (s, 2H), 6.15 ( s, 1H), 7.64 (d, J = 8.1Hz, 1H), 7.69 (d, J = 2.3Hz, 1H), 7.77 (dd, J = 8.5,1.7Hz, 1H), 8.02-8.08 (m, 1H ), 8.17 (d, J = 1.3 Hz, 1H), 8.43 (s, 1H), 8.47-8.51 (m, 1H).

Intermediate 35

4-(((1-ethyl-1H-pyrazol-3-yl) methyl) amino) -3-nitrobenzoate

(1-Ethyl-1H-pyrazol-3-yl) methylamine (1.23 g, 9.84 mmol) and K ₂ CO ₃ (1.496 g, 10.83 mmol) were added to 4-fluoro- in DMF (20 mL) Methyl 3-nitrobenzoate (1.96 g, 9.84 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with water (50 mL) and extracted with EtOAc (3 x 50 mL). The organic extracts were combined and washed with brine, dried (MgSO _4), filtered, and concentrated. Purification by flash chromatography on SiO ₂ (gradient of 0 to 60% EtOAc / hexane) provided 4-(((1-ethyl-1H-pyrazol-3-yl) methyl) as a clear oil ) Amino) -3-nitrobenzoate (2.14 g). LC-MS (ES) m / z = 305 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.36 (t, J = 7.2Hz, 3H), 3.83 (s, 3H), 4.11 (q, J = 7.4Hz, 2H), 4.60 (d, J = 5.6Hz, 2H), 6.19 (s, 1H), 7.20 (d, J = 9.1Hz, 1H), 7.70 (d, J = 2.3Hz, 1H), 7.98 (dd, J = 9.0, 1.7Hz, 1H) , 8.64 (s, 1H), 8.98 (s, 1H).

Intermediate 36

3-amino-4-(((1-ethyl-1H-pyrazol-3-yl) methyl) amino) benzoate

Over 15 minutes _{NiCl 2 ‧6H 2 O (4.15g,} 17.42mmol) followed by sodium borohydride (1.318g, 34.8mmol) was added in small portions to 4 in CH ₃ OH (20mL) of - (((1- B Methyl-1H-pyrazol-3-yl) methyl) amino) -3-nitrobenzoate (2.12 g, 6.97 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. The reaction was diluted with concentrated NH ₄ OH (20mL) and extracted with _{CH 2 Cl 2 (3 x 30mL} ). The organic extracts were combined and washed with brine, dried (MgSO _4), filtered, and concentrated to provide a clear oil of 3-amino-4 - (((1-ethyl--1H- pyrazol-3-yl) methyl Methyl) amino) benzoate (1.74 g). LC-MS (ES) m / z = 275 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.35 (t, J = 7.2Hz, 3H), 3.72 (s, 3H), 4.08 (q, J = 7.4Hz, 2H), 4.27 (d, J = 5.6Hz, 2H), 4.79 (s, 2H), 5.66 (m, 1H), 6.14 (d, J = 2.3Hz, 1H), 6.53 (d, J = 8.1Hz, 1H), 7.15-7.20 (m, 2H), 7.63 (d, J = 2.3Hz, 1H).

Intermediate 37

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl ) Methyl) -1H-benzo [d] imidazole-5-formate

Add 6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (89 mg, 0.437 mmol) and potassium oxone (175 mg, 0.284 mmol) to 3-Amino-4-(((1-ethyl-1H-pyrazol-3-yl) methyl) amino) benzoate in DMF (3mL) and water (3mL) (120 mg, 0.437 mmol), and the reaction mixture was stirred at room temperature for 0.5 hours. The reaction was washed with water (20mL) followed by saturated aqueous NaHCO ₃ (5mL) and quenched. The resulting solid was isolated by filtration to provide 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-(( 1-Ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxylic acid methyl ester (188 mg). LC-MS (ES) m / z = 459 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 1.15 (d, J = 6.1 Hz, 6H), 1.29-1.34 (m, 3H), 1.66 (d, J = 5.6 Hz, 2H), 2.24 (br. s., 2H), 3.88 (s, 3H), 4.04-4.10 (m, 2H), 4.29 (br.s., 2H), 5.48 (s, 2H), 6.12 (d, J = 2.3Hz, 1H) , 6.66 (d, J = 8.1Hz, 1H), 7.65 (d, J = 8.6Hz, 1H), 7.69 (d, J = 2.3Hz, 1H), 7.86 (dd, J = 8.5,1.7Hz, 1H) , 8.03 (d, J = 9.4 Hz, 1H), 8.23 (d, J = 1.3 Hz, 1H), 8.60 (d, J = 2.0 Hz, 1H).

Intermediate 38

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl ) Methyl) -1H-benzo [d] imidazole-5-carboxylic acid

10N NaOH (0.615 mL, 6.15 mmol) was added to 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridine-3 in CH ₃ OH (5 mL) -Yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxylic acid methyl ester (188 mg, 0.410 mmol), and react The mixture was stirred at 45 ° C for 48 hours. The reaction was partially concentrated under vacuum, diluted with water (5 mL), and then neutralized by adding 6N HCl solution until pH ~ 7. The resulting precipitate was filtered and purified by chromatography on SiO ₂ (gradient of 0 to 10% CH ₃ OH / CH ₂ Cl ₂ ) to provide 2- (6-((2S, 5S) -2 as a light brown solid , 5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole 5--5-carboxylic acid (110 mg). ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.14 (d, J = 6.4Hz, 6H), 1.31 (t, J = 7.2Hz, 3H), 1.65 (d, J = 5.3Hz, 2H), 2.24 (br.s., 2H), 4.07 (q, J = 7.3Hz, 2H), 4.26 (br.s., 2H), 5.46 (s, 2H), 6.10 (d, J = 2.3Hz, 1H), 6.63 (d, J = 8.9Hz, 1H), 7.59 (d, J = 8.4Hz, 1H), 7.69 (d, J = 2.0Hz, 1H), 7.83 (dd, J = 8.5,1.4Hz, 1H), 8.01 (dd, J = 8.9, 2.5 Hz, 1H), 8.20 (d, J = 1.5 Hz, 1H), 8.59 (d, J = 2.3 Hz, 1H), 12.72 (s, 1H).

Example 14

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl ) Methyl) -N- (2-hydroxyethyl) -1H-benzo [d] imidazole-5-carboxamide

Add 2-aminoethyl-l-ol (0.012 mL, 0.192 mmol), EDC (52.6 mg, 0.274 mmol), HOBt (42.0 mg, 0.274 mmol), and N-methylmorpholine (0.091 mL, 0.823 mmol) ) Was added to 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl -1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxylic acid (61 mg, 0.137 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with water (5 mL), and the resulting solid was filtered and purified by chromatography on SiO ₂ (0 to 35% (80: 20: 2 CH ₂ Cl ₂ : CH ₃ OH: NH ₄ OH) / CH ₂ Cl ₂ gradient) to provide a clear oil of 2- (6 - ((2S, 5S) -2,5- dimethyl-pyrrolidin-l-yl) pyridin-3-yl) -1 - (( 1-ethyl-1H-pyrazol-3-yl) methyl) -N- (2-hydroxyethyl) -1H-benzo [d] imidazole-5-carboxamide (52 mg). LC-MS (ES) m / z = 488 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.14 (d, J = 6.3Hz, 6H), 1.32 (t, J = 7.4Hz, 3H), 1.65 (d, J = 5.3Hz, 2H), 2.24 (br.s., 2H), 3.53 (q, J = 6.0Hz, 2H), 4.07 (q, J = 7.2Hz, 2H), 4.25 (br.s., 2H), 4.74 (t, J = 5.7 Hz, 1H), 5.44 (s, 2H), 6.08 (d, J = 2.3Hz, 1H), 6.63 (d, J = 8.9Hz, 1H), 7.56 (d, J = 8.6Hz, 1H), 7.68 ( d, J = 2.3Hz, 1H), 7.75 (dd, J = 8.6, 1.52Hz, 1H), 8.01 (dd, J = 8.9, 2.53Hz, 1H), 8.18 (d, J = 1.3Hz, 1H), 8.41 (t, J = 5.7Hz, 1H), 8.59 (d, J = 2.3Hz, 1H).

Example 15

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl ) Methyl) -1H-benzo [d] imidazole-5-carboxamide

NH ₄ Cl (10.40 mg, 0.194 mmol), EDC (41.4 mg, 0.216 mmol), HOBt (33.1 mg, 0.216 mmol), and N-methylmorpholine (0.071 mL, 0.648 mmol) were added to DMSO ( 2 (2)) of 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazole -3-yl) methyl) -1H-benzo [d] imidazole-5-carboxylic acid (48 mg, 0.108 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with water (5 mL), and the resulting solid was filtered and dried under a vacuum oven. Purification by flash chromatography on SiO ₂ (Condition: 2 minutes at 100% hexane, then 2 minutes at 100% CH ₂ Cl ₂ , then 0 to 10% CH ₃ OH in CH ₂ Cl ₂ Gradient over 25 minutes) provided 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl -1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide (40 mg). LC-MS (ES) m / z = 444 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.14 (d, J = 6.3Hz, 6H), 1.29-1.35 (m, 3H), 1.65 (d, J = 5.6Hz, 2H), 2.24 (br. s., 2H), 4.07 (q, J = 7.4Hz, 2H), 4.25 (br.s., 2H), 5.44 (s, 2H), 6.09 (d, J = 2.3Hz, 1H), 6.63 (d , J = 8.9Hz, 1H), 7.27 (br.s., 1H), 7.55 (d, J = 8.4Hz, 1H), 7.68 (d, J = 2.0Hz, 1H), 7.77 (dd, J = 8.6 , 1.5Hz, 1H), 7.96 (br.s., 1H), 8.01 (dd, J = 9.0, 2.4Hz, 1H), 8.21 (d, J = 1.3Hz, 1H), 8.59 (d, J = 2.5 Hz, 1H).

Intermediate 39

(S) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl)- 1H-Benzo [d] imidazole-5-carboxylic acid methyl ester

(S) -6- (2-methylpyrrolidin-1-yl) nicotinaldehyde (347 mg, 1.823 mmol) followed by oxone (728 mg, 1.185 mmol) was added to DMF (5 mL) and Methyl 3-amino-4-(((1-ethyl-1H-pyrazol-3-yl) methyl) amino) benzoate (500 mg, 1.823 mmol) in water (5 mL), and react The mixture was stirred at room temperature for 0.5 hours. The reaction was quenched with saturated aqueous NH ₄ Cl (3 mL) followed by saturated aqueous NaHCO ₃ (5 mL), and then the resulting mixture was extracted with EtOAc (3 x 20 mL). The organic extracts were then combined and washed with brine, dried (MgSO _4), filtered, and concentrated. Purification by flash chromatography on SiO ₂ (Condition: 100% hexane in 2 minutes, then 100% CH ₂ Cl ₂ in 2 minutes, then 0 to 8% CH ₃ OH in CH ₂ Cl ₂ Gradient over 28 minutes) provided a clear oil which was triturated with 9: 1 hexane: EtOAc to provide (S) -1-((1-ethyl-1H-pyrazol-3-yl) formaldehyde) as a light brown solid Methyl) -2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-5-carboxylic acid methyl ester (416 mg). LC-MS (ES) m / z = 445 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.20 (d, J = 6.3Hz, 3H), 1.31 (t, J = 7.2Hz, 3H), 1.71 (d, J = 3.6Hz, 1H), 1.93 -2.13 (m, 3H), 3.53-3.60 (m, 1H), 3.87 (s, 3H), 4.07 (q, J = 7.4Hz, 2H), 4.23 (br.s., 1H), 5.46 (s, 2H), 6.11 (d, J = 2.3Hz, 1H), 6.61 (d, J = 8.9Hz, 1H), 7.64 (d, J = 8.6Hz, 1H), 7.69 (d, J = 2.3Hz, 1H) , 7.85 (dd, J = 8.5, 1.65 Hz, 1H), 8.03 (dd, J = 8.9, 2.53 Hz, 1H), 8.23 (d, J = 1.3 Hz, 1H), 8.60 (d, J = 2.0 Hz, 1H).

Intermediate 40

(S) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl)- 1H-benzo [d] imidazole-5-carboxylic acid

10N NaOH (0.119 mL, 1.192 mmol) was added to (S) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -2- (CH ₃ OH (3 mL)) 6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-5-carboxylic acid methyl ester (53 mg, 0.119 mmol), and the reaction mixture was at 40 ° C Stir overnight. An additional 10 N NaOH (0.119 mL, 1.192 mmol) was added, and the reaction mixture was stirred at 40 ° C overnight. The reaction was then partially concentrated under reduced pressure. Water (5 mL) was added followed by 6N HCl slowly to a pH of 7. The resulting solid was collected by filtration and dried in a vacuum oven overnight to provide (S) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-5-carboxylic acid (40 mg). LC-MS (ES) m / z = 431 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.22 (d, J = 6.3Hz, 3H), 1.31 (t, J = 7.2Hz, 3H), 1.78 (d, J = 9.9Hz, 1H), 2.00 -2.16 (m, 3H), 3.46 (d, J = 6.3Hz, 1H), 3.69 (br.s., 1H), 4.07 (q, J = 7.2Hz, 2H), 4.35 (br.s., 1H ), 5.59 (s, 2H), 6.32 (d, J = 2.0Hz, 1H), 6.98 (br.s., 1H), 7.75 (d, J = 2.3Hz, 1H), 7.86 (d, J = 8.6 Hz, 1H), 8.02 (d, J = 8.6 Hz, 1H), 8.23-8.30 (m, 2H), 8.68 (d, J = 2.3Hz, 1H), 12.77-13.56 (br.s., 1H).

Example 16

(S) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl)- 1H-benzo [d] imidazole-5-carboxamide

NH ₄ Cl (8.95 mg, 0.167 mmol), EDC (35.6 mg, 0.186 mmol), HOBt (28.5 mg, 0.186 mmol), and N-methylmorpholine (0.061 mL, 0.557 mmol) were added to DMSO ( 2S) of (S) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -2- (6- (2-methylpyrrolidin-1-yl) pyridine-3 -Yl) -1H-benzo [d] imidazole-5-carboxylic acid (40 mg, 0.093 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with water (5 mL), and the resulting solid was collected and purified by flash chromatography on SiO ₂ (conditions: 2 minutes in 100% hexane, then 2 minutes in 100% CH ₂ Cl ₂ , and then in the CH of 0 to 10% CH ₃ OH gradient ₂ Cl ₂ over 28 minutes) to provide a white solid of (S) -1 - ((1- ethyl--1H- pyrazol-3-yl) methyl) 2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-5-carboxamide (18 mg). LC-MS (ES) m / z = 430 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.18-1.22 (m, 3H), 1.32 (t, J = 7.2Hz, 3H), 1.71 (br.s., 1H), 1.94-2.12 (m, 4H), 3.52-3.59 (m, 1H), 4.07 (q, J = 7.3Hz, 2H), 4.23 (br.s., 1H), 5.43 (s, 2H), 6.09 (d, J = 2.3Hz, 1H), 6.61 (d, J = 9.1Hz, 1H), 7.27 (br.s., 1H), 7.55 (d, J = 8.6Hz, 1H), 7.68 (d, J = 2.0Hz, 1H), 7.77 (dd, J = 8.3, 1.5Hz, 1H), 7.96 (br.s., 1H), 8.03 (dd, J = 8.9, 2.5Hz, 1H) 8.21 (d, J = 1.3Hz, 1H), 8.59 ( d, J = 2.3Hz, 1H).

Intermediate 41

2- (6-((2S, 5R) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl ) Methyl) -1H-benzo [d] imidazole-5-carboxylic acid

10N NaOH (0.142 mL, 1.417 mmol) was added to 2- (6-((2S, 5R) -2,5-dimethylpyrrolidin-1-yl) pyridine-3 in CH ₃ OH (2 mL) -Yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxylic acid methyl ester (65 mg, 0.142 mmol), and react The mixture was stirred at 40 ° C overnight. The reaction was then partially concentrated under reduced pressure. Water (5 mL) was added followed by 6N HCl solution slowly to a pH of 7. The resulting solid was collected by filtration and dried in a vacuum oven overnight to provide 2- (6-((2S, 5R) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl as a white solid. ) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxylic acid (40 mg). LC-MS (ES) m / z = 445 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.28-1.35 (m, 9H), 1.71-1.81 (m, 2H), 2.03-2.14 (m, 2H), 4.03-4.17 (m, 4H), 5.48 (s, 2H) 6.14 (d, J = 2.3Hz, 1H), 6.69 (d, J = 8.9Hz, 1H), 7.64 (d, J = 8.4Hz, 1H), 7.70 (d, J = 2.3Hz, 1H), 7.84-7.89 (m, 1H), 8.06 (dd, J = 8.9, 2.3 Hz, 1H), 8.22 (s, 1H), 8.61 (d, J = 2.3 Hz, 1H), 12.80 (br.s ., 1H).

Example 17

2- (6-((2S, 5R) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl ) Methyl) -1H-benzo [d] imidazole-5-carboxamide

NH ₄ Cl (8.66 mg, 0.162 mmol), EDC (34.5 mg, 0.180 mmol), HOBt (27.6 mg, 0.180 mmol), and N-methylmorphine (0.059 mL, 0.540 mmol) were added to 2 (2)) of 2- (6-((2S, 5R) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazole -3-yl) methyl) -1H-benzo [d] imidazole-5-carboxylic acid (40 mg, 0.090 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with water (5 mL), and the resulting solid was collected by filtration and dried in a vacuum oven to provide 2- (6-((2S, 5R) -2,5-dimethylpyrrolidine- 1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide (30 mg) . LC-MS (ES) m / z = 444 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.27-1.35 (m, 9H), 1.70-1.80 (m, 2H), 2.02-2.13 (m, 2H), 4.03-4.16 (m, 4H), 5.44 (s, 2H), 6.10 (d, J = 2.3Hz, 1H), 6.64 (d, J = 8.9Hz, 1H), 7.27 (br.s., 1H), 7.55 (d, J = 8.3Hz, 1H ), 7.69 (d, J = 2.3Hz, 1H), 7.77 (dd, J = 8.6, 1.5Hz, 1H), 7.97 (br.s., 1H), 8.03 (dd, J = 8.9, 2.5Hz, 1H ), 8.21 (d, J = 1.3 Hz, 1H), 8.60 (d, J = 2.5 Hz, 1H).

Intermediate 42

3-chloro-N-((1-ethyl-1H-pyrazol-3-yl) methyl) -2-nitroaniline

Add 1-chloro-3-fluoro-2-nitrobenzene (250 mg, 1.424 mmol), (1-ethyl-1H-pyrazol-3-yl) methylamine (196 mg, 1.567 mmol) and N, N-diiso A solution of propylethylamine (0.298 mL, 1.709 mmol) in DMF (20 mL) was stirred at room temperature for 2 hours. The reaction was then heated to 60 ° C for 16 hours. The reaction was concentrated, and the resulting residue was purified via silica chromatography (0% to 27% EtOAc / hexane) to give 3-chloro-N-((1-ethyl-1H-pyrazole-3) as an oil -Yl) methyl) -2-nitroaniline (263 mg). LC-MS (ES) m / z = 281,283 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 7.39 (d, J = 2.0Hz, 1H), 7.25 (dd, J = 7.9, 8.6Hz, 1H), 6.86 (dd, J = 1.0, 8.6Hz, 1H) , 6.80 (dd, J = 1.3, 7.9 Hz, 1H), 6.28 (br.s., 1H), 6.21 (d, J = 2.0 Hz, 1H), 4.44 (d, J = 4.3 Hz, 2H), 4.19 (q, J = 7.3Hz, 2H), 1.53 (t, J = 7.2Hz, 3H).

Intermediate 43

3-chloro-N-((1-ethyl-1H-pyrazol-3-yl) methyl) -2-nitroaniline

3-Chloro-N-((1-ethyl-1H-pyrazol-3-yl) methyl) -2-nitroaniline (116 mg, 0.413 mmol) and NiCl ₂ ‧ 6H ₂ O (246 mg, 1.033 mmol) mixture in CH ₃ OH (20mL) cooled in an ice-water bath. Sodium borohydride (78 mg, 2.066 mmol) was added, and the reaction mixture was stirred in an ice-water bath for 10 minutes. The reaction was concentrated. Adding NH ₄ OH (28% of water), and the resulting mixture was extracted with CH _{2 2} Cl. The dried CH ₂ Cl ₂ the combined extracts were washed with MgSO _4, filtered, and concentrated. The resulting residue was purified via silica gel column chromatography (0% to 100% EtOAc / hexane) to provide 3-chloro-N-((1-ethyl-1H-pyrazol-3-yl) methyl) 2-nitroaniline (58 mg). LC-MS (ES) m / z = 251,253 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 7.39 (d, J = 2.3Hz, 1H), 6.86 (dd, J = 1.5, 7.9Hz, 1H), 6.59-6.80 (m, 2H), 6.26 (d, J = 2.3Hz, 1H), 4.36 (s, 2H), 4.20 (q, J = 7.4Hz, 2H), 1.53 (t, J = 7.34Hz, 3H).

Example 18

5- (4-chloro-1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethyl Pyridin-2-amine

3-Chloro-N1-((1-ethyl-1H-pyrazol-3-yl) methyl) benzene-1,2-diamine (58 mg, 0.185 mmol), 6- (diethylamino) smoke A mixture of alkali aldehyde (33.0 mg, 0.185 mmol) and potassium oxone (74.0 mg, 0.120 mmol) in DMF (10 mL) and water (4 mL) was stirred at room temperature for 30 minutes. Saturated aqueous NaHCO ₃ was added, and the resulting mixture was extracted with EtOAc. The combined extracts were washed with water of EtOA, washed with brine, dried over MgSO _4, filtered and concentrated. The resulting residue was purified via silica chromatography (0% to 100% EtOAc / hexane) to give 5- (4-chloro-1-((1-ethyl-1H-pyrazole) as a dark brown glass / solid -3-yl) methyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine (16 mg). LC-MS (ES) m / z = 409,411 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.59 (d, J = 1.8Hz, 1H), 7.98 (dd, J = 2.4, 9.0Hz, 1H), 7.26-7.38 (m, 3H), 7.04-7.21 ( m, 1H), 6.59 (d, J = 9.1Hz, 1H), 5.95 (d, J = 2.3Hz, 1H), 5.44 (s, 2H), 4.18 (q, J = 7.4Hz, 2H), 3.60 ( q, J = 7.1 Hz, 4H), 1.51 (t, J = 7.4 Hz, 3H), 1.24 (t, J = 7.1 Hz, 6H).

Intermediate 44

N-((1-ethyl-1H-pyrazol-3-yl) methyl) -3-methyl-2-nitroaniline

1-fluoro-3-methyl-2-nitrobenzene (176 mg, 1.135 mmol), (1-ethyl-1H-pyrazol-3-yl) methylamine (156 mg, 1.248 mmol), and N, N- A solution of diisopropylethylamine (0.238 mL, 1.361 mmol) in DMF (15 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated and the resulting residue was purified via silica chromatography (0% to 30% EtOAc / hexanes) to give N-((1-ethyl-1H-pyrazol-3-yl as a yellow oil ) Methyl) -3-methyl-2-nitroaniline (72 mg). LC-MS (ES) m / z = 261 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 7.39 (d, J = 2.3Hz, 1H), 7.25 (dd, J = 7.6, 8.4Hz, 1H), 6.81 (d, J = 8.6Hz, 1H), 6.58 (d, J = 7.4Hz, 1H), 6.23 (d, J = 2.3Hz, 1H), 4.47 (s, 2H), 4.21 (q, J = 7.4Hz, 2H), 2.51 (s, 3H), 1.54 (t, J = 7.4Hz, 3H).

Intermediate 45

N ¹ -((1-ethyl-1H-pyrazol-3-yl) methyl) -3-methylbenzene-1,2-diamine

N-((1-ethyl-1H-pyrazol-3-yl) methyl) -3-methyl-2-nitroaniline (70 mg, 0.269 mmol) and NiCl ₂ ‧ 6H ₂ O (160 mg, 0.672 mmol ) in a mixture of CH ₃ OH (20mL) cooled in an ice-water bath. Sodium borohydride (50.9 mg, 1.345 mmol) was added, and the reaction mixture was stirred in an ice-water bath for 10 minutes. The reaction mixture was concentrated. Adding NH ₄ OH (28% of water), and the resulting mixture was extracted with CH _{2 2} Cl. The combined CH ₂ Cl ₂ extracts were dried over MgSO ₄ , filtered, and concentrated to give N ¹ -((1-ethyl-1H-pyrazol-3-yl) methyl) -3-methyl as an oil. Benzene-1,2-diamine (60 mg). LC-MS (ES) m / z = 231 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 7.38 (d, J = 2.0Hz, 1H), 6.64-6.88 (m, 3H), 6.26 (d, J = 2.0Hz, 1H), 4.36 (s, 2H) , 4.21 (q, J = 7.4 Hz, 2H), 2.26 (s, 3H), 1.42-1.59 (m, 3H).

Example 19

N, N-diethyl-5- (1-((1-ethyl-1H-pyraol-3-yl) methyl) -4-methyl-1H-benzo [d] imidazole- 2-yl) pyridin-2-amine

N1-((1-ethyl-1H-pyrazol-3-yl) methyl) -3-methylbenzene-1,2-diamine (60 mg, 0.208 mmol), 6- (diethylamino) A mixture of nicotinaldehyde (37.1 mg, 0.208 mmol), and potassium oxone (83 mg, 0.135 mmol) in DMF (10 mL) and water (4 mL) was stirred at room temperature for 30 minutes. Saturated aqueous NaHCO ₃ was then added, and the resulting mixture was extracted with EtOAc. The organic layer was separated, washed sequentially with water and brine, dried over MgSO _4, filtered and concentrated. The resulting residue was purified via silica chromatography (0% to 100% EtOAc / hexane). Further purification via phase HPLC (10% CH ₃ CN / H ₂ O, 0.1% formic acid to 40% CH ₃ CN / H ₂ O, 0.1% formic acid) provided N, N-diethyl-5- as tar / solid (1-((1-ethyl-1H-pyrazol-3-yl) methyl) -4-methyl-1H-benzo [d] imidazol-2-yl) pyridin-2-amine (32 mg). LC-MS (ES) m / z = 389 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.58 (d, J = 1.8Hz, 1H), 7.95 (dd, J = 2.3, 8.9Hz, 1H), 7.32 (d, J = 2.3Hz, 1H), 7.21 -7.26 (m, 1H), 7.17 (t, J = 7.5Hz, 1H), 7.09-7.13 (m, 1H), 6.60 (d, J = 9.1Hz, 1H), 5.97 (d, J = 2.3Hz, 1H), 5.43 (s, 2H), 4.19 (q, J = 7.4Hz, 2H), 3.61 (q, J = 7.1Hz, 4H), 2.76 (s, 3H), 1.53 (t, J = 7.2Hz, 3H), 1.25 (t, J = 7.1Hz, 6H).

Intermediate 46

3-chloro-N-((1-ethyl-1H-pyrazol-4-yl) methyl) -2-nitroaniline

1-chloro-3-fluoro-2-nitrobenzene (157 mg, 0.894 mmol), (1-ethyl-1H-pyrazol-3-yl) methylamine (123 mg, 0.984 mmol), and N, N-di A solution of isopropylethylamine (0.187 mL, 1.073 mmol) in DMF (15 mL) was stirred at room temperature for 16 hours. The reaction was concentrated, and the resulting residue was purified via silica chromatography (0% to 35% EtOAc / hexanes) to provide 3-chloro-N-((1-ethyl-1H-pyrazole- 4-yl) methyl) -2-nitroaniline (142 mg). LC-MS (ES) m / z = 281,283 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 7.38 (d, J = 2.3Hz, 1H), 7.24 (t, J = 8.2Hz, 1H), 6.85 (dd, J = 1.0, 8.6Hz, 1H), 6.79 (dd, J = 1.1, 8.0Hz, 1H), 6.29 (br.s., 1H), 6.20 (d, J = 2.3Hz, 1H), 4.43 (d, J = 5.1Hz, 2H), 4.18 (q , J = 7.3Hz, 2H), 1.51 (t, J = 7.4Hz, 3H).

Example 20

4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazole -3-yl) methyl) -1H-benzo [d] imidazole

3-chloro-N-((1-ethyl-1H-pyrazol-3-yl) methyl) -2-nitroaniline (142 mg, 0.506 mmol), sodium bisulfite (264 mg, 85%, 1.287 mmol) , And a mixture of 6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (108 mg, 0.531 mmol) in EtOH (4 mL) and water (2 mL) under microwave conditions It was heated at 130 ° C for 30 minutes. The reaction was filtered and concentrated to dryness. CH ₂ Cl _{2 was added} , and the resulting mixture was filtered again. The filtrate was purified via silica gel chromatography (0% to 100% EtOAc / hexanes) to provide 4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrole) as a white solid. 1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole (68 mg). LC-MS (ES) m / z = 435 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.60 (d, J = 2.3Hz, 1H), 7.96 (dd, J = 2.3, 8.9Hz, 1H), 7.25-7.35 (m, 3H), 7.09-7.19 ( m, 1H), 6.50 (d, J = 8.9 Hz, 1H), 5.95 (d, J = 2.0 Hz, 1H), 5.45 (s, 2H), 4.28 (dd, J = 7.2, 14.6 Hz, 2H), 4.18 (q, J = 7.4Hz, 2H), 2.21-2.36 (m, 2H), 1.65-1.80 (m, 2H), 1.51 (t, J = 7.4Hz, 3H), 1.22 (d, J = 6.1Hz , 6H).

Intermediate 47

2-chloro-N-((1-ethyl-1H-pyrazol-3-yl) methyl) -6-nitroaniline

1-chloro-2-fluoro-3-nitrobenzene (172 mg, 0.980 mmol), (1-ethyl-1H-pyrazol-3-yl) methylamine (135 mg, 1.078 mmol), and N, N-di A solution of isopropylethylamine (0.205 mL, 1.176 mmol) in DMF (20 mL) was stirred for 16 hours. The reaction was concentrated and the resulting residue was purified via silica chromatography (0% to 30% EtOAc / hexanes) to provide 2-chloro-N-((1-ethyl-1H-pyrazole- 3-yl) methyl) -6-nitroaniline (194 mg). LC-MS (ES) m / z = 281,283 [M + H] ⁺ . _{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.95 (dd, J = 1.7,8.5Hz, 1H), 7.56 (dd, J = 1.5,7.9Hz, 1H), 7.35 (d, J = 2.3Hz, 1H) , 6.82 (t, J = 8.1Hz, 1H), 6.15 (d, J = 2.3Hz, 1H), 4.63 (s, 2H), 4.16 (q, J = 7.2Hz, 2H), 1.49 (t, J = 7.4Hz, 3H).

Intermediate 48

6-chloro-N1-((1-ethyl-1H-pyrazol-3-yl) methyl) benzene-1,2-diamine

2-Chloro-N-((1-ethyl-1H-pyrazol-3-yl) methyl) -6-nitroaniline (190 mg, 0.677 mmol) and NiCl ₂ ‧6H ₂ O (403 mg, 1.692 mmol) in mixture of CH ₃ OH (20mL) was cooled in an ice-water bath. Then sodium borohydride (128 mg, 3.38 mmol) was added, and the reaction mixture was stirred in an ice-water bath for 10 minutes. The reaction was concentrated. Adding NH ₄ OH (28% of water), and the resulting mixture was extracted with CH _{2 2} Cl. The dried CH ₂ Cl ₂ the combined extracts were washed with MgSO _4, filtered, and concentrated to provide a brown oil ratio of 6-chloro -N1 - ((1-ethyl--1H- pyrazol-3-yl) methyl) benzene -1,2-diamine (160 mg). LC-MS (ES) m / z = 251,253 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 7.37 (d, J = 2.0Hz, 1H), 6.74-6.92 (m, 2H), 6.66 (dd, J = 1.5, 7.9Hz, 1H), 6.18 (d, J = 2.3Hz, 1H), 4.09-4.28 (m, 4H), 1.53 (t, J = 7.4Hz, 3H).

Example 21

5- (7-chloro-1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethyl Pyridin-2-amine

Add 6-chloro-N1-((1-ethyl-1H-pyrazol-3-yl) methyl) benzene-1,2-diamine (155 mg, 0.495 mmol), 6- (diethylamino) smoke A mixture of alkali aldehyde (88 mg, 0.495 mmol), and potassium oxone (198 mg, 0.321 mmol) in DMF (10 mL) and water (4 mL) was stirred at room temperature for 30 minutes. Saturated aqueous NaHCO ₃ was then added, and the resulting mixture was extracted with EtOAc. The organic extract was washed sequentially with water and brine, dried over MgSO _4, filtered, and concentrated. By reverse-phase HPLC (25% CH ₃ CN / H ₂ O, 0.1% formic acid to 55% CH ₃ CN / H ₂ O, 0.1% formic acid) followed by silica gel chromatography (0% to 100% EtOAc / hexane) Purification provided 5- (7-chloro-1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazol-2-yl)-as a brown oil N, N-diethylpyridine-2-amine (35 mg). LC-MS (ES) m / z = 409,411 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.50 (d, J = 1.8 Hz, 1 H), 7.82 (dd, J = 2.5, 9.1 Hz, 1 H), 7.74 (dd, J = 3.7, 5.2 Hz, 1 H) , 7.32 (d, J = 2.0Hz, 1H), 7.19-7.24 (m, 2H), 6.54 (d, J = 8.9Hz, 1H), 5.88 (d, J = 2.3Hz, 1H), 5.79 (s, 2H), 4.17 (q, J = 7.4Hz, 2H), 3.59 (q, J = 7.1Hz, 4H), 1.50 (t, J = 7.2Hz, 3H), 1.24 (t, J = 7.1Hz, 6H) .

Intermediate 49

4-bromo-N-((1-ethyl-1H-pyrazol-3-yl) methyl) -2-nitroaniline

4-Bromo-1-fluoro-2-nitrobenzene (400 mg, 1.818 mmol), (1-ethyl-1H-pyrazol-3-yl) methylamine (228 mg, 1.818 mmol), and N, N-di A solution of isopropylethylamine (0.381 mL, 2.182 mmol) in DMF (15 mL) was stirred at room temperature for 16 hours. The reaction was concentrated, and the resulting residue was purified via silica chromatography (0% to 30% EtOAc / hexane) to provide 4-bromo-N-((1-ethyl-1H-pyrazole- 3-yl) methyl) -2-nitroaniline (533 mg). LC-MS (ES) m / z = 325,327 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.49 (br.s., 1H), 8.37 (d, J = 2.3Hz, 1H), 7.52 (dd, J = 2.0, 9.1Hz, 1H), 7.41 (d , J = 2.3Hz, 1H), 6.94 (d, J = 9.1Hz, 1H), 6.23 (d, J = 2.3Hz, 1H), 4.55 (d, J = 5.3Hz, 2H), 4.21 (q, J = 7.2Hz, 2H), 1.54 (t, J = 7.4Hz, 3H).

Example 22

5-bromo-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazole -3-yl) methyl) -1H-benzo [d] imidazole

4-Bromo-N-((1-ethyl-1H-pyrazol-3-yl) methyl) -2-nitroaniline (225 mg, 0.692 mmol), 6-((2S, 5S) -2,5 -Dimethylpyrrolidin-1-yl) nicotinaldehyde (141 mg, 0.692 mmol), and sodium bisulfite (120 mg, 85%, 0.588 mmol) in a mixture of EtOH (4 mL) and water (2 mL) It was heated at 130 ° C for 20 minutes under the conditions. The reaction mixture was filtered, and the filtrate was concentrated to dryness. Followed by addition of CH ₂ Cl _2, and the resulting mixture was filtered again. The filtrate was purified via silica gel chromatography (0% to 40% (3: 1 EtOAc: EtOH) / hexane) to provide 5-bromo-2- (6-((2S, 5S) -2, 5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole ( 195 mg). LC-MS (ES) m / z = 479,481 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.63 (br.s., 1H), 7.97 (s, 2H), 7.32-7.41 (m, 2H), 7.24-7.30 (m, 1H), 6.54 (d, J = 8.6Hz, 1H), 6.00 (br.s., 1H), 5.45 (s, 2H), 4.39 (br.s., 2H), 4.20 (q, J = 7.4Hz, 2H), 2.22-2.42 (m, 2H), 1.74 (d, J = 5.6 Hz, 2H), 1.53 (t, J = 7.4 Hz, 3H), 1.24 (d, J = 6.3 Hz, 6H).

Example 23

(2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazole-3- Yl) methyl) -1H-benzo [d] imidazol-5-yl) boronic acid

Tetrahydroxydiboric acid (45.4mg, 0.507mmol), 1,3-bis (diphenylphosphino) propane-nickel (II) chloride (9.16mg, 0.017mmol), 5-bromo-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl Group) -1H-benzo [d] imidazole (162 mg, 0.338 mmol), triphenylphosphine (8.86 mg, 0.034 mmol), and N, N-diisopropylethylamine (0.177 mL, 1.014 mmol) in EtOH ( 10 mL) was bubbled through argon for 10 minutes, and the reaction mixture was heated at 80 ° C. for 16 hours. The reaction was concentrated, and the resulting residue was purified via silica gel chromatography (0% to 20% CH ₃ OH / CH ₂ Cl ₂ ) to provide (2- (6-((2S, 5S) -2) as an off-white solid. , 5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole -5-yl) boronic acid (11 mg). LC-MS (ES) m / z = 445 [M + H] ⁺ . ¹ H NMR (400MHz, CH ₃ OD): δ 8.53 (d, J = 2.0Hz, 1H), 7.91-8.06 (m, 2H), 7.57-7.68 (m, 2H), 7.46-7.55 (m, 1H) , 6.70 (d, J = 8.9Hz, 1H), 6.11 (d, J = 2.3Hz, 1H), 5.49 (s, 2H), 4.31 (br.s, 2H), 4.16 (q, J = 7.2Hz, 2H), 2.28-2.45 (m, 2H), 1.75 (d, J = 5.8Hz, 2H), 1.43 (t, J = 7.4Hz, 3H), 1.22 (d, J = 6.1Hz, 6H).

Example 24

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl ) Methyl) -5- (1H-pyrazol-3-yl) -1H-benzo [d] imidazole

5-Bromo-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyridine Azole-3-yl) methyl) -1H-benzo [d] imidazole (74 mg, 0.154 mmol), 3- (4,4,5,5-tetramethyl-1,3,2-dioxaboron Heteropentyl-2-yl) -1H-pyrazole (44.9 mg, 0.232 mmol), (triphenylphosphine) palladium (0) (17.84 mg, 0.015 mmol), and Na ₂ CO ₃ (40.9 mg, 0.386 A mixture of mmol) in EtOH (4 mL) and water (1 mL) was bubbled with argon for 15 minutes. The reaction vial was capped and the reaction mixture was heated at 75 ° C for 6 hours. The reaction was filtered and the filtrate was concentrated. Followed by addition of CH ₂ Cl _2, and the resulting mixture was filtered again. The filtrate was purified via silica gel chromatography (0% to 100% (3: 1 EtOAc: EtOH) / hexane) to provide 2- (6-((2S, 5S) -2,5-dimethyl) as a white solid. Pyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -5- (1H-pyrazol-3-yl)- 1H-benzo [d] imidazole (35 mg). LC-MS (ES) m / z = 467 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.68 (d, J = 1.8 Hz, 1 H), 8.19 (s, 1 H), 8.07 (d, J = 6.1 Hz, 1 H), 7.75 (d, J = 7.9 Hz , 1H), 7.68 (d, J = 2.0Hz, 1H), 7.45 (d, J = 8.4Hz, 1H), 7.37 (d, J = 2.3Hz, 1H), 6.70 (d, J = 2.0Hz, 1H ), 6.56 (d, J = 9.1Hz, 1H), 6.04 (d, J = 2.0Hz, 1H), 5.51 (s, 2H), 4.32 (br.s., 2H), 4.17-4.26 (m, 2H ), 2.32 (br.s., 2H), 1.74 (d, J = 5.8 Hz, 2H), 1.54 (t, J = 7.4 Hz, 3H), 1.25 (d, J = 6.1 Hz, 6H).

Example 25

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl ) Methyl) -5- (1H-pyrazol-4-yl) -1H-benzo [d] imidazole

5-Bromo-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyridine Azol-3-yl) methyl) -1H-benzo [d] imidazole (74 mg, 0.154 mmol), 4- (4,4,5,5-tetramethyl-1,3,2-dioxaboron Heteropentyl-2-yl) -1H-pyrazole-1-carboxylic acid tert-butyl ester (68.1 mg, 0.232 mmol), tris (triphenylphosphine) palladium (0) (8.92 mg, 7.72 μmol), and Na ₂ CO _{3 (32.7mg, 0.309mmol)} in EtOH (4.00mL) and water (1mL) in a mixture of argon was bubbled through for 15 minutes. The reaction vial was capped, and the mixture was heated at 95 ° C for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated. CH ₂ Cl _{2 was added} , and the resulting mixture was filtered again. The filtrate was purified via silica gel chromatography (0% to 20% CH ₃ OH / CH ₂ Cl ₂ ) to provide 2- (6-((2S, 5S) -2,5-dimethylpyrrole) as a white solid. -1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -5- (1H-pyrazol-4-yl) -1H-benzene And [d] imidazole (24 mg). LC-MS (ES) m / z = 467 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.64 (d, J = 2.0 Hz, 1H), 7.95-8.05 (m, 2H), 7.88-7.94 (m, 2H), 7.33-7.46 (m, 3H), 6.53 (d, J = 8.9Hz, 1H), 6.01 (d, J = 2.0Hz, 1H), 5.48 (s, 2H), 4.31 (br.s, 2H) 4.21 (q, J = 7.3Hz, 2H) , 2.25-2.40 (m, 2H), 1.73 (d, J = 5.6 Hz, 2H), 1.54 (t, J = 7.4 Hz, 3H), 1.24 (d, J = 6.3 Hz, 6H).

Intermediate 50

3,4-dichloro-N-((1-ethyl-1H-pyrazol-3-yl) methyl) -2-nitroaniline

1,2-dichloro-4-fluoro-3-nitrobenzene (200 mg, 0.952 mmol), (1-ethyl-1H-pyrazol-3-yl) methylamine (131 mg, 1.048 mmol), and N, A solution of N-diisopropylethylamine (0.200 mL, 1.143 mmol) in DMF (20 mL) was stirred for 16 hours. The reaction was concentrated and the resulting residue was purified via silica chromatography (0% to 50% EtOAc / hexanes) to provide 3,4-dichloro-N-((1-ethyl-1H- Pyrazol-3-yl) methyl) -2-nitroaniline (185 mg). LC-MS (ES) m / z = 315 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.35-7.53 (m, 2H), 6.85 (d, J = 9.4 Hz, 1H), 6.20 (d, J = 2.3 Hz, 1H), 5.98 (br.s. , 1H), 4.43 (d, J = 5.1 Hz, 2H), 4.19 (q, J = 7.4 Hz, 2H), 1.53 (t, J = 7.4 Hz, 3H).

Intermediate 51

3,4-dichloro-N1-((1-ethyl-1H-pyrazol-3-yl) methyl) benzene-1,2-diamine

3,4-Dichloro-N-((1-ethyl-1H-pyrazol-3-yl) methyl) -2-nitroaniline (185 mg, 0.587 mmol) and NiCl ₂ ‧ 6H ₂ O (349 mg, 1.468mmol) was cooled in a mixture of ₃ OH (20mL) CH in an ice-water bath. Sodium borohydride (111 mg, 2.94 mmol) was added, and the reaction mixture was stirred in an ice-water bath for 10 minutes. The reaction was concentrated. Adding NH ₄ OH (28% of water), and the resulting mixture was extracted with CH _{2 2} Cl. The dried CH ₂ Cl ₂ the combined extracts were washed with MgSO _4, filtered, and concentrated to provide 3,4-dichloro -N1 - ((1- ethyl--1H- pyrazol-3-yl) methyl) benzene - 1,2-diamine (196 mg). LC-MS (ES) m / z = 285 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 7.39 (d, J = 2.0Hz, 1H), 6.90 (d, J = 8.6Hz, 1H), 6.64 (d, J = 8.6Hz, 1H), 6.23 (d , J = 2.3Hz, 1H), 4.33 (s, 2H), 4.20 (q, J = 7.2Hz, 2H), 3.99 (br.s., 1H), 1.53 (t, J = 7.4Hz, 3H).

Example 26

5- (4,5-dichloro-1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazol-2-yl) -N, N- Diethylpyridine-2-amine

3,4-Dichloro-N1-((1-ethyl-1H-pyrazol-3-yl) methyl) benzene-1,2-diamine (95 mg, 0.267 mmol), 6- (diethylamine Base) A mixture of nicotinaldehyde (47.5 mg, 0.267 mmol) and oxone (106 mg, 0.173 mmol) in DMF (10 mL) and water (4 mL) was stirred for 30 minutes. Saturated aqueous NaHCO ₃ was then added, and the resulting mixture was extracted with EtOAc. The washed sequentially with water and brine, the combined organic extracts were dried over MgSO _4, filtered, and concentrated. Purification by reverse-phase HPLC (28% CH ₃ CN / H ₂ O, 0.1% formic acid to 58% CH ₃ CN / H ₂ O, 0.1% formic acid) provided 5- (4,5-dichloro) as a white solid -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine ( 65mg). LC-MS (ES) m / z = 443 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.93 (s, 1H), 8.45 (d, J = 7.9Hz, 1H), 7.35-7.50 (m, 3H), 6.92 (d, J = 9.4Hz, 1H) , 6.22 (d, J = 1.8Hz, 1H), 5.44 (s, 2H), 4.18 (q, J = 7.4Hz, 2H), 3.76 (d, J = 6.8Hz, 4H), 1.48 (t, J = 7.4Hz, 3H), 1.38 (t, J = 7.1Hz, 6H).

Intermediate 52

N-((1-ethyl-1H-pyrazol-3-yl) methyl) -4-fluoro-2-nitroaniline

Add 1,4-difluoro-2-nitrobenzene (310 mg, 1.949 mmol), (1-ethyl-1H-pyrazol-3-yl) methylamine (268 mg, 2.143 mmol), and N, N-diiso A solution of propylethylamine (0.408 mL, 2.338 mmol) in DMF (15 mL) was stirred at room temperature for 16 hours. The reaction was concentrated and the resulting residue was purified via silica chromatography (0% to 35% EtOAc / hexanes) to provide N-((1-ethyl-1H-pyrazol-3-yl) as an orange solid Methyl) -4-fluoro-2-nitroaniline (390 mg). LC-MS (ES) m / z = 265 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.39 (br.s., 1H), 7.94 (dd, J = 2.9, 9.25 Hz, 1H), 7.41 (d, J = 2.3 Hz, 1H), 7.24-7.30 (m, 1H), 7.01 (dd, J = 4.6, 9.4Hz, 1H), 6.24 (d, J = 2.3Hz, 1H), 4.57 (d, J = 5.3Hz, 2H), 4.22 (q, J = 7.2Hz, 2H), 1.54 (t, J = 7.4Hz, 3H).

Example 27

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl ) Methyl) -5-fluoro-1H-benzo [d] imidazole

N-((1-ethyl-1H-pyrazol-3-yl) methyl) -4-fluoro-2-nitroaniline (125 mg, 0.473 mmol), sodium bisulfite (247 mg, 85%, 1.206 mmol ), And a mixture of 6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (101 mg, 0.497 mmol) in EtOH (4 mL) and water (2 mL) in the microwave It was heated at 130 ° C for 20 minutes under the conditions. The reaction was filtered and the filtrate was concentrated to dryness. CH ₂ Cl _{2 was added} , and the resulting mixture was filtered again. The filtrate was purified via silica gel chromatography (0% to 40% (3: 1 EtOAc: EtOH) / hexane) to provide 2- (6-((2S, 5S) -2,5-dimethyl) as a thick oil Pyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -5-fluoro-1H-benzo [d] imidazole ( 114mg). LC-MS (ES) m / z = 419 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.60 (d, J = 2.0 Hz, 1 H), 7.93 (dd, J = 2.5, 8.9 Hz, 1 H), 7.47 (dd, J = 2.3, 9.4 Hz, 1 H) , 7.34 (d, J = 2.3Hz, 1H), 7.24-7.32 (m, 1H), 6.98 (dt, J = 2.3, 9.1Hz, 1H), 6.51 (d, J = 8.9Hz, 1H), 5.98 ( d, J = 2.0Hz, 1H), 5.44 (s, 2H), 4.29 (br.s., 2H), 4.19 (q, J = 7.3Hz, 2H), 2.30 (br.s., 2H), 1.64 -1.81 (m, 2H), 1.52 (t, J = 7.2Hz, 3H), 1.23 (d, J = 6.1Hz, 6H).

Intermediate 53

N-((1-ethyl-1H-pyrazol-3-yl) methyl) -4-methoxy-2-nitroaniline

1-fluoro-4-methoxy-2-nitrobenzene (151 mg, 0.882 mmol), (1-ethyl-1H-pyrazol-3-yl) methylamine (121 mg, 0.971 mmol), and N, N -A solution of diisopropylethylamine (185 μl, 1.059 mmol) in DMF is stirred at room temperature for 16 hours. The reaction was concentrated and the resulting residue was purified via silica chromatography (0% to 50% EtOAc / hexanes) to provide N-((1-ethyl-1H-pyrazol-3-yl) as a red oil Methyl) -4-methoxy-2-nitroaniline (76 mg). LC-MS (ES) m / z = 277 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.40 (br.s., 1H), 7.66 (d, J = 3.0 Hz, 1 H), 7.39 (d, J = 2.3 Hz, 1 H), 7.17 (dd, J = 3.0, 9.4Hz, 1H), 6.98 (d, J = 9.4Hz, 1H), 6.23 (d, J = 2.3Hz, 1H), 4.56 (d, J = 5.1Hz, 2H), 4.20 (d, J = 7.1Hz, 2H), 3.83 (s, 3H), 1.53 (t, J = 7.4Hz, 3H).

Intermediate 54

N1-((1-ethyl-1H-pyrazol-3-yl) methyl) -4-methoxybenzene-1,2-diamine

N-((1-ethyl-1H-pyrazol-3-yl) methyl) -4-methoxy-2-nitroaniline (76 mg, 0.275 mmol) and NiCl ₂ ‧ 6H ₂ O (164 mg, 0.688 mmol) in a mixture of CH ₃ OH (20mL) cooled in an ice-water bath. Sodium borohydride (52.0 mg, 1.375 mmol) was added, and the reaction mixture was stirred in an ice-water bath for 10 minutes. The reaction was concentrated, added NH ₄ OH (28% of water), and the resulting mixture was extracted with CH _{2 2} Cl. The combined organic extracts were dried with MgSO _4, filtered and concentrated to provide N1 - ((1- ethyl--1H- pyrazol-3-yl) methyl) -4-methoxybenzene-1,2-dicarboxylic Amine (73 mg). LC-MS (ES) m / z = 247 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 7.37 (d, J = 2.3Hz, 1H), 6.75 (d, J = 8.4Hz, 1H), 6.32-6.42 (m, 2H), 6.24 (d, J = 2.3Hz, 1H), 4.28 (s, 2H), 4.14-4.23 (m, 2H), 3.74-3.79 (m, 3H), 1.52 (t, J = 7.4Hz, 3H).

Example 28

N, N-diethyl-5- (1-((1-ethyl-1H-pyrazol-3-yl) methyl) -5-methoxy-1H-benzo [d] imidazole-2- ) Pyridin-2-amine

N1-((1-ethyl-1H-pyrazol-3-yl) methyl) -4-methoxybenzene-1,2-diamine (73 mg, 0.237 mmol), 6- (diethylamino) ) A mixture of nicotinaldehyde (42.3 mg, 0.237 mmol) and potassium oxone (95 mg, 0.154 mmol) in DMF (10 mL) and water (4 mL) was stirred at room temperature for 30 minutes. Saturated aqueous NaHCO ₃ was filtered, and the resulting mixture was extracted with EtOAc. The organic extract was washed sequentially with water and brine, dried over MgSO _4, filtered, and concentrated. The resulting residue was purified via silica chromatography (0% to 80% EtOAc / hexanes) to provide N, N-diethyl-5- (1-((1-ethyl-1H-pyrazole) as an oil -3-yl) methyl) -5-methoxy-1H-benzo [d] imidazol-2-yl) pyridin-2-amine (23 mg). LC-MS (ES) m / z = 405 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.59 (d, J = 2.0 Hz, 1H), 7.97 (dd, J = 2.4, 9.00 Hz, 1H), 7.34 (d, J = 2.0 Hz, 2H), 7.26 (d, J = 8.9Hz, 1H), 6.90 (dd, J = 2.4, 8.7Hz, 1H), 6.61 (d, J = 8.9Hz, 1H), 5.99 (d, J = 2.3Hz, 1H), 5.43 (s, 2H), 4.20 (q, J = 7.2Hz, 2H), 3.90 (s, 3H), 3.61 (q, J = 7.1Hz, 4H), 1.54 (t, J = 7.4Hz, 3H), 1.26 (t, J = 7.1 Hz, 6H).

Intermediate 55

N-((1-ethyl-1H-pyrazol-3-yl) methyl) -5-methyl-2-nitroaniline

Add 2-fluoro-4-methyl-1-nitrobenzene (184 mg, 1.186 mmol), (1-ethyl-1H-pyrazol-3-yl) methylamine (163 mg, 1.305 mmol), and N, N- A solution of diisopropylethylamine (0.249 mL, 1.423 mmol) in DMF (15 mL) was stirred at room temperature for 16 hours. The reaction was concentrated and the resulting residue was purified via silica chromatography (0% to 30% EtOAc / hexanes) to provide N-((1-ethyl-1H-pyrazol-3-yl) as a yellow solid Methyl) -5-methyl-2-nitroaniline (152 mg). LC-MS (ES) m / z = 261 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.52 (br.s., 1H), 8.12 (d, J = 8.6Hz, 1H), 7.41 (d, J = 2.3Hz, 1H), 6.79 (s, 1H ), 6.52 (dd, J = 1.5, 8.6 Hz, 1H), 6.25 (d, J = 2.3 Hz, 1H), 4.56 (d, J = 5.3 Hz, 2H), 4.22 (q, J = 7.4 Hz, 2H ), 2.37 (s, 3H), 1.55 (t, J = 7.4Hz, 3H).

Intermediate 56

N1-((1-ethyl-1H-pyrazol-3-yl) methyl (methy))-5-methylbenzene-1,2-diamine

N-((1-ethyl-1H-pyrazol-3-yl) methyl) -5-methyl-2-nitroaniline (150 mg, 0.576 mmol) and NiCl ₂ ‧6H ₂ O (343 mg, 1.441 mmol ) in a mixture of CH ₃ OH (20mL) cooled in an ice-water bath. Sodium borohydride (109 mg, 2.88 mmol) was added, and the reaction mixture was stirred in an ice-water bath for 10 minutes. The reaction was concentrated, added NH ₄ OH (28% of water), and the resulting mixture was extracted with CH _{2 2} Cl. The combined organic extracts were dried with MgSO _4, filtered, and concentrated to provide N1 - ((1- ethyl--1H- pyrazol-3-yl) methyl) -5-methyl-1,2-benzene Amine (136 mg). LC-MS (ES) m / z = 231 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 7.36 (br.s., 1H), 6.56-6.72 (m, 2H), 6.52 (d, J = 6.8Hz, 1H), 6.24 (br.s., 1H ), 4.34 (br.s., 2H), 4.18 (q, J = 7.1 Hz, 2H), 2.29 (br.s., 3H), 1.51 (t, J = 7.1 Hz, 3H).

Example 29

N, N-diethyl-5- (1-((1-ethyl-1H-pyrazol-3-yl) methyl) -6-methyl-1H-benzo [d] imidazol-2-yl Pyridine-2-amine

N1-((1-ethyl-1H-pyrazol-3-yl) methyl) -5-methylbenzene-1,2-diamine (136 mg, 0.591 mmol), 6- (diethylamino) A mixture of nicotinaldehyde (105 mg, 0.591 mmol), and potassium oxone (236 mg, 0.384 mmol) in DMF (5 mL) and water (5 mL) was stirred at room temperature for 30 minutes. Saturated aqueous NaHCO ₃ was then added, and the resulting mixture was extracted with EtOAc. The washed sequentially with water and brine, the combined organic extracts were dried over MgSO _4, filtered, and concentrated. The resulting residue was purified via silica chromatography (0% to 100% EtOAc / hexanes) to provide N, N-diethyl-5- (1-((1-ethyl-1H-pyrazole) as a solid -3-yl) methyl) -6-methyl-1H-benzo [d] imidazol-2-yl) pyridin-2-amine (119 mg). LC-MS (ES) m / z = 389 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.58 (d, J = 2.5Hz, 1H), 7.96 (dd, J = 2.4, 9.0Hz, 1H), 7.70 (d, J = 8.4Hz, 1H), 7.34 (d, J = 2.3Hz, 1H), 7.17 (s, 1H), 7.12 (dd, J = 1.1, 8.2Hz, 1H), 6.59 (d, J = 8.9Hz, 1H), 5.97 (d, J = 2.3Hz, 1H), 5.43 (s, 2H), 4.21 (q, J = 7.2Hz, 2H), 3.60 (q, J = 7.1Hz, 4H), 2.49 (s, 3H), 1.55 (t, J = 7.2Hz, 3H), 1.25 (t, J = 7.0Hz, 6H).

Intermediate 57

2-(((1-ethyl-1H-pyrazol-3-yl) methyl) amino) -3-nitrobenzonitrile

Add 2-fluoro-3-nitrobenzonitrile (150 mg, 0.903 mmol), (1-ethyl-1H-pyrazol-3-yl) methylamine (124 mg, 0.993 mmol), and N, N-diisopropyl A solution of methylethylamine (0.189 mL, 1.084 mmol) in DMF (15 mL) was stirred at room temperature for 16 hours. The reaction was concentrated and the resulting residue was purified via silica chromatography (0% to 50% EtOAc / hexanes) to provide 2-(((1-ethyl-1H-pyrazol-3-yl) as a yellow solid ) Methyl) amino) -3-nitrobenzonitrile (210 mg). LC-MS (ES) m / z = 272 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 9.03 (br.s., 1H), 8.45 (dd, J = 1.8, 8.4 Hz, 1H), 7.81 (dd, J = 1.7, 7.5 Hz, 1H), 7.44 (d, J = 2.3Hz, 1H), 6.79 (dd, J = 7.6, 8.6Hz, 1H), 6.30 (d, J = 2.3Hz, 1H), 5.11 (d, J = 4.6Hz, 2H), 4.23 (q, J = 7.4Hz, 2H), 1.55 (t, J = 7.4Hz, 3H).

Intermediate 58

3-amine 2-(((1-ethyl-1H-pyrazol-3-yl) methyl) amino) benzonitrile

Tin (II) chloride (294 mg, 1.548 mmol) was added to 2-(((1-ethyl-1H-pyrazol-3-yl) methyl) amino) -3-nitrobenzonitrile (210 mg, 0.774 mmol) in EtOH (25 mL) and the reaction mixture was refluxed for 2 hours. The reaction was poured into ice and treated until pH ~ 9 with saturated aqueous NaHCO _3. EtOAc was then added and the resulting mixture was filtered through celite. The organic layer was separated, and the aqueous phase was further extracted with EtOAc (3x). Dried combined organic extracts were washed with brine, MgSO _4, filtered, and concentrated. The resulting residue was purified via silica chromatography (0% to 100% EtOAc / hexanes) to provide 3-amine 2-(((1-ethyl-1H-pyrazol-3-yl) methyl) as an oil ) Amino) benzonitrile (69 mg). LC-MS (ES) m / z = 242 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 7.38 (d, J = 2.3Hz, 1H), 7.06 (dt, J = 1.5, 8.0Hz, 2H), 6.86-6.98 (m, 1H), 6.17 (d, J = 2.3Hz, 1H), 4.51 (s, 2H), 4.40 (s, 3H), 4.20 (q, J = 7.2Hz, 2H), 1.50 (t, J = 7.2Hz, 3H).

Example 30

2- (6- (diethylamino) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-7 -Nitrile

3-Amine 2-(((1-ethyl-1H-pyrazol-3-yl) methyl) amino) benzonitrile (69 mg, 0.229 mmol), 6- (diethylamino) nicotinaldehyde (44.9 mg, 0.252 mmol), and a mixture of oxone (91 mg, 0.149 mmol) in DMF (10 mL) and water (4 mL) was stirred at room temperature for 30 minutes. Saturated aqueous NaHCO ₃ was added, and the resulting mixture was extracted with EtOAc. The washed sequentially with water and brine, the combined organic extracts were dried over MgSO _4, filtered, and concentrated. The resulting residue was purified via silica chromatography (0% to 100% EtOAc / hexanes) to provide 2- (6- (diethylamino) pyridin-3-yl) -1-((1 -Ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-7-carbonitrile (67 mg). LC-MS (ES) m / z = 400 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.61 (br.s., 1H), 8.06 (d, J = 8.1 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.60 (dd, J = 0.8, 7.6Hz, 1H), 7.34-7.45 (m, 2H), 6.58 (d, J = 8.9Hz, 1H), 6.08 (br.s., 1H), 5.77 (s, 2H), 4.15 (q , J = 7.3Hz, 2H), 3.62 (q, J = 6.7Hz, 4H), 1.48 (t, J = 7.4Hz, 3H), 1.26 (d, J = 13.9Hz, 6H).

Intermediate 59

4-(((1-ethyl-1H-pyrazol-3-yl) methyl) amino) -3-nitrobenzonitrile

Add 4-fluoro-3-nitrobenzonitrile (150 mg, 0.903 mmol), (1-ethyl-1H-pyrazol-3-yl) methylamine (124 mg, 0.993 mmol), and N, N-diisopropyl A solution of methylethylamine (0.189 mL, 1.084 mmol) in DMF (15 mL) was stirred at room temperature for 16 hours. The reaction was concentrated and the resulting residue was purified via silica chromatography (0% to 50% EtOAc / hexane) to provide 4-(((1-ethyl-1H-pyrazol-3-yl) as a yellow solid ) Methyl) amino) -3-nitrobenzonitrile (197 mg). LC-MS (ES) m / z = 272 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.89 (br.s., 1H), 8.57 (d, J = 2.0 Hz, 1H), 7.64 (dd, J = 2.0, 8.9 Hz, 1H), 7.43 (d , J = 2.3Hz, 1H), 7.10 (d, J = 8.9Hz, 1H), 6.25 (d, J = 2.0Hz, 1H), 4.61 (d, J = 5.1Hz, 2H), 4.22 (q, J = 7.4Hz, 2H), 1.54 (t, J = 7.4Hz, 3H).

Intermediate 60

3-amino-4-(((1-ethyl-1H-pyrazol-3-yl) methyl) amino) benzonitrile

Tin (II) chloride (268 mg, 1.416 mmol) was added to 4-(((1-ethyl-1H-pyrazol-3-yl) methyl) amino) -3-nitrobenzonitrile (192 mg, 0.708 mmol) in EtOH (30 mL) and the reaction mixture was refluxed for 2 hours. Additional tin (II) chloride (268 mg, 1.416 mmol) was added and the reaction mixture was refluxed for 1 hour. The reaction mixture was then stirred at room temperature for 16 hours. The reaction was poured into ice and treated until pH ~ 9 with saturated aqueous NaHCO _3. EtOAc was then added and the resulting mixture was filtered through celite. The organic layer was separated, and the aqueous phase was further extracted with EtOAc (3x). Dried combined organic extracts were washed with brine, MgSO _4, filtered, and concentrated. The residue obtained via silica chromatography (0% to 100% EtOAc / hexane) was purified to provide 3-amino-4-(((1-ethyl-1H-pyrazol-3-yl) as a white solid ) Methyl) amino) benzonitrile (113 mg). LC-MS (ES) m / z = 242 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 7.41 (d, J = 2.0Hz, 1H), 7.20 (dd, J = 1.9, 8.2Hz, 1H), 6.98 (d, J = 1.8Hz, 1H), 6.72 (d, J = 8.4Hz, 1H), 6.24 (d, J = 2.3Hz, 1H), 4.41 (s, 2H), 4.20 (q, J = 7.4Hz, 2H), 1.53 (t, J = 7.4Hz , 3H).

Example 31

2- (6- (diethylamino) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5 -Nitrile

3-Amino-4-(((1-ethyl-1H-pyrazol-3-yl) methyl) amino) benzonitrile (113 mg, 0.375 mmol), 6- (diethylamino) smoke A mixture of alkali aldehyde (66.8 mg, 0.375 mmol) and potassium oxone (150 mg, 0.244 mmol) in DMF (10 mL) and water (4 mL) was stirred at room temperature for 30 minutes. Saturated aqueous NaHCO ₃ was then added, and the resulting mixture was extracted with EtOAc. The washed sequentially with water and brine, the combined organic extracts were dried over MgSO _4, filtered, and concentrated. The resulting residue was purified via silica chromatography (0% to 100% EtOAc / hexanes) to provide 2- (6- (diethylamino) pyridin-3-yl) -1-((1- Ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carbonitrile (124 mg). LC-MS (ES) m / z = 400 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.64 (br.s., 1H), 8.13 (s, 1H), 7.99 (d, J = 7.6 Hz, 1H), 7.45-7.54 (m, 2H), 7.37 (d, J = 2.3Hz, 1H), 6.63 (d, J = 8.9Hz, 1H), 6.02 (s, 1H), 5.48 (s, 2H), 4.20 (q, J = 7.3Hz, 2H), 3.63 (q, J = 7.1 Hz, 4H), 1.53 (t, J = 7.4 Hz, 3H), 1.27 (t, J = 7.1 Hz, 6H).

Intermediate 61

3-(((1-ethyl-1H-pyrazol-3-yl) methyl) amino) -2-nitrobenzonitrile

Add 3-fluoro-2-nitrobenzonitrile (150 mg, 0.903 mmol), (1-ethyl-1H-pyrazol-3-yl) methylamine (124 mg, 0.993 mmol), and N, N-diisopropyl A solution of methylethylamine (0.189 mL, 1.084 mmol) in DMF (15 mL) was stirred at room temperature for 16 hours. The reaction was concentrated, and the resulting residue was purified via silica chromatography (0% to 50% EtOAc / hexanes) to provide 3-(((1-ethyl-1H-pyrazol-3-yl) as an orange solid ) Methyl) amino) -2-nitrobenzonitrile (177 mg). LC-MS (ES) m / z = 272 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.55 (br.s., 1H), 7.51 (dd, J = 7.5, 8.7 Hz, 1H), 7.43 (d, J = 2.0 Hz, 1H), 7.33 (d , J = 1.0Hz, 1H), 7.17 (dd, J = 1.3, 7.1Hz, 1H), 6.25 (d, J = 2.3Hz, 1H), 4.60 (d, J = 5.3Hz, 2H), 4.23 (q , J = 7.4Hz, 2H), 1.55 (t, J = 7.4Hz, 3H).

Intermediate 62

2-amino (Smino) -3-(((1-ethyl-1H-pyrazol-3-yl) methyl) amino) benzonitrile

Tin (II) chloride (371 mg, 1.957 mmol) was added to 3-(((1-ethyl-1H-pyrazol-3-yl) methyl) amino) -2-nitrobenzonitrile (177 mg, 0.652 mmol) in EtOH (25 mL), and the reaction mixture was refluxed for 4 hours, followed by stirring at room temperature for 16 hours. Additional tin (II) chloride (371 mg, 1.957 mmol) was added and the reaction mixture was refluxed for 4 hours. The reaction was poured into ice and treated until pH ~ 9 with saturated aqueous NaHCO _3. EtOAc was then added and the resulting mixture was filtered through celite. The organic layer was separated and the aqueous phase was extracted with additional EtOAc (3x). Dried combined organic extracts were washed with brine, MgSO _4, filtered, and concentrated. The resulting residue was purified via silica chromatography (0% to 100% EtOAc / hexane) to provide 2-amino-3-(((1-ethyl-1H-pyrazol-3-yl ) Methyl) amino) benzonitrile (98 mg). LC-MS (ES) m / z = 242 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 7.40 (d, J = 2.3Hz, 1H), 7.00 (dd, J = 1.3, 7.9Hz, 1H), 6.95 (dd, J = 1.3, 7.9Hz, 1H) , 6.76-6.85 (m, 1H), 6.26 (d, J = 2.3Hz, 1H), 4.36 (s, 2H), 4.20 (q, J = 7.4Hz, 2H), 1.53 (t, J = 7.4Hz, 3H).

Example 32

2- (6- (diethylamino) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-4 -Nitrile

Add 2-amino-3-(((1-ethyl-1H-pyrazol-3-yl) methyl) amino) benzonitrile (98mg, 0.325mmol), 6- (diethylamino) smoke A mixture of alkali aldehyde (63.7 mg, 0.357 mmol) and potassium oxone (130 mg, 0.211 mmol) in DMF (10 mL) and water (4 mL) was stirred at room temperature for 30 minutes. Saturated aqueous NaHCO ₃ was then added, and the resulting mixture was extracted with EtOAc. The washed sequentially with water and brine, the combined organic extracts were dried over MgSO _4, filtered, and concentrated. Silica chromatography (0% to 100% EtOAc / hexane) followed by reverse-phase HPLC (15% CH ₃ CN / H ₂ O, 0.1% formic acid to 45% CH ₃ CN / H ₂ O, 0.1% formic acid) The resulting residue was purified to provide 2- (6- (diethylamino) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl)-as a white solid 1H-benzo [d] imidazole-4-carbonitrile (60 mg). LC-MS (ES) m / z = 400 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 8.63 (d, J = 2.3Hz, 1H), 8.34 (dd, J = 2.2, 9.5Hz, 1H), 7.92 (dd, J = 0.9, 8.2Hz, 1H ), 7.75 (dd, J = 0.9, 7.5 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 7.43-7.51 (m, 1H), 7.26 (d, J = 9.4 Hz, 1H), 6.28 (d, J = 2.3Hz, 1H), 5.58 (s, 2H), 4.15 (q, J = 7.2Hz, 2H), 3.73 (q, J = 7.1Hz, 4H), 1.41 (t, J = 7.2Hz , 3H), 1.34 (t, J = 7.1Hz, 6H).

Example 33

2- (6- (diethylamino) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-4 -Formamidine

2- (6- (Diethylamino) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole- A solution of 4-carbonitrile (40 mg, 0.100 mmol) and 1 N NaOH (0.501 mL, 0.501 mmol) in water (5 mL) and EtOH (5 mL) was heated at 132 ° C. for 100 minutes under microwave conditions. The reaction was concentrated and the resulting material was purified by reverse-phase HPLC (10% CH ₃ CN / H ₂ O, 0.1% formic acid to 50% CH ₃ CN / H ₂ O, 0.1% formic acid) to provide 2 as an off-white solid. -(6- (diethylamino) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-4- Formamidine (26-mg). LC-MS (ES) m / z = 418 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 9.79 (br.s., 1H), 8.93 (d, J = 1.5 Hz, 1 H), 8.34 (dd, J = 1.8, 9.4 Hz, 1 H), 8.18 (d , J = 7.4Hz, 1H), 7.67 (d, J = 8.1Hz, 1H), 7.36-7.50 (m, 2H), 6.89 (d, J = 9.4Hz, 1H), 6.68 (br.s., 1H ), 6.17 (d, J = 2.3Hz, 1H), 5.48 (s, 2H), 4.17 (q, J = 7.4Hz, 2H), 3.73 (q, J = 7.1Hz, 4H), 1.48 (t, J = 7.4Hz, 3H), 1.36 (t, J = 7.1Hz, 6H).

Intermediate 63

N-((1-ethyl-1H-pyrazol-3-yl) methyl) -4-methyl-2-nitroaniline

1-fluoro-4-methyl-2-nitrobenzene (158 mg, 1.019 mmol), (1-ethyl-1H-pyrazol-3-yl) methylamine (140 mg, 1.120 mmol), and N, N- A solution of diisopropylethylamine (213 μl, 1.222 mmol) in DMF was stirred at room temperature for 16 hours. The reaction was concentrated and the resulting residue was purified via silica chromatography (0% to 30% EtOAc / hexane) to provide N-((1-ethyl-1H-pyrazole-3- as a yellow / orange oil Yl) methyl) -4-methyl-2-nitroaniline (77 mg). LC-MS (ES) m / z = 261 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.34 (br.s., 1H), 8.00 (d, J = 1.0Hz, 1H), 7.37 (d, J = 2.3Hz, 1H), 7.22-7.31 (m , 1H), 6.90 (d, J = 8.6Hz, 1H), 6.21 (d, J = 2.3Hz, 1H), 4.53 (d, J = 5.1Hz, 2H), 4.18 (q, J = 7.2Hz, 2H ), 2.28 (s, 3H), 1.51 (t, J = 7.2Hz, 3H).

Intermediate 64

N1-((1-ethyl-1H-pyrazol-3-yl) methyl) -4-methylbenzene-1,2-diamine

N-((1-ethyl-1H-pyrazol-3-yl) methyl) -4-methyl-2-nitroaniline (77 mg, 0.296 mmol) and NiCl ₂ ‧ 6H ₂ O (176 mg, 0.740 mmol ) in a mixture of CH ₃ OH (20mL) cooled in an ice-water bath. Sodium borohydride (56.0 mg, 1.479 mmol) was added, and the reaction mixture was stirred in an ice-water bath for 10 minutes. The reaction was concentrated, added NH ₄ OH (28%), and the resulting mixture was extracted with CH _{2 2} Cl. The combined dried organic extracts with MgSO _4, filtered, and concentrated. The resulting residue was purified via silica chromatography (0% to 100% EtOAc / hexane) to provide N1-((1-ethyl-1H-pyrazol-3-yl) methyl) -4-methylbenzene -1,2-diamine (53 mg). LC-MS (ES) m / z = 231 [M + H] ⁺ . Use this material immediately for the next step.

Example 34

N, N-diethyl-5- (1-((1-ethyl-1H-pyrazol-3-yl) methyl) -5-methyl-1H-benzo [d] imidazol-2-yl Pyridine-2-amine

N1-((1-ethyl-1H-pyrazol-3-yl) methyl) -4-methylbenzene-1,2-diamine (54 mg, 0.234 mmol), 6- (diethylamino) A mixture of nicotinaldehyde (41.8 mg, 0.234 mmol) and oxone (94 mg, 0.152 mmol) in water (10 mL) and DMF (10 mL) was stirred at room temperature for 30 minutes. Saturated aqueous NaHCO ₃ was added, and the resulting mixture was extracted with EtOAc. The combined extracts were washed with water and the EtOA brine sequentially, dried with MgSO _4, filtered, and concentrated. Silica chromatography (0% to 100% EtOAc / hexane) followed by reverse-phase HPLC (10% CH ₃ CN / H ₂ O, 0.1% formic acid to 40% CH ₃ CN / H ₂ O, 0.1% formic acid) The resulting residue was purified to provide N, N-diethyl-5- (1-((1-ethyl-1H-pyrazol-3-yl) methyl) -5-methyl-1H- as a white solid Benzo [d] imidazol-2-yl) pyridin-2-amine (18 mg). LC-MS (ES) m / z = 389 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.60 (s, 1H), 8.01 (br.s., 1H), 7.66 (br.s., 1H), 7.10 (d, J = 8.1 Hz, 1H), 6.62 (d, J = 8.9Hz, 1H), 5.99 (s, 1H), 5.38-5.54 (m, 2H), 4.20 (q, J = 7.2Hz, 2H), 3.61 (q, J = 7.0Hz, 4H ), 2.52 (s, 3H), 1.54 (t, J = 7.4 Hz, 3H), 1.15-1.36 (m, 6H).

Intermediate 65

4-chloro-N-((1-ethyl-1H-pyrazol-3-yl) methyl) -2-nitroaniline

Add 4-chloro-1-fluoro-2-nitrobenzene (225 mg, 1.282 mmol), (1-ethyl-1H-pyrazol-3-yl) methylamine (176 mg, 1.410 mmol), and N, N-di A solution of isopropylethylamine (269 μl, 1.538 mmol) in DMF was stirred at room temperature for 16 hours. The reaction was concentrated and the resulting residue was purified via silica chromatography (0% to 27% EtOAc / hexanes) to provide 4-chloro-N-((1-ethyl-1H-pyridine) as a yellow / orange oil Azol-3-yl) methyl) -2-nitroaniline (289 mg). LC-MS (ES) m / z = 281,283 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.47 (br.s., 1H), 8.21 (d, J = 2.5 Hz, 1H), 7.40 (dt, J = 2.7, 4.37 Hz, 2H), 6.98 (d , J = 9.4Hz, 1H), 6.23 (d, J = 2.0Hz, 1H), 4.55 (d, J = 5.3Hz, 2H), 4.20 (q, J = 7.4Hz, 2H), 1.53 (t, J = 7.4Hz, 3H).

Intermediate 66

4-chloro-N1-((1-ethyl-1H-pyrazol-3-yl) methyl) benzene-1,2-diamine

4-Chloro-N-((1-ethyl-1H-pyrazol-3-yl) methyl) -2-nitroaniline (100 mg, 0.356 mmol) and NiCl ₂ ‧ 6H ₂ O (212 mg, 0.891 mmol) mixture in CH ₃ OH (20mL) cooled in an ice-water bath. Sodium borohydride (67.4 mg, 1.781 mmol) was added, and the reaction mixture was stirred in an ice-water bath for 10 minutes. The reaction was concentrated, added NH ₄ OH (28%), and the resulting mixture was extracted with CH _{2 2} Cl. The dried extracts were combined with the EtOA MgSO _4, filtered, and concentrated to provide 4-chloro -N1 - ((1- ethyl--1H- pyrazol-3-yl) methyl) benzene-1,2-diamine (79mg). LC-MS (ES) m / z = 251,253 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 7.38 (d, J = 2.0Hz, 1H), 6.63-6.87 (m, 3H), 6.25 (d, J = 2.3Hz, 1H), 4.34 (s, 2H) , 4.19 (q, J = 7.4 Hz, 2H), 1.52 (t, J = 7.4 Hz, 3H).

Example 35

5- (5-chloro-1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethyl Pyridin-2-amine

4-Chloro-N1-((1-ethyl-1H-pyrazol-3-yl) methyl) benzene-1,2-diamine (79 mg, 0.252 mmol), 6- (diethylamino) smoke A mixture of alkali aldehyde (44.9 mg, 0.252 mmol), and oxone (101 mg, 0.164 mmol) in DMF (10 mL) and water (4 mL) was stirred at room temperature for 30 minutes. Saturated aqueous NaHCO ₃ was added, and the resulting mixture was extracted with EtOAc. The washed sequentially with water and brine, the combined organic extracts were dried over MgSO _4, filtered, and concentrated. The resulting residue was purified via silica chromatography (0% to 80% EtOAc / hexanes) to provide 5- (5-chloro-1-((1-ethyl-1H-pyrazol-3-yl) as a glass ) Methyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine (47 mg). LC-MS (ES) m / z = 409/411 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.60 (d, J = 2.3Hz, 1H), 7.97 (dd, J = 2.3, 9.1Hz, 1H), 7.80 (d, J = 1.5Hz, 1H), 7.35 (d, J = 2.3Hz, 1H), 7.29-7.33 (m, 1H), 7.21 (dd, J = 1.9, 8.5Hz, 1H), 6.62 (d, J = 8.6Hz, 1H), 5.99 (d, J = 2.3Hz, 1H), 5.44 (s, 2H), 4.20 (q, J = 7.4Hz, 2H), 3.62 (q, J = 7.1Hz, 4H), 1.53 (t, J = 7.4Hz, 3H) , 1.26 (t, J = 7.1 Hz, 6H).

Intermediate 67

N-((1-ethyl-1H-pyrazol-3-yl) methyl) -2-methyl-6-nitroaniline

Add 2-fluoro-1-methyl-3-nitrobenzene (172 mg, 1.109 mmol), (1-ethyl-1H-pyrazol-3-yl) methylamine (153 mg, 1.220 mmol), and N, N- A solution of diisopropylethylamine (0.232 mL, 1.331 mmol) in DMF (20 mL) was heated at 60 ° C for 16 hours. The reaction was concentrated, and the resulting residue was purified via silica chromatography (0% to 27% EtOAc / hexane) to provide N-((1-ethyl-1H-pyrazole-3- as a yellow / orange oil (Methyl) methyl) -2-methyl-6-nitroaniline (99 mg). LC-MS (ES) m / z = 261 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 7.89 (dd, J = 1.0, 8.4 Hz, 1H), 7.26-7.45 (m, 2H), 6.91-7.25 (m, 1H), 6.82 (dd, J = 7.4 , 8.4Hz, 1H), 6.09 (d, J = 2.4Hz, 1H), 4.43 (s, 2H), 4.13 (q, J = 7.4Hz, 2H), 2.51 (s, 3H), 1.47 (t, J = 7.4Hz, 3H).

Intermediate 68

N1-((1-ethyl-1H-pyrazol-3-yl) methyl) -6-methylbenzene-1,2-diamine

N-((1-ethyl-1H-pyrazol-3-yl) methyl) -2-methyl-6-nitroaniline (99 mg, 0.380 mmol) and NiCl ₂ ‧ 6H ₂ O (226 mg, 0.951 mmol ) in a mixture of CH ₃ OH (20mL) cooled in an ice-water bath. Sodium borohydride (71.9 mg, 1.902 mmol) was added, and the reaction mixture was stirred in an ice-water bath for 10 minutes. The reaction was concentrated, added NH ₄ OH (28%), and the resulting mixture was extracted with CH _{2 2} Cl. The combined dried organic extracts with MgSO _4, filtered and concentrated. The resulting residue was purified via silica chromatography (0% to 100% EtOAc / hexane) to provide N1-((1-ethyl-1H-pyrazol-3-yl) methyl) -6-methylbenzene -1,2-diamine (57 mg). LC-MS (ES) m / z = 231 [M + H] ⁺ . This material was immediately carried forward to the next step without further purification.

Example 36

N, N-diethyl-5- (1-((1-ethyl-1H-pyrazol-3-yl) methyl) -7-methyl-1H-benzo [d] imidazol-2-yl Pyridine-2-amine

N1-((1-ethyl-1H-pyrazol-3-yl) methyl) -6-methylbenzene-1,2-diamine (54 mg, 0.188 mmol), 6- (diethylamino) A mixture of nicotinaldehyde (33.4 mg, 0.188 mmol), and oxone (75.0 mg, 0.122 mmol) in DMF (10 mL) and water (4 mL) was stirred at room temperature for 30 minutes. Saturated aqueous NaHCO ₃ was added, and the resulting mixture was extracted with EtOAc. The washed sequentially with water and brine, the combined organic extracts were dried over MgSO _4, filtered, and concentrated. The resulting residue was purified via silica chromatography (0% to 100% EtOAc / hexane) to provide N, N-diethyl-5- (1-((1-ethyl-1H-pyrazole) as a glass -3-yl) methyl) -7-methyl-1H-benzo [d] imidazol-2-yl) pyridin-2-amine (18 mg). LC-MS (ES) m / z = 389 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.49 (d, J = 1.8 Hz, 1 H), 7.86 (d, J 7.6 Hz, 1 H), 7.70 (d, J = 8.1 Hz, 1 H), 7.33 (d, J = 2.0Hz, 1H), 7.19 (t, J = 7.7Hz, 1H), 6.99 (d, J = 7.1Hz, 1H), 6.57 (d, J = 9.1Hz, 1H), 5.81 (d, J = 2.0Hz, 1H), 5.64 (s, 2H), 4.19 (q, J = 7.4Hz, 2H), 3.59 (q, J = 7.1Hz, 4H), 2.57 (s, 3H), 1.52 (t, J = 7.4Hz, 3H), 1.24 (t, J = 7.1Hz, 6H).

Intermediate 69

N-((1-ethyl-1H-pyrazol-3-yl) methyl) -3-methoxy-2-nitroaniline

1-fluoro-3-methoxy-2-nitrobenzene (154 mg, 0.900 mmol), (1-ethyl-1H-pyrazol-3-yl) methylamine (124 mg, 0.990 mmol), and N, N -A solution of diisopropylethylamine (0.189 mL, 1.080 mmol) in DMF (15 mL) was stirred at room temperature for 16 hours. The reaction was concentrated and the resulting residue was purified via silica chromatography (0% to 50% EtOAc / hexanes) to provide N-((1-ethyl-1H-pyrazol-3-yl) as a yellow oil Methyl) -3-methoxy-2-nitroaniline (60 mg). LC-MS (ES) m / z = 277 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 7.37 (d, J = 2.3Hz, 1H), 7.19-7.32 (m, 1H), 6.58 (br.s., 1H), 6.51 (dd, J = 0.8, 8.6Hz, 1H), 6.32 (dd, J = 0.9, 8.2Hz, 1H), 6.21 (d, J = 2.0Hz, 1H), 4.43 (d, J = 2.0Hz, 2H), 4.18 (q, J = 7.4Hz, 2H), 3.91 (s, 3H), 1.52 (t, J = 7.2Hz, 3H).

Intermediate 70

N1-((1-ethyl-1H-pyrazol-3-yl) methyl) -3-methoxybenzene-1,2-diamine

N-((1-ethyl-1H-pyrazol-3-yl) methyl) -3-methoxy-2-nitroaniline (60 mg, 0.217 mmol) and NiCl ₂ ‧ 6H ₂ O (129 mg, 0.543 mmol) in a mixture of CH ₃ OH (20mL) cooled in an ice-water bath. Sodium borohydride (41.1 mg, 1.086 mmol) was added, and the reaction mixture was stirred in an ice-water bath for 10 minutes. The reaction was concentrated, added NH ₄ OH (28%), and the resulting mixture was extracted with CH _{2 2} Cl. The combined organic extracts were dried with MgSO _4, filtered, and concentrated to provide a brown solid of N1 - ((1-ethyl--1H- pyrazol-3-yl) methyl) -3-methoxybenzoate - 1,2-diamine (61 mg). LC-MS (ES) m / z = 247 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 7.37 (d, J = 2.0 Hz, 1H), 6.81 (t, J = 8.1 Hz, 1H), 6.50 (dd, J = 8.0, 19.0 Hz, 2H), 6.25 (d, J = 2.0Hz, 1H), 4.38 (s, 2H), 4.20 (q, J = 7.4Hz, 2H), 3.89 (s, 3H), 3.68 (br.s., 2H), 1.53 (t , J = 7.2Hz, 3H).

Example 37

N, N-diethyl-5- (1-((1-ethyl-1H-pyrazol-3-yl) methyl) -4-methoxy-1H-benzo [d] imidazole-2- ) Pyridin-2-amine

N1-((1-ethyl-1H-pyrazol-3-yl) methyl) -3-methoxybenzene-1,2-diamine (61 mg, 0.198 mmol), 6- (diethylamino) ) A mixture of nicotinaldehyde (35.3 mg, 0.198 mmol) and oxone (79 mg, 0.129 mmol) in DMF (10 mL) and water (4 mL) was stirred at room temperature for 16 hours. Saturated aqueous NaHCO ₃ was added, and the resulting mixture was extracted with EtOAc. The washed sequentially with water and brine, the combined organic extracts were dried over MgSO _4, filtered, and concentrated. The resulting residue was purified and lyophilized via silica chromatography (0% to 100% EtOAc / hexanes) to provide N, N-diethyl-5- (1-((1-ethyl- 1H-pyrazol-3-yl) methyl) -4-methoxy-1H-benzo [d] imidazol-2-yl) pyridin-2-amine (25 mg). LC-MS (ES) m / z = 405 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.52-8.67 (m, 1H), 8.03 (dd, J = 2.4, 9.0 Hz, 1H), 7.28-7.38 (m, 1H), 7.09-7.24 (m, 1H ), 6.99 (dd, J = 0.8, 8.1 Hz, 1H), 6.74 (d, J = 7.4 Hz, 1H), 6.51-6.61 (m, 1H), 5.94 (d, J = 2.0 Hz, 1H), 5.45 (s, 2H), 4.20 (q, J = 7.4 Hz, 2H), 4.08 (s, 3H), 3.60 (q, J = 7.1 Hz, 4H), 1.53 (t, J = 7.2 Hz, 3H), 1.25 (t, J = 7.1 Hz, 6H).

Intermediate 71

N-((1-ethyl-1H-pyrazol-4-yl) methyl) -2-nitro-3- (trifluoromethyl) aniline

1-fluoro-2-nitro-3- (trifluoromethyl) benzene (150 mg, 0.717 mmol), (1-ethyl-1H-pyrazol-3-yl) methylamine (99 mg, 0.789 mmol), And a solution of N, N-diisopropylethylamine (0.150 mL, 0.861 mmol) in DMF (15 mL) was stirred for 16 hours. The reaction was concentrated, and the resulting residue was purified via silica chromatography (0% to 35% EtOAc / hexane) to provide N-((1-ethyl-1H-pyrazol-4-yl) as an orange oil Methyl) -2-nitro-3- (trifluoromethyl) aniline (204 mg). LC-MS (ES) m / z = 315 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 7.41-7.48 (m, 1H), 7.39 (d, J = 2.0Hz, 1H), 7.19 (d, J = 8.6Hz, 1H), 7.07 (d, J = 7.6Hz, 1H), 6.40 (br.s., 1H), 6.20 (d, J = 2.3Hz, 1H), 4.47 (d, J = 5.1Hz, 2H), 4.19 (q, J = 7.4Hz, 2H ), 1.52 (t, J = 7.4 Hz, 3H).

Example 38

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl ) Methyl) -4- (trifluoromethyl) -1H-benzo [d] imidazole

N-((1-ethyl-1H-pyrazol-3-yl) methyl) -2-nitro-3- (trifluoromethyl) aniline (100 mg, 0.318 mmol), sodium bisulfite (166 mg, 85%, 0.812 mmol), and 6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (68.2 mg, 0.334 mmol) in EtOH (4 mL) and water (2 mL The mixture in) was heated at 130 ° C for 40 minutes under microwave conditions. The reaction was filtered and the filtrate was concentrated to dryness. Followed by addition of CH ₂ Cl _2, and the resulting mixture was filtered again. The filtrate was purified via silica chromatography (0% to 80% EtOAc / hexanes) to provide 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl as a white solid ) Pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -4- (trifluoromethyl) -1H-benzo [d] imidazole (28 mg) . LC-MS (ES) m / z = 469 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.61 (d, J = 1.8Hz, 1H), 7.95 (dd, J = 2.0, 8.9Hz, 1H), 7.51-7.60 (m, 2H), 7.33 (d, J = 2.3Hz, 1H), 7.20-7.30 (m, 1H), 6.49 (d, J = 8.9Hz, 1H), 5.97 (d, J = 2.0Hz, 1H), 5.46 (s, 2H), 4.23- 4.37 (m, 2H), 4.08-4.22 (m, 2H), 2.22-2.38 (m, 2H), 1.71 (d, J = 5.6Hz, 2H), 1.47-1.55 (m, 3H), 1.21 (d, J = 6.1 Hz, 6H).

Intermediate 72

5- (5-bromo-1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethyl Pyridin-2-amine

4-Bromo-N-((1-ethyl-1H-pyrazol-3-yl) methyl) -2-nitroaniline (261 mg, 0.803 mmol), 6- (diethylamino) nicotinaldehyde ( 157 mg, 0.883 mmol), ethanol (2 mL), water (1 mL), and sodium bisulfite (419 mg, 85%, 2.047 mmol) were added to a microwave vial, and the reaction mixture was heated at 130 ° C. for 30 minutes under microwave conditions. The reaction was diluted with water (10 mL) and extracted with EtOAc (4 x 5 mL). The organic extracts were combined, washed with brine, dried over MgSO _4, filtered, and concentrated. Purification by flash chromatography on SiO ₂ (gradient from 0 to 70% EtOAc / hexanes) provided 5- (5-bromo-1-((1-ethyl-1H-pyrazole) as a light brown oil -3-yl) methyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine (246 mg). LC-MS (ES) m / z = 454 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 1.24 (t, J = 7.0Hz, 6H), 1.51 (t, J = 7.4Hz, 3H), 3.59 (q, J = 7.1Hz, 4H), 4.14-4.22 (m, 2H), 5.42 (s, 2H), 5.95 (d, J = 2.3Hz, 1H), 6.58 (s, 1H), 7.22-7.26 (m, 1H), 7.29-7.34 (m, 2H), 7.90-7.97 (m, 2H), 8.58 (d, J = 2.3Hz, 1H).

Example 39

(2- (6- (diethylamino) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole- 5-yl) boronic acid

Tetrahydroxydiboric acid (73.0mg, 0.814mmol), triphenylphosphine (14.23mg, 0.054mmol), 1,3-bis (diphenylphosphino) propane-nickel (II) chloride (29.4mg , 0.054 mmol), 5- (5-bromo-1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazol-2-yl) -N, N-Diethylpyridin-2-amine (246 mg, 0.543 mmol), and EtOH (5 mL) were sequentially added to a 20 mL microwave vial, and the resulting mixture was degassed with argon for 10 minutes. Next, N, N-diisopropylethylamine (0.284 mL, 1.628 mmol) was added, and the reaction mixture was heated under microwave conditions at 80 ° C. for 1 hour. The reaction was filtered through celite and washed with EtOH. The filtrate was concentrated and the resulting residue was purified by chromatography on SiO ₂ (0 to 50% (gradient of 80: 20: 2 CH ₂ Cl ₂ : CH ₃ OH: NH ₄ OH) / CH ₂ Cl ₂ ) Provides (2- (6- (diethylamino) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole -5-yl) boronic acid (107 mg), lyophilized as a white solid. LC-MS (ES) m / z = 419 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.24 (t, J = 7.0Hz, 6H), 1.43 (t, J = 7.4Hz, 3H), 3.63 (q, J = 7.0Hz, 4H), 4.16 ( q, J = 7.4Hz, 2H), 5.49 (s, 2H), 6.09 (d, J = 2.3Hz, 1H), 6.78 (d, J = 8.9Hz, 1H), 7.48-7.60 (m, 3H), 7.95 (dd, J = 8.9, 2.5 Hz, 1H), 7.99 (s, 1H), 8.53 (d, J = 2.3 Hz, 1H).

Intermediate 73

N- (2- (tertiary butoxy) ethyl) -2-nitroaniline

1-fluoro-2-nitrobenzene (3.61 g, 25.6 mmol) and K ₂ CO ₃ (3.54 g, 25.6 mmol) were added to 2- (tertiary butoxy) ethane-1- in DMF (100 mL) Amine (3.00 g, 25.6 mmol), and the reaction mixture was stirred at room temperature overnight. The solid was filtered and washed with Et ₂ O. The filtrate was washed with water (600 mL) was diluted, and the resulting mixture was extracted with _{Et 2 O (200mL, 3x)} . The combined organic layers were washed (20mL) with brine, dried over Na ₂ SO _4, filtered, and concentrated. The resulting residue was purified by flash chromatography on SiO ₂ (0-60% EtOAc / hexane) to give N- (2- (tertiary butoxy) ethyl) -2-nitrate as a yellow oil Aniline (4.85 g). LC-MS (ES) m / z = 239 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.31 (br.s., 1H), 8.22 (dd, J = 1.5, 8.6 Hz, 1H), 7.47 (ddd, J = 1.7, 7.0, 8.6 Hz, 1H) , 6.90 (dd, J = 1.0, 8.6 Hz, 1H), 6.68 (ddd, J = 1.3, 7.0, 8.5 Hz, 1H), 3.71 (t, J = 5.5 Hz, 2H), 3.48 (t, J = 5.5 Hz, 2H), 1.30 (s, 9H).

Intermediate 74

N1- (2- (tertiary butoxy) ethyl) benzene-1,2-diamine

A solution of N- (2- (tertiary butoxy) ethyl) -2-nitroaniline (4.85 g, 20.35 mmol) and NiCl ₂ ‧ 6H ₂ O (12.09 g, 50.9 mmol) was rinsed with N ₂ , followed by Cool in an ice bath. Sodium borohydride (3.85 g, 102 mmol) was added to the frozen solution in 4 portions, and the reaction mixture was stirred at room temperature for 2 hours. The reaction was concentrated and the remaining residue was partitioned between concentrated NH ₄ OH (200mL) and CH ₂ Cl ₂ (300mL). [Caution: Effervescent / Loss of Some Solution]. The aqueous phase was extracted with CH ₂ Cl ₂ (3 x 200 mL). The combined organic layers were washed (20mL) with brine, dried over Na ₂ SO _4, filtered, and concentrated. The remaining residue was purified by flash chromatography on SiO ₂ (0-60% EtOAc / hexanes) to provide N1- (2- (tertiary butoxy) ethyl) as a green waxy solid) Benzene-1,2-diamine (4.52 g). LC-MS (ES) m / z = 209 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 6.61-6.95 (m, 4H), 3.77-4.27 (m, 2H), 3.67 (br.s., 2H), 3.10 3.44 (m, 2H), 1.27 (s , 9H).

Example 40

(S) -1- (2- (tertiary butoxy) ethyl) -2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d ] Imidazole

Add potassium oxone (207 mg, 0.337 mmol) to N1- (2- (tertiary butoxy) ethyl) benzene-1,2-diamine (108 mg, 0.518 mmol) and (S)- 6- (2-methylpyrrolidin-1-yl) nicotinaldehyde (109 mg, 0.570 mmol) in DMF (4 mL) and water (3 mL), and the reaction mixture was stirred at room temperature for 45 minutes. The reaction was quenched with saturated aqueous NH ₄ Cl (8 mL) was quenched, and the resulting mixture was extracted with EtOAc (6 x 25mL) followed by _{3% CH 3 OH / EtOAc (} 3 x 25mL). ₄ OH The pH of the aqueous layer was adjusted to 1-9 with NH, and the resulting aqueous mixture was extracted with EtOAc (3 x 20mL). The combined organic layers were washed with brine (6 mL), dried over Na ₂ SO _4, filtered, and concentrated. The resulting residue was purified by flash chromatography on SiO ₂ (0-100% EtOAc / hexanes) to provide (S) -1- (2- (tertiary butoxy) ethyl) as a golden brown solid ) -2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole (96 mg). LC-MS (ES) m / z = 379 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.62-8.80 (m, 1H), 8.06-8.28 (m, 1H), 7.79-8.03 (m, 1H), 7.51-7.65 (m, 1H), 7.38 (br .s., 2H), 6.43-6.70 (m, 1H), 4.46 (br.s., 2H), 4.19-4.38 (m, 1H), 3.78-3.91 (m, 2H), 3.60- 3.76 (m, 1H), 3.39-3.57 (m, 1H), 2.18 (br.s., 3H), 1.75-1.90 (m, 1H), 1.25-1.32 (m, 3H), 1.04-1.11 (m, 9H).

Example 41

1- (2- (tertiary butoxy) ethyl) -2- (6-((2S, 5R) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H -Benzo [d] imidazole

Add potassium oxone monohydrate (199 mg, 0.325 mmol) to N1- (2- (tertiary butoxy) ethyl) benzene-1,2-diamine in DMF (3 mL) and water (3 mL) Amine (104 mg, 0.499 mmol) and 6-((2S, 5R) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (112 mg, 0.549 mmol) and the reaction mixture was stirred at room temperature 45 minutes. The reaction was quenched with saturated aqueous NH ₄ Cl (8mL), and treated with NH ₄ OH (10mL) the pH was adjusted to ~ 10. The resulting mixture was extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with brine (3 mL), dried over Na ₂ SO ₄ , filtered, and concentrated. The remaining residue was purified by flash chromatography on SiO ₂ (0-100% EtOAc / hexanes) to provide 1- (2- (tertiary butoxy) ethyl)-as a red-brown solid 2- (6-((2S, 5R) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole (117 mg). LC-MS (ES) m / z = 393 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.63 (d, J = 2.0Hz, 1H), 7.97-8.10 (m, 1H), 7.76-7.93 (m, 1H), 7.53 (d, J = 4.1Hz, 1H), 7.32 (d, J = 4.1Hz, 2H), 6.55 (d, J = 9.1Hz, 1H), 4.41 (t, J = 5.7Hz, 2H), 4.19 (d, J = 5.3Hz, 2H) , 3.82 (t, J = 5.8Hz, 2H), 2.07-2.25 (m, 2H), 1.74-1.92 (m, 2H), 1.40 (d, J = 6.1Hz, 6H), 0.91-1.18 (m, 9H ).

Intermediate 75

4-((2- (tertiary butoxy) ethyl) amino) -3-nitrobenzoate

Add 2- (tertiary butoxy) ethylamine (353 mg, 3.01 mmol) and K ₂ CO ₃ (416 mg, 3.01 mmol) to methyl 4-fluoro-3-nitrobenzoate (600 mg, 3.01 mmol) in DMF (20 mL), and the mixture was stirred at room temperature for 18 hours. The mixture was quenched with water (30 mL) and extracted with EtOAc (3x). The extracts were dried (Na ₂ SO ₄₎ and concentrated. The residue was purified using column chromatography (silica, 0 to 60% EtOAc / hexanes) to give the desired product (590 mg) as a white solid. LC-MS (ES) m / z = 297 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 1.30 (s, 9H), 3.53 (d, J = 4.8Hz, 2H), 3.69-3.75 (m, 2H), 3.94 (s, 3H), 6.92 (d, J = 9.1Hz, 1H), 8.09 (dd, J = 8.9, 2.0Hz, 1H), 8.93 (d, J = 2.0Hz, 1H).

Intermediate 76

3-Amino-4-((2- (tertiary butoxy) ethyl) amino) benzoic acid methyl ester

NiCl ₂ ‧ 6H ₂ O (1084 mg, 4.56 mmol) and sodium borohydride (345 mg, 9.11 mmol) were added to 4-((2- (tertiary butoxy) ethyl) amino) -3 at 0 ° C. - nitro benzoic acid methyl ester (540mg, 1.822mmol), and the mixture was stirred at 0 ℃ in the ₃ OH (13mL) solution of CH 20 minutes. The reaction mixture was concentrated, and the residue was treated with saturated aqueous NH ₄ OH and extracted with EtOAc (3x). The extracts were dried (Na ₂ SO ₄₎ and concentrated to give the desired product as a light brown oil (430mg). LC-MS (ES) m / z = 267 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 1.26 (s, 9H), 3.34 (t, J = 5.3Hz, 2H), 3.67 (t, J = 5.3Hz, 2H), 3.89 (s, 3H), 6.65 (d, J = 8.4Hz, 1H,) 7.44 (d, J = 2.0Hz, 1H), 7.61 (dd, J = 8.2, 1.9Hz, 1H).

Example 42

1- (2- (tertiary butoxy) ethyl) -2- (6- (diethylamino) pyridin-3-yl) -1H-benzo [d] imidazole-5-carboxylic acid methyl ester

Add 6- (diethylamino) nicotinaldehyde (167 mg, 0.939 mmol) and potassium oxone (577 mg, 0.939 mmol) to 3-amino-4-((2- ( A solution of tertiary butoxy) ethyl) amino) benzoic acid methyl ester (250 mg, 0.939 mmol) in DMF (5 mL) and water (1 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with EtOAc (3x) with 10% K ₂ CO ₃ solution (5mL) and quenched. The extracts were dried (Na ₂ SO ₄₎ and concentrated. The residue was purified using column chromatography (silica, 0 to 60% EtOAc / hexanes) to give the desired product (280 mg) as a white solid. LC-MS (ES) m / z = 425 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 0.98 (s, 9H), 1.25 (t, J = 7.1Hz, 6H), 3.65 (q, J = 7.1Hz, 4H), 3.82 (t, J = 5.1 Hz, 2H), 3.97 (s, 3H), 4.49 (t, J = 5.1Hz, 2H), 6.78 (d, J = 9.1Hz, 1H), 7.72 (d, J = 8.6Hz, 1H), 7.98- 8.12 (m, 2H), 8.36 (d, J = 1.3 Hz, 1H), 8.60 (d, J = 2.0 Hz, 1H).

Example 43

1- (2- (tertiary butoxy) ethyl) -2- (6- (diethylamino) pyridin-3-yl) -1H-benzo [d] imidazole-5-carboxamide

8N NaOH (0.2 mL, 1.60 mmol) was added to 1- (2- (tertiary butoxy) ethyl) -2- (6- (diethylamino) pyridin-3-yl) -1H-benzo [d] A solution of methyl imidazole-5-carboxylate (80 mg, 0.188 mmol) in CH ₃ OH (1 mL), and the mixture was stirred at 40 ° C. for 18 hours. The reaction mixture was neutralized by adding 6N aqueous HCl (0.267 mL, 1.602 mmol) and concentrated. The residue was dried under vacuum and treated with dimethylsulfine (DMSO) (1 mL). NH ₄ Cl (18.14 mg, 0.339 mmol), N-methylmorphine (0.124 mL, 1.131 mmol), EDC (72.2 mg, 0.377 mmol), and 1-hydroxy-7-azabenzotriazole ( 51.3 mg, 0.377 mmol) was added to the mixture, and the mixture was stirred at room temperature for 18 hours. The reaction was quenched with water (5 mL). The precipitate was collected by filtration and dried under vacuum to give the desired product (69 mg) as an off-white solid. LC-MS (ES) m / z = 410 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 0.99 (s, 9H), 1.25 (t, J = 7.1Hz, 6H), 3.65 (q, J = 7.1Hz, 4H), 3.82 (t, J = 5.1 Hz, 2H), 4.48 (t, J = 5.1 Hz, 2H), 6.78 (d, J = 9.1 Hz, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.89 (dd, J = 8.5, 1.7 Hz, 1H), 8.05 (dd, J = 9.0, 2.4 Hz, 1H), 8.24 (d, J = 1.3 Hz, 1H), 8.60 (d, J = 2.3 Hz, 1H).

Example 44

1- (2- (tertiary butoxy) ethyl) -N- (cyclopropylmethyl) -2- (6- (diethylamino) pyridin-3-yl) -1H-benzo [d ] Imidazole-5-carboxamide

8N NaOH (0.2 mL, 1.600 mmol) was added to 1- (2- (tertiary butoxy) ethyl) -2- (6- (diethylamino) pyridin-3-yl) -1H-benzo [d] A solution of methyl imidazole-5-carboxylic acid methyl ester (80 mg, 0.188 mmol) in CH ₃ OH (1.5 mL), and the mixture was stirred at 40 ° C. for 18 hours. The reaction mixture was neutralized by adding 6N aqueous HCl (0.267 mL, 26.8 mg, 1.602 mmol) and concentrated. The residue was dried under vacuum and treated with DMSO (1.5 mL). Cyclopropylmethylamine (32.7 μl, 0.377 mmol), N -methylmorphine (124 μl, 1.131 mmol), EDC (72.2 mg, 0.377 mmol), and 1-hydroxy-7-azabenzotriazole (51.3 mg, 0.377 mmol) was added to this mixture, and the mixture was stirred at room temperature for 18 hours. The reaction was quenched with water (5 mL). The precipitate was collected by filtration and dried under vacuum to give the desired product (72 mg) as an off-white solid. LC-MS (ES) m / z = 464 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 0.27-0.37 (m, 2H), 0.50-0.62 (m, 2H), 0.98 (s, 9H), 1.12-1.19 (m, 1H), 1.19-1.31 ( m, 6H), 3.30 (m, 2H), 3.64 (q, J = 7.1Hz, 4H), 3.82 (t, J = 5.1Hz, 2H), 4.48 (t, J = 4.9Hz, 2H), 6.78 ( d, J = 9.1Hz, 1H), 7.71 (d, J = 8.6Hz, 1 H), 7.81-7.89 (m, 1H), 8.05 (dd, J = 9.1, 2.3Hz, 1H), 8.18 (d, J = 1.0Hz, 1H), 8.60 (d, J = 2.0Hz, 1H).

Example 45

1- (2- (tertiary butoxy) ethyl) -2- (6- (diethylamino) pyridin-3-yl) -N- (2-hydroxyethyl) -1H-benzo [d ] Imidazole-5-carboxamide

NaOH (0.200 mL, 1.602 mmol) was added to 1- (2- (tertiary butoxy) ethyl) -2- (6- (diethylamino) pyridin-3-yl) -1H-benzo [ d] A solution of methyl imidazole-5-carboxylate (85 mg, 0.200 mmol) in CH ₃ OH (1.5 mL), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was neutralized by adding 6N aqueous HCl (0.267 mL, 1.602 mmol) and concentrated to give crude 1- (2- (tertiary butoxy) ethyl) -2- (6- (diethylamino) Pyridin-3-yl) -1H-benzo [d] imidazole-5-carboxylic acid. The residue was dried under vacuum and treated with DMSO (1.5 mL). Add 2-aminoethyl-1-ol (0.024 mL, 0.400 mmol), N-methylmorpholine (0.132 mL, 1.201 mmol), EDC (77 mg, 0.400 mmol), and 1-hydroxy-7-aza Benzotriazole (54.5 mg, 0.400 mmol) was added to this mixture, and the mixture was stirred at room temperature for 18 hours. The reaction was quenched with water (5 mL). The precipitate was collected by filtration and dried under vacuum to give the desired product (81 mg) as an off-white solid. LC-MS (ES) m / z = 454 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 0.92-1.03 (m, 9H), 1.25 (t, J = 7.0Hz, 6H), 2.68 (s, 2H), 3.54-3.63 (m, 3H), 3.63 -3.71 (m, 3H), 3.72-3.86 (m, 4H), 4.48 (t, J = 5.1Hz, 2H), 6.78 (d, J = 8.9Hz, 1H), 7.71 (d, J = 8.1Hz, 1H), 7.82-7.91 (m, 1H), 8.05 (dd, J = 9.0, 2.1Hz, 1H), 8.20 (d, J = 1.0Hz, 1 H), 8.60 (d, J = 2.3Hz, 1H) .

Intermediate 77

N- (2- (tertiary butoxy) ethyl) -3-chloro-2-nitroaniline

Add 2- (tertiary butoxy) ethylamine (200 mg, 1.709 mmol) and K ₂ CO ₃ (236 mg, 1.709 mmol) to 1-chloro-3-fluoro-2-nitrobenzene (300 mg, 1.709 mmol) at A solution in DMF (8 mL), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with water (15 mL) and extracted with EtOAc (3x). The extracts were dried (Na ₂ SO ₄₎ and concentrated. The residue was purified using column chromatography (silica gel, 0 to 50% EtOAc / hexanes) to give the desired product (230 mg) as a light brown oil. LC-MS (ES) m / z = 273,275 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 1.24-1.30 (m, 9H), 3.34 (t, J = 5.3Hz, 2H), 3.63 (t, J = 5.3Hz, 2H), 6.72-6.82 (m, 1H), 6.77 (dd, J = 6.0, 1.14 Hz, 1H), 7.20-7.29 (m, 1H).

Example 46

5- (1- (2- (tertiary butoxy) ethyl) -4-chloro-1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridine-2-amine

N- (2- (tertiary butoxy) ethyl) -3-chloro-2-nitroaniline (130 mg, 0.477 mmol), 6- (diethylamino) nicotinaldehyde (85 mg, 0.477 mmol), Sodium bisulfite (295mg, 85%, 1.216mmol), EtOH (3mL), and water (2mL) were added to a 30-mL microwave tube, the tube was sealed, and the reaction mixture was heated under microwave conditions at 135 ° C for 20 minutes . The reaction mixture was cooled, quenched with water (10 mL) and extracted with EtOAc (3x). The extracts were dried (Na ₂ SO ₄₎ and concentrated by silica gel and chromatography (0 to 90% EtOAc / hexanes) resulting residue was purified form to produce the desired product as a white solid (27mg). LC-MS (ES) m / z = 401,403 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 0.99 (s, 9H), 1.22-1.32 (m, 6H), 3.65 (q, J = 7.1Hz, 4H), 3.80 (t, J = 5.1Hz, 2 H), 4.44 (t, J = 5.2Hz, 2H), 6.78 (d, J = 9.1Hz, 1H), 7.23-7.37 (m, 2H), 7.59 (dd, J = 7.9, 1.3Hz, 1H), 8.04 (dd, J = 8.9, 2.5 Hz, 1H), 8.59 (d, J = 2.5 Hz, 1H).

Intermediate 78

N1- (2- (tertiary butoxy) ethyl) -3- (trifluoromethyl) benzene-1,2-diamine

NiCl ₂ ‧ 6H ₂ O (253 mg, 1.061 mmol) was added to N- (2- (tertiary butoxy) ethyl) -2-nitro-3- (trifluoromethyl) in portions at 0 ° C. aniline (130mg, 0.424mmol) and sodium borohydride (80mg, 2.122mmol) in CH ₃ OH (3mL) the solution was stirred, and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was concentrated, and the resulting residue was dissolved in concentrated NH ₄ OH and extracted with CH ₂ Cl ₂ (3x). The extracts were dried (Na ₂ SO ₄₎ and concentrated to give the desired product as a light brown oil (110mg). LC-MS (ES) m / z = 277 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 1.20-1.29 (m, 9H), 3.26 (t, J = 5.1Hz, 2H), 3.68 (t, J = 5.2Hz, 2H), 6.77-6.93 (m, 2H), 7.02-7.08 (m, 1H).

Example 47

5- (1- (2- (tertiary butoxy) ethyl) -4- (trifluoromethyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridine -2-amine

Add oxone (245 mg, 0.398 mmol) and 6- (diethylamino) nicotinaldehyde (71.0 mg, 0.398 mmol) to N1- (2- (tertiary butoxy) at 0 ° C. ) Ethyl) -3- (trifluoromethyl) benzene-1,2-diamine (110 mg, 0.398 mmol) in DMF (2.5 mL) and water (0.500 mL), the mixture was stirred at room temperature 2 hours. The reaction mixture 10% K ₂ CO ₃ was basified and extracted with EtOAc (3x). The extracts were dried (Na ₂ SO ₄₎ and concentrated using column chromatography (silica gel, 0 to 60% EtOAc / hexanes) resulting residue was purified to yield an off-white solid was the desired product (136mg). LC-MS (ES) m / z = 435 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 0.99 (s, 9H), 1.25 (t, J = 7.1Hz, 6H), 3.65 (q, J = 7.1Hz, 4H), 3.80 (t, J = 5.1 Hz, 2H), 4.48 (t, J = 5.1 Hz, 2H), 6.78 (d, J = 9.1 Hz, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 8.03 (dd, J = 9.1, 2.5 Hz, 1H), 8.58 (d, J = 2.0 Hz, 1H).

Intermediate 79

4-bromo-N- (2- (tertiary butoxy) ethyl) -2-nitroaniline

4-Bromo-1-fluoro-2-nitrobenzene (625 mg, 2.84 mmol), 2- (tertiary butoxy) ethyl-1-amine (366 mg, 3.13 mmol), and N, N-diisopropyl A solution of ethylamine (595 μl, 3.41 mmol) in DMF was stirred at room temperature for 16 hours. The reaction was concentrated, and the residue was purified via silica chromatography (0% to 30% EtOAc / hexane) to give 4-bromo-N- (2- (tertiary butoxy) ethyl)-as an oil. 2-Nitroaniline (860mg) l. LC-MS (ES) m / z = 261,263 [MC ₄ H ₈ + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.25-8.49 (m, 1H), 7.51 (dd, J = 2.3, 9.12 Hz, 1H), 6.82 (d, J = 9.1 Hz, 1H), 3.70 (t, J = 5.3 Hz, 2H), 3.45 (q, J = 5.1 Hz, 2H), 1.29 (s, 9H).

Intermediate 80

4-bromo-N1- (2- (tertiary butoxy) ethyl) benzene-1,2-diamine

4-Bromo-N- (2- (tertiary butoxy) ethyl) -2-nitroaniline (600 mg, 1.892 mmol) and NiCl ₂ ‧ 6H ₂ O (1.126 g, 4.73 mmol) in CH ₃ OH ( 20 mL) was cooled in an ice-water bath. Sodium borohydride (358 mg, 9.46 mmol) was added, and the reaction mixture was stirred in an ice-water bath for 10 minutes. The reaction was concentrated. Adding NH ₄ OH (28% of water), and the resulting mixture was extracted with CH _{2 2} Cl. The dried CH ₂ Cl ₂ the combined extracts were washed with brine, MgSO _4, filtered, and concentrated. The resulting residue was purified via silica chromatography (0% to 35% EtOAc / hexane) to give 4-bromo-N1- (2- (tertiary butoxy) ethyl) benzene-1 as a white solid, 2-diamine (375 mg). LC-MS (ES) m / z = 287,289 [M + H] ⁺ . _{^{1 H NMR (400MHz, CDCl 3}} ): δ 6.90 (dd, J = 2.3,8.4Hz, 1H), 6.85 (d, J = 2.3Hz, 1H), 6.54 (d, J = 8.4Hz, 1H), 3.62 (t, J = 5.2Hz, 2H), 3.21 (t, J = 5.2Hz, 2H), 1.24 (s, 9H).

Example 48

5- (5-bromo-1- (2- (tertiary butoxy) ethyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridine-2-amine

4-Bromo-N1- (2- (tertiary butoxy) ethyl) benzene-1,2-diamine (375 mg, 1.306 mmol) and 6- (diethylamino) nicotinaldehyde monopotassium hydrogen sulfate (oxone) (522 mg, 0.849 mmol) in water (10 mL) and DMF (10 mL) was stirred at room temperature for 16 hours. Saturated aqueous NaHCO ₃ was added, and the resulting mixture was extracted with EtOAc. The washed sequentially with water and brine the organic extract was dried over MgSO _4, filtered and concentrated. The resulting residue was purified via silica chromatography (0% to 50% EtOAc / hexanes) to give 5- (5-bromo-1- (2- (tertiary butoxy) ethyl)-as a brown solid 1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine (527 mg). LC-MS (ES) m / z = 445,447 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.56 (d, J = 2.0 Hz, 1 H), 7.97 (dd, J = 2.4, 9.0 Hz, 1 H), 7.92 (d, J = 1.3 Hz, 1 H), 7.35 -7.43 (m, 2H), 6.59 (d, J = 9.1Hz, 1H), 4.36 (t, J = 5.3Hz, 2H), 3.77 (t, J = 5.5Hz, 2H), 3.61 (q, J = 6.9Hz, 4H), 1.25 (t, J = 7.0Hz, 6H), 1.06 (s, 9H).

Example 49

(1- (2- (tertiary butoxy) ethyl) -2- (6- (diethylamino) pyridin-3-yl) -1H-benzo [d] imidazol-5-yl) boronic acid

Tetrahydroxydiboric acid (31.4mg, 0.350mmol), 1,3-bis (diphenylphosphino) propane-nickel (II) chloride (6.33mg, 0.012mmol), 5- (5-bromo -1- (2- (tertiary butoxy) ethyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine (104 mg, 0.233 mmol), A mixture of triphenylphosphine (6.12 mg, 0.023 mmol) and N, N-diisopropylethylamine (0.122 mL, 0.700 mmol) in EtOH (10 mL) was bubbled through argon for 10 minutes, and the reaction mixture was passed Heated at 80 ° C for 16 hours. The reaction was concentrated and the resulting material was purified by reverse-phase HPLC (20% CH ₃ CN / (H ₂ O, 0.1% formic acid) to 60% CH ₃ CN / (H ₂ O, 0.1% formic acid)) to provide the (1- (2- (tertiary butoxy) ethyl) -2- (6- (diethylamino) pyridin-3-yl) -1H-benzo [d] imidazol-5-yl) as a solid Boric acid (16 mg). LC-MS (ES) m / z = 411 [M + H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 8.60 (d, J = 2.0 Hz, 1 H), 8.05 (dd, J = 2.4, 9.0 Hz, 1 H), 7.92-8.02 (m, 1 H), 7.64 (br .s., 2H), 6.78 (d, J = 8.9Hz, 1H), 4.46 (t, J = 5.1Hz, 2H), 3.83 (t, J = 5.2Hz, 2H), 3.65 (q, J = 6.9 Hz, 4H), 1.25 (t, J = 7.1 Hz, 6H), 0.99 (s, 9H).

Example 50

5- (1- (2- (tertiary butoxy) ethyl) -5- (1H-pyrazol-3-yl) -1H-benzo [d] imidazol-2-yl) -N, N- Diethylpyridine-2-amine

5- (5-Bromo-1- (2- (tertiary butoxy) ethyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridine-2-amine (80mg, 0.180mmol), 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (41.8mg, 0.216 mmol), (triphenylphosphine) palladium (0) (10.38 mg, 8.98 μmol), and Na ₂ CO ₃ (47.6 mg, 0.449 mmol) A mixture of alkane (3 mL) and water (1 mL) was bubbled through with argon for 10 minutes, and the reaction mixture was heated in a covered container at 75 ° C for 6 hours. Add additional (triphenylphosphine) palladium (0) (10.38mg, 8.98μmol), 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl) -1H-pyrazole (84 mg), and Na ₂ CO ₃ (47.6 mg, 0.449 mmol), and the reaction mixture was heated at 80 ° C. for 6 hours. Water was added, and the resulting mixture was extracted with CH ₂ Cl ₂ . The combined organic extracts were washed with water, dried with MgSO _4, filtered and concentrated. Purification by reverse-phase HPLC (10% CH ₃ CN / (H ₂ O, 0.1% formic acid) to 80% CH ₃ CN / (H ₂ O, 0.1% formic acid)) provided 5- (1- (2- (tertiary butoxy) ethyl) -5- (1H-pyrazol-3-yl) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridine- 2-amine (16 mg). LC-MS (ES) m / z = 433 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.64 (d, J = 2.0Hz, 1H), 8.15 (s, 1H), 8.05 (dd, J = 2.3, 8.9Hz, 1H), 7.76 (d, J = 8.1Hz, 1H), 7.69 (d, J = 2.3Hz, 1H), 7.58 (d, J = 8.4Hz, 1H), 6.71 (d, J = 2.0Hz, 1H), 6.63 (d, J = 8.9Hz , 1H), 4.43 (t, J = 5.5Hz, 2H), 3.83 (t, J = 5.6Hz, 2H), 3.64 (q, J = 7.1Hz, 4H), 1.21-1.41 (m, 6H), 1.09 (s, 9H).

Intermediate 81

N- (2- (tertiary butoxy) ethyl) -4-fluoro-2-nitroaniline

Add 1,4-difluoro-2-nitrobenzene (150 mg, 0.943 mmol), 2- (tertiary butoxy) ethyl-1-amine (110 mg, 0.943 mmol), and N, N-diisopropylethylamine A solution of (0.198 mL, 1.131 mmol) in DMF (15 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated and the resulting residue was purified via silica chromatography (0% to 12% EtOAc / hexanes) to provide N- (2- (tertiary butoxy) ethyl) -4 as an orange oil -Fluoro-2-nitroaniline (126 mg). LC-MS (ES) m / z = 201 [MC ₄ H ₈ + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.20 (br.s., 1H), 7.90 (dd, J = 3.0, 9.1 Hz, 1H), 7.21-7.37 (m, 1H), 6.88 (dd, J = 4.6, 9.4 Hz, 1H), 3.70 (t, J = 5.3 Hz, 2H), 3.45 (t, J = 5.2 Hz, 2H), 1.28 (s, 9H).

Example 51

5- (1- (2- (tertiary butoxy) ethyl) -5-fluoro-1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridine-2-amine

N- (2- (tertiary butoxy) ethyl) -4-fluoro-2-nitroaniline (120 mg, 0.468 mmol), sodium bisulfite (245 mg, 85%, 1.194 mmol), and 6- ( A mixture of diethylamino) nicotinaldehyde (88 mg, 0.492 mmol) in EtOH (4 mL) and water (32 mL) was heated at 130 ° C for 30 minutes under microwave conditions. Then added NH ₄ OH (28% of water) was added and the resulting mixture was extracted with EtOAc. The washed sequentially with water and brine merger EtOA extracts were dried over MgSO _4, filtered and concentrated. The resulting residue was purified via silica chromatography (0% to 50% EtOAc / hexane) to provide 5- (1- (2- (tertiary butoxy) ethyl) -5-fluoro- as a white solid 1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine (37 mg). LC-MS (ES) m / z = 385 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.58 (d, J = 2.0 Hz, 1H), 7.99 (dd, J = 2.4, 9.0 Hz, 1H), 7.42-7.53 (m, 2H), 7.05 (dt, J = 2.4,9.2Hz, 1H), 6.61 (d, J = 8.9Hz, 1H), 4.38 (t, J = 5.6Hz, 2H), 3.80 (t, J = 5.5Hz, 2H), 3.63 (q, J = 7.1 Hz, 4H), 1.27 (t, J = 7.1 Hz, 6H), 1.09 (s, 9H).

Intermediate 82

N- (2- (tertiary butoxy) ethyl) -3-fluoro-2-nitroaniline

Add 1,3-difluoro-2-nitrobenzene (150 mg, 0.943 mmol), 2- (tertiary butoxy) ethyl-1-amine (110 mg, 0.943 mmol), and N, N-diisopropylethyl A solution of amine (0.198 mL, 1.131 mmol) in DMF (20 mL) was stirred for 16 hours. The reaction was concentrated and the residue was purified via silica chromatography (0% to 22% EtOAc / hexanes) to provide N- (2- (tertiary butoxy) ethyl) -3-fluoro- as an orange oil 2-Nitroaniline (179 mg). ¹ H NMR (400MHz, CDCl ₃ ): δ 7.51 (br.s., 1H), 7.18-7.37 (m, 1H), 6.62 (d, J = 8.9Hz, 1H), 6.45 (ddd, J = 1.0, 8.1, 11.4Hz, 1H), 3.67 (t, J = 5.3Hz, 2H), 3.40 (t, J = 5.3Hz, 2H), 1.16-1.33 (m, 9H).

Example 52

5- (1- (2- (tertiary butoxy) ethyl) -4-fluoro-1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridine-2-amine

N- (2- (tertiary butoxy) ethyl) -3-fluoro-2-nitroaniline (179 mg, 0.698 mmol), sodium bisulfite (365 mg, 85%, 1.781 mmol), and 6- ( A mixture of diethylamino) nicotinaldehyde (143 mg, 0.803 mmol) in EtOH (4 mL) and water (2 mL) was heated at 125 ° C for 30 minutes under microwave conditions. Adding NH ₄ OH (28% of water) was added and the resulting mixture was extracted with EtOAc. The combined extracts were washed with water and the EtOA brine sequentially, dried with MgSO _4, filtered, and concentrated. The resulting residue was purified via silica chromatography (0% to 60% EtOAc / hexanes) to provide 5- (1- (2- (tertiary butoxy) ethyl) -4-fluoro- as a white solid 1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine (75 mg). LC-MS (ES) m / z = 385 [M + H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 8.59 (d, J = 2.0 Hz, 1 H), 8.04 (dd, J = 9.1, 2.5 Hz, 1 H), 7.45 (d, J = 8.1 Hz, 1 H), 7.28 (td, J = 8.1, 4.6 Hz, 1H), 7.03 (dd, J = 10.8, 8.0 Hz, 1H), 6.77 (d, J = 8.9 Hz, 1H), 4.45 (t, J = 5.2 Hz, 2H ), 3.81 (t, J = 5.1 Hz, 2H), 3.64 (q, J = 7.1 Hz, 4H), 1.25 (t, J = 7.1 Hz, 6H), 0.99 (s, 9H).

Intermediate 83

3-((2- (tertiary butoxy) ethyl) amino) -2-nitrobenzonitrile

Add 3-fluoro-2-nitrobenzonitrile (300 mg, 1.806 mmol), 2- (tertiary butoxy) ethyl-1-amine (233 mg, 1.987 mmol), and N, N-diisopropylethylamine A solution of (0.379 mL, 2.167 mmol) in DMF (20 mL) was stirred for 16 hours. The reaction was concentrated, and the resulting residue was purified via silica chromatography (0% to 40% EtOAc / hexanes) to provide 3-((2- (tertiary butoxy) ethyl) amine as an orange solid ) -2-Nitrobenzonitrile (450 mg). LC-MS (ES) m / z = 264 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.39 (br.s., 1H), 7.49 (dd, J = 7.1, 8.9 Hz, 1H), 7.19 (dd, J = 1.0, 8.9 Hz, 1H), 7.14 (dd, J = 1.1, 7.2 Hz, 1H), 3.63-3.82 (m, 2H), 3.48 (q, J = 5.1 Hz, 2H), 1.29 (s, 9H).

Intermediate 84

2-amino-3-((2- (tertiary butoxy) ethyl) amino) benzonitrile

Add tin (II) chloride (1296 mg, 6.84 mmol) to 3-((2- (tertiary butoxy) ethyl) amino) -2-nitrobenzonitrile (450 mg, 1.709 mmol) in EtOH ( 25 mL), and the reaction mixture was refluxed for 16 hours. The reaction was concentrated and then ice water was added, followed by saturated aqueous NaHCO ₃ until pH ~ 9. EtOAc was added and the resulting mixture was filtered through celite. The organic layer was separated and the aqueous phase was back extracted with EtOAc (3x). Dried combined organic extracts were washed with brine, MgSO _4, filtered, and concentrated. The resulting residue was purified via silica chromatography (0% to 100% EtOAc / hexanes) to provide 2-amino-3-((2- (tertiary butoxy) ethyl) amino) as a solid) Benzonitrile (129 mg). LC-MS (ES) m / z = 177.96 [MC ₄ H ₈ + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.98 (dd, J = 1.5, 7.9 Hz, 1H), 6.83-6.89 (m, 1H), 6.74-6.82 (m, 1H), 3.60-3.71 (m, 2H ), 3.25 (t, J = 5.1Hz, 2H), 1.27 (s, 9H).

Example 53

1- (2- (tertiary butoxy) ethyl) -2- (6- (diethylamino) pyridin-3-yl) -1H-benzo [d] imidazole-4-carbonitrile

2-Amino-3-((2- (tertiary butoxy) ethyl) amino) benzonitrile (129 mg, 0.442 mmol), 6- (diethylamino) nicotinaldehyde (87 mg, 0.487 mmol), and a mixture of oxone (177 mg, 0.288 mmol) in DMF (10 mL) and water (4 mL) was stirred for 16 hours. Saturated aqueous NaHCO ₃ was added, and the resulting mixture was extracted with EtOAc. The washed sequentially with water and brine, the combined organic extracts were dried over MgSO _4, filtered, and concentrated. The resulting residue was purified via silica chromatography (0% to 50% EtOAc / hexane) to provide 1- (2- (tertiary butoxy) ethyl) -2- (6- (diethyl) as an oil Amine) pyridin-3-yl) -1H-benzo [d] imidazole-4-carbonitrile (98 mg). LC-MS (ES) m / z = 392 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.60 (d, J = 2.3Hz, 1H), 8.05 (dd, J = 2.5, 8.9Hz, 1H), 7.78 (dd, J = 0.8, 8.4Hz, 1H) , 7.60 (dd, J = 0.8, 7.4 Hz, 1H), 7.30 (t, J = 7.9 Hz, 1H), 6.61 (d, J = 8.9 Hz, 1H), 4.43 (t, J = 5.3 Hz, 2H) , 3.80 (t, J = 5.2Hz, 2H), 3.62 (q, J = 7.1Hz, 4H), 1.19-1.34 (m, 6H), 1.06 (s, 9H).

Example 54

1- (2- (tertiary butoxy) ethyl) -2- (6- (diethylamino) pyridin-3-yl) -1H-benzo [d] imidazole-4-carboxamide

1- (2- (tertiary butoxy) ethyl) -2- (6- (diethylamino) pyridin-3-yl) -1H-benzo [d] imidazole-4-carbonitrile (75 mg , 0.192 mmol) and sodium hydroxide (0.958 mL, 0.958 mmol) in water (2 mL) and EtOH (2 mL) were heated under microwave conditions at 128 ° C. for 90 minutes. The reaction was concentrated, water was added, and the resulting mixture was extracted with CH ₂ Cl ₂ . The washed CH ₂ Cl ₂ The combined extracts were washed with 1N NaOH, water, and brine sequentially. The organic extracts were then dried MgSO _4, filtered, and concentrated to provide an off-white solid of 1- (2- (three-butoxy) ethyl) -2- (6- (diethylamino) pyridin-3 -Yl) -1H-benzo [d] imidazole-4-carboxamide (41 mg). LC-MS (ES) m / z = 410 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 9.86 (br.s., 1H), 8.69 (br.s., 1H), 8.19 (dd, J = 0.9, 7.7 Hz, 1H), 8.07 (d, J = 7.6Hz, 1H), 7.68 (dd, J = 1.0, 7.9 Hz, 1H), 7.40 (t, J = 7.9 Hz, 1H), 6.63 (d, J = 8.9 Hz, 1H), 5.92 (d, J = 3.6Hz, 1H), 4.45 (t, J = 5.5Hz, 2H), 3.84 (t, J = 5.5Hz, 2H), 3.65 (q, J = 6.9Hz, 4H), 1.29 (t, J = 7.1 Hz, 6H), 1.09 (s, 9H).

Intermediate 85

N- (2-isopropoxyethyl) -2-nitroaniline

1-fluoro-2-nitrobenzene (0.302 mL, 2.86 mmol) and K ₂ CO ₃ (434 mg, 3.14 mmol) were added to 2-isopropoxyethyl-1-amine (324 mg, 3.14 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with water (40 mL) and then extracted with EtOAc (4 x 30 mL). The organic extracts were combined and washed with brine, dried (MgSO _4), filtered, and concentrated. Purification by flash chromatography on SiO ₂ (gradient from 0 to 25% EtOAc / hexane) provided N- (2-isopropoxyethyl) -2-nitroaniline as an orange / amber oil ( 545 mg). LC-MS (ES) m / z = 225 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.12 (d, J = 6.1Hz, 6H), 3.47 (m, 2H), 3.58-3.67 (m, 3H), 6.70 (m, 1H), 7.08 ( dd, J = 8.7, 0.9 Hz, 1H), 7.51-7.62 (m, 1H), 8.07 (dd, J = 8.6, 1.5Hz, 1H), 8.22 (br.s., 1H).

Intermediate 86

N1- (2-isopropoxyethyl) benzene-1,2-diamine

NiCl ₂ ‧ 6H ₂ O (1.45 g, 6.08 mmol) followed by sodium borohydride (460 mg, 12.15 mmol) was added in small portions to N- (2-isopropoxyethyl) cooled in an ice bath over 10 minutes A solution of 2-nitroaniline (545 mg, 2.430 mmol) in CH ₃ OH (15 mL), and the reaction mixture was stirred at room temperature for 30 minutes. The reaction was then diluted with concentrated NH ₄ OH (20mL) and extracted with _{CH 2 Cl 2 (3 x 30mL} ). The organic extracts were combined and washed with brine, dried (MgSO _4), filtered, and concentrated to provide a pale amber oil of N1- (2-isopropoxy-ethyl) benzene-1,2-diamine (458mg). LC-MS (ES) m / z = 195 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.11 (d, J = 6.1Hz, 6H), 3.15 (m, 2H), 3.54-3.63 (m, 3H), 4.34 (t, J = 5.7Hz, 1H), 4.44 (s, 2H), 6.39-6.58 (m, 4H).

Example 55

N, N-diethyl-5- (1- (2-isopropoxyethyl) -1H-benzo [d] imidazol-2-yl) pyridin-2-amine

6- (diethylamino) nicotinaldehyde (81 mg, 0.453 mmol) followed by oxone (165 mg, 0.268 mmol) was added to N1- (2 in DMF (2 mL) and water (2 mL) -Isopropoxyethyl) benzene-1,2-diamine (80 mg, 0.412 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. The reaction was quenched with saturated aqueous NH ₄ Cl followed by saturated aqueous NaHCO ₃ (5mL) was quenched, and the resulting mixture was extracted with EtOAc (3 x 20mL). The organic extracts were combined and washed with brine, dried (MgSO _4), filtered, and concentrated. Purification by flash chromatography on SiO ₂ (gradient from 0 to 45% EtOAc / hexane) provided N, N-diethyl-5- (1- (2-isopropoxyethyl) as a yellow oil Yl) -1H-benzo [d] imidazol-2-yl) pyridin-2-amine (97 mg). LC-MS (ES) m / z = 353 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 0.93 (d, J = 6.1Hz, 6H), 1.13-1.18 (m, 6H), 3.42 (m, 1H), 3.58 (q, J = 6.9Hz, 4H), 3.76 (t, J = 5.3Hz, 2H), 4.39 (t, J = 5.3Hz, 2H), 6.73 (d, J = 9.1Hz, 1H), 7.18-7.27 (m, 2H), 7.61- 7.65 (m, 2H), 7.99 (dd, J = 8.9, 2.5 Hz, 1H), 8.55 (d, J = 1.8 Hz, 1H).

Intermediate 87

3-chloro-N- (2-isopropoxyethyl) -2-nitroaniline

Add 2-isopropoxyethyl-1-amine (470 mg, 4.56 mmol) and potassium carbonate (630 mg, 4.56 mmol) to 1-chloro-3-fluoro-2-nitrobenzene (800 mg, 4.56 mmol) in DMF ( 20 mL), and the mixture was stirred at room temperature for 18 hours. The mixture was quenched with water (15 mL) and extracted with EtOAc (3x). The extract was dried and concentrated, and the resulting residue was purified using column chromatography (silica, 0 to 60% EtOAc / hexane) to give the desired product (900 mg) as a light brown oil. LC-MS (ES) m / z = 259,261 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 1.23 (d, J = 6.1Hz, 6H), 3.36 (t, J = 5.3Hz, 2H), 3.63-3.73 (m, 3H), 6.73-6.83 (m, 2H) 7.20-7.30 (m, 1H).

Intermediate 88

3-chloro-N1- (2-isopropoxyethyl) benzene-1,2-diamine

Sodium borohydride (256 mg, 6.76 mmol) was added to 3-chloro-N- (2-isopropoxyethyl) -2-nitroaniline (350 mg, 1.353 mmol) and NiCl ₂ ‧H _{A solution of 2} O (805 mg, 3.38 mmol) in CH ₃ OH (8 mL) was stirred, and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was concentrated, and the resulting residue was dissolved in concentrated NH ₄ OH and the extracted with EtOAc (3x). The extracts were dried (Na ₂ SO ₄₎ and concentrated to give the desired product as a light brown oil (300mg). LC-MS (ES) m / z = 229,231 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 1.19-1.27 (m, 6H), 3.25-3.34 (m, 2H), 3.64-3.76 (m, 3H), 3.84 (br.s., 2H), 6.59- 6.65 (m, 1H), 6.70-6.79 (m, 1H), 6.81-6.89 (m, 1H).

Example 56

5- (4-chloro-1- (2-isopropoxyethyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridine-2-amine

Add 6- (diethylamino) nicotinaldehyde (218 mg, 1.224 mmol) and oxone (753 mg, 1.224 mmol) to 3-chloro-N1- (2-isopropoxylate) at 0 ° C. Of ethyl ethyl) benzene-1,2-diamine (280 mg, 1.224 mmol) in DMF (8 mL) and water (1 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture 10% K ₂ CO ₃ aq and extracted with EtOAc (3x). The extracts were dried (Na ₂ SO ₄₎ and concentrated. The residue was purified using column chromatography (silica, 0 to 70% EtOAc / hexanes) to give the desired product (178 mg) as a light brown oil. LC-MS (ES) m / z = 387,389 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.00 (d, J = 6.1Hz, 6H), 1.25 (t, J = 7.1Hz, 6H), 3.45 (dt, J = 12.2, 6.1Hz, 1H), 3.64 (q, J = 7.1Hz, 4H), 3.85 (t, J = 5.2Hz, 2H), 4.46 (t, J = 5.2Hz, 2H), 6.77 (d, J = 9.1Hz, 1H), 7.23- 7.36 (m, 2H), 7.58 (dd, J = 7.9, 1.3 Hz, 1H), 8.02 (dd, J = 9.0, 2.4 Hz, 1H), 8.57 (dd, J = 2.5, 0.8 Hz, 1H).

Intermediate 89

4-((2-isopropoxyethyl) amino) -3-nitrobenzoate

Methyl 4-fluoro-3-nitrobenzoate (3.86 g, 19.39 mmol) and K ₂ CO ₃ (2.68 g, 19.39 mmol) were added to 2-isopropoxyethyl-1-amine (2.0 g, 19.39 mmol ) In DMF (100 mL), and the reaction mixture was stirred at room temperature overnight. The reaction was diluted with water (200 mL), and the resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed (20mL) with brine, dried over Na ₂ SO _4, filtered, and concentrated. The resulting residue was purified by flash chromatography on SiO ₂ (0-60% EtOAc / hexanes) to provide 4-((2-isopropoxyethyl) amino) -3 as a bright yellow solid -Methyl n-benzoate (5.43 g). LC-MS (ES) m / z = 283 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.91 (d, J = 2.0 Hz, 1H), 8.63 (br.s., 1H), 8.07 (dd, J = 2.2, 9.0 Hz, 1H), 6.90 (d , J = 9.1Hz, 1H), 3.92 (s, 3H), 3.74-3.79 (m, 2H), 3.70 (td, J = 6.1, 12.2Hz, 1H), 3.54 (q, J = 5.1Hz, 2H) , 1.24 (d, J = 6.1 Hz, 6H).

Intermediate 90

3-Amino-4-((2-isopropoxyethyl) amino) benzoate

Methyl 4-((2-isopropoxyethyl) amino) -3-nitrobenzoate (5.43 g, 19.24 mmol) and NiCl ₂ ‧ 6H ₂ O (11.43 g, 48.1 mmol) in CH ₃ OH The solution in (200 mL) was flushed with N ₂ and then cooled in an ice bath for 20 minutes. Sodium borohydride (3.64 g, 96 mmol) was added to the frozen solution in four portions, then the ice bath was removed, and the reaction mixture was stirred at room temperature for 2 hours. The reaction was concentrated in vacuo, and the remaining residue was dissolved in concentrated NH ₄ OH (150mL) and EtOAc (200mL). The resulting mixture was filtered through celite and rinsed with EtOAc (2 x 100 mL). The organic layer was separated and the aqueous phase was further extracted with EtOAc (2 x 100 mL). The organic extracts were washed with brine (6mL), dried with Na ₂ SO _4, filtered, concentrated, and dried under high vacuum overnight to provide a light brown solid 3-amino-4 - ((2- isopropoxy Methyl) amino) benzoic acid methyl ester (4.88 g). LC-MS (ES) m / z = 253 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 7.59 (d, J = 7.9Hz, 1H), 7.44 (s, 1H), 6.64 (d, J = 8.4Hz, 1H), 3.87 (s, 3H), 3.72 (t, J = 5.2Hz, 2H), 3.69-3.62 (m, 1H), 3.36 (br.s., 2H), 1.21 (d, J = 6.1Hz, 6H).

Intermediate 91

2- (6- (diethylamino) pyridin-3-yl) -1- (2-isopropoxyethyl) -1H-benzo [d] imidazole-5-carboxylic acid methyl ester

Add 6- (diethylamino) nicotinaldehyde (247 mg, 1.387 mmol) and potassium oxone (853 mg, 1.387 mmol) to 3-amino-4-((2-iso A solution of methyl propoxyethyl) amino) benzoate (350 mg, 1.387 mmol) in DMF (8 mL) and water (1.6 mL), the mixture was stirred at room temperature for 2 hours. The reaction mixture 10% K ₂ CO ₃ aq and extracted with EtOAc (3x). The extract was dried (Na ₂ SO ₄ ) and concentrated, and the resulting residue was purified using column chromatography (silica, 0 to 70% EtOAc / hexanes) to give the desired product (380 mg) as a light brown solid . LC-MS (ES) m / z = 411 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 0.99 (d, J = 6.1Hz, 6H), 1.21-1.30 (m, 6H), 3.46 (quin, J = 6.1Hz, 1H), 3.64 (q, J = 7.0Hz, 4H), 3.87 (t, J = 5.2Hz, 2H), 3.96 (s, 3H), 4.50 (t, J = 5.2Hz, 2H), 6.78 (d, J = 9.1Hz, 1H), 7.71 (d, J = 8.6 Hz, 1H), 8.02 (dt, J = 8.7, 2.2 Hz, 2H), 8.36 (d, J = 1.5 Hz, 1H), 8.53-8.63 (m, 1H).

Example 57

2- (6- (diethylamino) pyridin-3-yl) -1- (2-isopropoxyethyl) -1H-benzo [d] imidazole-5-carboxamide

8N NaOH (0.200 mL, 1.600 mmol) was added to 2- (6- (diethylamino) pyridin-3-yl) -1- (2-isopropoxyethyl) -1H-benzo [d] A solution of imidazole-5-carboxylic acid methyl ester (80 mg, 0.195 mmol) in CH ₃ OH (2 mL), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was neutralized by adding 6N aqueous HCl (0.267 mL, 1.600 mmol) and then concentrated to give crude 2- (6- (diethylamino) pyridin-3-yl) -1- (2-isopropyl (Oxyethyl) -1H-benzo [d] imidazole-5-carboxylic acid. The residue was dried under vacuum and treated with DMSO (2 mL). NH ₄ Cl (20.85 mg, 0.390 mmol), N-methylmorpholine (0.129 mL, 1.169 mmol), EDC (74.7 mg, 0.390 mmol), and 1-hydroxy-7-azabenzotriazole ( 53.1 mg, 0.390 mmol) was added to the mixture, and the mixture was stirred at room temperature for 18 hours. The reaction was quenched with water (5 mL), and the resulting precipitate was collected by filtration and dried under vacuum to give the desired product (37 mg) as an off-white solid. LC-MS (ES) m / z = 396 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.00 (d, J = 6.1Hz, 6H), 1.25 (t, J = 7.0Hz, 6H), 3.46 (dt, J = 12.2, 5.9Hz, 1H), 3.65 (q, J = 7.1Hz, 4H), 3.88 (t, J = 5.1Hz, 2H), 4.50 (t, J = 5.1Hz, 2H), 6.78 (d, J = 9.12Hz, 1H), 7.71 ( d, J = 8.36 Hz, 1H), 7.89 (dd, J = 8.6, 1.5 Hz, 1H), 8.02 (dd, J = 9.0, 2.4 Hz, 1H), 8.24 (d, J = 1.0 Hz, 1H), 8.58 (d, J = 2.0Hz, 1H).

Intermediate 92

1- (2-isopropoxyethyl) -2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-5-carboxylic acid ( S) -methyl ester

Oxone (190 mg, 0.309 mmol) was added to methyl 3-amino-4-((2-isopropoxyethyl) amino) benzoate (120 mg, 0.476 mmol) and (S ) -6- (2-methylpyrrolidin-1-yl) nicotinaldehyde (100 mg, 0.523 mmol) in DMF (4 mL) and water (3 mL), and the reaction mixture was stirred at room temperature for 45 minutes . The reaction was diluted with saturated Na ₂ CO ₃ solution (7 mL) and EtOAc (15mL). The aqueous solution was washed with EtOAc (2 x 15 mL). The combined organic layers were washed with brine (6 mL), dried over Na ₂ SO _4, filtered, and concentrated. The resulting residue was purified on silica (0-100% EtOAc / hexanes) to provide (S) -1- (2-isopropoxyethyl) -2- (6- (2- Methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-5-carboxylic acid methyl ester (183 mg). LC-MS (ES) m / z = 423 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 8.57 (d, J = 2.0Hz, 1H), 8.23 (d, J = 1.0Hz, 1H), 8.01 (dd, J = 2.3, 8.9Hz, 1H) , 7.88 (dd, J = 1.7, 8.5 Hz, 1H), 7.76 (d, J = 8.6 Hz, 1H), 6.61 (d, J = 8.9 Hz, 1H), 4.44 (t, J = 5.2 Hz, 2H) , 4.24 (t, J = 5.6Hz, 1H), 3.88 (s, 3H), 3.76 (t, J = 5.3Hz, 2H), 3.53-3.61 (m, 1H), 3.34-3.37 (m, 3H), 2.01-2.12 (m, 2H), 1.68-1.75 (m, 1H), 1.21 (d, J = 6.3Hz, 3H), 0.91 (dd, J = 0.8, 6.1Hz, 6H).

Example 58

(S) -1- (2-isopropoxyethyl) -2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole- 5-formamidine

The 10N NaOH (0.043mL, 0.426mmol) and THF (1mL; to aid solubility) was added to in CH ₃ OH (4mL) of (S) -1- (2- isopropoxy-ethyl) -2- ( 6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-5-carboxylic acid methyl ester (180 mg, 0.426 mmol), and the reaction mixture was at 40 ° C Stir overnight. Then additional 10N NaOH (0.298 mL, 2.98 mmol) was added and the reaction was stirred at 40 ° C for another 2 hours. The heat was removed and the pH was adjusted to near neutral with 6N HCl (0.575 mL, 3.45 mmol). The solvent was removed in vacuo and the remaining solid was dissolved in DMSO (3 mL). The DMSO solution was decanted and transferred to a 20 mL vial. EDC (163 mg, 0.852 mmol), HOAT (131 mg, 0.852 mmol), ammonium chloride (45.6 mg, 0.852 mmol), and N-methylmorpholine (0.281 mL, 2.56 mmol) were added to the DMSO solution, and The reaction mixture was stirred at room temperature overnight. The reaction was quenched with water (6 mL), and the resulting aqueous solution was extracted with Et ₂ O (3 x 9 mL) followed by EtOAc (3 x 6 mL). The combined organic layers were washed with 0.5 N HCl (6 mL). With 1N Na ₂ CO ₃ (3mL) the aqueous acidic extracts were made basic, and the aqueous mixture was extracted with EtOAc (2 x 6mL). The combined organic extracts were washed with brine (2mL), dried over Na ₂ SO _4, filtered, concentrated, and dried under high vacuum. The resulting residue was freeze-dried to provide (S) -1- (2-isopropoxyethyl) -2- (6- (2-methylpyrrolidin-1-yl) pyridine-3- as a brown solid Yl) -1H-benzo [d] imidazole-5-carboxamide (15 mg). LC-MS (ES) m / z = 408 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.69 (s, 1H), 8.27 (s, 1H), 8.18-8.06 (m, J = 6.6Hz, 1H), 7.96 (dd, J = 1.5,8.6Hz, 1H), 7.61 (d, J = 8.6Hz, 1H), 6.59 (d, J = 8.9Hz, 1H), 4.47 (t, J = 5.3Hz, 2H), 3.88 (t, J = 5.4Hz, 3H) , 3.51 (td, J = 6.1, 12.2 Hz, 2H), 2.25-2.08 (m, 5H), 1.31 (d, J = 6.3 Hz, 4H), 1.07 (d, J = 6.1 Hz, 8H).

Example 59

(S) -1- (2-isopropoxyethyl) -2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole- 5-formamidine

(S) -1- (2-isopropoxyethyl) -2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole Solution of 5--5-formic acid (58.0mg, 0.142mmol) in DMSO (1mL) with EDC (54.4mg, 0.284mmol), HOAT (43.8mg, 0.284mmol), NMM (0.094mL, 0.852mmol), and methylamine hydrochloride Treat with salt (19.17 mg, 0.284 mmol) and stir the reaction mixture at room temperature overnight. The reaction was quenched with water (6 mL), and the resulting aqueous mixture was washed with EtOAc (3 x 9 mL). , Brine (2mL) sequentially combined organic layer was washed with _{1N Na 2 CO 3 (3mL)} , dried over Na ₂ SO _4, filtered, concentrated, and dried under high vacuum. The remaining residue was purified by silica gel chromatography (0-100%, EtOAc / hexane) and lyophilized to provide (S) -1- (2-isopropoxyethyl)-as a brown solid N-methyl-2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-5-carboxamide (20 mg). LC-MS (ES) m / z = 422 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.60 (d, J = 2.0 Hz, 1 H), 8.13 (d, J = 1.3 Hz, 1 H), 7.99 (dd, J = 2.4, 9.0 Hz, 1 H), 7.85 (dd, J = 1.7, 8.5Hz, 1H), 7.55 (d, J = 8.6Hz, 1H), 6.52 (d, J = 1.8Hz, 1H), 6.25-6.35 (m, J = 4.6Hz, 1H) , 4.42 (t, J = 5.6 Hz, 2H), 4.27 (t, J = 5.8 Hz, 1H), 3.84 (t, J = 5.6 Hz, 2H), 3.74 (q, J = 7.0 Hz, 1H), 3.62 -3.70 (m, 1H), 3.48 (m, 2H), 3.07 (d, J = 4.8Hz, 3H), 2.10-2.21 (m, 2H), 1.27-1.31 (m, 4H), 1.06 (dd, J = 1.0,6.1Hz, 6H).

Intermediate 93

4-bromo-3-chloro-N- (2-isopropoxyethyl) -2-nitroaniline

NBS (482 mg, 2.71 mmol) was added to a solution of 3-chloro-N- (2-isopropoxyethyl) -2-nitroaniline (700 mg, 2.71 mmol) in acetic acid (15 mL), and the mixture was dissolved in Stir at 100 ° C for 3 hours. The reaction mixture was concentrated, and the resulting residue was purified using column chromatography (silica, 0 to 60% EtOAc / hexanes) to give the desired product (790 mg) as a light brown solid. LC-MS (ES) m / z = 337,339 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 1.21 (d, J = 6.1Hz, 6H), 3.32 (t, J = 5.3Hz, 2H), 3.60-3.69 (m, 3H), 6.67 (d, J = 9.4Hz, 1H), 7.53 (d, J = 9.1Hz, 1H).

Intermediate 94

4-bromo-3-chloro-N1- (2-isopropoxyethyl) benzene-1,2-diamine

NiCl ₂ ‧6H ₂ O (952 mg, 4.00 mmol) and sodium borohydride (303 mg, 8.00 mmol) were added to 4-bromo-3-chloro-N- (2-isopropoxyethyl)-at 0 ° C. A solution of 2-nitroaniline (540 mg, 1.600 mmol) in CH ₃ OH (10 mL), and the mixture was stirred at 0 ° C. for 20 minutes. The reaction mixture was concentrated and the resulting residue was treated with NH ₄ OH and extracted with EtOAc (3x). The extracts were dried (Na ₂ SO ₄₎ and concentrated to give the desired product as a light brown oil (470mg). LC-MS (ES) m / z = 307,309 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 1.21-1.26 (m, 6H), 3.22-3.30 (m, 2H), 3.95 (m , 3H), 3.63-3.76 (m, 3H), 6.51 (d, J = 8.6 Hz, 1H), 7.02-7.09 (m, 1H).

Intermediate 95

5- (5-bromo-4-chloro-1- (2-isopropoxyethyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridine-2-amine

Add 6- (diethylamino) nicotinaldehyde (272 mg, 1.528 mmol) and potassium oxone (751 mg, 1.222 mmol) to 4-bromo-3-chloro-N1- (2 at 0 ° C. -Isopropoxyethyl) benzene-1,2-diamine (470 mg, 1.528 mmol) in DMF (10 mL) and water (2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture 10% K ₂ CO ₃ aq and extracted with EtOAc (3x). The organic extract was dried (Na ₂ SO ₄ ) and concentrated, and the resulting residue was purified using column chromatography (silica, 0 to 70% EtOAc / hexanes) to give the desired product as a light brown solid (430 mg ). LC-MS (ES) m / z = 465,467 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 1.05-1.13 (m, 6H), 1.22-1.31 (m, 6H), 3.51 (dt, J = 12.2, 6.2Hz, 1H), 3.62 (q, J = 7.1 Hz, 4H), 3.80-3.88 (m, 2H), 4.34-4.44 (m, 2H), 6.60 (d, J = 8.9Hz, 1H), 7.30-7.38 (m, 1H), 7.50 (d, J = 8.6Hz, 1H), 7.94-8.02 (m, 1H), 8.54-8.58 (m, 1H).

Intermediate 96

4-chloro-2- (6- (diethylamino) pyridin-3-yl) -1- (2-isopropoxyethyl) -1H-benzo [d] imidazole-5-carbonitrile

Zn (CN) ₂ (55.5 mg, 0.472 mmol) was added to 5- (5-bromo-4-chloro-1- (2-isopropoxyethyl) -1H-benzo [d] imidazole-2- ) -N, N-diethylpyridin-2-amine (100 mg, 0.215 mmol) in N-methyl-2-pyrrolidone (NMP) (2 mL) and the mixture was bubbled with N ₂ Degas for 5 minutes. Then Pd (PPh ₃ ) ₄ (37.2 mg, 0.032 mmol) was added and the mixture was stirred at 120 ° C. for 18 hours. The mixture was cooled to room temperature, quenched with water (5 mL), and extracted with EtOAc (3x). The extracts were dried (Na ₂ SO ₄₎ and concentrated. The resulting residue was purified using column chromatography (silica, 0 to 70% EtOAc / hexanes) to give the desired product (31 mg) as a brown solid. LC-MS (ES) m / z = 412,414 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 1.02-1.10 (m, 6H), 1.26 (t, J = 7.1Hz, 6H), 3.44-3.54 (m, 1H), 3.62 (q, J = 6.9Hz, 4H), 3.83 (t, J = 5.3Hz, 2H), 4.42 (t, J = 5.2Hz, 2H), 6.61 (d, J = 9.1Hz, 1H), 7.50-7.54 (m, 2H), 7.99 ( dd, J = 9.0, 1.9 Hz, 1H), 8.56 (d, J = 2.0 Hz, 1H).

Example 60

4-chloro-2- (6- (diethylamino) pyridin-3-yl) -1- (2-isopropoxyethyl) -1H-benzo [d] imidazole-5-carboxamide

1N NaOH aqueous solution (0.728 mL, 0.728 mmol) was added to 4-chloro-2- (6- (diethylamino) pyridin-3-yl) -1- (2-isopropoxyethyl) -1H- A solution of benzo [d] imidazole-5-carbonitrile (30 mg, 0.073 mmol) in EtOH (2 mL), and the mixture was stirred at 85 ° C for 10 hours. The mixture was concentrated, and the resulting residue was treated with 1N NaOH (3 mL) and extracted with EtOAc (3x). The extract was dried (Na ₂ SO ₄ ) and concentrated, and the resulting residue was purified by silica gel chromatography (0 to 100% (3: 1 EtOAc: EtOH) / hexane) to give the desired as an off-white solid Product (20 mg). LC-MS (ES) m / z = 430,432 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 0.99 (d, J = 6.3Hz, 6H), 1.25 (t, J = 7.0Hz, 6H), 3.46 (dt, J = 12.2, 6.1Hz, 1H), 3.61-3.72 (m, 4H), 3.85 (t, J = 5.2Hz, 2H), 4.48 (t, J = 5.1Hz, 2H), 6.78 (d, J = 9.6Hz, 1H), 7.50 (d, J = 8.4Hz, 1H), 7.66 (d, J = 8.4Hz, 1H), 8.02 (dd, J = 9.1,2.5Hz, 1H), 8.58 (d, J = 1.8Hz, 1H).

Intermediate 97

4-chloro-2- (6- (diethylamino) pyridin-3-yl) -1- (2-isopropoxyethyl) -1H-benzo [d] imidazole-5-carboxaldehyde

Add n-butyllithium (2M, 0.213mL, 0.425mmol) in hexane to 5- (5-bromo-4-chloro-1- (2-isopropoxyethyl) -1H-benzo [ d] A solution of imidazol-2-yl) -N, N-diethylpyridine-2-amine (180 mg, 0.386 mmol) in THF (3 ml), and the mixture was stirred at -78 ° C for 30 minutes. DMF (0.045 mL, 0.580 mmol) was added, and the mixture was slowly heated to -10 ° C and stirred for 1 hour. The reaction was quenched with aqueous NH ₄ Cl and extracted with EtOAc (3x). The extracts were dried (Na ₂ SO ₄₎ and concentrated. The resulting residue was purified using column chromatography (silica, 0 to 100% EtOAc / hexanes) to give the desired product (33 mg) as a white solid. LC-MS (ES) m / z = 415,417 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.02-1.12 (m, 6H), 1.23-1.32 (m, 6H), 3.50 (dt, J = 12.2, 6.1Hz, 1H), 3.63 (q, J = 7.1Hz, 4H), 3.84 (t, J = 5.3Hz, 2H), 4.44 (t, J = 5.3Hz, 2H), 6.61 (d, J = 9.1Hz, 1H), 7.47-7.56 (m, 1H) , 7.91 (d, J = 8.4 Hz, 1H), 8.00 (dd, J = 9.0, 2.4 Hz, 1H), 8.59 (d, J = 2.0 Hz, 1H), 10.66 (s, 1H).

Example 61

5- (4-chloro-1- (2-isopropoxyethyl) -5- (morpholinylmethyl) -1H-benzo [d] imidazol-2-yl) -N, N-di Ethylpyridin-2-amine

Morpholine (8.06 μl, 0.093 mmol) and sodium triethoxyalkoxyborohydride (32.7 mg, 0.154 mmol) were added to 4-chloro-2- (6- (diethylamino) pyridin-3-yl) A solution of -1- (2-isopropoxyethyl) -1H-benzo [d] imidazole-5-carboxaldehyde (32 mg, 0.077 mmol) in 1,2-dichloroethane (1 mL), and The reaction mixture was stirred at room temperature overnight. The mixture was quenched with saturated NaHCO ₃ and extracted with CH ₂ Cl ₂ (3x). The organic extract was dried over Na ₂ SO _4, filtered, and concentrated. The resulting residue was purified using column chromatography (silica gel, 0 to 100% EtOAc / heptane) to give the desired product (27 mg) as a colorless oil. LC-MS (ES) m / z = 486,488 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.00 (d, J = 6.1Hz, 6H), 1.21-1.31 (m, 6H), 2.54-2.63 (m, 4H), 3.46 (dt, J = 12.2, 6.1Hz, 1H), 3.64 (q, J = 7.1Hz, 4H), 3.69-3.76 (m, 4H), 3.81-3.88 (m, 4H), 4.45 (t, J = 5.2Hz, 2H), 6.78 ( d, J = 8.9Hz, 1H), 7.46 (d, J = 8.4Hz, 1H), 7.57 (d, J = 8.4Hz, 1H), 8.01 (dd, J = 9.1, 2.5Hz, 1H), 8.57 ( d, J = 2.0Hz, 1H).

Intermediate 98

N- (2-ethoxyethyl) -2-nitroaniline

1-fluoro-2-nitrobenzene (7.91 g, 56.1 mmol) and K ₂ CO ₃ (7.75 g, 56.1 mmol) were added to 2-ethoxyethyl-1-amine (5.00 g) in DMF (100 mL) , 56.1 mmol), and the reaction mixture was stirred at room temperature overnight. The mixture was filtered and rinsed with EtOAc (20 mL). The filtrate was diluted with water (250 mL), and the resulting mixture was extracted with EtOAc (5 x 120 mL). The combined organic layers were washed (20mL) with brine, dried over Na ₂ SO _4, filtered, and concentrated in vacuo. The remaining residue was purified by silica chromatography (0-60%, EtOAc / hexane) to provide the desired product (11.18 g) as an orange oil. LC-MS (ES) m / z = 211 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.17-8.28 (m, 1H), 8.07 (dd, J = 1.5, 8.6 Hz, 1H), 7.55 (ddd, J = 1.1, 7.1, 8.5 Hz, 1H ), 7.09 (dd, J = 1.0, 8.6 Hz, 1H), 6.70 (ddd, J = 1.1, 7.1, 8.5 Hz, 1H), 3.59-3.69 (m, 2H), 3.45-3.55 (m, 4H), 1.14 (t, J = 7.0Hz, 3H).

Intermediate 99

N1- (2-ethoxyethyl) benzene-1,2-diamine

A solution of N- (2-ethoxyethyl) -2-nitroaniline (11.18 g, 53.2 mmol) and NiCl ₂ ‧ 6H ₂ O (31.6 g, 133 mmol) in CH ₃ OH (400 mL) was treated with N ₂ Rinse and then cool to 0 ° C. Sodium borohydride (10.06 g, 266 mmol) was added to this solution in portions to keep the reaction temperature around 0 ° C. After the addition was complete, the reaction mixture was heated to 20 ° C. The reaction was filtered through celite, and the filtrate was then concentrated in vacuo. The remaining residue was dissolved in concentrated NH ₄ OH (150mL) and EtOAc (200mL), and the resulting mixture was filtered through diatomaceous earth, washed with EtOAc (2 x 100mL). The organic phase was separated and the aqueous phase was further extracted with EtOAc (2 x 100 mL). The organic extract was filtered through a pad by the silicone on diatomaceous earth, and the filtrate was concentrated and the remaining residue was dissolved in CH ₂ Cl ₂ and NH ₄ OH in. The organic layer was separated and filtered through a pad of diatomaceous earth on silica. The organic filtrate was washed with brine (6 mL), dried over Na ₂ SO _4, filtered, and concentrated in vacuo, and dried overnight under high vacuum to provide the desired product as a black-oil (3.15g). LC-MS (ES) m / z = 181 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 6.39-6.59 (m, 4H), 4.47 (s, 2H), 4.38 (t, J = 5.7Hz, 1H), 3.57 (t, J = 5.8Hz, 2H), 3.48 (q, J = 6.9Hz, 2H), 3.18 (q, J = 5.8Hz, 2H), 1.10-1.19 (m, 3H).

Example 62

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [ d) imidazole

Add potassium oxone (344 mg, 0.559 mmol) to N1- (2-ethoxyethyl) benzene-1,2-diamine (155 mg, in DMF (3 mL) and water (3 mL) 0.860 mmol) and 6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (193 mg, 0.946 mmol), and the reaction mixture was stirred at room temperature for 45 minutes. The reaction was quenched with saturated aqueous NH ₄ Cl (8mL), and treated with NH ₄ OH (10mL) the pH was adjusted to ~ 10. The product was extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with brine (3 mL), dried over Na ₂ SO ₄ , filtered, and concentrated. The remaining residue was purified and lyophilized by silica gel chromatography (0-100%, EtOAc / hexanes) to provide the desired product (228 mg) as a reddish brown viscous solid. LC-MS (ES) m / z = 365 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 8.54 (d, J = 1.8Hz, 1H), 7.93-7.98 (m, 1H), 7.58-7.66 (m, 2H), 7.16-7.28 (m, 2H ), 6.62 (d, J = 8.9Hz, 1H), 4.42 (t, J = 5.3Hz, 2H), 4.25 (br.s., 2H), 3.76 (t, J = 5.5Hz, 2H), 3.26- 3.34 (m, 2H), 2.24 (br.s., 2H), 1.66 (d, J = 5.6Hz, 2H), 1.15 (d, J = 6.1Hz, 6H), 0.97 (t, J = 7.0Hz, 3H).

Example 63

2- (6-((2S, 5R) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [ d) imidazole

Add potassium oxone (488 mg, 0.793 mmol) to N1- (2-ethoxyethyl) benzene-1,2-diamine (220 mg, 1.221 mmol) and 6-((2S, 5R) -2,5-Dimethylpyrrolidin-1-yl) nicotinaldehyde (274 mg, 1.343 mmol) in DMF (3 mL) and water (3 mL), and the reaction mixture was stirred at room temperature for 45 minutes. The reaction was quenched with saturated aqueous NH ₄ Cl (8mL), and treated with conc. NH ₄ OH (10mL) the pH was adjusted to ~ 10. The product was extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with brine (3 mL), dried over Na ₂ SO ₄ , filtered, and concentrated. The resulting residue was purified by silica chromatography (0-60%, EtOAc / hexanes) to provide the desired product (390 mg) as a red-brown sticky solid. LC-MS (ES) m / z = 365 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 8.55 (d, J = 2.3Hz, 1H), 7.98 (dd, J = 2.5, 8.9Hz, 1H), 7.57-7.69 (m, 2H), 7.15- 7.29 (m, 2H), 6.63 (d, J = 8.9Hz, 1H), 4.42 (t, J = 5.3Hz, 2H), 4.06-4.20 (m, 2H), 3.77 (t, J = 5.3Hz, 2H ), 3.28-3.34 (m, 2H), 2.08 (d, J = 2.0Hz, 2H), 1.75 (d, J = 7.4Hz, 2H), 1.31 (d, J = 6.3Hz, 6H), 0.98 (t , J = 7.0Hz, 3H).

Example 64

(S) -1- (2-ethoxyethyl) -2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole

Add oxone (100 mg, 0.162 mmol) to N1- (2-ethoxyethyl) benzene-1,2-diamine (45.0 mg, 0.250 mmol) and (S) -6- ( A mixture of 2-methylpyrrolidin-1-yl) nicotinaldehyde (52.2 mg, 0.275 mmol) in DMF (1.5 mL) and water (1.5 mL), and the reaction mixture was stirred at room temperature for 45 minutes. The reaction was quenched with saturated aqueous NH ₄ Cl (8mL), and treated with NH ₄ OH (10mL) and the pH was adjusted to ~ 10 (paper). The product was extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with brine (3 mL), dried over Na ₂ SO ₄ , filtered, and concentrated. By reverse phase HPLC (0-25% CH ₃ CN / 0.1% TFA in water of) the remaining residue was purified to provide (19mg) as a pale yellow sticky solid. LC-MS (ES) m / z = 351 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 8.73 (d, J = 1.8Hz, 1H), 8.21 (dd, J = 2.5, 9.1Hz, 1H), 7.93-8.02 (m, 1H), 7.79- 7.87 (m, 1H), 7.60-7.69 (m, 2H), 6.83-7.03 (m, 1H), 4.65-4.74 (m, 2H), 4.28-4.49 (m, 1H), 4.00 (t, J = 5.1 Hz, 2H), 3.70-3.80 (m, 1H), 3.52-3.62 (m, 1H), 3.48 (q, J = 7.1Hz, 2H), 2.09-2.38 (m, 3H), 1.84-1.95 (m, 1H), 1.33 (d, J = 6.3Hz, 3H), 1.10 (t, J = 7.0Hz, 3H).

Example 65

1- (2-ethoxyethyl) -2- (1-ethyl-2,2-dimethyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridine-5- Yl) -1H-benzo [d] imidazole

N1- (2-ethoxyethyl) benzene-1,2-diamine (37.9 mg, 0.211 mmol), 1-ethyl-2,2-dimethyl-2,3-dihydro-1H- A mixture of pyrrolo [2,3-b] pyridine-5-carboxaldehyde (43 mg, 0.211 mmol), and potassium oxone (129 mg, 0.211 mmol) in water (10 mL) and DMF (10 mL) was in the chamber Stir all weekend. Saturated aqueous NaHCO ₃ was then added, and the resulting aqueous mixture was extracted with EtOAc. The combined organic extracts were washed with water then brine, dried over MgSO _4, filtered, and concentrated. The resulting residue was purified via SiO ₂ chromatography (0% to 100% (3: 1 EtOAc: EtOH) / heptane) to provide a purple solid. Additional purification by reverse-phase HPLC (5% to 95% CH ₃ CN / (0.1% NH ₄ OH in H ₂ O)) provided 1- (2-ethoxyethyl) -2 as a brown solid -(1-ethyl-2,2-dimethyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1H-b] pyridin-5-yl) -1H-benzo [d] imidazole (40 mg). LC-MS (ES) m / z = 365 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.20-8.36 (m, 1H), 7.76-7.88 (m, 1H), 7.66 (d, J = 1.8Hz, 1H), 7.45-7.56 (m, 1H), 7.19-7.35 (m, 2H), 4.44 (t, J = 6.0Hz, 2H), 3.86 (t, J = 6.0Hz, 2H), 3.43 (m, 4H), 2.90 (s, 2H), 1.35 (s , 6H), 1.31 (t, J = 7.1 Hz, 3H), 1.15 (t, J = 7.0 Hz, 3H).

Example 66

7- (1- (2-ethoxyethyl) -1H-benzo [d] imidazol-2-yl) -4-ethyl-3-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4]

4-ethyl-3-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] -7-formaldehyde (280 mg, 1.358 mmol), N1- (2-ethoxyethyl) benzene-1,2-diamine (245 mg, 1.358 mmol), and sodium metabisulfite (336 mg, 1.765 mmol) in DMF ( 15 mL) was stirred at 90 ° C for 12 hours. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated. The resulting residue was purified by silica chromatography (dialysis with 0 to 20% EtOAc / hexanes) to give the desired product (160 mg) as a brown solid. LC-MS (ES) m / z = 367 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.20 (d, J = 1.5 Hz, 1H), 7.86-7.77 (m, 1H), 7.53-7.44 (m, 2H), 7.34-7.27 (m, 2H), 4.42 (t, J = 5.8Hz, 2H), 4.13-4.01 (m, 3H), 3.84 (t, J = 5.8Hz, 2H), 3.76-3.67 (m, 1H), 3.49-3.32 (m, 3H) , 1.32 (d, J = 6.6 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H), 1.14 (t, J = 7.0 Hz, 3H).

Example 67

5- (1- (2-ethoxyethyl) -1H-benzo [d] imidazol-2-yl) -N-ethyl-N- (2,2,2-trifluoroethyl) pyridine- 2-amine

Add N1- (2-methoxyethyl) benzene-1,2-diamine (143 mg, 0.861 mmol) to 6- (ethyl (2,2,2-trifluoroethyl) amino) nicotine A solution of aldehyde (200 mg, 0.861 mmol) and sodium metabisulfite (213 mg, 1.120 mmol) in DMF (10 mL), and the mixture was stirred at 90 ° C for 12 hours. The mixture was poured into water (150 ml) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated. The resulting residue was purified by silica chromatography (dialysis with 0 to 20% EtOAc / hexanes) to give the desired product (260 mg) as a pale yellow solid. LC-MS (ES) m / z = 393 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.64 (s, 1H), 8.07 (d, J = 8.9Hz, 1H), 7.85-7.78 (m, 1H), 7.51-7.44 (m, 1H), 7.34- 7.28 (m, 2H), 6.74 (d, J = 8.9Hz, 1H), 4.44-4.31 (m, 4H), 3.85 (t, J = 5.6Hz, 2H), 3.65 (q, J = 7.1Hz, 2H ), 3.43 (q, J = 7.0 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H), 1.13 (t, J = 7.0 Hz, 3H).

Intermediate 100

3-chloro-N- (2-ethoxyethyl) -2-nitroaniline

Add 2-ethoxyethyl-1-amine (203 mg, 2.279 mmol) and K ₂ CO ₃ (315 mg, 2.279 mmol) to 1-chloro-3-fluoro-2-nitrobenzene (400 mg, 2.279 mmol) in DMF (10 mL), and the mixture was stirred at room temperature for 18 hours. The mixture was quenched with water (20 mL) and extracted with EtOAc (3x). The extract was dried and concentrated, and the resulting residue was purified using column chromatography (silica gel, 0 to 60% EtOAc / hexanes) to give the desired product (400 mg) as a light brown oil. LC-MS (ES) m / z = 245,247 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 1.17-1.44 (m, 3H), 3.34-3.44 (m, 2H), 3.49-3.65 (m, 2H), 3.65-3.76 (m, 2H), 6.66-6.89 (m, 2H), 7.17-7.38 (m, 1H).

Intermediate 101

3-chloro-N1- (2-ethoxyethyl) benzene-1,2-diamine

NiCl ₂ ‧ 6H ₂ O (584 mg, 2.452 mmol) and sodium borohydride (186 mg, 4.90 mmol) were added to 3-chloro-N- (2-ethoxyethyl) -2-nitroaniline ( 240 mg, 0.981 mmol) in CH ₃ OH (6 mL), and the mixture was stirred at 0 ° C. for 20 minutes. The reaction mixture was concentrated and the resulting residue was treated with NH ₄ OH and extracted with EtOAc (3x). The extracts were dried (Na ₂ SO ₄₎ and concentrated to give the desired product as a light brown oil (203mg). LC-MS (ES) m / z = 215,217 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 1.25-1.30 (m, 3H), 3.31 (t, J = 4.9Hz, 2H), 3.59 (q, J = 7.0Hz, 2H), 3.69-3.78 (m, 2H), 6.56-6.66 (m, 1H), 6.75 (t, J = 8.0Hz, 1H), 6.81-6.89 (m, 1H).

Example 68

5- (4-chloro-1- (2-ethoxyethyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridine-2-amine

Add 6- (diethylamino) nicotinaldehyde (174 mg, 0.978 mmol) and potassium oxone (601 mg, 0.978 mmol) to 3-chloro-N1- (2-ethoxy) at 0 ° C. A solution of ethyl) benzene-1,2-diamine (210 mg, 0.978 mmol) in DMF (5 mL) and water (1 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture 10% K ₂ CO ₃ aq and extracted with EtOAc (3x). The extracts were dried (Na ₂ SO ₄₎ and concentrated. The resulting residue was purified using column chromatography (silica gel, 0 to 70% EtOAc / hexanes) to give the desired product (195 mg) as a light brown oil. LC-MS (ES) m / z = 373,375 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.07 (t, J = 7.1Hz, 3H), 1.28 (t, J = 7.1Hz, 6H), 3.35-3.48 (m, 2H), 3.67 (q, J = 7.1Hz, 4H), 3.88 (t, J = 5.1Hz, 2H), 4.52 (t, J = 5.1Hz, 2H), 6.91 (d, J = 9.1Hz, 1H), 7.31-7.42 (m, 2H ), 7.64 (dd, J = 8.0, 1.14 Hz, 1H), 8.04-8.13 (m, 1H), 8.59 (d, J = 1.8 Hz, 1H).

Intermediate 102

4-bromo-N- (2-ethoxyethyl) -3-methyl-2-nitroaniline

2-ethoxyethyl-1-amine (0.381 g, 4.27 mmol) and K ₂ CO ₃ (0.591 g, 4.27 mmol) were added to 1-bromo-4-fluoro-2-methyl-3-nitrobenzene ( 1 g, 4.27 mmol) in DMF (20 mL), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered, and the filtrate was concentrated. The resulting residue was purified using column chromatography (silica, 0 to 60% EtOAc / hexanes) to give the desired product (760 mg) as a light brown oil. LC-MS (ES) m / z = 303,305 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 1.27 (t, J = 7.1Hz, 3H), 2.47 (s, 3H), 3.36 (t, J = 5.3Hz, 2H), 3.58 (q, J = 7.1Hz , 2H), 3.65-3.72 (m, 2H), 6.61 (d, J = 9.1Hz, 1H), 7.51 (d, J = 9.1Hz, 1H).

Intermediate 103

4-bromo-N1- (2-ethoxyethyl) -3-methylbenzene-1,2-diamine

NiCl ₂ ‧6H ₂ O (785 mg, 3.30 mmol) and sodium borohydride (250 mg, 6.60 mmol) were added to 4-bromo-N- (2-ethoxyethyl) -3-methyl- at 0 ° C. A solution of 2-nitroaniline (400 mg, 1.319 mmol) in CH ₃ OH (7 mL), and the mixture was stirred at 0 ° C. for 20 minutes. The reaction mixture was concentrated, and the residue was treated with concentrated aqueous NH ₄ OH and extracted with EtOAc (3x). The extracts were dried (Na ₂ SO ₄₎ and concentrated to give the desired product as a light brown solid (352mg). LC-MS (ES) m / z = 273,275 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.19-1.30 (m, 3H), 2.29 (s, 3H), 3.22-3.28 (m, 2H), 3.53-3.63 (m, 2H), 3.66-3.73 ( m, 2H), 6.47 (d, J = 8.6 Hz, 1H) 6.89 (d, J = 8.6 Hz, 1H).

Intermediate 104

5-bromo-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -4 -Methyl-1H-benzo [d] imidazole

6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (262 mg, 1.281 mmol) and oxone (591 mg, 0.961 mmol) at 0 ° C ) To 4-bromo-N1- (2-ethoxyethyl) -3-methylbenzene-1,2-diamine (350 mg, 1.281 mmol) in DMF (6 mL) and water (1.2 mL) Solution, and the mixture was stirred at room temperature for 2 hours. The reaction mixture 10% K ₂ CO ₃ aq and extracted with EtOAc (3x). The extracts were dried (Na ₂ SO ₄₎ and concentrated. The resulting residue was purified using column chromatography (silica gel, 0 to 100% EtOAc / hexane) to give the desired product (320 mg) as a light brown solid. LC-MS (ES) m / z = 457,459 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 1.11-1.20 (m, 3H), 1.24 (d, J = 6.3Hz, 6H), 1.65-1.82 (m, 2H), 2.27-2.40 (m, 2H), 2.79 (s, 3H), 3.45 (q, J = 6.9Hz, 2H), 3.77-3.91 (m, 2H), 4.25-4.43 (m, 4H), 6.52 (d, J = 8.9Hz, 1H), 7.23 (d, J = 8.6 Hz, 1H), 7.46 (d, J = 8.6 Hz, 1H), 7.92 (d, J = 7.9 Hz, 1H), 8.57 (s, 1H).

Example 69

(2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -4-methyl -1H-benzo [d] imidazol-5-yl) boronic acid

5-Bromo-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl)- 4-methyl-1H-benzo [d] imidazole (300mg, 0.656mmol), ethanol (4mL), tetrahydroxydiboric acid (88mg, 0.984mmol), 1,3-bis (diphenylphosphino) ) Propane-nickel (II) chloride (10.67 mg, 0.020 mmol), and triphenylphosphine (10.32 mg, 0.039 mmol) were added to a microwave tube, and the mixture was degassed by bubbling argon for 10 minutes. N, N-Diisopropylethylamine (0.344 mL, 1.968 mmol) was added, the tube was sealed, and the mixture was stirred at 80 ° C for 3 hours. The mixture was concentrated and the resulting residue was purified using column chromatography (silica gel, 0 to 60% (3: 1 EtOAc: EtOH) / heptane) to give the desired product (150 mg) as a light brown solid. LC-MS (ES) m / z = 423 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.07 (t, J = 7.1Hz, 3H), 1.18-1.29 (m, 6H), 1.76 (d, J = 5.8Hz, 2H), 2.31-2.43 (m , 2H), 2.64 (s, 3H), 3.35-3.44 (m, 4H), 3.85 (t, J = 5.2Hz, 2H), 4.33 (br.s., 2H), 4.44 (t, J = 5.2Hz , 2H), 6.70 (d, J = 8.9Hz, 1 H), 7.23 (d, J = 8.1Hz, 1H), 7.45 (d, J = 8.1Hz, 1H), 7.98 (dd, J = 9.0,2.4 Hz, 1H), 8.54 (d, J = 2.3Hz, 1H).

Intermediate 105

3-((2-ethoxyethyl) amino) -2-nitrobenzoate

Add 2-ethoxyethyl-1-amine (0.448 g, 5.02 mmol) and K ₂ CO ₃ (0.694 g, 5.02 mmol) to methyl 3-fluoro-2-nitrobenzoate (1 g, 5.02 mmol) at A solution in DMF (20 mL), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered, and the filtrate was concentrated. The resulting residue was purified using column chromatography (silica gel, 0 to 60% EtOAc / hexanes) to give the desired product (980 mg) as a light brown oil. LC-MS (ES) m / z = 268 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 1.23-1.34 (m, 3H), 3.50 (t, J = 5.4Hz, 2H), 3.61 (q, J = 7.0Hz, 2H), 3.71-3.78 (m, 2H), 3.93 (s, 3H), 6.82 (dd, J = 7.1, 1.3Hz, 1H), 6.99 (dd, J = 8.7, 1.1Hz, 1H), 7.44 (dd, J = 8.7, 7.2Hz, 1H ).

Intermediate 106

6-bromo-3-((2-ethoxyethyl) amino) -2-nitrobenzoate

NBS (481 mg, 2.70 mmol) was added to a solution of methyl 3-((2-ethoxyethyl) amino) -2-nitrobenzoate (725 mg, 2.70 mmol) in acetic acid (15 mL), and The mixture was stirred at 100 ° C for 2 hours. The reaction mixture was concentrated, and the residue was purified using column chromatography (silica, 0 to 60% EtOAc / hexanes) to give the desired product (715 mg) as a light brown solid. LC-MS (ES) m / z = 347,349 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 1.23-1.33 (m, 3H), 3.48-3.56 (m, 2H), 3.61 (q, J = 7.1Hz, 2H), 3.73-3.81 (m, 2H), 6.90 (d, J = 9.1Hz, 1H), 7.59 (d, J = 9.4Hz, 1H).

Intermediate 107

Methyl 2-amino-6-bromo-3-((2-ethoxyethyl) amino) benzoate

Add tin (II) chloride dihydrate (2437mg, 10.80mmol) to 6-bromo-3-((2-ethoxyethyl) amino) -2-nitrobenzoate (375mg, 1.080mmol ) In ethanol (10 mL), and the mixture was stirred at 70 ° C for 3 hours. The mixture was cooled, quenched with water (10 mL), neutralized with 1 N NaOH, treated with EtOAc (30 mL), and filtered. The organic layer was collected, and the aqueous layer was further extracted with EtOAc (3x). The combined organic layers were dried (Na ₂ SO ₄₎ and concentrated to give the desired product as a light brown oil (196mg). LC-MS (ES) m / z = 317,319 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 1.27 (t, J = 7.1Hz, 3H), 3.18-3.32 (m, 2H), 3.58 (q, J = 6.9Hz, 2H), 3.69-3.77 (m, 2H), 3.98 (s, 3H), 6.61 (d, J = 8.6Hz, 1H), 7.01 (d, J = 8.4Hz, 1H).

Intermediate 108

5-bromo-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H -Methyl benzo [d] imidazole-4-carboxylic acid

Add 6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (161 mg, 0.788 mmol) and oxone (363 mg, 0.591 mmol) at 0 ° C. ) Was added to methyl 2-amino-6-bromo-3-((2-ethoxyethyl) amino) benzoate (250 mg, 0.788 mmol) in DMF (3 mL) and water (0.600 mL). Solution, and the mixture was stirred at room temperature for 2 hours. The reaction mixture 10% K ₂ CO ₃ aq and extracted with EtOAc (3x). The extracts were dried (Na ₂ SO ₄₎ and concentrated. The residue was purified using column chromatography (silica gel, 0 to 100% EtOAc / hexane) to give the desired product (273 mg) as a light brown solid. LC-MS (ES) m / z = 501,503 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 1.10-1.20 (m, 3H), 1.21-1.29 (m, 6H), 1.64 (br .s., 2H), 1.74 (br.s., 2H), 2.33 (br.s., 2H), 3.46 (q, J = 6.8Hz, 2H), 3.83 (t, J = 5.3Hz, 2H) , 4.11 (s, 3H), 4.37-4.47 (m, 2H), 7.42-7.48 (m, 2H).

Intermediate 109

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -5- (4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-benzo [d] imidazole-4-carboxylic acid methyl ester

Add 4,4,4 ', 4', 5,5,5 ', 5'-octamethyl-2,2'-bi (1,3,2-dioxaborolane) (191mg, 0.754 mmol) and potassium acetate (238 mg, 2.423 mmol) were added to 5-bromo-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] imidazole-4-carboxylic acid methyl ester (270 mg, 0.538 mmol) in 1,4-di Of dioxane (4mL) was added and the mixture was degassed by bubbling ₂ N 10 minutes. PdCl ₂ (dppf) (19.70 mg, 0.027 mmol) was added, and the mixture was stirred at 90 ° C. for 14 hours. The mixture was cooled to room temperature, diluted with EtOAc, and filtered through a short pad of celite. The filtrate was concentrated, and the resulting residue was purified using column chromatography (silica, 0 to 90% EtOAc / hexane) to give the desired product (195 mg) as a light brown solid. LC-MS (ES) m / z = 549 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.06 (t, J = 7.1Hz, 3H), 1.23 (d, J = 6.1Hz, 6H), 1.35-1.44 (m, 12H), 1.76 (d, J = 5.8Hz, 2H), 2.30-2.41 (m, 2H), 3.35-3.44 (m, 2H), 3.85 (t, J = 5.2Hz, 2H), 3.97-4.05 (m, 3H), 4.33 (br. s., 2H), 4.50 (t, J = 5.2Hz, 2H), 6.70 (d, J = 8.9Hz, 1H), 7.57 (d, J = 8.1Hz, 1H), 7.78 (d, J = 8.1Hz , 1H), 7.99 (dd, J = 9.0, 2.4Hz, 1H), 8.54-8.59 (m, 1H).

Example 70

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3- (2-ethoxyethyl) -3H- [1, 2] oxaborolo [4 ', 3': 3,4] benzo [1,2-d] imidazole-6 (8H) -alcohol

Sodium borohydride (41.0 mg, 1.083 mmol) was added to 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl)-at 0 ° C. 1- (2-ethoxyethyl) -5- (4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-benzo [d] A solution of methyl imidazole-4-carboxylic acid methyl ester (90 mg, 0.164 mmol) in ethanol (3 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was quenched with 2N HCl, stirred for 10 minutes, and then concentrated. The resulting residue was treated with 10% NaHCO ₃ and extracted with EtOAc (3x). The extract was dried (Na ₂ SO ₄ ) and concentrated, and the resulting residue was purified using column chromatography (silica gel, 0 to 80% (3: 1 EtOAc: EtOH) / heptane) to give a white solid The desired product (39 mg). LC-MS (ES) m / z = 421 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.02-1.11 (m, 3H), 1.19-1.29 (m, 6H), 1.76 (d, J = 5.8Hz, 2H), 2.30-2.45 (m, 2H) , 3.35-3.44 (m, 4H), 3.88 (t, J = 5.2Hz, 2H), 4.33 (br.s., 1H), 4.52 (t, J = 5.3Hz, 2H), 5.40 (s, 2H) , 6.70 (d, J = 8.6 Hz, 1H), 7.53-7.68 (m, 2H), 8.00 (dd, J = 8.9, 2.5 Hz, 1H), 8.50-8.63 (m, 1H).

Intermediate 110

3-chloro-N- (2-ethoxyethyl) -2-nitroaniline

1-Chloro-3-fluoro-2-nitrobenzene (158 mg, 0.900 mmol), 2-ethoxyethyl-1-amine (88 mg, 0.990 mmol), and N, N-diisopropylethylamine (0.189 mL, 1.080 mmol) in DMF (15 mL) was stirred at room temperature for 16 hours. The reaction was concentrated to dryness and the residue was purified via a silica gel column (0% to 30% EtOAc / hexanes) to provide 3-chloro-N- (2-ethoxyethyl) -2-nitroaniline as an oil. (98mg). LC-MS (ES) m / z = 245,247 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 7.25 (dd, J = 7.9, 8.6 Hz, 1H), 6.77 (ddd, J = 1.0, 8.2, 16.1 Hz, 2H), 3.69 (t, J = 5.3 Hz, 2H), 3.58 (q, J = 7.0Hz, 2H), 3.38 (t, J = 5.3Hz, 2H), 1.27 (t, J = 7.0Hz, 3H).

Example 71

4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H -Benzo [d] imidazole

3-Chloro-N- (2-ethoxyethyl) -2-nitroaniline (98 mg, 0.401 mmol), sodium bisulfite (209 mg, 85%, 1.022 mmol), and 6-((2S, 5S ) A mixture of -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (86 mg, 0.421 mmol) in EtOH (4 mL) and water (2 mL) was heated to 130 ° C under microwave conditions for 20 minutes. The reaction was filtered and the filtrate was concentrated to dryness. CH ₂ Cl _{2 was} added to the obtained residue and the mixture was filtered again. The filtrate was purified via a silica gel column (0% to 100% EtOAc / hexanes) to provide 4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrole-1) as a solid. -Yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] imidazole (38 mg). LC-MS (ES) m / z = 399,401 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.54-8.78 (m, 1H), 7.40 (dd, J = 0.9, 8.0 Hz, 1H), 7.27-7.34 (m, 2H), 7.12-7.25 (m, 1H ), 6.53 (d, J = 6.6 Hz, 1H), 4.42 (dt, J = 2.0, 5.7 Hz, 2H), 4.31 (br.s, 2H), 3.84 (t, J = 5.7 Hz, 2H), 3.44 (q, J = 7.1Hz, 2H), 2.23-2.40 (m, 2H), 1.74 (d, J = 5.6Hz, 2H), 1.24 (d, J = 6.1Hz, 6H), 1.14 (t, J = 7.0Hz, 3H).

Intermediate 111

N- (2-ethoxyethyl) -4-fluoro-2-nitroaniline

Add 1,4-difluoro-2-nitrobenzene (400 mg, 2.51 mmol), 2-ethoxyethyl-1-amine (247 mg, 2.77 mmol), and N, N-diisopropylethylamine (0.527 mL, 3.02 mmol) in DMF (15 mL) was stirred for 16 hours. The reaction was concentrated and the resulting residue was purified via silica chromatography (0% to 30% EtOAc / hexanes) to provide N- (2-ethoxyethyl) -4-fluoro-2- as an orange oil Nifedipine (452 mg). LC-MS (ES) m / z = 229 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.17 (br.s., 1H), 7.91 (dd, J = 3.0, 9.12 Hz, 1H), 7.22-7.36 (m, 1H), 6.89 (dd, J = 4.6, 9.4Hz, 1H), 3.72-3.88 (m, 2H), 3.61 (q, J = 7.0Hz, 2H), 3.50 (t, J = 4.7Hz, 2H), 1.28 (t, J = 7.0Hz, 3H).

Example 72

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -5-fluoro-1H -Benzo [d] imidazole

N- (2-ethoxyethyl) -4-fluoro-2-nitroaniline (131 mg, 0.574 mmol), sodium bisulfite (300 mg, 85%, 1.464 mmol), and 6-((2S, 5S ) A mixture of -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (123 mg, 0.603 mmol) in EtOH (4 mL) and water (2 mL) was heated at 130 ° C for 20 minutes under microwave conditions. Adding NH ₄ OH (28% of water) was added and the resulting mixture was extracted with EtOAc. The washed sequentially with water and brine merger EtOA extracts were dried over MgSO _4, filtered and concentrated. The resulting residue was purified via silica chromatography (0% to 100% EtOAc / hexanes) to provide 2- (6-((2S, 5S) -2,5-dimethylpyrrolidine-1) as a viscous oil. -Yl) pyridin-3-yl) -1- (2-ethoxyethyl) -5-fluoro-1H-benzo [d] imidazole (152 mg). LC-MS (ES) m / z = 383 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.58 (d, J = 2.0 Hz, 1H), 7.95 (dd, J = 2.3, 8.9 Hz, 1H), 7.48 (dd, J = 2.3, 9.4 Hz, 1H) , 7.44 (dd, J = 4.6, 8.9 Hz, 1H), 7.05 (dt, J = 2.5, 9.1 Hz, 1H), 6.53 (d, J = 8.9 Hz, 1H), 4.40-4.46 (m, 2H), 4.20-4.39 (m, 2H), 3.87 (t, J = 5.7Hz, 2H), 3.47 (q, J = 7.0Hz, 2H), 2.27-2.42 (m, 2H), 1.74 (d, J = 5.8Hz , 2H), 1.25 (d, J = 6.3 Hz, 6H), 1.17 (t, J = 7.0 Hz, 3H).

Intermediate 112

4-bromo-3-chloro-N- (2-ethoxyethyl) -2-nitroaniline

A solution of 3-chloro-N- (2-ethoxyethyl) -2-nitroaniline (2.11 g, 8.62 mmol) and N-bromosuccinimide (1.535 g, 8.62 mmol) in acetic acid was dissolved in Heated at 100 ° C for 4 hours. The reaction mixture was concentrated and the resulting residue was purified via silica chromatography (0% to 35% EtOAc / hexanes) to provide 4-bromo-3-chloro-N- (2-ethoxyethyl) as an orange solid ) -2-nitroaniline (2.15 g). LC-MS (ES) m / z = 322,324 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 7.55 (d, J = 9.1Hz, 1H), 6.69 (d, J = 9.1Hz, 1H), 5.71 (br.s., 1H), 3.64-3.73 (m , 2H), 3.57 (q, J = 7.1Hz, 2H), 3.36 (t, J = 5.2Hz, 2H), 1.27 (t, J = 7.0Hz, 3H).

Example 73

5- (5-bromo-4-chloro-1- (2-ethoxyethyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridine-2-amine

4-Bromo-3-chloro-N- (2-ethoxyethyl) -2-nitroaniline (200 mg, 0.618 mmol), sodium bisulfite (323 mg, 85%, 1.576 mmol), and 6- ( A mixture of diethylamino) nicotinaldehyde (116 mg, 0.649 mmol) in EtOH (4 mL) and water (2 mL) was heated at 130 ° C for 20 minutes under microwave conditions. The reaction was then filtered and concentrated to dryness. CH ₂ Cl _{2 was added} , and the resulting mixture was filtered again. The filtrate was purified via silica chromatography (0% to 100% EtOAc / hexane) to provide 5- (5-bromo-4-chloro-1- (2-ethoxyethyl) -1H-benzene as an oil Benzo [d] imidazol-2-yl) -N, N-diethylpyridine-2-amine (134 mg). LC-MS (ES) m / z = 451,453 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.57 (br.s., 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.51 (d, J = 8.6 Hz, 1H), 7.33 (d, J = 8.6Hz, 1H), 6.61 (d, J = 8.9Hz, 1H), 4.42 (t, J = 5.5Hz, 2H), 3.84 (t, J = 5.6Hz, 2H), 3.63 (q, J = 7.0 Hz, 4H), 3.45 (q, J = 6.9 Hz, 2H), 1.27 (t, J = 7.1 Hz, 6H), 1.16 (t, J = 7.0 Hz, 3H).

Example 74

(4-chloro-2- (6- (diethylamino) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] imidazol-5-yl) boronic acid

Add n-butyllithium (0.132mL, 0.329mmol, 1.6M in hexane) dropwise to 5- (5-bromo-4-chloro-1- (2-ethoxyethyl) cooled in a dry ice acetone bath ) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine (124 mg, 0.274 mmol) and triisopropyl borate (0.076 mL, 0.329 mmol) in THF (4 mL) and toluene (16 mL), and the reaction mixture was stirred for 30 minutes. The reaction was then heated to -20 ° C. 1N HCl (10 mL) was added dropwise, and the resulting mixture was allowed to warm to room temperature. The aqueous layer was separated, and the organic layer was further extracted with water. The combined aqueous extracts were concentrated by freeze-drying, and the resulting residue was purified by reverse-phase HPLC (5% to 35% CH ₃ CN / (0.1% formic acid in H ₂ O) to provide a white solid (4-chloro-2- (6- (diethylamino) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] imidazol-5-yl) boronic acid ( 40mg). LC-MS (ES) m / z = 417 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 8.57 (d, J = 2.0Hz, 1H), 8.00 (dd, J = 2.5,9.1Hz, 1H), 7.60 (d, J = 7.9Hz, 1H), 7.25 (d, J = 8.1Hz, 1H), 6.78 (d, J = 8.9Hz, 1H), 4.48 (t, J = 5.1Hz, 2H), 3.85 (t, J = 5.2Hz, 2H), 3.65 (q, J = 7.1Hz, 4H), 3.36-3.44 (m, 2H), 1.25 (t, J = 7.0Hz, 6H ), 1.07 (t, J = 7.0 Hz, 3H).

Example 75

5-bromo-4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl Yl) -1H-benzo [d] imidazole

4-bromo-3-chloro-N- (2-ethoxyethyl) -2-nitroaniline (1.53 g, 4.73 mmol), sodium bisulfite (2.470 g, 85%, 12.062 mmol), and 6 -((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (1.111 g, 5.44 mmol) in ethanol (30 mL) and water (8 mL) was mixed in 2 microwaves The vials were each heated at 130 ° C for 80 minutes under microwave conditions. The reactions were combined, filtered, and concentrated. Water was added, and the resulting mixture was extracted with CH ₂ Cl ₂ . The combined organic extracts were washed with water then brine, dried over MgSO _4, filtered, and concentrated. The resulting residue was purified via silica chromatography (0% to 100% EtOAc / hexanes) to provide 5-bromo-4-chloro-2- (6-((2S, 5S) -2,5- Dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] imidazole (1.55 g). LC-MS (ES) m / z = 476,478 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.57 (br.s., 1H), 7.96 (d, J = 7.9 Hz, 1H), 7.51 (d, J = 8.6 Hz, 1H), 7.34 (d, J = 8.6Hz, 1H), 6.52 (d, J = 8.9Hz, 1H), 4.42 (dt, J = 1.9, 5.5Hz, 2H), 4.3-4.0 (br.s, 2H), 3.84 (t, J = 5.6Hz, 2H), 3.46 (q, J = 7.1Hz, 2H), 2.20-2.43 (m, 2H), 1.75 (d, J = 5.6Hz, 2H), 1.25 (d, J = 6.3Hz, 6H) , 1.16 (t, J = 7.0 Hz, 3H).

Example 76

(4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl)- 1H-benzo [d] imidazol-5-yl) boronic acid

N-butyllithium (2.5M, 9.94mL, 24.86mmol) in hexane was added dropwise to 5-bromo-4-chloro-2- (6-((2S, 5S) at -78 ° C over 5 minutes. -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] imidazole (9.90 g, 20.72 mmol) and A solution of triisopropyl borate (5.74 mL, 24.86 mmol) in THF (8 mL) and toluene (32 mL), and the reaction mixture was stirred for 30 minutes. The reaction was heated to -25 ° C and quenched by the dropwise addition of 2N aqueous HCl (40 mL), keeping the reaction temperature below -20 ° C. The resulting mixture was warmed to room temperature and then washed with EtOAc. Saturated aqueous NaHCO ₃ was added to the aqueous phase until pH ~ 7-8. The resulting alkaline aqueous mixture was extracted with EtOAc. The organic extracts were combined and washed sequentially with water and brine, dried over MgSO _4, filtered, and concentrated. Via silica gel chromatography (0% to 60% (3: 1 EtOAc: EtOH) / hexanes (1.5% NH ₄ OH)) The resulting residue was purified to provide after freeze-drying as a white solid of 4-chloro -2 -(6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d ] Imidazol-5-yl) boronic acid (1.88 g). LC-MS (ES) m / z = 443 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 8.58 (d, J = 1.8Hz, 1H), 8.00 (dd, J = 2.4, 9.0Hz, 1H), 7.60 (d, J = 8.1Hz, 1H), 7.25 (d, J = 8.1Hz, 1H), 6.70 (d, J = 8.6Hz, 1H), 4.48 (t, J = 5.2Hz, 2H), 4.33 (br.s., 2H), 3.86 (t, J = 5.2 Hz, 2H), 3.40 (q, J = 7.1 Hz, 2H), 2.28-2.42 (m, 2H), 1.76 (d, J = 5.6 Hz, 2H), 1.23 (d, J = 6.1 Hz, 6H), 1.07 (t, J = 7.1Hz, 3H).

Example 77

5- (5-bromo-4-chloro-1- (2-ethoxyethyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethyl-3-fluoropyridine- 2-amine

4-bromo-3-chloro-N- (2-ethoxyethyl) -2-nitroaniline (160 mg, 0.494 mmol), sodium bisulfite (258 mg, 85%, 1.260 mmol), and 6- ( A mixture of diethylamino) -5-fluoronicotinaldehyde (97 mg, 0.494 mmol) in EtOH (4 mL) and water (2 mL) was heated at 130 ° C for 50 minutes under microwave conditions. The reaction was filtered and the filtrate was concentrated to dryness. Followed by addition of CH ₂ Cl _2, and the resulting mixture was filtered again. The filtrate was purified via silica chromatography (0% to 100% EtOAc / hexane) to provide 5- (5-bromo-4-chloro-1- (2-ethoxyethyl) -1H- as a white solid Benzo [d] imidazol-2-yl) -N, N-diethyl-3-fluoropyridine-2-amine (89 mg). LC-MS (ES) m / z = 468,471 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.40 (t, J = 1.8Hz, 1H), 7.85 (dd, J = 1.8, 15.0Hz, 1H), 7.53 (d, J = 8.4Hz, 1H), 7.30 (d, J = 2.0Hz, 1H), 4.42 (t, J = 5.3Hz, 2H), 3.86 (t, J = 5.3Hz, 2H), 3.66 (dq, J = 1.5, 7.0Hz, 4H), 3.46 (q, J = 6.9Hz, 2H), 1.29 (t, J = 7.0Hz, 6H), 1.17 (t, J = 7.0Hz, 3H).

Example 78

(4-chloro-2- (6- (diethylamino) -5-fluoropyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] imidazole-5- ) Boronic acid

N-butyllithium (0.062 mL, 0.156 mmol, 1.6 M in hexane) was added dropwise to 5- (5-bromo-4-chloro-1- (2-ethyl) in a dry ice acetone bath over 5 minutes. (Oxyethyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethyl-3-fluoropyridine-2-amine (61 mg, 0.130 mmol) and triisopropyl borate (0.036 mL, 0.156 mmol) in THF (4 mL) and toluene (16 mL), and the reaction mixture was stirred for 30 minutes. The reaction was then heated to -20 ° C. 1N HCl (10 mL) was added dropwise, and the resulting mixture was allowed to warm to room temperature. The aqueous phase was separated and the organic phase was further extracted with water. The combined aqueous extracts were concentrated by freeze-drying. The resulting residue was purified via reverse-phase HPLC (5% to 90% CH ₃ CN / (0.1% NH ₄ OH in H ₂ O)) to provide (4-chloro-2- (6- (dichloromethane) as a white solid Ethylamino) -5-fluoropyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] imidazol-5-yl) boronic acid (17 mg). LC-MS (ES ) m / z = 435,437 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 8.43 (t, J = 1.8Hz, 1H), 7.94 (dd, J = 1.9, 15.3Hz, 1H) , 7.60 (d, J = 8.1Hz, 1H), 7.27 (d, J = 8.1Hz, 1H), 4.49 (t, J = 5.1Hz, 2H), 3.87 (t, J = 5.1Hz, 2H), 3.68 (dq, J = 1.7, 7.0 Hz, 4H), 3.42 (q, J = 7.0 Hz, 2H), 1.28 (t, J = 7.0 Hz, 6H), 1.09 (t, J = 7.0 Hz, 3H).

Intermediate 113

N- (2-ethoxyethyl) -2-nitro-3- (trifluoromethyl) aniline

1-fluoro-2-nitro-3- (trifluoromethyl) benzene (150 mg, 0.717 mmol), 2-ethoxyethyl-1-amine (77 mg, 0.861 mmol), and N, N-diiso A solution of propylethylamine (0.163 mL, 0.933 mmol) in DMF (15 mL) was stirred at room temperature for 16 hours. The reaction was concentrated and the resulting residue was purified via silica chromatography (0% to 35% EtOAc / hexanes) to provide N- (2-ethoxyethyl) -2-nitro-3 as an orange oil -(Trifluoromethyl) aniline (190 mg). LC-MS (ES) m / z = 279 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.46 (dt, J = 0.8, 8.1 Hz, 1H), 7.00-7.16 (m, 2H), 6.17 (br.s., 1H), 3.66-3.75 (m, 2H), 3.59 (q, J = 7.0 Hz, 2H), 3.42 (t, J = 5.3 Hz, 2H), 1.27 (t, J = 7.0 Hz, 3H).

Example 79

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -4- (trifluoro (Methyl) -1H-benzo [d] imidazole

N- (2-ethoxyethyl) -2-nitro-3- (trifluoromethyl) aniline (95 mg, 0.341 mmol), sodium bisulfite (178 mg, 85%, 0.87 mmol), and 6 -((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (73.2 mg, 0.359 mmol) in a mixture of EtOH (4 mL) and water (2 mL) under microwave conditions at Heat at 130 ° C for 20 minutes. The reaction was filtered and the filtrate was concentrated to dryness. Followed by addition of CH ₂ Cl _2, and the resulting mixture was filtered again. The filtrate was purified via silica gel chromatography (0% to 70% EtOAc / hexane) to provide 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl as a viscous oil. ) Pyridin-3-yl) -1- (2-ethoxyethyl) -4- (trifluoromethyl) -1H-benzo [d] imidazole (54 mg). LC-MS (ES) m / z = 433 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.59 (d, J = 1.8 Hz, 1 H), 7.96 (dd, J = 2.3, 8.9 Hz, 1 H), 7.71 (d, J = 8.1 Hz, 1 H), 7.58 (d, J = 7.4Hz, 1H), 7.27-7.42 (m, 1H), 6.51 (d, J = 8.9Hz, 1H), 4.46 (dt, J = 2.4, 5.6Hz, 2H), 4.31 (br. s., 2H), 3.86 (t, J = 5.6 Hz, 2H), 3.47 (q, J = 6.8 Hz, 2H), 2.19-2.37 (m, 2H), 1.73 (d, J = 5.6 Hz, 2H) , 1.24 (d, J = 6.1 Hz, 6H), 1.16 (t, J = 7.0 Hz, 3H).

Intermediate 114

4-bromo-N- (2-ethoxyethyl) -2-nitroaniline

Add 2-ethoxyethyl-1-amine (972 mg, 10.91 mmol) to 4-bromo-1-fluoro-2-nitrobenzene (2.0 g, 9.09 mmol) and N, N-diisopropylethylamine ( 1.905 mL, 10.91 mmol) in DMF (20 mL), and the reaction mixture was stirred at room temperature for 16 hours. The reaction was concentrated and the resulting residue was purified via silica chromatography (0% to 30% EtOAc / hexane) to provide 4-bromo-N- (2-ethoxyethyl) -2- as an orange oil Nifedipine (2.49g). LC-MS (ES) m / z = 288,290 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.34 (d, J = 2.5Hz, 1H), 8.28 (br.s., 1H), 7.52 (dd, J = 2.5, 9.1Hz, 1H), 6.82 (d , J = 9.1Hz, 1H), 3.72-3.80 (m, 2H), 3.61 (q, J = 6.9Hz, 2H), 3.50 (m, 2H), 1.28 (t, J = 7.0Hz, 3H).

Example 80

5- (5-bromo-1- (2-ethoxyethyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridine-2-amine

4-Bromo-N- (2-ethoxyethyl) -2-nitroaniline (230 mg, 0.795 mmol), sodium bisulfite (416 mg, 85%, 2.028 mmol), and 6- (diethylamino) ) A mixture of nicotinaldehyde (149 mg, 0.835 mmol) in EtOH (4 mL) and water (2 mL) was heated at 130 ° C. for 20 minutes under microwave conditions. The reaction was filtered and concentrated to dryness. Followed by addition of CH ₂ Cl _2, and the resulting mixture was filtered again. The resulting residue was purified via silica chromatography (0% to 100% EtOAc / hexane) to provide 5- (5-bromo-1- (2-ethoxyethyl) -1H-benzo as a white solid. [d] Imidazol-2-yl) -N, N-diethylpyridin-2-amine (213 mg). LC-MS (ES) m / z = 417,418 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.58 (d, J = 2.0Hz, 1H), 7.91-8.05 (m, 2H), 7.41 (d, J = 1.0Hz, 2H), 6.62 (d, J = 8.9Hz, 1H), 4.42 (t, J = 5.7Hz, 2H), 3.86 (t, J = 5.6Hz, 2H), 3.63 (q, J = 7.1Hz, 4H), 3.47 (q, J = 7.1Hz , 2H), 1.23-1.34 (m, 6H), 1.17 (t, J = 7.0 Hz, 3H).

Example 81

(2- (6- (diethylamino) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] imidazol-5-yl) boronic acid

Bubbling argon through hypodiboric acid (53.2 mg, 0.593 mmol), 1,3-bis (diphenylphosphino) propane-nickel (II) chloride (10.71 mg, 0.020 mmol), 5 -(5-bromo-1- (2-ethoxyethyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine (165 mg, 0.395 mmol ), Triphenylphosphine (10.37mg, 0.040mmol), and a mixture of N, N-diisopropylethylamine (0.207mL, 1.186mmol) in EtOH (10mL) over 15 minutes, and the reaction mixture was at 80 ° C Heat for 16 hours. The reaction was concentrated and the resulting residue was purified via silica chromatography (0% to 100% (3: 1 EtOAc: EtOH) / hexane) to provide (2- (6- (diethylamino) as a white solid ) Pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] imidazol-5-yl) boronic acid (55 mg). LC-MS (ES) m / z = 383 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 8.57 (d, J = 2.0Hz, 1H), 7.94-8.04 (m, 2H), 7.62 (s, 2H), 6.78 (d, J = 8.6Hz, 1H ), 4.49 (t, J = 5.2Hz, 2H), 3.88 (t, J = 5.2Hz, 2H), 3.64 (q, J = 7.1Hz, 4H), 3.36-3.45 (m, 2H), 1.25 (t , J = 7.0Hz, 6H), 1.07 (t, J = 7.0Hz, 3H).

Intermediate 115

(S) -5-bromo-1- (2-ethoxyethyl) -2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d ] Imidazole

4-Bromo-N- (2-ethoxyethyl) -2-nitroaniline (142 mg, 0.491 mmol), sodium bisulfite (257 mg, 85%, 1.252 mmol), and (S) -6- ( A mixture of 2-methylpyrrolidin-1-yl) nicotinaldehyde (98 mg, 0.516 mmol) in EtOH (4 mL) and water (2 mL) was heated at 130 ° C for 20 minutes under microwave conditions. The reaction was filtered and the filtrate was concentrated to dryness. Followed by addition of CH ₂ Cl _2, and the resulting mixture was filtered again. The filtrate was concentrated and the resulting residue was purified via silica chromatography (0% to 90% EtOAc / hexane) to provide (S) -5-bromo-1- (2-ethoxyethyl) as a viscous oil ) -2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole (105 mg). LC-MS (ES) m / z = 429,431 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.59 (d, J = 1.8Hz, 1H), 7.91-8.07 (m, 2H), 7.41 (d, J = 1.0Hz, 2H), 6.53 (d, J = 8.9Hz, 1H), 4.42 (t, J = 5.7Hz, 2H), 4.29 (br.s., 1H), 3.86 (t, J = 5.7Hz, 2H), 3.68 (t, J = 7.7Hz, 1H ), 3.46 (q, J = 7.1Hz, 3H), 2.03-2.33 (m, 3H), 1.77-1.87 (m, 1H), 1.28-1.42 (m, 3H), 1.17 (t, J = 7.0Hz, 3H).

Example 82

(S)-(1- (2-ethoxyethyl) -2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole- 5-yl) boronic acid

Tetrahydroxydiboric acid (106mg, 1.181mmol), 1,3-bis (diphenylphosphino) propane-nickel (II) chloride (21.34mg, 0.039mmol), (S) -5-bromo -1- (2-ethoxyethyl) -2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole (338 mg, 0.787 mmol ), Triphenylphosphine (20.65mg, 0.079mmol), and N, N-diisopropylethylamine (0.412mL, 2.362mmol) in EtOH (10mL) were bubbled through argon for 15 minutes, and The reaction mixture was heated at 80 ° C for 16 hours. The reaction was concentrated, and the resulting residue was purified via silica gel chromatography (0% to 100% (3: 1 EtOAc: EtOH) / hexane) to provide (S)-(1- (2-ethyl (Oxyethyl) -2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-5-yl) boronic acid (159 mg). LC-MS (ES) m / z = 395 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 8.56 (d, J = 2.0Hz, 1H), 8.00 (dd, J = 2.3, 8.9Hz, 2H), 7.61 (br.s., 2H), 6.66 ( d, J = 8.9Hz, 1H), 4.46 (t, J = 5.1Hz, 2H), 4.27 (quin, J = 5.9Hz, 1H), 3.86 (t, J = 5.2Hz, 2H), 3.60-3.69 ( m, 1H), 3.35-3.52 (m, 3H), 2.01-2.29 (m, 3H), 1.77-1.93 (m, 1H), 1.27 (d, J = 6.3Hz, 3H), 1.07 (t, J = 7.0Hz, 3H).

Example 83

5-bromo-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H -Benzo [d] imidazole

4-Bromo-N- (2-ethoxyethyl) -2-nitroaniline (833 mg, 2.88 mmol), 6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl ) Nicotinaldehyde (647 mg, 3.17 mmol), ethanol (4 mL), water (2 mL), and sodium bisulfite (1505 mg, 85%, 7.344 mmol) were added to a microwave vial, and the reaction mixture was microwaved at 130 Heated at 120 ° C for 120 minutes. The reaction was diluted with water (20 mL) and extracted with EtOAc (4 x 20 mL). The organic extracts were combined, washed with brine, dried over MgSO _4, filtered, and concentrated. Purification by chromatography on SiO ₂ (gradient from 0 to 60% EtOAc / hexanes) provided 5-bromo-2- (6-(((2S, 5S) -2,5-dimethyl) as a clear oil Pyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] imidazole (1.02 g). LC-MS (ES) m / z = 444 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 0.95 (t, J = 7.0 Hz, 3 H), 1.12-1.17 (m, 6 H), 1.66 (d, J = 5.1 Hz, 2 H), 2.24 (br. s., 2H), 3.27-3.32 (m, 2H), 3.74 (t, J = 5.2Hz, 2H), 4.26 (br.s., 2H), 4.43 (t, J = 5.2Hz, 2H), 6.62 (d, J = 8.9Hz, 1H), 7.37 (dd, J = 8.5, 1.9Hz, 1H), 7.64 (d, J = 8.6Hz, 1H), 7.82 (d, J = 2.0Hz, 1H), 7.96 (dd, J = 8.9, 2.5 Hz, 1H), 8.54 (d, J = 2.3 Hz, 1H).

Example 84

(2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo (d) imidazol-5-yl) boronic acid

Tetrahydroxydiboric acid (160mg, 1.783mmol), triphenylphosphine (31.2mg, 0.119mmol), 1,3-bis (diphenylphosphino) propane-nickel (II) chloride (64.4mg, 0.119 mmol), 5-bromo-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl Group) -1H-benzo [d] imidazole (527 mg, 1.189 mmol), and EtOH (5 mL) were sequentially added to a 20 mL microwave vial, and the mixture was degassed with argon for 10 minutes. Next, N, N-diisopropylethylamine (0.623 mL, 3.57 mmol) was added, and the reaction mixture was heated under microwave conditions at 80 ° C. for 1 hour. The reaction was filtered through celite, washed with EtOH, and the filtrate was concentrated. Purification by chromatography on SiO ₂ (0 to 50% (gradient of 80: 20: 2 CH ₂ Cl ₂ : CH ₃ OH: NH ₄ OH) / CH ₂ Cl ₂ ) followed by freeze drying provided a white solid Of (2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzene And [d] imidazol-5-yl) boronic acid (312 mg). LC-MS (ES) m / z = 409 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 0.94-1.01 (m, 3H), 1.12-1.18 (m, 6H), 1.61-1.72 (m, 2H), 2.25 (br.s., 2H), 3.28-3.32 (m, 2H), 3.71-3.81 (m, 2H), 4.27 (br.s., 2H), 4.41 (t, J = 5.5Hz, 2H), 6.59-6.65 (m, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.62-7.70 (m, 1H), 7.93-7.99 (m, 3H), 8.11 (s, 1H), 8.53-8.58 (m, 1H).

Intermediate 116

N- (2-ethoxyethyl) -4,5-difluoro-2-nitroaniline

1,2,4-trifluoro-5-nitrobenzene (1.0 g, 5.65 mmol), 2-ethoxyethyl-1-amine (554 mg, 6.21 mmol), and N, N-diisopropylethylamine A solution of (1.184 mL, 6.78 mmol) in DMF (15 mL) was stirred at room temperature for 16 hours. The reaction was concentrated and the resulting residue was purified via silica chromatography (0% to 20% (3: 1 EtOAc: EtOH) / hexane) to provide N- (2-ethoxyethyl) as a yellow / orange solid ) -4,5-difluoro-2-nitroaniline (230 mg). LC-MS (ES) m / z = 247 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.33 (br.s., 1H), 8.09 (dd, J = 8.5, 10.8 Hz, 1H), 6.70 (dd, J = 6.8, 12.7 Hz, 1H), 3.76 (t, J = 5.3Hz, 2H), 3.62 (q, J = 6.8Hz, 2H), 3.47 (q, J = 5.1Hz, 2H), 1.29 (t, J = 7.0Hz, 3H).

Example 85

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -5,6-di Fluoro-1H-benzo [d] imidazole

N- (2-ethoxyethyl) -4,5-difluoro-2-nitroaniline (125 mg, 0.508 mmol), sodium bisulfite (265 mg, 85%, 1.294 mmol), and 6-((2S , 5S) -2,5-Dimethylpyrrolidin-1-yl) nicotinaldehyde (109 mg, 0.533 mmol) in EtOH (4 mL) and water (2 mL) was heated at 130 ° C for 20 minutes under microwave conditions . The reaction was filtered and the filtrate was concentrated. Followed by addition of CH ₂ Cl _2, and the resulting mixture was filtered again. The filtrate was purified via silica gel chromatography (0% to 100% EtOAc / hexanes) to provide 2- (6-((2S, 5S) -2,5-dimethylpyrrole-1) as a white / yellow solid. -Yl) pyridin-3-yl) -1- (2-ethoxyethyl) -5,6-difluoro-1H-benzo [d] imidazole (105 mg). LC-MS (ES) m / z = 401 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.49-8.55 (m, 1H), 7.88 (dd, J = 2.5, 8.9 Hz, 1H), 7.54 (dd, J = 7.4, 10.7 Hz, 1H), 7.36 ( dd, J = 7.1,10.4Hz, 1H), 6.50 (d, J = 8.9Hz, 1H), 4.33-4.39 (m, 4H), 3.84 (t, J = 5.5Hz, 2H), 3.47 (q, J = 7.1Hz, 2H), 2.26-2.36 (m, 2H), 1.72 (d, J = 5.6Hz, 2H), 1.23 (d, J = 6.7Hz, 6H), 1.17 (t, J = 7.0Hz, 3H ).

Intermediate 117

N- (2-ethoxyethyl) -3-fluoro-2-nitroaniline

Add 1,3-difluoro-2-nitrobenzene (400 mg, 2.51 mmol), 2-ethoxyethyl-1-amine (247 mg, 2.77 mmol), and N, N-diisopropylethylamine (0.527 mL , 3.02 mmol) in DMF (15 mL) was stirred at room temperature for 16 hours. The reaction was concentrated and the resulting residue was purified via silica chromatography (0% to 30% EtOAc / hexanes) to provide N- (2-ethoxyethyl) -3-fluoro-2- as an orange oil Nifedipine (421 mg). LC-MS (ES) m / z = 229 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 7.44 (br.s., 1H), 7.26-7.37 (m, 1H), 6.59-6.70 (m, 1H), 6.47 (ddd, J = 1.3, 8.1, 11.4 Hz, 1H), 3.70-3.77 (m, 2H), 3.60 (q, J = 7.1Hz, 2H), 3.45 (t, J = 5.5Hz, 2H), 1.28 (t, J = 7.0Hz, 3H).

Example 86

(S) -1- (2-ethoxyethyl) -4-fluoro-2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d ] Imidazole

N- (2-ethoxyethyl) -3-fluoro-2-nitroaniline (125 mg, 0.548 mmol), sodium bisulfite (286 mg, 85%, 1.40 mmol), and (S) -6- (2 -Methylpyrrolidin-1-yl) nicotinaldehyde (109 mg, 0.575 mmol) in EtOH (4 mL) and water (2 mL) was heated at 130 ° C for 20 minutes under microwave conditions. Then added NH ₄ OH (28%), and the resulting mixture was extracted with EtOAc. The combined organic extracts were washed sequentially with water and brine, dried over MgSO _4, filtered, and concentrated. The residue was purified via silica chromatography (0% to 100% EtOAc / hexane) to provide (S) -1- (2-ethoxyethyl) -4-fluoro-2- (6) as a viscous oil -(2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole (100 mg). LC-MS (ES) m / z = 369 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.63 (br.s., 1H), 8.03 (d, J = 8.4Hz, 1H), 7.29 (d, J = 1.0Hz, 1H), 7.22 (dt, J = 4.6, 8.0Hz, 1H), 7.02 (ddd, J = 0.9, 7.98, 10.4Hz, 1H), 6.53 (d, J = 8.9Hz, 1H), 4.44 (t, J = 5.7Hz, 3H), 4.29 (br.s., 1H), 3.87 (t, J = 5.8Hz, 2H), 3.69 (br.s., 1H), 3.39-3.55 (m, 2H), 2.04-2.30 (m, 4H), 11.23 -1.39 (m, 3H), 1.17 (t, J = 7.1Hz, 3H).

Intermediate 118

4-((2-ethoxyethyl) amino) -3-nitrobenzoate

Methyl 4-fluoro-3-nitrobenzoate (3.35 g, 16.82 mmol) and K ₂ CO ₃ (2.325 g, 16.82 mmol) were added to 2-ethoxyethyl-1-amine in DMF (100 mL) (1.500 g, 16.82 mmol), and the reaction mixture was stirred at room temperature overnight. The mixture was filtered and washed with Et ₂ O. The filtrate was diluted with water (250 mL), and the resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed (20mL) with brine, dried over Na ₂ SO _4, filtered, and concentrated in vacuo. The remaining residue was purified by silica chromatography (0-60%, EtOAc / hexane). The portions containing the desired product were combined and concentrated until almost dry. Crystallization from the remaining solvent provided the desired product (4.2 g) as yellow hexagonal crystals. LC-MS (ES) m / z = 269 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.64 (d, J = 2.0 Hz, 1 H), 8.61 (t, J = 4.9 Hz, 1 H), 7, 99 (dd, J = 2.0, 9.1 Hz, 1H), 7.21 (d, J = 9.1Hz, 1H), 3.84 (s, 3H), 3.56-3.67 (m, 4H), 3.51 (q, J = 7.0Hz, 2H), 1.13 (t, J = 7.0 Hz, 3H).

Intermediate 119

3-Amino-4-((2-ethoxyethyl) amino) benzoic acid methyl ester

4-((2-ethoxyethyl) amino) -3-nitrobenzoate (4.20 g, 15.66 mmol) and NiCl ₂ ‧ 6H ₂ O (9.30 g, 39.1 mmol) in CH ₃ OH (150 mL The mixture in) was stirred at 70 ° C. under an inert atmosphere until the 4-((2-ethoxyethyl) amino) -3-nitrobenzoate was dissolved. The reaction was cooled to 0 ° C (ice bath) and sodium borohydride (2.96 g, 78 mmol) was fed in 3 equal portions. The reaction was gradually warmed to room temperature and filtered through celite, then concentrated in vacuo. The remaining residue was dissolved in concentrated NH ₄ OH (150mL) and CH ₂ Cl ₂ (200mL) and filtered. The filter cake was washed with CH ₂ Cl ₂ (2 x 100 ml). The aqueous layer was washed with CH ₂ Cl ₂ (2 x 100 mL). The combined organic layers were filtered through a diatomaceous earth layer on a silica pad. The organic layer was washed with brine (6 mL), dried over Na ₂ SO _4, filtered, concentrated, and dried overnight under high vacuum to provide the desired product as a brown solids (3.58g). LC-MS (ES) m / z = 239 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 7.15-7.25 (m, 2H), 6.47 (d, J = 8.4Hz, 1H), 5.25 (t, J = 5.5Hz, 1H), 4.78 (s, 2H), 3.73 (s, 3H), 3.57 (t, J = 5.8Hz, 2H), 3.48 (q, J = 7.1Hz, 2H), 3.29 (q, J = 5.6Hz, 2H), 1.13 (t, J = 7.0 Hz, 3H).

Example 87

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [ d) methyl imidazole-5-carboxylate

Add potassium oxone (335 mg, 0.546 mmol) to methyl 3-amino-4-((2-ethoxyethyl) amino) benzoate (200 mg, 0.839 mmol) and 6- ( (2S, 5S) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (189 mg, 0.923 mmol) in DMF (4 mL) and water (4 mL), and the reaction mixture was at room temperature Stir overnight. The reaction was diluted with water (7 mL), saturated aqueous Na ₂ CO ₃ (7 mL) and EtOAc (15 mL). The organic layer was separated, and the aqueous layer was further extracted with EtOAc (2 x 15 mL). The combined organic layers were washed with brine (6 mL), dried over Na ₂ SO _4, filtered, and concentrated. The resulting residue was purified by silica chromatography (0-100%, EtOAc / hexanes) to provide the desired product (153 mg) as a golden oil. LC-MS (ES) m / z = 423 [M + H] ⁺ . ¹ H NMR (400MHz, MeOD-d ₄ ): δ 8.62-8.55 (m, 1H), 8.37 (d, J = 1.0Hz, 1H), 8.02 (ddd, J = 2.0, 6.9, 8.8Hz, 2H), 7.72 (d, J = 8.6Hz, 1H), 6.72 (s, 1H), 4.53 (d, J = 5.3Hz, 2H), 4.42-4.24 (m, 2H), 3.97 (s, 3H), 3.88 (t , J = 5.2Hz, 2H), 3.45-3.37 (m, 2H), 2.43-2.28 (m, 2H), 1.76 (d, J = 5.8Hz, 2H), 1.24 (d, J = 6.3Hz, 6H) 1.07 (t, J = 7.0 Hz, 3H).

Example 88

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -N-methyl- 1H-benzo [d] imidazole-5-carboxamide

Step 1: 10N NaOH (0.426mL, 4.26mmol) was added to the CH ₃ OH (4mL, 0.533mmol) and THF (4mL, 0.533mmol) of the 2- (6 - ((2S, 5S) -2,5 -Dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] imidazole-5-carboxylic acid methyl ester (225 mg, 0.533 mmol) , And the reaction mixture was stirred at 40 ° C for 3 hours. The heat was removed and the pH was neutralized with 6N HCl (0.719 mL, 4.31 mmol). The mixture was concentrated and the remaining solid was dissolved in DMSO (3 mL). The DMSO solution was decanted, diluted to 6 mL with DMSO and divided into 3 equal (2 mL) portions. Step 2: EtOAc (4 mL), triethylamine (0.256 mL, 1.836 mmol), T3P propylphosphonic anhydride (0.328 mL, 0.551 mmol) in EtOAc, and methylamine hydrochloride (49.6 mg, 0.734 mmol) Added to 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzene [D] A solution of imidazole-5-carboxylic acid in DMSO (2 mL from the previous step 1)), and the reaction mixture was stirred at room temperature overnight. The reaction was diluted with DMF (4.00 mL), fresh T3P propylphosphonic anhydride and methylamine hydrochloride (49.6 mg, 0.734 mmol) in EtOAc (0.328 mL, 0.551 mmol) were fed, and the reaction mixture was stirred for another 4 hour. The reaction was quenched with water (9 mL) and extracted with EtOAc (3 x 9 mL). The combined organics were washed with brine (3mL), dried over Na ₂ SO _4, filtered and concentrated. By reverse phase HPLC (15-55% CH ₃ CN / 0.1% formic acid in the water) of the remaining residue was purified for presenting the desired product as a white solid (14.8mg). LC-MS (ES) m / z = 422 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 8.58 (d, J = 2.3Hz, 1H), 8.17 (d, J = 1.3Hz, 1H), 8.01 (dd, J = 2.3, 8.9Hz, 1H), 7.84 (dd, J = 1.7,8.5Hz, 1H), 7.71 (d, J = 8.4Hz, 1H), 6.71 (d, J = 9.1Hz, 1H), 4.52 (t, J = 4.9Hz, 2H), 3.88 (t, J = 5.1Hz, 2H), 3.41 (q, J = 7.0Hz, 2H), 3.37 (s, 1H), 2.95-3.02 (m, 3H), 2.68 (s, 1H), 2,36 (t, J = 7.6 Hz, 2H), 1.76 (d, J = 5.8 Hz, 2H), 1.23 (d, J = 6.1 Hz, 6H), 1.02-1.10 (m, 3H).

Intermediate 120

N- (2-ethoxyethyl) -5-fluoro-2-nitroaniline

Add 2,4-difluoro-1-nitrobenzene (400 mg, 2.51 mmol), 2-ethoxyethyl-1-amine (247 mg, 2.77 mmol), and N, N-diisopropylethylamine (0.527 mL , 3.02 mmol) in DMF (15 mL) was stirred at room temperature for 16 hours. The reaction was concentrated and the resulting residue was purified via a silica purification column (0% to 30% EtOAc / hexane) to provide N- (2-ethoxyethyl) -5-fluoro-2- as an orange oil Nifedipine (499 mg). LC-MS (ES) m / z = 229 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.41 (br.s., 1H), 8.25 (dd, J = 6.2, 9.5 Hz, 1H), 6.54 (dd, J = 2.5, 11.4 Hz, 1H), 6.40 (ddd, J = 2.5, 7.2, 9.6 Hz, 1H), 3.71-3.79 (m, 2H), 3.62 (q, J = 6.8 Hz, 2H), 3.47 (q, J = 5.2 Hz, 2H), 1.24- 1.33 (m, 3H).

Example 89

(S) -1- (2-ethoxyethyl) -6-fluoro-2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d ] Imidazole

N- (2-ethoxyethyl) -5-fluoro-2-nitroaniline (125 mg, 0.548 mmol), sodium bisulfite (286 mg, 85%, 1.40 mmol), and (S) -6- ( A mixture of 2-methylpyrrolidin-1-yl) nicotinaldehyde (109 mg, 0.575 mmol) in EtOH (4 mL) and water (2 mL) was heated at 130 ° C for 20 minutes under microwave conditions. Then added 28% NH ₄ OH, and the resulting mixture was extracted with EtOAc. The combined organic extracts were washed with water then brine, dried over MgSO _4, filtered, and concentrated. The resulting residue was purified via silica chromatography (0% to 100% EtOAc / hexanes) to provide (S) -1- (2-ethoxyethyl) -6-fluoro-2- ( 6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole (67 mg). LC-MS (ES) m / z = 369 [M + H] ⁺ . ¹ H NMR (400MHz CDCl ₃ ): δ 8.57 (d, J = 1.8Hz, 1H), 7.95 (dd, J = 2.5,8.9Hz, 1H), 7.73 (dd, J = 4.8,8.9Hz, 1H), 7.24 (dd, J = 2.4,9.0Hz, 1H), 7.06 (ddd, J = 2.5,8.8,9.7Hz, 1H), 6.52 (d, J = 8.9Hz, 1H), 4.38 (t, J = 5.7Hz , 2H), 4.28 (m, 1H), 3.85 (t, J = 5.7 Hz, 2H), 3.67 (m, 1H), 3.42-3.53 (m, 3H), 2.02-2.23 (m, 3H), 1.77- 1.89 (m, 1H), 1.25-1.38 (m, 3H), 1.18 (t, J = 7.0Hz, 3H).

Intermediate 121

N- (2-ethoxyethyl) -3-nitropyridine-2-amine

Add 2-chloro-3-nitropyridine (490 mg, 3.09 mmol), 2-ethoxyethyl-1-amine (303 mg, 3.40 mmol), and N, N-diisopropylethylamine (0.648 mL, 3.71) A solution of mmol) in DMSO (20 mL) was heated to 80 ° C for 45 minutes. Water was added and the resulting mixture was extracted with EtOAc. The combined organic extracts were washed with water then brine, dried over MgSO _4, filtered, and concentrated. The resulting residue was purified via silica chromatography (0% to 30% EtOAc / hexanes) to provide N- (2-ethoxyethyl) -3-nitropyridine-2-amine (567 mg as a yellow oil ). LC-MS (ES) m / z = 212 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.44-8.57 (m, 1H), 8.40-8.44 (m, 2H), 6.67 (dd, J = 4.7, 8.2Hz, 1H), 3.86 (q, J = 5.3 Hz, 2H), 3.67-3.75 (m, 2H), 3.59 (q, J = 6.9Hz, 2H), 1.27 (t, J = 7.1Hz, 3H).

Example 90

5- (3- (2-ethoxyethyl) -3H-imidazo [4,5-b] pyridin-2-yl) -N, N-diethylpyridin-2-amine

N- (2-ethoxyethyl) -3-nitropyridine-2-amine (125 mg, 0.592 mmol), sodium bisulfite (309 mg, 85%, 1.509 mmol), and 6- (diethylamine) Base) A mixture of nicotinaldehyde (127 mg, 0.710 mmol) in EtOH (4 mL) and water (2 mL) was heated at 130 ° C. for 20 minutes under microwave conditions. The reaction was then filtered and the filtrate was concentrated to dryness. CH ₂ Cl _{2 was added} , and the resulting mixture was filtered again. The filtrate was purified via silica gel chromatography (0% to 100% EtOAc / hexanes) to provide 5- (3- (2-ethoxyethyl) -3H-imidazo [4,5-b ] Pyridin-2-yl) -N, N-diethylpyridin-2-amine (814 mg). LC-MS (ES) m / z = 340 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.71-8.77 (m, 1H), 8.36 (dd, J = 1.5, 4.8 Hz, 1H), 8.08 (dd, J = 2.5, 9.1 Hz, 1H), 8.04 ( dd, J = 1.4,8.0Hz, 1H), 7.25 (dd, J = 4.8,7.9Hz, 1H), 6.60 (d, J = 9.1Hz, 1H), 4.57 (t, J = 5.8Hz, 2H), 3.98 (t, J = 5.7Hz, 2H), 3.62 (q, J = 6.9Hz, 4H), 3.44 (q, J = 7.1Hz, 2H), 1.26 (t, J = 7.1Hz, 6H), 1.11 ( t, J = 7.0 Hz, 3H).

Intermediate 122

6-((2-ethoxyethyl) amino) -5-nitronicotinic acid methyl ester

Add 6-Amino-5-nitronicotinic acid methyl ester (400 mg, 2.029 mmol) and K ₂ CO ₃ (421 mg, 3.04 mmol) to 1-bromo-2-ethoxy in DMF (3 mL) Ethane (342 mg, 2.232 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was diluted with water (5 mL) and extracted with EtOAc (4 x 5 mL). The organic extracts were combined and washed with brine, dried over MgSO _4, filtered, and concentrated. Purification by chromatography on SiO ₂ (gradient of 0 to 25% EtOAc / hexane) provided 6-((2-ethoxyethyl) amino) -5-nitronicotinine as a yellow oil Methyl ester (398 mg). LC-MS (ES) m / z = 270 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.12 (t, J = 7.0Hz, 3H), 3.49 (q, J = 7.0Hz, 2H), 3.60 (t, J = 5.8Hz, 2H), 3.80 (q, J = 5.9 Hz, 2H), 3.86 (s, 3H), 8.75 (d, J = 2.3 Hz, 1H), 8.92 (m, 2H).

Intermediate 123

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3- (2-ethoxyethyl) -3H-imidazo [ 4,5-b] pyridine-6-carboxylic acid methyl ester

Methyl 6-((2-ethoxyethyl) amino) -5-nitronicotinate (250 mg, 0.928 mmol), 6-((2S, 5S) -2,5-dimethylpyrrole Pyridin-1-yl) nicotinaldehyde (209 mg, 1.021 mmol), EtOH (4 mL), water (2 mL), and sodium bisulfite (485 mg, 85%, 2.372 mmol) were added to a microwave vial, and the reaction mixture was The reaction was heated at 130 ° C for 30 minutes under microwave conditions. The reaction was diluted with water (10 mL) and then extracted with EtOAc (4 x 5 mL). The organic extracts were combined, washed with brine, dried over MgSO _4, filtered, and concentrated. Purification by chromatography on SiO ₂ (gradient of 0 to 60% EtOAc / hexanes) provided 2- (6-((2S, 5S) -2,5-dimethylpyrrole- 1-yl) pyridin-3-yl) -3- (2-ethoxyethyl) -3H-imidazo [4,5-b] pyridine-6-carboxylic acid methyl ester (176 mg). LC-MS (ES) m / z = 424 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 0.92 (t, J = 7.0 Hz, 3H), 1.16 (d, J = 7.0 Hz, 6H), 1.66 (d, J = 5.6 Hz, 2H), 2.25 (br.s., 2H), 3.27-3.33 (m, 2H), 3.82 (t, J = 5.5Hz, 2H), 3.92 (s, 3H), 4.27 (br.s., 2H), 4.57 (t , J = 5.5Hz, 2H), 6.66 (d, J = 9.1Hz, 1H), 8.07 (dd, J = 9.0, 2.4Hz, 1H), 8.49 (d, J = 2.0Hz, 1H), 8.68 (d , J = 2.3Hz, 1H), 8.92 (d, J = 1.8Hz, 1H).

Intermediate 124

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3- (2-ethoxyethyl) -3H-imidazo [ 4,5-b] pyridine-6-carboxylic acid

10N NaOH (0.803 mL, 8.03 mmol) was added to 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridine-3 in CH ₃ OH (3 mL) -Yl) -3- (2-ethoxyethyl) -3H-imidazo [4,5-b] pyridine-6-carboxylic acid methyl ester (170 mg, 0.401 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was concentrated under vacuum, water (5 mL) was added, and the pH was adjusted with 6N HCl (1.4 mL, 8.0 mmol). The resulting solid was then separated by filtration and dried under a vacuum oven to provide 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridine-3 as a white solid. -Yl) -3- (2-ethoxyethyl) -3H-imidazo [4,5-b] pyridine-6-carboxylic acid (112 mg). LC-MS (ES) m / z = 424 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 0.92 (t, J = 7.0Hz, 3H), 1.16 (d, J = 6.3Hz, 6H), 1.66 (d, J = 5.3Hz, 2H), 2.25 (br.s., 2H), 3.28-3.32 (m, 2H), 3.83 (t, J = 5.5Hz, 2H), 4.27 (br.s., 2H), 4.56 (t, J = 5.5Hz, 2H ), 6.66 (d, J = 8.9Hz, 1H), 8.07 (dd, J = 9.0,2.4Hz, 1H), 8.46 (d, J = 2.0Hz, 1H), 8.67 (d, J = 2.3Hz, 1H ), 8.90 (d, J = 1.8 Hz, 1H), 13.18 (s, 1H).

Example 91

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3- (2-ethoxyethyl) -N-methyl- 3H-imidazo [4,5-b] pyridine-6-formamidine

Add EDC (48.7 mg, 0.254 mmol), HOBt (38.9 mg, 0.254 mmol), methylamine hydrochloride (15.43 mg, 0.229 mmol), and N-methylmorpholine (0.112 mL, 1.016 mmol) to 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3- (2-ethoxyethyl) in DMSO (2mL) -3H-imidazo [4,5-b] pyridine-6-carboxylic acid (52 mg, 0.127 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with water (5 mL) and extracted with EtOAc (4 x 5 mL). The organic extracts were combined and washed with brine, dried over MgSO _4, filtered, and concentrated. Purification by chromatography on SiO ₂ (gradient of 0 to 10% CH ₃ OH / CH ₂ Cl ₂ ) provided 2- (6-((2S, 5S) -2,5-dimethylpyrrolidine- 1-yl) pyridin-3-yl) -3- (2-ethoxyethyl) -N-methyl-3H-imidazo [4,5-b] pyridine-6-formamidine (47 mg), White solid after lyophilization. LC-MS (ES) m / z = 423 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 0.92 (t, J = 7.0Hz, 3H) 1.11-1.19 (m, 6H), 1.59-1.72 (m, 2H), 2.19-2.29 (m, 2H) , 2.84 (d, J = 4.6Hz, 3H), 3.28-3.32 (m, 2H), 3.82 (t, J = 5.6Hz, 2H), 4.28 (br.s., 2H), 4.54 (t, J = 5.3Hz, 2H), 6.65 (d, J = 9.1Hz, 1H), 8.06 (dd, J = 9.0, 2.4Hz, 1H), 8.43 (d, J = 1.8Hz, 1H), 8.57-8.63 (m, 1H), 8.66 (d, J = 2.5Hz, 1H), 8.81 (d, J = 1.8Hz, 1H).

Intermediate 125

N- (2-ethoxyethyl) -4-methyl-3-nitropyridine-2-amine

Add 2-fluoro-4-methyl-3-nitropyridine (1.05 g, 6.73 mmol) and K ₂ CO ₃ (1.022 g, 7.40 mmol) to 2-ethoxyethyl- in DMF (10 mL) 1-amine (0.659 g, 7.40 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was diluted with water (30 mL) and extracted with EtOAc (4 x 20 mL). The organic extracts were combined and washed with brine, dried over MgSO _4, filtered, and concentrated. Purification by chromatography on silica gel (0 to 30% EtOAc / hexane) provided N- (2-ethoxyethyl) -4-methyl-3-nitropyridine-2- as an orange oil Amine (1.52 g). LC-MS (ES) m / z = 226 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.11 (t, J = 7.0Hz, 3H), 2.39 (s, 3H), 3.46 (q, J = 6.8Hz, 2H), 3.50-3.55 (m, 2H), 3.56-3.63 (m, 2H), 6.64 (d, J = 4.8Hz, 1H), 7.54 (t, J = 5.1Hz, 1H), 8.16 (d, J = 4.8Hz, 1H).

Example 92

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3- (2-ethoxyethyl) -7-methyl- 3H-imidazo [4,5-b] pyridine

N- (2-ethoxyethyl) -4-methyl-3-nitropyridine-2-amine (55 mg, 0.244 mmol), 6-((2S, 5S) -2,5-dimethyl Pyrrolidin-1-yl) nicotinaldehyde (54.9 mg, 0.269 mmol), EtOH (1.5 mL), water (0.75 mL), and sodium bisulfite (128 mg, 85%, 0.623 mmol) were added to a microwave vial, and The reaction mixture was heated under microwave conditions at 130 ° C for 30 minutes. The reaction was then diluted with water (10 mL) and extracted with EtOAc (4 x 5 mL). The organic extracts were combined, washed with brine, dried over MgSO _4, filtered, and concentrated. Purification by chromatography on SiO ₂ (gradient from 0 to 70% EtOAc / hexanes) provided 2- (6-((2S, 5S) -2,5-dimethylpyrrolidine as a light transparent oil 1-yl) pyridin-3-yl) -3- (2-ethoxyethyl) -7-methyl-3H-imidazo [4,5-b] pyridine (30 mg). LC-MS (ES) m / z = 380 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 10.94 (t, J = 7.0Hz, 3H), 1.15 (d, J = 6.1Hz, 6H), 1.66 (d, J = 5.8Hz, 2H), 2.20 -2.29 (m, 2H), 2.59 (s, 3H), 3.30 (q, J = 1.0Hz, 2H), 3.81 (t, J = 5.7Hz, 2H), 4.27 (br.s., 2H), 4.47 (t, J = 5.6Hz, 2H), 6.64 (d, J = 8.9Hz, 1H), 7.12 (d, J = 5.1Hz, 1H), 8.02 (dd, J = 8.9, 2.5Hz, 1H), 8.18 (d, J = 5.1Hz, 1H), 8.61 (d, J = 2.3Hz, 1H).

Intermediate 126

5-bromo-N- (2-ethoxyethyl) -3-nitropyridine-2-amine

5-Bromo-2-fluoro-3-nitropyridine (1.5 g, 6.79 mmol) and K ₂ CO ₃ (0.938 g, 6.79 mmol) were added to ethoxymethylamine (0.510 g) in DMF (10 mL) , 6.79 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with water (30 mL) and extracted with EtOAc (4 x 20 mL). The organic extracts were combined and washed with brine, dried over MgSO _4, filtered, and concentrated. Purification by chromatography on SiO ₂ (gradient of 0 to 25% EtOAc / hexane) provided 5-bromo-N- (2-ethoxyethyl) -3-nitropyridine- as an orange oil 2-amine (1.81 g). LC-MS (ES) m / z = 291 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.12 (t, J = 7.0Hz, 3H), 3.48 (q, J = 6.8Hz, 2H), 3.55-3.60 (m, 2H), 3.71 (m, 2H), 8.53 (t, J = 5.3Hz, 1H), 8.56-8.62 (m, 2H).

Intermediate 127

5- (6-bromo-3- (2-ethoxyethyl) -3H-imidazo [4,5-b] pyridin-2-yl) -N, N-diethylpyridin-2-amine

5-Bromo-N- (2-ethoxyethyl) -3-nitropyridine-2-amine (292 mg, 1.006 mmol), 6- (diethylamino) nicotinaldehyde (215 mg, 1.208 mmol) , EtOH (3 mL), water (1.5 mL), and sodium bisulfite (526 mg, 85%, 2.566 mmol) were added to a microwave vial, and the reaction mixture was heated at 130 ° C for 90 minutes under microwave conditions. The reaction was then diluted with water (10 mL) and extracted with EtOAc (4 x 5 mL). The organic extracts were combined, washed with brine, dried over MgSO _4, filtered, and concentrated. Purification by chromatography on SiO ₂ (gradient from 0 to 30% EtOAc / hexane) provided 5- (6-bromo-3- (2-ethoxyethyl) -3H-imidazole as a transparent solid And [4,5-b] pyridin-2-yl) -N, N-diethylpyridin-2-amine (240 mg). LC-MS (ES) m / z = 419 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 0.94 (t, J = 7.0Hz, 3H), 1.12-1.18 (m, 6H), 3.28-3.34 (m, 2H), 3.58 (q, J = 7.1 Hz, 4H), 3.82 (t, J = 5.5 Hz, 2H), 4.50 (t, J = 5.3 Hz, 2H), 6.77 (d, J = 8.9 Hz, 1H), 8.07 (dd, J = 9.0, 2.4 Hz, 1H), 8.33 (d, J = 2.0 Hz, 1H), 8.42 (d, J = 2.0 Hz, 1H), 8.66 (d, J = 2.3 Hz, 1H).

Example 93

(2- (6- (diethylamino) pyridin-3-yl) -3- (2-ethoxyethyl) -3H-imidazo [4,5-b] pyridin-6-yl) boronic acid

Tetrahydroxydiboric acid (51.4mg, 0.574mmol), triphenylphosphine (10.03mg, 0.038mmol), 1,3-bis (diphenylphosphino) propane-nickel (II) chloride (20.73mg , 0.038 mmol), 5- (6-bromo-3- (2-ethoxyethyl) -3H-imidazo [4,5-b] pyridin-2-yl) -N, N-diethylpyridine 2-Amine (160 mg, 0.382 mmol), and EtOH (5 mL) were added to a 20 mL microwave vial, and the resulting mixture was flushed with argon for 10 minutes. Next, N, N-diisopropylethylamine (0.20 mL, 1.147 mmol) was added, and the reaction mixture was heated under microwave conditions at 80 ° C. for 1 hour. The reaction was filtered and the filtrate was concentrated. Water (10 mL) was then added and the resulting aqueous mixture was extracted with EtOAc (4 x 10 mL). The organic extracts were combined, washed with brine, dried over MgSO _4, filtered, and concentrated. Purification by chromatography on SiO ₂ (0 to 100% (80: 20: 2 CH ₂ Cl ₂ : CH ₃ OH: formic acid) / CH ₂ Cl ₂ gradient) provided (2- ( 6- (Diethylamino) pyridin-3-yl) -3- (2-ethoxyethyl) -3H-imidazo [4,5-b] pyridin-6-yl) boronic acid (67 mg). LC-MS (ES) m / z = 384 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 0.95 (t, J = 1.0Hz, 3H), 1.16 (t, J = 1.0Hz, 6H), 3.32 (q, J = 6.9Hz, 2H), 3.58 (q, J = 6.8Hz, 4H), 3.83 (t, J = 5.6Hz, 2H), 4.49 (t, J = 5.5Hz, 2H), 6.76 (d, J = 9.1Hz, 1H), 8.05 (dd , J = 9.1, 2.5 Hz, 1H), 8.32 (d, J = 1.5 Hz, 1H), 8.63 (d, J = 2.0 Hz, 1H), 8.66 (d, J = 1.3 Hz, 1H).

Intermediate 128

6-bromo-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3- (2-ethoxyethyl) -3H -Imidazo [4,5-b] pyridine

5-Bromo-N- (2-ethoxyethyl) -3-nitropyridine-2-amine (200 mg, 0.689 mmol), 6-((2S, 5S) -2,5-dimethylpyrrole Pyridin-1-yl) nicotinaldehyde (155 mg, 0.758 mmol), EtOH (2 mL), water (1 mL), and sodium bisulfite (360 mg, 85%, 1.758 mmol) were added to a microwave vial, and the reaction mixture was placed in It was heated at 130 ° C for 30 minutes under microwave conditions. The reaction was diluted with water (10 mL) and extracted with EtOAc (4 x 5 mL). The organic extracts were combined, washed with brine, dried over MgSO _4, filtered, and concentrated. Purification by chromatography on SiO ₂ (gradient from 0 to 70% EtOAc / hexanes) provided 6-bromo-2- (6-((2S, 5S) -2,5-di Methylpyrrolidin-1-yl) pyridin-3-yl) -3- (2-ethoxyethyl) -3H-imidazo [4,5-b] pyridine (156 mg). LC-MS (ES) m / z = 445 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 0.93 (t, J = 7.0 Hz, 3 H), 1.12-1.18 (m, 6 H), 1.66 (d, J = 5.3 Hz, 2 H), 2.25 (br. s., 2H), 3.28-3.32 (m, 2H), 3.81 (t, J = 5.5Hz, 2H), 4.26 (br.s., 2H), 4.51 (t, J = 5.5Hz, 2H), 6.65 (d, J = 8.9Hz, 1H), 8.05 (dd, J = 9.0, 2.4Hz, 1H), 8.32 (d, J = 2.0Hz, 1H), 8.42 (d, J = 2.0Hz, 1H), 8.66 (d, J = 2.3Hz, 1H).

Example 94

(2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3- (2-ethoxyethyl) -3H-imidazo [4,5-b] pyridine-6-yl) boronic acid

Tetrahydroxydiboric acid (30.3mg, 0.338mmol), triphenylphosphine (5.90mg, 0.023mmol), 1,3-bis (diphenylphosphino) propane-nickel (II) chloride (12.20mg , 0.023 mmol), 6-bromo-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3- (2-ethoxy Ethyl) -3H-imidazo [4,5-b] pyridine (100 mg, 0.225 mmol), and EtOH (5 mL) were added to a microwave vial, and the resulting mixture was flushed with argon for 10 minutes. Next, N, N-diisopropylethylamine (0.118 mL, 0.675 mmol) was added, and the reaction mixture was heated under microwave conditions at 80 ° C. for 1 hour. The reaction was filtered, washed with EtOH, and the filtrate was concentrated. Purification by chromatography on SiO ₂ (0 to 50% (80: 20: 2) CH ₂ Cl ₂ : CH ₃ OH: NH ₄ OH / CH ₂ Cl ₂ gradient) provided an off-white solid (2 -(6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3- (2-ethoxyethyl) -3H-imidazo [4 , 5-b] pyridin-6-yl) boronic acid (28 mg). The solid was dissolved in CH ₃ OH (2 mL) and treated with 7N NH ₃ in CH ₃ OH (200 uL), and the resulting mixture was stirred for 0.5 hours. The solution was concentrated and the resulting residue was freeze-dried to provide the desired product. LC-MS (ES) m / z = 445 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 0.90-0.96 (m, 3H), 1.15 (br.s., 6H), 1.66 (d, J = 5.1 Hz, 2H), 2.25 (br.s. , 2H), 3.28-3.32 (m, 2H), 3.82 (t, J = 5.6Hz, 2H), 4.26 (br.s., 2H), 4.47-4.57 (m, 2H), 6.64 (d, J = 8.9Hz, 1H), 8.02-8.09 (m, 1H), 8.26 (s, 2H), 8.37 (d, J = 1.5Hz, 1H), 8.63 (d, J = 2.5Hz, 1H), 8.68 (d, J = 1.3Hz, 1H).

Intermediate 129

5-bromo-N- (2-ethoxyethyl) -4-methyl-3-nitropyridine-2-amine

N-bromosuccinimide (217 mg, 1.221 mmol) was added to N- (2-ethoxyethyl) -4-methyl-3- nitrate in DMF (3 mL) cooled in an ice bath. Pyridin-2-amine (250 mg, 1.110 mmol), and the reaction mixture was slowly warmed to room temperature and stirred at room temperature overnight. The reaction was quenched with water (5 mL) and extracted with EtOAc (4 x 5 mL). The organic extracts were combined, washed with brine, dried over MgSO _4, filtered, and concentrated. Purification by chromatography on SiO ₂ (gradient from 0 to 20% EtOAc / hexane) provided 5-bromo-N- (2-ethoxyethyl) -4-methyl-3 as a yellow oil -Nitropyridine-2-amine (240 mg, 0.789 mmol). LC-MS (ES) m / z = 305 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.06-1.13 (m, 3H), 2.34 (s, 3H), 3.44 (q, J = 7.1Hz, 2H), 3.47-3.58 (m, 4H), 7.32 (t, J = 5.1Hz, 1H), 8.39 (s, 1H).

Intermediate 130

6-bromo-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3- (2-ethoxyethyl) -7 -Methyl-3H-imidazo [4,5-b] pyridine

5-Bromo-N- (2-ethoxyethyl) -4-methyl-3-nitropyridine-2-amine (240 mg, 0.789 mmol), 6-((2S, 5S) -2,5 -Dimethylpyrrolidin-1-yl) nicotinaldehyde (177 mg, 0.868 mmol), EtOH (3 mL), water (1.5 mL), and sodium bisulfite (412 mg, 85%, 2.012 mmol) were added to a microwave vial The reaction mixture was heated at 130 ° C for 30 minutes under microwave conditions. The reaction was diluted with water (10 mL) and extracted with EtOAc (4 x 5 mL). The organic extracts were combined, washed with brine, dried over MgSO _4, filtered, and concentrated. Purification by chromatography on SiO ₂ (gradient from 0 to 30% EtOAc / hexanes) provided 6-bromo-2- (6-((2S, 5S) -2,5-dimethyl) as a yellow oil Pyrrolidin-1-yl) pyridin-3-yl) -3- (2-ethoxyethyl) -7-methyl-3H-imidazo [4,5-b] pyridine (270 mg). LC-MS (ES) m / z = 459 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 0.93 (t, J = 7.0 Hz, 3 H), 1.13-1.18 (m, 6 H), 1.66 (d, J = 5.6 Hz, 2 H), 2.25 (br. s., 2H), 2.63 (s, 3H), 3.30 (q, J = 7.0 Hz, 2H), 3.79 (t, J = 5.6 Hz, 2H), 4.27 (br.s., 2H), 4.48 (t , J = 5.5 Hz, 2H), 6.64 (d, J = 8.9 Hz, 1H), 8.03 (dd, J = 8.9, 2.28 Hz, 1H), 8.40 (s, 1H), 8.63 (s, 1H).

Example 95

(2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3- (2-ethoxyethyl) -7-methyl -3H-imidazo [4,5-b] pyridin-6-yl) boronic acid

Tetrahydroxydiboric acid (79mg, 0.884mmol), triphenylphosphine (15.45mg, 0.059mmol), 1,3-bis (diphenylphosphino) propane-nickel (II) chloride (31.9mg, 0.059mmol), 6-bromo-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3- (2-ethoxyethyl ) -7-methyl-3H-imidazo [4,5-b] pyridine (270 mg, 0.589 mmol), and EtOH (5 mL) were added to a 20 mL microwave vial, and the resulting mixture was flushed with argon for 10 minutes. Next, N, N-diisopropylethylamine (0.309 mL, 1.767 mmol) was added, and the reaction mixture was heated under microwave conditions at 80 ° C. for 1 hour. The reaction was filtered, washed with EtOH, and the filtrate was concentrated. The resulting material was diluted with water (10 mL), followed by extraction with EtOAc (4 x 10 mL). The organic extracts were combined, washed with brine, dried over MgSO _4, filtered, and concentrated. Purification by chromatography on SiO ₂ (0 to 100% (80: 20: 2) CH ₂ Cl ₂ : CH ₃ OH: NH ₄ OH / CH ₂ Cl ₂ gradient) provided an off-white solid (2 -(6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3- (2-ethoxyethyl) -7-methyl-3H -Imidazo [4,5-b] pyridin-6-yl) boronic acid (77 mg). LC-MS (ES) m / z = 424 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 0.91-0.97 (m, 3H), 1.15 (d, J = 6.1 Hz, 6H), 1.66 (d, J = 5.1 Hz, 2H), 2.25 (br. s., 2H), 2.71 (s, 3H), 3.26-3.32 (m, 2H), 3.76-3.85 (m, 2H), 4.27 (br.s., 2H), 4.43-4.52 (m, 2H), 6.64 (d, J = 8.9Hz, 1H), 8.02 (dd, J = 8.9, 2.53Hz, 1H), 8.15 (s, 2H), 8.39 (s, 1H), 8.60-8.65 (m, 1H).

Intermediate 131

3-chloro-N1- (2-propoxyethyl) benzene-1,2-diamine

3-Chloro-2-nitro-N- (2-propoxyethyl) aniline (190 mg, 0.734 mmol) and NiCl ₂ ‧ 6H ₂ O (437 mg, 1.836 mmol) in CH ₃ OH (20 mL) The mixture was cooled in an ice-water bath. Sodium borohydride (139 mg, 3.67 mmol) was added, and the reaction mixture was stirred in an ice-water bath for 10 minutes. The reaction was concentrated to dryness. Adding NH ₄ OH (28% of water), and the resulting mixture was extracted with CH _{2 2} Cl. The dried CH ₂ Cl ₂ the combined extracts were washed with MgSO _4, filtered, and concentrated. The residue was purified via flash chromatography on SiO ₂ (0% to 50% EtOAc / hexanes) to give the desired product (99 mg) as a solid. LC-MS (ES) m / z = 229,231 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 6.81-6.91 (m, 1H), 6.76 (t, J = 8.0Hz, 1H), 6.61 (dd, J = 1.3, 7.9Hz, 1H), 3.67-3.77 ( m, 2H), 3, 49 (t, J = 6.7 Hz, 2H), 3.31 (t, J = 5.2 Hz, 2H), 1.67 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H).

Example 96

5- (4-chloro-1- (2-propoxyethyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine

3-chloro-N1- (2-propoxyethyl) benzene-1,2-diamine (99 mg, 0.346 mmol), 6- (diethylamino) nicotinaldehyde (61.7 mg, 0.346 mmol), And a mixture of potassium oxone monohydrate (oxone) (138 mg, 0.225 mmol) in DMF (10 mL) and water (4 mL) was stirred at room temperature for 16 hours. Saturated aqueous NaHCO ₃ was added, and the resulting mixture was extracted with EtOAc. The combined extracts were washed with water of EtOA, washed with brine, dried over MgSO _4, filtered and concentrated. The resulting residue was purified via silica chromatography (0% to 50% EtOAc / hexanes) to give 5- (4-chloro-1- (2-propoxyethyl) -1H-benzo [ d] imidazol-2-yl) -N, N-diethylpyridin-2-amine (65 mg). LC-MS (ES) m / z = 387,389 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.55-8.61 (m, 1H), 7.99 (dd, J = 2.4, 9.0 Hz, 1H), 7.41 (dd, J = 0.9, 8.0 Hz, 1H), 7.28- 7.35 (m, 1H), 7.16-7.24 (m, 1H), 6.59 (d, J = 8.9Hz, 1H), 4.42 (t, J = 5.7Hz, 2H), 3.84 (t, J = 5.6Hz, 2H ), 3.61 (q, J = 7.1Hz, 4H), 3.34 (t, J = 6.6Hz, 2H), 1.46-1.62 (m, 2H), 1.26 (t, J = 7.1Hz, 6H), 0.85 (t , J = 7.4Hz, 3H).

Intermediate 132

3-chloro-N- (2- (cyclopentyloxy) ethyl) -2-nitroaniline

Add 2- (cyclopentyloxy) ethylamine (221 mg, 1.709 mmol) and K ₂ CO ₃ (236 mg, 1.709 mmol) to 1-chloro-3-fluoro-2-nitrobenzene (300 mg, 1.709 mmol) in DMF (8 mL), and the mixture was stirred at room temperature for 18 hours. The mixture was quenched with water (15 mL) and extracted with EtOAc (3x). The extract was dried and concentrated, and the resulting residue was purified using column chromatography (silica, 0 to 60% EtOAc / hexane) to give the desired product (360 mg) as a light brown oil. LC-MS (ES) m / z = 285,287 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 1.52-1.82 (m, 9H), 3.36 (t, J = 5.3Hz, 2H), 3.62-3.69 (m, 2H), 3.93-4.02 (m, 1H), 6.69-6.84 (m, 2H), 7.25 (t, J = 8.2Hz, 1H).

Intermediate 133

3-chloro-N1- (2- (cyclopentyloxy) ethyl) benzene-1,2-diamine

Sodium borohydride (219 mg, 5.79 mmol) was added in portions to N- (2- (cyclopentyloxy) ethyl) -2-nitroaniline (290 mg, 1.159 mmol) and NiCl ₂ ‧ 6H ₂ O at 0 ° C. (689mg, 2.90mmol) was stirred in CH ₃ OH (8mL) of, and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was concentrated, and the residue was taken up and extracted with CH ₂ Cl ₂ (3x) in concentrated NH ₄ OH. The extracts were dried (Na ₂ SO ₄₎ and concentrated to give the desired product as a light brown oil (220mg). LC-MS (ES) m / z = 255,257 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 1.54-1.84 (m, 8H), 3.24-3.34 (m, 2H), 3.65-3.72 (m, 2H), 3.95-4.06 (m, 1H), 6.61 (dd , J = 7.9, 1.3 Hz, 1H), 6.71-6.78 (m, 1H), 6.81-6.86 (m, 1H).

Example 97

5- (4-chloro-1- (2- (cyclopentyloxy) ethyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridine-2-amine

Add oxone (507 mg, 0.824 rmmol) and 6- (diethylamino) nicotinaldehyde (147 mg, 0.824 mmol) to 3-chloro-N1- (2- (cyclopentane) at 0 ° C. A solution of oxy) ethyl) benzene-1,2-diamine (210 mg, 0.824 mmol) in DMF (5 mL) and water (1 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture 10% K ₂ CO ₃ aq and extracted with EtOAc (3x). The extract was dried (Na ₂ SO ₄ ) and concentrated, and the resulting residue was purified using column chromatography (silica gel, 0 to 70% EtOAc / hexanes) to give the desired product (180 mg) as a light brown oil. . LC-MS (ES) m / z = 413,415 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.19-1.31 (m, 6H), 1.37-1.61 (m, 8H), 3.64 (q, J = 7.1Hz, 4H), 3.74-3.84 (m, 3H) , 4.46 (t, J = 5.2 Hz, 2H), 6.77 (d, J = 8.9 Hz, 1H), 7.24-7.36 (m, 2H), 7.58 (dd, J = 7.9, 1.3 Hz, 1H), 8.00 ( dd, J = 9.0, 2.4 Hz, 1H), 8.53-8.61 (m, 1H).

Intermediate 134

3-chloro-N- (2- (2,2-difluoroethoxy) ethyl) -2-nitroaniline

1-chloro-3-fluoro-2-nitrobenzene (272 mg, 1.547 mmol), 2- (2,2-difluoroethoxy) ethyl-1-amine hydrochloride (250 mg, 1.547 mmol), and N , N-Diisopropylethylamine (0.324 mL, 1.857 mmol) in DMF (20 mL) was stirred at room temperature for 16 hours. The reaction was then heated at 80 ° C for 16 hours. The reaction was concentrated and the resulting residue was purified via SiO ₂ chromatography (0% to 30% EtOAc / hexanes) to provide 3-chloro-N- (2- (2,2-difluoroethyl) as an orange oil (Oxy) ethyl) -2-nitroaniline (251 mg). LC-MS (ES) m / z = 281 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.24 (dd, J = 7.9, 8.6 Hz, 1H), 6.66-6.88 (m, 2H), 5.75-6.08 (m, 2H), 3.68-3.83 (m, 4H ), 3.41 (t, J = 5.2Hz, 2H).

Intermediate 135

4-bromo-3-chloro-N- (2- (2,2-difluoroethoxy) ethyl) -2-nitroaniline

3-Chloro-N- (2- (2,2-difluoroethoxy) ethyl) -2-nitroaniline (251 mg, 0.894 mmol) and N-bromosuccinimide (159 mg, 0.894 mmol) The solution in acetic acid (25 mL) was heated at 80 ° C for 2 hours. The reaction was concentrated and the resulting residue was purified by SiO ₂ chromatography (0% to 25% EtOAc / hexane) to provide 4-bromo-3-chloro-N- (2- (2,2- Difluoroethoxy) ethyl) -2-nitroaniline (267 mg). LC-MS (ES) m / z = 258,260 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 7.54 (d, J = 9,1Hz, 1H), 6.67 (d, J = 9.1Hz, 1H), 5.73-6.08 (m, 1H), 5.46-5.72 (m , 1H), 3.68-3.82 (m, 4H), 3.39 (t, J = 5.2Hz, 2H).

Example 98

5-bromo-4-chloro-1- (2- (2,2-difluoroethoxy) ethyl) -2- (6-((2S, 5S) -2,5-dimethylpyrrolidine- 1-yl) pyridin-3-yl) -1H-benzo [d] imidazole

4-Bromo-3-chloro-N- (2- (2,2-difluoroethoxy) ethyl) -2-nitroaniline (267 mg, 0.743 mmol), sodium bisulfite (388 mg, 85%, 1.894mmol), and 6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (174mg, 0.854mmol) in EtOH (4mL) and water (1mL) Heated at 130 ° C for 75 minutes under microwave conditions. The reaction was filtered and the filtrate was concentrated to dryness. Water was then added, and the resulting aqueous mixture was extracted with CH ₂ Cl ₂ . The combined organic extracts were washed with water then brine, dried over MgSO _4, filtered, and concentrated. The resulting residue was purified via SiO ₂ chromatography (0% to 100% EtOAc / hexane) to provide 5-bromo-4-chloro-1- (2- (2,2-difluoroethoxy) ethyl ) -2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole (209 mg). LC-MS (ES) m / z = 515,517 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.51 (br.s., 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 8.6 Hz, 1H), 7.28 (s, 1H ), 6.51 (d, J = 8.9Hz, 1H), 5.54-6.08 (m, 1H), 4.2-4.37 (br.s., 2H), 4.37-4.60 (m, 2H), 3.96 (t, J = 5.5Hz, 2H), 3.61 (dt, J = 4.1, 13.8Hz, 2H), 2.31 (t, J = 7.4Hz, 2H), 1.60-1.89 (m, 2H), 1.22 (d, J = 6.3Hz, 6H).

Example 99

(4-chloro-1- (2- (2,2-difluoroethoxy) ethyl) -2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl ) Pyridin-3-yl) -1H-benzo [d] imidazol-5-yl) boronic acid

Example 100

4-chloro-1- (2- (2,2-difluoroethoxy) ethyl) -2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) Pyridin-3-yl) -1H-benzo [d] imidazole

N-butyllithium (0.180 mL, 0.451 mmol, 2.5 M in hexane) was added dropwise to 5-bromo-4-chloro-1- (2- (2,2,2) in a dry ice acetone bath over 5 minutes. -Difluoroethoxy) ethyl) -2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d ] A solution of imidazole (193 mg, 0.376 mmol) and triisopropyl borate (0.113 mL, 0.488 mmol) in THF (4 mL) and toluene (12 mL), and the reaction mixture was stirred for 30 minutes. 2N HCl (6 mL) was added dropwise, and the resulting mixture was allowed to warm to room temperature. The mixture was washed with EtOAc, and the aqueous phase until pH ~ 7-8 treated with saturated aqueous NaHCO _3. The resulting aqueous mixture was extracted with EtOAc, and the combined organic extracts were washed with water followed by brine, dried over MgSO _4, filtered, and concentrated. The resulting residue was purified by SiO ₂ chromatography (0% to 100% (3: 1 EtOAc: EtOH) / hexane) followed by reverse phase HPLC purification (20% to 60% CH ₃ CN / (in H ₂ O 0.1% NH ₄ OH) to provide (4-chloro-1- (2- (2,2-difluoroethoxy) ethyl) -2- (6-((2S, 5S) after freeze-drying -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-5-yl) boronic acid (31 mg). LC-MS (ES) m / z = 479,481 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.55 (br.s., 1H), 7.91 (d, J = 8.4Hz, 2H), 7.44 (d, J = 8.4Hz, 1H), 6.53 (d, J = 8.1Hz, 1H), 5.60-6.06 (m, 1H), 4.23-4.60 (m, 4H), 3.99 (t, J = 5.3Hz, 2H), 3.62 (dt, J = 3.8, 13.8Hz, 2H), 2.33 (br.s., 2H), 1.75 (d = 5.3Hz, 2H), 1.25 (d, J = 6.1Hz, 6H). 4-Chloro-1- ( 2- (2,2-difluoroethoxy) ethyl) -2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl)- 1H-benzo [d] imidazole (46 mg). LC-MS (ES) m / z = 435,437 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.54 (br.s., 1H) , 7.94 (d, J = 5.6Hz, 1H), 7.33-7.42 (m, 2H), 7.21-7.27 (m, 1H), 6.53 (d, J = 8.1Hz, 1H), 5.54-6.11 (m, 1H ), 4.42-4.60 (m, 2H), 4.21-4.30 (br.s., 2H), 3.99 (t, J = 5.5Hz, 2H), 3.63 (dt, J = 4.1, 13.8Hz, 2H), 2.25 -2.39 (m, 2H), 1.75 (d, J = 5.6Hz, 2H), 1.25 (d, J = 6.3Hz, 6H).

Intermediate 136

5- (1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridine-2-amine

6- (Diethylamino) nicotinaldehyde (8.6 g, 48.3 mmol), sodium metadisulfite (11.92 g, 62.7 mmol) and benzene-1,2-diamine (5.22 g, 48.3 mmol) in DMF (150 mL) The mixture in) was stirred at 40 ° C for 12 hours. The reaction mixture was cooled to room temperature and poured into water (450 mL), and the resulting solid was collected by filtration to give the desired product (9.0 g) as a yellow solid. LC-MS (ES) m / z = 267 [M + H] ⁺ .

Example 101

N, N-diethyl-5- (1-((2-ethyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-2-yl) pyridin-2-amine

5- (1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine (400 mg, 1.502 mmol), 4- (chloromethyl) -2-ethyl A mixture of azole (328 mg, 2.253 mmol), and NaH (60%, 240 mg, 6.01 mmol) in THF (20 mL) was placed in a sealed tube and stirred at 95 ° C for 18 hours. Water (5 mL) was then added and the mixture was concentrated under vacuum. The resulting residue was poured into water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated. The resulting residue was purified by silica gel chromatography (eluted with 20: 1 CH ₂ Cl ₂ / CH ₃ OH) to give the desired product (150 mg) as a light-colored gum. LC-MS (ES) m / z = 376 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.54 (d, J = 2.0Hz, 1H), 7.97 (dd, J = 8.9, 2.2Hz, 1H), 7.81 (d, J = 7.8Hz, 1H), 7.36 -7.24 (m, 3H), 7,23 (s, 1H), 6.58 (d, J = 9.0Hz, 1H), 5.31 (s, 2H), 3.58 (q, J = 7.0Hz, 4H), 2.80 ( q, J = 7.6 Hz, 2H), 1.35 (t, J = 7.6 Hz, 3H), 1.22 (t, J = 7.0 Hz, 6H).

Intermediate 137

7- (1H-benzo [d] imidazol-2-yl) -4-ethyl-3-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4]

Benzene-1,2-diamine (262 mg, 2.424 mmol) was added to 4-ethyl-3-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] A solution of -7-formaldehyde (500 mg, 2.424 mmol) and sodium metabisulfite (599 mg, 3.15 mmol) in DMF (10 mL), and the reaction mixture was stirred at 90 ° C for 12 hours. The mixture was poured into water (150 ml) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated. The resulting residue was purified by silica chromatography (dialysis with 0 to 20% EtOAc / hexanes) to give the desired product (300 mg) as a yellow solid. LC-MS (ES) m / z = 295 [M + H] ⁺ .

Example 102

4-ethyl-7- (1-((2-ethyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-2-yl) -3-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1, 4]

Add NaH (60%, 82mg, 2.038mmol) to 7- (1H-benzo [d] imidazol-2-yl) -4-ethyl-3-methyl-3,4-dihydro-2H-pyridine And [3,2-b] [1,4] (300 mg, 1.019 mmol) in DMF (5 mL), and the mixture was stirred for 10 minutes. 4- (chloromethyl) -2-ethyl Azole (223 mg, 1.529 mmol), and the reaction mixture was stirred at 75 ° C for 12 hours. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated. The resulting residue was purified by silica chromatography (dialysis with 1: 1 EtOAc / hexanes) to give the desired product (100 mg) as a white solid. LC-MS (ES) m / z = 404 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.17 (s, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.49 (s, 1H), 7.37-7.29 (m, 2H), 7.29-7.27 ( m, 1H), 7.23 (s, 1H), 5.32 (s, 2H), 4.03 (dd, J = 7.3Hz, 3H), 3.74-3.68 (m, 1H), 3.41-3.34 (m, 1H), 2.80 (q, J = 7.6Hz, 2H), 1.35 (t, J = 7.6Hz, 3H), 1.32 (d, J = 6.6Hz, 3H), 1.23 (t, J = 7.1Hz, 3H).

Intermediate 138

7- (1H-benzo [d] imidazol-2-yl) -4-ethyl-3,3-dimethyl-3,4-dihydro-2H-pyrido [3,2-b] [1 , 4]

Add sodium metadisulfite (381 mg, 2.007 mmol) and benzene-1,2-gum (167 mg, 1.544 mmol) to 4-ethyl-3,3-dimethyl-3,4-dihydro-2H-pyridine And [3,2-b] [1,4] A solution of -7-formaldehyde (340 mg, 1.544 mmol) in DMF (10 mL), and the reaction mixture was stirred at 90 ° C for 12 hours. The mixture was poured into water (150 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated. The resulting residue was purified by silica gel chromatography (eluted with 0 to 20% EtOAc / hexanes) to give the desired product (237 mg) as a yellow solid. LC-MS (ES) m / z = 309 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.40 (d, J = 1,8 Hz, 1H), 7.65 (d, J = 1.7 Hz, 1H), 7.58 (s, 2H), 7.21 (dd, J = 5.9 , 3.1Hz, 2H), 3.85 (s, 2H), 3.60 (q, J = 6.9Hz, 2H), 2.05 (s, 1H), 1.31 (s, 6H), 1.24 (t, J = 7.3Hz, 3H ).

Example 103

4-ethyl-7- (1-((2-ethyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-2-yl) -3,3-dimethyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4]

NaH (36.9 mg, 1.537 mmol) was added to 7- (1H-benzo [d] imidazol-2-yl) -4-ethyl-3,3-dimethyl-3,4-dihydro-2H- Pyrido [3,2-b] [1,4] (237 mg, 0.769 mmol) in DMF (10 mL), and the mixture was stirred for 10 minutes. 4- (chloromethyl) -2-ethyl Azole (224 mg, 1.537 mmol), and the reaction mixture was stirred at 75 ° C for 12 hours. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated. The obtained residue was purified by silica gel chromatography (eluted with 20: 1 CH ₂ Cl ₂ / CH ₃ OH) to give the desired product (70 mg) as a white solid. LC-MS (ES) m / z = 418 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 8.32 (d, J = 1.3Hz, 1H), 8.11 (s, 1H), 7.69-7.61 (m, 2H), 7.58-7.52 (m, 1H), 7.25-7.16 (m, 2H), 5.31 (s, 2H), 3.93 (s, 2H), 3.61 (q, J = 6.5Hz, 2H), 2.72 (q, J = 7.5Hz, 2H), 1.29 (s , 6H), 1.23-1.16 (m, 6H).

Intermediate 139

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole

Add sodium metabisulfite (494mg, 2.60mmol) and 6-((2R, 5R) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (409mg, 2mmol) to benzene-1,2- A solution of diamine (260 mg, 2.400 mmol) in DMF (10 mL), and the reaction mixture was stirred at 80 ° C for 12 hours. The reaction mixture was quenched with water (80 mL), and the resulting precipitate was collected by filtration and dried under vacuum to give the desired product (530 mg) as a brown solid. LC-MS (ES) m / z = 293 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 13.50-12.98 (m, 10H), 8.85 (s, 1H), 8.16 (d, J = 9.0Hz, 1H), 7.57 (dd, J = 5.8, 3.1 Hz, 2H), 7.22 (dd, J = 5.8, 3.2 Hz, 2H), 6.67 (d, J = 9.0 Hz, 1H), 4.27 (s, 1H), 2.24 (s, 2H), 1.66 (d, J = 5.5Hz, 2H), 1.15 (d, J = 6.1Hz, 6H).

Synthesis Example 104

2-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-1-yl) (Methyl) -4-ethyl Azole

2- (chloromethyl) -5-ethyl (106 mg, 0.728 mmol), 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole ( A mixture of 213 mg, 0.728 mmol) and NaH (60%, 35 mg, 0.88 mmol) in DMF (15 mL) was stirred at 80 ° C for 12 hours. The mixture was concentrated under vacuum, and the residue was treated with water (20 mL) and extracted with EtOAc (2 x 40 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated. By silica gel chromatography (with 0 to _{3.5% CH 3 OH / CH 2} Cl 2 elution) resulting residue was purified to yield the desired product as a gray solids (200mg). LC-MS (ES) m / z = 402 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 8.56 (d, J = 1.9 Hz, 1H), 7.94 (dd, J = 8.9, 2.1 Hz, 1H), 7.69-7.61 (m, 1H), 7.59- 7.51 (m, 1H), 7.28-7.20 (m, 2H), 6.84 (s, 1H), 6.63 (d, J = 8.9Hz, 1H), 5.59 (s, 2H), 4.40-4.08 (m, 2H) , 2.61 (q, J = 7.6 Hz, 2H), 2.30-2.16 (m, 2H), 1.70-1.59 (m, 2H), 1.19-1.08 (m, 9H).

Example 105

4-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-1-yl) (Methyl) -2-ethyl Azole

NaH (60%, 49 mg, 1.23 mmol) was added to 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] A solution of imidazole (180 mg, 0.616 mmol) in DMF (6 mL), and the reaction mixture was stirred at 60 ° C for 30 minutes. 4- (chloromethyl) -2-ethyl Azole (179 mg, 1.231 mmol), and the reaction mixture was stirred at 80 ° C overnight. The reaction mixture was washed with water (2mL) was quenched, concentrated, poured into water (50mL) and extracted with _{CH 2 Cl 2 (2 x 50mL} ). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated. By silica gel chromatography (with 0 to _{5% CH 3 OH / CH 2} Cl 2 elution) resulting residue was purified to yield the desired product as a white solid (60mg). LC-MS (ES) m / z = 402 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.53 (s, 1H), 7.95 (d, J = 8.8Hz, 1H), 7.81 (d, J = 7.7Hz, 1H), 7.36-7.27 (m, 2H) , 7.26-7.18 (m, 3H), 6.49 (d, J = 8.9Hz, 1H), 5.31 (s, 2H), 4.45-4.00 (m, 2H), 2.81 (q, J = 7.6Hz, 2H), 2.35-2.20 (m, 2H), 1.76-1.61 (m, 2H), 1.36 (t, J = 7.6Hz, 3H), 1.20 (d, J = 6.2Hz, 6H).

Intermediate 140

4-(((2-ethyl Azole-4-yl) methyl) amino) -N-methyl-3-nitrobenzamide

4-Fluoro-N-methyl-3-nitrobenzamide (400 mg, 2.019 mmol), triethylamine (817 mg, 8.07 mmol), and (2-ethyl A mixture of azole-4-yl) methylamine (255 mg, 2.019 mmol) in DMF (20 mL) was stirred at 70 ° C for 12 hours. The mixture was concentrated under vacuum, and the resulting residue was poured into water (150 mL) and extracted with EtOAc (2 x 150 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated. By silica gel chromatography (with 0 to _{5% CH 3 OH / CH 2} Cl 2 elution) resulting residue was purified to yield the desired product as a yellow solids (600mg, 94% yield). LC-MS (ES) m / z = 305 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.55 (d, J = 2.0Hz, 2H), 7.98 (dd, J = 9.0, 2.0Hz, 1H), 7.50 (s, 1H), 6.98 (d, J = 9.0Hz, 1H), 4.48 (d, J = 4.7Hz, 2H), 3.02 (d, J = 4.6Hz, 3H), 2.81 (q, J = 7.6Hz, 2H), 1.35 (t, J = 7.6Hz , 3H).

Intermediate 141

3-amino-4-(((2-ethyl Azole-4-yl) methyl) amino) -N-methylbenzidine

Add 4-(((2-ethyl Azole-4-yl) methyl) amino) -N-methyl-3-nitrobenzamide (250 mg, 0.822 mmol) and palladium on carbon (8.74 mg, 0.082 mmol) in CH ₃ OH (15 mL) The mixture was stirred at 25 ° C for 4 hours under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to provide the desired product (213 mg) as a brown solid. LC-MS (ES) m / z = 275 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 7.45 (s, 1H), 7.25 (d, J = 1.8Hz, 1H), 7.19-7.15 (1H), 6.63 (d, J = 8.2Hz, 1H), 6.05 (s, 1H), 4.25 (s, 2H), 3.49 (s, 1H), 2.97 (d, J = 4.8Hz, 3H), 2.78 (q, J = 7.6Hz, 2H), 1.34 (t, J = 7.6Hz, 3H).

Example 106

2- (4-ethyl-3-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] -7-yl) -1-((2-ethyl Azole-4-yl) methyl) -N-methyl-1H-benzo [d] imidazole-5-carboxamide

Combine sodium metadisulfite (292 mg, 1.535 mmol) and 3-amino-4-(((2-ethyl Azole-4-yl) methyl) amino) -N-methylbenzamide (324 mg, 1.181 mmol) was added to 4-ethyl-3-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] A solution of -7-formaldehyde (244 mg, 1.181 mmol) in DMF (15 mL), and the reaction mixture was stirred at 90 ° C for 12 hours. The mixture was concentrated in vacuo and the resulting residue was washed with water (20mL) and aqueous NaHCO ₃ (4mL) process. The aqueous mixture was extracted with CH ₂ Cl ₂ (2 x 40 mL), and the combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated. By silica gel chromatography (with 0 to _{3.5% CH 3 OH / CH 2} Cl 2 elution) resulting residue was purified to yield the desired product as a white solid (290mg). LC-MS (ES) m / z = 461 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 8.44-8.38 (m, 1H), 8.31 (d, J = 1.9Hz, 1H), 8.15 (s, 1H), 8.12 (s, 1H), 7.74 ( dd, J = 8.5, 1.1 Hz, 1H), 7.64 (d, J = 1.9 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 5.34 (s, 2H), 4.12 (dd, J = 10.8 , 2.4Hz, 1H), 4.04-3.90 (m, 2H), 3.86-3.78 (m, 1H), 3.43-3.35 (m, 1H), 2.81 (d, J = 4.4Hz, 3H), 2.71 (q, J = 7.6 Hz, 2H), 1.24 (d, J = 6.5 Hz, 3H), 1.20-1.10 (m, 6H).

Example 107

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((2-ethyl Azole-4-yl) methyl) -N-methyl-1H-benzo [d] imidazole-5-carboxamide

Add 3-amino-4-(((2-ethyl Azole-4-yl) methyl) amino) -N-methylbenzylamine (213 mg, 0.776 mmol) was added to 6-((2S, 5S) -2,5-dimethylpyrrolidine-1- A solution of nicotinaldehyde (159 mg, 0.776 mmol) and sodium metabisulfite (192 mg, 1.009 mmol) in DMF (10 mL), and the reaction mixture was stirred at 90 ° C for 12 hours. The mixture was concentrated in vacuo and the resulting residue was washed with water (20mL) and saturated aqueous NaHCO ₃ (4mL) process. The resulting aqueous mixture was extracted with CH ₂ Cl ₂ (2 x 40 mL), and the combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated. By silica gel chromatography (with 0 to _{3.5% CH 3 OH / CH 2} Cl 2 elution) resulting residue was purified to yield the desired product as a white solid (145mg). LC-MS (ES) m / z = 459 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 8.67 (s, 1H), 8.43-8.37 (m, 1H), 8.17-8.08 (m, 3H), 7.73 (d, J = 8.4Hz, 1H), 7.60 (d, J = 8.5Hz, 1H), 6.65 (d, J = 9.0Hz, 1H), 5.34 (s, 2H), 4.34-4.17 (m, 2H), 2.80 (d, J = 4.3Hz, 3H ), 2.71 (dd, J = 15.1, 7.6 Hz, 2H), 2.29-2.18 (m, 2H), 1.71-1.60 (m, 2H), 1.21-1.12 (m, 9H).

Intermediate 142

4-(((2-ethyl Azole-4-yl) methyl) amino) -3-nitrobenzamide

Add 4-fluoro-3-nitrobenzamide (400mg, 2.172mmol), (2-ethyl A mixture of azole-4-yl) methylamine (274 mg, 2.172 mmol), and triethylamine (879 mg, 8.69 mmol) in DMF (20 mL) was stirred at 70 ° C for 12 hours. The mixture was concentrated under vacuum, and the resulting residue was poured into water (150 mL) and extracted with EtOAc (2 x 150 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated. By silica gel chromatography (with 0 to _{5% CH 3 OH / CH 2} Cl 2 elution) resulting residue was purified form to produce the desired product as a yellow solid (510mg). LC-MS (ES) m / z = 291 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 8.77-8.62 (m, 2H), 8.00 (d, J = 8.2Hz, 2H), 7.31 (s, 1H), 7.14 (d, J = 9.1Hz, 1H), 4.53 (d, J = 5.7Hz, 2H), 2.74 (q, J = 7.6Hz, 2H), 1.26-1.15 (m, 3H).

Intermediate 143

3-amino-4-(((2-ethyl Azole-4-yl) methyl) amino) benzamide

Add 4-(((2-ethyl A mixture of azole-4-yl) methyl) amino) -3-nitrobenzamide (260 mg, 0.896 mmol) and palladium on carbon (9.53 mg, 0.090 mmol) in CH ₃ OH (15 mL) under a hydrogen atmosphere The mixture was stirred at 25 ° C for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to provide the desired product (233 mg) as a yellow solid. LC-MS (ES) m / z = 261 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 7.46 (s, 1H), 7.29 (s, 1H), 7.23 (s, 1H), 6.65 (d, J = 8.4Hz, 1H), 4.27 (s, 2H) , 3.49 (s, 1H), 2.79 (q, J = 7.6Hz, 2H), 1.34 (t, J = 7.6Hz, 3H).

Example 108

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((2-ethyl Azol-4-yl) methyl) -1H-benzo [d] imidazol-5-carboxamide

Combine sodium metadisulfite (221 mg, 1.164 mmol) and 3-amino-4-(((2-ethyl Azole-4-yl) methyl) amino) benzamide (233 mg, 0.895 mmol) was added to 6-((2S, 5S) -2,3,5-trimethylpyrrolidin-1-yl) smoke A solution of alkaline aldehyde (195 mg, 0.895 mmol) in DMF (10 mL), and the mixture was stirred at 90 ° C for 12 hours. The mixture was concentrated in vacuo and the resulting residue was washed with water (20mL) and saturated NaHCO ₃ (2mL) process. The resulting aqueous mixture was extracted with CH ₂ Cl ₂ (2 x 40 mL), and the combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated. By silica gel chromatography (with 0 to _{3.5% CH 3 OH / CH 2} Cl 2 elution) resulting residue was purified to yield the desired product as a white solid (149mg). LC-MS (ES) m / z = 445 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 8.67 (d, J = 2.3Hz, 1H), 8.20 (s, 1H), 8.15-8.06 (m, 2H), 7.95 (br s, 1H), 7.77 (dd, J = 8.4,1.4Hz, 1H), 7.59 (d, J = 8.5Hz, 1H), 7.26 (br s, 1H), 6.65 (d, J = 9.0Hz, 1H), 5.34 (s, 2H ), 4.33-4.17 (m, 2H), 2.71 (q, J = 7.6Hz, 2H), 2.28-2.19 (m, 2H), 1.71-1.60 (m, 2H), 1.21-1.12 (m, 9H).

Intermediate 144

4-(((2-ethyl Azole-4-yl) methyl) amino) -3-nitrobenzoate

Will (2-ethyl Azole-4-yl) methylamine (507 mg, 4,02 mmol) and K ₂ CO ₃ (555 mg, 4.02 mmol) were added to methyl 4-fluoro-3-nitrobenzoate (800 mg, 4.02 mmol) in DMF (20 mL) The solution was stirred and the mixture was stirred at room temperature for 18 hours. The mixture was filtered, and the filtrate was concentrated. The resulting residue was washed with water and dried under vacuum to give the desired product (1.05 g) as a light brown solid. LC-MS (ES) m / z = 306 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 1.31-1.41 (m, 3H), 2.77-2.87 (m, 2H), 3.92 (s , 3H), 4.49 (dd, J = 5.4, 0.9 Hz, 2H), 6.96 (d, J = 8.9 Hz, 1H), 7.48-7.57 (m, 1H), 8.09 (dd, J = 9.4, 1.8 Hz, 1H), 8.65 (br.s., 1H), 8.91 (d, J = 2.0Hz, 1H).

Intermediate 145

3-amino-4-(((2-ethyl Azole-4-yl) methyl) amino) methyl benzoate

NiCl ₂ ‧ 6H ₂ O (1.949 g, 8.19 mmol) and sodium borohydride (0.620 g, 16.38 mmol) were added to 4-(((2-ethyl 4-yl) methyl) amino) -3-nitro benzoate (1g, 3.28mmol), and the mixture was stirred in the ₃ OH (20mL) was CH at 0 ℃ 20 minutes. The reaction mixture was concentrated, and the residue was treated with concentrated aqueous NH ₄ OH and extracted with EtOAc (3x). The extracts were dried (Na ₂ SO ₄₎ and concentrated to give the desired product as a light brown solid (860mg). LC-MS (ES) m / z = 276 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.33 (t, J = 7.6Hz, 3H), 1.95 (s, 2H), 2.81 (q, J = 7.6Hz, 2H), 3.82 (s, 3H), 4.31-4.37 (m, 2H), 6.60 (d, J = 8.4Hz, 1H), 7.36-7.45 (m, 2H), 7.68 (s, 1H).

Intermediate 146

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((2-ethyl Azole-4-yl) methyl) -1H-benzo [d] imidazole-5-carboxylic acid methyl ester

6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (445 mg, 2.179 mmol) and oxone (1005 mg, 1.635 mmol) at 0 ° C ) To 3-amino-4-(((2-ethyl A solution of azole-4-yl) methyl) amino) benzoic acid methyl ester (600 mg, 2.179 mmol) in DMF (9 mL) and water (1.8 mL), the mixture was stirred at room temperature for 2 hours. The reaction mixture 10% K ₂ CO ₃ aq and extracted with EtOAc (3x). The extracts were dried (Na ₂ SO ₄₎ and concentrated. The resulting residue was purified using column chromatography (silica gel, 0 to 100% EtOAc / hexanes) to give the desired product (690 mg) as a light brown solid. LC-MS (ES) m / z = 460 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.18-1.34 (m, 9H), 1.76 (d, J = 5.8Hz, 2H), 2.30-2.41 (m, 2H), 2.77 (q, J = 7.6Hz , 2H), 3.95 (s, 3H), 4.33 (br.s., 2H), 5.39-5.43 (m, 2H), 6.72 (d, J = 9.1Hz, 1H), 7.62 (d, J = 8.4Hz , 1H), 7.84 (s, 1 H), 7.99 (dd, J = 8.6, 1.5Hz, 1H), 8.08 (dd, J = 9.1, 2.5Hz, 1H), 8.36 (d, J = 1.3Hz, 1H ), 8.65 (d, J = 2.0 Hz, 1H).

Example 109

(2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((2-ethyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-5-yl) methanol

LiAlH ₄ (2M, 1.480 mL, 2.96 mmol) in THF was added to 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridine- 3-yl) -1-((2-ethyl A solution of azole-4-yl) methyl) -1H-benzo [d] imidazole-5-carboxylic acid methyl ester (680 mg, 1.480 mmol) in THF (8 mL), and the mixture was stirred at 0 ° C for 2 hours. The mixture was quenched by adding water dropwise until no H _{2 was} produced, then diluted with EtOAc (30 mL) and filtered. The filtrate was dried (Na ₂ SO ₄₎ and concentrated. The resulting residue was purified using column chromatography (silica gel, 0 to 100% (3: 1 EtOAc: EtOH) / heptane) to give the desired product (420 mg) as a white solid. LC-MS (ES) m / z = 432 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.17-1.33 (m, 9H), 1.70-1.79 (m, 2H), 2.29-2.40 (m, 2H), 2.77 (q, J = 7.6Hz, 2H) , 4.32 (br.s., 2H), 4.74 (s, 2H), 5.36 (s, 2H), 6.71 (d, J = 8.9Hz, 1H), 7.31 (dd, J = 8.4, 1.5Hz, 1H) , 7.50 (d, J = 8.4Hz, 1H), 7.69 (s, 1H), 7.78 (s, 1H), 8.05 (dd, J = 9.0, 2.4Hz, 1H), 8.61 (d, J = 2.3Hz, 1H).

Intermediate 147

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((2-ethyl Azole-4-yl) methyl) -1H-benzo [d] imidazole-5-carbaldehyde

Add Dess-Martin periodinane (575mg, 1.356mmol) to (2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1 -((2-ethyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-5-yl) methanol (390 mg, 0.904 mmol) in CH ₂ Cl ₂ (5 mL), the mixture was stirred at room temperature for 4 hour. The mixture was concentrated, and the resulting residue was purified using column chromatography (silica, 0 to 60% EtOAc / hexanes) to give the desired product (310 mg) as a light brown solid. LC-MS (ES) m / z = 430 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.20-1.34 (m, 9H), 1.72-1.82 (m, 2H), 2.28-2.43 (m, 2H), 2.77 (q, J = 7.6Hz, 2H) , 4.33 (m, 2H), 5.44 (s, 2H), 6.73 (d, J = 8.9Hz, 1H), 7.72 (d, J = 8.6Hz, 1H), 7.85-7.91 (m, 2H), 8.10 ( dd, J = 8.9, 2.5Hz, 1H), 8.24 (d, J = 1.0Hz, 1H), 8.67 (d, J = 2.3Hz, 1H), 10.07 (s, 1H).

Example 110

N-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((2-ethyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-5-yl) methyl) -2,2,2-trifluoroethylamine

Add 2,2,2-trifluoroethyl-1-amine (34.6 mg, 0.349 mmol) and sodium triacetoxyborohydride (99 mg, 0.466 mmol) to 1,2-dichloroethane (2 mL) 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((2-ethyl Azol-4-yl) methyl) -1H-benzo [d] imidazole-5-carboxaldehyde (100 mg, 0.233 mmol), and the reaction mixture was stirred at room temperature overnight. The mixture was quenched with saturated NaHCO ₃ and extracted with CH ₂ Cl ₂ (3x). The extract was dried over Na ₂ SO _4, filtered, and concentrated. The residue was purified using column chromatography (silica, 0 to 100% EtOAc / heptane) to give the desired product (83 mg) as a white solid. LC-MS (ES) m / z = 513 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.22 (d, J = 6.3Hz, 6H), 1.29 (t, J = 7.6Hz, 3H), 1.75 (d, J = 5.6Hz, 2H), 2.30- 2.43 (m, 2H), 2.77 (q, J = 7.6Hz, 2H), 3.19 (q, J = 9.9Hz, 2H), 3.99 (s, 2H), 4.32 (br.s ,, 2H), 5.32- 5.40 (m, 2H), 6.71 (d, J = 8,9Hz, 1H), 7.31 (dd, J = 8.4,1.5Hz, 1H), 7.51 (d, J = 8.1Hz, 1H), 7.66-7.71 ( m, 1H), 7.78 (s, 1H), 8.05 (dd, J = 9.0, 2.4 Hz, 1H), 8.62 (d, J = 2.3 Hz, 1H).

Intermediate 148

(S) -2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole

Benzene-1,2-diamine (0.433 g, 4 mmol), (S) -6- (2-methylpyrrolidin-1-yl) nicotinaldehyde (0.761 g, 4.00 mmol), and sodium metabisulfite ( A solution of 0.989 g, 5.20 mmol) in DMF (40 mL) was stirred at 80 ° C for 12 hours. The reaction mixture was quenched with water (50 mL), and the precipitate was collected by filtration and dried to give the desired product (1 g) as an off-white solid. LC-MS (ES) m / z = 279 [M + H] ⁺ .

Intermediate 149

3- (chloromethyl) -1-methyl-1H-pyrazole

Thionyl chloride (3075 μL, 42.1 mmol) was added dropwise to (1-methyl-1H-pyrazol-3-yl) methanol (315 mg, 2.81 mmol) cooled in an ice bath, followed by DMF (20 μL), and The reaction mixture was stirred at room temperature for 2 hours. The reaction was slowly added to ice and the resulting mixture was treated with saturated aqueous NaHCO ₃ solution and solid NaHCO ₃ until the pH was alkaline. With EtOAc (3 x 20mL) aqueous mixture is extracted, and then the organic extracts were combined, washed with brine, dried over MgSO _4, filtered, and concentrated to provide a clear oil of 3- (chloromethyl) -1-methyl -1H-pyrazole (289 mg). LC-MS (ES) m / z = 131 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 3.81 (s, 3H), 4.67 (s, 2H), 6.28 (s, 1H), 7.65 (d, J = 2.0 Hz, 1H).

Example 111

(S) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl)- 1H-benzo [d] imidazole

NaH (120 mg, 3.00 mmol, 60%) was added to (S) -2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole ( A solution of 418 mg, 1.5 mmol) in THF (20 mL), and the reaction mixture was stirred at 60 ° C for 30 minutes. Next, 3- (chloromethyl) -1-methyl-1H-pyrazole (294 mg, 2.250 mmol) was added, and the reaction mixture was stirred at 90 ° C for 12 hours. The reaction mixture was poured into water (50 mL) and extracted with CH ₂ Cl ₂ (2 x 50 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated. By silica gel chromatography (with a _{1:20 CH 3 OH / CH 2 Cl} 2 elution) resulting residue was purified to yield an off-white solid was the desired product (120mg). LC-MS (ES) m / z = 373 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.58 (d, J = 2.1Hz, 1H), 7.96 (dd, J = 8.8, 2.1Hz, 1H), 7.80 (d, J = 7.9 Hz, 1H), 7.35 (d, J = 7.8Hz, 1H), 7.31-7.27 (m, 1H), 7.26-7.17 (m, 2H), 6.48 (d, J = 8.9Hz, 1H), 5.95 (d, J = 1.9Hz, 1H), 5.41 (s, 2H), 4.27-4.17 (m, 1H), 3.88 (s, 3H), 3.66-3.57 (m, 1H), 3.47-3.38 (m, 1H), 2.15-1.99 (m, 3H), 1.80-1.71 (m, 1H), 1.25 (d, J = 6.3Hz, 3H).

Intermediate 150

2-ethyl-4-methylfluorenyl-N, N-dimethyl-1H-imidazole-1-sulfonamide

Add n-butyllithium (7.87 mL, 18.89 mmol) in hexanes to 2-ethyl-N, N-dimethyl-1H-imidazole-1-sulfonamide (3.2 g, 15.74 mmol) in THF (100 mL) of a solution at -78 ° C, and the mixture was stirred at -78 ° C for 1 hour. Then DMF (7.31 mL, 94 mmol) was added, and the reaction mixture was warmed to room temperature and stirred for several hours. Water (5 mL) was added and the mixture was concentrated under vacuum. The resulting residue was poured into water (150 mL) and extracted with EtOAc (2 x 150 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated. The obtained residue was purified by silica gel chromatography (eluted with 1: 4 hexane / EtOAc) to give the desired product (2.5 g) as a white solid. LC-MS (ES) m / z = 232 [M + H] ⁺ .

Intermediate 151

2-ethyl-4- (hydroxymethyl) -N, N-dimethyl-1H-imidazole-1-sulfonamide

Add 2-ethyl-4-methylfluorenyl-N, N-dimethyl-1H-imidazole-1-sulfonamide (2.5 g, 10.81 mmol) and NaBH ₄ (0.818 g, 21.62 mmol) in CH ₃ OH (25 mL) was stirred at room temperature for 12 hours. Water (5 mL) was then added and the mixture was concentrated under vacuum. The resulting residue was poured into water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated. The resulting residue was purified by silica gel chromatography (eluted with 10: 1 CH ₂ Cl ₂ / CH ₃ OH) to give the desired product (1.8 g, 7.10 mmol) as a white solid. LC-MS (ES) m / z = 234 [M + H] ⁺ .

Intermediate 152

(1- (N, N-dimethylaminesulfonyl) -2-ethyl-1H-imidazol-4-yl) methyl methanesulfonate

Methanesulfonyl chloride (1.061 g, 9.26 mmol) was added to 2-ethyl-4- (hydroxymethyl) -N, N-dimethyl-1H-imidazole-1-sulfonamide (1.8 g, 7.72 mmol) ) And triethylamine (1.291 mL, 9.26 mmol) in CH ₂ Cl ₂ (40 mL), and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (150 mL), the aqueous was basified by the addition of NaHCO ₃ to pH 9, and extracted with _{CH 2 Cl 2 (2 x 150mL} ). The combined organic layers were dried with ₂ SO ₄ and concentrated to provide the crude product as a brown oil (1.2g), which was used without further purification in the next step over anhydrous Na. LC-MS (ES) m / z = 234 [M + H-Ms] ⁺

Intermediate 153

4-((2- (6- (diethylamino) pyridin-3-yl) -1H-benzo [d] imidazol-1-yl) methyl) -2-ethyl-N, N-dimethyl -1H-imidazole-1-sulfonamide

Add 5- (1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine (700 mg, 2.63 mmol), (1- (N, N-dimethyl) A mixture of sulfamethylsulfonyl) -2-ethyl-1H-imidazol-4-yl) methyl ester (1228 mg, 3.94 mmol) and NaH (60%, 105 mg, 2.63 mmol) in DMF (20 mL) Stir in a sealed tube at 90 ° C for 12 hours. Water (5 mL) was then added and the mixture was concentrated under vacuum. The resulting residue was poured into water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated. The resulting residue was purified by silica gel chromatography (eluted with 10: 1 CH ₂ Cl ₂ / CH ₃ OH) to give the desired product (420 mg) as a white solid. LC-MS (ES) m / z = 482 [M + H] ⁺ .

Synthesis Example 112

N, N-diethyl-5- (1-((2-ethyl-1H-imidazol-4-yl) methyl) -1H-benzo [d] imidazol-2-yl) pyridin-2-amine

HCl (2 mL, 33% w / w) in EtOH was added to 4-((2- (6- (diethylamino) pyridin-3-yl) -1H-benzo [d] imidazole-1- (Methyl) methyl) -2-ethyl-N, N-dimethyl-1H-imidazole-1-sulfonamide (450 mg, 0.934 mmol) in CH ₂ Cl ₂ (20 mL), and the reaction mixture Stir at room temperature for 12 hours. The mixture was concentrated under vacuum and the resulting residue was poured into water (50 mL). The resulting aqueous mixture was basified to pH 9 using aqueous NaHCO ₃ solution and extracted with CH ₂ Cl ₂ (2 x 50 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated. The resulting residue was purified by silica gel chromatography (eluted with 20: 1 CH ₂ Cl ₂ / CH ₃ OH) to give the desired product (200 mg) as a white solid. LC-MS (ES) m / z = 375 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 9.95 (br s, 1H), 8.50 (d, J = 2.2Hz, 1H), 7.89 (dd, J = 8.9, 2.0Hz, 1H), 7.71 (d, J = 7.8Hz, 1H), 7.32 (d, J = 7.7Hz, 1H), 7.25-7.15 (m, 2H), 6.51 (d, J = 9.0Hz, 1H), 6.41 (s, 1H), 5.35 (s , 2H), 3.53 (q, J = 7.0Hz, 4H), 2.72 (q, J = 7.6Hz, 2H), 1.29 (t, J = 7.6Hz, 3H), 1.18 (t, J = 7.0Hz, 6H ).

Intermediate 154

N-((2-ethyl-1H-imidazol-4-yl) methyl) -2-nitroaniline

Triethylamine (0.526 mL, 3.77 mmol) was added to (2-ethyl-1H-imidazol-4-yl) methylamine hydrochloride (122 mg, 0.755 mmol) and 1-fluoro-2-nitrobenzene (107 mg, 0.755 mmol) in DMF (8 mL), and the reaction mixture was stirred at 70 C for 15 hours. The mixture was concentrated, and by silica gel chromatography (with 0 to _{8% CH 3 OH / CH 2} Cl 2 elution) and the resulting residue was purified to provide the desired product as a yellow solid (180mg). LC-MS (ES) m / z = 247 [M + H] ⁺ .

Intermediate 155

N1-((2-ethyl-1H-imidazol-4-yl) methyl) benzene-1,2-diamine

N-((2-ethyl-1H-imidazol-4-yl) methyl) -2-nitroaniline (180 mg, 0.731 mmol) and Pd-C (78 mg, 0.731 mmol) in CH ₃ OH (20 mL) The mixture was stirred under a hydrogen atmosphere for 3 hours. The mixture was filtered, and the filtrate was concentrated to give the desired product (150 mg). LC-MS (ES) m / z = 217 [M + H] ⁺ .

Example 113

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((2-ethyl-1H-imidazol-4-yl) (Methyl) -1H-benzo [d] imidazole

Add 6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (85 mg, 0.416 mmol) and sodium metadisulfite (95 mg, 0.499 mmol) to N1-((2 -Ethyl-1H-imidazol-4-yl) methyl) benzene-1,2-diamine (90 mg, 0.416 mmol) in DMF (8 mL), and the reaction mixture was stirred at 70 ° C for 12 hours. The reaction mixture was concentrated, and by silica gel chromatography (with 0 to _{10% CH 3 OH / CH 2} Cl 2 elution) and the resulting residue was purified to yield the desired product as a yellow solid (145mg). LC-MS (ES) m / z = 401 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 11.71 (br s, 1H), 8.77 (s, 1H), 8.27 (d, J = 8.2Hz, 1H), 7.70-7.49 (m, 2H), 7.22 -7.13 (m, 2H), 7.02 (s, 1H), 6.63 (d, J = 8.9Hz, 1H), 5.24 (s, 2H), 4.44-4.10 (m, 2H), 2.58 (q, J = 7.6 Hz, 2H), 2.31-2.16 (m, 2H), 1.72-1.57 (m, 2H), 1.21-1.09 (m, 9H).

Intermediate 156

N-((4-ethyl-1H-imidazol-2-yl) methyl) -2-nitroaniline

Add 1-fluoro-2-nitrobenzene (130 mg, 0.919 mmol) and triethylamine (0.640 mL, 4.59 mmol) to (4-ethyl-1H-imidazol-2-yl) methylamine (115 mg, 0.919 mmol) A solution in DMF (8 mL), and the reaction mixture was stirred at 60 ° C for 12 hours. The reaction mixture was concentrated, and by silica gel chromatography (with 0 to _{4% CH 3 OH / CH 2} Cl 2 elution) and the resulting residue was purified to yield the desired product as a yellow oil. LC-MS (ES) m / z = 247 [M + H] ⁺ .

Intermediate 157

N1-((4-ethyl-1H-imidazol-2-yl) methyl) benzene-1,2-diamine

N-((4-ethyl-1H-imidazol-2-yl) methyl) -2-nitroaniline (220 mg, 0.893 mmol) and Pd-C (95 mg, 0.893 mmol) in CH ₃ OH (20 mL) The mixture was stirred at room temperature for 3 hours. The mixture was then filtered and the filtrate was concentrated. By silica gel chromatography (with 0 to _{4% CH 3 OH / CH 2} Cl 2 elution) resulting residue was purified form to produce the desired product as a yellow oil (160mg). LC-MS (ES) m / z = 217 [M + H] ⁺ .

Example 114

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((4-ethyl-1H-imidazol-2-yl) (Methyl) -1H-benzo [d] imidazole

Add 6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (151 mg, 0.740 mmol) and sodium metadisulfite (169 mg, 0.888 mmol) to N1-((4 -Ethyl-1H-imidazol-2-yl) methyl) benzene-1,2-diamine (160 mg, 0.740 mmol) in DMF (8 mL), and the reaction mixture was stirred at 70 ° C for 15 hours. The reaction mixture was concentrated, and by silica gel chromatography (with 0 to _{8% CH 3 OH / CH 2} Cl 2 elution) and the resulting residue was purified to yield the desired product as a yellow solid (65mg). LC-MS (ES) m / z = 401 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 12.66 (br s, 1H), 8.32 (d, J = 2.1 Hz, 1H), 7.24-7.16 (m, 1H), 7.11 (d, J = 8.0 Hz, 1H ), 7.06-6.98 (m, 1H), 6.92 (s, 1H), 6.85-6.75 (m, 2H), 5.99 (d, J = 8.9Hz, 1H), 5.42 (s, 2H), 4.61-3.69 ( m, 2H), 2.77 (q, J = 7.4Hz, 2H), 2.33-2.16 (m, 2H), 1.79-1.64 (m, 2H), 1.34 (t, J = 7.5Hz, 3H), 1.17 (s , 6H).

Intermediate 158

2- (2- (6- (diethylamino) pyridin-3-yl) -1H-benzo [d] imidazol-1-yl) ethyl acetate

NaH (0.144 g, 6.00 mmol) was added to 5- (1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine (1.065 g, 4 mmol) in THF (25 mL ), And the reaction mixture was stirred at 60 ° C for 30 minutes. A solution of ethyl 2-bromoacetate (0.802 g, 4.80 mmol) in THF (5 mL) was then added, and the reaction mixture was stirred at 80 ° C for 12 hours. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated. By silica gel chromatography (with 1:17 EtOAc / CH ₂ Cl ₂ elution) resulting residue was purified form to produce the desired product as a yellow oil (1g). LC-MS (ES) m / z = 353 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.44 (d, J = 2.4Hz, 1H), 7.92-7.77 (m, 2H), 7.30 (dt, J = 11.3, 3.8Hz, 2H), 7.26 (s, 1H), 6.59 (d, J = 9.0Hz, 1H), 4.92 (s, 2H), 4.27 (q, J = 7.1Hz, 2H), 3.58 (q, J = 7.1Hz, 4H), 2.07 (d, J = 16.9Hz, 3H), 1.30-1.24 (m, 6H).

Intermediate 159

2- (2- (6- (diethylamino) pyridin-3-yl) -1H-benzo [d] imidazol-1-yl) acetamidine

Add 2- (2- (6- (diethylamino) pyridin-3-yl) -1H-benzo [d] imidazol-1-yl) ethyl acetate (987 mg, 2.8 mmol) and hydrazine (1.758 mL, 56.0 mmol) solution in CH ₃ CN (20mL) the mixture was stirred at 50 ℃ 4 hours. The reaction mixture was concentrated to give the desired product (700 mg) as a pink solid. LC-MS (ES) m / z = 339 [M + H] ⁺ .

Example 115

N, N-diethyl-5- (1-((3-ethyl-1H-1,2,4-triazol-5-yl) methyl) -1H-benzo [d] imidazole-2- ) Pyridin-2-amine

Ethyl propionimidate hydrochloride (5780 mg, 42.0 mmol) was added to 2- (2- (6- (diethylamino) pyridin-3-yl) -1H-benzo [d] A solution of imidazol-1-yl) acetamidine (711 mg, 2.1 mmol) and sodium ethoxide (2858 mg, 42.0 mmol) in ethanol (30 mL), and the reaction mixture was heated to reflux for 36 hours. The reaction was concentrated, poured into ice water, and extracted with EtOAc (2 x 40 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated. The resulting residue was purified by silica gel chromatography (eluted with 0 to 10% DCM / EtOAc) to provide the crude product (150 mg). This material was washed with Et ₂ O / hexane (1: 1) to give the desired product (98 mg) as a white solid. LC-MS (ES) m / z = 376 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 12.50 (s, 1H), 8.69 (s, 1H), 8.04 (d, J = 8.3Hz, 1H), 7.65 (s, 1H), 7.46 (d, J = 4.9Hz, 1H), 7.22-7.14 (m, 2H), 6.48 (d, J = 9.0Hz, 1H), 5.40 (s, 2H), 3.53 (q, J = 7.0Hz, 4H), 2.72 (q, J = 7.6 Hz, 2H), 1.26 (t, J = 7.6 Hz, 3H), 1.19 (t, J = 7.1 Hz, 6H).

Example 116

N, N-diethyl-5- (1-((2-ethylthiazol-4-yl) methyl) -1H-benzo [d] imidazol-2-yl) pyridin-2-amine

Add 5- (1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine (400 mg, 1.502 mmol), 4- (chloromethyl) -2-ethylthiazole (364 mg, 2.253 mmol), and a mixture of NaH (60%, 180 mg, 4.51 mmol) in THF (15 mL) were placed in a sealed tube and stirred at 95 ° C for 18 hours. Water (5 mL) was then added and the mixture was concentrated under vacuum. The resulting residue was poured into water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated. The resulting residue was purified by silica gel chromatography (eluted with 20: 1 CH ₂ Cl ₂ / CH ₃ OH) to give the desired product (100 mg) as a white solid. LC-MS (ES) m / z = 392 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.52 (d, J = 1.9Hz, 1H), 7.98 (dd, J = 8.8, 1.8Hz, 1H), 7.86 (d, J = 7.8Hz, 1H), 7.34 -7.22 (m, 3H), 6.70 (s, 1H), 6.58 (d, J = 9.0Hz, 1H), 5.53 (s, 2H), 3.57 (q, J = 7.0Hz, 4H), 3.06 (q, J = 7.6Hz, 2H), 1.42 (t, J = 7.6Hz, 3H), 1.21 (t, J = 7.0Hz, 6H).

Example 117

N, N-diethyl-5- (1- ( Azol-2-ylmethyl) -1H-benzo [d] imidazol-2-yl) pyridin-2-amine

Add NaH (60%, 240 mg, 6.01 mmol) to 5- (1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine (400 mg, 1.502 mmol) in THF (20 mL), and the resulting mixture was stirred at room temperature for 30 minutes. Next add 2- (chloromethyl) Azole (265 mg, 2.253 mmol), and the reaction mixture was placed in a sealed tube and stirred at 95 ° C for 12 hours. Water (5 mL) was added, and the mixture was concentrated under vacuum. The resulting residue was poured into water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ dried and concentrated. The resulting residue was purified by silica gel chromatography (eluted with 20: 1 CH ₂ Cl ₂ / CH ₃ OH) to give the desired product (150 mg) as a white solid. LC-MS (ES) m / z = 348 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.68 (d, J = 2.2Hz, 1H), 7.99 (dd, J = 8.9, 2.4Hz, 1H), 7.83-7.75 (m, 1H), 7.65 (s, 1H), 7.52-7.42 (m, 1H), 7.32-7.26 (m, 2H), 7.15 (s, 1H), 6.61 (d, J = 9.0Hz, 1H), 5.48 (s, 2H), 3.59 (q , J = 7.0 Hz, 4H), 1.23 (t, J = 7.1 Hz, 6H).

Intermediate 159

1-methyl-1H-pyrazole-3-carbonitrile

A solution of 1H-pyrazole-3-carbonitrile (5.02 g, 53.9 mmol) in THF (25 mL) was added dropwise to NaH (2.80 g, 70.1 mmol, 60%) in THF (50 mL) cooled in an ice bath. The mixture was mixed, and the resulting mixture was stirred at room temperature for 1 hour. Then methyl iodide (3.71 mL, 59.3 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with water (30 mL) and extracted with EtOAc (3 × 30 mL). The organic extracts were combined, washed with brine, dried (MgSO _4), filtered, and concentrated. Purification by chromatography on SiO ₂ (0 to 50% EtOAc / hexanes) provided 1-methyl-1H-pyrazole-3-carbonitrile (2.7 g) as a white solid. LC-MS (ES) m / z = 108 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 3.95 (s, 3H), 6.96 (d, J = 2.3 Hz, 1H), 7.99 (s, 1H).

Intermediate 160

(1-methyl-1H-pyrazol-3-yl) methylamine

LiAlH ₄ (27.7 mL, 55.5 mmol, 2M in THF) was slowly added to 1-methyl-1H-pyrazole-3-carbonitrile in Et ₂ O (150 mL) cooled in an ice bath. (2.7 g, 25.2 mmol), and allowed the reaction mixture to warm to room temperature and stir overnight. The reaction was then cooled in an ice bath and quenched by adding water (4 mL), 15% NaOH solution (4 mL), and water (12 mL). The mixture was then stirred for 15 minutes, and the resulting solid was filtered. The filtrate was dried over MgSO ₄ and concentrated to provide (l-methyl -1H- pyrazol-3-yl) methanamine of a clear oil (1.28g). LC-MS (ES) m / z = 112 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.69 (br.s, J = 1.5Hz, 2H), 3.60 (s, 2H), 3.75 (s, 3H), 6.12 (d, J = 2.0Hz, 1H), 7.53 (d, J = 2.0Hz, 1H).

Intermediate 161

N-((1-methyl-1H-pyrazol-3-yl) methyl) -2-nitroaniline

(1-methyl-1H-pyrazol-3-yl) methylamine (248 mg, 2.232 mmol) and K ₂ CO ₃ (382 mg, 2.76 mmol) were added to 1-fluoro-2- in DMF (3 mL) Nitrobenzene (300 mg, 2.126 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was then quenched with water (10 mL) and extracted with EtOAc (4 x 8 mL). The organic extracts were combined and washed with brine, dried over MgSO _4, filtered, and concentrated. Purification by chromatography on SiO ₂ (0 to 60% EtOAc / hexane) provided N-((1-methyl-1H-pyrazol-3-yl) methyl)-as a dark amber oil 2-Nitroaniline (405 mg). LC-MS (ES) m / z = 233 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 3.81 (s, 3H), 4.51 (d, J = 5.3Hz, 2H), 6.19 (d, J = 2.3Hz, 1H), 6.70 (ddd, J = 8.5, 7.0, 1.3Hz, 1H), 7.07-7.12 (m, 1H), 7.49-7.57 (m, 1H), 7.64 (d, J = 2.3Hz, 1H), 8.08 (dd, J = 8.6, 1.5Hz , 1H), 8.53 (t, J = 5.5Hz, 1H).

Example 118

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-methyl-1H-pyrazol-3-yl ) Methyl) -1H-benzo [d] imidazole

N-((1-methyl-1H-pyrazol-3-yl) methyl) -2-nitroaniline (113 mg, 0.487 mmol), 6-((2S, 5S) -2,5-dimethyl Pyrrolidin-1-yl) nicotinaldehyde (109 mg, 0.535 mmol), ethanol (1.5 mL), water (0.750 mL), and sodium bisulfite (254 mg, 85%, 1.241 mmol) were added to a 20 mL microwave vial, and The reaction mixture was heated under microwave conditions at 130 ° C for 1.5 hours. The reaction was then diluted with water (10 mL) and extracted with EtOAc (4 x 5 mL). The organic extracts were combined, washed with brine, dried over MgSO _4, filtered, and concentrated. Purification by chromatography on SiO ₂ (0 to 10% CH ₃ OH / CH ₂ Cl ₂ ) provided 2- (6-((2S, 5S) -2,5-dimethylpyrrolidine-1- (Yl) pyridin-3-yl) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole (127 mg), lyophilized to a white solid. LC-MS (ES) m / z = 387 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.14 (d, J = 6.3Hz, 6H), 1.65 (m, 2H), 2.19-2.28 (m, 2H), 3.79 (s, 3H), 4.25 ( br.s., 2H), 5.40 (s, 2H), 6.12 (d, J = 2.3Hz, 1H), 6.63 (d, J = 8.9Hz, 1H), 7.16-7.23 (m, 2H), 7, 45-7.52 (m, 1H), 7.61-7.66 (m, 2H), 8.00 (dd, J = 8.9, 2.5 Hz, 1H), 8.59 (d, J = 1.8 Hz, 1H).

Intermediate 162

N-methyl-4-(((1-methyl-1H-pyrazol-3-yl) methyl) amino) -3-nitrobenzamide

(1-methyl-1H-pyrazol-3-yl) methylamine (206 mg, 1.855 mmol) and K ₂ CO ₃ (317 mg, 2.296 mmol) were added to 4-fluoro-N- in DMF (5 mL) Methyl-3-nitrobenzamide (350 mg, 1.766 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was then quenched with water (10 mL), and the resulting solid was separated by filtration, washed with water, and dried in a vacuum oven for 4 hours to provide N-methyl-4-(((1-methyl -1H-pyrazol-3-yl) methyl) amino) -3-nitrobenzamide (390 mg). LC-MS (ES) m / z = 290 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 2.76 (d, J = 4.3Hz, 3H), 3.81 (s, 3), 4.57 (d, J = 5.3Hz, 2H), 6,19 (d, J = 2.0Hz, 1H), 7.15 (d, J = 9.1Hz, 1H), 7.64 (d, J = 2.3Hz, 1H), 7.96 (dd, J = 9.0, 2.2Hz, 1H), 8.46 (d, J = 4.8 Hz, 1H), 8.63 (d, J = 2.3 Hz, 1H), 8.77 (t, J = 5.6 Hz, 1H).

Example 119

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -N-methyl-1-((1-methyl-1H-py Azol-3-yl) methyl) -1H-benzo [d] imidazol-5-carboxamide

N-methyl-4-(((1-methyl-1H-pyrazol-3-yl) methyl) amino) -3-nitrobenzamide (109 mg, 0.377 mmol), 6- ( (2S, 5S) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (85 mg, 0.414 mmol), ethanol (1.5 mL), water (0.750 mL), and sodium bisulfite (197 mg, 85%, 0.961 mmol) was added to a 20 mL microwave vial, and the reaction mixture was heated at 130 ° C for 1.5 hours under microwave conditions. The reaction was then diluted with water (10 mL) and extracted with EtOAc (4 x 5 mL). The organic extracts were combined, washed with brine, dried over MgSO _4, filtered, and concentrated. Purification by chromatography on SiO ₂ (0 to 10% CH ₃ OH / CH ₂ Cl ₂ ) provided 2- (6-((2S, 5S) -2,5-dimethylpyrrolidine-1- Yl) pyridin-3-yl) -N-methyl-1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide (101 mg, 0.228 mmol), lyophilized as a white solid. LC-MS (ES) m / z = 444 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.15 (d, J = 6.1Hz, 6H), 1.65 (d, J = 5.6Hz, 2H), 2.24 (br.s., 2H), 2.81 (d , J = 4.3Hz, 3H), 4.25 (br.s., 2H), 5.43 (s, 2H), 6.13 (d, J = 2.0Hz, 1H), 6.64 (d, J = 8.6Hz, 1H), 7.54 (d, J = 8.4Hz, 1H), 7.65 (d, J = 2.0Hz, 1H), 7.73 (dd, J = 8.5,1.65Hz, 1H), 8.01 (dd, J = 8.9,2.28Hz, 1H ), 8.14 (d, J = 1.0 Hz, 1H), 8.41 (q, J = 4.2 Hz, 1H), 8.60 (d, J = 2.5 Hz, 1H).

Example 120

2- (4-ethyl-3,3-dimethyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] -7-yl) -N-methyl-1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide

N-methyl-4-(((1-methyl-1H-pyrazol-3-yl) methyl) amino) -3-nitrobenzamide (60 mg, 0.207 mmol), 4-ethyl -3,3-dimethyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] -7-Formaldehyde (50.3mg, 0.228mmol), ethanol (1.5mL), water (0.750mL), and sodium bisulfite (108mg, 85%, 0.529mmol) were added to a microwave vial, and the reaction mixture was placed under microwave conditions It was heated at 130 ° C for 1.5 hours. The reaction was then diluted with water (10 mL) and extracted with EtOAc (4 x 5 mL). The organic extracts were combined, washed with brine, dried over MgSO _4, filtered, and concentrated. Purification by chromatography on SiO ₂ (0 to 10% CH ₃ OH / CH ₂ Cl ₂ ) provides 2- (4-ethyl-3,3-dimethyl-3,4-dihydro-2H -Pyrido [3,2-b] [1,4] -7-yl) -N-methyl-1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide (54 mg) , White solid after freeze-drying. LC-MS (ES) m / z = 460 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.20 (t, J = 6.8Hz, 3H), 1.30 (s, 6H), 2.81 (d, J = 4.6Hz, 3H), 3.61 (d, J = 6.8Hz, 2H), 3.78 (s, 3H), 3.93 (s, 2H), 5.43 (s, 2H), 6.15 (d, J = 2.0Hz, 1H), 7.51 (d, J = 2.0Hz, 1H) , 7.53 (d, J = 8.6 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H), 7.73 (dd, J = 8.5, 1.7 Hz, 1H), 8.15 (d, J = 1.3 Hz, 1H) , 8.24 (d, J = 2.0 Hz, 1H), 8.41 (d, J = 4.6 Hz, 1H).

Intermediate 163

4-(((1-methyl-1H-pyrazol-3-yl) methyl) amino) -3-nitrobenzoate

(1-methyl-1H-pyrazol-3-yl) methylamine (205 mg, 1.845 mmol) and K ₂ CO ₃ (316 mg, 2.285 mmol) were added to 4-fluoro-3- in DMF (5 mL) Methyl n-benzoate (350 mg, 1.758 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was then quenched with water (10 mL), and the resulting solid was separated by filtration, washed with water, and dried in a vacuum oven for 4 hours to provide 4-(((1-methyl-1H-pyrazole) as a yellow solid -3-yl) methyl) amino) -3-nitrobenzoate (395 mg). LC-MS (ES) m / z = 291 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 3.81 (s, 3H), 3.83 (s, 3H), 4.59 (d, J = 5.8Hz, 2H), 6.20 (d, J = 2.3Hz, 1H) , 7.19 (d, J = 9.4 Hz, 1H), 7.64 (d, J = 2.0 Hz, 1H), 7.97 (dd, J = 9.0, 1.9 Hz, 1H), 8.64 (d, J = 2.0 Hz, 1H) , 8.96 (t, J = 5.6 Hz, 1H).

Intermediate 164

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-methyl-1H-pyrazol-3-yl ) Methyl) -1H-benzo [d] imidazole-5-carboxylic acid methyl ester

4-(((1-methyl-1H-pyrazol-3-yl) methyl) amino) -3-nitrobenzoate (75 mg, 0.258 mmol), 6-((2S, 5S)- 2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (58.1 mg, 0.284 mmol), sodium bisulfite (135 mg, 85%, 0.642 mmol), ethanol (1.5 mL), and water (0.750 mL ) Was added to a 20 mL microwave vial, and the reaction mixture was heated at 130 ° C for 1.5 hours under microwave conditions. The reaction was then diluted with water (10 mL) and extracted with EtOAc (4 x 5 mL). The organic extracts were combined, washed with brine, dried over MgSO _4, filtered, and concentrated. Purification by chromatography on SiO ₂ (0 to 10% CH ₃ OH / CH ₂ Cl ₂ ) provided 2- (6-((2S, 5S) -2,5-dimethyl as a light brown solid Pyrrolidin-1-yl) pyridin-3-yl) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxylic acid methyl ester (84mg). LC-MS (ES) m / z = 445 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.12-1.16 (m, 6H), 1.65 (d, J = 5.3Hz, 2H), 2.24 (br.s., 2H), 3.78 (s, 3H) , 3.87 (s, 3H), 4.26 (br.s., 2H), 5.46 (s, 2H), 6.14 (d, J = 2.03Hz, 1H), 6.64 (d, J = 8.9Hz, 1H), 7.61 (d, J = 8.6Hz, 1H), 7.65 (d, J = 2.3Hz, 1H), 7.85 (dd, J = 8.5, 1.65Hz, 1H), 8.01 (dd, J = 9.0, 2.4Hz, 1H) , 8.23 (d, J = 1.3 Hz, 1H), 8.61 (d, J = 2.5 Hz, 1H).

Intermediate 165

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-methyl-1H-pyrazol-3-yl ) Methyl) -1H-benzo [d] imidazole-5-carboxylic acid

NaOH (0.391 mL, 3.91 mmol) was added to 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridine-3- in CH ₃ OH (3 mL) Methyl) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxylic acid methyl ester (87 mg, 0.196 mmol), and the reaction mixture Stir overnight at 45 ° C. The pH was adjusted with 1N HCl (3.91 mL, 3.91 mmol), and the resulting precipitate was separated by filtration and dried in a vacuum oven for 3 hours to provide 2- (6-((2S, 5S) -2, 5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole- 5-Formic acid (57 mg). LC-MS (ES) m / z = 431 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.15 (d, J = 6.1Hz, 6H), 1.66 (d, J = 5.6Hz, 2H), 2.24 (br.s., 2H), 3.78 (s 3H), 4.25 (br.s., 2H), 5.45 (s, 2H), 6.15 (d, J = 2.0Hz, 1H), 6.65 (d, J = 9.4Hz, 1H), 7.58 (d, J = 8.6Hz, 1H), 7.65 (d, J = 2.0Hz, 1H), 7.84 (dd, J = 8.4,1.5Hz, 1H), 8.02 (dd, J = 8.7,2.4Hz, 1H) 8.21 (d, J = 1.3Hz, 1H) 8.61 (d, J = 2.3Hz, 1H) 12.73 (s, 1H).

Example 121

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-methyl-1H-pyrazol-3-yl ) Methyl) -1H-benzo [d] imidazole-5-carboxamide

NH ₄ Cl (12.75 mg, 0.238 mmol), EDC (50.8 mg, 0.265 mmol), HOBt (40.6 mg, 0.265 mmol), and N-methylmorpholine (0.087 mL, 0.794 mmol) were added to DMSO ( 2 (2)) of 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-methyl-1H-pyrazole -3-yl) methyl) -1H-benzo [d] imidazole-5-carboxylic acid (57 mg, 0.132 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was then quenched with water (5 mL) and extracted with EtOAc (3 x 10 mL). The organic extracts were combined, dried over MgSO _4, filtered, and concentrated. Purification by chromatography on SiO ₂ (0 to 10% CH ₃ OH / CH ₂ Cl ₂ ) provided 2- (6-((2S, 5S) -2,5-dimethylpyrrolidine-1- Yl) pyridin-3-yl) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazol-5-carboxamide (37 mg), frozen White solid after drying. LC-MS (ES) m / z = 430 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.14 (d, J = 6.3Hz, 6H), 1.65 (d, J = 5.3Hz, 2H) 2.18-2.28 (m, 2H), 3.78 (s, 3 H) 4.25 (br.s., 2H), 5.43 (s, 2H), 6.13 (d, J = 2.3Hz, 1H), 6.64 (d, J = 9.1Hz, 1H), 7.27 (br.s., 1H), 7.53 (d, J = 8.6Hz, 1H), 7.65 (d, J = 2.3Hz, 1H), 7.77 (dd, J = 8.6, 1.5Hz, 1H), 7.97 (br.s., 1H) , 8.01 (dd, J = 8.9, 2.3 Hz, 1H), 8.20 (d, J = 1.3 Hz, 1H), 8.60 (d, J = 2.5 Hz, 1H).

Intermediate 166

2- (4-ethyl-3,3-dimethyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] -7-yl) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-formate

4-(((1-methyl-1H-pyrazol-3-yl) methyl) amino) -3-nitrobenzoate (75 mg, 0.258 mmol), 4-ethyl-3,3- Dimethyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] -7-Formaldehyde (62.6mg, 0.284mmol), ethanol (1.5mL), water (0.750mL), and sodium bisulfite (135mg, 85%, 0.659mmol) were added to a microwave vial, and the reaction mixture was placed under microwave conditions It was heated at 130 ° C for 1.5 hours. The reaction was then diluted with water (10 mL) and extracted with EtOAc (4 x 5 mL). Next, the organic extracts were combined, washed with brine, dried over MgSO _4, filtered, and concentrated. Purification by chromatography on SiO ₂ (0 to 10% CH ₃ OH / CH ₂ Cl ₂ ) provided 2- (4-ethyl-3,3-dimethyl-3,4 as a light brown solid -Dihydro-2H-pyrido [3,2-b] [1,4] -7-yl) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxylic acid methyl ester (80 mg). LC-MS (ES) m / z = 461 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.20 (t, J = 7.0Hz, 3H), 1.30 (s, 6H), 3.61 (q, J = 6.8Hz, 2H), 3.78 (s, 3H) , 3.87 (s, 3H), 3.93 (s, 2H), 5.45 (s, 2H), 6.16 (d, J = 2.3Hz, 1H), 7.51 (d, J = 2.0Hz, 1H), 7.60 (d, J = 8.6 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.85 (dd, J = 8.6, 1, 5 Hz, 1H), 8.23 (d, J = 1.3 Hz, 1H), 8.25 (d , J = 2.0Hz, 1H).

Intermediate 167

2- (4-ethyl-3,3-dimethyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] -7-yl) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxylic acid

The 10N NaOH (0.347mL, 3.47mmol) was added to the CH ₃ OH (3mL) of the 2- (4-ethyl-3,3-dimethyl-3,4-dihydro -2H- pyrido [3 , 2-b] [1,4] -7-yl) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxylic acid methyl ester (80 mg, 0.174 mmol), and The reaction mixture was stirred at 45 ° C overnight. The pH was adjusted with 1N HCl (3.47 mL, 3.47 mmol), and the resulting precipitate was separated by filtration and dried in a vacuum oven for 3 hours to provide 2- (4-ethyl-3,3-dimethyl) as a white solid -3,4-dihydro-2H-pyrido [3,2-b] [1,4] -7-yl) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxylic acid (63 mg). LC-MS (ES) m / z = 447 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.20 (t, J = 6.8Hz, 3H), 1.30 (s, 6H), 3.61 (q, J = 6.8Hz, 2H), 3.78 (s, 3H) , 3.93 (s, 2H), 5.45 (s, 2H), 6.16 (d, J = 2.0Hz, 1H), 7.51 (d, J = 2.0Hz, 1H), 7.57 (d, J = 8.4Hz, 1H) , 7.66 (d, J = 2.0 Hz, 1H), 7.83 (dd, J = 8.4, 1.5 Hz, 1H), 8.21 (d, J = 1.3 Hz, 1H), 8.25 (d, J = 2.0 Hz, 1H) , 12.73 (s, 1H).

Example 122

2- (4-ethyl-3,3-dimethyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] -7-yl) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide

NH ₄ Cl (17.25 mg, 0.323 mmol), EDC (68.7 mg, 0.358 mmol), HOBt (54.9 mg, 0.358 mmol), and N-methylmorpholine (0.118 mL, 1.075 mmol) were added to DMSO ( 2 mL) of 2- (4-ethyl-3,3-dimethyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] -7-yl) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxylic acid (80 mg, 0.179 mmol), and react The mixture was stirred at room temperature overnight. The reaction was quenched with water (5 mL) and extracted with EtOAc (3 x 10 mL). The organic extracts were combined, dried over MgSO _4, filtered, and concentrated. Purification by chromatography on SiO ₂ (0 to 10% CH ₃ OH / CH ₂ Cl ₂ ) provides 2- (4-ethyl-3,3-dimethyl-3,4-dihydro-2H -Pyrido [3,2-b] [1,4] -7-yl) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazol-5-carboxamide (57mg), freeze-dried as White solid. LC-MS (ES) m / z = 446 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.20 (t, J = 6.8Hz, 3H), 1.30 (s, 6H), 3.61 (q, J = 6.8Hz, 2H), 3.78 (s, 3H) , 3.93 (s, 2H), 5.43 (s, 2H), 6.15 (d, J = 2.3Hz, 1H), 7.27 (br.s., 1H), 7.49-7.54 (m, 2H), 7.65 (d, J = 2.3Hz, 1H), 7.77 (dd, J = 8.5, 1.4Hz, 1H), 7.97 (br.s., 1H), 8.22 (d, J = 1.3Hz, 1H), 8.24 (d, J = 2.0Hz, 1H).

Intermediate 168

2- (1-ethyl-2,2-dimethyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1-((1-methyl- 1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxylic acid methyl ester

4-(((1-methyl-1H-pyrazol-3-yl) methyl) amino) -3-nitrobenzoate (0.250 g, 0.861 mmol), 1-ethyl-2,2 -Dimethyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridine-5-carboxaldehyde (0.194 g, 0.947 mmol), ethanol (3 mL), water (1.5 mL), and sulfurous acid Sodium hydride (0.450 g, 85%, 2.193 mmol) was added to a 20 mL microwave vial. The vial was capped and the reaction mixture was heated under microwave conditions at 130 ° C for 90 minutes. The reaction was diluted with water (10 mL) and then extracted with EtOAc (4 x 10 mL). The combined organic layers were washed with brine, then dried over MgSO _4, filtered, and concentrated. The crude material was purified by silica gel chromatography with a gradient elution of 0 to 100% EtOAc in CH ₂ Cl ₂ to provide 2- (1-ethyl-2,2-dimethyl- 2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzene And [d] methyl imidazole-5-carboxylic acid methyl ester (259 mg). LC-MS (ES) m / z = 445 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.38 (d, J = 1.3Hz, 1H), 8.20 (d, J = 2.0Hz, 1H), 7.84 (dd, J = 1.5, 8.6Hz, 1H), 7.56 (d, J = 1.8Hz, 1H), 7.27 (d, J = 8.6Hz, 1H), 7.17 (d, J = 2.3Hz, 1H), 5.86 (d, J = 2.3Hz, 1H), 5.34 (s , 2H), 3.83 (s, 3H), 3.76 (s, 3H), 3.28 (q, J = 7.1Hz, 2H), 2.79 (s, 2H), 1.22 (s, 6H), 1.17 (t, J = 7.1Hz, 3H).

Intermediate 169

2- (1-ethyl-2,2-dimethyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1-((1-methyl- 1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxylic acid

10N aqueous sodium hydroxide solution (1.147 mL, 11.47 mmol) was added to 2- (1-ethyl-2,2-dimethyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridine -5-yl) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxylic acid methyl ester (0.255 g, 0.574 mmol) in in the CH ₃ OH (4mL) was added and the reaction mixture was stirred at 45 ℃ 2 hours. The reaction portion was concentrated and then a 1 N aqueous HCl solution (12.47 mL, 12.47 mmol) was added. The resulting white solid was separated by filtration and then dried in a vacuum oven overnight to provide 2- (1-ethyl-2,2-dimethyl-2,3-dihydro-1H-pyrrolo [ 2,3-b] pyridin-5-yl) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxylic acid (136 mg, 0.316 mmol). LC-MS (ES) m / z = 431 [M + H] ⁺ .

Example 123

2- (1-ethyl-2,2-dimethyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-5-yl) -N-methyl-1-(( 1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide

Add methylamine hydrochloride (33.9mg, 0.502mmol), EDC (107mg, 0.557mmol), HOBt hydrate (85mg, 0.557mmol), and N-methylmorpholine (0.184mL, 1.672mmol) to 2 -(1-ethyl-2,2-dimethyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1-((1-methyl-1H -Pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxylic acid (120 mg, 0.279 mmol) in DMSO (2 mL), and the reaction mixture was sealed and stirred at room temperature overnight. Next, the reaction (5mL) was quenched with saturated aqueous NaHCO ₃ and extracted with 10% CH ₃ OH containing the EtOAc (3 x 10mL). The combined dried organic extracts with MgSO _4, filtered, and concentrated. Purification by silica gel chromatography with a gradient elution of 0 to 15% CH ₃ OH in CH ₂ Cl ₂ provided 2- (1-ethyl-2,2-dimethyl-2 as a pale yellow oil , 3-dihydro-1H-pyrrolo [2,3-b] pyridin-5-yl) -N-methyl-1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-Benzo [d] imidazole-5-carboxamide (28.6 mg) was crystallized upon standing to provide a pale yellow solid. LC-MS (ES) m / z = 444 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.26 (s, 1H), 8.12 (s, 1H), 7.75 (d, J = 8.4Hz, 1H), 7.64 (s, 1H), 7.36 (d, J = 8.4Hz, 1H), 7.31-7.24 (m, 1H), 6.44 (d, J = 4.3Hz, 1H), 5.95 (d, J = 1.8Hz, 1H), 5.44 (s, 2H), 3.89 (s, 3H), 3.39 (q, J = 7.0Hz, 2H), 3.02 (d, J = 4.8Hz, 3H), 2.89 (s, 2H), 1.34 (s, 6H), 1.28 (t, J = 7.1Hz, 3H).

Example 124

2- (1-ethyl-2,2-dimethyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1-((1-methyl- 1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide

NH ₄ Cl (26.8 mg, 0.502 mmol), EDC (107 mg, 0.557 mmol), HOBt hydrate (85 mg, 0.557 mmol), and N-methylmorpholine (0.184 mL, 1.672 mmol) were added to 2- ( 1-ethyl-2,2-dimethyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1-((1-methyl-1H-pyridine A solution of azole-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxylic acid (120 mg, 0.279 mmol) in DMSO (2 mL), and the reaction mixture was sealed and stirred at room temperature overnight. The reaction was quenched with saturated NaHCO ₃ (5mL) solution, followed by extraction containing 10% CH ₃ OH of EtOAc (3 x 10mL). The combined dried organic extracts with MgSO _4, filtered, and concentrated. Purification by silica gel chromatography with a gradient elution of 0 to 15% CH ₃ OH in CH ₂ Cl ₂ provided 2- (1-ethyl-2,2-dimethyl-2 as a pale yellow oil , 3-dihydro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] Imidazole-5-carboxamide (84 mg), which crystallized upon standing to provide a pale yellow solid. LC-MS (ES) m / z = 430 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 8.26-8.21 (m, 2H), 7.84 (dd, J = 1.5, 8.6 Hz, 1H), 7.66-7.63 (m, 1H), 7.58-7.53 (m, 2H), 6.13 (d, J = 2.3Hz, 1H), 5.49 (s, 2H), 3.86 (s, 3H), 3.43 (q, J = 7.1Hz, 2H), 2.98 (s, 2H), 1.38 ( s, 6H), 1.27 (t, J = 7.1 Hz, 3H).

Intermediate 170

N-methyl-4-(((2-methyl Azole-4-yl) methyl) amino) -3-nitrobenzamide

Will (2-methyl A solution of azole-4-yl) methylamine (273 mg, 2.438 mmol) in DMF (2 mL) was added dropwise to 4-fluoro-N-methyl-3-nitrobenzamide (460 mg, 2.321 mmol) and tri A solution of ethylamine (0.356 mL, 2.55 mmol) in DMF (8 mL) at 70 ° C, and the reaction mixture was stirred at the same temperature for 15 minutes. The heat was removed and the reaction was quenched with water (25 mL) and extracted with EtOAc (3 x 25 mL). The combined organic extracts were dried over Na ₂ SO _4, filtered, and concentrated. The remaining residue was purified on silica (0-100%, EtOAc / hexanes) to provide the desired product (535 mg) as a bright gold-colored solid. LC-MS (ES) m / z = 291 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 8.68 (t, J = 5.7Hz, 1H), 8.64 (d, J = 2.3Hz, 1H), 8.47 (q, J = 4.2Hz, 1H), 7.96 (dd, J = 2.0,9.1Hz, 1H), 7.90 (s, 1H), 7.16 (d, J = 9.1Hz, 1H), 4.51 (d, J = 5.8Hz, 2H), 2.76 (d, J = 4.3Hz, 3H), 2.39 (s, 3H).

Example 125

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -N-methyl-1-((2-methyl Azol-4-yl) methyl) -1H-benzo [d] imidazol-5-carboxamide

Add N-methyl-4-(((2-methyl Azole-4-yl) methyl) amino) -3-nitrobenzamide (160 mg, 0.551 mmol), 6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl ) A solution of nicotinaldehyde (118 mg, 0.579 mmol) and sodium bisulfite (288 mg, 85%, 1.406 mmol) in ethanol (3 mL) and water (0.75 mL) was heated at 110 ° C. for 1 hour under microwave conditions. The solid was filtered off, and the reaction was partitioned between CH ₂ Cl ₂ (10mL) and water (4mL). The aqueous layer was extracted with CH ₂ Cl ₂ (4 x 8 mL). The combined organic layers were washed (2mL) with brine, dried over Na ₂ SO _4, filtered, and concentrated. The remaining residue was dissolved in DMSO (1mL) and precipitated with CH ₃ OH (6 ml). The solid was collected and dried under high vacuum overnight to provide the title compound (60 mg) as a white solid. LC-MS (ES) m / z = 445 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 8.70 (d, J = 2.3Hz, 1H), 8.42 (q, J = 4.5Hz, 1H), 8.14 (d, J = 1.3Hz, 1H), 8.13 (s, 1H), 8.10 (dd, J = 2.4,9.0Hz, 1H), 7.73 (dd, J = 1.5,8.6Hz, 1H), 7.60 (d, J = 8,4Hz, 1H), 6.66 (d , J = 8.9Hz, 1H), 5.34 (s, 2H), 4.27 (br.s., 2H), 2.81 (d, J = 4.3Hz, 3H), 2.36 (s, 3H), 2.25 (t, J = 7.0Hz, 2H), 1.66 (d, J = 5.8Hz, 2H), 1.15 (d, J = 6.3Hz, 6H).

Intermediate 171

1-bromo-2,4-difluoro-3-nitrobenzene

Mix 1,3-difluoro-2-nitrobenzene (6.77 g, 42.6 mmol) and N-bromosuccinimide (7.57 g, 42.6 mmol) in trifluoroacetic acid (TFA) (24 mL) and concentrated sulfuric acid (12.00 The solution in mL) was stirred at 70 ° C for 1 hour. The reaction was quenched on ice and extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with water (20 mL), washed with saturated aqueous NaHCO _3, dried over Na ₂ SO _4, filtered, and concentrated. The residual oil was purified on silicone (0-10%, CH ₂ Cl ₂ / hexane) to provide the desired product (6.7 g) as a clear, colorless oil. GC-MS (ES) m / z = 238,240 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.18 (ddd, J = 5.4, 7.6, 9.3 Hz, 1H), 7.55 (dt, J = 1.9, 9.6 Hz, 1H).

Intermediate 172

4-bromo-3-fluoro-N-((2-methyl Azole-4-yl) methyl) -2-nitroaniline

Will (2-methyl A solution of azole-4-yl) methylamine (396 mg, 3.53 mmol) in DMF (4 mL) was added dropwise to 1-bromo-2,4-difluoro-3-nitrobenzene (800 mg, 3.36 mmol) and triethylamine (0.515 mL, 3.70 mmol) in DMF (16 mL) at 70 ° C, and the reaction mixture was stirred at the same temperature for 15 minutes. The heat was removed and the reaction was quenched with water (25 mL) and extracted with EtOAc (3 x 25 mL). The combined organic layers were dried over Na ₂ SO _4, filtered, and concentrated. The remaining residue was purified on silica (0-80%, EtOAc / hexanes) to provide the desired product (337 mg) as a white solid. LC-MS (ES) m / z = 230,232 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 7.85 (s, 1H), 7.71 (t, J = 5.8Hz, 1H), 7.66 (dd, J = 7.6, 9.4Hz, 1H), 6.84 (d, J = 9.4 Hz, 1H), 4.36 (d, J = 5.6 Hz, 2H), 2.38 (s, 3H).

Intermediate 173

4-((5-bromo-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-1H-benzo [ d) imidazol-1-yl) methyl) -2-methyl Azole

4-Bromo-3-fluoro-N-((2-methyl Azole-4-yl) methyl) -2-nitroaniline (330 mg, 1.00 mmol), 6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (214 mg, 1.050 mmol), and a solution of sodium bisulfite (522 mg, 85%, 2.55 mmol) in ethanol (6 mL) and water (1.500 mL) was heated at 110 ° C. for 1 hour under microwave conditions. The solid was filtered off and the organic solvent was removed in vacuo. The remaining residue was partitioned between CH ₂ Cl ₂ (10mL) and water (4mL). The aqueous layer was extracted with CH ₂ (2X) ₂ Cl, and the combined organic layers were washed (3mL) with brine, dried over Na ₂ SO _4, filtered, and concentrated. The remaining residue was purified on silica (0-100%, EtOAc / hexanes) to provide the desired product (322 mg) as a brown foam. LC-MS (ES) m / z = 484,486 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 8.69 (d, J = 2.3Hz, 1H), 8.11 (s, 2H), 7.41 (s, 2H), 6.66 (d, J = 9.1Hz, 1H) , 5.35 (s, 2H), 4.15-3.99 (m, J = 5.6Hz, 1H), 2.36 (s, 3H), 2.25 (t, J = 7.7Hz, 2H), 1.66 (d, J = 5.6Hz, 2H), 1.15 (d, J = 6.3Hz, 6H).

Intermediate 174

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-1-((2-methyl Azole-4-yl) methyl) -1H-benzo [d] imidazole-5-carboxylic acid

Degassing N-methyl-2-pyrrolidone (NMP) (10 mL) by bubbling N ₂ , followed by feeding 4-((5-bromo-2- (6-((2S, 5S) -2 , 5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-1H-benzo [d] imidazol-1-yl) methyl) -2-methyl Azole (322 mg, 0.665 mmol), potassium 2-ethoxy-2- pentooxyacetate (156 mg, 0.997 mmol), 1,3-bis (diphenylphosphino) propane (82 mg, 0.199 mmol), and trifluoroacetic acid Palladium (II) (44.2 mg, 0.133 mmol), and the reaction mixture was stirred at 150 ° C for 6 hours. After cooling to room temperature, the reaction was filtered through celite and rinsed with EtOAc (2 x 10 mL). The filtrate was concentrated in vacuo and the remaining oil was dissolved between EtOAc (30 mL) and 1 N Na ₂ CO ₃ . The aqueous layer was extracted with EtOAc (3 x 15 mL), and the combined organic extracts were concentrated in vacuo. The resulting residue was dissolved in CH ₃ OH (2 mL) and then purified by reverse-phase HPLC (50-99% CH ₃ CN / 0.1% NH ₄ OH in water) to provide the desired product as a brown foam (63 mg ). LC-MS (ES) m / z = 450 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 10.02 (br.s., 1H), 8.74 (br.s., 1H), 8.09 (br.s., 1H), 7.86 (br.s., 1H) , 7.47 (br.s., 1H), 7.21 (d, J = 7.1 Hz, 1H), 6.62 (br.s., 1H), 5.45-5.24 (m, 2H), 3.50 (br.s., 2H ), 2.45 (br.s., 3H), 2.31 (br.s., 2H), 1.74 (br.s., 2H), 1.23 (br.s., 6H).

Example 126

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-N-methyl-1-((2-methyl Azol-4-yl) methyl) -1H-benzo [d] imidazol-5-carboxamide

Add EDC (52.9 mg, 0.276 mmol), HOAT (42.5 mg, 0.276 mmol), and N-methylmorpholine (0.091 mL, 0.828 mmol) followed by methylamine hydrochloride (9.31 mg, 0.138 mmol) to 2 -(6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-1-((2-methyl A solution of azole-4-yl) methyl) -1H-benzo [d] imidazole-5-carboxylic acid (62 mg, 0.138 mmol) in DMSO (2 mL), and the reaction mixture was stirred at room temperature overnight. By reverse phase HPLC (15-55% CH ₃ CN / water in 0.1% of formic acid) as a reaction to afford the desired product as a white solid (37mg). LC-MS (ES) m / z = 463 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.61 (d, J = 2.3Hz, 1H), 8.07-7.92 (m, 2H), 7.33 (s, 1H), 7.22 (d, J = 8.6Hz, 1H) , 6.89 (dd, J = 4.7, 12.5 Hz, 1H), 6.52 (d, J = 8.9 Hz, 1H), 5.31 (s, 2H), 4.30 (br.s., 2H), 3.10 (d, J = 4.3Hz, 3H), 2.48 (s, 3H), 2.38-2.22 (m, 2H), 1.72 (d, J = 5.8Hz, 2H), 1.22 (d, J = 6.1Hz, 6H).

Example 127

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-1-((2-methyl Azol-4-yl) methyl) -1H-benzo [d] imidazol-5-carboxamide

Add EDC (46.9 mg, 0.245 mmol), HOAT (37.7 mg, 0.245 mmol), and N-methylmorpholine (0.081 mL, 0.734 mmol) followed by NH ₄ Cl (11.78 mg, 0.220 mmol) to 2- ( 6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-1-((2-methyl A solution of azole-4-yl) methyl) -1H-benzo [d] imidazole-5-carboxylic acid (55 mg, 0.122 mmol) in DMSO (2 mL), and the reaction mixture was stirred at room temperature overnight. The solid was filtered off and by reverse phase HPLC (15-55% CH ₃ CN / 0.1% formic acid in water of) the reaction solution was purified to provide the desired product as a solid (24mg). LC-MS (ES) m / z = 449 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.66 (br.s., 1H), 8.05 (dd, J = 6.8, 8.6 Hz, 2H), 7.38 (br.s., 1H), 7.27 (d, J = 8.6Hz, 1H), 6.87 (d, J = 11.2Hz, 1H), 6.56 (d, J = 8.9Hz, 1H), 5.95 (br.s., 1H), 5.34 (s, 2H), 4.31 ( br.s., 2H), 2.50 (s, 3H), 2.39-2.26 (m, 2H), 1.76 (d, J = 5.6Hz, 2H), 1.25 (d, J = 6.3Hz, 6H).

Intermediate 175

4-bromo-N- (2-ethoxyethyl) -3-fluoro-2-nitroaniline

1-bromopyrrolidine-2,5-dione (2.53 g, 14.24 mmol) was added to N- (2-ethoxyethyl) -3-fluoro-2-nitroaniline at 0 ° C under an inert atmosphere ( 3.25 g, 14.24 mmol) in DMF (100 mL), and the reaction mixture was stirred at room temperature for 30 minutes. The reaction was poured into stirred water (300 mL), and the resulting precipitate was extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with brine (15mL), dried ₂ SO ₄ Na, filtered, and concentrated. The remaining oil was purified on silica gel (0-30% EtOAc / hexanes) to provide the desired product (3.57 g) as a yellow solid. LC-MS (ES) m / z = 309 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 7.68 (dd, J = 7.6, 9.3 Hz, 1H), 7.39 (t, J = 5.3 Hz, 1H), 6.87 (dd, J = 1.7, 9.6 Hz, 1H), 3.53-3.61 (m, 2H), 3.40-3.51 (m, 4H), 1.08-1.16 (m, 3H).

Example 128

5-bromo-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -4 -Fluoro-1H-benzo [d] imidazole

A solution of 4-bromo-N- (2-ethoxyethyl) -3-fluoro-2-nitroaniline (450 mg, 1.465 mmol) in ethanol (8 mL) and water (2 mL) was fed into sodium bisulfite (765 mg, 85%, 3.74 mmol), and the reaction mixture was stirred under microwave conditions at 110 ° C for 60 minutes. The solid was filtered off and the remaining residue was partitioned between CH ₂ Cl ₂ (60ml) and water (10mL). The aqueous layer was extracted with CH ₂ Cl ₂ (2 x 15 ml), and the combined organic extracts were washed with brine (3 mL), dried over Na ₂ SO ₄ , filtered, and concentrated on silica. The silica-adsorbed residue was purified by flash chromatography (0-100% EtOAc / hexanes) to provide the desired product (1.04 g) as a pale yellow solid. LC-MS (ES) m / z = 461,463 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 8.56 (d, J = 2.2Hz, 1H), 7.97 (dd, J = 2.5, 8.87Hz, 1H), 7.32-7.63 (m, 2H), 6.63 ( d, J = 8.8Hz, 1H), 4.46 (t, J = 5.2Hz, 2H), 3.74 (t, J = 5.2Hz, 2H), 3.27-3.34 (m, 4H), 2.25 (t, J = 6.8 Hz, 2H), 1.66 (d, J = 5.5 Hz, 2H), 1.15 (d, J = 6.0 Hz, 6H), 0.95 (t, J = 6.9 Hz, 3H).

Intermediate 176

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -4-fluoro-1H -Benzo [d] imidazole-5-carboxylic acid ethyl ester

5-Bromo-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxy A solution of ethyl) -4-fluoro-1H-benzo [d] imidazole (584 mg, 0.886 mmol) in N-methyl-2-pyrrolidone (NMP) (2 mL) was fed with 2-ethoxy- Potassium 2-oxoacetate (208 mg, 1.329 mmol), 1,3-bis (diphenylphosphino) propane (54.8 mg, 0.133 mmol), and palladium (II) trifluoroacetate (29.5 mg, 0.089 mmol), and The reaction mixture was stirred at 150 ° C for 18 hours. The reaction was cooled to room temperature and filtered through celite. The filtrate was washed with EtOAc (2 x 10 mL). The solvent was concentrated in vacuo and the remaining oil was dissolved between EtOAc (30 mL) and 1N Na ₂ CO ₃ . The aqueous layer was extracted with EtOAc (3 x 15 mL), and the combined organic extracts were concentrated in vacuo. By reverse phase HPLC (50-99% CH ₃ CN / 0.1% NH ₄ OH in the water) The resulting residue was purified to provide the desired product as a brown foam (100mg). LC-MS (ES) m / z = 455 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.57 (d, J = 2.3 Hz, 1 H), 7.98 (dd, J = 2.4, 9.0 Hz, 1 H), 7.74 (dd, J = 6.3, 8.4 Hz, 1H), 7.59 (d, J = 8.6Hz, 1H), 6.64 (d, J = 8.9Hz, 1H), 4.48 (t, J = 5.2Hz, 2H), 4.35 (q, J = 7.1Hz, 2H) , 3.75 (t, J = 5.2Hz, 2H), 3.30 (d, J = 7.1Hz, 2H), 2.29-2.19 (m, 2H), 1.66 (d, J = 6.3Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H), 1.15 (d, J = 6.3 Hz, 6H), 0.94 (t, J = 7.0 Hz, 3H).

Intermediate 177

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -4-fluoro-1H -Benzo [d] imidazole-5-carboxylic acid

5N NaOH (0.627 mL, 3.13 mmol) was added to 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2- A solution of ethoxyethyl) -4-fluoro-1H-benzo [d] imidazole-5-carboxylic acid ethyl ester (95 mg, 0.209 mmol) in ethanol (2 mL) and water (0.667 mL), and the reaction mixture Stir at 98 ° C for 1 hour. The organic solvent was removed in vacuo and the pH was adjusted to ~ 2 with 6N aqueous HCl (0.488 mL, 2.93 mmol) at 0 ° C. The solid was collected, washed with water (2 mL), and dried under vacuum to provide the desired product (91 mg) as a white solid. LC-MS (ES) m / z = 427 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 8.57 (d, J = 2.0Hz, 1H), 8.24 (br.s., 1H), 7.79 (dd, J = 6.5, 8.5Hz, 1H), 7.62 (d, J = 8.6Hz, 1H), 7.09 (br.s., 1H), 4.51 (t, J = 5.1Hz, 2H), 4.47-4.33 (m, 2H), 3.76 (t, J = 5.1Hz , 2H), 3.33 (dq, J = 1.4, 7.0 Hz, 2H), 2.34-2.28 (m, 2H), 1.74 (d, J = 5.8 Hz, 2H), 1.19 (d, J = 6.3 Hz, 6H) , 0.96 (t, J = 7.1 Hz, 3H).

Example 129

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -4-fluoro-N -Methyl-1H-benzo [d] imidazole-5-carboxamide

HATU (65.3 mg, 0.172 mmol) and triethylamine (0.080 mL, 0.572 mmol) were added to 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridine- 3-yl) -1- (2-ethoxyethyl) -4-fluoro-1H-benzo [d] imidazole-5-carboxylic acid (61 mg, 0.143 mmol) in DMF (2 mL), and The resulting mixture was stirred at room temperature for 20 minutes. Then methylamine hydrochloride (14.49 mg, 0.215 mmol) was added and the reaction mixture was stirred overnight. After the reaction was completed, the solid was collected and washed with CH ₂ Cl ₂ (3 mL). The combined organic solvents were removed in vacuo and the remaining residue was purified via reverse phase HPLC (30-85% CH ₃ CN / 0.1% NH ₄ OH in water) to provide the desired product as a glassy solid (18mg). LC-MS (ES) m / z = 440 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 8.56 (d, J = 2.3Hz, 1H), 8.24-8.15 (m, 1H), 7.99 (d, J = 7.9Hz, 1H), 7.58-7.46 ( m, 2H), 6.65 (d, J = 8.6 Hz, 1H), 4.47 (t, J = 5.1 Hz, 2H), 4.28 (br.s., 2H), 3.74 (t, J = 5.1 Hz, 2H) , 3.30 (q, J = 6.8Hz, 2H), 2.82 (d, J = 4.3Hz, 3H), 2.25 (t, J = 7.9Hz, 2H), 1.66 (d, J = 5.6Hz, 2H), 1.15 (d, J = 6.1 Hz, 6H), 0.95 (t, J = 7.1 Hz, 3H).

Example 130

(2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo (d) Imidazol-5-yl) methanol

LiAlH ₄ (0.143 mL, 0.286 mmol) was added to 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2- A solution of ethoxyethyl) -4-fluoro-1H-benzo [d] imidazole-5-carboxylic acid (61 mg, 0.143 mmol) in THF (0.5 mL) at 0 ° C, and the reaction mixture was stirred for 2 hours . Then a saturated aqueous Na ₂ SO ₄ solution (0.05 mL) was added, and the resulting mixture was stirred for 20 minutes, followed by filtration. The precipitate was washed with EtOAc (2 x 8 mL). The combined organic solvents were removed in vacuo, and the remaining residue was purified via reverse phase HPLC (30-85% CH ₃ CN / 0.1% NH ₄ OH in water) to provide a thin film on glass. The desired product (12 mg). LC-MS (ES) m / z = 395 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.57 (d, J = 2.0Hz, 1H), 7.94 (dd, J = 2.5, 8.9Hz, 1H), 7.78 (s, 1H), 7.49 (d, J = 8.1Hz, 1H), 7.34 (dd, J = 1.5, 8.4Hz, 1H), 6.51 (d, J = 8.9Hz, 1H), 4.83 (s, 2H), 4.43 (t, J = 5.7Hz, 2H) , 4.30 (br.s., 2H), 3.85 (t, J = 5.8Hz, 2H), 3.45 (q, J = 7.1Hz, 2H), 2.36-2.22 (m, 2H), 1.77-1.68 (m, 2H), 1.23 (d, J = 6.3Hz, 6H), 1.15 (t, J = 7.0Hz, 3H).

Intermediate 178

6-(((1-methyl-1H-pyrazol-3-yl) methyl) amino) -5-nitronicotinic acid methyl ester

(1-methyl-1H-pyrazol-3-yl) methylamine (462 mg, 4.16 mmol) and N, N-diisopropylethylamine (0.944 mL, 5.40 mmol) were added to 6-chloro-5- A solution of methyl nitronicotinate (900 mg, 4.16 mmol) in CH ₂ Cl ₂ (20 mL), and the mixture was stirred at room temperature for 20 hours. The mixture was concentrated and the residue was washed with water and dried under vacuum to give the desired product (1.10 g) as a pale yellow solid. LC-MS (ES) m / z = 292 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 3.94-3.99 (m, 6H), 4.89-4.98 (m, 2H), 6.28 (d, J = 2.3Hz, 1H), 7.38 (d, J = 2.3Hz, 1H), 8.95 (br.s., 1H), 9.05-9.09 (m, 2H).

Intermediate 179

2- (6- (diethylamino) pyridin-3-yl) -3-((1-methyl-1H-pyrazol-3-yl) methyl) -3H-imidazo [4,5-b ] Methyl pyridine-6-formate

6-(((1-methyl-1H-pyrazol-3-yl) methyl) amino) -5-nitronicotinic acid methyl ester (0.150 g, 0.515 mmol), 6- (diethylamine Group) Nicotinaldehyde (0.101 g, 0.566 mmol), ethanol (3 mL), water (1.5 mL), and sodium bisulfite (0.269 g, 85%, 1.313 mmol) were combined in a microwave vial. The vial was sealed and the reaction mixture was heated under microwave conditions at 130 ° C for 90 minutes. The reaction was diluted with water (10 mL) and then extracted with EtOAc (4 x 5 mL). The combined organic layers were washed with brine, dried over MgSO _4, filtered, and concentrated. By using silica gel chromatography in the gradient 0 to 10% CH ₃ OH in CH ₂ Cl ₂ to provide the crude material was purified as a pale yellow solid of 2- (6- (diethylamino) pyridin-3-yl ) -3-((1-methyl-1H-pyrazol-3-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-carboxylic acid methyl ester (0.200 g). LC-MS (ES) m / z = 420 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 8.90 (d, J = 2.0Hz, 1H), 8.66 (d, J = 2.3Hz, 1H), 8.48 (d, J = 2.0Hz, 1H), 8.08 (dd, J = 2.5,9.1Hz, 1H), 7.61 (d, J = 2.3Hz, 1H), 6.75 (d, J = 9.1Hz, 1H), 6.09 (d, J = 2.3Hz, 1H), 5.55 (s, 2H), 3.91 (s, 3H), 3.75 (s, 3H), 3.57 (q, J = 6.9Hz, 4H), 1.14 (t, J = 7.0Hz, 6H).

Intermediate 180

2- (6- (diethylamino) pyridin-3-yl) -3-((1-methyl-1H-pyrazol-3-yl) methyl) -3H-imidazo [4,5-b ] Pyridine-6-formic acid

10N aqueous sodium hydroxide solution (0.954 mL, 9.54 mmol) was added to 2- (6- (diethylamino) pyridin-3-yl) -3-((1-methyl-1H-pyrazol-3-yl ) Methyl) -3H-imidazo [4,5-b] pyridine-6-carboxylic acid methyl ester (0.200 g, 0.477 mmol) in CH ₃ OH (4 mL), and the reaction mixture was stirred at 45 ° C. 2 hours. The reaction portion was concentrated, and then a 1 N aqueous HCl solution (10.54 mL, 10.54 mmol) was added. The resulting mixture was filtered, the white solid was discarded, and the filtrate was concentrated. Purification by silica gel chromatography with a gradient of 0 to 15% CH ₃ OH in CH ₂ Cl ₂ provides 2- (6- (diethylamino) pyridin-3-yl)-as a white solid 3-((1-methyl-1H-pyrazol-3-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-carboxylic acid (149 mg, 0.367 mmol). LC-MS (ES) m / z = 406 [M + H] ⁺ .

Example 131

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

Add methylamine hydrochloride (36.0 mg, 0.533 mmol), EDC (113 mg, 0.592 mmol), HOBt hydrate (91 mg, 0.592 mmol), and N-methylmorphine (0.195 mL, 1.776 mmol) to 2 -(6- (diethylamino) pyridin-3-yl) -3-((1-methyl-1H-pyrazol-3-yl) methyl) -3H-imidazo [4,5-b] A solution of pyridine-6-formic acid (120 mg, 0.296 mmol) in DMSO (2 mL), and the reaction mixture was sealed and stirred at room temperature overnight. The reaction (5mL) was quenched with saturated aqueous NaHCO _3, followed by (3 x 10 mL) and extracted containing 10% CH ₃ OH of EtOAc. The combined dried organic extracts with MgSO _4, filtered, and concentrated. Purification by silica gel chromatography with 0 to 15% CH ₃ OH in CH ₂ Cl ₂ provides 2- (6- (diethylamino) pyridin-3-yl) -N- as a colorless oil Methyl-3-((1-methyl-1H-pyrazol-3-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-formamidine (105.9 mg, 0.253 mmol) , Crystallized after standing to provide a white solid. LC-MS (ES) m / z = 419 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 8.79 (d, J = 1.8Hz, 1H), 8.65 (d, J = 2.3Hz, 1H), 8.60 (d, J = 4.6Hz, 1H), 8.43 (d, J = 1.8Hz, 1H), 8.07 (dd, J = 2.4, 9.0Hz, 1H), 7.61 (d, J = 2.0Hz, 1H), 6.75 (d, J = 9.1Hz, 1H), 6.07 (d, J = 2.3Hz, 1H), 5.53 (s, 2H), 3.76 (s, 3H), 3.57 (q, J = 6.9Hz, 4H), 2.84 (d, J = 4.6Hz, 3H), 1.15 (t, J = 7.0 Hz, 6H).

Intermediate 181

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3-((1-methyl-1H-pyrazol-3-yl ) Methyl) -3H-imidazo [4,5-b] pyridine-6-carboxylic acid methyl ester

6-(((1-methyl-1H-pyrazol-3-yl) methyl) amino) -5-nitronicotinic acid methyl ester (157 mg, 0.539 mmol), 6-((2S, 5S ) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (121 mg, 0.593 mmol), ethanol (3 mL), water (1.5 mL), and sodium bisulfite (282 mg, 85%, 1.374 mmol ) A microwave vial was added and the reaction mixture was heated at 130 ° C for 1.5 hours under microwave conditions. The reaction was then diluted with water (10 mL) and extracted with EtOAc (4 x 20 mL). The organic extracts were combined, washed with brine, dried over MgSO _4, filtered, and concentrated. Purification by chromatography on SiO ₂ (0 to 70% EtOAc / hexanes) provided 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1- Yl) pyridin-3-yl) -3-((1-methyl-1H-pyrazol-3-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-carboxylic acid methyl ester ( 130mg). LC-MS (ES) m / z = 446 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.14 (d, J = 6.3Hz, 6H), 1.65 (d, J = 5.1Hz, 2H), 2.24 (br.s., 2H), 3.75 (s , 3H), 3.92 (s, 3H), 4.26 (br.s., 2H), 5.56 (s, 2H), 6.08 (d, J = 2.3Hz, 1H), 6.64 (d, J = 9.1Hz, 1H ), 7.61 (d, J = 2.3Hz, 1H), 8.07 (dd, J = 9.0,2.4Hz, 1H), 8.49 (d, J = 1.8Hz, 1H), 8.67 (d, J = 2.3Hz, 1H ), 8.90 (d, J = 1.8 Hz, 1H).

Intermediate 182

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3-((1-methyl-1H-pyrazol-3-yl ) Methyl) -3H-imidazo [4,5-b] pyridine-6-carboxylic acid

10N NaOH (0.584 mL, 5.84 mmol) was added to 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridine-3 in CH ₃ OH (5 mL) -Yl) -3-((1-methyl-1H-pyrazol-3-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-carboxylic acid methyl ester (130 mg, 0.292 mmol) The reaction mixture was stirred at room temperature overnight. The reaction was concentrated and diluted with water (10 mL) followed by 6N HCl (0.973 mL, 5.84 mmol). The resulting mixture was extracted with EtOAc (4 x 10mL), and then the organic extracts were combined, washed with brine, dried over MgSO _4, filtered, and concentrated to provide a pale yellow solid of 2- (6 - ((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3-((1-methyl-1H-pyrazol-3-yl) methyl) -3H-imidazo [4 , 5-b] pyridine-6-carboxylic acid (115 mg). LC-MS (ES) m / z = 432 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.14 (d, J = 6.3Hz, 6H), 1.66 (d, J = 5.3Hz, 2H), 2.24 (br.s., 2H), 3.75 (s , 3H), 4.26 (br.s., 2H), 5.56 (s, 2H), 6.07 (d, J = 2.0Hz, 1H), 6.65 (d, J = 9.1Hz, 1H), 7.61 (d, J = 2.3Hz, 1H), 8.04-8.09 (m, 1H), 8.46 (d, J = 1.8Hz, 1H), 8.67 (d, J = 2.3Hz, 1H), 8.89 (d, J = 1.8Hz, 1H ), 13.17 (br.s., 1H).

Example 132

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -N-methyl-3-((1-methyl-1H-pyridine Azol-3-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-carboxamide

Methylamine hydrochloride (15.49mg, 0.229mmol), EDC (58.6mg, 0.306mmol), HOBt (46.8mg, 0.306mmol), and N-methylmorpholine (0.118mL, 1.071mmol) were added to 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3-((1-methyl-1H- Pyrazol-3-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-carboxylic acid (66 mg, 0.153 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was then diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The organic extracts were combined, dried over MgSO _4, filtered, and concentrated. Purification by chromatography on SiO ₂ (0 to 10% CH ₃ OH / CH ₂ Cl ₂ ) provided 2- (6-((2S, 5S) -2,5-dimethylpyrrolidine-1- Yl) pyridin-3-yl) -N-methyl-3-((1-methyl-1H-pyrazol-3-yl) methyl) -3H-imidazo [4,5-b] pyridine-6 -Formamidine (54 mg) as a white solid after freeze drying. LC-MS (ES) m / z = 445 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.14 (d, J = 6.1Hz, 6H), 1.65 (d, J = 5.3Hz, 2H), 2.23 (br.s., 2H), 2.84 (d , J = 4.6Hz, 3H), 3.75 (s, 3H), 4.25 (br.s., 2H), 5.54 (s, 2H), 6.06 (d, J = 2.3Hz, 1H), 6.63 (d, J = 8.9Hz, 1H), 7.61 (d, J = 2.0Hz, 1H), 8.06 (dd, J = 9.0,2.4Hz, 1H), 8.43 (d, J = 2.0Hz, 1H), 8.60 (d, J = 4.6Hz, 1H), 8.66 (d, J = 2.3Hz, 1H), 8.79 (d, J = 1.8Hz, 1H).

Example 133

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3-((1-methyl-1H-pyrazol-3-yl ) Methyl) -3H-imidazo [4,5-b] pyridine-6-carboxamide

NH ₄ Cl (11.38 mg, 0.213 mmol), EDC (45.3 mg, 0.236 mmol), HOBt (36.2 mg, 0.236 mmol), and N-methylmorpholine (0.078 mL, 0.709 mmol) were added to DMSO ( 2 (2)) of 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3-((1-methyl-1H-pyrazole -3-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-carboxylic acid (51 mg, 0.118 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with water (5 mL) and extracted with EtOAc (3 x 10 mL). The organic extracts were combined, washed with brine, dried over MgSO _4, filtered, and concentrated. Purification by chromatography on SiO ₂ (0 to 10% CH ₃ OH / CH ₂ Cl ₂ ) provided 2- (6-((2S, 5S) -2,5-dimethylpyrrolidine-1- Yl) pyridin-3-yl) -3-((1-methyl-1H-pyrazol-3-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-formamidine ( 38 mg), lyophilized as a white solid. LC-MS (ES) m / z = 431 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 1.14 (d, J = 6.01 Hz, 6H), 1.65 (m, J = 5.6 Hz, 2H), 2.17-2.28 (m, 2H), 3.75 (s, 3H), 4.25 (br.s., 2H), 5.54 (s, 2H), 6.06 (d, J = 2.3Hz, 1H), 6.63 (d, J = 9.1Hz, 1H), 7.51 (s, 1H) , 7.61 (d, J = 2.3Hz, 1H), 8.06 (dd, J = 9.0, 2.41Hz, 1H), 8.14 (s, 1H), 8.48 (d, J = 1.8Hz, 1H), 8.66 (d, J = 2.5Hz, 1H), 8.83 (d, J = 1.8Hz, 1H).

Intermediate 183

2- (1-ethyl-2,2-dimethyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-5-yl) -3-((1-methyl- 1H-pyrazol-3-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-carboxylic acid methyl ester

6-(((1-methyl-1H-pyrazol-3-yl) methyl) amino) -5-nitronicotinic acid methyl ester (0.150 g, 0.515 mmol), 1-ethyl-2 , 2-dimethyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridine-5-carboxaldehyde (0.116 g, 0.566 mmol), ethanol (3 mL), water (1.500 mL), and Sodium bisulfite (0.269 g, 85%, 1.313 mmol) was combined in a 20 mL microwave vial. The mixture was then capped and heated at 130 ° C for 90 minutes under microwave conditions. The reaction was diluted with water (10 mL), followed by extraction with EtOAc (4 x 10 mL). The combined organic layers were washed with brine, dried over MgSO _4, filtered, and concentrated. The crude material was purified by silica gel chromatography with a gradient elution of 0 to 100% EtOAc in CH ₂ Cl ₂ to provide 2- (1-ethyl-2,2-di as a slightly impure yellow solid. Methyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-5-yl) -3-((1-methyl-1H-pyrazol-3-yl) methyl)- 3H-imidazo [4,5-b] pyridine-6-carboxylic acid methyl ester (0.151 g). LC-MS (ES) m / z = 446 [M + H] ⁺ .

Intermediate 184

2- (1-ethyl-2,2-dimethyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-5-yl) -3-((1-methyl- 1H-pyrazol-3-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-carboxylic acid

10N aqueous NaOH (0.678 mL, 6.78 mmol) was added to 2- (1-ethyl-2,2-dimethyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridine-5 -Yl) -3-((1-methyl-1H-pyrazol-3-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-carboxylic acid methyl ester (0.151 g, 0.339 mmol ) In CH ₃ OH (4 mL), and the reaction mixture was stirred at 45 ° C. for 2 hours. The reaction portion was concentrated, followed by addition of a 1 N aqueous HCl solution (7.78 mL, 7.78 mmol), and the resulting mixture was filtered. The filtrate was concentrated and chromatographed by silica gel used in the method of to 0 CH ₂ Cl ₂ to 15% CH ₃ OH gradient elution and the resulting residue was purified to provide a white solid of 2- (1-ethyl-2 , 2-dimethyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-5-yl) -3-((1-methyl-1H-pyrazol-3-yl) (Methyl) -3H-imidazo [4,5-b] pyridine-6-carboxylic acid (121 mg). LC-MS (ES) m / z = 432 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 9.15 (d, J = 1.8Hz, 1H), 8.70 (s, 1H), 8.69 (d, J = 1.8Hz, 1H), 8.06 (s, 1H), 7.63 (d, J = 2.3Hz, 1H), 6.48 (d, J = 2.3Hz, 1H), 5.76 (s, 2H), 3.90 (s, 3H), 3.75 (q, J = 7.3Hz, 2H), 3.31 (s, 2H), 1.59 (s, 6H), 1.42 (t, J = 7.2Hz, 3H).

Example 134

2- (1-ethyl-2,2-dimethyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-5-yl) -N-methyl-3-(( 1-methyl-1H-pyrazol-3-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-carboxamide

NH ₄ Cl (25.7 mg, 0.480 mmol), EDC (102 mg, 0.533 mmol), HOBt (82 mg, 0.533 mmol), and N-methylmorpholine (0.176 mL, 1.599 mmol) were added to 2- (1- Ethyl-2,2-dimethyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-5-yl) -3-((1-methyl-1H-pyrazole- 3-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-carboxylic acid (115 mg, 0.267 mmol) in DMSO (2 mL), and the reaction mixture was placed in a sealed container at room temperature Stir overnight. The reaction (5mL) was quenched with saturated aqueous NaHCO ₃ and then extracted in EtOAc with the _{10% CH 3 OH (3 x} 10mL). The combined dried organic extracts with MgSO _4, filtered, and concentrated. Purification by silica gel chromatography with a gradient elution of 0 to 25% CH ₃ OH in CH ₂ Cl ₂ provided 2- (1-ethyl-2,2-dimethyl-2, 3-dihydro-1H-pyrrolo [2,3-b] pyridin-5-yl) -N-methyl-3-((1-methyl-1H-pyrazol-3-yl) methyl)- 3H-imidazo [4,5-b] pyridine-6-carboxamide (93.7 mg) was crystallized after standing to provide a white solid. LC-MS (ES) m / z = 445 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 8.78 (d, J = 2.0Hz, 1H), 8.59 (d, J = 4.3Hz, 1H), 8.40 (d, J = 1.8Hz, 1H), 8.36 (d, J = 1.8Hz, 1H), 7.77 (d, J = 1.8Hz, 1H), 7.61 (d, J = 2.3Hz, 1H), 6.06 (d, J = 2.3Hz, 1H), 5.51 (s , 2H), 3.76 (s, 3H), 3.38-3.30 (m, 2H), 2.90 (s, 2H), 2.84 (d, J = 4.6Hz, 3H), 1.30 (s, 6H), 1.19 (t, J = 7.1 Hz, 3H).

Intermediate 185

Methyl 2-((2-nitrophenyl) amino) acetate

A mixture of 1-fluoro-2-nitrobenzene (2.82 g, 19.99 mmol) and methyl 2-aminoacetate (2.137 g, 23.98 mmol) in DMF (60 mL) was stirred at 60 ° C for 12 hours. The mixture was concentrated under vacuum, and the resulting residue was treated with water (30 mL) and extracted with EtOAc (2x). The combined organic layers were concentrated and the resulting residue was purified by silica chromatography (0 to 40% EtOAc / hexanes) to give the desired product (3.4 g) as a yellow solid. LC-MS (ES) m / z = 211 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.40 (s, 1H), 8.22 (d, J = 8.5Hz, 1H), 7.47 ( t, J = 7.8Hz, 1H), 6.77-6.66 (m, 2H), 4.12 (s, 2H), 3.83 (s, 3H).

Intermediate 186

2-((2-((tertiary butoxycarbonyl) amino) phenyl) amino) acetic acid methyl ester

Add methyl 2-((2-nitrophenyl) amino) acetate (1.05 g, 5.00 mmol), di-tertiary butyl dicarbonate (2.181 g, 9.99 mmol), and palladium on carbon (10%, 0.106) g) in a mixture of CH ₃ OH (30mL) was stirred for 12 hours at the 25 deg.] C under a hydrogen atmosphere. The reaction mixture was filtered to remove the catalyst, and the filtrate was concentrated by silica gel chromatography (0 to 3.5% CH ₃ OH / CH ₂ Cl ₂ ). The resulting residue was purified to give the desired product (798 mg) as a white solid. LC-MS (ES) m / z = 281 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 7.36 (d, J = 7.0Hz, 1H), 7.12-7.03 (m, 1H), 6.82 (t, J = 7.4Hz, 1H), 6.64 (d, J = 8.0Hz, 1H), 3.92 (s, 2H), 3.79 (s, 3H), 1.54-1.50 (m, 9H).

Intermediate 187

(2-((2-hydrazino-2-oxoethyl) amino) phenyl) carbamic acid tert-butyl ester (N60912-66-A1)

A mixture of 2-((2-((tertiary butoxycarbonyl) amino) phenyl) amino) acetic acid methyl ester (798 mg, 2.85 mmol) and hydrazine (0.279 mL, 5.69 mmol) in ethanol (25 mL) Stir at 80 ° C for 12 hours. The reaction mixture was concentrated and chromatographed by silica gel (0 to _{8.5% CH 3 OH / CH 2} Cl 2) The resulting residue was purified form to produce the desired product as a white solid (500mg). LC-MS (ES) m / z = 281 [M + H] ⁺ .

Intermediate 188

(2-(((3-ethyl-1H-1,2,4-triazol-5-yl) methyl) amino) phenyl) carbamic acid tert-butyl ester

Tert-Butyl (2-((2-hydrazino-2-oxoethyl) amino) phenyl) carbamate (500 mg, 1.784 mmol), sodium ethoxide (364 mg, 5.35 mmol), and propionite A mixture of Ethyl propionimidate-hydrochloride (491 mg, 3.57 mmol) in ethanol (25 mL) was stirred at 90 ° C for 12 hours. The mixture was concentrated, and the resulting residue was treated with water (20 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated. By silica gel chromatography (0 to _{4% CH 3 OH / CH 2} Cl 2) The resulting residue was purified form to produce the desired product as a yellow solid (468mg). LC-MS (ES) m / z = 318 [M + H] ⁺ .

Intermediate 189

N1-((3-ethyl-1H-1,2,4-triazol-5-yl) methyl) benzene-1,2-diamine

HCl (33% in ethanol, 3.81 mL, 18.27 mmol) and (2-((((3-ethyl-1H-1,2,4-triazol-5-yl) methyl) amino) benzene A mixture of tert-butyl carbamate (580 mg, 1.827 mmol) in CH ₂ Cl ₂ (25 mL) was stirred at 25 ° C. for 4 hours. The mixture was concentrated in vacuo and the resulting residue was treated with EtOAc (20mL) and washed with saturated aqueous NaHCO ₃ (20mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated to provide the desired product as a yellow oil (270mg). LC-MS (ES) m / z = 218 [M + H] ⁺ . 1H NMR (400MHz, CDCl ₃ ): δ 6.83-6.76 (m, 1H), 6.70 (d, J = 3.6Hz, 2H), 6.66 (d, J = 7.8Hz, 1H), 5.35-5.0 (m, 3H ), 4.42 (s, 2H), 2.76 (q, J = 7.6Hz, 2H), 1.31 (t, J = 7.6Hz, 3H).

Example 135

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((3-ethyl-1H-1,2,4- Triazol-5-yl) methyl) -1H-benzo [d] imidazole

N1-((3-ethyl-1H-1,2,4-triazol-5-yl) methyl) benzene-1,2-diamine (270 mg, 1.243 mmol), 6-((2S, 5S ) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (305 mg, 1.491 mmol), and sodium metabisulfite (307 mg, 1.615 mmol) in DMF (15 mL) were stirred at 80 ° C for 12 hour. The mixture was concentrated in vacuo, and by silica gel chromatography (0 to _{3.5% CH 3 OH / CH 2} Cl 2) The resulting residue was purified form to produce the desired product as a white solid (170mg). LC-MS (ES) m / z = 402 [M + H] ⁺ . 1H NMR (400MHz, DMSO- d ₆ ): δ 13.65 (br s, 1H), 8.71 (d, J = 1.9Hz, 1H), 8.13 (dd, J = 8.9, 2.1Hz, 1H), 7.65-7.59 ( m 1H), 7.59-7.49 (m, 1H), 7.23-7.17 (m, 2H), 6.63 (d, J = 8.9Hz, 1H), 5.39 (s, 2H), 4.37-4.05 (m, 2H), 2.70 (q, J = 7.6Hz, 2H), 2.30-2.18 (m, 2H), 1.71-1.60 (m, 2H), 1.20 (t, J = 7.6Hz, 3H), 1.14 (d, J = 6.1Hz , 6H).

Intermediate 190

4-((5- (bromomethyl) -2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [ d) imidazol-1-yl) methyl) -2-ethyl Azole

NBS (199 mg, 1.117 mmol) was added portionwise to (3-chloro-4-iodophenyl) methanol (250 mg, 0.931 mmol) and triphenylphosphine (293 mg, 1.117 mmol) in THF (5 mL) at 0 ° C. Solution, and the mixture was stirred at room temperature for 40 minutes. The reaction was quenched with water and extracted with EtOAc (3x). The extracts were dried (Na ₂ SO ₄₎ and concentrated. The resulting residue was purified by silica chromatography (0 to 50% EtOAc / hexanes) to give the desired product (140 mg) as a white solid. LC-MS (ES) m / z = 494,496 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.25-1.33 (m, 9H), 1.74-1.91 (m, 2H), 2.40 (br.s., 2H), 2.78 (q, J = 7.6Hz, 2H ), 4.65 (s, 2H), 5.56 (s, 2H), 6.93 (d, J = 8.9Hz, 1H), 7.49-7.57 (m, 1H), 7.74-7.86 (m, 2H), 8.11 (s, 1H), 8.28 (dd, J = 9.1, 2.3 Hz, 1H), 8.82 (d, J = 2.0 Hz, 1H).

Intermediate 191

4-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -5-((methylthio) methyl) -1H -Benzo [d] imidazol-1-yl) methyl) -2-ethyl Azole

Sodium methyl mercaptan (18.43 mg, 0.263 mmol) was added to 4-((5- (bromomethyl) -2- (6-((2S, 5S) -2,5-dimethylpyrrolidine-1- Yl) pyridin-3-yl) -1H-benzo [d] imidazol-1-yl) methyl) -2-ethyl A solution of azole (130 mg, 0.263 mmol) in ethanol (2 mL) was stirred at room temperature for 4 hours. The reaction mixture was concentrated, and the resulting residue was washed with water and dried under vacuum to give the desired product (110 mg) as a white solid. LC-MS (ES) m / z = 462 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.14-1.25 (m, 6H), 1.26-1.36 (m, 3H), 1.67-1.82 (m, 2H), 1.89 (s, 3H), 2.32-2.42 ( m, 2H), 2.78 (q, J = 7.6Hz, 2H), 3.83 (s, 2H), 4.32 (br.s., 2H), 5.35 (s, 2H), 6.71 (d, J = 8.9Hz, 1H), 7.29 (dd, J = 8.4, 1.5Hz, 1H), 7.48 (d, J = 8.4Hz, 1H), 7.59-7.63 (m, 1H), 7.79 (s, 1H), 8.05 (dd, J = 8.9, 2.5Hz, 1H), 8.62 (d, J = 2.0Hz, 1H).

Example 136

4-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -5-((methylsulfonyl) methyl)- 1H-benzo [d] imidazol-1-yl) methyl) -2-ethyl Azole

A solution of potassium oxone monohydrate (322 mg, 0.524 mmol) in water (1.60 mL) was added to 4-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidine -1-yl) pyridin-3-yl) -5-((methylthio) methyl) -1H-benzo [d] imidazol-1-yl) methyl) -2-ethyl Oxazole (110mg, 0.238mmol) in CH ₃ OH (4mL) the solution, and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated, and the residue was treated with water (3 mL) and extracted with CH ₂ Cl ₂ (3 ×). The extracts were dried (Na ₂ SO ₄₎ and concentrated. The resulting residue was purified by silica chromatography (0 to 100% EtOAc / heptane) to give the desired product (58 mg) as a white solid. LC-MS (ES) m / z = 494 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.23 (d, J = 6.3Hz, 6H), 1.25-1.35 (m, 3H), 1.76 (d, J = 5.8Hz, 2H), 2.29-2.42 (m , 2H), 2.78 (q, J = 7.7Hz, 2H), 2.89 (s, 3H), 4.32 (br.s., 2H), 4.57 (s, 2H), 5.39 (s, 2H), 6.72 (d , J = 8.6Hz, 1H), 7.39 (dd, J = 8.5, 1.6Hz, 1H), 7.59 (d, J = 8.4Hz, 1H), 7.79 (d, J = 1.0Hz, 1H), 7.83 (s , 1H), 8.07 (dd, J = 8.9, 2.5Hz, 1H), 8.62-8.68 (m, 1H)

Example 137

2- (4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl ) -1H-benzo [d] imidazol-5-yl -6-methyl-1,3,6,2-dioxazepine-4,8-dione

Add 2,2 '-(methylazanediyl) diacetic acid (74.8 mg, 0.508 mmol) and magnesium sulfate (408 mg, 3.39 mmol) to (4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] imidazol-5-yl) boronic acid (150 mg , 0.339 mmol) in toluene (6 mL) and DMSO (0.667 mL), and the mixture was stirred at reflux for 1 hour. The mixture was cooled to room temperature and concentrated. The resulting residue was purified by silica gel chromatography (0 to 100% (3: 1 EtOAc: EtOH) / heptane) to give the desired product (160 mg) as a white solid. LC-MS (ES) m / z = 554 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.07 (t, J = 7.0Hz, 3H), 1.18-1.26 (m, 6H), 1.72-1.81 (m, 2H), 2.27-2.42 (m, 2H) , 2.77 (s, 3H), 3.40 (q, J = 7.1Hz, 2H), 3.86 (t, J = 5.2Hz, 2H), 4.19-4.43 (m, 6H), 4.48 (t, J = 5.1Hz, 2H), 6.70 (d, J = 8.9Hz, 1H), 7.56-7.68 (m, 2H), 8.00 (dd, J = 9.0, 2.4Hz, 1H), 8.57 (d, J = 2.0Hz, 1H)

Intermediate 192

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((2-ethyl Azole-4-yl) methyl) -1H-benzo [d] imidazole-5-carbaldehyde

Add Dess-Martin periodinane (575mg, 1.356mmol) to (2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1 -((2-ethyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-5-yl) methanol (390 mg, 0.904 mmol) in CH ₂ Cl ₂ (5 mL), the mixture was stirred at room temperature for 4 hour. The mixture was concentrated, and the resulting residue was purified by silica chromatography (0 to 60% EtOAc / hexanes) to give the desired product (310 mg) as a light brown solid. LC-MS (ES) m / z = 430 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.18-1.25 (m, 6H), 1.25-1.33 (m, 3H), 1.71-1.82 (m, 2H), 2.31-2.43 (m, 2H), 2.77 ( q, J = 7.6Hz, 2H), 4.33 (d, J = 6.8Hz, 2H), 5.44 (s, 2H), 6.73 (d, J = 8.9Hz, 1H), 7.72 (d, J = 8.7Hz, 1H), 7.84-7.93 (m, 2H), 8.10 (dd, J = 8.9, 2.5Hz, 1H), 8.24 (d, J = 1.0Hz, 1H), 8.67 (d, J = 2.3Hz, 1H), 10.07 (s, 1H).

Example 138

1- (2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((2-ethyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-5-yl) -2,2,2-trifluoroethanol

Trimethyl (trifluoromethyl) silane (185 mg, 1.304 mmol) and K ₂ CO ₃ (36.0 mg, 0.261 mmol) were added to 2- (6-((2S, 5S) -2,5-dimethyl Pyrrolidin-1-yl) pyridin-3-yl) -1-((2-ethyl A solution of azole-4-yl) methyl) -1H-benzo [d] imidazole-5-carbaldehyde (56 mg, 0.130 mmol) in DMF (1 mL), and the reaction mixture was stirred at room temperature for 48 hours. The mixture was quenched with water (5 mL) and extracted with EtOAc (3x). The extracts were dried (Na ₂ SO ₄₎ and concentrated. The residue was dissolved in THF (2.00 mL), treated slowly with 6N aqueous HCl, and the mixture was stirred at room temperature for 3 hours. Water (10 mL) was then added and the resulting mixture was extracted with EtOAc (3 x 10 mL). The extract was dried over Na ₂ SO _4, filtered, and concentrated. The resulting residue was purified by silica chromatography (0 to 100% EtOAc / heptane) to give the desired product (41 mg) as a white solid. LC-MS (ES) m / z = 500 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.17-1.25 (m, 6H), 1.30 (t, J = 7.6Hz, 3H), 1.69-1.81 (m, 2H), 2.31-2.40 (m, 2H) , 2.72-2.81 (m, 2H), 4.32 (br.s., 2H), 5.17 (q, J = 7.1Hz, 1H), 5.33-5.43 (m, 2H), 6.72 (d, J = 8.6Hz, 1H), 7.44 (d, J = 8.4Hz, 1H), 7.56 (d, J = 8.6Hz, 1H), 7.79-7.87 (m, 2H), 8.06 (dd, J = 8.9, 2.5Hz, 1H), 8.63 (d, J = 1.8Hz, 1H).

Intermediate 193

N- (4-((2-ethoxyethyl) amino) -3-nitrophenyl) acetamidine

Add 2-ethoxyethyl-1-amine (396 mg, 4.44 mmol) and Na ₂ CO ₃ (941 mg, 8.88 mmol) to N- (4-fluoro-3-nitrophenyl) acetamide (800 mg, 4.04 mmol) in ethanol (20 mL), and the reaction mixture was stirred at 60 ° C. for 20 hours. The mixture was filtered, and the filtrate was concentrated. The resulting residue was treated with EtOAc (30 mL) and filtered. The filtrate was concentrated to give the desired product (1.02 g) as a brown solid. LC-MS (ES) m / z = 268 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.19-1.28 (m, 3H), 2.12 (m, 3H), 3.48-3.65 (m, 4H), 3.68-3.78 (m, 2H), 7.03 (d, J = 9.4Hz, 1H), 7.66 (dd, J = 9.1, 2.5Hz, 1H), 8.18 (br.s., 1H), 8.42 (d, J = 2.8Hz, 1H).

Example 139

N- (2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H- Benzo [d] imidazol-5-yl) acetamide

N- (4-((2-ethoxyethyl) amino) -3-nitrophenyl) acetamidamine (250 mg, 0.935 mmol), 4-((2S, 5S) -2,5-di Methylpyrrolidin-1-yl) benzaldehyde (228mg, 1.122mmol), sodium bisulfite (574mg, 85%, 2.81mmol), ethanol (4mL) and water (1mL) were added to a 20-mL microwave tube, and The mixture was stirred at 130 ° C for 80 minutes under microwave conditions. The mixture was then cooled to room temperature, filtered and concentrated. The residue was treated with water and extracted with CH ₂ Cl ₂ (3x). The extracts were dried (Na ₂ SO ₄₎ and concentrated. The resulting residue was purified by silica gel chromatography (0% to 100% (3: 1 EtOAc: EtOH) / heptane) to give the desired product (240 mg) as an off-white solid. LC-MS (ES) m / z = 422 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.08 (t, J = 7.0Hz, 3H), 1.18-1.29 (m, 6H), 1.72-1.80 (m, 2H), 2.18 (s, 3H), 2.30 -2.41 (m, 2H), 3.36-3.46 (m, 2H), 3.87 (t, J = 5.3Hz, 2H), 4.33 (br.s., 2H), 4.47 (t, J = 5.2Hz, 2H) , 6.69 (d, J = 8.9Hz, 1H), 7.44-7.50 (m, 1H), 7.56 (d, J = 8.9Hz, 1H), 7.93-8.00 (m, 2H), 8.55 (d, J = 2.5 Hz, 1H).

Intermediate 194

6-(((2-methyl Azole-4-yl) methyl) amino) -5-nitronicotinic acid methyl ester

Will (2-methyl Azole-4-yl) methylamine (362 mg, 3.23 mmol) and N, N-diisopropylethylamine (0.734 mL, 4.20 mmol) were added to 6-chloro-5-nitronicotinic acid methyl ester (700 mg, 3.23 mmol) in CH ₂ Cl ₂ (20 mL), and the reaction mixture was stirred at room temperature for 20 hours. The mixture was concentrated, and the resulting residue was washed with water and dried under vacuum to give the desired product (920 mg) as a pale yellow solid. LC-MS (ES) m / z = 293 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 2.45 (s, 3H), 3.93 (s, 3H), 4.79 (d, J = 1.0Hz, 2H), 7.74 (t, J = 1.0Hz, 1H), 8.93-8.96 (m, 1H), 8.96-8.99 (m, 1H).

Intermediate 195

5-amino-6-(((2-methyl Azole-4-yl) methyl) amino) nicotinic acid methyl ester

NiCl ₂ ‧ 6H ₂ O (1873 mg, 7.87 mmol) and sodium borohydride (595 mg, 15.74 mmol) were added to 6-(((2-methyl 4-yl) methyl) amino) -5-nitro-nicotinic acid methyl ester (920mg, 3.15mmol), and the mixture was stirred in the ₃ OH (18mL) was CH at 0 ℃ 20 minutes. The reaction mixture was washed with water (10 mL) and saturated aqueous NH ₄ OH (8 mL) was quenched, and the resulting mixture was filtered through diatomaceous earth. The blue solid was washed with EtOAc. The organic layer was collected, and the aqueous layer was further extracted with EtOAc (3x). The combined organic layers were dried (Na ₂ SO ₄₎ and concentrated to give an off-white solid of the desired product (710mg). LC-MS (ES) m / z = 263 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 2.45 (s, 3H), 3.85 (s, 3H), 4.56 (d, J = 1.0Hz, 2H), 7.36 (d, J = 2.0Hz, 1H), 7.67 (t, J = 1.1 Hz, 1H), 8.19 (d, J = 2.0 Hz, 1H).

Intermediate 196

2- (4-ethyl-3-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] -7-yl) -3-((2-methyl (Azol-4-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-carboxylic acid (R) -methyl ester

(R) -4-ethyl-3-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] at 0 ° C -7-Formaldehyde (157 mg, 0.763 mmol) and potassium oxone (352 mg, 0.572 mmol) were added to 5-amino-6-(((2-methyl A solution of azole-4-yl) methyl) amino) nicotinic acid methyl ester (200 mg, 0.763 mmol) in DMF (5 mL) and water (1 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture 10% K ₂ CO ₃ aq and extracted with EtOAc (3x). The organic extracts were dried (Na ₂ SO ₄₎ and concentrated. The resulting residue was purified by silica chromatography (0 to 100% EtOAc / hexanes) to give the desired product (110 mg) as a pale yellow solid. LC-MS (ES) m / z = 449 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.27 (t, J = 7.1Hz, 3H), 1.32-1.37 (m, 3H), 2.40 (s, 3H), 3.47 (dd, J = 13.9, 7.1Hz , 1H), 3.79-3.91 (m, 1H), 3.95-4.08 (m, 5H), 4.12-4.20 (m, 1H), 5.53 (s, 2H), 7.58 (d, J = 2.0Hz, 1H), 7.75 (s, 1H), 8.32 (d, J = 2.0Hz, 1H), 8.58 (d, J = 1.8Hz, 1H), 9.01 (d, J = 1.8Hz, 1H).

Example 140

(R) -2- (4-ethyl-3-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] -7-yl) -N-methyl-3-((2-methyl Azole-4-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-carboxamide

Aqueous NaOH (5N, 0.2 mL, 1.000 mmol) was added to (R) -2- (4-ethyl-3-methyl-3,4-dihydro-2H-pyrido [3,2-b] [ 1,4] -7-yl) -3-((2-methyl Azole-4-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-carboxylic acid methyl ester (46 mg, 0.103 mmol) in CH ₃ OH (1 mL), and the reaction mixture was Stir at 40 ° C for 18 hours. The reaction mixture was neutralized by adding HCl (6N, 0.167 mL, 1.000 mmol) and concentrated. The resulting residue was dried under vacuum and treated with DMSO (1.000 mL). Methylamine hydrochloride (11.08mg, 0.164mmol), N-methylmorpholine (0.079mL, 0.718mmol), EDC (39.3mg, 0.205mmol), and 1-hydroxy-7-azabenzotriazine An azole (27.9 mg, 0.205 mmol) was added to this mixture, and the reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with water (5 mL) and extracted with EtOAc (3x). The extracts were dried (Na ₂ SO ₄₎ and concentrated. The resulting residue was purified by silica gel chromatography (0 to 100% (3: 1 EtOAc: EtOH) / heptane) to give the desired product (28 mg) as a pale yellow solid. LC-MS (ES) m / z = 448 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.21-1.31 (m, 3H), 1.35 (d, J = 6.6Hz, 3H), 2.40 (s, 3H), 2.99 (s, 3H), 3.39-3.55 (m, 1H), 3.81-3.88 (m, 1H), 3.97-4.09 (m, 2H), 4.11-4.19 (m, 1H), 5.52 (s, 2H), 7.57 (d, J = 2.0Hz, 1H ), 7.74 (s, 1H), 8.31 (d, J = 2.0Hz, 1H), 8.45 (d, J = 2.0Hz, 1H), 8.85 (d, J = 2.0Hz, 1H).

Intermediate 197

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3-((2-methyl Azole-4-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-carboxylic acid methyl ester

6-(((2-methyl Azole-4-yl) methyl) amino) -5-nitronicotinic acid methyl ester (150 mg, 0.513 mmol), 6-((2S, 5S) -2,5-dimethylpyrrolidin-1- Base) nicotinaldehyde (126 mg, 0.616 mmol), sodium bisulfite (268 mg, 85%, 1.308 mmol), ethanol (4 mL), and water (1 mL) were added to a 20-mL microwave tube, and the reaction mixture was microwaved Stir at 130 ° C for 80 minutes. The mixture was then cooled to room temperature, filtered, and concentrated. The residue was treated with water and extracted with CH ₂ Cl ₂ (3x). The organic extracts were dried (Na ₂ SO ₄₎ and concentrated. The resulting residue was purified by silica chromatography (0% to 100% EtOAc / heptane) to give the desired product (148 mg) as an off-white solid. LC-MS (ES) m / z = 447 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.16-1.27 (m, 6H), 1.76 (d, J = 5.6Hz, 2H), 2.33-2.42 (m, 5H), 4.00 (s, 3H), 4.33 (m, 2H), 5.33 (s, 2H), 6.72 (d, J = 8.9Hz, 1H), 7.72-7.81 (m, 1H), 8.11 (dd, J = 8.9,2.5Hz, 1H), 8.58 ( d, J = 2.0 Hz, 1H), 8.69 (d, J = 2.0 Hz, 1H), 9.01 (d, J = 1.8 Hz, 1H).

Example 141

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -N-methyl-3-((2-methyl Azole-4-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-carboxamide

Aqueous NaOH (5N, 0.26 mL, 1.30 mmol) was added to 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3- ( (2-methyl Azole-4-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-carboxylic acid methyl ester (70 mg, 0.157 mmol) in CH ₃ OH (1.5 mL) and the reaction mixture Stir at 40 ° C for 18 hours. The reaction mixture was neutralized by adding HCl (6N, 0.217 mL, 1.30 mmol) and concentrated. The resulting residue was dried under vacuum and treated with DMSO (1.50 mL). Methylamine hydrochloride (16.94 mg, 0.251 mmol), EDC (60.1 mg, 0.314 mmol), 1-hydroxy-7-azabenzotriazole (42.7 mg, 0.314 mmol), and N-methylmorphine Lin (0.103 mL, 0.941 mmol) was added to this mixture, and the reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with water (5 mL) and extracted with EtOAc (3x). The extracts were dried (Na ₂ SO ₄₎ and concentrated. The resulting residue was purified by silica gel chromatography (0 to 100% (3: 1 EtOAc: EtOH) / heptane) to give the desired product (49 mg) as an off-white solid. LC-MS (ES) m / z = 446 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.17-1.28 (m, 6H), 1.76 (d, J = 5.6Hz, 2H), 2.29-2.43 (m, 5H), 2.99 (s, 3H), 4.32 (br.s., 2H), 5.52 (m, 2H), 6.71 (d, J = 8.9Hz, 1H), 7.75 (s, 1H), 8.09 (dd, J = 8.9, 2.5Hz, 1H), 8.44 (d, J = 2.0Hz, 1H), 8.68 (d, J = 2.0Hz, 1H), 8.85 (d, J = 2.0Hz, 1H).

Intermediate 198

4-bromo-3-chloro-N-((2-methyl Azole-4-yl) methyl) -2-nitroaniline

Will (2-methyl Azole-4-yl) methylamine (405 mg, 3.62 mmol) and K ₂ CO ₃ (500 mg, 3.62 mmol) were added to 1-bromo-2-chloro-4-fluoro-3-nitrobenzene (920 mg, 3.62 mmol) at CHCl ₃ (10 mL) and the reaction mixture was stirred at room temperature for 16 hours. The mixture was quenched with 1M aq. HCl (10 mL) and then extracted with EtOAc (3x). The combined organic extracts were dried, filtered, and concentrated. The resulting residue was purified using silica gel chromatography with a gradient elution of 0 to 60% EtOAc in hexanes to provide 4-bromo-3-chloro-N-((2-methyl Azol-4-yl) methyl) -2-nitroaniline (852 mg, 2.458 mmol). LC-MS (ES) m / z = 346,348,350 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 7.53 (d, J = 9.1Hz, 1H), 7.45 (s, 1H), 6.71 (d, J = 9.1Hz, 1H), 5.75 (br.s., 1H ), 4.28 (d, J = 4.6 Hz, 2H), 2.46 (s, 3H).

Intermediate 199

4-((5-bromo-4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [ d) imidazol-1-yl) methyl) -2-methyl Azole

4-Bromo-3-chloro-N-((2-methyl Azole-4-yl) methyl) -2-nitroaniline (250mg, 0.721mmol), 6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (177mg, 0.866 mmol), sodium bisulfite (443 mg, 85%, 2.164 mmol), ethanol (8 mL), and water (2 mL) were combined in a microwave vial. The vial was sealed and the mixture was stirred at 130 ° C for 80 minutes under microwave conditions. The mixture was then cooled to room temperature, filtered, and concentrated. The resulting residue was treated with water and extracted with CH ₂ Cl ₂ (3x). The combined organic extracts were dried over Na ₂ SO ₄ and then concentrated. The resulting residue was purified using silica gel chromatography with a gradient of 0% to 100% EtOAc in heptane to provide 4-((5-bromo-4-chloro-2- (6-(( 2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-1-yl) methyl) -2-methyl Azole (0.340 g). LC-MS (ES) m / z = 500,502,504 [M + H] ⁺ .

Example 142

(4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((2-methyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-5-yl) boronic acid

4-((5-Bromo-4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo (d) Imidazol-1-yl) methyl) -2-methyl A solution of azole (340 mg, 0.679 mmol) and triisopropyl borate (0.188 mL, 0.815 mmol) in a mixture of THF (0.5 mL) and toluene (2 mL) was cooled to -78 ° C in a dry ice acetone bath. N-butyllithium (2.5M in hexane, 0.726 mL, 1.815 mmol) was added dropwise in 3 portions over 5 minutes, and the reaction mixture was stirred at -78 ° C for a total of 90 minutes. The reaction mixture was heated to -25 ° C, and then 2N aqueous HCl (5 mL) was added dropwise while maintaining the reaction temperature below -20 ° C. The mixture was then allowed to warm to room temperature and washed with EtOAc. Saturated aqueous NaHCO ₃ was added to the aqueous phase until the pH is between 7 and 8. The aqueous phase was extracted with EtOAc, and the combined organic extracts were washed with water, brine, dried over MgSO _4, filtered, and concentrated. The resulting residue was purified by silica gel chromatography with a gradient of 0% to 60% [3: 1 EtOAc / 1.5% ammonium hydroxide in EtOH] in hexane to provide a yellowish solid (4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((2-methyl Azol-4-yl) methyl) -1H-benzo [d] imidazol-5-yl) boronic acid (21.1 mg). LC-MS (ES) m / z = 466 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 8.65 (d, J = 2.3Hz, 1H), 8.06 (dd, J = 2.4, 9.0Hz, 1H), 7.81 (s, 1H), 7.48 (d, J = 7.9Hz, 1H), 7.20 (d, J = 7.9Hz, 1H), 6.69 (d, J = 9.1Hz, 1H), 5.33 (s, 2H), 4.31 (br.s., 2H), 2.40 ( s, 3H), 2.37-2.29 (m, 2H), 1.74 (d, J = 5.6 Hz, 2H), 1.21 (d, J = 6.1 Hz, 6H).

Intermediate 200

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [ d) Imidazole-5-carboxylic acid

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] A solution of methyl imidazole-5-carboxylate (800 mg, 1.893 mmol) in CH ₃ OH (8 mL) and THF (8.00 mL) was treated with 10 N sodium hydroxide (0.947 mL, 9.47 mmol) at 55 ° C overnight . The heat was removed and the solvent was evaporated in vacuo. The remaining white solid was dissolved in water (7 mL) and the pH was adjusted to ~ 4 with 6N HCl (1.325 mL, 7.95 mmol). The pH was returned to about 6-7 (paper) with 1N NaOH (0.568 mL, 0.568 mmol). The white solid was collected via filtration and dried under vacuum at 50 ° C to provide the desired product (416 mg) as a white powder. LC-MS (ES) m / z = 409 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 13.01 (br.s., 1H), 8.61 (d, J = 1.7 Hz, 1H), 8.25 (s, 1H), 8.08 (br.s., 1H ), 7.87-8.00 (m, 2H), 6.81 (br.s., 1H), 4.56 (t, J = 4.6Hz, 2H), 3.80 (d, J = 10.1Hz, 3H), 3.33 (d, J = 6.8Hz, 3H), 1.67-1.72 (m, 2H), 1.17 (d, J = 6.0Hz, 8H), 0.96 (t, J = 6.9Hz, 3H).

Example 143

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -N-((1r , 3S) -3-hydroxycyclobutyl) -1H-benzo [d] imidazole-5-carboxamide

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] A solution of imidazole-5-carboxylic acid (50.0 mg, 0.122 mmol), N-methylmorpholine (0.047 mL, 0.428 mmol), and HATU (55.8 mg, 0.147 mmol) in DMF (1.5 mL) Stir for 15 minutes at room temperature. (1r, 3r) -3-Aminocyclobut-1-ol hydrochloride (18.15 mg, 0.147 mmol) was then added, and the reaction mixture was stirred at room temperature overnight. The reaction was filtered and then (15 to 55% CH ₃ CN / (water (0.1% by reverse-phase HPLC - acid)) to afford the desired product as a white solid (20mg) .LC-MS (ES ) m / z = 478 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ CN): δ 8.56 (d, J = 2.0Hz, 1H), 8.15 (s, 1H), 8.13 (s, 1H), 7.94 ( dd, J = 2.4,9.0Hz, 1H), 7.79 (dd, J = 1.0,8.4Hz, 1H), 7.61 (d, J = 8.4Hz, 1H), 7.37 (d, J = 5.6Hz, 1H), 6.60 (d, J = 8.9Hz, 1H), 4.62-4.50 (m, 3H), 4.44 (t, J = 5.1Hz, 2H), 4.29 (br.s., 2H), 3.82 (t, J = 5.3 Hz, 2H), 3.37 (q, J = 6.9Hz, 2H), 2.45-2.21 (m, 6H), 1.77-1.62 (m, 2H), 1.20 (d, J = 6.1Hz, 6H), 1.02 (t , J = 7.0Hz, 3H).

Example 144

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -N-methoxy -1H-benzo [d] imidazole-5-carboxamide

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] A solution of imidazole-5-carboxylic acid (50.0 mg, 0.122 mmol), N-methylmorpholine (0.047 mL, 0.428 mmol), and HATU (55.8 mg, 0.147 mmol) in DMF (1.5 mL) Stir for 15 minutes at room temperature. O-methylhydroxylamine hydrochloride (10.22 mg, 0.122 mmol) was then added, and the reaction mixture was stirred at room temperature for 45 minutes. By reverse phase HPLC (15 to 55% CH ₃ CN / H ₂ O in the in 0.1% TFA) and the reaction to afford the desired product as a white solid (36.8mg). LC-MS (ES) m / z = 438 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 11.72 (s, 1H), 8.56 (d, J = 2.0Hz, 1H), 8.05 (s, 1H), 7.97 (dd, J = 2.5, 8.8Hz, 1H), 7.65-7.75 (m, 2H), 6.63 (d, J = 8.6Hz, 1H), 4.46 (t, J = 5.2Hz, 2H), 3.69-3.79 (m, 5H), 3.26-3.34 (m , 4H), 2.25 (m, 2H), 1.66 (m, 2H), 1.15 (d, J = 6.3Hz, 6H), 0.95 (t, J = 6.9Hz, 3H).

Example 145

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -N- (2- (Hydroxyethyl) -1H-benzo [d] imidazole-5-carboxamide

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] A solution of imidazole-5-carboxylic acid (50.0 mg, 0.122 mmol) in DMF (1.5 mL) was treated with N-methylmorpholine (0.047 mL, 0.428 mmol) and HATU (55.8 mg, 0.147 mmol), And the resulting mixture was stirred at room temperature for 15 minutes. Then 2-aminoethyl-1-ol (5.16 μl, 0.122 mmol) was added, and the reaction mixture was stirred at room temperature for 45 minutes. By reverse phase HPLC (15 to 55% CH ₃ CN / 0.1% of formic acid in water) to provide the desired product (48.2 mg) purified, as a white powder after freeze-drying. LC-MS (ES) m / z = 452 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 8.56 (d, J = 2.2Hz, 1H), 8.39-8.47 (m, 1H), 8.18 (s, 1H), 7.97 (dd, J = 2.2,8.8 Hz, 1H), 7.76-7.82 (m, J = 1.5Hz, 1H), 7.63-7.73 (m, 1H), 6.63 (d, J = 8.6Hz, 1H), 4.75 (t, J = 5.8Hz, 1H ), 4.46 (t, J = 5.5Hz, 2H), 3.76 (t, J = 5.3Hz, 2H), 3.54 (q, J = 6.0Hz, 2H), 3.35-3.43 (m, J = 6.0Hz, 2H ), 3.32 (s, 5H), 2.21-2.28 (m, 2H), 1.66 (d, J = 5.3Hz, 2H), 1.15 (d, J = 6.0Hz, 6H), 0.95 (t, J = 6.9Hz , 3H).

Example 146

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -N- (2- (Methanesulfonyl) ethyl) -1H-benzo [d] imidazole-5-carboxamide

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] A solution of imidazole-5-carboxylic acid (85 mg, 0.208 mmol), N-methylmorpholine (0.080 mL, 0.728 mmol), and HATU (95 mg, 0.250 mmol) in DMF (1.5 mL) at room temperature Stir for 15 minutes. Then 2- (methanesulfonyl) ethyl-1-amine hydrochloride (33.2 mg, 0.208 mmol) was added, and the reaction mixture was stirred at room temperature for 45 minutes. Additional portions of HATU, N-methylmorphine, and 2- (methanesulfonyl) ethyl-1-amine hydrochloride were added and the reaction continued to stir at room temperature for 3 days. The solvent was removed in vacuo and the remaining residue was purified (0.1% formic acid in water of 15-55% CH ₃ CN /) via a reverse phase HPLC. The desired portion was concentrated and dried under high vacuum, followed by lyophilization to provide the desired product (45.5 mg) as a white powder. LC-MS (ES) m / z = 514 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ): δ 8.72 (s, 1H), 8.56 (d, J = 2.2Hz, 1H), 8.16 (d, J = 1.2Hz, 1H), 7.97 (dd, J = 2.5, 8.8Hz, 1H), 7.76 (d, J = 1.7Hz, 1H), 7.66-7.74 (m, 1H), 6.56-6.68 (m, 1H), 4.46 (t, J = 5.2Hz, 2H), 3.67-3.81 (m, 4H), 3.42 (t, J = 6.8Hz, 2H), 3.26-3.33 (m, 4H), 3.06 (s, 3H), 2.25 (t, J = 7.8Hz, 2H), 1.66 (d, J = 5.5Hz, 2H), 1.15 (d, J = 6.3Hz, 6H), 0.95 (t, J = 6.9Hz, 3H).

Example 147

N-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H -Benzo [d] imidazol-5-yl) methyl) -2- (methylsulfonyl) ethylamine

BH ₃ ‧THF (0.192 mL, 0.192 mmol) was added dropwise to 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -N- (2- (methylsulfonyl) ethyl) -1H-benzo [d] imidazole-5-carboxamide (32.9 mg, 0.064 mmol) in THF (1.5 mL), and the reaction mixture was stirred at room temperature for 2 hours. The reaction was cooled to 8 ° C, quenched with 2.5N NaOH (0.102 mL, 0.256 mmol), and then stirred at 50 ° C for 1 hour. The reaction was concentrated and the remaining residue was partitioned between water (1 mL) and EtOAc (3 mL). The organic layer and the aqueous layer was extracted with EtOAc (2 x 2mL), and the combined dried over Na ₂ SO _4, filtered and concentrated. The remaining residue was purified by reverse-phase HPLC (5 to 70% CH ₃ CN / 0.1% NH ₄ OH in water) to provide the desired product (3 mg), which was lyophilized as a thin film on glass. LC-MS (ES) m / z = 500 [M + H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 8.56 (d, J = 2.2 Hz, 1 H), 7.99 (dd, J = 2.5, 8.8 Hz, 1 H), 7.6 (s, 1 H), 7.60 (d, J = 8.3Hz, 1H), 7.35 (dd, J = 1.52, 8.36Hz, 1H), 6.70 (d, J = 9.1Hz, 1H), 4.48 (t, J = 5.2Hz, 2H), 4.25-4.40 (m , 2H), 3.95 (s, 2H), 3.87 (t, J = 5.2Hz, 2H), 3.40 (q, J = 7.1Hz, 2H), 3.09-3.16 (m, 2H), 3.03 (s, 3H) , 2.31-2.40 (m, 2H), 1.76 (d, J = 5.5 Hz, 2H), 1.23 (d, J = 6.0 Hz, 6H), 1.07 (t, J = 6.9 Hz, 3H).

Intermediate 201

(2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo (d) Imidazol-5-yl) (morpholinyl) methanone

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] A solution of imidazole-5-carboxylic acid (85 mg, 0.208 mmol), N-methylmorpholine (0.080 mL, 0.728 mmol), and HATU (95 mg, 0.250 mmol) in DMF (1.5 mL) at room temperature Stir for 15 minutes. Morpholin (0.020 mL, 0.229 mmol) was then added, and the reaction mixture was stirred at room temperature for 1 hour. The DMF was removed in vacuo and the remaining residue was purified by reverse-phase HPLC (15 to 55% CH ₃ CN / 0.1% formic acid in water) to provide the desired product (65 mg), white after lyophilization powder. LC-MS (ES) m / z = 478 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 8.56 (d, J = 2.2Hz, 1H), 7.94-8.01 (m, J = 11.1Hz, 1H), 7.70 (d, J = 8.3Hz, 2H) , 7.30 (d, J = 9.6Hz, 1H), 6.63 (d, J = 8.8Hz, 1H), 4.45 (t, J = 5.3Hz, 2H), 3.77 (d, J = 10.3Hz, 2H), 3.43 -3.68 (m, 8H), 3.28-3.33 (m, 3H), 2.25 (t, J = 8.1Hz, 3H), 1.66 (d, J = 5.5Hz, 2H), 1.15 (d, J = 6.3Hz, 6H), 0.97 (t, J = 6.9Hz, 3H).

Example 148

4-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H -Benzo [d] imidazol-5-yl) methyl) morpholin

BH ₃ ‧THF (0.289 mL, 0.289 mmol) was added dropwise to (2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1 -(2-ethoxyethyl) -1H-benzo [d] imidazol-5-yl) (morpholinyl) methanone (46.0 mg, 0.096 mmol) in THF (1.5 mL), and The reaction mixture was stirred at room temperature overnight. The reaction was then cooled to 8 ° C (jacketed) and quenched with 2.5N NaOH (0.154 mL, 0.385 mmol). The reaction was heated to 50 ° C and stirred for 1 hour. The solvent was concentrated in vacuo and the remaining residue was partitioned between water (1 mL) and EtOAc (3 mL). The aqueous layer was extracted with EtOAc (2 x 2 mL), and the combined organic extracts were washed with brine. The product remained in the aqueous solution. All solvent was removed in vacuo and the remaining residue was dissolved in CH ₃ OH (3mL) and the solid was filtered off. Via reverse phase HPLC (5 to 35% CH ₃ CN / 0.1% NH ₄ OH in the water) of the purified solution to provide the desired product as a film on glass (4mg). LC-MS (ES) m / z = 464 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 8.56 (d, J = 2.2Hz, 1H), 7.99 (dd, J = 2.4, 9.0Hz, 1H), 7.66 (s, 1H), 7.59 (d, J = 8.3Hz, 1H), 7.35 (dd, J = 1.3, 8.2Hz, 1H), 6.70 (d, J = 9.1Hz, 1H), 4.48 (t, J = 5.2Hz, 2H), 4.33 (br.s ., 2H), 3.87 (t, J = 5.2Hz, 2H), 3.71-3.74 (m, 4H), 3.70 (s, 2H), 3.40 (q, J = 6.8Hz, 2H), 2.54 (br.s ., 4H), 2.32-2.40 (m, 2H), 1.76 (d, J = 5.83Hz, 2H), 1.23 (d, J = 6.3Hz, 6H), 1.07 (t, J = 6.9Hz, 3H)

Intermediate 202

7- (5-bromo-4-chloro-1- (2-ethoxyethyl) -1H-benzo [d] imidazol-2-yl) -4-ethyl-3,3-dimethyl- 3,4-dihydro-2H-pyrido [3,2-b] [1,4]

Add sodium bisulfite (234 mg, 85%, 1.142 mmol) to 4-bromo-3-chloro-N- (2-ethoxyethyl) -2-nitroaniline (145 mg, 0.448 mmol) and 4-ethyl -3,3-dimethyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] The 7-formaldehyde was in ethanol (4 mL), water (1 mL), and CH ₂ Cl ₂ (1 mL), and the reaction mixture was heated under microwave conditions at 130 ° C. for 80 minutes, and then for another 60 minutes. The solid was filtered off and the filtrate was concentrated in vacuo. The remaining residue was partitioned between _{CH 2 Cl 2 (2 x 10mL} ) and water (3mL). The combined organic extracts were washed with brine (3 mL), dried over Na ₂ SO _4, filtered, and concentrated. The resulting residue was purified by silica chromatography (0 to 100% EtOAc / hexanes) to provide the desired product (153 mg) as a pale yellow solid. LC-MS (ES) m / z = 493,495 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 8.19 (d, J = 2.0Hz, 1H), 7.61-7.68 (m, 1H), 7.53-7.60 (m, 1H), 7.48 (d, J = 2.0 Hz, 1H), 4.46 (t, J = 4.9 Hz, 2H), 3.94 (s, 2H), 3.74 (t, J = 5.1 Hz, 2H), 3.62 (q, J = 6.8 Hz, 2H), 3.27- 3.32 (m, J = 7.1 Hz, 2H), 1.30 (s, 6H), 1.21 (t, J = 7.0 Hz, 3H), 0.95 (t, J = 7.0 Hz, 3H).

Example 149

(4-chloro-1- (2-ethoxyethyl) -2- (4-ethyl-3,3-dimethyl-3,4-dihydro-2H-pyrido [3,2-b ] [1,4] -7-yl) -1H-benzo [d] imidazol-5-yl) boronic acid

Add n-butyllithium (0.146 mL, 0.364 mmol) dropwise to 7- (5-bromo-4-chloro-1- (2-ethoxyethyl) -1H-benzo [d] imidazol-2-yl ) -4-ethyl-3,3-dimethyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] (150 mg, 0.304 mmol) and triisopropyl borate (0.084 mL, 0.364 mmol) in toluene (8 mL) and THF (2.000 mL) were cooled to a solution of -69 ° C (internal) and the reaction mixture was stirred for 40 minutes. The reaction was then heated to -25 ° C (internal), quenched with 2N HCl (0.456 mL, 0.911 mmol), and then heated to room temperature. The mixture was partitioned between EtOAc (20mL) and water (2mL), and the pH of the aqueous layer was adjusted to 7 (paper) with saturated NaHCO ₃ (1.5mL). Water (2 mL) was then added, and the aqueous layer was extracted with EtOAc (20 mL). The combined organic extracts were washed with brine (2mL), dried over Na ₂ SO _4, filtered, and concentrated. The resulting residue was dried under high vacuum and purified by silica gel chromatography (30 to 100% (3: 1 EtOAc: EtOH) / hexane) to provide the desired product (25.5 mg), which was a white solid after freeze drying . LC-MS (ES) m / z = 459 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 8.14-8.22 (m, 2H), 7.57 (d, J = 8.1Hz, 1H), 7.48 (d, J = 1.7Hz, 1H), 7.30 (d, J = 8.1Hz, 1H), 4.44 (t, J = 4.8Hz, 2H), 3.94 (s, 2H), 3.74 (t, J = 5.0Hz, 2H), 3.62 (q, J = 6.9Hz, 2H) , 3.25-3.33 (m, 3H), 1.30 (s, 6H), 1.17-1.25 (m, 3H), 0.92-1.00 (m, 3H)

Intermediate 203

N- (2-ethoxyethyl) -2-nitroaniline

1-fluoro-2-nitrobenzene (1 g, 7.09 mmol), 2-ethoxyethyl-1-amine (0.735 mL, 7.09 mmol), K ₂ CO ₃ (0.979 g, 7.09 mmol), and CHCl ₃ ( 10 mL) was added to a 25 mL screw-cap vial, and the reaction mixture was stirred at 50 ° C overnight. The solution was diluted with EtOAc and 1N HCl, and the layers were separated. The aqueous layer was further extracted with EtOAc, and the combined organic layers were washed with brine, dried (MgSO _4), and concentrated to provide an orange oil under reduced pressure. The resulting residue was adsorbed on silica and purified by silica gel chromatography (0 to 50% EtOAc / hexane) to provide N- (2-ethoxyethyl) -2-nitroaniline (837 mg as an orange oil) ). LC-MS (ES) m / z = 211 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 1.27 (t, J = 7.0Hz, 3H), 3.50 (q, J = 5.3Hz, 2H), 3.60 (q, J = 6.8Hz, 2H), 3.69-3.80 (m, 2H), 6.66 (m, 1H), 6.88 (dd, J = 8.9,1.0Hz, 1H), 7.45 (m, 1H), 8.19 (dd, J = 8.6,1.5Hz, 1H).

Intermediate 204

N1- (2-ethoxyethyl) benzene-1,2-diamine

N- (2-ethoxyethyl) -2-nitroaniline (837 mg, 3.98 mmol) was dissolved in CH ₃ OH (100 mL) and hydrogenated by continuous flow through a 10% Pd / C column at 1 bar . The final solution was evaporated to give N1- (2-ethoxyethyl) benzene-1,2-diamine (698 mg) as a dark brown oil. LC-MS (ES) m / z = 181 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.19-1.25 (m, 3H), 3.24-3.29 (m, 2H), 3.56 (q, J = 7.0Hz, 2H), 3.64-3.70 (m, 2H) , 6.59-6.68 (m, 2H), 6.70-6.76 (m, 2H).

Example 150

5- (1- (2-ethoxyethyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridine-2-amine

Add potassium oxone (443 mg, 0.721 mmol) to N1- (2-ethoxyethyl) benzene-1,2-diamine (200 mg, 1.110 mmol) and 6- (diethylamino) Nicotinaldehyde (218 mg, 1.221 mmol) was dissolved in DMF (3 mL) and water (3 mL), and the reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with aqueous (5mL) ₄ Cl saturated NH, and (~ 8 mL) and the pH was adjusted to ~ 10 with NH ₄ OH. The resulting aqueous mixture was extracted with EtOAc (3 x 20mL), and the combined organic extracts were washed with water (2 x 10mL), brine (10 mL), dried (MgSO _4), filtered, and concentrated. The resulting residue was adsorbed on silica and purified by silica gel chromatography (0 to 50% (3: 1 EtOAc: ethanol) / hexane) to provide 5- (1- (2-ethoxyethyl)- 1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine (202 mg) was freeze-dried to an oily white solid. LC-MS (ES) m / z = 339 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.06 (t, J = 7.0Hz, 3H), 1.24 (t, J = 7.1Hz, 6H), 3.35-3.45 (m, 2H), 3.63 (q, J = 7.1Hz, 4H) 3.86 (t, J = 5.3Hz, 2H), 4.46 (t, J = 5.2Hz, 2H), 6.71-6.82 (m, 1H), 7.24-7.35 (m, 2H), 7.54- 7.77 (m, 2H), 7.98 (dd, J = 9.1, 2.5 Hz, 1H), 8.51-8.61 (m, 1H).

Intermediate 205

N- (2-ethoxyethyl) -2-methoxy-6-nitroaniline

References: Patent WO2012172043

Add 2-bromo-1-methoxy-3-nitrobenzene (1 g, 4.31 mmol), 2-ethoxyethyl-1-amine (2.233 mL, 21.55 mmol), and 1,4-bis Alkane (15 mL) was added to a 40 mL screw-cap vial, and the resulting solution was stirred at 100 ° C all weekend. The reaction mixture was evaporated, and the resulting residue was adsorbed on silica and purified by silica gel chromatography (0 to 50% EtOAc / hexane) to provide N- (2-ethoxyethyl)-as an orange oil 2-methoxy-6-nitroaniline (825 mg). LC-MS (ES) m / z = 241 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 1.25 (t, J = 7.1Hz, 3H), 3.55 (q, J = 6.9Hz, 2H), 3.58-3.63 (m, 2H), 3.74-3.80 (m, 2H), 3.88 (s, 3H), 6.69 (dd, J = 8.6, 7.9 Hz, 1H), 6.96 (dd, J = 7.9, 1.3 Hz, 1H), 7.74 (dd, J = 8.7, 1.4 Hz, 1H ).

Intermediate 206

N1- (2-ethoxyethyl) -6-methoxybenzene-1,2-diamine

N- (2-ethoxyethyl) -2-methoxy-6-nitroaniline (825 mg, 3.43 mmol) was dissolved in CH ₃ OH (100 mL) -0.034 mol / L by continuous at 1 bar Hydrogenation was passed through a 10% Pd / C column. The solution was evaporated to provide N1- (2-ethoxyethyl) -6-methoxybenzene-1,2-diamine (807 mg) as a dark amber oil. LC-MS (ES) m / z = 211 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.16-1.31 (m, 3H), 3.14 (t, J = 5.1Hz, 2H), 3.45-3.60 (m, 4H), 3.82 (s, 3H), 6.36 -6.49 (m, 2H), 6.86 (t, J = 8.1Hz, 1H).

Example 151

5- (1- (2-ethoxyethyl) -7-methoxy-1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridine-2-amine

Add potassium oxone (190 mg, 0.309 mmol) to N1- (2-ethoxyethyl) -6-methoxybenzene-1,2-diamine (100 mg, 0.476 mmol) and 6- A mixture of (diethylamino) nicotinaldehyde (93 mg, 0.523 mmol) in DMF (2 mL) and water (2 mL), and the reaction mixture was stirred for 1 hour. The reaction was quenched with saturated aqueous NH ₄ Cl (10mL) and by the addition of NH ₄ OH (~ 20mL) and the pH was adjusted to ~ 10. The resulting aqueous mixture was extracted with EtOAc (3 x 20mL), and the combined extracts were washed with water (2 x 10mL) followed by brine (10mL), dried (MgSO _4), and concentrated. The resulting residue was adsorbed on silica and purified by silica gel chromatography (0 to 50% (3: 1 EtOAc: ethanol) / hexane) to provide 5- (1- (2-ethoxyethyl)- 7-Methoxy-1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine (67.9 mg) was lyophilized to a gray solid. LC-MS (ES) m / z = 369 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.01 (t, J = 7.0Hz, 3H), 1.14-1.27 (m, 6H), 3.21-3.34 (m, 2H), 3.52-3.67 (m, 4H) , 3.78 (t, J = 5.3Hz, 2H), 3.90-4.00 (m, 3H), 4.52 (t, J = 5.3Hz, 2H), 6.71 (dd, J = 9.1, 0.8Hz, 1H), 6.81 ( dd, J = 8.1, 0.8Hz, 1H), 7.12-7.23 (m, 1H), 7.24-7.31 (m, 1H), 7.82-7.98 (m, 1H), 8.43-8.55 (m, 1H).

Example 152

N, N-diethyl-5- (1-((2-methyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-2-yl) pyridin-2-amine

NaH (60% dispersion in oil, 9.8 mg, 0.24 mmol) was added to 5- (1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridine at 0 ° C. A cold solution of -2-amine (50 mg, 0.19 mmol) in DMF (1.9 mL). After 5 minutes, 4- (bromomethyl) -2-methyl was added Azole (36 mg, 0.21 mmol), and the mixture was warmed to room temperature. After 15 minutes, the reaction was heated and stirred at 60 ° C for 4 hours. The reaction was quenched with saturated NH ₄ Cl (2mL) and diluted with aq quenched with EtOAc (20mL) and water (20mL). The phases were separated, and the aqueous layer was further extracted with EtOAc (2 x 10 mL). The combined organic extracts were washed with water (10mL) and brine (20 mL), dried over anhydrous Na ₂ SO _4, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (eluted with 10 to 70% EtOAc / hexanes) to provide the desired product (28 mg) as a transparent film. LC-MS (ES) m / z = 362 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.57 (d, J = 1.8Hz, 1H), 7.99 (dd, J = 9.0, 2.4Hz, 1H), 7.85 (s, 1H), 7.38-7.26 (m, 4H), 6.62 (d, J = 8.9Hz, 1H), 5.33 (s, 2H), 3.61 (q, J = 7.1Hz, 4H), 2.51 (s, 3H), 1.26 (t, J = 7.1Hz, 6H).

Example 153

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [ d) imidazol-5-amine

N- (2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H -A mixture of benzo [d] imidazol-5-yl) acetamide (230 mg, 0.546 mmol) and an aqueous HCl solution (1 N, 3 mL, 3.0 mmol) was stirred at 40 ° C for 2 hours. The mixture was concentrated and the residue was dried under vacuum to give the desired product (210 mg) (HCl salt) as a light brown solid. LC-MS (ES) m / z = 380 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.09-1.17 (m, 3H), 1.26-1.41 (m, 6H), 1.85-1.98 (m, 2H), 2.50 (br.s., 2H), 3.46 -3.58 (m, 2H), 4.00 (br.s., 2H), 4.53 (br.s., 2H), 4.75 (br.s., 2H), 7.45 (d, J = 8.1Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.81-7.91 (m, 1H), 8.17 (m, 1H), 8.34-8.47 (m, 1H), 8.77-8.90 (m, 1H).

Example 154

N- (2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H- Benzo [d] imidazol-5-yl) methanesulfonamide

Methanesulfonyl chloride (0.020 mL, 0.253 mmol) and N, N-diisopropylethylamine (0.074 mL, 0.422 mmol) were added to 2- (6-((2S, 5S) -2,5-dimethyl Pyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] imidazol-5-amine (80 mg, 0.211 mmol) in CH ₂ Cl ₂ (2 mL), and the reaction mixture was stirred under reflux for 2 hours. The mixture was concentrated, and the resulting residue was purified by silica chromatography (0 to 100% (3: 1 EtOAc: EtOH) / heptane) to give the desired product (36 mg) as an off-white solid. LC-MS (ES) m / z = 458 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.03-1.18 (m, 3H), 1.24-1.33 (m, 6H), 1.85 (d, J = 5.6Hz, 2H), 2.42 (br.s., 2H ), 3.05 (s, 3H), 3.45-3.52 (m, 2H), 3.99 (t, J = 4.9Hz, 2H), 4.34 (br.s., 1H), 4.51 (br.s., 1H), 4.62-4.73 (m, 2H), 7.04 (d, J = 9.1Hz, 1H), 7.46 (dd, J = 8.9, 2.0Hz, 1H), 7.76 (d, J = 1.8Hz, 1H), 7.89-7.96 (m, 1H), 8.22 (dd, J = 9.4, 2.5 Hz, 1H), 8.74 (d, J = 2.0 Hz, 1H).

Intermediate 207

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

(1-methyl-1H-pyrazol-3-yl) methylamine (281 mg, 2.53 mmol) and N, N-diisopropylethylamine (0.530 mL, 3.03 mmol) were added to 5-bromo-2- A solution of chloro-3-nitropyridine (600 mg, 2.53 mmol) in CH ₃ CN (12 mL), and the reaction mixture was stirred at room temperature for 20 hours. The mixture was concentrated, and the resulting residue was washed with water and dried under vacuum to give the desired product (750 mg) as a pale yellow solid. LC-MS (ES) m / z = 312,314 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 3.87 (s, 3H), 4.80 (d, J = 5.6Hz, 2H), 6.25 (d, J = 2.3Hz, 1H), 7.52 (d, J = 2.3 Hz, 1H), 8.51 (d, J = 2.3 Hz, 1H), 8.63 (d, J = 2.3 Hz, 1H).

Intermediate 208

6-bromo-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3-((1-methyl-1H-pyrazole -3-yl) methyl) -3H-imidazo [4,5-b] pyridine

5-Bromo-N-((1-methyl-1H-pyrazol-3-yl) methyl) -3-nitropyridin-2-amine (400 mg, 1.282 mmol), 6-((2S, 5S ) -2,5-Dimethylpyrrolidin-1-yl) nicotinaldehyde (314mg, 1.538mmol), sodium bisulfite (85%, 787mg, 3.84mmol), ethanol (6mL), and water (1.5mL ) To a 20-mL microwave tube. The tube was sealed and the reaction mixture was stirred at 130 ° C for 80 minutes under microwave conditions. The mixture was then cooled to room temperature, diluted with EtOAc, filtered, and concentrated. The resulting residue was washed with water and dried to give the desired product (380 mg) as an off-white solid. LC-MS (ES) m / z = 466,468 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.17-1.24 (m, 6H), 1.75 (d, J = 5.6Hz, 2H), 2.34 (br.s., 2H), 3.81-3.88 (m, 3H ), 4.31 (br.s., 2H), 5.58 (s, 2H), 6.15 (d, J = 2.3Hz, 1H), 6.68 (d, J = 8.6Hz, 1H), 7.53 (d, J = 2.3 Hz, 1H), 7.99 (dd, J = 9.0, 2.4 Hz, 1H), 8.20 (d, J = 2.0 Hz, 1H), 8.43 (d, J = 2.0 Hz, 1H), 8.54-8.62 (m, 1H ).

Example 155

4- (2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3-((1-methyl-1H-pyrazole- 3-yl) methyl) -3H-imidazo [4,5-b] pyridin-6-yl) morpholin

Morpholine (0.056 mL, 0.643 mmol), 2-dicyclohexylphosphino-2 ′-( N , N -dimethylamino) biphenyl (6.33 mg, 0.016 mmol), Pd ₂ (dba) ₃ ( 5.89 mg, 6.43 μmol), and sodium tert-butoxide (93 mg, 0.965 mmol) were added to 6-bromo-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl ) Pyridin-3-yl) -3-((1-methyl-1H-pyrazol-3-yl) methyl) -3H-imidazo [4,5-b] pyridine (150 mg, 0.322 mmol) at 2 -A solution in methyltetrahydrofuran (3 mL) and the resulting mixture was degassed by bubbling argon for 10 minutes. The reaction mixture was then stirred at 80 ° C for 2 hours. The reaction was cooled to room temperature, quenched with brine (10 mL), and extracted with EtOAc (2x). The combined organic extracts were dried and concentrated. The resulting residue was purified by silica gel column chromatography (0 to 100% (3: 1 EtOAc: EtOH) / heptane) to give the desired product (93 mg) as a white solid. LC-MS (ES) m / z = 473 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.17-1.24 (m, 6H), 1.75 (d, J = 5.8Hz, 2H), 2.28-2.39 (m, 2H), 3.19-3.26 (m, 4H) , 3.85 (s, 3H), 3.89-3.95 (m, 4H), 4.30 (br.s., 2H), 5.54 (s, 2H), 6.10 (d, J = 2.3Hz, 1H), 6.67 (d, J = 8.9Hz, 1H), 7.52 (d, J = 2.3Hz, 1H), 7.63 (d, J = 2.5Hz, 1H), 7.94 (dd, J = 8.9, 2.5Hz, 1H), 8.20 (d, J = 2.5Hz, 1H), 8.46-8.59 (m, 1H).

Intermediate 209

2- (4-ethyl-3-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] -7-yl) -3-((1-methyl-1H-pyrazol-3-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-carboxylic acid (R) -methyl ester

6-(((1-methyl-1H-pyrazol-3-yl) methyl) amino) -5-nitronicotinic acid methyl ester (110 mg, 0.378 mmol), (R) -4-ethyl Methyl-3-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] -7-Formaldehyde (86 mg, 0.415 mmol), sodium bisulfite (85%, 232 mg, 1.133 mmol), ethanol (2 mL), and water (0.5 mL) were added to a 20-mL microwave tube. The tube was sealed and the reaction mixture was stirred at 130 ° C for 80 minutes under microwave conditions. The mixture was then cooled to room temperature, filtered, and concentrated. The resulting residue was treated with water and extracted with CH ₂ Cl ₂ (3x). The combined organic extracts were dried (Na ₂ SO ₄₎ and concentrated. The resulting residue was purified by silica chromatography (0% to 100% EtOAc / heptane) to give the desired product (140 mg) as a pale yellow solid. LC-MS (ES) m / z = 448 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.20-1.29 (m, 3H), 1.30-1.37 (m, 3H), 3.45 (dq, J = 14.1, 7.0Hz, 1H), 3.80-3.88 (m, 4H), 3.96-4.06 (m, 5H), 4.10-4.17 (m, 1H), 5.62 (s, 2H) 6.16 (d, J = 2.3Hz, 1H), 7.47 (d, J = 2.0Hz, 1H) , 7.54 (d, J = 2.3Hz, 1H), 8.22 (d, J = 2.0Hz, 1H), 8.58 (d, J = 1.8Hz, 1H), 9.01 (d, J = 1.8Hz, 1H).

Example 156

(R) -2- (4-ethyl-3-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] -7-yl) -N-methyl-3-((1-methyl-1H-pyrazol-3-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-formamidine amine

Aqueous NaOH (5N, 0.36 mL, 1.800 mmol) was added to (R) -2- (4-ethyl-3-methyl-3,4-dihydro-2H-pyrido [3,2-b] [ 1,4] -7-yl) -3-((1-methyl-1H-pyrazol-3-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-carboxylic acid methyl ester (98 mg, 0.219 mmol) in CH ₃ OH (1.5 mL), and the reaction mixture was stirred at 40 ° C. for 18 hours. The reaction was neutralized by adding HCl (6N, 0.3 mL, 1.8 mmol) and concentrated. Methylamine hydrochloride (23.66 mg, 0.350 mmol), EDC (84 mg, 0.438 mmol), 1-hydroxy-7-azabenzotriazole (59.6 mg, 0.438 mmol), and N-methylmorphine (0.144 mL, 1.314 mmol) was added to the resulting residue in DMSO (1.5 mL), and the reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with water (5 mL) and extracted with EtOAc (3x). The combined organic extracts were dried (Na ₂ SO ₄₎ and concentrated. The resulting residue was purified by silica gel chromatography (0 to 100% (3: 1 EtOAc: EtOH) / heptane) to give the desired product (72 mg) as a pale yellow solid. LC-MS (ES) m / z = 447 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.20-1.28 (m, 3H), 1.33 (d, J = 6.6Hz, 3H), 2.99 (s, 3H), 3.45 (dq, J = 14.2, 7.0Hz , 1H), 3.79-3.89 (m, 4H), 3.95-4.05 (m, 2H), 4.09-4.18 (m, 1H), 5.62 (s, 2H), 6.15 (d, J = 2.3Hz, 1H), 7.46 (d, J = 2.3Hz, 1H), 7.53 (d, J = 2.3Hz, 1H), 8.21 (d, J = 2.0Hz, 1H), 8.45 (d, J = 2.0Hz, 1H), 8.86 ( d, J = 1.8Hz, 1H).

Intermediate 210

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((2-methyl Azole-4-yl) methyl) -1H-benzo [d] imidazole-5-carboxylic acid methyl ester

The 4-(((2-methyl Azole-4-yl) methyl) amino) -3-nitrobenzoate (300 mg, 1.030 mmol), 6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) Nicotinaldehyde (231 mg, 1.133 mmol), sodium bisulfite (85%, 633 mg, 3.09 mmol), ethanol (4 mL), and water (1 mL) were added to a 20-mL microwave tube, and the reaction mixture was placed under microwave conditions Stir at 130 ° C for 80 minutes. The mixture was then cooled to room temperature, diluted with EtOAc, and concentrated. The resulting residue was washed with water and dried under vacuum to give the desired product (350 mg) as an off-white solid. LC-MS (ES) m / z = 446 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.23 (d, J = 6.1Hz, 6H), 1.69-1.79 (m, 2H), 2.30-2.38 (m, 2H), 2.41 (s, 3H), 3.95 (s, 3H), 4.32 (br.s., 1H), 5.40 (s, 2H), 6.72 (d, J = 8.9Hz, 1H), 7.61 (d, J = 8.6Hz, 1H), 7.85 (s , 1H), 7.99 (dd, J = 8.6,1.5Hz, 1H), 8.07 (dd, J = 8.9,2.5Hz, 1H), 8.36 (d, J = 1.0Hz, 1H), 8.66 (d, J = 2.0Hz, 1H).

Example 157

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((2-methyl Azol-4-yl) methyl) -1H-benzo [d] imidazol-5-carboxamide

Aqueous NaOH (5N, 400 μl, 2.000 mmol) was added to 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-(( 2-methyl Azole-4-yl) methyl) -1H-benzo [d] imidazole-5-carboxylic acid methyl ester (100 mg, 0.224 mmol) in CH ₃ OH (2 mL), and the reaction mixture was stirred at 40 ° C. 18 hours. The reaction was neutralized by adding aqueous HCl (6N, 333 μl, 2.000 mmol) and concentrated. NH ₄ Cl (20.41 mg, 0.382 mmol), EDC (86 mg, 0.449 mmol), 1-hydroxy-7-azabenzotriazole (61.1 mg, 0.449 mmol), and N-methylmorpholine (148 μl (1.347 mmol) was added to the resulting residue in DMSO (2 mL), and the reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with water (5 mL) and extracted with EtOAc (3x). The combined organic extracts were dried (Na ₂ SO ₄₎ and concentrated. The resulting residue was purified by silica gel chromatography (0 to 100% (3: 1 EtOAc: EtOH) / heptane) to give the desired product (51 mg) as a light brown solid. LC-MS (ES) m / z = 431 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.18-1.29 (m, 6H), 1.72-1.81 (m, 2H), 2.29-2.39 (m, 2H), 2.42 (s, 3H), 2.68 (s, 3H), 4.33 (br.s., 2 H), 5.36-5.43 (m, 2H), 6.73 (d, J = 8.9Hz, 1H), 7.61 (d, J = 8.6Hz, 1H), 7.83-7.92 (m, 2H), 8.07 (dd, J = 9.0, 2.4 Hz, 1H), 8.21-8.27 (m, 1H), 8.66 (d, J = 2.3 Hz, 1H).

Example 158

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3-((2-methyl Azole-4-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-carboxamide

NaOH (5N, 260 μl, 1.30 mmol) was added to 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3-((2 -methyl Azole-4-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-carboxylic acid methyl ester (69 mg, 0.155 mmol) in CH ₃ OH (2 mL), and the reaction mixture was Stir at 40 ° C for 18 hours. The reaction was neutralized by adding aqueous HCl (6N, 217 μl, 1.300 mmol) and then concentrated. NH ₄ Cl (14.88 mg, 0.278 mmol), EDC (59.2 mg, 0.309 mmol), 1-hydroxy-7-azabenzotriazole (42.1 mg, 0.309 mmol), and N-methylmorpholine ( 102 μl, 0.927 mmol) was added to the obtained residue in DMSO (2 mL), and the reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with water (5 mL) and extracted with EtOAc (3x). The combined organic extracts were dried (Na ₂ SO ₄₎ and concentrated. The resulting residue was purified by silica gel chromatography (0 to 100% (3: 1 EtOAc: EtOH) / heptane) to give the desired product (48 mg) as a pale yellow solid. LC-MS (ES) m / z = 432 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.23 (d, J = 6.1Hz, 6H), 1.76 (d, J = 5.8Hz, 2 H), 2.29-2.44 (m, 5H), 2.68 (s, 2H), 4.25-4.45 (m, 2H), 5.49-5.57 (m, 2H), 6.72 (d, J = 9.1Hz, 1H), 7.75 (s, 1H), 8.10 (dd, J = 9.1, 2.5Hz , 1H), 8.52 (d, J = 2.0Hz, 1H), 8.69 (d, J = 1.8Hz, 1H), 8.91 (d, J = 2.0Hz, 1H).

Intermediate 211

N-methyl-6-(((1-methyl-1H-pyrazol-3-yl) methyl) amino) -5-nitronicotinamide

Aqueous NaOH (10N, 48.8 mL, 488 mmol) was added to 6-(((1-methyl-1H-pyrazol-3-yl) methyl) amino) -5-nitronicotinic acid methyl ester (7.1 g, 24.38mmol) solution in CH ₃ OH (350mL), the reaction mixture was stirred at room temperature overnight. The mixture was then concentrated, washed with water (100 mL) was diluted to remove most of the CH ₃ OH, and treated with aqueous HCl (6N, 81mL). The resulting precipitate was collected by filtration and dried under vacuum overnight to provide 6-(((1-methyl-1H-pyrazol-3-yl) methyl) amino) -5-nitrate as a pale yellow solid. Nicotinic acid (6.71 g). LC-MS (ES) m / z = 278 [M + H] ⁺ . Add HOBt (4.81 g, 31.4 mmol), EDC (6.02 g, 31.4 mmol), methylamine hydrochloride (1.958 g, 29.0 mmol), and N-methylmorpholine (21.26 mL, 193 mmol) to 6- (((1-methyl-1H-pyrazol-3-yl) methyl) amino) -5-nitronicotinic acid (6.7 g, 24.17 mmol) in DMSO (150 mL), and the mixture Stir overnight at room temperature. The reaction was quenched with water (200 mL). The resulting precipitate was collected by filtration and dried under vacuum to give N-methyl-6-(((1-methyl-1H-pyrazol-3-yl) methyl) amino) as a bright yellow solid. -5-nitronicotinamide (5.64 g). LC-MS (ES) m / z = 291 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 2.79 (d, J = 4.3Hz, 3H), 3.80 (s, 3H), 4.76 (d, J = 5.6Hz, 2H), 6.17 (d, J = 2.0Hz, 1H), 7.61 (d, J = 2.0Hz, 1H), 8.60 (d, J = 4.6Hz, 1H), 8.88 (d, J = 2.3Hz, 1H), 8.91 (d, J = 2.0Hz , 1H), 9.03 (t, J = 5.3Hz, 1H).

Example 159

2- (4-ethyl-3,3-dimethyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] -7-yl) -N-methyl-3-((1-methyl-1H-pyrazol-3-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-formamidine amine

N-methyl-6-(((1-methyl-1H-pyrazol-3-yl) methyl) amino) -5-nitronicotinamide (80 mg, 0.276 mmol), 4-ethyl -3,3-dimethyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] -7-Formaldehyde (60.7mg, 0.276mmol), sodium bisulfite (85%, 169mg, 0.827mmol), ethanol (2mL), and water (0.5mL) were added to a 10-mL microwave tube, and the reaction mixture was Stir at 130 ° C for 80 minutes under microwave conditions. The mixture was then cooled to room temperature, diluted with EtOAc, filtered, and concentrated. The resulting residue was washed with water and dried under vacuum to give the desired product (98 mg) as a light brown solid. LC-MS (ES) m / z = 461 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.25-1.31 (m, 3H), 1.33-1.40 (m, 6H), 3.00 (s, 3H), 3.62-3.76 (m, 2H), 3.84 (s, 3H), 3.90-3.96 (m, 2H), 5.63 (s, 2H), 6.14 (d, J = 2.3Hz, 1H), 7.45 (d, J = 2.0Hz, 1H), 7.54 (d, J = 2.3 Hz, 1H), 8.23 (d, J = 2.0 Hz, 1H), 8.45 (d, J = 1.8 Hz, 1H), 8.86 (d, J = 2.3 Hz, 1H).

Intermediate 212

4-bromo-3-chloro-N-((1-methyl-1H-pyrazol-3-yl) methyl) -2-nitroaniline

1-bromo-2-chloro-4-fluoro-3-nitrobenzene (2621 mg, 10.30 mmol), (1-methyl-1H-pyrazol-3-yl) methylamine (954 mg, 8.58 mmol), and K _{A solution of 2} CO ₃ (3559 mg, 25.8 mmol) in CH ₃ CN (20 mL) was stirred at 70 ° C. for 30 hours. The reaction mixture was filtered, and the filtrate was concentrated. By silica gel chromatography (0 to _{20% EtOAc / CH 2 Cl 2} ) The resulting residue was purified to yield the desired product as a light yellow solids (891mg). LC-MS (ES) m / z = 345,347 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 1.80 (s, 1H). 3.92 (s, 3H), 4.41 (s, 2H), 5.87 (s, 1H), 6.19 (d, J = 2.0Hz, 1H), 6.77 (d, J = 9.2Hz, 1H), 7.34 (d, J = 2.0Hz, 1H), 7.53 (d, J = 9.2Hz, 1H).

Intermediate 213

4-bromo-3-chloro-N1-((1-methyl-1H-pyrazol-3-yl) methyl) benzene-1,2-diamine

4-Bromo-3-chloro-N-((1-methyl-1H-pyrazol-3-yl) methyl) -2-nitroaniline (891 mg, 2.58 mmol) and tin (II) chloride dihydrate A solution of the compound (1164 mg, 5.16 mmol) in ethanol (20 mL) was stirred at 80 ° C for 2 hours. The mixture was concentrated in vacuo, and the resulting residue was treated with saturated NaHCO ₃ solution (20mL) and extracted with EtOAc (2 x 30mL). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated. By silica gel chromatography (0 to _{20% EtOAc / CH 2 Cl 2} ) The resulting residue was purified to yield the desired product as a light yellow solids (640mg). LC-MS (ES) m / z = 315,317 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 3.41 (m, 3H), 3.88 (s, 3H), 4.30 (s, 2H), 6.20 (s, 1H), 6.55 (d, J = 8.6Hz, 1H) , 7.01 (d, J = 8.6 Hz, 1H), 7.31 (s, 1H).

Intermediate 214

7- (5-bromo-4-chloro-1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazol-2-yl) -4-ethyl -3,3-dimethyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4]

4-ethyl-3,3-dimethyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] -7-formaldehyde (370mg, 1.679mmol) and 4-bromo-3-chloro-N1-((1-methyl-1H-pyrazol-3-yl) methyl) benzene-1,2-diamine (530mg , 1.679 mmol) in acetic acid (20 mL) was stirred at 80 ° C. for 16 hours. The mixture was concentrated in vacuo, and the residue was poured into water (50mL), the solution was basified using NaHCO ₃ to pH 9, and extracted with _{CH 2 Cl 2 (2 x 50mL} ). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated. By silica gel chromatography (0 to _{5% EtOAc / CH 2 Cl 2} ) The resulting residue was purified form to produce the desired product as a white solid (452mg). LC-MS (ES) m / z = 515,517 [M + H] ⁺ . 1H NMR (400MHz, CDCl ₃ ): δ 1.26 (d, J = 6.9Hz, 3H), 1.33 (s, 6H), 3.63 (d, J = 6.7Hz, 2H), 3.86 (s, 2H), 3.89 ( s, 3H), 5.41 (d, J = 6.8 Hz, 2H), 5.93 (s, 1H), 7.14 (d, J = 8.5 Hz, 1H), 7.27 (s, 1H), 7.41 (d, J = 8.6 Hz, 1H), 7.45 (s, 1H), 8.20 (s, 1H).

Example 160

(4-chloro-2- (4-ethyl-3,3-dimethyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] -7-yl) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazol-5-yl) boronic acid

Add n-butyllithium (0.244 mL, 0.586 mmol) to 7- (5-bromo-4-chloro-1-((1-methyl-1H-pyrazol-3-yl) at -78 ° C under N ₂ ) Methyl) -1H-benzo [d] imidazol-2-yl) -4-ethyl-3,3-dimethyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] (252 mg, 0.489 mmol) and a solution of triisopropyl borate (276 mg, 1.466 mmol) in THF (5 mL) and toluene (1.25 mL), and the resulting mixture was stirred at -78 ° C for 1 hour. The reaction was then warmed to room temperature and stirred overnight. The reaction mixture was quenched with NH ₄ Cl and the aqueous solution (4mL) and concentrated in vacuo. The resulting residue was poured into water (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated. By silica gel chromatography (0 to _{5% CH 3 OH / CH 2} Cl 2) The residue was purified to yield the desired product as a yellow solid (55mg). LC-MS (ES) m / z = 481 [M + H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ): δ 1.26 (s, 3H), 1.32 (s, 6H), 3.63 (dd, J = 13.9, 6.9Hz, 2H), 3.86 (s, 2H), 3.88 (s, 3H ), 5.41 (s, 2H), 5.90 (d, J = 2.0Hz, 1H), 7.25 (s, 1H), 7.29 (d, J = 12.2Hz, 1H), 7.44 (d, J = 1.8Hz, 1H ), 7.71 (d, J = 8.2Hz, 1H), 8.19 (d, J = 1.7Hz, 1H).

Intermediate 215

4-bromo-3-chloro-N-((2-ethyl Azole-4-yl) methyl) -2-nitroaniline

Add 1-bromo-2-chloro-4-fluoro-3-nitrobenzene (1.5g, 5.90mmol), (2-ethyl A mixture of azole-4-yl) methylamine hydrochloride (0.959 g, 5.90 mmol) and K ₂ CO ₃ (2.444 g, 17.69 mmol) in CH ₃ CN (30 mL) was stirred at 70 ° C. for 5 hours. The reaction mixture was filtered, and the filtrate was concentrated. By silica gel chromatography (0 to _{3% CH 3 OH / CH 2} Cl 2) The resulting residue was purified to yield the desired product as a yellow solid (1.0g). LC-MS (ES) m / z = 360,362 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 1.34 (t, J = 7.6Hz, 3H), 2.78 (q, J = 7.6Hz, 2H), 4.29 (d, J = 4.5Hz, 2H), 5.71 (s , 1H), 6.70 (d, J = 9.2Hz, 1H), 7.44 (s, 1H), 7.52 (d, J = 9.2Hz, 1H).

Intermediate 216

4-bromo-3-chloro-N1-((2-ethyl Azole-4-yl) methyl) benzene-1,2-diamine

Add zinc (453mg, 6.93mmol) to 4-bromo-3-chloro-N-((2-ethyl A stirred solution of azole-4-yl) methyl) -2-nitroaniline (500 mg, 1.387 mmol) and ammonium chloride (742 mg, 13.87 mmol) in THF (10 mL) and water (5 mL), and the resulting mixture was dried in Stir at room temperature for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was poured into water (100 mL), the aqueous was basified using NaHCO ₃ to pH 9, and extracted with EtOAc (2 x 100mL). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated. By silica gel chromatography _{(0-5% CH 3 OH / CH} 2 Cl 2) The resulting residue was purified form to produce the desired product as a brown oil (360mg). LC-MS (ES) m / z = 330,332 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 1.34 (t, J = 7.6Hz, 3H), 2.78 (m, 2H), 4.18 (s, 2H), 6.50 (d, J = 8.6Hz, 1H), 7.01 (d, J = 8.5Hz, 1H), 7.45 (d, J = 5.5Hz, 1H).

Intermediate 217

4-((5-bromo-4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [ d) imidazol-1-yl) methyl) -2-ethyl Azole

4-Bromo-3-chloro-N1-((2-ethyl Azole-4-yl) methyl) benzene-1,2-diamine (360mg, 1.089mmol) and 6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde A mixture of (222 mg, 1.089 mmol) in ethanol (15 mL) and acetic acid (0.5 mL) was stirred at 80 ° C for 12 hours. The mixture was concentrated in vacuo, and the resulting residue was poured into water (50mL), the solution was basified using NaHCO ₃ to pH 9, and extracted with _{CH 2 Cl 2 (2 x 50mL} ). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated. By silica gel chromatography _{(0-5% CH 3 OH / CH} 2 Cl 2) The resulting residue was purified form to produce the desired product as a brown oil (390mg). LC-MS (ES) m / z = 514,516 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 1.26-1.12 (m, 6H), 1.34 (t, J = 7.6Hz, 3H), 1.71 (d, J = 5.3Hz, 2H), 2.29 (s, 2H) , 2.79 (q, J = 7.6Hz, 2H), 4.14 (d, J = 7.1Hz, 2H), 5.27 (s, 1H), 6.51 (s, 1H), 7.18 (s, 1H), 7.45 (d, J = 8.6Hz, 1H), 7.97 (s, 1H), 8.55 (s, 1H).

Example 161

(4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((2-ethyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-5-yl) boronic acid

Add n-butyllithium (0.379 mL, 0.909 mmol) to 4-((5-bromo-4-chloro-2- (6-((2S, 5S) -2,5 -Dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-1-yl) methyl) -2-ethyl A stirred solution of azole (390 mg, 0.758 mmol) and triisopropyl borate (0.528 mL, 2.273 mmol) in toluene (8 mL) and THF (2 mL), and the reaction mixture was stirred at -78 ° C for 1 hour. Triisopropyl borate (0.528 mL, 2.273 mmol) and THF (4 mL) were added followed by n-butyllithium (0.379 mL, 0.909 mmol), and the resulting mixture was warmed to room temperature and stirred overnight. The reaction was quenched and the mixture was concentrated under vacuum ₄ Cl aq NH (2mL). The residue was poured into water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated. By silica gel chromatography _{(0-5% CH 3 OH / CH} 2 Cl 2) The resulting residue was purified form to produce the desired product as a white solid (65mg). LC-MS (ES) m / z = 480,481,482 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.23 (d, J = 6.2Hz, 6H), 1.29 (t, J = 7.6Hz, 3H), 1.80-1.70 (m, 2H), 2.42-2.29 (m , 2H), 2.77 (q, J = 7.6Hz, 2H), 4.33 (s, 2H), 5.36 (s, 2H), 6.72 (d, J = 9.0Hz, 1H), 7.22 (d, J = 8.1Hz , 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.81 (s, 1H), 8.07 (dd, J = 8.9, 2.3 Hz, 1H), 8.64 (d, J = 2.2 Hz, 1H).

Intermediate 218

1,3-difluoro-4-iodo-2-nitrobenzene

N-iodobutanediamine (7.07 g, 31.4 mmol) was added to 1,3-difluoro-2-nitrobenzene (5.0 g, 31.4 mmol) in trifluoroacetic acid (TFA) (20.0 mL) and concentrated sulfuric acid (10 mL), and the reaction mixture was heated at 60 ° C for 45 minutes. The reaction was cooled to room temperature and poured into ice. The resulting mixture was extracted with EtOAc, and the combined organic extracts were washed with water and then washed with saturated NaHCO ₃ solution, dried with MgSO _4, filtered, and concentrated to provide 1,3-difluoro-2-nitrophenyl of benzene as a white solid (5.0 g). GC-MS (CI) m / z = 286 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.97 (ddd, J = 5.7, 6.6, 9.0 Hz, 1H), 6.90-7.08 (m, J = 1.8, 9.0, 9.0 Hz, 1H).

Intermediate 219

3-fluoro-4-iodo-N-((1-methyl-1H-pyrazol-3-yl) methyl) -2-nitroaniline

A solution of 1,3-difluoro-4-iodo-2-nitrobenzene (1.0 g, 3.51 mmol) and triethylamine (0.538 mL, 3.86 mmol) in DMF (25 mL) was heated at 75 ° C. A solution of 1-methyl-1H-pyrazol-3-yl) methylamine (410 mg, 3.68 mmol) in DMF (3 mL) was then added dropwise, and the reaction mixture was stirred at 75 ° C for 2 hours. The reaction was cooled, then concentrated, and treated with ₂ CH ₂ Cl. The resulting organic mixture was washed with water then brine, dried over MgSO _4, filtered, and concentrated. Purification by flash chromatography on SiO ₂ (0% to 60% EtOAc / hexane) provided 3-fluoro-4-iodo-N-((1-methyl-1H-pyrazole- 3-yl) methyl) -2-nitroaniline (697 mg). LC-MS (ES) m / z = 377 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.61 (dd, J = 6.3, 9.4 Hz, 1 H), 7.54 (br.s., 1 H), 7.35 (d, J = 2.3 Hz, 1 H), 6.60 (dd , J = 1.5, 9.4 Hz, 1H), 6.21 (d, J = 2.3 Hz, 1H), 4.47 (d, J = 5.1 Hz, 2H), 3.93 (s, 3H).

Intermediate 220

3-fluoro-4-iodo-N1-((1-methyl-1H-pyrazol-3-yl) methyl) benzene-1,2-diamine

Add 3-fluoro-4-iodo-N-((1-methyl-1H-pyrazol-3-yl) methyl) -2-nitroaniline (200 mg, 0.532 mmol) and sodium bisulfite (278 mg, 85 %, 1.356 mmol) in ethanol (4 mL) and water (2 mL) was heated at 130 ° C for 10 minutes under microwave conditions. The reaction was then filtered and concentrated to dryness. Water was added, and the resulting aqueous mixture was extracted with CH ₂ Cl ₂ . The organic extracts were washed with water, dried with MgSO _4, filtered, and concentrated. Purification by flash chromatography on SiO ₂ (0% to 100% EtOAc / hexane) provided 3-fluoro-4-iodo-N1-((1-methyl-1H-pyrazol-3-yl) (Methyl) benzene-1,2-diamine (98 mg). LC-MS (ES) m / z = 347 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 7.35 (d, J = 2.3Hz, 1H), 7.12 (dd, J = 6.8, 8.6Hz, 1H), 6.40 (dd, J = 1.1, 8.5Hz, 1H) , 6.24 (d, J = 2.3Hz, 1H), 4.35 (s, 2H), 3.93 (s, 3H).

Intermediate 221

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-5-iodo-1-((1-methyl- 1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole

Add 3-fluoro-4-iodo-N1-((1-methyl-1H-pyrazol-3-yl) methyl) benzene-1,2-diamine (98 mg, 0.226 mmol), 6-((2S , 5S) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (46.3 mg, 0.226 mmol), and potassium oxone (91 mg, 0.147 mmol) in DMF (10 mL) and water The mixture in (4 mL) was stirred at room temperature for 16 hours. Then a saturated aqueous NaHCO ₃ solution was added, and the resulting mixture was extracted with CH ₂ Cl ₂ . The combined organic extracts were washed with water then brine, dried over MgSO _4, filtered, and concentrated. Purification by flash chromatography on SiO ₂ (0% to 70% (3: 1 EtOAc: EtOH): heptane) provided 2- (6-((2S, 5S) -2,5 as a brown solid -Dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-5-iodo-1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H- Benzo [d] imidazole (108 mg). LC-MS (ES) m / z = 531 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.59 (br.s., 1H), 7.95 (d, J = 7.9 Hz, 1 H), 7.48 (dd, J = 5.6, 8.4 Hz, 1 H), 7.30 (d , J = 2.3Hz, 1H), 6.96 (d, J = 8.4Hz, 1H), 6.50 (d, J = 7.9Hz, 1H), 5.96 (br.s., 1H), 5.41 (s, 2H), 4.3 (br.s, 2H), 3.91 (s, 3H), 2.30 (br.s., 2H), 1.72 (d, J = 5.6Hz, 2H), 1.22 (d, J = 6.3Hz, 6H).

Intermediate 222

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-1-((1-methyl-1H-pyrazole -3-yl) methyl) -1H-benzo [d] imidazole-5-carboxylic acid

Argon 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-5-iodo-1-((1 -Methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole (110 mg, 0.207 mmol), potassium 2-ethoxy-2-lanthoxyacetate (48.6 mg, 0.311 mmol ), 1,3-bis (diphenylphosphino) propane (25.7 mg, 0.062 mmol), and palladium (II) trifluoroacetate (13.79 mg, 0.041 mmol) in N-methyl-2-pyrrolidone (NMP ) (4 mL) for 10 minutes. The reaction vial was then capped and the reaction mixture was stirred at 150 ° C for 60 minutes. The reaction was filtered and purified via reverse-phase HPLC (10 to 100% CH ₃ CN / 0.1% NH ₄ OH in H ₂ O) to provide 2- (6-((2S, 5S) -2, 5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [ d] Imidazole-5-carboxylic acid (24 mg). LC-MS (ES) m / z = 449 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.65 (d, J = 2.3Hz, 1H), 8.01 (dd, J = 2.3, 9.1Hz, 1H), 7.90 (dd, J = 6.3, 8.4Hz, 1H) , 7.33 (d, J = 2.0Hz, 1H), 7.21 (d, J = 8.9Hz, 1H), 6.54 (d, J = 8.9Hz, 1H), 6.02 (d, J = 2.3Hz, 1H), 5.48 (s, 2H), 4.3 (br.s., 2H), 3.93 (s, 3H), 2.31 (br.s., 2H), 1.73 (d, J = 5.6Hz, 2H), 1.24 (d, J = 6.34Hz, 6H).

Example 162

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-N-methyl-1-((1-methyl -1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-1-((1-methyl-1H-pyridine Azole-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxylic acid (46 mg, 0.103 mmol), EDC (39.3 mg, 0.205 mmol), 1-hydroxy-7-azabenzotriazole (27.9 mg, 0.205 mmol), methylamine hydrochloride (7.96 mg, 0.118 mmol) and N-methylmorpholine (67.7 μl, 0.615 mmol) in DMSO (20 mL) were stirred at room temperature for 16 hours . Water was added and the resulting mixture was extracted with EtOAc. The combined organic extracts were washed with water then brine, dried over MgSO _4, filtered, and concentrated. Purification by flash chromatography on SiO ₂ (0% to 15% CH ₃ OH / CH ₂ Cl ₂ ) provided 2- (6-((2S, 5S) -2,5-dimethyl) as a brown solid. Pyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-N-methyl-1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] Imidazole-5-carboxamide (43 mg). LC-MS (ES) m / z = 462 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.61 (br.s., 1H), 7.90-8.13 (m, 2H), 7.30 (d, J = 2.0Hz, 1H), 7.21 (d, J = 8.6Hz , 1H), 6.88 (dd, J = 4.7, 12.8Hz, 1H), 6.50 (d, J = 8.9Hz, 1H), 5.98 (d, J = 1.8Hz, 1H), 5.42 (s, 2H), 4.27 (br.s., 2H), 3.91 (s, 3H), 3.09 (d, J = 4.1Hz, 3H), 2.19-2.39 (m, 2H), 1.71 (d, J = 5.6Hz, 2H), 1.21 (d, J = 6.3Hz, 6H).

Example 163

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-1-((1-methyl-1H-pyrazole -3-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-1-((1-methyl-1H-pyridine Azole-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxylic acid (30 mg, 0.067 mmol), EDC (25.6 mg, 0.134 mmol), 1-hydroxy-7-azabenzotriazole (18.21 mg, 0.134 mmol), N-methylmorphine (44.1 μl, 0.401 mmol), and a solution of NH ₄ Cl (3.58 mg, 0.067 mmol) in DMSO (20 mL) were stirred at room temperature for 16 hours. Water was then added and the resulting mixture was extracted with EtOAc. The combined organic extracts were washed with water then brine, dried over MgSO _4, filtered, and concentrated. Purification of SiO ₂ by flash chromatography (0% to 15% CH ₃ OH / CH ₂ Cl ₂ ) provides 2- (6-((2S, 5S) -2,5-dimethylpyrrolidine- 1-yl) pyridin-3-yl) -4-fluoro-1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxamidine Amine (19 mg), lyophilized as a white solid. LC-MS (ES) m / z = 448 [M + H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 8.56 (d, J = 2.0 Hz, 1 H), 7.97 (dd, J = 2.4, 9.0 Hz, 1 H), 7.74 (dd, J = 6.5, 8.6 Hz, 1 H ), 7.56 (d, J = 2.3Hz, 1H), 7.38 (d, J = 8.4Hz, 1H), 6.69 (d, J = 9.1Hz, 1H), 6.16 (d, J = 2.3Hz, 1H), 5.49 (s, 2H), 4.3 (br.s, 2H), 3.86 (s, 3H), 2.27-2.45 (m, 2H), 1.75 (d, J = 5.8Hz, 2H), 1.22 (d, J = 6.1Hz, 6H).

Intermediate 223

4- (azidomethyl) -N, N, 2-trimethyl-1H-imidazole-1-sulfonamide

DBU (2.67 mL, 17.73 mmol) was added dropwise to 4- (hydroxymethyl) -N, N, 2-trimethyl-1H-imidazole-1-sulfonamide (3.24 g, 14.78) cooled in an ice-water bath mmol) and a solution of diphenylphosphonium azide (4.88 g, 17.73 mmol) in THF, and the reaction mixture was stirred at room temperature for 16 hours. Water was then added, and the mixture was acidified to pH ~ 6 and then extracted with EtOAc. The combined organic extracts were washed with water then brine, dried over MgSO _4, filtered, and concentrated. Purification by flash chromatography on SiO ₂ (0% to 60% (3: 1 EtOAc: EtOH) / heptane) provided 4- (azidomethyl) -N, N, 2 as a clear oil -Trimethyl-1H-imidazole-1-sulfonamide (2.79 g). LC-MS (ES) m / z = 245 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.96 (s, 1H), 4.53 (s, 2H), 2.99 (s, 6H), 2,64 (s, 3H).

Intermediate 224

((1- (N, N-dimethylaminosulfonyl) -2-methyl-1H-imidazol-4-yl) methyl) carbamic acid tert-butyl ester

4- (Azidomethyl) -N, N, 2-trimethyl-1H-imidazole-1-sulfonamide (3.24 g, 13.26 mmol), di-tertiary butyl dicarbonate) (6.16 mL , 26.5 mmol), and a mixture of 10% palladium on carbon (30 mg, 0.282 mmol) in CH ₃ OH was exposed to a hydrogen atmosphere via a vial hydrogenation for 16 hours. The reaction was filtered and concentrated. Purification by flash chromatography on SiO ₂ (0% to 100% (3: 1 EtOAc: EtOH) / heptane) provided ((1- (N, N-dimethylaminesulfonate) as a white solid Propyl) -2-methyl-1H-imidazol-4-yl) methyl) carbamic acid tert-butyl ester (2.95 g). LC-MS (ES) m / z = 319 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 6.89 (s, 1H), 5.23 (br.s., 1H), 4.41 (d, J = 6.1Hz, 2H), 2.96 (s, 6H), 2.63 (s 3H), 1.46 (s, 9H).

Intermediate 225

4- (aminemethyl) -N, N, 2-trimethyl-1H-imidazole-1-sulfonamide

((1- (N, N-dimethylaminosulfonyl) -2-methyl-1H-imidazol-4-yl) methyl) carbamic acid tert-butyl ester (1.5 g, 4.71 mmol) in 1 The solution in 1,1,3,3,3-hexafluoro-2-propanol (15 mL) was heated at 120 ° C for 150 minutes under microwave conditions. The reaction was concentrated to dryness to provide crude 4- (aminemethyl) -N, N, 2-trimethyl-1H-imidazole-1-sulfonamide (1.64 g) as an oil, which was used as such in the next step . LC-MS (ES) m / z = 219 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.80 (s, 1H), 3.91 (s, 2H), 2.95 (s, 6H), 2.62 (s, 3H).

Intermediate 226

N, N, 2-trimethyl-4-(((3-nitropyridin-2-yl) amino) methyl) -1H-imidazole-1-sulfonamide

Add 2-chloro-3-nitropyridine (100 mg, 0.631 mmol), 4- (aminemethyl) -N, N, 2-trimethyl-1H-imidazole-1-sulfonamide (236 mg, 0.757 mmol) And a solution of N, N-diisopropylethylamine (0.165 mL, 0.946 mmol) in DMSO (30 mL) was heated at 85 ° C for 16 hours. The reaction was poured into water and extracted with EtOAc. The organic extracts were washed with water, followed by brine, dried over MgSO _4, filtered, and concentrated. Purification by flash chromatography on SiO ₂ (0% to 70% (3: 1 EtOAc: EtOH) / heptane) provided N, N, 2-trimethyl-4-(((( 3-nitropyridin-2-yl) amino) methyl) -1H-imidazole-1-sulfosulfanilamide (188 mg). LC-MS (ES) m / z = 341 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.65 (t, J = 5.5Hz, 1H), 8.34-8.48 (m, 2H), 6.88 (s, 1H), 6.60-6.73 (m, 1H), 4.96 ( d, J = 6.1Hz, 2H), 2.95 (s, 6H), 2.56 (s, 3H).

Example 164

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3-((2-methyl-1H-imidazol-4-yl) (Methyl) -3H-imidazo [4,5-b] pyridine

Add N, N, 2-trimethyl-4-(((3-nitropyridin-2-yl) amino) methyl) -1H-imidazole-1-sulfonamide (188 mg, 0.552 mmol), 6 -((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (124 mg, 0.608 mmol), and sodium bisulfite (289 mg, 85%, 1.41 mmol) in ethanol (4 mL ) And water (2 mL) were heated under microwave conditions at 130 ° C for 4 hours. The reaction was concentrated. Followed by addition of CH ₂ Cl _2, and the resulting organic mixture was washed with water, dried over MgSO _4, filtered, and concentrated. Purification by flash chromatography on SiO ₂ (0% to 100% (3: 1 EtOAc: EtOH) / heptane) provided impure 2- (6-((2S, 5S) -2,5-dimethyl Pyrrolidin-1-yl) pyridin-3-yl) -3-((2-methyl-1H-imidazol-4-yl) methyl) -3H-imidazo [4,5-b] pyridine. Further purification by reverse-phase HPLC (5 to 70% CH ₃ CN / 0.1% NH ₄ OH in H ₂ O) provided 2- (6-((2S, 5S) -2,5-dimethylpyrrolidine -1-yl) pyridin-3-yl) -3-((2-methyl-1H-imidazol-4-yl) methyl) -3H-imidazo [4,5-b] pyridine (33mg), frozen White solid after drying. LC-MS (ES) m / z = 388 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 8.53 (d, J = 2.0Hz, 1H), 8.35 (dd, J = 1.4,4.9Hz, 1H), 8.06 (dd, J = 1.3,7.9Hz, 1H ), 7.95 (dd, J = 2.4, 9.0 Hz, 1H), 7.36 (dd, J = 4.9, 8.0 Hz, 1H), 6.62-6.69 (m, 2H), 5.52 (s, 2H), 4.29 (br. s., 2H), 2.32 (s, 5H), 1.73 (d, J = 5.6Hz, 2H), 1.20 (d, J = 6.3Hz, 6H).

Intermediate 227

5-fluoro-N-((1-methyl-1H-pyrazol-3-yl) methyl) -3-nitropyridine-2-amine

(1-methyl-1H-pyrazol-3-yl) methylamine (211 mg, 1.901 mmol) and K ₂ CO ₃ (310 mg, 2.246 mmol) were added to 2-chloro-5- in DMSO (5 mL) Fluoro-3-nitropyridine (305 mg, 1.728 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was then quenched with water (10 mL), and the resulting precipitate was separated by filtration, washed with water, and then dried in a vacuum oven for 4 hours to provide 5-fluoro-N-((1-methyl -1H-pyrazol-3-yl) methyl) -3-nitropyridine-2-amine (210 mg). LC-MS (ES) m / z = 252 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 3.80 (s, 3H), 4.69 (d, J = 5.3Hz, 2H), 6.16 (d, J = 2.3Hz, 1H), 7.60 (d, J = (2.3Hz, 1H), 8.44 (dd, J = 8.5, 2.9Hz, 1H), 8.66 (d, J = 2.8Hz, 1H), 8.69 (t, J = 5.3Hz, 1H).

Example 165

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -6-fluoro-3-((1-methyl-1H-pyrazole -3-yl) methyl) -3H-imidazo [4,5-b] pyridine

5-Fluoro-N-((1-methyl-1H-pyrazol-3-yl) methyl) -3-nitropyridin-2-amine (75 mg, 0.299 mmol), 6-((2S, 5S ) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (67.1 mg, 0.328 mmol), sodium bisulfite (156 mg, 85%, 0.762 mmol), ethanol (1.5 mL), and water ( 0.75 mL) was added to a microwave vial, and the reaction mixture was heated at 130 ° C for 90 minutes under microwave conditions. The reaction was then diluted with water (10 mL) and extracted with EtOAc (4 x 5 mL). The organic extracts were combined, washed with brine, dried over MgSO _4, filtered, and concentrated. Purification by chromatography on SiO ₂ (0 to 10% CH ₃ OH / CH ₂ Cl ₂ ) provided 2- (6-((2S, 5S) -2,5-dimethyl as a light brown solid Pyrrolidin-1-yl) pyridin-3-yl) -6-fluoro-3-((1-methyl-1H-pyrazol-3-yl) methyl) -3H-imidazo [4,5-b ] Pyridine (45 mg). LC-MS (ES) m / z = 406 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.14 (d, J = 6.1Hz, 6H), 1.65 (d, J = 5.3Hz, 2H), 2.23 (br.s., 2H), 3.76 (s , 3H), 4.26 (br.s., 2H), 5.50 (s, 2H), 6.06 (d, J = 2.3Hz, 1H), 6.63 (d, J = 8.9Hz, 1H), 7.61 (d, J = 2.3Hz, 1H), 8.02 (dd, J = 9.4, 2.5Hz, 1H) 8.06 (dd, J = 9.0, 2.4Hz, 1H), 8.32 (t, J = 2.2Hz, 1H), 8.66 (d, J = 2.5Hz, 1H).

Intermediate 228

N-((1-methyl-1H-pyrazol-3-yl) methyl) -3-nitropyridine-2-amine

(1-methyl-1H-pyrazol-3-yl) methylamine (97 mg, 0.873 mmol) and K ₂ CO ₃ (157 mg, 1.134 mmol) were added to 2-fluoro-3- in DMSO (3 mL) Nitropyridine (124 mg, 0.873 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was then quenched with water (20 mL), and the resulting precipitate was isolated by filtration and dried in a vacuum oven overnight to provide N-((1-methyl-1H-pyrazol-3-yl) as a yellow solid Methyl) -3-nitropyridine-2-amine (160 mg). LC-MS (ES) m / z = 234 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 3.80 (s, 3H), 4.71 (d, J = 5.3Hz, 2H), 6.16 (d, J = 2.3Hz, 1H), 6.81 (dd, J = 8.4, 4.6 Hz, 1H), 7.61 (d, J = 2.3 Hz, 1H), 8.46 (dd, J = 8.4, 1.8 Hz, 1H), 8.51 (dd, J = 4.3, 1.8 Hz, 1H), 8.73 ( t, J = 4.9Hz, 1H).

Example 166

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3-((1-methyl-1H-pyrazol-3-yl ) Methyl) -3H-imidazo [4,5-b] pyridine

N-((1-methyl-1H-pyrazol-3-yl) methyl) -3-nitropyridin-2-amine (160 mg, 0.686 mmol), 6-((2S, 5S) -2, 5-dimethylpyrrolidin-1-yl) nicotinaldehyde (154 mg, 0.755 mmol), ethanol (2 mL), water (1 mL), and sodium bisulfite (358 mg, 85%, 1.749 mmol) were added to a microwave vial The reaction mixture was heated at 130 ° C for 90 minutes under microwave conditions. The reaction was then diluted with water (10 mL) and extracted with EtOAc (4 x 5 mL). Next, the organic extracts were combined, washed with brine, dried over MgSO _4, filtered, and concentrated. Purification by chromatography on SiO ₂ (0 to 10% CH ₃ OH / CH ₂ Cl ₂ ) provided 2- (6-((2S, 5S) -2,5-dimethylpyrrolidine-1- Yl) pyridin-3-yl) -3-((1-methyl-1H-pyrazol-3-yl) methyl) -3H-imidazo [4,5-b] pyridine (160 mg), freeze-dried Yellow solid. LC-MS (ES) m / z = 388 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.14 (d, J = 6.1Hz, 6H), 1.65 (d, J = 5.6Hz, 2H), 2.23 (br.s., 2H), 3.76 (s , 3H), 4.25 (br.s., 2H), 5.51 (s, 2H), 6.04 (d, J = 2.3Hz, 1H), 6.63 (d, J = 8.9Hz, 1H), 7.29 (dd, J = 8.0, 4.7Hz, 1H), 7.60 (s, 1H), 8.02-8.08 (m, 2H), 8.30 (dd, J = 4.7, 1.4Hz, 1H), 8.65 (d, J = 2.3Hz, 1H) .

Intermediate 229

2- (6- (diethylamino) pyridin-3-yl) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5 -Methyl formate

4-(((1-methyl-1H-pyrazol-3-yl) methyl) amino) -3-nitrobenzoate (75 mg, 0.258 mmol), 6- (diethylamino) smoke Alkaline aldehyde (50.7 mg, 0.284 mmol), ethanol (1.5 mL), water (0.750 mL), and sodium bisulfite (135 mg, 85%, 0.659 mmol) were added to a microwave vial, and the reaction mixture was heated under microwave conditions at Heat at 130 ° C for 90 minutes. The reaction was then diluted with water (10 mL) and extracted with EtOAc (4 x 5 mL). The organic extracts were combined, washed with brine, dried over MgSO _4, filtered, and concentrated. Purification by chromatography on SiO ₂ (0 to 10% CH ₃ OH / CH ₂ Cl ₂ ) provided 2- (6- (diethylamino) pyridin-3-yl) -1 as a pale yellow solid -((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxylic acid methyl ester (71 mg). LC-MS (ES) m / z = 419 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.12-1.18 (m, 6H), 3.57 (q, J = 7.0Hz, 4H), 3.78 (s, 3H), 3.88 (s, 3H), 5.45 ( s, 2H), 6.15 (d, J = 2.3Hz, 1H), 6.76 (d, J = 8.9Hz, 1H), 7.61 (d, J = 8.4Hz, 1H), 7.66 (d, J = 2.3Hz, 1H), 7.85 (dd, J = 8.5, 1.7 Hz, 1H), 8.03 (dd, J = 9.0, 2.4 Hz, 1H), 8.23 (d, J = 1.3 Hz, 1H), 8.61 (d, J = 2.0 Hz, 1H).

Intermediate 230

2- (6- (diethylamino) pyridin-3-yl) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5 -Formic acid

The NaOH (0.335mL, 3.35mmol, 10N) was added to the CH ₃ OH (3mL) of the 2- (6- (diethylamino) pyridin-3-yl) -1 - ((1-methyl -1H -Pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxylic acid methyl ester (70 mg, 0.167 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was concentrated, HCl (3.35 mL, 3.35 mmol, 1N) was added, and the resulting precipitate was separated by filtration to give the desired product (28 mg) as a white solid. The filtrate was extracted with EtOAc (4 x 5mL), and the organic extracts were combined, dried over MgSO _4, filtered, and concentrated to provide additional desired product as a white solid of (18mg). The separated solids were then combined to produce 2- (6- (diethylamino) pyridin-3-yl) -1-((1-methyl-1H-pyrazol-3-yl) methyl as a white solid. Yl) -1H-benzo [d] imidazole-5-carboxylic acid (46 mg). LC-MS (ES) m / z = 405 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.17 (t, J = 7.0Hz, 6H), 3.61 (q, J = 6.8Hz, 4H), 3.78 (s, 3H), 5.53 (s, 2H) , 6.26 (d, J = 1.8 Hz, 1H), 6.88 (d, J = 8.9 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.9Hz, 1H), 8.10 (d, J = 7.6Hz, 1H), 8.24 (s, 1H), 8.65 (d, J = 2.3Hz, 1H), 12.87-13.05 (m, 1H) .

Example 167

2- (6- (diethylamino) pyridin-3-yl) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5 -Formamidine

NH ₄ Cl (11.43 mg, 0.214 mmol), EDC (45.5 mg, 0.237 mmol), HOBt (36.3 mg, 0.237 mmol), and N-methylmorpholine (0.078 mL, 0.712 mmol) were added to DMSO ( 2 (2)) of 2- (6- (diethylamino) pyridin-3-yl) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d ] Imidazole-5-carboxylic acid (48 mg, 0.119 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with water (5 mL) and extracted with EtOAc (3 x 10 mL). The organic extracts were combined, dried over MgSO _4, filtered, and concentrated. Purification by chromatography on SiO ₂ (0 to 10% CH ₃ OH / CH ₂ Cl ₂ ) provides 2- (6- (diethylamino) pyridin-3-yl) -1-((1- Methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide (32 mg), lyophilized as a white solid. LC-MS (ES) m / z = 405 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ1.15 (t, J = 7.0Hz, 6H), 3.57 (q, J = 7.1Hz, 4H), 3.78 (s, 3H), 5.43 (s, 2H ), 6.14 (d, J = 2.0Hz, 1H), 6.76 (d, J = 8.9Hz, 1H), 7.27 (br.s., 1H), 7.53 (d, J = 8.4Hz, 1H), 7.65 ( d, J = 2.3Hz, 1H), 7.77 (dd, J = 8.4, 1.52Hz, 1H), 7.96 (br.s., 1H), 8.03 (dd, J = 9.1, 2.5Hz, 1H), 8.21 ( d, J = 1.3 Hz, 1H), 8.60 (d, J = 2.3 Hz, 1H).

Example 168

2- (6- (diethylamino) pyridin-3-yl) -N-methyl-1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [ d) imidazol-5-carboxamide

N-methyl-4-(((1-methyl-1H-pyrazol-3-yl) methyl) amino) -3-nitrobenzamide (78.4 mg, 0.271 mmol), 6- (Diethylamino) nicotinaldehyde (53.1 mg, 0.298 mmol), ethanol (1.5 mL), water (0.75 mL), and sodium bisulfite (142 mg, 85%, 0.693 mmol) were added to a microwave vial, and The reaction mixture was heated under microwave conditions at 130 ° C for 90 minutes. The reaction was then diluted with water (10 mL) and extracted with EtOAc (4 x 5 mL). The organic extracts were combined, washed with brine, dried over MgSO _4, filtered, and concentrated. Purification by chromatography on SiO ₂ (0 to 10% CH ₃ OH / CH ₂ Cl ₂ ) provides 2- (6- (diethylamino) pyridin-3-yl) -N-methyl-1 -((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide (65 mg), lyophilized to a white solid. LC-MS (ES) m / z = 418 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.15 (t, J = 7.1Hz, 6H), 2.81 (d, J = 4.6Hz, 3H), 3.57 (q, J = 7.1Hz, 4H), 3.78 (s, 3H), 5.43 (s, 2H), 6.14 (d, J = 2.3Hz, 1H), 6.76 (d, J = 9.1Hz, 1H), 7.54 (d, J = 8.4Hz, 1H), 7.65 (d, J = 2.3Hz, 1H), 7.73 (dd, J = 8.5, 1.7Hz, 1H), 8.03 (dd, J = 9.1, 2.5Hz, 1H), 8.15 (d, J = 1.3Hz, 1H) , 8.41 (d, J = 4.6 Hz, 1H), 8.60 (d, J = 2.3 Hz, 1H).

Intermediate 231

2-nitro-N-((tetrahydrofuran-2-yl) methyl) aniline

(Tetrahydrofuran-2-yl) methylamine (300 mg, 2.97 mmol) and K ₂ CO ₃ (410 mg, 2.97 mmol) were added to 1-fluoro-2-nitrobenzene (419 mg, 2.967 mmol) in DMF (5 mL). Solution, and the mixture was stirred at room temperature for 6 hours. The mixture was then quenched with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined extracts were dried over sodium sulfate and concentrated. The residue was then purified using column chromatography (silica gel, gradient from 0 to 60% EtOAc / hexane) to provide 2-nitro-N-((tetrahydrofuran-2-yl) methyl) as a reddish brown oil Aniline (0.64 g). LC-MS (ES) m / z = 223 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.25 (br.s., 1H), 8.18 (dd, J = 1.5, 8.6 Hz, 1H), 7.44 (ddd, J = 1.6, 7.0, 8.6 Hz, 1H) , 6.90 (dd, J = 0.9, 8.7 Hz, 1H), 6.66 (ddd, J = 1.3, 7.2, 8.6 Hz, 1H), 4.22 (dq, J = 4.4, 6.8 Hz, 1H), 3.97 (td, J = 6.5, 8.5Hz, 1H), 3.84 (td, J = 6.9, 8.3Hz, 1H), 3.51-3.44 (m, 1H), 3.41-3.34 (m, 1H), 2.15-2.07 (m, 1H), 2.03-1.92 (m, 2H), 1.73 (tdd, J = 7.2,8.6,12.0Hz, 1H).

Intermediate 232

N1-((tetrahydrofuran-2-yl) methyl) benzene-1,2-diamine

Sodium borohydride (0.545 g, 14.40 mmol) was added portionwise to 2-nitro-N-((tetrahydrofuran-2-yl) methyl) aniline (0.64 g, 2.88 mmol) and NiCl ₂ cooled to 0 ° C A stirred solution of 6H ₂ O (1.706 g, 7.20 mmol) in CH ₃ OH (5 mL). The reaction mixture was allowed to warm to room temperature, and then stirred at room temperature for 30 minutes [the reaction turned black after 30 seconds]. The mixture was concentrated and the resulting residue was dissolved in concentrated aqueous NH ₄ OH and extracted with _{CH 2 Cl 2 (3 x 10mL} ). The combined organic extracts were dried (Na ₂ SO _4), filtered, and concentrated. The residue was purified by flash chromatography on silica with a gradient from 0 to 70% EtOAc / hexanes to provide N1-((tetrahydrofuran-2-yl) methyl) benzene-1 as a pale yellow oil, 2-diamine (0.341 g). LC-MS (ES) m / z = 193 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 6.92-6.85 (m, 1H), 6.80-6.70 (m, 3H), 4.29-4.19 (m, 1H), 3.96 (td, J = 6.7, 8.1Hz, 1H ), 3.90-3.83 (m, 1H), 3.65 (br.s., 3H), 3.27 (dd, J = 3.5, 12.2 Hz, 1H), 3.14 (dd, J = 8.0, 12.0 Hz, 1H), 2.15 -2.05 (m, 1H), 2.04-1.92 (m, 2H), 1.78-1.67 (m, 1H).

Example 169

N, N-diethyl-5- (1-((tetrahydrofuran-2-yl) methyl) -1H-benzo [d] imidazol-2-yl) pyridin-2-amine

A solution of 6- (diethylamino) nicotinaldehyde (0.210 g, 1.181 mmol) followed by oxone (0.726 g, 1.181 mmol) in water (2 mL) was added to N1-((tetrahydrofuran- A solution of 2-yl) methyl) benzene-1,2-diamine (0.227 g, 1.181 mmol) in DMF (2 mL) at 0 ° C, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was basified with 10% NaHCO ₃ and then extracted with EtOAc (3 x 15 mL). The combined extracts were dried (Na ₂ SO _4), then concentrated. The residue was then purified by silica gel chromatography (gradient: 0 to 70% EtOAc / hexane) to provide N, N-diethyl-5- (1-((tetrahydrofuran-2-yl) as a yellow oil Methyl) -1H-benzo [d] imidazol-2-yl) pyridin-2-amine (0.166 g, 0.474 mmol). LC-MS (ES) m / z = 351 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ); δ 8.51 (d, J = 2.5 Hz, 1 H), 7.86 (dd, J = 2.5, 8.9 Hz, 1 H), 7.78-7.73 (m, 1 H), 7.46 (td, J = 2.3, 4.6 Hz, 1H), 7.26-7.20 (m, 2H), 6.53 (d, J = 8.9Hz, 1H), 4.31-4.22 (m, 3H), 3.78 (td, J = 6.9, 8.3Hz , 1H), 3.67 (td, J = 6.8, 8.4 Hz, 1H), 3.54 (q, J = 7.1 Hz, 4H), 1.93 (td, J = 6.2, 12.4 Hz, 1H), 1.84-1.74 (m, 2H), 1.53-1.43 (m, 1H), 1.19 (t, J = 7.1Hz, 6H).

Intermediate 233

(S) -2-nitro-N-((tetrahydrofuran-2-yl) methyl) aniline

(S)-(Tetrahydrofuran-2-yl) methylamine (300 mg, 2.97 mmol) and K ₂ CO ₃ (410 mg, 2.97 mmol) were added to 1-fluoro-2-nitrobenzene (419 mg, 2.967 mmol) in CHCl ₃ (5 mL), and the reaction mixture was stirred at room temperature for 18 hours. The mixture was quenched with 1M aq. HCl (10 mL) and extracted with EtOAc (3x). The combined extracts were dried and concentrated. The resulting residue was purified on silica gel using a column chromatography using a gradient from 0 to 60% EtOAc / hexanes to provide (S) -2-nitro-N-((tetrahydrofuran-2) as an orange-yellow oil. -Yl) methyl) aniline (384 mg). LC-MS (ES) m / z = 223 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.22 (br.s., 1H), 8.13 (dd, J = 1.3, 8.6 Hz, 1H), 7.40 (ddd, J = 1.5, 6.9, 8.6 Hz, 1H) , 6.86 (d, J = 8.6 Hz, 1H), 6.61 (ddd, J = 1.0, 7.0, 8.4 Hz, 1H), 4.18 (dq, J = 4.3, 6.8 Hz, 1H), 3.94 (td, J = 6.8 , 8.2Hz, 1H), 3.84-3.75 (m, 1H), 3.48-3.39 (m, 1H), 3.37-3.28 (m, 1H), 2.13-2.01 (m, 1H), 2.01-1.87 (m, 2H ), 1.75-1.63 (m, 1H).

Intermediate 234

(S) -N1-((tetrahydrofuran-2-yl) methyl) benzene-1,2-diamine

NiCl ₂ ‧6H ₂ O (821 mg, 3.46 mmol) followed by sodium borohydride (261 mg, 6.91 mmol) was added to (S) -2-nitro-N-((tetrahydrofuran-2-yl) formaldehyde) cooled to 0 ° C. Solution of phenyl) aniline (384 mg, 1.728 mmol) in CH ₃ OH (5 mL), and the reaction mixture was stirred at room temperature for 30 minutes [the reaction turned black after 20 sec]. The reaction mixture was basified with NH ₄ OH, followed by extraction with CH ₂ Cl ₂ (3 x 10 mL). The combined extracts were dried (Na ₂ SO ₄ ) and then concentrated to provide (S) -N1-((tetrahydrofuran-2-yl) methyl) benzene-1,2-diamine (156 mg) as an amber oil. . LC-MS (ES) m / z = 193 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 6.91-6.83 (m, 1H), 6.80-6.70 (m, 3H), 4.24 (dq, J = 3.8, 7.3Hz, 1H), 3.95 (td, J = 6.7 , 8.4Hz, 1H), 3.90-3.82 (m, 1H), 3.64 (br.s., 3H), 3.27 (dd, J = 3.8, 12.2Hz, 1H), 3.13 (dd, J = 7.9, 12.2Hz , 1H), 2.15-2.04 (m, 1H), 2.03-1.90 (m, 2H), 1.78-1.66 (m, 1H).

Example 170

(S) -N, N-diethyl-5- (1-((tetrahydrofuran-2-yl) methyl) -1H-benzo [d] imidazol-2-yl) pyridin-2-amine

A solution of 6- (diethylamino) nicotinaldehyde (145 mg, 0.811 mmol) followed by potassium oxone (349 mg, 0.568 mmol) in water (3 mL) was added to (S) at 0 ° C. -N1-((tetrahydrofuran-2-yl) methyl) benzene-1,2-diamine (156 mg, 0.811 mmol) in DMF (3 mL), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was basified with saturated aqueous NaHCO ₃ and extracted with EtOAc (3 x 10mL). The combined extracts were dried (Na ₂ SO _4), then concentrated. The resulting residue was purified on silica using column chromatography with a gradient from 0 to 70% EtOAc / hexanes to provide (S) -N, N-diethyl-5- (1) as a reddish brown oil -((Tetrahydrofuran-2-yl) methyl) -1H-benzo [d] imidazol-2-yl) pyridin-2-amine (240 mg). LC-MS (ES) m / z = 351 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.49 (d, J = 1.8 Hz, 1 H), 7.80 (dd, J = 2.4, 9.0 Hz, 1 H), 7.74-7.68 (m, 1 H), 7.42-7.36 ( m, 1H), 7.21-7.14 (m, 2H), 6.47 (d, J = 9.1Hz, 1H), 4.24-4.14 (m, 3H), 3.71 (td, J = 6.9, 8.3Hz, 1H), 3.59 (td, J = 6.8,8.4Hz, 1H), 3.48 (q, J = 7.1Hz, 4H), 1.87 (dd, J = 6.2,12.5Hz, 1H), 1.76-1.67 (m, 2H), 1.41 ( dd, J = 7.4, 12.4 Hz, 1H), 1.13 (t, J = 7.1 Hz, 6H).

Intermediate 235

5- (1- (3-bromobenzyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine

NaH (29.3 mg, 0.732 mmol, 60% in oil) was added to 5- (1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridine-2 at 0 ° C. -A solution of amine (150 mg, 0.563 mmol) in DMF (5.6 L). After 5 minutes, 1-bromo-3- (bromomethyl) -benzene (155 mg, 0.619 mmol) was added and the reaction mixture was allowed to warm to room temperature. After 30 minutes, the reaction was quenched with saturated aqueous NH ₄ Cl (2mL), diluted with water (20 mL), and then extracted with EtOAc (3 x 20mL). The combined organic extracts were washed with water (20mL) and brine (20mL), dried over Na ₂ SO _4, filtered, and concentrated. The resulting residue was purified via silica chromatography (10 to 100% EtOAc / hexanes) to provide the desired product (195 mg) as a beige solid. LC-MS (ES) m / z = 437 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.39 (d, J = 2.5Hz, 1H), 7.93-7.77 (m, 2H), 7.46 (d, J = 7.9Hz, 1H), 7.39-7.29 (m, 2H), 7.26-7.12 (m, 3H), 7.03 (d, J = 7.9Hz, 1H), 6.57 (d, J = 9.1Hz, 1H), 5.46 (s, 2H), 3.58 (q, J = 7.1 Hz, 4H), 1.23 (t, J = 7.0Hz, 6H).

Example 171

N, N-diethyl-5- (1- (3- (pyrimidin-5-yl) benzyl) -1H-benzo [d] imidazol-2-yl) pyridin-2-amine

[1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (4.2 mg, 0.0057 mmol) was added to 5- (1- (3-bromobenzyl) under a nitrogen atmosphere ) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine (50 mg, 0.12 mmol), pyrimidin-5-ylboronic acid (17 mg, 0.14 mmol), and Cs A suspension of ₂ CO ₃ (112 mg, 0.345 mmol) in 10: 1 THF: water (2.5 mL), and the reaction mixture was stirred in a sealed container at 100 ° C. for 4 hours, at which time the solvent had evaporated. The residue was redissolved in THF (2.5 mL), and additional pyrimidin-5-ylboronic acid (17 mg, 0.14 mmol) and [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium ( II) (4.2 mg, 0.0057 mmol). The mixture was flushed with nitrogen, capped, heated at 80 ° C for 19 hours, then cooled to room temperature and concentrated. The resulting residue was purified by silica gel chromatography (eluted with 0 to 100% EtOAc / hexane) to provide the desired product (30 mg) as a transparent film. LC-MS (ES) m / z = 435 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 9.21 (s, 1H), 8.87 (s, 2H), 8.41 (d, J = 2.3Hz, 1H), 7.99-7.77 (m, 2H), 7.59-7.44 ( m, 2H), 7.38-7.11 (m, 5H), 6.58 (d, J = 8.9Hz, 1H), 5.59 (s, 2H), 3.57 (q, J = 7.1Hz, 4H), 1.22 (t, J = 7.1Hz, 6H).

Example 172

2- (6- (diethylamino) pyridin-3-yl) -N-methyl-1- (3- (pyrimidin-5-yl) benzyl) -1H-benzo [d] imidazole-5 -Formamidine

Add 4-fluoro-N-methyl-3-nitrobenzamide (60 mg, 0.303 mmol) and N, N-diisopropylethylamine (0.058 mL, 0.333 mmol) to (3- (pyrimidine- 5-yl) phenyl) methylamine (62.0 mg, 0.333 mmol) in ethanol (0.7 mL), and the reaction mixture was heated at 150 ° C. under microwave conditions for 20 minutes under nitrogen. The resulting mixture was transferred into a scintillation vial (25 mL) with a minimal amount of ethanol (~ 4 mL). Next, sodium dithiosulfinate (0.75 g, 4.31 mmol) in water (3 mL) was added, and the reaction mixture was heated at 70 ° C. for about 1 hour. Next, 6- (diethylamino) nicotinaldehyde (54 mg, 0.30 mmol) was added, and the reaction mixture was heated at 60 ° C for 48 hours. The reaction was partitioned between 2N NH ₄ OH and EtOAc (40mL). The aqueous layer was further extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with brine (2 x 20mL), dried with Na ₂ SO _4, and evaporated to yield the crude product as a colorless oil ratio in vacuo. By reverse phase HPLC (12 to 42% CH ₃ CN / 0.1% TFA in water of) providing the TFA salt of the desired product (90 mg of) purified, as a white solid after lyophilization. LC-MS (ES) m / z = 492 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ1.24 (t, J = 7.2Hz, 6H), 3.03 (d, J = 4.4Hz, 3H), 3.60 (m, 4H), 5.74 (s, 2H), 6.72 (d, J = 9.2Hz, 1H), 7.08 (m, 1H), 7.16 (d, J = 7.2Hz, 1H), 7.38 (m, 2H), 7.55-7.62 (m, 2H), 8.05 (m , 2H), 8.40 (s, 1H), 8.47 (s, 1H), 8.92 (bs, 1H), 9.25 (bs, 1H).

Intermediate 236

(R) -2-(((3-fluoro-6-methoxy-2-nitrophenyl) amino) methyl) morpholin 4-carboxylic acid tert-butyl ester

(R) -2- (Aminemethyl) morpholin-4-carboxylic acid tert-butyl ester, acetate (4.02 g, 14.54 mmol) and K ₂ CO ₃ (4.57 g, 33.0 mmol) were added to 1,3 -A solution of difluoro-4-methoxy-2-nitrobenzene (2.5 g, 13.22 mmol) in DMF (45 mL), and the reaction mixture was stirred at 55 ° C for 30 hours. The mixture was filtered, and the filtrate was concentrated. The resulting residue was purified by column chromatography on silica gel (gradient: 0 to 100% EtOAc / heptane) to give the desired product (4.60 g) as a brown oil. LC-MS (ES) m / z = 386 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 1.45-1.52 (m, 9H), 2.70 (m, 1H), 2.91-3.03 (m, 1H), 3.17 (dd, J = 13.2, 8.1Hz, 1H), 3.40 (m, 1H), 3.47-3.59 (m, 2H), 3.82-3.97 (m, 6H), 6.57 (t, J = 9.5Hz, 1H), 6.82 (dd, J = 9.0, 4.7Hz, 1H) .

Example 173

(S) -2-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-7-methoxy -1H-benzo [d] imidazol-1-yl) methyl) morpholin

Add sodium bisulfite (339 mg, 85%, 1.658 mmol) to (R) -2-(((3-fluoro-6-methoxy-2-nitrophenyl) amino) methyl) morpholin Tert-butyl 4-carboxylic acid (250 mg, 0.649 mmol) and 6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (139 mg, 0.681 mmol) in CH ₃ A solution in a mixture of OH: water 2: 1 (3 mL), and the reaction mixture was stirred at 100 ° C. for 18 hours in a sealed container. The reaction was then cooled to room temperature and diluted with saturated aqueous NaHCO ₃ (10mL). The organic layer was extracted with an aqueous solution of EtOAc (4 x 10mL), and the combined (10 mL) and washed with brine, dried over anhydrous Na ₂ SO _4, filtered, and concentrated. Trifluoroacetic acid (0.50 mL, 6.5 mmol) was added to a solution of the crude residue in CH ₂ Cl ₂ (2 mL), and the reaction mixture was stirred at room temperature for 20 hours. The reaction was then diluted with additional CH ₂ Cl ₂ (30 mL), and the resulting organic solution was washed with saturated aqueous NaHCO ₃ (2 x 15 mL) followed by brine (15 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. By silica gel chromatography (with 0 to _{10% CH 3 OH / CH 2} Cl 2 elution) and the resulting residue was purified to provide the desired product as a white solid (170mg). LC-MS (ES) m / z = 440 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.60 (d, J = 2.0 Hz, 1 H), 7.89 (dd, J = 8.9, 2.3 Hz, 1 H), 6.87 (dd, J = 9.8, 8.7 Hz, 1 H ), 6.58 (dd, J = 8.9, 3.3 Hz, 1H), 6.49 (d, J = 8.9 Hz, 1H), 4.52-4.33 (m, 2H), 4.29 (br s, 1H), 3.95 (s, 3H ), 3.94-3.87 (m, 2H), 3.81 (dd, J = 11.5, 1.9Hz, 1H), 3.46-3.37 (m, 1H), 2.92-2.81 (m, 1H), 2.76 (d, J = 11.7 Hz, 2H), 2.52 (dd, J = 11.9, 10.4 Hz, 1H), 2.40-2.22 (m, 2H), 1.71 (d, J = 5.6 Hz, 2H), 1.26-1.14 (m, 6H).

Example 174

(S) -2-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-7-methoxy -1H-benzo [d] imidazol-1-yl) methyl) -4-methylmorpholin

Add formaldehyde (36.5% solution, 0.034mL, 0.46mmol) and sodium triacetoxyborohydride (58mg, 0.27mmol) to (S) -2-((2- (6-((2S, 5S)- 2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-7-methoxy-1H-benzo [d] imidazol-1-yl) methyl) morpholin (40 mg, 0.091 mmol) in 1,2-dichloroethane (2 mL), and the reaction mixture was stirred at room temperature for 30 minutes. The reaction was then concentrated in vacuo and the resulting residue was purified by reverse-phase HPLC (0.1% 10 mM NH ₄ HCO ₃ with NH ₄ OH modifier, eluting with 50 to 99% CH ₃ CN / water). The product-containing portion was concentrated and lyophilized to provide the desired product (32 mg) as a white solid. LC-MS (ES) m / z = 454 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.60 (d, J = 2.3 Hz, 1 H), 7.88 (dd, J = 8.9, 2.5 Hz, 1 H), 6.86 (dd, J = 9.6, 8.9 Hz, 1 H) , 6.56 (dd, J = 8.7, 3.2 Hz, 1H), 6.48 (d, J = 8.9 Hz, 1H), 4.83 (br s, 5H), 4.59-4.15 (m, 4H), 4.06-3.95 (m, 1H), 3.94 (s, 3H), 3.81 (dd, J = 11.5, 1.6Hz, 1H), 3.59-3.41 (m, 1H), 2.59 (d, J = 11.4Hz, 2H), 2.35-2.27 (m , 1H), 2.11 (td, J = 11.5, 3.3Hz, 1H), 1.79 (t, J = 10.6Hz, 1H), 1.71 (d, J = 5.8Hz, 1H), 1.22 (d, J = 6.3Hz , 6H).

Example 175

(S) -2-((4-fluoro-7-methoxy-2- (6-((S) -2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo (d) imidazol-1-yl) methyl) morpholin

Add sodium bisulfite (108 mg, 85%, 0.529 mmol) to (R) -2-(((3-fluoro-6-methoxy-2-nitrophenyl) amino) methyl) morpholin Tert-butyl-4-carboxylic acid (80 mg, 0.21 mmol) and (S) -6- (2-methylpyrrolidin-1-yl) nicotinaldehyde (42 mg, 0.22 mmol) in CH ₃ OH: water 2: 1 (3 mL) of the solution, and the reaction mixture was stirred in a sealed container at 100 ° C for 3 days. The reaction was then cooled to room temperature and diluted with saturated aqueous NaHCO ₃ (10mL). The organic layer was extracted with an aqueous solution of EtOAc (4 x 10mL), and the combined (10 mL) and washed with brine, dried over anhydrous Na ₂ SO _4, filtered, and concentrated. TFA (0.16 mL, 2.1 mmol) was added to a solution of the crude residue in CH ₂ Cl ₂ (5 mL), and the reaction mixture was stirred at room temperature for 21 hours. The reaction was concentrated in vacuo, and the resulting residue was purified by reverse-phase HPLC (0.1% 10 mM NH ₄ HCO ₃ with NH ₄ OH modifier, eluting with 30 to 85% CH ₃ CN / water). The product-containing portion was concentrated and lyophilized to provide the desired product (49 mg) as an off-white solid. LC-MS (ES) m / z = 426 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.62 (d, J = 2.0 Hz, 1 H), 7.93 (dd, J = 8.9, 2.3 Hz, 1 H), 6.88 (dd, J = 9.8, 8.7 Hz, 1 H) , 6.59 (dd, J = 8.9,3.3Hz, 1H), 6.52-6.41 (m, 1H), 4.54-4.35 (m, 2H), 4.34-4.17 (m, 1H), 4.05-3.87 (m, 1H) , 3.97 (s, 3H), 3.81 (dd, J = 11.5, 2.2Hz, 1H), 3.74-3.58 (m, 1H), 3.56-3.39 (m, 1H), 3.36-3.17 (m, 1H), 2.92 -2.80 (m, 1H), 2.75 (d, J = 11.9Hz, 2H), 2.51 (dd, J = 11.8, 10.5Hz, 1H), 2.30-2.08 (m, 2H), 1.80 (dt, J = 4.9 , 2.3Hz, 1H), 1.64 (dt, J = 7.9, 4.2Hz, 1H), 1.50-1.36 (m, 1H), 1.33-1.21 (m, 3H).

Intermediate 237

(2S, 4S) -1-benzyl-2,4-dimethylazepine

Reference: J. Org. Chem. 1989 , 54, 1755.

Triethylamine (13.38 mL, 96 mmol) was added to a solution of (2R, 4R) -pentane-2,4-diol (4 g, 38.4 mmol) in CH ₂ Cl ₂ (70 mL). The solution was cooled to -20 ° C, and methanesulfonyl chloride (6.67 mL, 86 mmol) was added dropwise and the temperature was maintained between -20 ° C and -15 ° C with vigorous stirring over 40 minutes. After the addition was complete, the mixture was heated to 0 ° C, stirred at 0 ° C for 2 hours, and then poured into cold 1N aqueous HCl (50 mL). The organic layer was separated, and the aqueous layer was extracted with CH ₂ Cl ₂ (3 x 30 mL). The combined organic extracts were washed with saturated aqueous NaHCO _3, dried over Na ₂ SO _4, filtered, and concentrated to provide an oil of the crude dimesylate (2R, 4R) - pentane-2,4-diyl ester (10.0g). ¹ H NMR (400MHz, CDCl ₃ ): δ 4.97-4.86 (m, 2H), 3.07 (s, 6H), 1.91 (dd, J = 5.6,7.1Hz, 2H), 1.47 (d, J = 6.1Hz, 6H).

This material was dissolved in benzylamine (29.4 mL, 269 mmol), and the resulting mixture was stirred at room temperature for 40 hours. The mixture was then transferred to an ice-cooled 2N NaOH aqueous solution (50 mL), and the resulting solution was extracted with hexane (4 x 70 mL). The combined organic extracts were concentrated by silica gel chromatography and eluted with a gradient at 0-10% CH ₂ Cl ₂ is (CH ₃ OH in the in 2M NH ₃₎ 3 The crude product was partially purified to provide (2S, 4S) -1-benzyl-2,4-dimethylazine (5.2 g) as a pale yellow oil. LC-MS (ES) m / z = 176 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 7.40-7.28 (m, 5H), 7.25 (d, J = 7.1Hz, 1H), 3.80-3.74 (m, 1H), 3.73-3.64 (m, 2H), 3.63-3.58 (m, 1H), 1.92 (t, J = 6.3Hz, 2H), 1.15 (d, J = 6.6Hz, 6H).

Intermediate 238

(2S, 4S) -2,4-dimethylazine, acetate

Reference: J. Org. Chem. 1989 , 54, 1755.

(2S, 4S) -1-benzyl-2,4-dimethylazine (5.1 g, 29.1 mmol) was dissolved in acetic acid (20 mL), and the residue was washed into Parr with CH ₃ OH (20 mL) In the flask. Palladium hydroxide carbon (20%) (6.19 g, 44.1 mmol) was added followed by a palladium carbon (10%) (5.8 g, 54.5 mmol) of the slurry in EtOAc (10 mL), and the resulting mixture was connected to a Parr shaker And shake for 3 days under 55 psi of hydrogen pressure. The reaction was filtered and the catalyst was washed with EtOAc. The filtrate was further acidified to prevent the free base from being lost during the concentration process. The amine was collected to provide (2S, 4S) -2,4-dimethylazine, acetate (2.04 g). LC-MS (ES) m / z = 86 [M + H] ⁺ .

Intermediate 239

6-((2S, 4S) -2,4-dimethylazepine-1-yl) nicotinaldehyde

Add 6-fluoronicotinaldehyde (2.96 g, 23.64 mmol), (2S, 4S) -2,4-dimethylazine, acetate (2.5 g, 20.56 mmol), and N, N-diisopropyl A solution of ethylamine (12.57 mL, 72.0 mmol) in DMSO (30 mL) was stirred at 80 ° C for 16 hours. The reaction was quenched with water, and the resulting mixture was extracted with EtOAc. The organic extracts were washed with water then brine, dried over Na ₂ SO _4, filtered, and concentrated. The resulting residue was purified via silica gel chromatography (0-30% EtOAc / hexane) to provide 6-((2S, 4S) -2,4-dimethylazepine-1-yl) as a pale yellow solid Nicotinaldehyde (1.75 g). LC-MS (ES) m / z = 191 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 9.73 (s, 1H), 8.50 (d, J = 2.0Hz, 1H), 7.85 (dd, J = 2.2, 8.7Hz, 1H), 6.24 (d, J = 8.9Hz, 1H), 4.81-4.38 (m, 2H), 2.18 (t, J = 6.6Hz, 2H), 1.50 (br.s., 6H).

Example 176

(S) -2-((2- (6-((2S, 4S) -2,4-dimethylazine-1-yl) pyridin-3-yl) -4-fluoro-7-methoxy -1H-benzo [d] imidazol-1-yl) methyl) morpholin

Add sodium bisulfite (108 mg, 85%, 0.529 mmol) to (R) -2-(((3-fluoro-6-methoxy-2-nitrophenyl) amino) methyl) morpholin Tert-Butyl 4-carboxylic acid (80 mg, 0.222 mmol) and 6-((2S, 4S) -2,4-dimethylazepine-1-yl) nicotinaldehyde (42 mg, 0.22 mmol) in CH ₃ A solution of a 2: 1 mixture of OH: water (3 mL), and the reaction mixture was stirred at 100 ° C for 3 days in a sealed container. The reaction was then cooled to room temperature and diluted with saturated aqueous NaHCO ₃ (10mL). The organic layer was extracted with an aqueous solution of EtOAc (4 x 10mL), and the combined (10 mL) and washed with brine, dried over anhydrous Na ₂ SO _4, filtered, and concentrated. Trifluoroacetic acid (0.16 mL, 2.1 mmol) was added to a solution of the crude residue in CH ₂ Cl ₂ (2 mL), and the reaction mixture was stirred at room temperature for 21 hours. The reaction was concentrated in vacuo, and the resulting residue was purified by reverse-phase HPLC (0.1% 10 mM NH ₄ HCO ₃ with NH ₄ OH modifier, eluting with 30 to 85% CH ₃ CN / water). The product-containing portion was concentrated and lyophilized to provide the desired product (36 mg) as a white solid. LC-MS (ES) m / z = 426 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.59 (d, J = 1.8Hz, 1H), 7.88 (dd, J = 8.6, 2.3Hz, 1H), 6.87 (dd, J = 9.8, 8.7Hz, 1H), 6.58 (dd, J = 8.6, 3.3 Hz, 1H), 6.34 (d, J = 8.6 Hz, 1H), 4.72-4.49 (m, 2H), 4.47-4.28 (m, 2H), 3.96 (s , 3H), 3.96-3.86 (m, 1H), 3.79 (dd, J = 11.5, 2.2Hz, 1H), 3.50-3.34 (m, 1H), 2.96-2.71 (m, 3H), 2.52 (dd, J = 11.9, 10.4 Hz, 1H), 2.17 (t, J = 6.46 Hz, 2H), 1.49 (d, J = 6.1 Hz, 6H).

Intermediate 240

(R) -2-(((2-methoxy-4- (methoxycarbonyl) -6-nitrophenyl) amino) methyl) morpholin 4-carboxylic acid tert-butyl ester

K ₂ CO ₃ (223 mg, 1.61 mmol) was added to (R) -2- (aminomethyl) morpholin-4-carboxylic acid tert-butyl ester (291 mg, 1.34 mmol) and 4-chloro-3-methoxy A solution of methyl-5-nitrobenzoate (330 mg, 1.34 mmol) in DMF (3 mL), and the reaction mixture was stirred at 60 ° C. for 19 hours in a sealed container. The reaction was then cooled to room temperature and diluted with EtOAc (20 mL). The organic solution was washed with water (2 x 15 mL), and the combined aqueous portions were back extracted with EtOAc (15 mL). The combined organic fractions were washed with brine (15 mL), dried over anhydrous Na ₂ SO _4, filtered, and concentrated. The resulting residue was purified by silica chromatography (dialysis with 0 to 40% EtOAc / hexanes) to provide the desired product (572 mg) as an orange oil. LC-MS (ES) m / z = 426 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.67-8.39 (m, 1H), 7.54 (d, J = 1.8Hz, 1H), 4.04-3.83 (m, 10H), 3.78-3.48 (m, 3H), 3.01 (br s, 1H), 2.76 (br s, 1H), 1.59-1.41 (m, 9H).

Intermediate 241

(R) -2-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-5- ( (Methoxycarbonyl) -1H-benzo [d] imidazol-1-yl) methyl) morpholin 4-carboxylic acid tert-butyl ester

Intermediate 242

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1-(((S) -morpholin -2-yl) methyl) -1H-benzo [d] imidazole-5-carboxylic acid methyl ester

Add sodium bisulfite (700mg, 85%, 3.417mmol) to (R) -2-(((2-methoxy-4- (methoxycarbonyl) -6-nitrophenyl) amino) methyl ) Morpholine (tereline) tert-butyl terephthalate (570 mg, 1.34 mmol) and 6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (287 mg , 1.41 mmol) in CH ₃ OH: 2 water: the mixture of 1 (4.5 mL) was added and the reaction mixture was stirred for 3 days at 100 deg.] C in a sealed vessel. The reaction was then cooled to room temperature and diluted with saturated aqueous NaHCO ₃ (10mL). The organic layer was extracted with an aqueous solution of EtOAc (4 x 10mL), and the combined (10 mL) and washed with brine, dried over anhydrous Na ₂ SO _4, filtered, and concentrated. By silica gel chromatography (with 0 to _{5% CH 3 OH / CH 2} Cl 2 elution) and the resulting residue was purified to provide the product as a desired transparent film.

Intermediate 241:

Transparent film (263 mg). LC-MS (ES) m / z = 590 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.65 (d, J = 2.0 Hz, 1 H), 8.16 (d, J = 1.0 Hz, 1 H), 7.89 (dd, J = 8.9, 2.3 Hz, 1 H), 7.46 (d, J = 0.8Hz, 1H), 6.50 (d, J = 8.9Hz, 1H), 4.63-4.16 (m, 5H), 4.07 (s, 3H), 3.96 (s, 3H), 3.93-3.64 ( m, 2H), 3.36 (br s, 1H), 3.10-2.81 (m, 1H), 2.63 (t, J = 11.7Hz, 1H), 2.42-2.23 (m, 2H), 2.06 (d, J = 10.4 Hz, 1H), 1.72 (d, J = 5.6 Hz, 2H), 1.55-1.36 (m, 9H), 1.26-1.14 (m, 6H).

Intermediate 242:

Transparent film (169 mg). LC-MS (ES) m / z = 480 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.61 (d, J = 2.0Hz, 1H), 8.14 (d, J = 1.3Hz, 1H), 7.88 (dd, J = 8.9, 2.5Hz, 1H), 7.44 (d, J = 1.0Hz, 1H), 6.49 (d, J = 8.9Hz, 1H), 4.63-4.10 (m, 4H), 4.03 (s, 3H), 3.96 (s, 3H), 3.96-3.91 ( m, 1H), 3.89-3.73 (m, 2H), 2.97-2.70 (m, 3H), 2.68-2.40 (m, 2H), 2.37-2.17 (m, 2H), 1.72 (d, J = 5.6Hz, 2H), 1.32-1.11 (m, 6H).

Intermediate 243

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1-(((S) -morpholin -2-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide

NaOH (5M aqueous solution, 0.055mL, 0.28mmol) was added to (R) -2-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridine- 3-yl) -7-methoxy-5- (methoxycarbonyl) -1H-benzo [d] imidazol-1-yl) methyl) morpholin 4-carboxylic acid tert-butyl ester (80 mg, 0.14 mmol) in CH ₃ OH (2 mL), and the reaction mixture was stirred at 60 ° C. for 17 hours. The reaction was then cooled to room temperature and concentrated in vacuo. NH ₄ Cl (22 mg, 0.41 mmol), EDC (53 mg, 0.28 mmol), 1-hydroxy-7-azabenzotriazole (38 mg, 0.28 mmol), and N, N-diisopropylethylamine ( 0.14 mL, 0.83 mmol) was added to a solution of the resulting residue in DMSO (1.4 mL), and the reaction mixture was stirred at room temperature for 3.5 hours. Add additional EDC (53 mg, 0.28 mmol), 1-hydroxy-7-azabenzotriazole (38 mg, 0.28 mmol), and diisopropylethylamine (0.14 mL, 0.83 mmol), and stir the reaction mixture for additional 17 hours. The reaction was quenched with water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed (10 mL) with brine, dried over anhydrous Na ₂ SO _4, filtered, and concentrated. Trifluoroacetic acid (0.053 mL, 0.69 mmol) was added to a solution of the obtained residue in CH ₂ Cl ₂ (3 mL), and the reaction mixture was stirred at room temperature for 1 hour. Additional trifluoroacetic acid (0.053 mL, 0.69 mmol) was added, and after 18 hours, the mixture was concentrated in vacuo. The resulting residue was purified by reverse-phase HPLC (0.1% 10 mM NH ₄ HCO ₃ with NH ₄ OH modifier, eluting with 30 to 85% CH ₃ CN / water). The portion containing the product was concentrated and lyophilized to provide the desired product (38 mg) as a white solid. LC-MS (ES) m / z = 465 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.71-8.52 (m, 1H), 7.99-7.75 (m, 2H), 7.44 (s, 1H), 6.92 (br s, 1H), 6.51 (d, J = 8.9Hz, 1H), 5.62 (br s, 1H), 4.62-4.18 (m, 4H), 4.05 (s, 3H), 4.00-3.87 (m, 1H), 3.82 (dd, J = 11.4, 2.0Hz, 1H), 3.57-3.33 (m, 1H), 3.00-2.72 (m, 3H), 2.55 (dd, J = 11.8, 10.5Hz, 1H), 2.43-2.19 (m, 2H), 1.81-1.59 (m, 2H), 1.29-1.16 (m, 6H).

Example 177

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1-(((S) -4-methyl Morpholin-2-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide

Add formaldehyde (36.5% solution), 0.015 mL, 0.20 mmol) and sodium triacetoxyborohydride (26 mg, 0.12 mmol) to 2- (6-((2S, 5S) -2,5-dimethyl Pyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1-((((S) -morpholin-2-yl) methyl) -1H-benzo [d] imidazole-5 -A solution of formamidine (19 mg, 0.041 mmol) in 1,2-dichloroethane (2 mL), and the reaction mixture was stirred at room temperature for 1 hour. The reaction was then concentrated in vacuo and the resulting residue was purified by reverse-phase HPLC (0.1% 10 mM NH ₄ HCO ₃ with NH ₄ OH modifier, eluting with 30 to 85% CH ₃ CN / water). The product-containing portion was concentrated and lyophilized to provide the desired product (13 mg) as a white solid. LC-MS (ES) m / z = 479 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.74-8.40 (m, 1H), 7.92 (d, J = 1.3Hz, 1H), 7.90-7.81 (m, 1H), 7.43 (d, J = 1.3Hz, 1H), 7.11-6.87 (m, 1H), 6.50 (d, J = 8.9Hz, 1H), 5.64 (br s, 1H), 4.67-4.13 (m, 3H), 4.04 (s, 3H) 4.04-3.94 (m, 1H), 3.90-3.79 (m, 1H), 3.78-3.72 (m, 2H), 3.60-3.35 (m, 2H), 2.63 (dd, J = 16.9, 11.3Hz, 2H), 2.40-2.24 (m, 4H), 1.89-1.77 (m, 1H), 1.75-1.60 (m, 2H), 1.32-1.14 (m, 6H).

Example 178

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-N-methyl-1-(((S ) -4-methylmorpholin-2-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide

Add formaldehyde (36.5% solution, 0.059 mL, 0.78 mmol) and sodium triacetoxyborohydride (99 mg, 0.47 mmol) to 2-((6-((2S, 5S) -2,5-dimethyl Pyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1-((((S) -morpholin-2-yl) methyl) -1H-benzo [d] imidazole-5 -A solution of methyl formate (75 mg, 0.16 mmol) in 1,2-dichloroethane (2 mL), and the reaction mixture was stirred at room temperature for 30 minutes. The reaction was then diluted with CH ₂ Cl ₂ (20 mL) , And the obtained organic solution was washed with saturated aqueous NaHCO ₃ solution (15 mL) followed by brine (15 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. NaOH (5 M aqueous solution, 0.065 mL, 0.32 mmol) was added to the obtained residue. A solution in CH ₃ OH (2 mL) and the reaction mixture was stirred at 60 ° C. for 1 hour, then at 80 ° C. for 20 hours. The reaction was cooled to room temperature and concentrated in vacuo. Methylamine hydrochloride (33 mg, 0.49 mmol), EDC (62 mg, 0.32 mmol), 1-hydroxy-7-azabenzotriazole (44 mg, 0.32 mmol), and N, N-diisopropylethylamine (0.17 mL, 0.97 mmol) was added to a solution of the resulting residue in DMSO (1.6 mL), and the reaction mixture was stirred at room temperature for 2.5 hours. Additional methylamine was added Acid (33mg, 0.49mmol), and the reaction mixture was stirred for an additional 2 hours. The mixture was filtered and by reverse phase HPLC (with _{0.1% 10mM NH 4 HCO 3 NH} 4 OH of modifier, of 30 to 85% CH ₃ CN / water dissolution) purification. The fraction containing the product was concentrated and lyophilized to provide the desired product (32 mg) as a white solid. LC-MS (ES) m / z = 493 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.62 (d, J = 2.0Hz, 1H), 7.88 (dd, J = 8.9, 2.3Hz, 1H), 7.71 (d, J = 1.0Hz, 1H), 7.39 (d , J = 1.3Hz, 1H), 6.61-6.40 (m, 2H), 4.57-4.37 (m, 2H), 4.35-4.17 (m, 1H), 4.05 (s, 3H), 4.05-3.94 (m, 1H ), 3.82 (dd, J = 11.5, 1.6Hz, 1H), 3.52 (s, 3H), 3.52-3.43 (m, 2H), 3.04 (d, J = 4.8Hz, 3H), 2.73-2.53 (m, 2H), 2.39-2.24 (m, 2H), 2.19-2.09 (m, 1H), 1.77-1.62 (m, 3H), 1.24 (d, J = 6.3Hz, 6H).

Example 179

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -N-ethyl-7-methoxy-1-(((S ) -Morpholin-2-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide

NaOH (5M aqueous solution, 0.055mL, 0.28mmol) was added to (R) -2-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridine- 3-yl) -7-methoxy-5- (methoxycarbonyl) -1H-benzo [d] imidazol-1-yl) methyl) morpholin 4-carboxylic acid tert-butyl ester (80 mg, 0.14 mmol) in CH ₃ OH (2 mL), and the reaction mixture was stirred at 60 ° C. for 17 hours. The reaction was then cooled to room temperature and concentrated in vacuo. Ethylamine (2M in THF, 0.21 mL, 0.41 mmol), EDC (53 mg, 0.28 mmol), 1-hydroxy-7-azabenzotriazole (38 mg, 0.28 mmol), and N, N-di Isopropylethylamine (0.14 mL, 0.83 mmol) was added to a solution of the resulting residue in DMSO (1.4 mL), and the reaction was stirred at room temperature for 2 hours. Additional ethylamine (2M in THF, 0.21 mL, 0.41 mmol) was then added. After 1.5 hours, additional EDC (53 mg, 0.28 mmol), 1-hydroxy-7-azabenzotriazole (38 mg, 0.28 mmol), and ethylamine (2M in THF, 0.21 mL, 0.41 mmol) were added. After 21 hours, ethylamine hydrochloride (56 mg, 0.69 mmol) was added. After 2 hours, additional ethylamine hydrochloride (56 mg, 0.69 mmol) was added. After 19 hours, ethylamine hydrochloride (56mg, 0.69mmol), EDC (53mg, 0.28mmol), N, N-diisopropylethylamine (0.14mL, 0.83mmol), and 1-hydroxy-7- Azabenzotriazole (38 mg, 0.28 mmol). After 5 hours, the reaction was diluted with EtOAc (20 mL), followed by 1N HCl to pH = 4. The organic and aqueous layers were back extracted with EtOAc (3 x 20mL), and the combined and dried over anhydrous Na ₂ SO _4, filtered, and concentrated. Ethylamine hydrochloride (56 mg, 0.69 mmol), EDC (53 mg, 0.28 mmol), 1-hydroxy-7-azabenzotriazole (38 mg, 0.28 mmol), and N, N-diisopropylethyl Amine (0.14 mL, 0.83 mmol) was added to a solution of the resulting residue in DMSO (1.4 mL). The reaction was stirred at room temperature for 3 days, then quenched with water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed (10 mL) with brine, dried over anhydrous Na ₂ SO _4, filtered, and concentrated. Trifluoroacetic acid (0.053 mL, 0.69 mmol) was added to a solution of the resulting residue in CH ₂ Cl ₂ (1.4 mL). The reaction was stirred at room temperature for 1 hour, and then additional trifluoroacetic acid (0.053 mL, 0.69 mmol) was added. After 20 hours, the mixture was concentrated in vacuo, and _{(0.1% 10mM NH 4 HCO 3} , of 30 to 85% CH ₃ CN / water soluble Analysis) The obtained residue was purified by reverse-phase HPLC. The portion containing the product was concentrated and lyophilized to provide the desired product (39 mg) as a white solid. LC-MS (ES) m / z = 493 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.62 (d, J = 1.8Hz, 1H), 7.89 (dd, J = 8.9, 2.5Hz, 1H), 7.68 (s, 1H), 7.39 (d, J = 1.3Hz, 1H), 6.65-6.29 (m, 2H), 4.63-4.36 (m, 4H), 4.35-4.15 (m, 3H), 3.99-3.86 (m, 1H), 3.81 (dd, J = 11.4, 2.0Hz, 1H), 3.64-3.49 (m, 2H), 3.44 (td, J = 11.3, 2.8Hz, 1H), 2.98-2.69 (m, 3H), 2.55 (dd, J = 11.9, 10.4Hz, 1H ), 2.38-2.23 (m, 2H), 1.84-1.61 (m, 2H), 1.30 (t, J = 7.2Hz, 3H), 1.25-1.22 (m, 6H).

Example 180

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -N-ethyl-7-methoxy-1-(((S ) -4-methylmorpholin-2-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide

Add formaldehyde (36.5% solution, 0.017 mL, 0.22 mmol) and sodium triacetoxyborohydride (28 mg, 0.13 mmol) to 2- (6-((2S, 5S) -2,5-dimethylpyrrole Pyridin-1-yl) pyridin-3-yl) -N-ethyl-7-methoxy-1-((((S) -morpholin-2-yl) methyl) -1H-benzo [d ] A solution of imidazole-5-carboxamide (22 mg, 0.045 mmol) in 1,2-dichloroethane (2 mL), and the reaction mixture was stirred at room temperature for 1 hour, then concentrated in vacuo. The resulting residue was purified by reverse-phase HPLC (0.1% 10 mM NH ₄ HCO ₃ with NH ₄ OH modifier, eluting with 30 to 85% CH ₃ CN / water). The product-containing portion was concentrated and lyophilized to provide the desired product (22 mg) as a white solid. LC-MS (ES) m / z = 507 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.62 (d, J = 2.0Hz, 1H), 7.89 (dd, J = 8.9, 2.3Hz, 1H), 7.68 (d, J = 1.3Hz, 1H), 7.38 (d, J = 1.3Hz, 1H), 6.50 (d, J = 8.9Hz, 1H), 6.35 (t, J = 5.2Hz, 1H), 4.60-4.39 (m, 2H), 4.38-4.18 (m, 1H), 4.20-4.11 (m, 1H), 4.04 (s, 3H), 4.09-3.96 (m, 1H), 3.82 (dd, J = 11.4, 1.8Hz, 1H), 3.51 (s, 3H), 3.65 -3.37 (m, 2H), 2.63 (t, J = 10.8Hz, 2H), 2.39-2.24 (m, 3H), 2.20-2.09 (m, 1H), 1.92-1.76 (m, 1H), 1.76-1.65 (m, 2H), 1.34-1.26 (m, 3H), 1.24 (d, J = 6.1 Hz, 6H).

Intermediate 244

(R) -2-(((3-fluoro-6-hydroxy-2-nitrophenyl) amino) methyl) morpholin 4-carboxylic acid tert-butyl ester

N, N-diisopropylethylamine (0.100 mL, 0.571 mmol) was added to (R) -2- (aminemethyl) morpholin-4-carboxylic acid tert-butyl ester (124 mg, 0.571 mmol) and 2 1,4-difluoro-3-nitrophenol (100 mg, 0.571 mmol) Solution in hexane (6 mL), and the reaction mixture was stirred at room temperature for 2 hours, then at 50 ° C for 18 hours. The reaction was then heated to 70 ° C for 1 hour and at 80 ° C for 22 hours. The mixture was concentrated in vacuo, and the resulting residue was purified by silica chromatography (eluted with 0 to 60% EtOAc / hexanes) to provide the desired product (98 mg) as an orange oil. LC-MS (ES) m / z = 386 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 7.65 (br s, 1H), 6.99 (dd, J = 9.0Hz, 1H), 6.76 (t, J = 9.5Hz, 1H), 4.99 (br s, 1H) , 4.10-3.79 (m, 3H), 3.73-3.51 (m, 2H), 3.35 (d, J = 14.4Hz, 1H), 3.20-2.57 (m, 3H), 1.54-1.40 (m, 9H).

Intermediate 245

(R) -2-((2-6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-7-hydroxy-1H- Benzo [d] imidazole-7-ol-1-yl) methyl) morpholin-4-carboxylic acid tert-butyl ester

Add sodium bisulfite (127 mg, 85%, 0.618 mmol) to (R) -2-(((3-fluoro-6-hydroxy-2-nitrophenyl) amino) methyl) morpholin-4 -Tert-butyl formate (90 mg, 0.24 mmol) and 6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (52 mg, 0.25 mmol) in CH ₃ OH: A solution of a 2: 1 mixture of water (5 mL) and the reaction mixture was heated in a microwave reactor at 120 ° C for 90 minutes. The reaction was then cooled to room temperature and diluted with saturated aqueous NaHCO ₃ (10mL). The organic layer was extracted with an aqueous solution of EtOAc (4 x 10mL), and the combined (10 mL) and washed with brine, dried over anhydrous Na ₂ SO _4, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (dialysis with 0 to 60% EtOAc / hexanes) to provide the desired product (526 mg) as a pale yellow solid. LC-MS (ES) m / z = 526 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.47 (br s, 1H), 7.80 (dd, J = 8.9, 2.5 Hz, 1H), 6.93-6.79 (m, 1H), 6.69 (dd, J = 8.5, 3.7Hz, 1H), 6.51 (d, J = 8.9Hz, 1H), 4.65-4.51 (m, 1H), 4.44 (d, J = 14.7Hz, 1H), 4.37-4.21 (m, 2H), 4.06- 3.84 (m, 3H), 3.66-3.47 (m, 1H), 2.99 (br s, 1H), 2.67 (br s, 1H), 2.41-2.11 (m, 3H), 1.74 (d, J = 5.8Hz, 2H), 1.56-1.42 (m, 9H), 1.26-1.18 (m, 6H).

Example 181

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-1-(((S) -morpholin-2 -Yl) methyl) -1H-benzo [d] imidazole-7-ol

Add trifluoroacetic acid (0.93 mL, 1.2 mmol) to (R) -2-((2-6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridine-3- Phenyl) -4-fluoro-7-hydroxy-1H-benzo [d] imidazol-7-ol-1-yl) methyl) morpholin 4-carboxylic acid tert-butyl ester (96 mg, 0.18 mmol) in CH in the ₂ Cl ₂ (5mL) was added and the reaction mixture was stirred at room temperature for 3 hours. The reaction was then concentrated in vacuo and the resulting residue was purified by reverse-phase HPLC (0.1% 10 mM NH ₄ HCO ₃ with NH ₄ OH modifier, eluting with 30 to 85% CH ₃ CN / water). The portion containing the product was concentrated and lyophilized to provide the desired product (27 mg) as an off-white solid. LC-MS (ES) m / z = 426 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 8.54 (d, J = 2.0Hz, 1H), 7.94 (dd, J = 8.9, 2.3Hz, 1H), 6.80 (dd, J = 10.1, 8.6Hz, 1H ), 6.68 (d, J = 8.9Hz, 1H), 6.58 (dd, J = 8.5, 3.4Hz, 1H), 4.57 (dd, J = 14.4, 3.0Hz, 1H), 4.29 (dd, J = 14.4, 8.6Hz, 3H), 4.14-4.01 (m, 1H), 3.81 (dd, J = 11.8, 1.9Hz, 1H), 3.50-3.38 (m, 1H), 2.91 (dd, J = 12.2, 1.8Hz, 1H ), 2.85-2.66 (m, 2H), 2.52 (dd, J = 12.3, 10.5Hz, 1H), 2.40-2.25 (m, 2H), 1.85-1.57 (m, 2H), 1.26-1.15 (m, 6H ).

Intermediate 246

(R) -2-(((3-Chloro-2-nitrophenyl) amino) methyl) morpholin-4-carboxylic acid tert-butyl ester

A solution of (R) -2- (aminemethyl) morpholin-4-carboxylic acid tert-butyl ester (183 mg, 0.845 mmol) in DMF (5 mL) was added to 1-chloro-3-fluoro-2- A mixture of nifediphen (144 mg, 0.820 mmol) and K ₂ CO ₃ (136 mg, 0.984 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was then stirred at 35 ° C for 3 hours and at 40 ° C for an additional 3 hours. The reaction was then allowed to stir at 30 ° C for 2 days. The reaction was diluted with saturated aqueous NH ₄ Cl and stirred ₂ Cl ₂ and treated with CH. The resulting mixture was stirred for 10 minutes. The organic layer was separated, and the aqueous layer was further extracted with CH ₂ Cl ₂ . The combined organic extracts were dried with MgSO _4, filtered, and concentrated in vacuo to provide a crude form (R) orange residue of 2 - (((3- chloro-2-nitrophenyl) amino) methyl ) Morpholin-4-carboxylic acid tert-butyl ester (330 mg). LC-MS (ES) m / z = 316 [M + Ht butyl] ⁺ .

Intermediate 247

(R) -2-((4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [ d) imidazol-1-yl) methyl) morpholin-4-carboxylic acid tert-butyl ester

(R) -2-(((3-Chloro-2-nitrophenyl) amino) methyl) morpholin-4-carboxylic acid tert-butyl ester (321 mg, 0.863 mmol) in hot ethanol (6 mL) The solution was then added to 6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (176 mg, 0.863 mmol) and sodium bisulfite (481 mg, 85%, 2.346 mmol), and the resulting mixture was stirred for 5 minutes. The vessel was then sealed and the reaction mixture was stirred at 130 ° C for 60 minutes under microwave conditions. Next, the reaction was poured into saturated aqueous NH ₄ Cl and stirred and extracted with EtOAc (2X). The combined dried organic extracts with MgSO _4, filtered, and concentrated in vacuo. The resulting residue was purified by flash chromatography on SiO ₂ (0 to 75% (3: 1 EtOAc: EtOH with 2% NH ₄ OH) / heptane) to provide (R) -2- as a solid ((4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-1- (Methyl) methyl) morpholin-4-carboxylic acid tert-butyl ester (190 mg). LC-MS (ES) m / z = 526 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 8.55 (d, J = 2.0Hz, 1H), 7.94 (dd, J = 8.9, 2.5Hz, 1H), 7.67 (d, J = 7.9Hz, 1H) , 7.30 (dd, J = 7.7, 0.9 Hz, 1H), 7.23 (t, J = 7.9 Hz, 1H), 6.63 (d, J = 8.9 Hz, 1H), 4.42-4.50 (m, 1H), 4.34 ( dd, J = 15.2, 8.6Hz, 2H), 4.26 (br.s., 1H), 3.72 (d, J = 11.7Hz, 2H), 3.64 (d, J = 12.9Hz, 1H), 3.22 (td, J = 11.7, 2.7Hz, 1H), 2.83 (br.s., 1H), 2.57-2.71 (m, 1H), 2.24 (br.s., 2H), 1.66 (d, J = 5.6Hz, 2H) , 1.38 (s, 9H), 1.33 (br.s., 1H), 1.07-1.19 (m, 6H).

Example 182

(S) -2-((4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [ d) imidazol-1-yl) methyl) morpholin

Add TFA (0.551 mL, 7.15 mmol) to (R) -2-((4-chloro-2- (6-((2S, 5S) -2,5-di) in CH ₂ Cl ₂ (8 mL) Methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-1-yl) methyl) morpholin-4-carboxylic acid tert-butyl ester (188 mg, 0.357 mmol), The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated and the resulting residue was purified by flash chromatography on SiO ₂ (25-100% (3: 1 EtOAc: EtOH with 2% NH ₄ OH) / heptane). The portions containing the desired product are combined and concentrated. The resulting residue was dissolved in CH ₂ Cl ₂ and concentrated again. The resulting white solid was then stirred in a mixture of water, EtOAc and saturated NaHCO ₃ the solution (1mL) 15 min. The organic layer was separated, and the aqueous layer was further extracted with EtOAc. The combined dried organic extracts with MgSO _4, filtered, and concentrated in vacuo. The resulting residue was dissolved in CH ₂ Cl ₂ and heptane, and the mixture was concentrated and dried in a vacuum oven at 40 ° C. overnight to provide (S) -2-((4-chloro- 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-1-yl) methyl) Forint (115 mg). LC-MS (ES) m / z = 426 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.57 (d, J = 2.0 Hz, 1 H), 7.95 (dd, J = 8.9, 2.3 Hz, 1 H), 7.62 (dd, J = 7.9, 1.0 Hz, 1H), 7.30 (dd, J = 7.9, 1.0Hz, 1H), 7.23 (t, J = 7.9Hz, 1H), 6.63 (d, J = 8.9Hz, 1H), 4.10-4.40 (m, 4H), 3.74-3.82 (m, 1H), 3.65 (d, J = 10.9Hz, 1H), 3.21-3.29 (m, 1H), 2.82 (dd, J = 12.2,2.0Hz, 1H), 2.56-2.67 (m, 2H), 2.41 (dd, J = 12.0, 10.3Hz, 1H), 2.25 (br.s., 2H), 1.66 (d, J = 5.6Hz, 2H), 1.09-1.19 (m, 6H).

Example 183

(S) -2-((4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [ d) imidazol-1-yl) methyl) -4-methylmorpholin

Acetic acid (0.026 mL, 0.458 mmol) followed by formaldehyde (0.057 mL, 0.763 mmol) was added to (S) -2-((4-chloro-2- (1)) in 1,2-dichloroethane (4.0 mL). 6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-1-yl) methyl) morpholin ( 65 mg, 0.153 mmol), and the resulting mixture was stirred for 5 minutes. Then, sodium triacetoxyborohydride (113 mg, 0.534 mmol) was added, the vessel was capped, and the reaction mixture was stirred at room temperature for 90 minutes. The reaction by dropwise quenched with saturated aqueous NaHCO _3, then with saturated aqueous Na ₂ CO ₃ until pH = 10. Followed by addition of CH ₂ Cl _2, and the resulting mixture was stirred for 10 min. The organic layer was separated, and the aqueous layer was further extracted with CH ₂ Cl ₂ . The combined dried organic extracts with MgSO _4, filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel, gradient: 10-100% (90: 10: 1 CH ₂ Cl ₂ : CH ₃ OH: NH ₄ OH) / CH ₂ Cl ₂ ) to provide a pale (S) -2-((4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H as a yellow glass solid -Benzo [d] imidazol-1-yl) methyl) -4-methylmorpholin (53 mg). LC-MS (ES) m / z = 440 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 8.56 (d, J = 2.5Hz, 1H), 7.95 (dd, J = 9.0, 2.4Hz, 1H), 7.63 (dd, J = 8.0, 0.9Hz, 1H), 7.30 (dd, J = 7.9, 1.0 Hz, 1H), 7.23 (t, J = 7.9 Hz, 1H), 6.63 (d, J = 8.9 Hz, 1H), 4.11-4.41 (m, 4H), 3.84 (dt, J = 5.0, 2.4Hz, 1H), 3.69 (d, J = 11.4Hz, 1H), 3.26-3.32 (m, 1H), 2.73 (d, J = 10.9Hz, 1H), 2.54 (d , J = 12.7Hz, 1H), 2.24 (br.s., 2H), 2.15 (s, 3H), 1.1-2 (02, 02H), 1.75 (t, J = 10.6Hz, 1H), 1.66 (d , J = 5.6Hz, 2H), 1.15 (d, J = 6.1Hz, 6H).

Intermediate 248

2-(((2-methoxy-6-nitrophenyl) amino) methyl) morpholin-4-carboxylic acid (R) -tertiary butyl ester

Add 2-fluoro-1-methoxy-3-nitrobenzene (100 mg, 0.584 mmol), (R) -2- (aminemethyl) morpholin-4-carboxylic acid tert-butyl ester (126 mg, 0.584 mmol) , And a solution of triethylamine (0.090 mL, 0.643 mmol) in DMF (10 mL) was stirred at room temperature overnight. The reaction was quenched with water (12 mL) and extracted with CH ₂ Cl ₂ (20 mL). The organic layer was concentrated, and the resulting residue was purified on silica gel (0-100% EtOAc / hexane) to provide (R) -2-(((2-methoxy-6-nitrophenyl) as an orange oil ) Amino) methyl) morpholin-4-carboxylic acid tert-butyl ester (144 mg). LC-MS (ES) m / z = 368 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.74 (dd, J = 1.3, 8.6 Hz, 1H), 6.97 (dd, J = 1.3, 7.9 Hz, 1H), 6.72 (t, J = 8.2 Hz, 1H) , 4.09-3.68 (m, 8H), 3.52 (s, 3H), 2.97 (t, J = 12.2Hz, 1H), 2.73 (br.s., 1H), 1.48 (s, 9H).

Intermediate 249

2-((7-methoxy-2- (6-((S) -2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole (-1-yl) methyl) morpholin-4-carboxylic acid (R) -tertiary butyl ester

(R) -2-(((2-methoxy-6-nitrophenyl) amino) methyl) morpholin 4-carboxylic acid tert-butyl ester (200 mg, 0.544 mmol), (S)- 6- (2-methylpyrrolidin-1-yl) nicotinaldehyde (104 mg, 0.544 mmol), sodium bisulfite (334 mg, 85%, 1.633 mmol), ethanol (3 mL), and water (0.75 mL) were added To a 10-mL microwave tube. The tube was sealed and the reaction mixture was stirred at 130 ° C for 80 minutes under microwave conditions. The mixture was then cooled to room temperature, diluted with EtOAc, and filtered. The filtrate was concentrated and the resulting residue was purified using column chromatography (silica gel, 0 to 100% EtOA / heptane) to give the desired product (91 mg) as a white solid. LC-MS (ES) m / z = 508 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.25-1.30 (m, 3H), 1.48 (s, 9H), 1.80-1.88 (m, 1H), 2.05-2.28 (m, 3H), 2.68 (m, 1H), 2.93 (m, 1H), 3.40-3.52 (m, 1H), 3.60-3.69 (m, 1H), 3.82 (m, 4H), 4.04 (s, 3H), 4.22-4.44 (m, 2H) , 4.57 (dd, J = 14.7, 2.8 Hz, 1H), 6.67 (d, J = 8.9 Hz, 1H), 6.89 (d, J = 7.4 Hz, 1H), 7.18-7.32 (m, 2H), 7.95 ( dd, J = 8.9, 2.5Hz, 1H), 8.53 (d, J = 2.0Hz, 1H).

Example 184

(S) -2-((7-methoxy-2- (6-((S) -2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole -1-yl) methyl)

TFA (800 μl, 10.38 mmol) was added to (R) -2-((7-methoxy-2- (6-((S) -2-methylpyrrolidin-1-yl) pyridin-3-yl ) -1H-benzo [d] imidazol-1-yl) methyl) morpholin-4carboxylic acid tert-butyl ester (50 mg, 0.098 mmol) in CH ₂ Cl ₂ (2 mL), and the reaction The mixture was stirred at room temperature for 4 hours. The mixture was treated with 6N HCl (1 mL) and concentrated. The resulting residue was dried under vacuum, (3mL) was treated with ₂ CO ₃ saturated aqueous Na, and extracted with CH ₂ Cl ₂ (3X). The organic extracts were dried (Na ₂ SO ₄₎ and concentrated and the resulting residue was dried under vacuum to yield an off-white solid was the desired product (34mg). LC-MS (ES) m / z = 408 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.28 (d, J = 6.3Hz, 3H), 1.79-1.88 (m, 1H), 2.05-2.27 (m, 3H), 2.82 (dd, J = 12.4, 11.2Hz, 1H), 3.00-3.08 (m, 2H), 3.17-3.25 (m, 1H), 3.37-3.59 (m, 2H), 3.61-3.70 (m, 1H), 3.90-3.99 (m, 1H) , 4.04 (s, 3H), 4.10-4.19 (m, 1H), 4.27 (t, J = 5.7Hz, 1H), 4.38 (dd, J = 14.7, 8.4Hz , 1H), 4.62 (dd, J = 14.7 , 2.8Hz, 1H), 6.67 (d, J = 8.9Hz, 1H), 6.90 (dd, J = 7.6, 1.0Hz, 1H), 7.21-7.33 (m, 2H), 7.91 (dd, J = 9.0, 2.4Hz, 1H), 8.50 (d, J = 2.0Hz, 1H).

Intermediate 250

2-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [d] Imidazol-1-yl) methyl) morpholin-4carboxylic acid (R) -tertiary butyl ester

(R) -2-(((2-methoxy-6-nitrophenyl) amino) methyl) morpholin 4-carboxylic acid tert-butyl ester (144 mg, 0.392 mmol), 6-(( 2S, 5S) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (84 mg, 0.412 mmol), and sodium bisulfite (205 mg, 85%, 1.00 mmol) in ethanol (5 mL) and water (0.750 mL) was heated under microwave conditions at 110 ° C for 1 hour. The solid was filtered off and the filtrate was concentrated. The resulting residue was purified on silica gel (0-100% EtOAc / hexanes) to provide (R) -2-((2- (6-((2S, 5S) -2,5-dimethyl) as a white solid Pyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [d] imidazol-1-yl) methyl) morpholin 4-carboxylic acid tert-butyl ester (100 mg ). LCMS (ES) m / z = 522 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 8.51 (d, J = 2.3Hz, 1H), 7.91 (dd, J = 2.5, 8.9Hz, 1H), 7.24 (d, J = 7.9Hz, 1H) , 7.14 (t, J = 8.0 Hz, 1H), 6.83 (d, J = 7.6 Hz, 1H), 6.60 (d, J = 8.9 Hz, 1H), 4.46 (s, 1H), 4.31 (s, 3H) , 3.95 (s, 3H), 3.71 (s, 4H), 3.32 (s, 1H), 3.27-3.17 (m, 1H), 2.47-2.43 (m, 1H), 2.24 (t, J = 7.6Hz, 2H ), 1.65 (d, J = 5.3Hz, 2H), 1.39 (s, 9H), 1.14 (d, J = 6.1Hz, 6H).

Example 185

(S) -2-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H-benzene Benzo [d] imidazol-1-yl) methyl) morpholin

Will be at 1,4-two 4N HCl (5090 μl, 20.36 mmol) in alkane was added to (R) -2-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridine-3 -Yl) -7-methoxy-1H-benzo [d] imidazol-1-yl) methyl) morpholin-4-carboxylic acid tert-butyl ester (90 mg, 0.173 mmol), and the reaction mixture was placed in a chamber Stir overnight at warm temperature. The resulting precipitate was collected, washed with Et ₂ O, and dried under high vacuum to provide (S) -2-((2- (6-((2S, 5S) -2,5-dimethyl) as a white solid Pyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [d] imidazol-1-yl) methyl) morphine (45 mg) of the HCl salt. LCMS (ES) m / z = 422 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.81 (br.s., 1H), 9.52 (br.s., 1H), 8.69 (br.s., 1H), 8.09 (d, J = 9.1 Hz, 1H), 7.55-7.46 (m, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.17 (d, J = 7.6 Hz, 1H), 6.91 (br.s., 1H), 4.64 ( d, J = 12.4Hz, 3H), 4.57-4.14 (m, 3H), 4.06 (s, 3H), 3.94 (d, J = 11.9Hz, 1H), 3.64 (t, J = 11.8Hz, 1H), 3.39 (d, J = 12.4Hz, 1H), 3.21-3.13 (m, 1H), 3.03 (s, 2H), 2.29 (br.s., 2H), 1.72 (br.s., 2H), 1.18 ( br.s., 6H).

Intermediate 251

(2R, 6S) -2-(((2-methoxy-6-nitrophenyl) amino) methyl) -6-methylmorpholin-4-carboxylic acid tert-butyl ester

K ₂ CO ₃ (36.0 mg, 0.261 mmol) was added to (2R, 6S) -2- (aminemethyl) -6-methylmorpholin-4-carboxylic acid tert-butyl ester (generally according to US patent publication: 20150105370 Preparation of Compound 73, 16 Apr 2015) (60 mg, 0.261 mmol) and 2-fluoro-1-methoxy-3-nitrobenzene (44.6 mg, 0.261 mmol) in DMF (2 mL), and reacted The mixture was stirred at 23 ° C for 18 hours. The reaction was concentrated under vacuum, and the resulting residue was resuspended in EtOAc (10 mL), the solid was filtered off, and the filtrate was concentrated under vacuum. The resulting residue was purified using a silica gel column (0-60% EtOAc / heptane) to give the desired product (2R, 6S) -2-(((2-methoxy-6-nitrobenzene) as a bright orange oil. Group) amino) methyl) -6-methylmorpholin-4-carboxylic acid tert-butyl ester (68 mg). LC-MS (ES) m / z = 382 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.87 (br.s, 1H), 7.76 (dd, J = 1.3, 8.6 Hz, 1H), 6.98 (d, J = 7.1 Hz, 1H), 6.73 (dd, J = 7.9, 8.6 Hz, 1H), 3.94-4.10 (m, 2H), 3.90 (s, 3H), 3.73-3.87 (m, 1H), 3.54-3.66 (m, 2H), 3.42-3.53 (m, 1H), 2.42-2.75 (m, 2H), 1.53 (s, 9H), 1.23 (d, J = 6.1Hz, 3H).

Intermediate 252

2-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [d] Imidazol-1-yl) methyl) -6-methylmorpholin-4-carboxylic acid (2R, 6S) -tertiary butyl ester

Sodium bisulfite (226 mg, 85%, 1.105 mmol) was added to 6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (83 mg, 0.406 mmol), three Butyl (2R, 6S) -2-((((2-methoxy-6-nitrophenyl) amino) methyl) -6-methylmorpholin-4-formate (155mg, 0.406 mmol) in ethanol (2 mL) and water (0.400 mL), and the mixture was heated in a 5 mL microwave vial under microwave conditions at 130 ° C. for 60 minutes. The mixture was then concentrated under vacuum and the resulting residue was resuspended in EtOAc. The solid was filtered off and the crude material was purified by silica chromatography (0-100% EtOAc / heptane) to give the desired product (2R, 6S) -2-((2- (6- ( (2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [d] imidazol-1-yl) methyl)- 6-methylmorpholin-4-carboxylic acid tert-butyl ester (160 mg). LC-MS (ES) m / z = 450 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 8.51 (d, J = 2.0Hz, 1H), 7.94 (dd, J = 2.3, 9.1Hz, 1H), 7.19-7.30 (m, 2H), 6.88 (d , J = 7.6Hz, 1H), 6.66 (d, J = 8.9Hz, 1H), 4.59 (dd, J = 2.7,14.6Hz, 1H), 4.23-4.42 (m, 3H), 3.99-4.07 (m, 3H), 3.78-3.96 (m, 3H), 2.54 (br.s., 2H), 2.28-2.39 (m, 2H), 1.75 (d, J = 5.8Hz, 2H), 1.46 (s, 9H), 1.22 (d, J = 6.3Hz, 6H), 1.09 (d, J = 6.1Hz, 3H).

Example 186

(2S, 6S) -2-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H -Benzo [d] imidazol-1-yl) methyl) -6-methylmorpholin

6N HCl (1 mL) was added to (2R, 6S) -2-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [d] imidazol-1-yl) methyl) -6-methylmorpholin-4-carboxylic acid tert-butyl ester (160 mg, 0.299 mmol), and the reaction mixture Stir at room temperature for 1 hour. The reaction mixture was concentrated under vacuum to give the desired product (2S, 6S) -2-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1- Yl) pyridin-3-yl) -7-methoxy-1H-benzo [d] imidazol-1-yl) methyl) -6-methylmorphine HCl salt (178 mg). LC-MS (ES) m / z = 436 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 8.51 (d, J = 1.8Hz, 1H), 7.95 (dd, J = 2.3, 8.9Hz, 1H), 7.19-7.30 (m, 2H), 6.87 (dd , J = 0.8,7.9Hz, 1H), 6.66 (d, J = 8.9Hz, 1H), 4.56 (dd, J = 3.2,14.3Hz, 1H), 4.23-4.38 (m, J = 8.4,14.4Hz, 3H), 3.99 (br.s, 3H), 3.90-4.00 (m, 1H), 3.43 (ddd, J = 2.3, 6.1, 10.4Hz, 1H), 2.75-2.90 (m, 2H), 2.26-2.45 ( m, 4H), 1.68-1.83 (m, J = 5.8Hz, 2H), 1.22 (d, J = 6.1Hz, 6H), 1.04 (d, J = 6.3Hz, 3H).

Example 187

(2S, 6S) -2-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H -Benzo [d] imidazol-1-yl) methyl) -4,6-dimethylmorpholine

Add formaldehyde (0.051mL, 0.661mmol) and NaBH ₃ CN (41.5mg, 0.661mmol) to (2S, 6S) -2-((2- (6-((2S, 5S) -2,5-dimethylamine Pyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [d] imidazol-1-yl) methyl) -6-methylmorpholin hydrochloride (120mg , 0.220 mmol) solution in CH ₃ OH (5mL), the reaction mixture was stirred at room temperature for 30 minutes. The reaction was concentrated under vacuum and purified by reverse-phase HPLC (30-60% CH ₃ CN / 0.1% NH ₄ OH) to give the desired product (2S, 6S) -2-((2- ( 6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [d] imidazol-1-yl) methyl Yl) -4,6-dimethylmorpholine (24 mg). LC-MS (ES) m / z = 450 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 8.49-8.53 (m, 1H), 7.94 (dd, J = 2.4, 9.0Hz, 1H), 7.19-7.30 (m, 2H), 6.87 (dd, J = (0.9, 7.7Hz, 1H), 6.66 (d, J = 8.9Hz, 1H), 4.58 (dd, J = 2.9, 14.3Hz, 1H), 4.22-4.41 (m, 3H), 4.05-4.13 (m, 1H ), 4.01 (s, 3H), 3.42-3.55 (m, 1H), 2.80 (d, J = 11.2Hz, 1H), 2.71 (d, J = 11.2Hz, 1H), 2.32-2.42 (m, 2H) , 2.29 (s, 3H), 1.69-1.84 (m, 4H), 1.22 (d, J = 6.1Hz, 6H), 1.08 (d, J = 6.3Hz, 3H).

Intermediate 253

(2R, 6S) -2-((((2-methoxy-4- (methoxycarbonyl) -6-nitrophenyl) amino) methyl) -6-methylmorpholin-4-carboxylic acid tri Butyl ester

K ₂ CO ₃ (67.5 mg, 0.489 mmol) was added to (2R, 6S) -2- (aminemethyl) -6-methylmorpholin-4-carboxylic acid tert-butyl ester (94 mg, 0.407 mmol) and A solution of methyl 4-chloro-3-methoxy-5-nitrobenzoate (100 mg, 0.407 mmol) in DMF (2 mL), and the reaction mixture was stirred at 50 ° C for 18 hours. The reaction mixture was concentrated under vacuum and the resulting material was then resuspended in EtOAc (10 mL) and filtered. The filtrate was concentrated and the resulting residue was purified by silica gel chromatography (0-60% EtOAc / heptane) to give the desired product (2R, 6S) -2-(((2-methoxy 4- (methoxycarbonyl) -6-nitrophenyl) amino) methyl) -6-methylmorpholin-4-carboxylic acid tert-butyl ester (110 mg). LC-MS (ES) m / z = 440 [M + H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 8.39 (d, J = 1.8 Hz, 1 H), 7.6 (d, J = 1.8 Hz, 1 H), 3.86-4.00 (m, 9H), 3.50-3.68 (m , 3H), 2.37-2.76 (m, 2H), 1.49 (s, 9H), 1.20 (s, 3H).

Intermediate 254

(2R, 6S) -2-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-5 -(Methoxycarbonyl) -1H-benzo [d] imidazol-1-yl) methyl) -6-methylmorpholin-4-carboxylic acid tert-butyl ester

Add sodium bisulfite (139 mg, 85%, 0.681 mmol) to 6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (51.1 mg, 0.250 mmol) and (2R, 6S) -2-((((2-methoxy-4- (methoxycarbonyl) -6-nitrophenyl) amino) methyl) -6-methylmorpholin-4-carboxylic acid tri A solution of grade butyl ester (110 mg, 0.250 mmol) in ethanol (2 mL) and water (0.400 mL), and the reaction mixture was heated in a microwave reactor at 130 ° C for 60 minutes. The mixture was concentrated under vacuum, and the resulting residue was dissolved in EtOAc and filtered to remove solids. The filtrate was concentrated under vacuum, and the resulting residue was purified by silica gel chromatography (0-100% EtOAc / heptane) to give the desired compound (2R, 6S) -2-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-5- (methoxycarbonyl) -1H-benzo [ d] Imidazol-1-yl) methyl) -6-methylmorpholin-4-carboxylic acid tert-butyl ester (85 mg). LC-MS (ES) m / z = 594 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): 88.54 (d, J = 2.3Hz, 1H), 8.01 (d, J = 1.3Hz, 1H), 7.97 (dd, J = 2.4, 9.0Hz, 1H), 7.52 (d, J = 0.8Hz, 1H), 6.64-6.72 (m, 1H), 4.64 (dd, J = 2.7, 14.6Hz, 1H), 4.25-4.47 (m, 3H), 4.07-4.13 (m, 3H ), 3.93-3.99 (m, 4H), 3.79-3.93 (m, 2H), 3.36-3.43 (m, 1H), 2.43-2.67 (m, 2H), 2.28-2.41 (m, 2H), 1.69-1.82 (m, 2H), 1.47 (s, 9H), 1.23 (d, J = 6.3 Hz, 6H), 1.09 (d, J = 6.1 Hz, 3H).

Intermediate 255

1-(((2S, 6S) -4,6-dimethylmorpholin-2-yl) methyl) -2- (6-((2S, 5S) -2,5-dimethylpyrrole -1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [d] imidazole-5-carboxylic acid methyl ester

6N HCl (2.386 mL, 14.32 mmol) was added to (2R, 6S) -2-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridine- 3-yl) -7-methoxy-5- (methoxycarbonyl) -1H-benzo [d] imidazol-1-yl) methyl) -6-methylmorpholin-4-carboxylic acid tert-butyl ester (85mg, 0.143mmol) in the ₃ OH (2mL) solution of CH, and the reaction mixture was stirred at room temperature for 1 hour. The reaction was then concentrated in vacuo, and the resulting crude mixture was dissolved in CH ₃ OH (2mL). Next, formaldehyde (0.020 mL, 0.716 mmol) and sodium cyanoborohydride (27.0 mg, 0.429 mmol) were added, and the reaction mixture was stirred at 23 ° C for 30 minutes. The mixture was concentrated under vacuum and purified by reverse-phase HPLC (30-60% CH ₃ CN / (0.1% NH ₄ OH)) to give the desired product as a white solid 1-(((2S, 6S) -4 , 6-dimethylmorpholin-2-yl) methyl) -2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [d] imidazole-5-carboxylic acid methyl ester (53 mg). LC-MS (ES) m / z = 508 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 8.47-8.56 (m, 1H), 7.88-8.04 (m, 2H), 7.46-7.57 (m, 1H), 6.63-6.70 (m, 1H), 4.61 ( dd, J = 2.8, 14.5Hz, 1H), 4.23-4.43 (m, 3H), 4.00-4.15 (m, 4H), 3.90-3.97 (m, 3H), 3.43-3.55 (m, 1H), 2.79- 2.86 (m, 1H), 2.72 (d, J = 11.4Hz, 1H), 2.33-2.41 (m, 2H), 2.30 (s, 3H), 1.67-1.83 (m, 4H), 1.17-1.28 (m, 6H), 0.99-1.13 (m, 3H).

Example 188

1-(((2S, 6S) -4,6-dimethylmorpholin-2-yl) methyl) -2- (6-((2S, 5S) -2,5-dimethylpyrrolidine -1-yl) pyridin-3-yl) -7-methoxy-N-methyl-1H-benzo [d] imidazole-5-carboxamide

The 5N NaOH (1mL, 5mmol) was added to the in CH ₃ OH (2mL) of 1 - (((2S, 6S ) -4,6- dimethylmorpholin phenylephrine-yl) methyl) -2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [d] imidazole-5-carboxylic acid methyl ester Ester (65 mg, 0.128 mmol), and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under vacuum, resuspended in 6N HCl (1 mL), and concentrated. 3-(((Ethylamino) methylene) amino) -N, N-dimethylprop-1-amine hydrochloride (49.1mg, 0.256mmol), 3H- [1,2,3] Triazolo [4,5-b] pyridin-3-ol (34.9 mg, 0.256 mmol), 4-methylmorpholine (0.099 mL, 0.896 mmol), and methylamine hydrochloride (17.29 mg, 0.256 mmol ) Was added to the resulting crude mixture in DMSO (2 mL), and the reaction mixture was stirred at room temperature for 18 hours. The reaction was then diluted with water (2 mL) and purified by reverse-phase HPLC (30-60% CH ₃ CN / (0.1% NH ₄ OH)) to provide 1-((((2S, 6S) -4, 6-dimethylmorpholin-2-yl) methyl) -2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl)- 7-methoxy-N-methyl-1H-benzo [d] imidazole-5-carboxamide (22 mg). LC-MS (ES) m / z = 507 [M + H] +. ¹ H NMR (400MHz, CD ₃ OD): δ 8.52 (d, J = 1.8Hz, 1H), 7.96 (dd, J = 2.4, 9.0 Hz, 1H), 7.78 (s, 1H), 7.37 (d, J = 1.3Hz, 1H), 6.67 (d, J = 8.9Hz, 1H), 4.61 (dd, J = 2.8, 14.5Hz, 1H), 4.25-4.42 (m, J = 8.6, 14.4Hz, 3H), 4.02 -4.12 (m, 4H), 3.42-3.52 (m, J = 2.3, 6.4, 10.3 Hz, 1H), 2.97 (s, 3H), 2.82 (d, J = 11.2 Hz, 1H), 2.72 (d, J = 11.2Hz, 1H), 2.33-2.41 (m, 2H), 2.28 (s, 3H), 1.69-1.84 (m, 4H), 1.21 (d, J = 6.3Hz, 6H), 1.08 (d, J = 6.1Hz, 3H).

Intermediate 256

2-((5-Aminomethylamidino-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy- 1H-benzo [d] imidazol-1-yl) methyl) -6-methylmorpholin-4-carboxylic acid (2R, 6S) -tertiary butyl ester

5N NaOH (2.69 mL, 13.47 mmol) was added to (2R, 6S) -2-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridine- 3-yl) -7-methoxy-5- (methoxycarbonyl) -1H-benzo [d] imidazol-1-yl) methyl) -6-methylmorpholin-4-carboxylic acid tert-butyl ester (800mg, 1.347mmol) in the ₃ OH (10mL) solution of CH, and the reaction mixture was stirred at room temperature overnight. The reaction was acidified using 1N HCl (13.4 mL), and the resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic extracts were dried over MgSO ₄ , filtered, and concentrated under vacuum to provide crude 1-((((2R, 6S) -4- (tertiary butoxycarbonyl) -6-methylmorpholin-2 -Yl) methyl) -2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [d] Imidazole-5-carboxylic acid. LC-MS (ES) m / z = 580 [M + H] ⁺ .

3-(((Ethylamino) methylene) amino) -N, N-dimethylpropan-1-amine hydrochloride (265mg, 1.380mmol), 3H- [1,2,3] Zolo [4,5-b] pyridin-3-ol (188 mg, 1.380 mmol), NH ₄ Cl (185 mg, 3.45 mmol), and 4-methylmorpholine (0.759 mL, 6.90 mmol) were added to 1- ((((2R, 6S) -4- (tertiary butoxycarbonyl) -6-methylmorpholin-2-yl) methyl) -2- (6-((2S, 5S) -2,5- Dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [d] imidazole-5-carboxylic acid (400 mg, 0.690 mmol) in DMSO (5 mL), The reaction mixture was stirred at room temperature all weekend. The reaction mixture was diluted with water (25 mL) and extracted with EtOAc (3x). The combined dried organic extracts with MgSO _4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (0-100% (3: 1 EtOAc: EtOH) / CH ₂ Cl ₂ ) to give the desired product (2R, 6S) -2-((5 as a white solid -Aminomethyl-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [ d] Imidazol-1-yl) methyl) -6-methylmorpholin-4-carboxylic acid tert-butyl ester (395 mg). LC-MS (ES) m / z = 579 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 8.53 (d, J = 2.0Hz, 1H), 7.96 (dd, J = 2.4, 9.0Hz, 1H), 7.87 (d, J = 1.3Hz, 1H), 7.43 (d, J = 1.0Hz, 1H), 6.66 (d, J = 8.9Hz, 1H), 4.62 (dd, J = 2.7, 14.6Hz, 1H), 4.22-4.45 (m, 3H), 4.10 (s , 3H), 3.80-4.04 (m, 3H), 3.36-3.42 (m, 1H), 2.43-2.65 (m, 2H), 2.25-2.41 (m, 2H), 1.66-1.81 (m, 2H), 1.47 (s, 9H), 1.21 (d, J = 6.3 Hz, 6H), 1.09 (d, J = 6.1 Hz, 3H).

Intermediate 257

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1-(((22,6S) -6 -Methylmorpholin-2-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide

6N aqueous HCl (2 mL, 12.00 mmol) was added to (2R, 6S) -2-((5-aminomethylmethyl-2- (6-((2S, 5S) -2,5-dimethylpyrrolidine) -1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [d] imidazol-1-yl) methyl) -6-methylmorpholin-4-carboxylic acid tert-butyl ester (395 mg, 0.683 mmol) in THF (2 mL), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum, and the resulting residue was triturated with Et ₂ O (3X) to give the desired product 2- (6-((2S, 5S) -2,5-dimethyl) as a white solid. Pyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1-((((2S, 6S) -6-methylmorpholin-2-yl) methyl) -1H-benzo [d] HCI salt of imidazole-5-carboxamide (404 mg). LC-MS (ES) m / z = 479 [M + H] ⁺ .

Example 189

1-(((2S, 6S) -4,6-dimethylmorpholin-2-yl) methyl) -2- (6-((2S, 5S) -2,5-dimethylpyrrolidine -1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [d] imidazole-5-carboxamide

NaBH ₄ CN (19.62 mg, 0.312 mmol) was added to 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy -1-((((2S, 6S) -6-methylmorpholin-2-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide, hydrochloride (65mg, 0.104 mmol) and formaldehyde (8.60 μl, 0.312 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. The reaction was diluted with NH ₄ OH (1 mL) and purified by reverse-phase HPLC (30-70% CH ₃ CN / 0.1% NH ₄ OH) to provide the desired product 1-(((2S, 6S) as a white solid -4,6-dimethylmorpholin-2-yl) methyl) -2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridine-3- ) -7-methoxy-1H-benzo [d] imidazole-5-carboxamide (36 mg). LC-MS (ES) m / z = 493 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 8.53 (d, J = 2.0Hz, 1H), 7.96 (dd, J = 2.5, 8.9Hz, 1H), 7.87 (d, J = 1.5Hz, 1H), 7.43 (d, J = 1.3Hz, 1H), 6.67 (d, J = 8.9Hz, 1H), 4.61 (dd, J = 2.8, 14.5Hz, 1H), 4.34 (dd, J = 8.9, 14.5Hz, 3H ), 4.01-4.13 (m, 4H), 3.40-3.53 (m, 1H), 2.83 (d, J = 11.2Hz, 1H), 2.72 (d, J = 11.2Hz, 1H), 2.33-2.43 (m, 2H), 2.31 (s, 3H), 1.68-1.83 (m, 4H), 1.23 (d, J = 6.3Hz, 6H), 1.07 (d, J = 6.1Hz, 3H).

Intermediate 258

(R) -2-(((2-fluoro-6-nitrophenyl) amino) methyl) morpholin-4-carboxylic acid tert-butyl ester

K ₂ CO ₃ (192 mg, 1.387 mmol) was added to (R) -2- (aminemethyl) morpholin-4-carboxylic acid tert-butyl ester (300 mg, 1.387 mmol) and 1,2-difluoro-3 -A solution of nifediene (221 mg, 1.387 mmol) in DMF (5 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic extracts were dried with MgSO _4, filtered, and concentrated in vacuo to provide a crude form (R) orange oil of 2 - (((2- fluoro-6-nitrophenyl) amino) methyl) Morpholin-4-carboxylic acid tert-butyl ester (493 mg). LC-MS (ES) m / z = 300 [[M-tBu] + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 7.93-7.99 (m, 1H), 7.86 (br.s., 1H), 7.35 (dd, J = 8.0, 14.1Hz, 1H), 6.66-6.77 (m , 1H), 3.90-4.01 (m, 2H), 3.85 (tdd, J = 1.4, 2.8, 13.4 Hz, 1H), 3.67-3.80 (m, 1H), 3.44-3.67 (m, 3H), 2.91-3.07 (m, 1H), 2.59-2.84 (m, 1H), 1.48 (s, 9H).

Intermediate 259

(R) -2-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-fluoro-1H-benzo [ d) -Imidazol-1-yl) methyl) morpholin-4-carboxylic acid tert-butyl ester

Add sodium bisulfite (776 mg, 85%, 3.791 mmol) to (R) -2-(((2-fluoro-6-nitrophenyl) amino) methyl) morpholin-4-carboxylic acid tertiary Butyl ester (480 mg, 1.351 mmol) and 6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (276 mg, 1.351 mmol) in ethanol (8 mL) and water (2 mL ), And the reaction vessel was sealed and heated at 130 ° C for 80 minutes under microwave conditions. After cooling, the reaction was concentrated under vacuum and the resulting residue was resuspended in EtOAc. The mixture was filtered, and the filtrate was concentrated under vacuum and purified by silica chromatography (0-100% EtOAc / heptane) to give the desired product (R) -2-((2- (6 -((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-fluoro-1H-benzo [d] imidazol-1-yl) methyl) Folin-4-carboxylic acid tert-butyl ester (302 mg). LC-MS (ES) m / z = 510 [M + H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 8.56-8.62 (m, 1H), 7.94-8.00 (m, 1H), 7.47-7.53 (m, 1H), 7.27 (dt, J = 4.8, 8.1 Hz, 1H), 7.09 (dd, J = 7.7, 11.8 Hz, 1H), 6.70 (d, J = 8.9 Hz, 1H), 4.39-4.54 (m, 2H), 4.18-4.38 (m, 2H), 3.97 (br .s., 1H), 3.75-3.91 (m, 3H), 2.87-3.11 (m, 1H), 2.58-2.84 (m, 1H), 2.26-2.44 (m, 2H), 1.68-1.82 (m, 2H ), 1.49 (s, 9H), 1.24 (d, J = 6.3Hz, 6H).

Example 190

(S) -2-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-fluoro-1H-benzo [ d] imidazol-1-yl) methyl) morpholin, 3 hydrochloride

6N aqueous HCl (2 mL, 12.00 mmol) was added to (R) -2-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridine-3- A solution of tert-butyl) -7-fluoro-1H-benzo [d] imidazol-1-yl) methyl) morpholin-4-carboxylic acid tert-butyl ester (302 mg, 0.593 mmol) in THF (5 mL), and The reaction mixture was stirred at room temperature for 1 hour. The reaction was concentrated under vacuum and the resulting material was triturated with Et ₂ O (2x) to give the desired product (S) -2-((2- (6-((2S, 5S) -2) as a white solid , 5-Dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-fluoro-1H-benzo [d] imidazol-1-yl) methyl) morphine HCl salt (307 mg). LC-MS (ES) m / z = 410 [M + H] +. ¹ H NMR (400MHz, CD ₃ OD): δ 8.94 (d, J = 1.8Hz, 1H), 8.30-8.39 (m, 1H), 7.67-7.82 (m, 2H), 7.46-7.61 (m, 2H) , 4.78-4.92 (m, 2H), 4.67-4.76 (m, 1H), 4.43-4.65 (m, 3H), 4.22 (dd, J = 2.7, 13.1Hz, 1H), 3.82 (ddd, J = 3.3, 11.5, 13.1Hz, 1H), 3.64 (d, J = 11.7Hz, 1H), 3.39-3.46 (m, 1H), 3.22-3.30 (m, 1H), 2.52 (t, J = 6.2Hz, 2H), 1.96 (t, J = 6.7 Hz, 2H), 1.30-1.43 (m, 6H).

Example 191

(S) -2-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-fluoro-1H-benzo [ d) imidazol-1-yl) methyl) -4-methylmorpholin

Add formaldehyde (0.015 mL, 0.193 mmol) followed by NaBH ₃ CN (22 mg, 0.350 mmol) to (S) -2-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidine -1-yl) pyridin-3-yl) -7-fluoro-1H-benzo [d] imidazol-1-yl) methyl) morpholin, 3 hydrochloride (50 mg, 0.096 mmol) in CH ₃ OH (5 mL), and the reaction mixture was stirred at room temperature for 30 minutes. The reaction was diluted with 0.1% NH ₄ OH (1 mL) and purified by reverse-phase HPLC (30-70% CH ₃ CN / 0.1% NH ₄ OH) to give the desired product (S) -2-(-) as a white solid (2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-fluoro-1H-benzo [d] imidazol-1-yl ) Methyl) -4-methylmorphine (23 mg). LC-MS (ES) m / z = 424 [M + H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 8.55-8.61 (m, 1H), 7.97 (dd, J = 2.5, 8.9 Hz, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.27 (dt , J = 4.8, 8.1 Hz, 1H), 7.08 (ddd, J = 0.8, 8.1, 11.9 Hz, 1H), 6.70 (d, J = 8.6 Hz, 1H), 4.38-4.50 (m, 2H), 4.33 ( br.s., 2H), 4.04 (ddt, J = 1.9, 4.1, 8.2 Hz, 1H), 3.78-3.90 (m, 1H), 3.47 (dt, J = 2.4, 11.6 Hz, 1H), 2.85 (d , J = 11.4Hz, 1H), 2.64-2.73 (m, 1H), 2.34-2.41 (m, 2H), 2.31 (s, 3H), 2.18 (dt, J = 3.3, 11.7Hz, 1H), 1.90- 1.99 (m, 1H), 1.68-1.82 (m, 2H), 1.23 (d, J = 6.1 Hz, 6H).

Intermediate 260

2-((4-chloro-2- (6-((S) -2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-1-yl) methyl (Formyl) morpholin-4-carboxylic acid (R) -tertiary butyl ester

(R) -2-((((3-Chloro-2-nitrophenyl) amino) methyl) morpholine-4-carboxylic acid tert-butyl ester (120 mg, 0.323 mmol) in ethanol (2 mL) Water (0.4 mL) was then added to (S) -6- (2-methylpyrrolidin-1-yl) nicotinaldehyde (61.4 mg, 0.323 mmol) and sodium bisulfite (180 mg, 85%, 0.878 mmol). The reaction mixture was heated at 130 ° C for 60 minutes under microwave conditions. Followed by addition of saturated aqueous NH ₄ Cl, and the resulting mixture was extracted with EtOAc (2x). The combined dried organic extracts with MgSO _4, filtered, and concentrated in vacuo. The resulting residue was purified by flash chromatography on SiO ₂ (5-70% (3: 1 EtOAc / EtOH with 2% NH ₄ OH) / heptane) to provide the desired product as a white solid (75 mg ). LC-MS (ES) m / z = 512 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 8.55 (d, J = 2.0Hz, 1H), 7.94 (dd, J = 8.9, 2.5Hz, 1H), 7.67 (d, J = 7.9Hz, 1H) , 7.30 (dd, J = 7.7, 0.9 Hz, 1H), 7.23 (t, J = 7.9 Hz, 1H), 6.63 (d, J = 8.9 Hz, 1H), 4.42-4.50 (m, 1H), 4.34 ( dd, J = 15.2, 8.6Hz, 2H), 4.26 (br.s., 1H), 3.72 (d, J = 11.7Hz, 2H), 3.64 (d, J = 12.9Hz, 1H), 3.22 (td, J = 11.7, 2.7Hz, 1H), 2.83 (br.s., 1H), 2.57-2.71 (m, 1H), 2.24 (br.s., 2H), 1.66 (d, J = 5.6Hz, 2H) , 1.38 (s, 9H), 1.33 (br.s., 1H), 1.07-1.19 (m, 6H).

Example 192

(S) -2-((4-chloro-2- (6-((S) -2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-1 -Yl) methyl) morpholin

TFA (0.316 mL, 4.10 mmol) was added to (R) -2-((4-chloro-2- (6-((S) -2-methylpyrrolidine-) in CH ₂ Cl ₂ (4 mL) 1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-1-yl) methyl) morpholin 4-carboxylic acid tert-butyl ester (70 mg, 0.137 mmol), and the reaction mixture was Stir at room temperature for 2 hours. The mixture was concentrated, and by flash chromatography on _{SiO 2 (25-100% (3:} 1 EtOAc / 2% NH ₄ OH having the EtOH) / heptane) and the resulting residue was purified. The portions containing the desired product are combined and concentrated. The resulting residue was dissolved in CH ₂ Cl ₂ , treated with heptane, and the mixture was concentrated. The resulting residue was then water mixture, CH ₂ Cl _2, and saturated aqueous NaHCO ₃ solution (0.5mL) of stirred for 15 minutes. The organic layer was separated, and the aqueous layer was further extracted with CH ₂ Cl ₂ . The organic extracts were combined and dried over MgSO _4, filtered, and concentrated in vacuo. The resulting residue was dissolved in CH ₂ Cl ₂ and treated with heptane. The mixture was then concentrated and dried in a vacuum oven at 40 ° C. overnight to provide (S) -2-((4-chloro-2- (6-((S) -2-methylpyrrolidine) as a white solid foam 1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-1-yl) methyl) morpholin (40 mg). LC-MS (ES) m / z = 412 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.57 (d, J = 2.0 Hz, 1 H), 7.98 (dd, J = 8.9, 2.3 Hz, 1 H), 7.62 (dd, J = 8.0, 0.9 Hz, 1H), 7.30 (dd, J = 7.6, 1.0Hz, 1H), 7.23 (t, J = 8.0Hz, 1H), 6.61 (d, J = 8.9Hz, 1H), 4.17-4.39 (m, 3H), 3.70-3.80 (m, 1H), 3.52-3.66 (m, 2H), 3.19-3.27 (m, 1H), 2.78 (dd, J = 12.0, 2.2Hz, 1H), 2.56-2.63 (m, 2H), 2.37 (dd, J = 12.0, 10.3 Hz, 3H), 1.93-2.14 (m, 3H), 1.66-1.77 (m, 1H), 1.21 (d, J = 6.3 Hz, 3H).

Example 193

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -N-ethyl-3-((1-methyl-1H-pyridine Azol-3-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-carboxamide

Follow a procedure similar to the procedure described in Example 132 from 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3-(( 1-methyl-1H-pyrazol-3-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-carboxylic acid (74 mg, 0.171 mmol) and ethylamine (2M, 0.171 mL, 0.342 mmol) of the title compound was prepared to provide the desired product (76 mg) as an off-white solid. LC-MS (ES) m / z = 459 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.17-1.26 (m, 6H), 1.26-1.34 (m, 3H), 1.67-1.85 (m, 2H), 2.34 (m, 2H), 3.43-3.54 ( m, 2H), 3.84 (s, 3H), 4.32 (m, 2H), 5.63 (s, 2H), 6.16 (d, J = 2.3Hz, 1H), 6.69 (d, J = 8.9Hz, 1H), 7.53 (d, J = 2.3Hz, 1H), 8.00 (dd, J = 9.1, 2.5Hz, 1H), 8.46 (d, J = 2.0Hz, 1H), 8.59 (d, J = 2.5Hz, 1H), 8.86 (d, J = 2.0Hz, 1H).

Example 194

N- (2,2-difluoroethyl) -2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3-(( 1-methyl-1H-pyridin-3-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-carboxamide

Follow a procedure similar to the procedure described in Example 132 from 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3-(( 1-methyl-1H-pyrazol-3-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-carboxylic acid (80 mg, 0.185 mmol) and 2,2-difluoroethyl-1 -Amine (27.1 mg, 0.334 mmol) to provide the desired product (32 mg) as an off-white solid. LC-MS (ES) m / z = 495 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.21 (d, J = 5.8Hz, 6H), 1.63-1.86 (m, 2H), 2.33 (m, 2H), 3.78-3.84 (m, 5H), 4.31 (m, 2H), 5.62 (s, 2H), 6.08 (br.s., 1H), 5.94-6.16 (m, 2H), 6.67 (d, J = 8.9Hz, 1H), 7.53 (br.s. , 1H), 8.00 (d, J = 8.1 Hz, 1H), 8.48 (br.s., 1H), 8.59 (br.s., 1H), 8.88 (br.s., 1H).

Intermediate 261

(R) -N-((1,4-two Alk-2-yl) methyl) -2- (methoxy-d3) -6-nitroaniline

Put (R)-(1,4-two Alk-2-yl) methylamine (161 mg, 1.378 mmol) and DIEA (0.261 mL, 1.493 mmol) were added to 2-fluoro-1- (methoxy-d3) -3-nitrobenzene (200 mg, 1.148 mmol) at A solution in DMSO (5 mL), and the reaction mixture was stirred at 60 ° C for 20 hours. The mixture was cooled to room temperature, quenched with water (10 mL), and extracted with EtOAc (3x). The organic extracts were dried (Na ₂ SO ₄₎ and concentrated. The resulting residue was purified using column chromatography (silica gel, 0 to 100% EtOAc / heptane) to give the desired product (210 mg) as a brown solid. LC-MS (ES) m / z = 272 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 3.41-3.54 (m, 2H), 3.61-3.91 (m, 8H), 6.74 (dd, J = 8.6, 7.9Hz, 1H), 6.98 (dd, J = 8.0 , 1.4Hz, 1H), 7.76 (dd, J = 8.7, 1.4Hz, 1H).

Example 195

1-(((R) -1,4-two Alk-2-yl) methyl) -2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7- (methoxy- d3) -1H-benzo [d] imidazole

Put (R) -N-((1,4-two Alk-2-yl) methyl) -2- (methoxy-d3) -6-nitroaniline (110 mg, 0.405 mmol), 6-((2S, 5S) -2,5-dimethylpyrrolidine- 1-yl) nicotinaldehyde (87 mg, 0.426 mmol), sodium bisulfite (85%, 249 mg, 1.216 mmol), ethanol (2 mL), and water (0.50 mL) were added to a microwave container. The vessel was sealed and the reaction mixture was stirred at 130 ° C for 80 minutes under microwave conditions. The mixture was then cooled to room temperature, diluted with EtOAc, and filtered. The filtrate was concentrated, and the resulting residue was purified using column chromatography (silica, 0 to 100% (3: 1 EtOAc: EtOH) / heptane) to give the desired product (31 mg) as an off-white solid. LC-MS (ES) m / z = 426 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.23 (d, J = 6.3Hz, 6H), 1.76 (d, J = 5.6Hz, 2H), 2.36 (d, J = 2.3Hz, 1H), 3.48- 3.85 (m, 6H), 4.08 (m, 1H), 4.28 (m, 3H), 4.50 (dd, J = 14.6, 2.9Hz, 1H), 6.69 (d, J = 8.6Hz, 1H), 6.88 (dd , J = 7.7, 1.1 Hz, 1H), 7.19-7.32 (m, 2H), 7.93 (dd, J = 9.0, 2.4Hz, 1H), 8.47-8.58 (m, 1H).

Example 196

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7- (methoxy-d3) -1- (pyridine 2-ylmethyl) -1H-benzo [d] imidazole

Follow a procedure similar to the preparation of intermediate 261 to prepare 2- (methoxy-d3) -6-nitro-N- (pyridine 2-ylmethyl) aniline. Follow a procedure similar to that described for the preparation of Example 195 from 2- (methoxy-d3) -6-nitro-N- (pyridine 2-ylmethyl) aniline (100 mg, 0.380 mmol) and 6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (81 mg, 0.399 mmol) To provide the desired product (42 mg) as a light brown solid. LC-MS (ES) m / z = 418 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.18-1.30 (m, 6H), 1.78-1.89 (m, 2H), 2.39 (m, 2H), 4.29 (br.s., 1H), 4.47 (br .s., 1H), 5.98 (s, 2H), 6.98 (d, J = 9.4Hz, 1H), 7.05 (d, J = 8.1Hz, 1H), 7.36-7.43 (m, 1H), 7.46-7.58 (m, 1H), 8.12 (dd, J = 9.2, 2.4 Hz, 1H), 8.54 (dd, J = 2.5, 1.5 Hz, 1H), 8.60 (d, J = 2.5 Hz, 1H).

Intermediate 262

2-((7-methoxy-5- (methoxycarbonyl) -2- (6-((S) -2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo (d) Imidazol-1-yl) methyl) morpholin-4-carboxylic acid (R) -tertiary butyl ester

(R) -2-(((2-methoxy-4- (methoxycarbonyl) -6-nitrophenyl) amino) methyl) morpholin-4-carboxylic acid tert-butyl ester (380 mg, 0.893 mmol), (S) -6- (2-methylpyrrolidin-1-yl) nicotinaldehyde (170 mg, 0.893 mmol), sodium bisulfite (85%, 549 mg, 2.68 mmol), ethanol (5 mL) , And water (1 mL) were added to a sealable container. The vessel was sealed and the reaction mixture was stirred at 110 ° C for 18 hours. The mixture was then cooled to room temperature, diluted with EtOAc, and filtered. The filtrate was concentrated, and the resulting residue was purified using column chromatography (silica gel, 0 to 100% EtOA / heptane) to give the desired product (339 mg) as a light brown solid. LC-MS (ES) m / z = 566 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.23-1.31 (m, 3H), 1.43-1.50 (m, 9H), 1.80-1.88 (m, 1H), 2.04-2.27 (m, 3H), 2.69 ( br.s., 1H), 2.96 (br.s., 1H), 3.42-3.52 (m, 1H), 3.61-3.70 (m, 1H), 3.76-3.92 (m, 3H), 3.96 (s, 3H ), 4.09 (s, 3H), 4.24-4.42 (m, 2H) 4.59 (dd, J = 14.7, 2.8Hz, 1H), 6.67 (d, J = 8.6Hz, 1H), 7.46-7.55 (m, 1H ), 7.91-8.04 (m, 2H), 8.56 (d, J = 2.0Hz, 1H).

Intermediate 263

2-((5- (ethylaminomethylmethyl) -7-methoxy-2- (6-((S) -2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H -Benzo [d] imidazol-1-yl) methyl) morpholin-4-carboxylic acid (R) -tertiary butyl ester

Add sodium hydroxide (5N, 800 μl, 4.00 mmol) to (R) -2-((7-methoxy-5- (methoxycarbonyl) -2- (6-((S) -2-methyl Pyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-1-yl) methyl) morpholin 4-carboxylic acid tert-butyl ester (130 mg, 0.230 mmol) in CH ₃ Solution in OH (2 mL), and the mixture was stirred at 40 ° C for 18 hours. The reaction mixture was neutralized by adding HCl (6N, 667 μl, 4.00 mmol) and concentrated. The resulting residue was dried under vacuum and treated with DMSO (2.0 mL). Will ethylamine (2N, 195 μl, 0.391 mmol), EDC (88 mg, 0.460 mmol), 1-hydroxy-7-azabenzotriazole (62.6 mg, 0.460 mmol), and N-methyl be added in THF? Forint (202 μl, 1.839 mmol) was added to this mixture, and the mixture was stirred at room temperature for 18 hours. The reaction was quenched with water (5 mL) and extracted with EtOAc (3x). The organic extracts were dried (Na ₂ SO ₄₎ and concentrated. The resulting residue was purified using column chromatography (silica gel, 0 to 100% 3: 1 EtOAc: EtOH / heptane) to give the desired product (81 mg) as an off-white solid. LC-MS (ES) m / z = 579.5 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.24-1.33 (m, 6H), 1.44-1.51 (m, 9H), 1.79-1.86 (m, 1H), 2.02-2.26 (m, 3H), 2.94 ( br.s., 1H), 3.39-3.53 (m, 3H), 3.59-3.71 (m, 1H), 3.77-4.06 (m, 5H), 4.10 (s, 3H), 4.27 (m, 1H), 4.37 (m, 1H), 4.53-4.65 (m, 1H), 6.66 (d, J = 8.9Hz, 1H), 7.36-7.42 (m, 1H), 7.79 (d, J = 1.5Hz, 1H), 7.96 ( dd, J = 9.0, 2.4 Hz, 1H), 8.55 (d, J = 2.0 Hz, 1H).

Intermediate 264

N-ethyl-7-methoxy-2- (6-((S) -2-methylpyrrolidin-1-yl) pyridin-3-yl) -1-((S) -morpholin- 2-ylmethyl) -1H-benzo [d] imidazole-5-carboxamide

TFA (500 μl, 6.49 mmol) was added to (R) -2-((5- (ethylaminemethylmethyl) -7-methoxy-2- (6-((S) -2-methylpyrrole) Pyridin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-1-yl) methyl) morpholin 4-carboxylic acid tert-butyl ester (76 mg, 0.131 mmol) in CH ₂ Cl ₂ (2 mL), and the mixture was stirred at room temperature for 4 hours. The mixture was treated with 6N HCl (1 mL) and concentrated. The residue was concentrated and basified with saturated Na ₂ CO ₃ (1mL), and dried under vacuum. The residue (5mL) was filtered and treated with CH ₂ Cl ₂ and dried under vacuum. The filtrate was concentrated to give the desired product (48 mg) as an off-white solid. LC-MS (ES) m / z = 479 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.25-1.31 (m, 6H), 1.83 (m, 1 H), 2.03-2.25 (m, 3H) 2.51 (m, 1H), 2.69-2.83 (m, 2H), 2.85-2.94 (m, 1H), 3.36-3.55 (m, 4H), 3.61-3.71 (m, 1H) 3.78 (dd, J = 11.7, 2.0Hz, 1H), 3.93-4.03 (m, 1H ), 4.08 (s, 3H), 4.23-4.35 (m, 2H), 4.53 (dd, J = 14.6, 2.9Hz, 1H), 6.59-6.73 (m, 1H), 7.35-7.42 (m, 1H), 7.79 (d, J = 1.27 Hz, 1H), 7.96 (dd, J = 8.8, 2.5 Hz, 1H), 8.54 (d, J = 1.8 Hz, 1H).

Example 197

N-ethyl-7-methoxy-1-(((S) -4-methylmorpholin-2-yl) methyl) -2- (6-((S) -2-methylpyrrole Pyridin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-5-carboxamide

Add formaldehyde (36.5% in water, 0.038 mL, 0.501 mmol) and acetic acid (0.017 mL, 0.301 mmol) to N-ethyl-7-methoxy-2- (6-((S) -2-formaldehyde) Pyrrolidin-1-yl) pyridin-3-yl) -1-(((S) -morpholin-2-yl) methyl) -1H-benzo [d] imidazol-5-carboxamide ( 48 mg, 0.100 mmol) in 1,2-dichloroethane (2 mL), and the mixture was stirred at room temperature for 10 minutes. Then, sodium triacetoxyborohydride (74.4 mg, 0.351 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction (2mL) was quenched with saturated aqueous NaHCO _3, then saturated Na ₂ CO ₃ in aqueous solution was adjusted to pH = 10. The resulting mixture CH ₂ Cl ₂ (3x) and extracted with, and the organic extract was dried with Na ₂ SO _4, filtered, and concentrated. The resulting residue was purified by column chromatography (silica gel, 0-100% (90: 10: 1 CH ₂ Cl ₂ : CH ₃ OH: NH ₄ OH) / heptane) to give the desired as an off-white solid Product (30 mg). LC-MS (ES) m / z = 493 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.23-1.32 (m, 6H), 1.79-1.96 (m, 2H), 2.00-2.27 (m, 4H), 2.32 (s, 3H), 2.67 (d, J = 11.7Hz, 1H), 2.84 (d, J = 11.1Hz, 1H), 3.39-3.54 (m, 4H), 3.61-3.70 (m, 1H), 3.82 (dd, J = 11.8, 1.9Hz, 1H ), 3.99-4.13 (m, 4H), 4.22-4.41 (m, 2H), 4.58 (dd, J = 14.4, 2.8Hz, 1H), 6.67 (d, J = 8.9Hz, 1H), 7.37 (d, J = 1.3Hz, 1H), 7.79 (d, J = 1.5Hz, 1H), 7.96 (dd, J = 9.0, 2.4Hz, 1H), 8.54 (d, J = 2.5Hz, 1H).

Intermediate 265

4-((2-ethoxyethyl) amino) -3-methoxy-5-nitrobenzoate

Add 2-ethoxyethyl-1-amine (1.63 g, 18.3 mmol) to methyl 4-chloro-3-methoxy-5-nitrobenzoate (3.00 g, 12.2 mmol) at 1.4 Solution in alkane (12 mL), and the reaction mixture was stirred in a sealed container at 80 ° C for 54 hours. The reaction was then cooled to room temperature and concentrated. The resulting residue was purified by silica gel chromatography (dialysis with 0 to 100% CH ₂ Cl ₂ / hexane) to provide the desired product (2.90 g) as an orange solid. LC-MS (ES) m / z = 299 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.51 (d, J = 2.0Hz, 2H), 7.50 (d, J = 1.5Hz, 1H), 4.07-3.82 (m, 8H), 3.64 (t, J = 5.2Hz, 2H), 3.57 (q, J = 6.8Hz, 2H), 1.26 (t, J = 7.0Hz, 3H).

Intermediate 266

1- (2-ethoxyethyl) -2- (6- (ethyl (2,2,2-trifluoroethyl) amino) pyridin-3-yl) -7-methoxy-1H- Benzo [d] imidazole-5-carboxylic acid methyl ester

Add sodium bisulfite (228 mg, 1.11 mmol) to 6- (ethyl (2,2,2-trifluoroethyl) amino) nicotinaldehyde (101 mg, 0.436 mmol) and 4-((2-ethyl Oxyethyl) amino) -3-methoxy-5-nitrobenzoate (130 mg, 0.436 mol) in 2: 1 ethanol: water (4.5 mL), and the reaction mixture was placed under microwave conditions It was heated at 120 ° C for 1 hour. The reaction was cooled to room temperature and then diluted with EtOAc (10 mL) and water (10 mL). The phases were separated and the aqueous layer was back extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (10 mL) was washed, dried over anhydrous Na ₂ SO _4, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (dialysis with 0 to 50% EtOAc / hexanes) to provide the desired product (210 mg) as a yellow solid. LC-MS (ES) m / z = 481 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.63 (d, J = 2.3Hz, 1H), 8.16 (s, 1H), 8.03 (dd, J = 8.9, 2.5Hz, 1H), 7.46 (s, 1H) , 6.74 (d, J = 8.9Hz, 1H), 4.58 (t, J = 5.6Hz, 2H), 4.37 (q, J = 9.1Hz, 2H), 4.04 (2, 3H), 3.97 (s, 3H) , 3.82 (t, J = 5.6Hz, 2H), 3.67 (q, J = 7.1Hz, 2H), 3.36 (q, J = 6.8Hz, 2H), 1.36-1.21 (m, 3H), 1.16-1.04 ( m, 3H).

Example 198

1- (2-ethoxyethyl) -2- (6- (ethyl (2,2,2-trifluoroethyl) amino) pyridin-3-yl) -7-methoxy-1H- Benzo [d] imidazole-5-carboxamide

Add sodium hydroxide (5M aqueous solution, 0.083mL, 0.42mmol) to 1- (2-ethoxyethyl) -2- (6- (ethyl (2,2,2-trifluoroethyl) amino) ) Pyridin-3-yl) -7-methoxy-1H-benzo [d] imidazole-5-carboxylic acid methyl ester (100 mg, 0.208 mmol) in CH ₃ OH (2 mL), and the reaction mixture was The sealed container was heated at 60 ° C for 18 hours. The reaction was then cooled to room temperature, concentrated, and dried under vacuum. The resulting residue was dissolved in DMSO (2 mL). NH ₄ Cl (56 mg, 1.0 mmol), EDC (80 mg, 0.42 mmol), 1-hydroxy-7-azabenzotriazole (57 mg, 0.42 mmol), and N, N-diisopropylethylamine ( 0.22 mL, 1.2 mmol) was added to this mixture. After 1 hour, additional _{NH 4 C (56mg, 1.0mmol)} , and the mixture was heated at 40 deg.] C 1 hour. The reaction was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (10 mL) was washed, dried over anhydrous Na ₂ SO _4, filtered, and concentrated. By reverse phase HPLC (of 30 to 85% CH ₃ CN / analysis containing 0.1% 10mM ammonium bicarbonate and aqueous ammonium hydroxide of the modifier) The resulting residue was purified. The fractions containing the desired product were combined, concentrated, and lyophilized to provide the desired product (65 mg) as a white solid. LC-MS (ES) m / z = 466 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.64 (d, J = 2.3Hz, 1H), 8.04 (dd, J = 8.9, 2.3Hz, 1H), 7.74 (d, J = 1.3Hz, 1H), 7.43 (d, J = 1.3Hz, 1H), 6.75 (d, J = 8.9Hz, 1H), 4.58 (t, J = 5.6Hz, 2H), 4.38 (q, J = 9.1Hz, 2H), 4.06 (s , 3H), 3.83 (t, J = 5.6Hz, 2H), 3.68 (q, J = 7.0Hz, 2H), 3.37 (q, J = 6.8Hz, 2H), 1.28 (t, J = 7.0Hz, 3H ), 1.09 (t, J = 7.0 Hz, 3H).

Example 199

1- (2-ethoxyethyl) -2- (6- (ethyl (2,2,2-trifluoroethyl) amino) pyridin-3-yl) -7-methoxy-N- (Methyl) 1H-benzo [d] imidazole-5-carboxamide

Add sodium hydroxide (5M aqueous solution, 0.083mL, 0.42mmol) to 1- (2-ethoxyethyl) -2- (6- (ethyl (2,2,2-trifluoroethyl) amino) ) Pyridin-3-yl) -7-methoxy-1H-benzo [d] imidazole-5-carboxylic acid methyl ester (100 mg, 0.208 mmol) in CH ₃ OH (2 mL), and the reaction mixture was The sealed container was heated at 60 ° C for 18 hours. The reaction was then cooled to room temperature, concentrated, and dried under vacuum. The resulting residue was dissolved in DMSO (2 mL). Methylamine hydrochloride (70 mg, 1.0 mmol), EDC (80 mg, 0.42 mmol), 1-hydroxy-7-azabenzotriazole (57 mg, 0.42 mmol), and N, N-diisopropylethyl Amine (0.22 mL, 1.2 mmol) was added to this mixture. After 4 hours, the reaction was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (10 mL) was washed, dried over anhydrous Na ₂ SO _4, filtered, and concentrated. The resulting residue was purified (diluting with 50 to 99% CH ₃ CN / analysis containing 0.1% 10mM ammonium bicarbonate and aqueous ammonium hydroxide modifier of) by reverse phase HPLC. The fractions containing the desired product were combined, concentrated, and lyophilized to provide the desired product (49 mg) as a white solid. LC-MS (ES) m / z = 480 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.62 (d, J = 2.3Hz, 1H), 8.20-7.92 (m, 1H), 7.65 (d, J = 1.0Hz, 1H), 7.40 (s, 1H) , 6,74 (d, J = 8.9Hz, 1H), 6.47-5.93 (m, 1H), 4.57 (t, J = 5.6Hz, 2H), 4.37 (d, J = 9.1Hz, 2H), 4.05 ( s, 3H), 3.82 (t, J = 5.6 Hz, 2H), 3.67 (d, J = 7.1 Hz, 2H), 3.36 (d, J = 6.8 Hz, 2H), 3.08 (d, J = 4.8 Hz, 3H), 1.28 (t, J = 7.0Hz, 3H), 1.09 (t, J = 7.0Hz, 3H).

Example 200

1- (2-ethoxyethyl) -2- (6- (ethyl (2,2,2-trifluoroethyl) amino) pyridin-3-yl) -7-hydroxy-1H-benzo [d] Imidazole-5-carboxamide

Preparation of 1- (2-ethoxyethyl) -2- (6- (ethyl (2,2,2-trifluoroethyl) amino) pyridine-3- following a procedure similar to the preparation of intermediate 266 Methyl) -7-hydroxy-1H-benzo [d] imidazole-5-carboxylic acid methyl ester. Follow a procedure similar to the preparation of Example 198 from 1- (2-Ethoxyethyl) -2- (6- (ethyl (2,2,2-trifluoroethyl) amino) pyridine-3- Methyl) -7-hydroxy-1H-benzo [d] imidazole-5-carboxylic acid methyl ester (65 mg, 0.14 mmol) The title compound was prepared to provide the desired product (38 mg) as an off-white solid. LC-MS (ES) m / z = 452 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.72 (br s, 1H), 8.48 (d, J = 2.0Hz, 1H), 7.96 (dd, J = 8.9, 2.3Hz, 1H), 7.85 (d, J = 1.3Hz, 1H), 7.28-7.19 (m, 1H), 6.80 (d, J = 8.9Hz, 1H), 6.28 (br s, 1H), 5.56 (br s, 1H), 4.61 (t, J = 4.6Hz, 2H), 4.38 (q, J = 8.9Hz, 2H), 3.81-3.60 (m, 4H), 3.54 (d, J = 5.1Hz, 2H), 1.30 (q, J = 7.1Hz, 6H) .

Example 201

1- (2-ethoxyethyl) -2- (6- (ethyl (2,2,2-trifluoroethyl) amino) pyridin-3-yl) -7-hydroxy-N-methyl -1H-benzo [d] imidazole-5-carboxamide

Preparation of 1- (2-ethoxyethyl) -2- (6- (ethyl (2,2,2-trifluoroethyl) amino) pyridine-3- following a procedure similar to the preparation of intermediate 266 Methyl) -7-hydroxy-1H-benzo [d] imidazole-5-carboxylic acid methyl ester. Follow a procedure similar to the preparation of Example 199 from 1- (2-Ethoxyethyl) -2- (6- (ethyl (2,2,2-trifluoroethyl) amino) pyridine-3- Methyl) -7-hydroxy-1H-benzo [d] imidazole-5-carboxylic acid methyl ester (65 mg, 0.14 mmol) The title compound was prepared to provide the desired product (3.5 mg) as a brown solid. LC-MS (ES) m / z = 466 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.59-8.44 (m, 1H), 8.13-7.87 (m, 1H), 7.77 (s, 1H), 7.50 (s, 1H), 6.87-6.71 (m, 1H ), 6.62 (br s, 1H), 4.68-4.47 (m, 2H), 4.38 (q, J = 8.9Hz, 2H), 3.97 (t, J = 4.6Hz, 2H), 3.69 (q, J = 7.1 Hz, 2H), 3.57-3.48 (m, 2H), 3.12-2.99 (m, 3H), 1.32-1.10 (m, 6H).

Intermediate 267

4-methoxy-N-((1-methyl) 1H-pyrazol-3-yl) methyl) -2-nitroaniline

(1-methyl-1H-pyrazol-3-yl) methylamine (156 mg, 1.40 mmol) was added to 1-fluoro-4-methoxy-2-nitrobenzene (200 mg, 1.17 mmol) at 1,4 two Solution in hexane (4 mL), and the reaction mixture was stirred in a sealed container at room temperature for 18 hours. The reaction was concentrated and the resulting residue was purified by silica chromatography (eluted with 0 to 70% CH ₂ Cl ₂ / hexane) to provide the desired product (48 mg) as a yellow-orange oil. LC-MS (ES) m / z = 263 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.39 (br s, 1H), 7.67 (d, J = 3.0Hz, 1H), 7.36 (d, J = 2.0Hz, 1H), 7.18 (dd, J = 9.4 , 3.0Hz, 1H), 6.98 (d, J = 9.4Hz, 1H), 6.23 (d, J = 2.0Hz, 1H), 4.56 (d, J = 5.1Hz, 2H), 3.97 (s, 3H), 3.83 (s, 3H).

Example 202

N, N-diethyl-5- (5-methoxy-1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-2- ) Pyridin-2-amine

Add sodium bisulfite (156 mg, 0.762 mmol) to 6- (diethylamino) nicotinaldehyde (42 mg, 0.23 mmol) and 4-methoxy-N-((1-methyl-1H-pyrazole A solution of 3--3-yl) methyl) -2-nitroaniline (47 mg, 0.18 mmol) in 2: 1 ethanol: water (3.5 mL), and the reaction mixture was heated under microwave conditions at 120 ° C for 90 minutes. The reaction was then cooled to room temperature and diluted with EtOAc (10 mL) and water (10 mL). The phases were separated and the aqueous layer was back extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (10 mL) was washed, dried over anhydrous Na ₂ SO _4, filtered, and concentrated. By reverse phase HPLC (of 30 to 85% CH ₃ CN / 0.1% formic acid-containing aqueous evolution of modifier) The resulting residue was purified. The fractions containing the desired product were combined, concentrated, and lyophilized to provide the desired product (9 mg) as a clear film. LC-MS (ES) m / z = 391 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.58 (d, J = 2.0 Hz, 1H), 7.95 (dd, J = 9.0, 2.4 Hz, 1H), 7.37-7.14 (m, 3H), 6.89 (dd, J = 8.6, 2.3 Hz, 1H), 6.60 (d, J = 8.9 Hz, 1H), 5.98 (d, J = 2.3 Hz, 1H), 5.41 (s, 2H), 3.93 (s, 3H), 3.90 ( s, 3H), 3.61 (q, J = 6.9Hz, 4H), 1.29-1.11 (m, 6H).

Example 203

2- (6- (diethylamino) pyridin-3-yl) -1-((1-methyl) 1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5 -alcohol

A solution of boron tribromide (in 1MCH ₂ Cl ₂ , 0.05 mL, 0.05 mmol) was added to N, N-diethyl-5- (5-methoxy-1-((1 -Methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazol-2-yl) pyridin-2-amine (4 mg, 0.01 mmol) in 1,2-dichloroethane (0.2 mL). After 15 minutes, the reaction was quenched with water (0.3 mL) and concentrated. By reverse phase HPLC (of 30 to 85% CH ₃ CN / 0.1% formic acid-containing aqueous evolution of modifier) The resulting residue was purified. The fractions containing the desired product were combined, concentrated, and lyophilized to provide the desired product (3 mg) as an off-white solid. LC-MS (ES) m / z = 377 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.48 (d, J = 2.0Hz, 1H), 7.91 (dd, J = 9.0, 2.4Hz, 1H), 7.54 (d, J = 2.3Hz, 1H), 7.27 (d, J = 8.6Hz, 1H), 7.06 (d, J = 2.3Hz, 1H), 6.86-6.65 (m, 2H), 6.08 (d, J = 2.3Hz, 1H), 5.39 (s, 2H) , 3.87 (br s, 3H), 3.62 (q, J = 6.9 Hz, 4H), 1.28-1.17 (m, 6H).

Intermediate 268

4- (2-((3-fluoro-6-methoxy-2-nitrophenyl) amino) ethyl) piper -2-one

4- (2-aminoethyl) piper -2-one dihydrochloride (103 mg, 0.476 mmol) and K ₂ CO ₃ (197 mg, 1.43 mmol) were added to 1,3-difluoro-4-methoxy-2-nitrobenzene (90 mg, 0.476 mmol) A solution in DMF (2.5 mL), and the reaction mixture was stirred in a sealed container at 50 ° C for 3 hours, then at 80 ° C for 18 hours, and at 100 ° C for 3 nights. The reaction was diluted with EtOAc (30mL) and washed with saturated aqueous NaHCO ₃ (3 x 20mL). The aqueous layer was further extracted with EtOAc (20mL), washed (30mL) with brine and the combined organic extracts were dried over Na ₂ SO _4, filtered, and concentrated. By silica gel chromatography (with 0 to _{5% CH 3 OH / CH 2} Cl 2 elution) and the resulting residue was purified to provide the desired product as an orange oil (31mg). LC-MS (ES) m / z = 313 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.79 (dd, J = 9.0, 4.7 Hz, 1H), 6.52 (dd, J = 9.9, 8.9 Hz, 1H), 6.16 (br s, 1H), 5.85 (br s, 1H), 3.87 (s, 3H), 3.53-3.37 (m, 2H), 3.35-3.25 (m, 2H), 3.21 (s, 2H), 2.70 (dt, J = 15.4, 5.5Hz, 4H) .

Example 204

4- (2- (2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-7-methoxy-1H -Benzo [d] imidazol-1-yl) ethyl) piper -2-one

Add sodium bisulfite (117 mg, 0.572 mmol) to 6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (46 mg, 0.22 mmol) and 4- (2 -((3-fluoro-6-methoxy-2-nitrophenyl) amino) ethyl) piper A solution of 2--2-one (70 mg, 0.22 mmol) in 2: 1 ethanol: water (4.5 mL), and the reaction mixture was heated at 100 ° C for 3 nights. The reaction was cooled to room temperature and diluted _aqueous (15mL) with EtOAc in (15mL) and saturated NaHCO. The phases were separated and the aqueous layer was further extracted with EtOAc (3 x 15 mL). The combined organic extracts were washed with brine (15mL) was washed, dried over anhydrous Na ₂ SO _4, filtered, and concentrated. By silica gel chromatography (with 0 to _{5% CH 3 OH / CH 2} Cl 2 elution) and the resulting residue was purified to provide the desired product as a white solid (79mg). LC-MS (ES) m / z = 467 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.50 (d, J = 2.0 Hz, 1H), 7.82 (dd, J = 8.9, 2.3 Hz, 1H), 6.88 (dd, J = 9.8, 8.7 Hz, 1H) , 6.59 (dd, J = 8.7, 3.2 Hz, 1H), 6.50 (d, J = 8.9 Hz, 1H), 6.29 (br s, 1H), 4.58 (t, J = 6.8 Hz, 2H), 4.30 (br s, 2H), 3.98 (s, 3H), 3.33-3.20 (m, 2H), 3.12 (s, 2H), 2.92-2.74 (m, 2H), 2.58 (dd, J = 6.2, 4.7Hz, 2H) , 2.43-2.19 (m, 2H), 1.85-1.63 (m, 2H), 1.23 (d, J = 6.1Hz, 6H).

Intermediate 269

1-chloro-3-fluoro-4-methoxy-2-nitrobenzene

Add 6-chloro-2-fluoro-3-methoxyaniline (500 mg, 2.85 mmol) and m-chloroperbenzoic acid (1.97 g, 11.4 mmol) in dichloroethane (19 mL) to the condensing air to condense 100mL round bottom flask. The reaction vessel was covered with aluminum foil and heated at 70 ° C for 17 hours. The reaction was diluted with EtOAc (150 mL) and washed with 0.1 N aqueous sodium hydroxide solution (5 x 50 mL). The organic extract was dried over Na ₂ SO _4, filtered, and concentrated to provide the desired product as an orange solid (444mg). ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.72-7.59 (m, 1H), 7.59-7.49 (m, 1H), 3.95 (s, 3H).

Intermediate 270

4-chloro-2-fluoro-3-nitrophenol

A solution of boron tribromide (1M in CH ₂ Cl ₂ , 2.4 mL, 2.4 mmol) was added to 1-chloro-3-fluoro-4-methoxy-2-nitrobenzene (98 mg) cooled at 0 ° C. , 0.48 mmol) in 1,2-dichloroethane (5 mL). The reaction was then warmed to room temperature and stirred for 3 hours. Adding additional boron tribromide (in CH ₂ Cl in the 1M _2, 1.2mL, 1.2mmol), and the reaction was stirred at room temperature for 18 hours. The reaction was quenched with water (2 mL, dropwise), dried over Na ₂ SO _4, filtered, and concentrated. By silica gel chromatography (with 0 to _{5% CH 3 OH / CH 2} Cl 2 elution) and the resulting residue was purified to provide the desired product as an orange solid (75mg). ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.25-7.15 (m, 1H), 7.14-6.99 (m, 1H).

Intermediate 271

(R) -2-(((3-Chloro-6-hydroxy-2-nitrophenyl) amino) methyl) morpholin-4-carboxylic acid tert-butyl ester

4-Chloro-2-fluoro-3-nitrophenol (75 mg, 0.39 mmol), (R) -2- (aminomethyl) morpholin-4-carboxylic acid tert-butyl acetate (141 mg, 0.509 mmol) ), And N, N-diisopropylethylamine (0.20 mL, 1.2 mmol) in 1,4-di The solution in alkane (2.6 mL) was added to a sealable container. The vessel was sealed and the reaction mixture was heated at 80 ° C for 18 hours and then at 100 ° C for 24 hours. Additional (R) -2- (aminemethyl) morpholin-4-carboxylic acid tert-butyl acetate (141 mg, 0.509 mmol) was added, and the mixture was heated at 100 ° C for 24 hours. The reaction was diluted with EtOAc (30mL), and the resulting mixture was washed with water (20mL) and brine (20mL), dried over Na ₂ SO _4, filtered, and concentrated. By silica gel chromatography (with 0 to _{5% CH 3 OH / CH 2} Cl 2 elution) and the resulting residue was purified to provide a dark orange oil containing the desired product (50mg). LC-MS (ES) m / z = 313 [M + H] ⁺ . The material is ~ 3: 2 to des-Cl: desired product.

Intermediate 272

(R) -2-((4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-hydroxy-1H -Benzo [d] imidazol-1-yl) methyl) morpholin-4-carboxylic acid tert-butyl ester

Add sodium bisulfite (76 mg, 0.37 mmol) to 6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (30 mg, 0.15 mmol) and (R)- 2-(((3-Chloro-6-hydroxy-2-nitrophenyl) amino) methyl) morpholin-4-carboxylic acid tert-butyl ester (50 mg, 0.17 mmol) in 2: 1 ethanol: water ( 3 mL), and the reaction mixture was heated at 100 ° C for 18 hours. The reaction was then cooled to room temperature and diluted with EtOAc (10 mL) and water (10 mL). The phases were separated and the aqueous layer was further extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (10 mL) was washed, dried over anhydrous Na ₂ SO _4, filtered, and concentrated. The resulting residue was purified by silica chromatography (dialysis with 20-100% EtOAc / hexanes) to provide the desired product (9 mg) as a white solid. LC-MS (ES) m / z = 542 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.47 (br s, 1H), 7.77 (dd, J = 8.9, 2.5 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 6.69 (d, J = 8.3Hz, 1H), 6.46 (d, J = 9.0Hz, 1H), 4.67-4.40 (m, 2H), 4.27 (br s, 1H), 4.06-3.77 (m, 4H), 3.51 (t, J = 10.8Hz, 1H), 2.94 (t, J = 11.5Hz, 1H), 2.63 (t, J = 11.8Hz, 1H), 2.39-2.19 (m, 2H), 1.78 (br s, 2H), 1.75- 1.60 (m, 2H), 1.56-1.39 (m, 9H), 1.21 (d, J = 6.3Hz, 6H).

Intermediate 273

4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-(((S) -morpholin-2 -Yl) methyl) -1H-benzo [d] imidazole-7-ol

Add trifluoroacetic acid (0.06 mL, 0.8 mmol) to (R) -2-((4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl ) Pyridin-3-yl) -7-hydroxy-1H-benzo [d] imidazol-1-yl) methyl) morpholin 4-carboxylic acid tert-butyl ester (8.6 mg, 0.016 mmol) in CH ₂ Cl ₂ (0.3 mL), and the reaction was stirred at room temperature for 16 hours. Next, the reaction (5mL) and extracted with EtOAc (3 x 5mL) with saturated aqueous NaHCO ₃ solution. The combined organic extracts were washed with water (5 mL), dried over anhydrous Na ₂ SO _4, filtered, and concentrated to provide the desired product as a pale yellow solid (7mg). LC-MS (ES) m / z = 442 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.55 (d, J = 2.0Hz, 1H), 8.16 (dd, J = 9.3, 2.0Hz, 1H), 7.22 (d, J = 8.3Hz, 1H), 7.07 (d, J = 9.3Hz, 1H), 6.79 (d, J = 8.3Hz, 1H), 4.83-4.73 (m, 1H), 4.49-4.34 (m, 4H), 4.09 (dd, J = 13.0, 3.3 (Hz, 1H), 3.70 (td, J = 12.6, 2.3Hz, 1H), 3.56-3.43 (m, 1H), 3.30-3.22 (m, 1H), 3.22-3.12 (m, 1H), 3.11-2.98 ( m, 1H), 2.53-2.36 (m, 2H), 1.95-1.76 (m, 2H), 1.29 (d, J = 6.3Hz, 6H).

Example 205

4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-(((S) -morpholin-2 -Yl) methyl) -1H-benzo [d] imidazole-7-ol

Add formaldehyde (36.5% in water, 0.004mL, 0.06mmol) and sodium triacetoxyborohydride (7mg, 0.03mmol) to 4-chloro-2- (6-((2S, 5S) -2, 5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((((S) -morpholin-2-yl) methyl) -1H-benzo [d] imidazole-7- A solution of an alcohol (5 mg, 0.01 mmol) in 1,2-dichloroethane (1 mL), and the reaction mixture was stirred at room temperature for 90 minutes. Then by silica gel chromatography (with _{0-10% CH 3 OH / CH 2} Cl 2 elution) to afford the direct reaction of the desired product as a white solid (2.5mg). LC-MS (ES) m / z = 456 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.54 (d, J = 2.0Hz, 1H), 7.93 (dd, J = 9.0, 2.4Hz, 1H), 7.08 (d, J = 8.4Hz, 1H), 6.82 -6.49 (m, 2H), 4.59 (dd, J = 14.4, 3.0Hz, 1H), 4.32 (dd, J = 14.4, 8.9Hz, 3H), 4.21-4.07 (m, 1H), 3.83 (dd, J = 11.8, 1.9Hz, 1H), 3.54-3.41 (m, 1H), 2.83 (d, J = 11.2Hz, 1H), 2.65 (d, J = 11.9Hz, 1H), 2.45-2.31 (m, 2H) , 2.29 (s, 3H), 2.16 (td, J = 11.6, 3.4Hz, 1H), 1.96-1.84 (m, 1H), 1.82-1.67 (m, 2H), 1.23 (d, J = 6.3Hz, 6H ).

Intermediate 274

4-methylbenzenesulfonic acid (S)-(5-oxomorpholin-2-yl) methyl ester

Triethylamine (1.063 mL, 7.63 mmol) was added to (S) -6- (hydroxymethyl) morpholin-3-one (1.0 g, 7.63 mmol), 4-methylbenzenesulfonate at 23 ° C. A solution of chlorine (1.890 g, 9.91 mmol) and N, N-dimethylpyridin-4-amine (0.186 g, 1.525 mmol) in CH ₂ Cl ₂ (15 mL), and the reaction mixture was stirred at room temperature. 3 hours. The reaction was quenched with saturated aqueous NH ₄ Cl (20 mL) and extracted with CH ₂ Cl ₂ (2 x 20 mL). The combined dried organic extracts with MgSO _4, filtered, and concentrated in vacuo. By silica gel chromatography (0-100% EtOAc / heptane and then 100% CH ₃ OH) The resulting residue was purified to provide the desired product as a white solid of 4-methylbenzenesulfonic acid (S) - (5 -Phenoxalolin-2-yl) methyl ester (2.0 g). LC-MS (ES) m / z = 286 [M + H] ^{+ 1} H NMR (400MHz, CD ₃ OD): δ 7.78-7.86 (m, 2H), 7.45-7.52 (m, 2H), 4.08-4.18 (m, 4H), 3.98 (m, 1H), 3.17-3.30 (m, 2H), 2.45-2.51 (m, 3H).

Intermediate 275

(R) -6- (Aminemethyl) morpholin-3-one

NaN ₃ (0.684 g, 10.51 mmol) was added to 4-methylbenzenesulfonic acid (S)-(5-oxomorpholin-2-yl) methyl ester (2.0 g, 7.01 mmol) in DMF (20 mL) The solution was neutralized, and the reaction mixture was stirred at 80 ° C overnight. The reaction mixture was concentrated in vacuo, and the resulting residue was resuspended in CH ₂ Cl ₂ and extracted with saturated aqueous NaHCO _3. The combined dried organic extracts with MgSO _4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (0-100% ((90: 10: 1 CH ₂ Cl ₂ : CH ₃ OH: NH ₄ OH) / CH ₂ Cl ₂ ) to give (S) -6- (Azidomethyl) morpholin-3-one (600 mg). CH ₃ OH (5 mL; slowly along the side of the flask) was added to (S) -6- (azido A mixture of methyl) morpholin-3-one (600 mg, 3.84 mmol) and palladium on carbon (0.075 g, 0.701 mmol), and the reaction mixture was stirred under H ₂ atmosphere at room temperature for 12 hours. Stopped through celite The reaction was filtered and the filtrate was concentrated under vacuum to give the desired product (500 mg) as a pale yellow oil. LC-MS (ES) m / z = 131 [M + H] ^{+ 1} H NMR (400 MHz, CH ₃ OD): δ 4.16-4.28 (m, 2H), 3.96 (m, 1H), 3.43 (d, J = 5.1 Hz, 2H), 3.32-3.36 (m, 2H).

Intermediate 276

(R) -6-(((2-methoxy-6-nitrophenyl) amino) methyl) morpholin-3-one

Triethylamine (0.214 mL, 1.537 mmol) was added to 2-fluoro-1-methoxy-3-nitrobenzene (263 mg, 1.537 mmol) and (R) -6- (aminemethyl) morpholin-3 -A solution of ketone (200 mg, 1.537 mmol) in DMF (10 mL) and the reaction mixture was heated at 80 ° C for 12 hours. The reaction mixture was concentrated under vacuum, and the resulting residue was resuspended in EtOAc and washed with brine. The combined organic layers were dried over MgSO _4, filtered, and concentrated in vacuo to yield the desired product as a red solid of (R) -6 - ((( 2- methoxy-6-nitrophenyl) amino) Methyl) morpholin-3-one (350 mg). LC-MS (ES) m / z = 282 [M + H] ^{+. 1} H NMR (400 MHz, CD ₃ OD): δ 7.67 (dd, J = 1.4, 8.7 Hz, 1H), 7.16 (dd, J = 1.1, 8.0 Hz, 1H), 6.80 (t, J = 8.2 Hz, 1H ), 4.18-4.27 (m, 1H), 4.07-4.16 (m, 1H), 3.91 (s, 3H), 3.78-3.90 (m, 2H), 3.53 (dd, J = 7.4, 13.9Hz, 1H), 3.24-3.31 (m, 2H).

Example 206

(R) -6-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H-benzene Benzo [d] imidazol-1-yl) methyl) morpholin-3-one

Sodium bisulfite (765 mg, 3.73 mmol) was added to (R) -6-(((2-methoxy-6-nitrophenyl) amino) methyl) morpholin-3-one (350 mg, 1.244mmol) and 6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (254mg, 1.244mmol) in ethanol (5mL) and water (1.25mL) The reaction mixture was heated in a sealed container at 110 ° C for 3 hours. The reaction mixture was concentrated in vacuo, resuspended in EtOAc, dried over MgSO _4, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (0-100% (3: 1 EtOAc: EtOH) / heptane) to give the desired product (R) -6-((2- (6- ((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [d] imidazol-1-yl) methyl) Morpholine-3-one (388 mg). LC-MS (ES) m / z = 436 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 8.49-8.55 (m, 1H), 7.92 (dd, J = 2.5, 8.9Hz, 1H), 7.21-7.32 (m, 2H), 6.89 (d, J = 7.9Hz, 1H), 6.68 (d, J = 8.9Hz, 1H), 4.67 (dd, J = 2.4, 14.6Hz, 1H), 4.38-4.47 (m, 1H), 4.22-4.38 (m, 3H), 4.11-4.21 (m, 1H), 4.03 (s, 3H), 3.94-4.01 (m, 1H), 3.35-3.41 (m, 1H), 3.23-3.31 (m, 1H), 2.27-2.42 (m, 2H ), 1.69-1.82 (m, 2H), 1.20 (d, J = 6.1 Hz, 6H).

Intermediate 277

5-benzyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine -2-carbonitrile

K ₂ CO ₃ (898 mg, 6.50 mmol) was added to 4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine A solution of 2-carbonitrile hydrochloride (600 mg, 3.25 mmol) and bromotoluene (0.387 mL, 3.25 mmol) in DMF (10 mL), and the reaction mixture was stirred at 23 ° C for 12 hours. The reaction mixture was concentrated in vacuo, and the resulting residue was resuspended in CH ₂ Cl ₂ in. The mixture was filtered, and the filtrate was concentrated under vacuum. The resulting residue was purified by silica gel chromatography (0-100% (20% CH ₃ OH / CH ₂ Cl ₂ ) / CH ₂ Cl ₂ ) to give the desired product 5-benzyl- 4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine 2-Carbononitrile (670 mg), solidified after standing. LC-MS (ES) m / z = 239 [M + H] ^{+. 1} H NMR (400MHz, CD ₃ OD): δ 7.26-7.43 (m, 5H), 6.54 (s, 1H), 4.22 (t, J = 5.6Hz, 2H), 3.78 (s, 2H), 3.71 (s , 2H), 2.96-3.08 (m, 2H).

Intermediate 278

(5-benzyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine -2-yl) methylamine

LiAlH ₄ (3.09 mL, 6.19 mmol, 2M in THF) was added to 5-benzyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine A solution of 2-carbonitrile (670 mg, 2.81 mmol) in THF (20 mL), and the reaction mixture was stirred at 23 ° C for 2 hours. The reaction was quenched according to the fieser method to obtain a crude product. LC-MS (ES) m / z = 243 [M + H] ^{+. 1} H NMR (400MHz, CD ₃ OD): δ 7.26-7.42 (m, 5H), 6.01 (s, 1H), 4.10 (t, J = 5.6Hz, 2H), 3.75 (s, 2H), 3.73 (s , 2H), 3.66 (s, 2H), 2.93-3.01 (m, 2H).

Intermediate 279

5-benzyl-2-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H -Benzo [d] imidazol-1-yl) methyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine

Triethylamine (0.138 mL, 0.990 mmol) was added to (5-benzyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine at 23 ° C. A solution of 2--2-yl) methylamine (200 mg, 0.825 mmol) and 2-fluoro-1-methoxy-3-nitrobenzene (141 mg, 0.825 mmol) in DMF (5 mL), and the reaction mixture was stirred for 3 days . The reaction was concentrated, and the resulting residue was dissolved in 3: 1 EtOH / H ₂ O and then with 6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde ( 169 mg, 0.825 mmol) and sodium bisulfite (507 mg, 2.476 mmol). The resulting mixture was heated in a sealed container at 110 ° C for 3 hours. After completion, the mixture was concentrated under vacuum and the residue was dissolved in EtOAc. The mixture was filtered, and the filtrate was concentrated under vacuum. The resulting residue was purified by silica gel chromatography (0-100% (3: 1 EtOAc: EtOH) / Hep) to give the desired product 5-benzyl-2-((2- (6 ( -((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [d] imidazol-1-yl) methyl ) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine (280 mg). LC-MS (ES) m / z = 548.2 [M + H ⁺ ]. ¹ H NMR (400MHz, CD ₃ OD): δ 8.39 (d, J = 2.3Hz, 1H), 7.81 (dd, J = 2.5, 8.9Hz, 1H), 7.25-7.39 (m, 6H), 7.13-7.23 (m, 1H), 6.81 (d, J = 8.1Hz, 1H), 6.62 (d, J = 9.1Hz, 1H), 5.68 (s, 1H), 5.61 (s, 2H), 4.16-4.36 (m, 2H), 4.07 (t, J = 5.6Hz, 2H), 3.86 (s, 3H), 3.67-3.71 (m, 2H), 3.59 (s, 2H), 2.90-2.96 (m, 2H), 2.24-2.37 (m, 2H), 1.67-1.80 (m, 2H), 1.18 (d, J = 6.1 Hz, 6H).

Example 207

2-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [d] Imidazol-1-yl) methyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine

Palladium on carbon (109 mg, 0.102 mmol) was added to 5-benzyl-2-((2- (6-((2S, 5S) -2,5-dimethylpyrrole) at 23 ° C under an N ₂ atmosphere. Pyridin-1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [d] imidazol-1-yl) methyl) -4,5,6,7-tetrahydropyrazolo [ 1,5-a] pyridine (280 mg, 0.511 mmol) in CH ₃ OH (10 mL), and the reaction mixture was stirred under H ₂ atmosphere at room temperature for 12 hours. The reaction was filtered through a plug of diatomaceous earth, and the filtrate was concentrated under vacuum. The resulting residue was purified by silica gel chromatography (0-100% (20% CH ₃ OH / CH ₂ Cl ₂ ) / CH ₂ Cl ₂ ) to give the desired product 2-((2- ( 6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [d] imidazol-1-yl) methyl ) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine (115 mg). LC-MS (ES) m / z = 458 [M + H ⁺ ] ^{. 1} H NMR (400MHz, CD ₃ OD): δ 8.40 (dd, J = 0.78, 2.5Hz, 1H), 7.82 (dd, J = 2.5, 9.1Hz, 1H), 7.26-7.30 (m, 1H), 7.16 -7.25 (m, 1H), 6.82 (dd, J = 0.8,7.9Hz, 1H), 6.63 (d, J = 8.6Hz, 1H), 5.71 (s, 1H), 5.64 (s, 2H), 4.28 ( br.s., 2H), 4.05 (t, J = 5.7Hz, 2H), 3.93 (s, 2H), 3.87 (s, 3H), 3.23 (t, J = 5.6Hz, 2H), 2.26-2.41 ( m, 2H), 1.67-1.80 (m, 2H), 1.20 (d, J = 6.3Hz, 6H).

Intermediate 280

(R) -6- (2- (trifluoromethyl) pyrrolidin-1-yl) nicotinaldehyde

DMSO (1.5 mL), triethylamine (0.691 mL, 4.96 mmol), and (R) -2- (trifluoromethyl) pyrrolidine (345 mg, 2.478 mmol) were added to 6-fluoronicotinaldehyde (310 mg, 2.478 mmol), and then the reaction mixture was capped and heated at 90 ° C all weekend. The reaction was then diluted with water (3 mL) and the resulting mixture was extracted with EtOAc (4 x 5 mL). The organic extracts were combined and then washed with brine, dried over MgSO _4, filtered, and concentrated. Purification by chromatography on SiO ₂ with a gradient of 0 to 25% EtOAc in hexanes provided (R) -6- (2- (trifluoromethyl) pyrrolidin-1-yl as a pale yellow oil ) Nicotinaldehyde (600 mg). LC-MS (ES) m / z = 245 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 2.04-2.23 (m, 4H) 3.47-3.57 (m, 1H) 3.72 (ddd, J = 10.7, 6.5, 4.2Hz, 1H) 5.18 (t, J = 7.9Hz, 1H), 6.88 (d, J = 8.9Hz, 1H) 7.99 (dd, J = 8.9, 2.3Hz, 1H), 8.67 (d, J = 2.3Hz, 1H), 9.83 (s, 1H).

Intermediate 281

2-methoxy-N-((1-methyl-1H-pyrazol-3-yl) methyl) -6-nitroaniline

Put (1-methyl-1H-pyrazol-3-yl) methylamine (383 mg, 3.45 mmol) and 2-bromo-1-methoxy-3-nitrobenzene (400 mg, 1.724 mmol) in 1,4- two The mixture in alkane (3.5 mL) was put into a sealed container and stirred at 120 ° C overnight. The reaction was then heated at 150 ° C for 24 hours, followed by 120 ° C all weekend. The reaction was concentrated in vacuo, and the resulting residue was purified by silica chromatography (0-50% EtOAc / hexanes) to provide the desired product (288 mg) as an orange oil. LC-MS (ES) m / z = 263 [M + H] ⁺ .

Example 208

(R) -7-methoxy-1-((1-methyl) 1H-pyrazol-3-yl) methyl) -2- (6- (2- (trifluoromethyl) pyrrolidine-1 -Yl) pyridin-3-yl) -1H-benzo [d] imidazole

(R) -6- (2- (trifluoromethyl) pyrrolidin-1-yl) nicotinaldehyde (63.3 mg, 0.259 mmol), sodium bisulfite (135 mg, 0.659 mmol), ethanol (2 mL), And water (1 mL) were added to 2-methoxy-N-((1-methyl-1H-pyrazol-3-yl) methyl) -6-nitroaniline (68 mg, 0.259 mmol), and the reaction mixture Enter into a sealed container and heat at 130 ° C for 1 hour under microwave conditions. The reaction was then quenched with water (5 mL) and extracted with EtOAc (3 x 10 mL). The organic extracts were then combined and washed with brine, dried over MgSO _4, filtered, and concentrated. Purification by chromatography on SiO ₂ with a gradient of 0 to 8% CH ₃ OH in CH ₂ Cl ₂ provided (R) -7-methoxy-1-((1-methyl-1H-pyridine Azole-3-yl) methyl) -2- (6- (2- (trifluoromethyl) pyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole (48 mg), White solid after lyophilization. LC-MS (ES) m / z = 457 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 2.06-2.19 (m, 4H), 3.41-3.50 (m, 1H), 3.67-3.72 (m, 1H), 3.74 (s, 3H), 3.85 (s , 3H), 5.09 (t, J = 7.7Hz, 1H), 5.55 (s, 2H), 5.90 (d, J = 2.3Hz, 1H), 6.79 (d, J = 7.9Hz, 1H), 6.86 (d , J = 8.9Hz, 1H), 7.13 (t, J = 8.0Hz, 1H), 7.25 (d, J = 7.9Hz, 1H), 7.56 (d, J = 2.3Hz, 1H), 8.08 (dd, J = 8.9, 2.5Hz, 1H), 8.59 (d, J = 2.0Hz, 1H).

Example 209

(R) -1-((1-methyl) 1H-pyridin-3-yl) methyl) -2- (6- (2- (trifluoromethyl) pyrrolidin-1-yl) pyridine-3- ) -1H-benzo [d] imidazol-7-ol

Boron tribromide (0.228 mL, 0.228 mmol) was added to (R) -7-methoxy-1-((1-methyl-1H-pyridine) in 1,2-dichloroethane (3 mL) Azol-3-yl) methyl) -2- (6- (2- (trifluoromethyl) pyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole (26 mg, 0.057 mmol), and the reaction mixture was stirred at 45 ° C for 2 hours. Additional boron tribromide (0.228 mL, 0.228 mmol) was added and the reaction mixture was stirred at 45 ° C overnight. The reaction was quenched with water, followed by NaHCO ₃ was added slowly until no gas evolution was observed. The resulting mixture was extracted with EtOAc (4 x 5mL), and then the organic extracts were combined and washed with brine, dried over MgSO _4, filtered, and concentrated. Purification by chromatography on SiO ₂ with a gradient of 0 to 10% CH ₃ OH in CH ₂ Cl ₂ provides (R) -1-((1-methyl-1H-pyrazol-3-yl) Methyl) -2- (6- (2- (trifluoromethyl) pyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-7-ol (21 mg), freeze-dried After a white solid. LC-MS (ES) m / z = 443 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 2.12 (d, J = 9.1Hz, 4H), 3.44 (d, J = 9.4Hz, 1H), 3.66-3.72 (m, 1H), 3.73 (s, 3H), 5.05-5.14 (m, 1H), 5.60 (s, 2H), 5.85 (d, J = 2.3Hz, 1H), 6.59 (d, J = 7.9Hz, 1H), 6.85 (d, J = 8.9 Hz, 1H), 6.94-7.01 (m, 1H), 7.10 (d, J = 7.9Hz, 1H), 7.55 (d, J = 2.3Hz, 1H), 8.03 (dd, J = 8.7, 2.4Hz, 1H ), 8.54 (d, J = 2.3Hz, 1H), 9.92 (s, 1H).

Intermediate 282

(R) -2-(((4-Bromo-3-fluoro-6-methoxy-2-nitrophenyl) amino) methyl) morpholin 4-carboxylic acid tert-butyl ester

Add NBS (2.182g, 12.26mmol) to (R) -2-(((3-fluoro-6-methoxy-2-nitrophenyl) amino) methyl) morpholin-4-carboxylic acid tri A solution of the first butyl ester (4.5 g, 11.68 mmol) in DMF (55 mL), and the reaction mixture was stirred at room temperature for 18 hours. The mixture was quenched with water (100 mL) and extracted with EtOAc (3x). The combined organic extracts were dried (Na ₂ SO ₄₎ and concentrated. The resulting residue was purified by column chromatography on silica gel (gradient: 0 to 80% EtOAc / heptane) to give the desired product (4.85 g) as a brown oil. LC-MS (ES) m / z = 464,466 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 1.42-1.52 (m, 9H), 2.69 (br.s., 1H), 2.89-3.04 (m, 1H), 3.14 (dd, J = 13.2, 8.1 Hz, 1H), 3.35 (br.s., 1H), 3.46-3.61 (m, 2H), 3.81-3.98 (m, 6H), 6.96 (d, J = 5.8 Hz, 1H).

Intermediate 283

(R) -2-((5-Bromo-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-7 -Methoxy-1H-benzo [d] imidazol-1-yl) methyl) morpholin-4-carboxylic acid tert-butyl ester

6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (1.628 g, 7.97 mmol), sodium bisulfite (85%, 4.90 g, 23.91 mmol) and Water (6.0 mL) was added to (R) -2-(((4-bromo-3-fluoro-6-methoxy-2-nitrophenyl) amino) methyl) morpholin-4-carboxylic acid tri A solution of the first butyl ester (3.7 g, 7.97 mmol) in DMSO (30 mL), and the reaction mixture was stirred at 97 ° C for 2 hours. The reaction mixture was cooled, quenched with water (60 mL), and extracted with EtOAc (3x). The combined organic extracts were dried (Na ₂ SO ₄₎ and concentrated. The resulting residue was purified by column chromatography on silica gel (gradient: 0 to 80% (3: 1 EtOAc: EtOH) / heptane) to give the desired product (3.40 g) as an off-white solid. LC-MS (ES) m / z = 618,620 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.18-1.25 (m, 6H), 1.44-1.51 (m, 9H), 1.71-1.83 (m, 2H), 2.29-2.44 (m, 2H), 2.68 ( m, 1H), 2.96 (br.s., 1H), 3.76-3.92 (m, 3H), 3.94-4.06 (m, 4H), 4.34 (dd, J = 14.6, 8.5Hz, 3H), 4.55 (dd , J = 14.7, 2.5Hz, 1H), 6.70 (d, J = 8.6Hz, 1H), 7.00 (d, J = 4.8Hz, 1H), 7.95 (dd, J = 8.9, 2.5Hz, 1H), 8.56 (d, J = 2.0Hz, 1H).

Intermediate 284

(R) -2-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -5- (ethylaminomethylmethyl) ) -4-fluoro-7-methoxy-1H-benzo [d] imidazol-1-yl) methyl) morpholin 4-carboxylic acid tert-butyl ester

Isopropyl magnesium chloride lithium chloride complex (0.826 mL, 1.073 mmol, 1.6 M in THF) was added to (R) -2-((5-bromo-2- (6- ((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-7-methoxy-1H-benzo [d] imidazol-1-yl ) Methyl) morpholin-4-carboxylic acid tert-butyl ester (166 mg, 0.268 mmol) in THF (3 ml), and the resulting mixture was stirred at -15 ° C for 15 minutes, then heated to 0 ° C and Stir for 1 hour. The reaction was then heated to 10 ° C and stirred for 1 hour. Then additional lithium isopropylmagnesium chloride complex (0.826 mL, 1.073 mmol, 1.6 M in THF) was added, and the resulting mixture was stirred for an additional hour. Carbon dioxide was slowly bubbled through the reaction mixture for 10 minutes. The reaction was then concentrated. Aqueous NaOH (5 mL, 1 N) was added followed by 1 N HCl until the pH was about 4. The resulting mixture was extracted (3 x 10mL), and then the organic extracts were combined, washed with brine, dried with MgSO _4, filtered, and concentrated with EtOAc. DMSO (3 mL), EDC (51.4 mg, 0.268 mmol), HOBt (41.1 mg, 0.268 mmol), ethylamine hydrochloride (43.8 mg, 0.537 mmol), and N-methylmorpholine (0.207 mL, 1.879 mmol) was added to the resulting yellow oil, and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with water (5 mL) and then extracted with EtOAc (4 x 10 mL). Next, the organic extracts were combined, washed with brine, dried over MgSO _4, filtered, and concentrated. Purification on HPLC system under NH ₄ OH conditions provided (R) -2-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridine-3 -Yl) -5- (ethylaminomethylmethyl) -4-fluoro-7-methoxy-1H-benzo [d] imidazol-1-yl) methyl) morpholin-4-carboxylic acid tertiary Butyl ester (32 mg), lyophilized as a white solid. LC-MS (ES) m / z = 611 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.11-1.17 (m, 9H), 1.40 (s, 9H), 1.66 (d, J = 5.8 Hz, 2H), 2.24 (br.s., 2H) , 3.17-3.26 (m, 1H), 3.28-3.32 (m, 2H), 3.62-3.81 (m, 4H), 3.97 (s, 3H), 4.19-4.39 (m, 3H), 4.46-4.54 (m, 1H), 6.62 (d, J = 8.9Hz, 1H), 6.98 (d, J = 4.3Hz, 1H), 7.93 (dd, J = 9.0, 2.4Hz, 1H), 8.23 (d, J = 3.0Hz, 1H), 8.54 (d, J = 2.3Hz, 1H).

Example 210

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -N-ethyl-4-fluoro-7-methoxy-1- ((((S) -morpholin-2-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide

Add a pre-mixed solution of CH ₂ Cl ₂ (1.5 mL) and TFA (0.5 mL, 6.49 mmol) to (R) -2-((2- (6-((2S, 5S) -2,5-dimethyl Pyrrolidin-1-yl) pyridin-3-yl) -5- (ethylaminomethylmethyl) -4-fluoro-7-methoxy-1H-benzo [d] imidazol-1-yl) methyl Propyl) morpholin-4-carboxylic acid tert-butyl ester (32 mg, 0.052 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the resulting material was diluted with saturated aqueous NaHCO ₃ (5mL) and extracted with EtOAc (3 x 1mL). The organic extracts were combined and washed with brine, dried over MgSO _4, filtered, and concentrated. The resulting material was diluted with MeCN (2 mL) and water (2 mL) and then freeze-dried to produce 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridine-3- ) -N-ethyl-4-fluoro-7-methoxy-1-((((S) -morpholin-2-yl) methyl) -1H-benzo [d] imidazole-5-methyl Amidine (23 mg) as a white solid. LC-MS (ES) m / z = 511 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.11-1.18 (m, 9H), 1.66 (d, J = 5.3Hz, 2H), 2.25 (br.s., 2H), 2.30-2.39 (m, 2H), 2.55-2.72 (m, 3H), 3.22m, 1H), 3.28-3.33 (m, 2H), 3.62 (d, J = 11.2Hz, 1H), 3.67-3.75 (m, 1H), 3.96 ( s, 3H), 4.29 (dd, J = 14.6, 8.2Hz, 3H), 4.38-4.46 (m, 1H), 6.62 (d, J = 8.6Hz, 1H), 6.97 (d, J = 4.6Hz, 1H ), 7.93 (dd, J = 8.9, 2.3 Hz, 1H), 8.22 (d, J = 3.3 Hz, 1H), 8.53 (d, J = 2.5 Hz, 1H).

Intermediate 285

(R) -2-((5-Bromo-4-fluoro-7-methoxy-2- (6-((S) -2-methylpyrrolidin-1-yl) pyridin-3-yl)- 1H-benzo [d] imidazol-1-yl) methyl) morpholin-4-carboxylic acid tert-butyl ester

Add ethanol (5mL), water (2.5mL), (S) -6- (2-methylpyrrolidin-1-yl) nicotinaldehyde (234mg, 1.228mmol), and sodium bisulfite (754mg, 3.68mmol) (85%) to (R) -2-(((4-bromo-3-fluoro-6-methoxy-2-nitrophenyl) amino) methyl) morpholin-4-carboxylic acid tertiary Butyl ester (570 mg, 1.228 mmol), and the reaction mixture was placed in a sealed container and heated at 130 ° C. for 1 hour under microwave conditions. The reaction was then quenched with water (5 mL) and extracted with EtOAc (4 x 5 mL). The organic extracts were combined, washed with brine, dried over MgSO _4, filtered, and concentrated. Purification by chromatography on SiO ₂ with a gradient from 0 to 10% CH ₃ OH in CH ₂ Cl ₂ provided (R) -2-((5-bromo-4-fluoro- 7-methoxy-2- (6-((S) -2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-1-yl) methyl) Morpholin-4-carboxylic acid tert-butyl ester (350 mg). LC-MS (ES) m / z = 605 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.18-1.21 (m, 3H), 1.39 (s, 9H), 1.68-1.76 (m, 1H), 1.98 (d, J = 2.3Hz, 1H), 2.02-2.12 (m, 2H), 2.57-2.69 (m, 1H), 2.82 (br.s., 1H), 2.78-2.78 (m, 1H), 3.21 (m, 1H), 3.34-3.39 (m, 1H), 3.56 (dd, J = 10.4,7.6Hz, 1H), 3.62-3.77 (m, 4H), 3.96 (s, 3H), 4.20-4.26 (m, 1H), 4.33 (dd, J = 15.0, 8.1Hz, 1H), 4.43-4.51 (m, 1H), 7.02 (d, J = 4.8Hz, 1H), 7.94 (dd, J = 8.9, 2.5Hz, 1H), 8.53 (d, J = 2.3Hz, 1H).

Intermediate 286

(S) -2-((5-Bromo-4-fluoro-7-methoxy-2- (6-((S) -2-methylpyrrolidin-1-yl) pyridin-3-yl)- 1H-benzo [d] imidazol-1-yl) methyl) -4-methylmorpholin

A premixed solution of CH ₂ Cl ₂ (1.5 mL) and TFA (0.5 mL, 6.49 mmol) was added to (R) -2-((5-bromo-4-fluoro-7-methoxy-2- (6 -((S) -2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-1-yl) methyl) morpholin-4-carboxylic acid tert-butyl Ester (165 mg, 0.273 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The reaction was concentrated and then (5mL) was quenched with saturated aqueous NaHCO _3. Drying the resulting mixture was extracted with EtOAc (4 x 5mL), and the combined organic extracts were washed with brine, MgSO _4, filtered, and concentrated. The resulting clear oil was diluted with 1,2-dichloroethane (5 mL) and treated with formaldehyde (0.106 mL, 1.365 mmol, 35.6% in water) and acetic acid (0.055 mL, 0.955 mmol). After the resulting mixture was stirred for 10 minutes, sodium triacetoxyborohydride (174 mg, 0.819 mmol) was added, and the reaction mixture was stirred for 1 hour. The reaction (2mL) was quenched with saturated aqueous NaHCO ₃ and treated with saturated aqueous Na ₂ CO ₃ (1 mL) until the pH was 10. The mixture was extracted with CH ₂ Cl ₂ (4 x 5 mL), and the combined organic extracts were washed with brine, dried over MgSO ₄ , filtered, and concentrated to give (S) -2-((5- Bromo-4-fluoro-7-methoxy-2- (6-((S) -2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-1 -Yl) methyl) -4-methylmorphine (134 mg). LC-MS (ES) m / z = 519 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.19-1.21 (m, 3H), 1.65-1.74 (m, 2H), 1.89-2.02 (m, 2H), 2.02-2.10 (m, 2H), 2.14 (s, 3H), 2.49 (br.s., 1H), 2.60 (d, J = 10.7Hz, 1H), 3.28 (td, J = 11.2,2.3Hz, 1H), 3.36-3.39 (m, 1H) , 3.52-3.61 (m, 1H), 3.65 (d, J = 10.9Hz, 1H), 3.2-3.80 (m, 1H), 3.95 (s, 3H), 4.20-4.28 (m, 1H), 4.28-4.37 (m, 1H), 4.40-4.47 (m, 1H), 6.59 (d, J = 9.1Hz, 1H), 7.00 (d, J = 4.6Hz, 1H), 7.94 (dd, J = 8.9, 2.3Hz, 1H), 8.52 (d, J = 2.3Hz, 1H).

Example 211

N-ethyl-4-fluoro-7-methoxy-1-((((S) -4-methylmorpholin-2-yl) methyl) -2- (6-((S) -2 -Methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-5-carboxamide

Isopropyl magnesium chloride lithium chloride complex (2.60 mL, 3.38 mmol, 1.6 M in THF) was added to (S) -2-((5-bromo-4-fluoro-7- Methoxy-2- (6-((S) -2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-1-yl) methyl) -4 -A solution of methylmorphine (175 mg, 0.338 mmol) in THF (3 ml), and the resulting mixture was stirred at 0 ° C for 15 minutes. Additional lithium isopropylmagnesium chloride complex (5.2 mL, 6.76 mmol, 1.6 M in THF) was added, and the resulting mixture was stirred for an additional 15 minutes. The reaction was cooled in a dry ice / acetone bath, and then CO _{2 was} bubbled through the reaction mixture for 5 minutes. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was concentrated and the resulting material was treated with 1N NaOH (5 mL) followed by 1N HCl until the pH was about 4. The resulting mixture was extracted with EtOAc (3 x 10 mL). The aqueous layer was freeze-dried all weekend. Add DMSO (10 mL), EDC (194 mg, 1.013 mmol), HOBt (155 mg, 1.013 mmol), ethylamine hydrochloride (138 mg, 1.688 mmol), and N-methylmorpholine (0.371 mL, 3.38 mmol). To the resulting solid, the reaction mixture was stirred at room temperature overnight. The reaction was quenched with water (5 mL) and extracted with EtOAc (4 x 10 mL). The organic extracts were combined, washed with brine, dried over MgSO _4, filtered, and concentrated. The crude oil was then diluted with DMSO (1 mL) and purified by reverse-phase HPLC (5-35% CH ₃ CN / (0.075% NH ₄ OH in water)) to give N-ethyl-4-fluoro-7-formaldehyde Oxy-1-(((S) -4-methylmorpholin-2-yl) methyl) -2- (6-((S) -2-methylpyrrolidin-1-yl) pyridine- 3-yl) -1H-benzo [d] imidazole-5-carboxamide (2.5mg), freeze-dried as a white solid. LC-MS (ES) m / z = 511 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.26-1.31 (m, 6H), 1.80-1.87 (m, 1H), 1.90 (t, J = 10.8Hz, 1H), 2.06-2.26 (m, 5H), 2.32 (s, 3H), 2.67 (d, J = 11.4Hz, 1H), 2.85 (d, J = 11.2Hz, 1H), 3.40-3.54 (m, 4H), 3.62-3.70 (m, 1H), 3.82 (d, J = 9.6Hz, 1H), 3.99-4.06 (m, 4H), 4.25-4.39 (m, 2H), 4.58 (dd, J = 14.5, 2.5Hz, 1H), 6.68 (d, J = 9.1 Hz, 1H), 7.17 (d, J = 4.6 Hz, 1H), 7.97 (dd, J = 9.0, 2.2 Hz, 1H), 8.55 (d, J = 2.0 Hz, 1H).

Intermediate 287

(R) -4-(((1,4-two Alk-2-yl) methyl) amino) -3-nitrobenzoate

Methyl 4-fluoro-3-nitrobenzoate (250 mg, 1.255 mmol), K ₂ CO ₃ (347 mg, 2.51 mmol), and (R)-(1,4-di A mixture of alk-2-yl) methylamine hydrochloride (199 mg, 1.293 mmol) in DMF (5 mL) was stirred at room temperature overnight. The reaction was slowly diluted with saturated aqueous NH ₄ Cl and stirred for 10 min. The resulting precipitate was collected by filtration, washed with a small amount of water, air-dried for 10 minutes, and dried under vacuum at 40 ° C for 3 hours to provide crude (R) -4-(((1,4-di Alk-2-yl) methyl) amino) -3-nitrobenzoate (372 mg). LC-MS (ES) m / z = 297 [M + H] ⁺ .

Intermediate 288

(S) -2-((4-chloro-2- (6-((S) -2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-1 -Yl) methyl) morpholin

6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (256 mg, 1.256 mmol), sodium bisulfite (699 mg, 4.02 mmol), and (R)- 4-(((1,4-two A mixture of alkyl-2-yl) methyl) amino) -3-nitrobenzoate (372 mg, 1.256 mmol) in ethanol (8 mL) and water (1.600 mL) in a sealed container under microwave conditions at 130 Heated at 60 ° C for 60 minutes. The reaction was poured into saturated aqueous NH ₄ Cl and stirred for 15 minutes. Drying the resulting mixture was extracted with EtOAc (2x), and the combined organic extracts with MgSO _4, filtered, and concentrated. The resulting residue was purified by silica gel chromatography using a gradient of 5% to 70% (3: 1 EtOAc / EtOH (2% NH ₄ OH)) / heptane to provide 1-((((R) -1,4-two Alk-2-yl) methyl) -2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] Methyl imidazole-5-carboxylic acid (410 mg). LC-MS (ES) m / z = 451 [M + H] ⁺ . 1H NMR (DMSO- d ₆ ): δ 8.58 (d, J = 2.0 Hz, 1H), 8.22 (d, J = 1.0 Hz, 1H), 7.97 (dd, J = 8.9, 2.5 Hz, 1H), 7.88 ( dd, J = 8.4, 1.5Hz, 1H), 7.79 (d, J = 8.4Hz, 1H), 6.63 (d, J = 8.9Hz, 1H), 4.13-4.42 (m, 4H), 3.93-4.00 (m , 1H), 3.83 (dd, J = 11.4, 2.3Hz, 1H), 3.59-3.69 (m, 2H), 3.37-3.52 (m, 2H), 3.26-3.33 (m, 2H), 2.24 (br.s ., 2H), 1.66 (d, J = 5.6Hz, 2H), 1.06-1.18 (m, 7H).

Intermediate 289

1-(((R) -1,4-two Alk-2-yl) methyl) -2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] Imidazole-5-carboxylic acid

5N NaOH (0.910 mL, 4.55 mmol) was slowly added to 1-((((R) -1,4-di) in CH ₃ OH (10 mL) and THF (2 mL) via a syringe at room temperature. Alk-2-yl) methyl) -2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] Methyl imidazole-5-carboxylic acid (410 mg, 0.910 mmol), and the reaction mixture was heated at 40-45 ° C for 18 hours. The reaction was cooled in an ice bath and then 6N HCl (6M) (0.766 mL, 4.60 mmol) was added very slowly via a syringe. The resulting mixture was concentrated to provide crude 1-(((R) -1,4-di Alk-2-yl) methyl) -2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] Imidazole-5-carboxylic acid. LC-MS (ES) m / z = 437 [M + H] ⁺ .

Example 212

1-(((R) -1,4-two Alk-2-yl) methyl) -2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -N-methyl) 1H- Benzo [d] imidazole-5-carboxamide

Add N-methylmorphine (0.242 mL, 2.199 mmol) to 1-((((R) -1,4-di Alk-2-yl) methyl) -2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] A mixture of imidazole-5-carboxylic acid (160 mg, 0.220 mmol), methylamine hydrochloride (148 mg, 2.199 mmol), HOAt (35.9 mg, 0.264 mmol), and EDC (50.6 mg, 0.264 mmol) in DMSO (3 mL) The reaction mixture was stirred at room temperature overnight. The reaction was diluted with saturated aqueous NH ₄ Cl solution, and the resulting precipitate was collected by filtration and washed with a small amount of water. The aqueous layer was extracted with CH ₂ Cl ₂ (2 x 8 mL), and the combined organic extracts were dried over MgSO ₄ , filtered, and then added to the solid collected by filtration. The resulting mixture was concentrated in vacuo, and by silica gel chromatography (gradient: 1 EtOAc / EtOH (2% NH 4 OH)) / heptane: 8-80% (3) The resulting residue was purified. The portion containing the desired product was dissolved in CH2Cl2 and treated with heptane (0.5 mL). The resulting mixture was concentrated under vacuum to provide 1-((((R) -1,4-di Alk-2-yl) methyl) -2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -N-methyl-1H- Benzo [d] imidazole-5-carboxamide (92 mg). LC-MS (ES) m / z = 450 [M + H] ⁺ . 1H NMR (DMSO- d ₆ ): δ 8.57 (d, J = 2.0Hz, 1H), 8.43 (q, J = 4.2Hz, 1H), 8.14 (d, J = 1.3Hz, 1H), 7.96 (dd, J = 8.9, 2.5 Hz, 1H), 7.77 (dd, J = 8.6, 1.5 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 6.63 (d, J = 8.9 Hz, 1H), 4.11- 4.41 (m, 4H), 3.92-4.01 (m, 1H), 3.83 (dd, J = 11.4, 2.3Hz, 1H), 3.64 (dd, J = 19.4, 10.3Hz, 2H), 3.37-3.52 (m, 2H), 3.29 (dd, J = 11.4, 10.1Hz, 1H), 2.82 (d, J = 4.6Hz, 3H), 2.24 (br.s., 2H), 1.66 (d, J = 5.3Hz, 2H) , 1.07-1.20 (m, 6H).

Intermediate 290

4- (2-((3-chloro-2-nitrophenyl) amino) ethyl) piper -2-one

1-chloro-3-fluoro-2-nitrobenzene (160 mg, .911 mmol), K ₂ CO ₃ (378 mg, 2.73 mmol), and 4- (2-aminoethyl) piper A mixture of -2-one, 2 hydrochloride (203 mg, 0.939 mmol) in DMF (6 mL) was stirred at room temperature for 10 minutes and then at 45 ° C overnight. Additional amine was added and the reaction mixture was stirred for an additional 12 hours. The reaction was diluted in ₄ Cl solution and extracted with CH ₂ Cl ₂ (2x) saturated NH. The combined organic extracts were dried over MgSO ₄ , filtered, and concentrated in vacuo to an orange residue, which was dried over hivac for 2 hrs. The resulting material was purified by silica gel chromatography using a gradient of 20-100% (3: 1 EtOAc / EtOH (2% NH ₄ OH)) / heptane to provide 4- (2-((3-chloro -2-nitrophenyl) amino) ethyl) piper -2-one (150 mg). LC-MS (ES) m / z = 299 [M + H] ⁺ . 1H NMR (DMSO- d ₆ ): δ 7.76 (br.s., 1H), 7.36 (t, J = 8.2Hz, 1H), 6.91-6.96 (m, 1H), 6.82 (dd, J = 7.9,1.0 Hz, 1H), 6.33 (t, J = 5.1Hz, 1H), 3.26-3.31 (m, 2H), 3.11-3.17 (m, 2H), 2.99 (s, 2H), 2.56-2.62 (m, 4H) .

Example 213

4- (2- (4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] Imidazol-1-yl) ethyl) piper -2-one

4- (2-((3-chloro-2-nitrophenyl) amino) ethyl) piper 2-one (150 mg, 0.502 mmol), 6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (118 mg, 0.577 mmol), and sodium bisulfite ( A mixture of 329 mg, 1.607 mmol) in ethanol (3 mL) and water (1.0 mL) was placed in a sealed container and stirred at 130 ° C for 55 minutes under microwave conditions. The reaction was poured into saturated aqueous NaHCO ₃ and stirred. After 15 minutes, the mixture was extracted with EtOAc (2x), and the combined organic extracts were dried with MgSO _4, filtered, and concentrated in vacuo. The resulting residue / foam was purified by silica gel chromatography (gradient: 8% to 75% (90: 10: 1 CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH) / CH ₂ Cl ₂ ) to provide a solid 4- (2- (4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d ] Imidazol-1-yl) ethyl) piper -2-one (170 mg). LC-MS (ES) m / z = 453 [M + H] ⁺ . 1H NMR (DMSO- d ₆ ): δ 8.53 (d, J = 2.0Hz, 1H), 7.91 (dd, J = 8.9, 2.5Hz, 1H), 7.60-7.72 (m, 2H), 7.18-7.33 (m , 2H), 6.63 (d, J = 8.6 Hz, 1H), 4.44 (t, J = 6.5 Hz, 2H), 4.26 (br.s., 2H), 2.92-3.02 (m, 2H), 2.79-2.90 (m, 2H), 2.70 (m, 2H), 2.43-2.48 (m, 2H), 2.18-2.31 (m, 2H), 1.65 (d, J = 5.6Hz, 2H), 1.10-1.17 (m, 6H ).

Intermediate 291

(R) -2-((5- (ethylaminomethylmethyl) -4-fluoro-7-methoxy-2- (6-((S) -2-methylpyrrolidin-1-yl) Pyridine-3-yl) -1H-benzo [d] imidazol-1-yl) methyl) morpholin 4-carboxylic acid tert-butyl ester

Isopropylmagnesium chloride and lithium chloride complex (0.891 mL, 1.158 mmol, 1.6 M in THF) were added to (R) -2-((5- Bromo-4-fluoro-7-methoxy-2- (6-((S) -2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-1 -Yl) methyl) morpholin-4-carboxylic acid tert-butyl ester (175 mg, 0.289 mmol), and the reaction mixture was stirred at -15 ° C for 15 minutes. The reaction was then stirred at 0 ° C for 1 hour and at 10 ° C for 1 hour. Then additional lithium isopropylmagnesium chloride complex (0.891 mL, 1.158 mmol, 1.6 M in THF) was added, and the reaction mixture was stirred at 10 ° C for 1 hour. Carbon dioxide was then bubbled through the reaction mixture for 15 minutes, and the reaction was stirred for an additional hour. The reaction was concentrated and then treated with 1 N NaOH (5 mL) followed by 1 N HCl until the pH was about 4. Drying the resulting mixture was extracted with EtOAc (3 x 10mL), and the combined organic extracts were washed with brine, MgSO _4, filtered, and concentrated. DMSO (3.00 mL), EDC (55.5 mg, 0.289 mmol), HOBt (44.3 mg, 0.289 mmol), ethylamine hydrochloride (47.2 mg, 0.579 mmol), and N-methylmorpholine (0.223 mL, 2.026 mmol) was added to the resulting yellow oil, and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with water (5 mL) and extracted with EtOAc (4 x 10 mL). The organic extracts were combined, washed with brine, dried over MgSO _4, filtered, and concentrated. The resulting material was purified by reverse-phase HPLC (gradient: 50-99% CH ₃ CN in 0.1% NH ₄ OH) to provide (R) -2-((5- (ethylaminemethylamidino) -4 -Fluoro-7-methoxy-2- (6-((S) -2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-1-yl) Methyl) morpholin-4-carboxylic acid tert-butyl ester (26 mg), lyophilized as a white solid. LC-MS (ES) m / z = 597 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.15 (t, J = 7.2Hz, 3H), 1.20 (d, J = 6.3Hz, 3H), 1.39 (s, 9H), 1.72 (br.s. , 1H), 1.96-2.14 (m, 3H), 2.45-2.49 (m, 2H), 3.16-3.24 (m, 1H), 3.28-3.32 (m, 3H), 3.53-3.59 (m, 1H), 3.61 -3.79 (m, 4H), 3.97 (s, 3H), 4.24 (br.s., 1H), 4.34 (dd, J = 15.1, 8.2Hz, 1H), 4.51 (d, J = 12.2Hz, 1H) , 6.60 (d, J = 8.9Hz, 1H), 6.98 (d, J = 4.6Hz, 1H), 7.95 (dd, J = 8.7,2.4Hz, 1H), 8.23 (d, J = 2.8Hz, 1H) , 8.53 (d, J = 2.3Hz, 1H).

Example 214

N-ethyl-4-fluoro-7-methoxy-2- (6-((S) -2-methylpyrrolidin-1-yl) pyridin-3-yl) -1-(((S) -Morpholin-2-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide

A premixed solution of CH ₂ Cl ₂ (1.5 mL) and TFA (0.5 mL, 6.49 mmol) was added to (R) -2-((5- (ethylaminemethylamidino) -4-fluoro-7-formaldehyde) Oxy-2- (6-((S) -2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-1-yl) methyl) morpholin Tert-butyl-4-carboxylic acid (26 mg, 0.044 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The reaction was concentrated, and the resulting material (2mL) was diluted with saturated aqueous NaHCO ₃ and then extracted with EtOAc (4 x 10 mL). The organic extracts were combined, washed with brine, dried over MgSO _4, filtered, and concentrated to provide N- ethyl-4-fluoro-7-methoxy -2- (6 - ((S) -2- methyl Pyrrolidin-1-yl) pyridin-3-yl) -1-(((S) -morpholin-2-yl) methyl) -1H-benzo [d] imidazol-5-carboxamide (20mg ), White solid after freeze-drying. LC-MS (ES) m / z = 497 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.15 (t, J = 7.2Hz, 3H), 1.20 (d, J = 6.3Hz, 3H), 1.69-1.77 (m, 1H), 1.95-2.13 ( m, 3H), 2.28-2.37 (m, 1H), 2.56-2.61 (m, 2H), 2.64-2.70 (m, 1H), 3.22 (m, 1H), 3.28-3.32 (m, 2H), 3.36- 3.41 (m, 1H), 3.53-3.64 (m, 2H), 3.64-3.72 (m, 1H), 3.96 (s, 3H), 4.20-4.34 (m, 2H), 4.39-4.46 (m, 1H), 6.60 (d, J = 8.9Hz, 1H), 6.98 (d, J = 4.6Hz, 1H), 7.95 (dd, J = 8.9,2.5Hz, 1H), 8.22 (d, J = 2.8Hz, 1H), 8.53 (d, J = 2.0Hz, 1H).

Intermediate 292

3-(((2-methoxy-6-nitrophenyl) amino) methyl) morpholin-4-carboxylic acid tert-butyl ester

3- (Aminemethyl) morpholin-4-carboxylic acid tert-butyl ester (506 mg, 2.337 mmol), K ₂ CO ₃ (323 mg, 2.337 mmol), and diisopropylethylamine (0.408 mL, 2.337 mmol) ) Was added to 2-fluoro-1-methoxy-3-nitrobenzene (400 mg, 2.337 mmol) in DMSO (3 mL), and the reaction mixture was heated in a microwave reactor at 90 ° C. for 1 hour. The reaction was diluted with water (10 mL) and extracted with EtOAc (4 x 5 mL). The organic extracts were combined, washed with brine, dried over MgSO _4, filtered, and concentrated. Purification by flash chromatography on SiO ₂ with a gradient of 0 to 40% EtOAc in hexane provided 3-(((2-methoxy-6-nitrophenyl) amino) as a red oil Methyl) morpholin-4-carboxylic acid tert-butyl ester (770 mg), which solidified upon standing. LC-MS (ES) m / z = 368 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.20 (br.s., 9H), 3.14 (m, 1H), 3.25-3.33 (m, 1H), 3.44 (m, 1H), 3.60-3.80 ( m, 4H), 3.84 (s, 3H), 3.86-3.93 (m, 1H), 4.05 (d, J = 9.9Hz, 1H), 6.68-6.75 (m, 1H), 7.17 (d, J = 7.6Hz , 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.62-7.75 (m, 1H).

Intermediate 293

3-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [d] Imidazol-1-yl) methyl) morpholin-4-carboxylic acid tert-butyl ester

Add 6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (45.6mg, 0.223mmol), sodium bisulfite (117mg, 0.571mmol), ethanol (1.5mL ), And water (0.750 mL) to 3-(((2-methoxy-6-nitrophenyl) amino) methyl) morpholin-4-carboxylic acid tert-butyl ester (82 mg, 0.223 mmol) , And the reaction mixture was heated at 130 ° C. for 1 hour under microwave conditions. The reaction was diluted with water and extracted with EtOAc (4 x 5 mL). The organic extracts were combined, washed with brine, dried over MgSO _4, filtered, and concentrated. Purification by chromatography on SiO ₂ with a gradient of 0 to 10% CH ₃ OH in CH ₂ Cl ₂ provided 3-((2- (6-((2S, 5S) -2 , 5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [d] imidazol-1-yl) methyl) morpholin-4-carboxylic acid tri Grade butyl ester (88 mg). LC-MS (ES) m / z = 522 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 0.72 (br.s., 9H), 1.13 (t, J = 5.8Hz, 6H), 1.60-1.71 (m, 2H), 1.85 (d, J = 11.7Hz, 1H), 2.18-2.29 (m, 2H), 3.17 (t, J = 12.0Hz, 1H), 3.25-3.32 (m, 1H), 3.44 (d, J = 11.4Hz, 1H), 3.49- 3.60 (m, 1H), 3.80-3.87 (m, 1H), 3.93 (s, 3H), 4.16 (d, J = 10.1Hz, 1H), 4.27 (br.s., 2H), 4.54-4.82 (m , 2H), 6.63 (d, J = 8.9Hz, 1H), 6.82 (d, J = 8.1Hz, 1H), 7.12 (t, J = 8.0Hz, 1H), 7.24 (dd, J = 7.6, 3.8Hz , 1H), 7.63 (dd, J = 12.7, 9.4Hz, 1H), 8.19-8.30 (m, 1H).

Example 215

3-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [d] Imidazol-1-yl) methyl) morpholin

HCl (2 mL, 65.8 mmol, 1.25 M in CH ₃ OH) was added to 3-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridine -3-yl) -7-methoxy-1H-benzo [d] imidazol-1-yl) methyl) morpholin 4-carboxylic acid tert-butyl ester (86 mg, 0.165 mmol), and the reaction mixture Stir for 2 hours. The mixture was concentrated, and by chromatography on SiO ₂ with 0 to 40% CH ₂ Cl ₂ in the ((80: 20: 2) CH 2 Cl 2: CH 3 OH: NH 4 OH) gradient to The resulting material was purified to provide 3-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H- Benzo [d] imidazol-1-yl) methyl) morphin (51 mg), lyophilized as a white solid. LC-MS (ES) m / z = 422 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.16 (d, J = 5.6Hz, 6H), 1.66 (d, J = 5.6Hz, 2H), 2.16 (br.s., 1H), 2.25 (br .s., 2H), 2.56-2.62 (m, 1H), 2.91-2.99 (m, 2H), 3.21-3.30 (m, 2H), 3.50 (d, J = 10.7Hz, 1H), 3.95 (s, 3H), 4.26 (br.s., 2H), 4.30-4.36 (m, 2H), 6.61 (d, J = 8.9Hz, 1H), 6.82 (d, J = 7.9Hz, 1H), 7.10-7.15 ( m, 1H), 7.20-7.25 (m, 1H), 7.86-7.91 (m, 1H), 8.47 (dd, J = 6.1, 2.3 Hz, 1H).

Intermediate 294

3-methoxy-4-(((1-methyl-1H-pyrazol-3-yl) methyl) amino) -5-nitrobenzoate

(1-methyl-1H-pyrazol-3-yl) methylamine (0.498 g, 4.48 mmol) and K ₂ CO ₃ (0.731 g, 5.29 mmol) were added to 4-chloro- in DMSO (8 mL) Methyl 3-methoxy-5-nitrobenzoate (1 g, 4.07 mmol), and the reaction mixture was stirred at 50 ° C for 48 hours. The reaction was quenched with water (25 mL), and the resulting precipitate was collected by filtration and dried in a vacuum oven (over) to provide 3-methoxy-4-(((1-methyl- 1H-pyrazol-3-yl) methyl) amino) -5-nitrobenzoate (740 mg). LC-MS (ES) m / z = 321 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 3.78 (s, 3H), 3.84 (s, 3H), 3.91 (s, 3H), 4.73 (s, 2H), 6.10 (d, J = 2.0Hz, 1H), 7.46 (d, J = 1.8 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H), 8.19 (d, J = 2.0 Hz, 1H), 8.36 (br.s., 1H).

Intermediate 295

(R) -7-methoxy-1-((1-methyl-1H-pyrazol-3-yl) methyl) -2- (6- (2- (trifluoromethyl) pyrrolidine-1 -Yl) pyridin-3-yl) -1H-benzo [d] imidazole-5-carboxylic acid methyl ester

(R) -6- (2- (trifluoromethyl) pyrrolidin-1-yl) nicotinaldehyde (76 mg, 0.312 mmol), sodium bisulfite (163 mg, 0.796 mmol), ethanol (2 mL), water (1mL) to 3-methoxy-4-(((1-methyl-1H-pyrazol-3-yl) methyl) amino) -5-nitrobenzoate (100 mg, 0.312 mmol) The reaction mixture was put into a sealed container and heated at 130 ° C. for 1 hour under microwave conditions. The reaction was quenched with water (5 mL) and extracted with EtOAc (3 x 10 mL). The organic extracts were combined, washed with brine, dried over MgSO _4, filtered, and concentrated. _{(: 20: 2) CH 2} Cl 2: CH 3 OH: (80 NH 4 OH) chromatography on SiO ₂ with 0 to 35% CH ₂ Cl ₂ in the purified gradients provided by an off-white solid (R) -7-methoxy-1-((1-methyl-1H-pyrazol-3-yl) methyl) -2- (6- (2- (trifluoromethyl) pyrrolidine- 1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-5-carboxylic acid methyl ester (92 mg). LC-MS (ES) m / z = 515 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 2.05-2.21 (m, 4H), 3.41-3.50 (m, 1H), 3.67-3.72 (m, 1H), 3.73 (s, 3H), 3.88 (s , 3H), 3.92 (s, 3H), 5.10 (t, J = 7.6Hz, 1H), 5.58 (s, 2H), 5.95 (d, J = 2.3Hz, 1H), 6.88 (d, J = 8.9Hz , 1H), 7.34 (d, J = 1.3Hz, 1H), 7.58 (d, J = 2.3Hz, 1H), 7.91 (d, J = 1.3Hz, 1H), 8.10 (dd, J = 8.7,2.4Hz , 1H), 8.61 (d, J = 2.3Hz, 1H).

Intermediate 296

(R) -7-methoxy-1-((1-methyl-1H-pyrazol-3-yl) methyl) -2- (6- (2- (trifluoromethyl) pyrrolidine-1 -Yl) pyridin-3-yl) -1H-benzo [d] imidazole-5-carboxylic acid

8N NaOH (0.447 mL, 3.58 mmol) was added to (R) -7-methoxy-1-((1-methyl-1H-pyrazol-3-yl) methyl) -2- (6- ( 2- (trifluoromethyl) pyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-5-carboxylic acid methyl ester (92 mg, 0.179 mmol) CH ₃ OH (3 mL), and The reaction mixture was stirred at room temperature overnight. The reaction was concentrated and treated with 1N HCl 1M (3.58 mL, 3.58 mmol). The resulting precipitate was collected by filtration and dried in a vacuum oven for 4 hours to give crude (R) -7-methoxy-1-((1-methyl-1H-pyrazole-3- (Methyl) methyl) -2- (6- (2- (trifluoromethyl) pyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-5-carboxylic acid (89 mg). LC-MS (ES) m / z = 501 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 2.06-2.19 (m, 4H), 3.40-3.51 (m, 1H), 3.70 (d, J = 5.1Hz, 1H), 3.75 (br.s., 3H), 3.91 (s, 3H), 5.11 (t, J = 6, 7Hz, 1H), 5.58 (s, 2H), 5.96 (d, J = 2.3Hz, 1H), 6.89 (d, J = 8.9Hz , 1H), 7.35 (d, J = 1.0Hz, 1H), 7.58 (d, J = 2.0Hz, 1H), 7.88 (d, J = 1.3Hz, 1H), 8.10 (dd, J = 8.7, 2.4Hz , 1H), 8.61 (d, J = 2.5 Hz, 1H), 12.84 (br.s., 1H).

Synthesis Example 216

(R) -7-methoxy-N-methyl-1-((1-methyl-1H-pyrazol-3-yl) methyl) -2- (6- (2- (trifluoromethyl ) Pyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-5-carboxamide

Methylamine hydrochloride (21.61 mg, 0.320 mmol), EDC (61.4 mg, 0.320 mmol), HOBt (49.0 mg, 0.320 mmol), and N-methylmorpholine (0.117 mL, 1.067 mmol) were added to (R) -7-methoxy-1-((1-methyl-1H-pyrazol-3-yl) methyl) -2- (6- (2- (trifluoro) in DMSO (1.5 mL) Methyl) pyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-5-carboxylic acid (89 mg, 0.178 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with water (5 mL) and extracted with EtOAc (4 x 5 mL). The organic extracts were combined, dried over MgSO _4, filtered, and concentrated. By chromatography on SiO ₂ using CH ₂ Cl ₂ in the 0 to _{40% ((80 NH 4 OH} : 20: 2) CH 2 Cl 2:: CH 3 OH) to provide (R) of the gradient purified -7-methoxy-N-methyl-1-((1-methyl-1H-pyrazol-3-yl) methyl) -2- (6- (2- (trifluoromethyl) pyrrolidine 1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-5-carboxamide (71 mg), lyophilized as a white solid. LC-MS (ES) m / z = 514 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 2.06-2.19 (m, 4H), 2.81 (d, J = 4.6Hz, 3H), 3.40-3.50 (m, 1H), 3.67-3.72 (m, 1H ), 3.73 (s, 3H), 3.90 (s, 3H), 5.06-5.15 (m, 1H), 5.56 (s, 2H), 5.93 (d, J = 2.3Hz, 1H), 6.87 (d, J = 8.9Hz, 1H), 7.29 (d, J = 1.3Hz, 1H), 7.57 (d, J = 2.0Hz, 1H), 7.80 (d, J = 1.3Hz, 1H), 8.09 (dd, J = 8.9, 2.5Hz, 1H), 8.43 (d, J = 4.6Hz, 1H), 8.59 (d, J = 2.3Hz, 1H).

Intermediate 297

4,4-dichloro-2-methylpyrrolidine-1-carboxylic acid (S) -tertiary butyl ester

DAST (5.64 mL, 42.7 mmol) was added to 2-methyl-4-oxopyrrolidine-1-carboxylic acid (S) -tertiary butyl ester (850 mg, 4.27 mmol) at 20 ° C at 1,2- A solution in dichloroethane (20 mL), and the reaction mixture was stirred in a sealed tube at 60 ° C for 3 hours. The reaction mixture was quenched with saturated aqueous NaHCO ₃ and washed with brine, dried over Na ₂ SO _4, filtered, and concentrated. ₂ by flash chromatography on SiO (2-5% EtOAc / heptane) The resulting yellow oil was purified to provide the desired product as a pale yellow oil ratio. LC-MS (ES) m / z = 166 [M-tertiary-butyl + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 4.23-4.01 (m, 1H), 3.88-3.60 (m, 2H), 2.61-2.43 (m, 1H), 2.03 (m, 1H), 1.45 (s, 9H ), 1.30 (d, J = 6.4 Hz, 3H).

Intermediate 298

(S) -4,4-difluoro-2-methylpyrrolidine

HCl (5 mL, 23.99 mmol, 33 wt% in water) was added to 4,4-difluoro-2-methylpyrrolidine-1-carboxylic acid (S) -tert-butyl ester (500 mg, 2.260 mmol) in CH ₂ A solution in Cl ₂ (12 mL), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to provide the crude product as the HCl salt. LC-MS (ES) m / z = 122 [M + H] ⁺ .

Intermediate 299

(S) -6- (4,4-difluoro-2-methylpyrrolidin-1-yl) nicotinaldehyde

Triethylamine (0.478 mL, 3.43 mmol) was added to (S) -4,4-difluoro-2-methylpyrrolidine hydrochloride (180 mg, 1.142 mmol) and 6-fluoronicotine at 20 ° C. A solution of aldehyde (143 mg, 1.142 mmol) in (DMF) (8 mL), and the reaction mixture was stirred at 70 ° C for 15 hours. The reaction mixture was concentrated and the crude product was purified by flash chromatography on SiO ₂ (0-15% EtOAc / hexanes) to provide the product (S) -6- (4,4-difluoro) as a colorless oil 2-methylpyrrolidin-1-yl) nicotinaldehyde (170 mg). LC-MS (ES) m / z = 227 [M + H] ⁺ . 1H NMR (400MHz, CDCl ₃ ): δ 9.82 (s, 1H), 8.60 (s, 1H), 7.98 (d, J = 8.9Hz, 1H), 6.44 (d, J = 8.9Hz, 1H), 4.61- 4.48 (m, 1H), 4.03-3.91 (m, 2H), 2.80-2.60 (m, 1H), 2.35-2.19 (m, 1H), 1.41 (d, J = 6.4Hz, 3H).

Intermediate 300

6-methoxy-N1-((1-methyl-1H-pyrazol-3-yl) methyl) benzene-1,2-diamine

Pd-C (81 mg, 0.076 mmol) was added to 2-methoxy-N-((1-methyl-1H-pyrazol-3-yl) methyl) -6-nitroaniline (200 mg, 0.763 mmol) A solution in CH ₃ OH (20 mL) and the reaction mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours by using a hydrogen bulb. The reaction was filtered and the filtrate was concentrated. The crude product was purified by flash chromatography on SiO ₂ (0-4% CH ₃ OH in CH ₂ Cl ₂ ) to provide 6-methoxy-N1-((1-methyl 1H-pyrazol-3-yl) methyl) benzene-1,2-diamine (80 mg). LC-MS (ES) m / z = 233 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 7.28 (d, J = 1.3Hz, 1H), 6.85 (t, J = 8.1Hz, 1H), 6.40 (d, J = 8.0Hz, 1H), 6.33 (d , J = 8.2Hz, 1H), 6.18 (d, J = 1.5Hz, 1H), 4.09 (s, 2H), 3.89 (s, 3H), 3.77 (s, 3H).

Example 217

(S) -2- (6- (4,4-difluoro-2-methylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1-((1-methyl- 1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole

Add sodium metadisulfite (65.5mg, 0.344mmol) to 6-methoxy-N1-((1-methyl-1H-pyrazol-3-yl) methyl) benzene-1,2-diamine (80mg , 0.344 mmol) and (S) -6- (4,4-difluoro-2-methylpyrrolidin-1-yl) nicotinaldehyde (78 mg, 0.344 mmol) in DMF (8 mL), and The reaction mixture was stirred at 70 ° C for 15 hours. The reaction was concentrated and the resulting crude product was purified by flash chromatography on SiO ₂ (0-8% CH ₃ OH in CH ₂ Cl ₂ ) to provide (S) -2- ( 6- (4,4-difluoro-2-methylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1-((1-methyl-1H-pyrazole-3- Yl) methyl) -1H-benzo [d] imidazole (110 mg). LC-MS (ES) m / z = 439 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.57 (d, J = 2.1Hz, 1H), 7.95 (dd, J = 8.8, 2.1Hz, 1H), 7.43 (d, J = 8.1Hz, 1H), 7.24 -7.15 (m, 2H), 6.71 (d, J = 7.9Hz, 1H), 6.44 (d, J = 8.8Hz, 1H), 5.89 (d, J = 2.0Hz, 1H), 5.62 (s, 2H) , 4.52-4.36 (m, 1H), 3.98-3.88 (m, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 2.76-2.57 (m, 1H), 2.29-2.17 (m, 1H) , 1.38 (d, J = 6.4 Hz, 3H).

Intermediate 301

4-fluoro-2-methylpyrrolidine-1-carboxylic acid (2S, 4S) -tertiary butyl ester

DAST (0.788 mL, 5.96 mmol) was added to (2S, 4R) -4-hydroxy-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (1000 mg, 4.97 mmol) at 0 ° C in CH ₂ Cl ₂ (3 mL), and the reaction mixture was stirred at 0 ° C for 20 minutes and then at room temperature for 16 hours. By the addition of saturated aqueous NaHCO ₃ The reaction was quenched. After stirring for 15 minutes to dry the aqueous layer was extracted with CH ₂ Cl ₂ and the combined organic extracts with MgSO _4, filtered, and concentrated. Purification by flash chromatography on SiO ₂ (0% to 15% EtOAc / hexane) provided (2S, 4S) -4-fluoro-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (391 mg ). ¹ H NMR (400MHz, CDCl ₃ ): δ 4.98-5.26 (m, 1H), 3.72-4.18 (m, 2H), 3.35-3.57 (m, 1H), 2.34-2.57 (m, 1H), 1.60-1.85 (m, 1H), 1.49 (s, 9H), 1.30 (br.s., 3H).

Intermediate 302

(2S, 4S) -4-fluoro-2-methylpyrrolidine

(2S, 4S) -4-fluoro-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (391 mg, 1.924 mmol) and hydrochloric acid (1.443 mL, 5.77 mmol, A solution of 4M in alkane) in CH ₂ Cl ₂ (20 mL) was heated at 40 ° C. for 2 hours. The reaction was concentrated to provide (2S, 4S) -4-fluoro-2-methylpyrrolidine hydrochloride (254 mg) as a brown solid. LC-MS (ES) m / z = 104 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 5.31-5.57 (m, 1H), 3.89-4.05 (m, 1H), 3.49-3.76 (m, 2H), 2.42-2.63 (m, 1H), 1.80- 2.06 (m, 1H), 1.50 (d, J = 6.6Hz, 3H).

Intermediate 303

6-((2S, 4S) -4-fluoro-2-methylpyrrolidin-1-yl) nicotinaldehyde

Add 6-fluoronicotinaldehyde (228 mg, 1.819 mmol), (2S, 4S) -4-fluoro-2-methylpyrrolidine hydrochloride (254 mg, 1.819 mmol), and diisopropylethylamine (1.430 mL , 8.19 mmol) in DMF (20 mL) was heated at 80 ° C for 16 hours. The reaction was concentrated and the resulting material was dissolved in EtOAc. The resulting organic mixture was washed with water then brine, dried over MgSO _4, filtered, and concentrated. The resulting residue was purified via silica chromatography (0% to 25% EtOAc: hexanes) to provide 6-((2S, 4S) -4-fluoro-2-methylpyrrolidin-1-yl) as an oil. Nicotinaldehyde (290 mg). LC-MS (ES) m / z = 209 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 9.81 (s, 1H), 8.60 (d, J = 2.3Hz, 1H), 7.96 (dd, J = 2.3, 8.9Hz, 1H), 6.50 (d, J = 8.9Hz, 1H), 5.19-5.49 (m, 1H), 4.33-4.57 (m, 1H), 4.03 -4.25 (m, 1H), 3.67-3.88 (m, 1H), 2.55-2.72 (m, 1H) , 1.87-2.12 (m, 1H), 1.39 (d, J = 6.3Hz, 3H).

Example 218

2- (6-((2S, 4S) -4-fluoro-2-methylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1-((1-methyl-1H -Pyridin-3-yl) methyl) -1H-benzo [d] imidazole

Add 2-methoxy-N-((1-methyl-1H-pyrazol-3-yl) methyl) -6-nitroaniline (90 mg, 0.343 mmol), sodium bisulfite (179 mg, 0.874 mmol) , And a mixture of 6-((2S, 4S) -4-fluoro-2-methylpyrrolidin-1-yl) nicotinaldehyde (71.5 mg, 0.343 mmol) in ethanol (4 mL) and water (2 mL) It was heated at 130 ° C for 1 hour under microwave conditions. The reaction was filtered and the filtrate was concentrated to dryness. Water was then added, and the resulting mixture was extracted with CH ₂ Cl ₂ . Dried combined organic extracts were washed with brine, MgSO _4, filtered, and concentrated. Purification by flash chromatography on SiO ₂ (0% to 100% (3: 1 (v / v) EtOAc / EtOH): heptane) provided 2- (6-((2S, 4S) -4- Fluoro-2-methylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H- Benzo [d] imidazole (74 mg). LC-MS (ES) m / z = 421 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.59 (d, J = 2.0 Hz, 1 H), 7.95 (d, J = 8.1 Hz, 1 H), 7.46 (d, J = 8.1 Hz, 1 H), 7.15-7.26 (m, 2H), 6.73 (d, J = 7.9 Hz, 1H), 6.52 (d, J = 8.9 Hz, 1H), 5.89 (d, J = 2.0 Hz, 1H), 5.66 (d, J = 2.0 Hz , 2H), 5.21-5.46 (m, 1H), 4.33 (q, J = 7.1 Hz, 1H), 3.96-4.10 (m, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.67- 3.84 (m, 1H), 2.52-2.82 (m, 1H), 1.83-2.06 (m, 1H), 1.37 (d, J = 6.1Hz, 3H).

Example 219

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1-((1-methyl-1H- Pyrazol-3-yl) methyl) -1H-benzo [d] imidazole

Add 2-methoxy-N-((1-methyl-1H-pyrazol-3-yl) methyl) -6-nitroaniline (65mg, 0.248mmol), 6-((2S, 5S) -2 , 5-dimethylpyrrolidin-1-yl) nicotinaldehyde (55.7 mg, 0.273 mmol), and sodium bisulfite (129 mg, 0.744 mmol, 85%) in ethanol (1271 μl) and water (635 μl) The mixture was heated in a sealed container at 100 ° C all weekend. The reaction was diluted with water (10 mL) and then extracted with EtOAc (4 x 10 mL). The organic portions were combined, washed with brine, dried over Na ₂ SO _4, filtered, and concentrated. By reverse phase HPLC (in H ₂ O (0.1% formic acid) in the 15-55% CH ₃ CN) The resulting material was purified. The fractions containing desired product was dissolved in EtOAc, and the resulting mixture was then washed with water, saturated aqueous NaHCO _3, dried over Na ₂ SO _4, filtered, and concentrated to provide the desired product as a clear film (73mg). LC-MS (ES) m / z = 417 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 1.21 (d, J = 6.1Hz, 6H), 1.71 (d, J = 5.6Hz, 2H), 2.20-2.40 (m, 2H), 3.80-3.87 (s, 3H), 3.89 (s, 3H), 4.28 (br.s., 2H), 5.68 (d, J = 1.8Hz, 2H), 5.88 (d, J = 2.3Hz, 1H), 6.46 (d, J = 8.4Hz, 1H), 6.66-6.78 (m, 1H), 7.13-7.28 (m, 2H), 7.44 (dd, J = 8.1, 0.8Hz, 1H), 7.86 (dd, J = 8.9, 2.5Hz, 1H ), 8.54 (dd, J = 2.5, 0.8 Hz, 1H).

Intermediate 304

2-methoxy-N- (2-morpholinylethyl) -6-nitroaniline

Add 2-fluoro-1-methoxy-3-nitrobenzene (317 mg, 1.852 mmol), 2-morpholinyl ethyl-1-amine (241 mg, 1.852 mmol), and diisopropylethylamine (0.485 mL) , 2.78 mmol) in DMF (15 mL) was heated at 60 ° C. for 16 hours. The mixture was concentrated, and the resulting material was dissolved in water and extracted with EtOAc. The combined organic extracts were washed with water then brine, dried over MgSO _4, filtered, and concentrated. Purification by flash chromatography on SiO ₂ (0% to 100% EtOAc: hexanes) provided 2-methoxy-N- (2-morpholinylethyl) -6-nitrate as an orange oil Aniline (473 mg). LC-MS (ES) m / z = 282 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.02 (br.s., 1H), 7.75 (dd, J = 1.4, 8.7 Hz, 1H), 6.96 (dd, J = 1.0, 7.9 Hz, 1H), 6.64 -6.75 (m, 1H), 3.90 (s, 3H), 3.77 (d, J = 4.1Hz, 4H), 3.68 (d, J = 5.3Hz, 2H), 2.60 (br.s., 2H), 2.51 (br.s., 4H).

Example 220

4- (2- (2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [ d) imidazol-1-yl) ethyl) morpholin

Add 2-methoxy-N- (2-morpholinylethyl) -6-nitroaniline (68 mg, 0.242 mmol), sodium bisulfite (126 mg, 0.615 mmol), and 6-((2S, 5S ) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (49.4 mg, 0.242 mmol) in ethanol (4 mL) and water (2 mL) was heated under microwave conditions at 130 ° C for 105 minutes. The reaction mixture was concentrated to dryness, and the resulting material was dissolved in water and extracted with EtOAc. Dried combined organic extracts were washed with brine, MgSO _4, filtered, and concentrated. Purification by flash chromatography on SiO ₂ (0% to 100% (3: 1 EtOAc / EtOH): heptane) provided 4- (2- (2- (6-((2S, 5S) -2 , 5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [d] imidazol-1-yl) ethyl) morpholin (34.3 mg), White solid after lyophilization. LC-MS (ES) m / z = 436 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 8.45 (d, J = 1.8Hz, 1H), 7.85 (dd, J = 2.5, 8.9Hz, 1H), 7.14-7.35 (m, 2H), 6.87 (dd , J = 0.9,7.7Hz, 1H), 6.71 (d, J = 8.6Hz, 1H), 4.61 (t, J = 6.6Hz, 2H), 4.3 (br., S, 2H), 4.02 (s, 3H ), 3.47-3.58 (m, 4H), 2.72 (m, 2H), 2.29-2.43 (m, 5H), 1.76 (d, J = 5.8Hz, 2H), 1.23 (d, J = 6.1Hz, 6H) .

Intermediate 305

2- (2-((2-methoxy-6-nitrophenyl) amino) ethoxy) ethan-1-ol

Add 2- (2-aminoethoxy) eth-1-ol (135 mg, 1.286 mmol), 2-fluoro-1-methoxy-3-nitrobenzene (200 mg, 1.169 mmol), and diisopropyl A solution of ethylamine (0.306 mL, 1.753 mmol) in DMF (10 mL) was heated at 80 ° C for 16 hours. The reaction was concentrated and the resulting material was purified by flash chromatography on SiO ₂ (0% to 50% EtOAc / hexanes) to provide 2- (2-((2-methoxy) as an orange / red oil -6-nitrophenyl) amino) ethoxy) ethan-1-ol (281 mg). LC-MS (ES) m / z = 257 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.76 (dd, J = 1.4, 8.7 Hz, 1H), 6.99 (dd, J = 1.5, 7.9 Hz, 1H), 6.74 (dd, J = 7.9, 8.6 Hz, 1H), 3.91 (s, 3H), 3.76-3.81 (m, 4H), 3.66-3.72 (m, 2H), 3.58-3.64 (m, 2H).

Example 221

2- (2- (2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [ d) imidazol-1-yl) ethoxy) ethan-1-ol

2- (2-((2-methoxy-6-nitrophenyl) amino) ethoxy) ethan-1-ol (140 mg, 0.546 mmol), sodium bisulfite (285 mg, 1.391 mmol), And a mixture of 6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (112 mg, 0.546 mmol) in ethanol (4 mL) and water (2 mL) under microwave conditions Heated at 130 ° C for 1 hour. The reaction mixture was concentrated to dryness, and the resulting material was dissolved in water and _extracted with CH ₂ Cl. Dried combined organic extracts were washed with brine, MgSO _4, filtered, and concentrated. Purification by flash chromatography on SiO ₂ (0% to 100% (3: 1 EtOAc: EtOH) / heptane) provided 2- (2- (2- (6-((2S, 5S) -2 , 5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [d] imidazol-1-yl) ethoxy) eth-1-ol (80mg ), White solid / foam after freeze-drying. LC-MS (ES) m / z = 411 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 8.48-8.55 (m, 1H), 7.98 (dd, J = 2.4, 9.0 Hz, 1H), 7.17-7.30 (m, 2H), 6.87 (dd, J = (0.9, 7.7 Hz, 1H), 6.69 (d, J = 9.1 Hz, 1H), 4.61 (t, J = 5.3 Hz, 2H), 4.32 (br.s., 2H), 4.01 (s, 3H), 3.92 (t, J = 5.5Hz, 2H), 3.53-3.60 (m, 2H), 3.36-3.42 (m, 2H), 2.31-2.40 (m, 2H), 1.75 (d, J = 5.8Hz, 2H), 1.23 (d, J = 6.3Hz, 6H).

Intermediate 306

N-((1-methyl-1H-pyrazol-3-yl) methyl) -2,6-dinitroaniline

Add 2-chloro-1,3-dinitrobenzene (700 mg, 3.46 mmol), (1-methyl-1H-pyrazol-3-yl) methylamine (403 mg, 3.63 mmol), and triethylamine (0.530 mL , 3.80 mmol) in DMF (10 mL) was stirred at room temperature overnight. The reaction was quenched with water (30 mL), and the resulting mixture was extracted with CH ₂ Cl ₂ (3 x 30 mL). The combined organic layers were dried over Na ₂ SO _4, filtered, and concentrated. The resulting residue was purified by silica chromatography (0% -50% EtOAc / hexane) to provide N-((1-methyl-1H-pyrazol-3-yl) methyl)-as a yellow solid 2,6-Dinitroaniline (821 mg). LCMS (ES) m / z = 278. ¹ H NMR (400MHz, DMSO- d ₆ ): δ 8.65 (t, J = 4.8Hz, 1H), 8.30 (d, J = 8.4Hz, 2H), 7.63 (d, J = 2.0Hz, 1H), 6.94 (t, J = 8.1 Hz, 1H), 6.15 (d, J = 2.3 Hz, 1H), 4.14 (d, J = 4.8 Hz, 2H), 3.79 (s, 3H).

Intermediate 307

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-methyl-1H-pyrazol-3-yl ) Methyl) -7-nitro-1H-benzo [d] imidazole

N-((1-methyl-1H-pyrazol-3-yl) methyl) -2,6-dinitroaniline (752 mg, 2.71 mmol), 6-((2S, 5S) -2,5- A solution of dimethyl pyrrolidin-1-yl) nicotinaldehyde (593 mg, 2.90 mmol), and sodium bisulfite (1417 mg, 8.14 mmol) in ethanol (15 mL) and water (3.75 mL) was subjected to microwave irradiation. Heat at 100 ° C for 1 hour. The mixture was filtered, and the filtrate was concentrated. The resulting residue was partitioned between CH ₂ Cl ₂ (20mL) and water (14mL). The layers were separated, and the aqueous layer was further extracted with CH ₂ Cl ₂ (2 x 18 mL). The combined organic extracts were washed with brine (3 mL), dried over Na ₂ SO ₄ , filtered, and concentrated. By silica gel chromatography (0% to 100% (in 3: 1 EtOAc: EtOH in the 0.1% NH ₄ OH) / hexanes) and the resulting residue was purified to provide a form of micro (Lite) of a brown solid of 2- ( 6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-methyl-1H-pyrazol-3-yl) methyl ) -7-nitro-1H-benzo [d] imidazole (225 mg). LCMS (ES) m / z = 432 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.64 (s, 1H), 8.06 (dd, J = 1.0, 7.9 Hz, 1H), 7.90 (dd, J = 2.5, 8.9 Hz, 1H), 7.82 (dd, J = 1.0, 8.1 Hz, 1H), 7.36-7.32 (m, 1H), 7.15 (d, J = 2.3 Hz, 1H), 6.54 (d, J = 8.6 Hz, 1H), 5.75 (d, J = 2.0 Hz, 1H), 5.70 (s, 2H), 3.75 (s, 3H), 2.39-2.27 (m, 2H), 1.80 (br.s., 2H), 1.74 (d, J = 5.8Hz, 2H), 1.28-1.20 (m, 6H).

Example 222

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-methyl-1H-pyrazol-3-yl ) Methyl) -1H-benzo [d] imidazole-7-amine

Pd-C (54.3 mg, 0.510 mmol) was added to 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-(( 1-methyl-1H-pyrazol-3-yl) methyl) -7-nitro-1H-benzo [d] imidazole (220 mg, 0.510 mmol) in CH ₃ OH (15 mL), and The reaction mixture was stirred at room temperature under a hydrogen atmosphere overnight. The mixture was filtered to remove Pd-C, and the filtrate was concentrated. The resulting residue was purified by silica gel chromatography (5% -100% (0.1% NH ₄ OH / hexane in 3: 1 EtOAc: EtOH)) to provide 2- (6-(( 2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H- Benzo [d] imidazole-7-amine (93 mg). LCMS (ES) m / z = 402 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 8.38 (d, J = 1.8Hz, 1H), 7.78 (dd, J = 2.4, 8.7Hz, 1H), 7.69 (d, J = 2.0Hz, 1H) , 6.96-6.86 (m, J = 1.5Hz, 2H), 6.60 (d, J = 8.9Hz, 1H), 6.48 (dd, J = 1.1, 7.2Hz, 1H), 6.01 (d, J = 2.0Hz, 1H), 5.48 (s, 2H), 4.99 (s, 2H), 4.24 (br.s., 2H), 3.81 (s, 3H), 3.31 (s, 1H), 2.24 (s, 1H), 1.65 ( d, J = 5.6 Hz, 2H), 1.14 (d, J = 6.1 Hz, 6H).

Intermediate 308

(R) -2-((5-cyano-4-fluoro-7-methoxy-2- (6-((S) -2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-1-yl) methyl) morpholin-4-carboxylic acid tert-butyl ester

N _{2 was} bubbled to (R) -2-((5-bromo-4-fluoro-7-methoxy-2- (6-((S) -2-methylpyrrole) in DMF (10 mL) Pyridin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-1-yl) methyl) morpholin 4-carboxylic acid tert-butyl ester (411 mg, 0.680 mmol) over 5 minutes. Then Pd ₂ (dba) ₃ (187 mg, 0.204 mmol), Davephos (80 mg, 0.204 mmol), and zinc cyanide (159 mg, 1.360 mmol) were added, and then the reaction mixture was capped and heated at 85 ° C. overnight. The reaction was filtered through celite, and the filtrate was diluted with water (30 mL) and extracted with EtOAc (3 x 20 mL). The organic extracts were combined and washed with brine, dried over MgSO _4, filtered, and concentrated. Purification by chromatography on SiO ₂ with a gradient of 0 to 60% EtOAc in hexanes provided (R) -2-((5-cyano-4-fluoro-7-methoxy) as a clear oil Yl-2- (6-((S) -2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-1-yl) methyl) morpholin- Tertiary butyl 4-formate (310 mg). LC-MS (ES) m / z = 551 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.18-1.22 (m, 3H), 1.40 (s, 9H), 1.67-1.77 (m, 1H), 1.95-2.12 (m, 3H), 2.46-2.49 (m, 1H), 2.58-2.66 (m, 1H), 3.21 (m, 1H), 3.35-3.40 (m, 1H), 3.57 (dd, J = 10.1, 7.6Hz, 1H), 3.61-3.85 (m , 4H), 4.00 (s, 3H), 4.25 (d, J = 5.6Hz, 1H), 4.37 (dd, J = 15.0, 8.1Hz, 1H), 4.55 (dd, J = 14.7, 2.3Hz, 1H) , 6.61 (d, J = 8.9 Hz, 1H), 7.22 (d, J = 4.1 Hz, 1H), 7.94-7.99 (m, 1H), 8.56 (d, J = 2.0 Hz, 1H).

Intermediate 309

(R) -2-((5-Aminomethyl-4-fluoro-7-methoxy-2- (6-((S) -2-methylpyrrolidin-1-yl) pyridine-3- Yl) -1H-benzo [d] imidazol-1-yl) methyl) morpholin-4-carboxylic acid tert-butyl ester

1N NaOH (2.4 mL, 2.4 mmol) followed by H ₂ O ₂ (0.37 mL, 3.60 mmol, 30% in water) was added dropwise to (R) -2- (DM) in DMSO (8 mL) and ethanol (8 mL) (5-cyano-4-fluoro-7-methoxy-2- (6-((S) -2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d ] Imidazol-1-yl) methyl) morpholin-4-carboxylic acid tert-butyl ester (1.1 g, 1.998 mmol), and the reaction mixture was stirred for 10 minutes. Water (50 mL) was then added (a gummy solid formed), and the resulting mixture was extracted with EtOAc (4 x 50 mL). The organic extracts were then combined and washed with brine, dried with MgSO _4, filtered, and concentrated to give crude (R) of a beige oil 2 - ((5- carbamoyl acyl-4-fluoro-7-methoxy 2- (6-((S) -2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-1-yl) methyl) morpholin-4 -Tert-butyl formate (1.32 g). LC-MS (ES) m / z = 569 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.18-1.22 (m, 3H), 1.39 (s, 9H), 1.72 (d, J = 3.0Hz, 1H), 1.95-2.02 (m, 1H), 2.02-2.11 (m, 2H), 2.46-2.49 (m, 1H), 3.16-3.25 (m, 1H), 3.37 (br.s., 1H), 3.57 (dd, J = 9.9, 7.6Hz, 1H) , 3.60-3.81 (m, 4H), 3.97 (s, 3H), 4.20-4.27 (m, 1H), 4.35 (dd, J = 15.0, 7.6Hz, 1H), 4.47-4.54 (m, 1H), 6.60 (d, J = 9.1Hz, 1H), 7.06 (d, J = 4.8Hz, 1H), 7.62 (d, J = 14.7Hz, 2H), 7.95 (dd, J = 8.7, 2.4Hz, 1H), 8.54 (d, J = 2.3Hz, 1H).

Example 223

4-fluoro-7-methoxy-1-(((S) -4-methylmorpholin-2-yl) methyl) -2- (6-((S) -2-methylpyrrolidine -1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-5-carboxamide

TFA (4 mL, 51.9 mmol) was added to (R) -2-((5-aminomethylmethyl-4-fluoro-7-methoxy-2- (6-) in CH ₂ Cl ₂ (10 mL) ((S) -2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-1-yl) methyl) morpholin 4-carboxylic acid tert-butyl ester (1.08 g, 1.9 mmol), and the reaction mixture was stirred at room temperature for 1 hour. Saturated aqueous NaHCO ₃ was then added, and the resulting alkaline mixture was extracted sequentially with EtOAc (2 x 30mL) in CH ₂ Cl ₂ in 20% of isopropanol (2 x 50mL), and EtOAc (2 x 30mL). The extracts were combined and washed with brine, dried over MgSO _4, filtered, and concentrated. 1,2-Dichloroethane (20 mL), acetic acid (0.326 mL, 5,70 mmol), and formaldehyde (0.717 mL, 9.50 mmol, 36.5% in water) were added to the resulting solid, and the resulting mixture was stirred for 10 minutes . Then, sodium triacetoxyborohydride (1409 mg, 6.65 mmol) was added, and the reaction mixture was stirred for 45 minutes. Saturated aqueous NaHCO ₃ was then added, and the resulting alkaline mixture is then (2 x 30mL) and extracted with _{CH 2 Cl 2 (2 x 30mL} ) EtOAc. The organic extracts were combined and washed with brine, dried over MgSO _4, filtered, and concentrated. _{(: 20: 2 CH 2 Cl} 2: CH 3 OH: 80 NH 4 OH) chromatography on SiO ₂ using in CH ₂ Cl 0 to 50% ₂ of the gradients provided by the purified -7-fluoro-4- -Methoxy-1-(((S) -4-methylmorpholin-2-yl) methyl) -2- (6-((S) -2-methylpyrrolidin-1-yl) Pyridin-3-yl) -1H-benzo [d] imidazol-5-carboxamide (520 mg), lyophilized as a white solid. LC-MS (ES) m / z = 483 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.18-1.22 (m, 3H), 1.65-1.74 (m, 2H), 1.89-2.02 (m, 2H), 2.03-2.12 (m, 2H), 2.14 (s, 3H), 2.49 (br.s., 1H), 2.60 (d, J = 10.9 Hz, 1H), 3.27 (m, 1H), 3.35-3.40 (m, 1H), 3.53-3.60 (m, 1H), 3.65 (d, J = 10.7Hz, 1H), 3.74-3.81 (m, 1H), 3.96 (s, 3H), 4.20-4.28 (m, 1H), 4.34 (dd, J = 14.7, 8.6Hz , 1H), 4.43-4.50 (m, 1H), 6.59 (d, J = 8.9Hz, 1H), 7.05 (d, J = 4.6Hz, 1H), 7.62 (d, J = 13.9Hz, 2H), 7.95 (dd, J = 8.9, 2.3 Hz, 1H), 8.52 (d, J = 2.0 Hz, 1H).

Intermediate 310

3-fluoro-6-methoxy-N- (2-morpholinylethyl) -2-nitroaniline

Add 2-morpholinylethyl-1-amine (0.688 g, 5.29 mmol) and K ₂ CO ₃ (1.096 g, 7.93 mmol) to 1,3-difluoro-4-formaldehyde in DMSO (15 mL) Oxy-2-nitrobenzene (1 g, 5.29 mmol), and the reaction mixture was heated at 50 ° C for 4 hours. Water (50 mL) was then added and the resulting mixture was extracted with EtOAc (3 x 50 mL). Next, the organic extracts were combined, washed with brine, dried with MgSO _4, filtered and concentrated. Purification by chromatography on SiO ₂ with a gradient of 0 to 70% EtOAc in hexane provided 3-fluoro-6-methoxy-N- (2-morpholinylethyl) as a dark red oil ) -2-nitroaniline (1.5 g, 5.01 mmol, 95% yield). LC-MS (ES) m / z = 300 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 2.45-2.50 (m, 4H), 2.58 (dd, J = 6.3, 5.3Hz, 2H), 3.26 (m, 2H), 3.73-3.77 (m, 4H), 3.90 (s, 3H), 6.06 (br.s., 1H), 6.50 (dd, J = 9.9, 9.1 Hz, 1H), 6.78 (dd, J = 9.0, 4.7 Hz, 1H).

Intermediate 311

4-bromo-3-fluoro-6-methoxy-N- (2-morpholinylethyl) -2-nitroaniline

NBS (838 mg, 4.71 mmol) was added to 3-fluoro-6-methoxy-N- (2-morpholinylethyl) -2-nitroaniline (940 mg, in CH ₂ Cl ₂ (45 mL) 3.14 mmol), and the reaction mixture was stirred at room temperature for 1 hour. Additional NBS (838 mg, 4.71 mmol) was added and the reaction mixture was stirred overnight. Water (50 mL) was then added and the resulting mixture was extracted with EtOAc (4 x 30 mL). The organic extracts were combined and washed with brine, dried over MgSO _4, filtered, and concentrated. Purification by chromatography on SiO ₂ with a gradient of 0 to 50% EtOAc in hexanes provided 4-bromo-3-fluoro-6-methoxy-N- (2-morphol as a bright red oil Linylethyl) -2-nitroaniline (250 mg). LC-MS (ES) m / z = 379 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 2.33 (br.s., 4H), 2.44-2.48 (m, 2H), 3.10 (m, 2H), 3.52-3.57 (m, 4H), 3.89 ( s, 3H), 6.19 (s, 1H), 7.30 (d, J = 6.3 Hz, 1H).

Intermediate 312

4- (2- (5-bromo-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-7-methyl Oxy-1H-benzo [d] imidazol-1-yl) ethyl) morpholin

Add 6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (214 mg, 1.047 mmol) and sodium bisulfite (585 mg, 2.86 mmol) to DMSO (10 mL ) And 4-bromo-3-fluoro-6-methoxy-N- (2-morpholinylethyl) -2-nitroaniline (360 mg, 0.952 mmol) in water (2 mL), and reacted at Heated at 97 ° C for 2 hours. Water (20 mL) was then added and the resulting mixture was extracted with EtOAc (4 x 20 mL). The organic extracts were combined and washed with brine, dried over MgSO _4, filtered, and concentrated. Purification by chromatography on SiO ₂ with a gradient of 0 to 100% EtOAc in hexane provided 4- (2- (5-bromo-2- (6-((2S, 5S) ) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-7-methoxy-1H-benzo [d] imidazol-1-yl) ethyl) Forint (220 mg). LC-MS (ES) m / z = 533 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.22 (d, J = 6.3Hz, 6H), 1.76 (d, J = 5.6Hz, 2H), 2.26-2.30 (m, 4H), 2.32-2.38 (m , 2H), 2.69 (m, 2H), 3.48-3.52 (m, 4H), 4.00 (s, 3H), 4.32 (br.s., 2H), 4.58 (m, 2H), 6.70 (d, J = 8.9Hz, 1H), 6.97 (d, J = 4.8Hz, 1H), 7.86 (dd, J = 9.0, 2.4Hz, 1H), 8.45-8.48 (m, 1H).

Intermediate 313

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-7-methoxy-1- (2-morphol Linylethyl) -1H-benzo [d] imidazole-5-carbonitrile

N ₂ gas was bubbled to 4- (2- (5-bromo-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) in DMF (5 mL)) Pyridine-3-yl) -4-fluoro-7-methoxy-1H-benzo [d] imidazol-1-yl) ethyl) morpholin (110 mg, 0.207 mmol) over 5 minutes. Pd ₂ (dba) ₃ (56.8 mg, 0.062 mmol), Davephos (24.39 mg, 0.062 mmol), and zinc cyanide (48.3 mg, 0.413 mmol) were added, and the reaction mixture was capped and then heated at 80 ° C overnight . The reaction was filtered through celite and the filtrate was extracted with diluted water (30 mL) and extracted with EtOAc (3 x 30 mL). The organic extracts were combined and washed with brine, dried over MgsO _4, filtered, and concentrated. _{(20:80 CH 3 OH: CH 2} Cl 2) chromatography on SiO ₂ with 0 to 40% CH ₂ Cl ₂ in the purified gradients provided by a clear oil of 2- (6 - (( 2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-7-methoxy-1- (2-morpholinylethyl) -1H -Benzo [d] imidazole-5-carbonitrile (90 mg). LC-MS (ES) m / z = 479 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.14 (d, J = 6.1 Hz, 6H), 1.66 (d, J = 5.6 Hz, 2H), 2.13-2.21 (m, 4H), 2.25 (br. s., 2H), 2.53-2.63 (m, 2H), 3.34-3.41 (m, 4H), 3.99 (s, 3H), 4.26 (br.s., 2H), 4.45-4.54 (m, 2H), 6.62-6.67 (m, 1H), 7.20 (d, J = 4.1 Hz, 1H), 7.89 (dd, J = 8.9, 2.5 Hz, 1H), 8.51 (d, J = 2.0 Hz, 1H).

Example 224

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-7-methoxy-1- (2-morphol Linylethyl) -1H-benzo [d] imidazole-5-carboxamide

K ₂ CO ₃ (5.20 mg, 0.038 mmol) followed by hydrogen peroxide (0.192 mL, 1.881 mmol, 30% in water) was added to 2- (6-((2S, 5S)-in DMSO (2 mL)- 2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-7-methoxy-1- (2-morpholinylethyl) -1H-benzo [d ] Imidazole-5-carbonitrile (90 mg, 0.188 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was filtered and the filtrate was purified by reverse-phase HPLC (30-85% CH ₃ CN in (0.1% NH ₄ OH in water)) to provide 2- (6-((2S, 5S) -2 , 5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-7-methoxy-1- (2-morpholinylethyl) -1H-benzo [d] Imidazole-5-carboxamide (55 mg), lyophilized as a white solid. LC-MS (ES) m / z = 497 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.14 (d, J = 6.1Hz, 6H), 2.17 (d, J = 4.1Hz, 4H), 2.25 (br.s., 2H), 2.54-2.61 (m, 2H), 3.31 (s, 2H), 3.37 (d, J = 4.3Hz, 4H), 3.96 (s, 3H), 4.26 (br.s., 2H), 4.49 (t, J = 6.2Hz , 2H), 6.63 (d, J = 8.6 Hz, 1H), 7.04 (d, J = 4.6 Hz, 1H), 7.61 (d, J = 15.0 Hz, 2H), 7.88 (dd, J = 8.9, 2.5 Hz , 1H), 8.49 (d, J = 1.8Hz, 1H).

Example 225

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-7-methoxy-N-methyl-1- (2-morpholinylethyl) -1H-benzo [d] imidazole-5-carboxamide

Potassium 2-ethoxy-2-oxoacetate (88 mg, 0.563 mmol), 4- (2- (5-bromo-2- (6-((2S, 5S) -2,5-dimethylpyrrole) Pyridin-1-yl) pyridin-3-yl) -4-fluoro-7-methoxy-1H-benzo [d] imidazol-1-yl) ethyl) morpholin (100 mg, 0.188 mmol), 1 , 3-bis (diphenylphosphino) propane (23.24 mg, 0.056 mmol), and palladium (II) trifluoroacetate (18.73 mg, 0.056 mmol) were added to NMP (2 mL) previously degassed with N _{2 for} 5 minutes, The reaction mixture was heated under microwave conditions at 120 ° C for 2 hours. The reaction was then filtered, and the filtrate was treated with 8N NaOH (0.235 mL, 1.878 mmol) and CH ₃ OH (1 mL). The resulting mixture was stirred at room temperature overnight. The reaction was concentrated under reduced pressure, and the resulting material was diluted with water (10 mL) and extracted with 20% isopropanol in CH ₂ Cl ₂ (3 x 10 mL). The aqueous layer was partially concentrated to remove any volatile organic solvents, and then treated with 6N HCl until the pH was slightly acidic. The resulting mixture was lyophilized to give crude 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-7 as a brown solid. -Methoxy-1- (2-morpholinylethyl) -1H-benzo [d] imidazole-5-carboxylic acid (230 mg). EDC (54.0 mg, 0.282 mmol), HOBt (43.1 mg, 0.282 mmol), methylamine hydrochloride (25.4 mg, 0.376 mmol), and N-methylmorpholine (0.145 mL, 1.315 mmol) were added to this material. The reaction mixture was stirred in DMSO (2 mL) at room temperature overnight. The reaction was filtered and the filtrate was purified by reverse-phase HPLC (50-80% CH ₃ CN in (0.1% NH4OH in water)) to provide 2- (6-((2S, 5S) -2,5 -Dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-7-methoxy-N-methyl-1- (2-morpholinylethyl) -1H-benzo [d] Imidazole-5-carboxamide (10 mg), lyophilized as an off-white solid. LC-MS (ES) m / z = 511 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.14 (d, J = 6.1Hz, 6H), 1.66 (d, J = 5.3Hz, 2H), 2.17 (d, J = 4.1Hz, 4H), 2.25 (br.s., 2H), 2.54-2.61 (m, 2H), 2.82 (d, J = 4.6Hz, 3H), 3.35-3.40 (m, 4H), 3.95 (s, 3H), 4.26 (br. s., 2H), 4.49 (t, J = 6.5Hz, 2H), 6.63 (d, J = 8.9Hz, 1H), 6.99 (d, J = 4.6Hz, 1H), 7.87 (dd, J = 8.9, 2.5Hz, 1H), 8.11-8.19 (m, 1H), 8.48 (d, J = 2.0Hz, 1H).

Intermediate 314

(R) -2-((5-cyano-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro- 7-methoxy-1H-benzo [d] imidazol-1-yl) methyl) morpholin 4-carboxylic acid tert-butyl ester

(R) -2-((5-Bromo-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) by bubbling nitrogen) 4-Fluoro-7-methoxy-1H-benzo [d] imidazol-1-yl) methyl) morpholin 4-carboxylic acid tert-butyl ester (2.10g, 3.40mmol), Zn (CN) _A mixture of ₂ (0.797 g, 6.79 mmol), and N-methyl-2-pyrrolidone (10 mL) was degassed into a sealable container for 10 minutes. Pd (PPh ₃ ) ₄ (0.588 g, 0.509 mmol) was added, the vessel was sealed, and the reaction mixture was stirred at 110 ° C. for 18 hours. The mixture was cooled, quenched with water (30 mL) and extracted with EtOAc (3x). The combined organic extracts were dried (Na ₂ SO ₄₎ and concentrated. The resulting residue was purified by column chromatography (gradient: 0 to 80% EtOAc / heptane) on silica to give the desired product (1.52 g) as a white solid. LC-MS (ES) m / z = 565 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.23 (d, J = 6.3Hz, 6H), 1.42-1.56 (m, 9H), 1.69-1.84 (m, 2H), 2.29-2.45 (m, 2H) , 2.70 (br.s., 1H), 2.95 (br.s., 1H), 3.77-3.92 (m, 3H), 3.94-4.12 (m, 4H), 4.25-4.48 (m, 3H), 4.62 ( dd, J = 14.8, 2.7 Hz, 1H), 6.69 (d, J = 8.6 Hz, 1H), 7.07 (d, J = 4.1 Hz, 1H), 7.96 (dd, J = 8.9, 2.5 Hz, 1H), 8.58 (d, J = 2.0 Hz, 1H).

Intermediate 315

(R) -2-((5-Aminomethylamidino-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4- Fluoro-7-methoxy-1H-benzo [d] imidazol-1-yl) methyl) morpholin-4-carboxylic acid tert-butyl ester

Aqueous NaOH (1N, 5.33 mL, 5.33 mmol) was added to (R) -2-((5-cyano-2- (6-((2S, 5S) -2,5-dimethylpyrrole-1) -Yl) pyridin-3-yl) -4-fluoro-7-methoxy-1H-benzo [d] imidazol-1-yl) methyl) morpholin 4-carboxylic acid tert-butyl ester (2.51g , 4.45 mmol) in DMSO (13 mL) and ethanol (13 mL), followed by the dropwise addition of H ₂ O ₂ (30%, 0.817 mL, 8.00 mmol), and the reaction mixture was stirred at room temperature for 1 hour. Water (50 mL) was added and the mixture was stirred for several minutes and then filtered. The solid was washed with water and dried under vacuum to give the desired product (2.31 g) as a white solid. LC-MS (ES) m / z = 583 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.23 (d, J = 6.3Hz, 6H), 1.43-1.54 (m, 9H), 1.70-1.83 (m, 2H), 2.27-2.43 (m, 2H) , 2.63-2.79 (m, 3H), 2.96 (br.s., 1H), 3.03 (s, 1H), 3.78-3.94 (m, 3H), 3.95-4.13 (m, 4H), 4.25 (br.s ., 1H), 4.39 (d, J = 8.4Hz, 1H), 4.35 (d, J = 8.4Hz, 2H), 4.60 (dd, J = 14.7,2.8Hz, 1H), 5.51 (s, 1H), 6.69 (d, J = 9.1 Hz, 1H), 7.28 (d, J = 4.8 Hz, 1H), 7.96 (dd, J = 9.0, 2.4 Hz, 1H), 8.57 (d, J = 2.0 Hz, 1H).

Intermediate 316

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-7-methoxy-1-((S)- Morpholin-2-ylmethyl) -1H-benzo [d] imidazole-5-carboxamide

Add TFA (6.0 mL, 78 mmol) to (R) -2-((5-aminomethylmethyl-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1- Yl) pyridin-3-yl) -4-fluoro-7-methoxy-1H-benzo [d] imidazol-1-yl) methyl) morpholin 4-carboxylic acid tert-butyl ester (2.3 g, 3.95 mmol) in CH ₂ Cl ₂ (20 mL), and the reaction mixture was stirred at room temperature for 4 hours. The mixture was concentrated, and the resulting residue was dried under vacuum for 1 hour. The residue was treated with aqueous HCl (6N, 10 mL) and concentrated. The residue was treated with CH ₂ Cl ₂ (30 mL) and saturated aqueous NaHCO ₃ (50 mL), and the resulting mixture was extracted with 10% CH ₃ OH (3 ×) in CH ₂ Cl ₂ . The combined organic extracts were dried (Na ₂ SO ₄₎ and concentrated to give the desired product as a white solid (1.85 g) under vacuum. LC-MS (ES) m / z = 483 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.18-1.27 (m, 6H), 1.70-1.83 (m, 2H), 2.26-2.43 (m, 2H), 2.48-2.60 (m, 1H), 2.71- 2.86 (m, 2H), 2.93 (dd, J = 12.4, 1.8Hz, 1H), 3.38-3.48 (m, 1H), 3.80 (dd, J = 11.7, 2.0Hz, 1H), 3.93-4.02 (m, 1H), 4.04 (s, 3H), 4.31 (dd, J = 14.7, 8.9Hz, 3H), 4.49-4.58 (m, 1H), 6.68 (d, J = 8.9Hz, 1H), 7.26 (d, J = 4.8Hz, 1H), 7.92-7.99 (m, 1H), 8.54-8.61 (m, 1H).

Example 226

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-7-methoxy-1-((((S) 4-methylmorpholin-2-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide

Add formaldehyde (36.5% in water, 1.431mL, 18.96mmol) and acetic acid (0.651mL, 11.38mmol) to 2- (6-((2S, 5S) -2,5-dimethylpyrrolidine-1- Yl) pyridin-3-yl) -4-fluoro-7-methoxy-1-((((S) -morpholin-2-yl) methyl) -1H-benzo [d] imidazole-5- A solution of formamidine (1.83 g, 3.79 mmol) in 1,2-dichloroethane (24 mL), and the mixture was stirred at room temperature for 10 minutes. Sodium triacetoxyborohydride (2.81 g, 13.27 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with saturated aqueous NaHCO ₃ (30mL), followed by saturated aqueous Na ₂ CO ₃ until pH = 10, and extracted with CH ₂ Cl ₂ (3x). The combined organic extracts were dried over Na ₂ SO _4, filtered, and concentrated. The resulting residue was purified by column chromatography (gradient: 0-100% (90: 10: 1 CH ₂ Cl ₂ : CH ₃ OH: NH ₄ OH) / heptane) on silica gel to give a white color The desired product as a solid (1.48 g). LC-MS (ES) m / z = 493 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 1.23-1.32 (m, 6H), 1.79-1.96 (m, 2H), 2.00-2.27 (m, 4H), 2.32 (s, 3H), 2.67 (d, J = 11.7Hz, 1H), 2.84 (d, J = 11.1Hz, 1H), 3.39-3.54 (m, 4H), 3.61-3.70 (m, 1H), 3.82 (dd, J = 11.8, 1.9Hz, 1H ), 3.99-4.13 (m, 4H), 4.22-4.41 (m, 2H), 4.58 (dd, J = 14.4, 2.8Hz, 1H), 6.67 (d, J = 8.9Hz, 1H), 7.37 (d, J = 1.3Hz, 1H), 7.79 (d, J = 1.5Hz, 1H), 7.96 (dd, J = 9.0, 2.4Hz, 1H), 8.54 (d, J = 2.5Hz, 1H).

Example 227

5- (1-((6-bromopyridin-2-yl) methyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridine-2-amine

NaH (60% dispersion in oil, 19.5 mg, 0.49 mmol) was added to 5- (1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridine cooled to 0 ° C. A solution of -2-amine (100 mg, 0.38 mmol) in DMF (3.7 mL). After 5 minutes, 2-bromo-6- (bromomethyl) pyridine (104 mg, 0.41 mmol) was added, and the reaction mixture was warmed to room temperature. After 30 minutes, the reaction (2mL) was quenched with aqueous saturated NH ₄ Cl and diluted with EtOAc (20mL) and water (20mL). The phases were separated and the aqueous layer was further extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with water (20 mL) and brine (50 mL), dried over anhydrous NasSO ₄ , filtered, and concentrated. The resulting residue was purified by silica gel chromatography (eluted with 10 to 100% EtOAc / hexanes) to provide the desired product (130 mg) as a yellow film. LC-MS (ES) m / z = 438 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.37 (d, J = 2.0 Hz, 1H), 7.94-7.73 (m, 2H), 7.50-7.44 (m, 2H), 7.34-7.29 (m, 1H), 7.24-7.15 (m, 2H), 6.80 (dd, J = 6.7, 1.6Hz, 1H), 6.58 (d, J = 8.9Hz, 1H), 5.57 (s, 2H), 3.57 (q, J = 7.1Hz , 4H), 1.23 (t, 3H), 1.45-1.28 (m, 6H).

Example 228

N, N-diethyl-5- (1-((6- (pyrimidin-5-yl) pyridin-2-yl) methyl) -1H-benzo [d] imidazol-2-yl) pyridine-2 -amine

[1,1'-Bis (diphenylphosphino) ferrocene] dichloropalladium (II) (5.4 mg, 0.0074 mmol) was added to 5- (1-((6-bromopyridine- 2-yl) methyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine (65 mg, 0.15 mmol), pyrimidin-5-ylboronic acid (22 mg, 0.18 mmol), and a suspension of Cs ₂ CO ₃ (146 mg, 0.447 mmol) in 10: 1 THF / water (3 mL), and the reaction mixture was stirred in a sealed container at 100 ° C. for 4 hours. The reaction was then cooled to room temperature. Add additional pyrimidin-5-ylboronic acid (22 mg, 0.18 mmol) and [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (5.4 mg, 0.0074 mmol) and reseal the container Under a nitrogen atmosphere, the reaction mixture was stirred at 80 ° C for 16.5 hours. The reaction was then cooled to room temperature and concentrated. The resulting residue was purified by silica gel chromatography (eluted with 0 to 100% EtOAc / hexane) to provide the desired product (30 mg) as a transparent film. LC-MS (ES) m / z = 436 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 9.34 (s, 2H), 9.30 (s, 1H), 8.45 (s, 1H), 7.93 (dd, J = 9.1, 2.5Hz, 1H), 7.87 (d, J = 7.9Hz, 1H), 7.81-7.72 (m, 2H), 7.33 (ddd, J = 8.0, 5.1, 3.0Hz, 1H), 7.24-7.23 (m, 2H), 7.01 (d, J = 7.4Hz , 1H), 6.59 (d, J = 8.9Hz, 1H), 5.68 (s, 2H), 3.56 (q, J = 7.1Hz, 4H), 1.21 (t, J = 7.1Hz, 6H).

Intermediate 317

(R) -2-(((2-Chloro-6-nitrophenyl) amino) methyl) morpholin-4-carboxylic acid tert-butyl ester

Add (R) -2- (aminomethyl) morpholin-4-carboxylic acid tert-butyl ester, hydrochloride (302 mg, 1.196 mmol), DIEA (0.298 mL, 1.709 mmol), and K ₂ CO ₃ (236 mg (1.709 mmol) was added to 1-chloro-2-fluoro-3-nitrobenzene (150 mg, 0.854 mmol) in DMSO (10 mL), and the reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with water (25 mL) and the product was extracted with EtOAc (3 x 75 mL). The organic extracts were combined, washed with brine, dried over MgSO _4, and concentrated. The mixture was purified by column chromatography on silica gel (gradient: 0-20% EtOAc / heptane) to give (R) -2-(((2-chloro-6-nitrophenyl)) as an orange oil. Amino) methyl) morpholin-4-carboxylic acid tert-butyl ester (315 mg). LCMS (ES) m / z = 372.2, 374.2 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.39 (s, 9H), 2.54-2.65 (m, 1H), 2.77-2.90 (m, 1H), 3.17-3.25 (m, 1H), 3.35-3.50 (m, 2H), 3.63-3.82 (m, 3H), 3.63-3.75 (m, 1H), 6.50 (t, J = 5.8Hz, 1H), 6.94 (t, J = 8.0Hz, 1H), 7.72 ( dd, J = 7.9, 1.5 Hz, 1H), 7.89 (dd, J = 8.5, 1.7 Hz, 1H).

Intermediate 318

(R) -2-((7-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [ d) imidazol-1-yl) methyl) morpholin-4-carboxylic acid tert-butyl ester

6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) nicotinaldehyde (224 mg, 1.095 mmol), sodium bisulfite (612 mg, 2.99 mmol, 85%), and water (2mL) was added to (R) -2-(((2-chloro-6-nitrophenyl) amino) methyl) morpholin-4carboxylic acid tert-butyl ester in DMSO (10mL) (370mg , 0.995 mmol), and the reaction mixture was stirred at 97 ° C for 2 hours. The reaction was quenched with water (150 mL), and the product was extracted with EtOAc (4 x 75 mL). The organic extracts were combined, washed with brine, dried over MgSO _4, and concentrated. The mixture was purified by column chromatography (gradient: 0-60% EtOAc / heptane) on silica to give (R) -2-((7-chloro-2- (6-(( 2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-1-yl) methyl) morpholin-4-carboxylic acid tri Grade butyl ester (264 mg). LCMS (ES) m / z = 526.6, 528.5 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.15 (d, J = 6.34Hz, 6H), 1.36 (s, 9H), 1.66 (m, 2H), 2.20-2.29 (m, 2H), 2.55- 2.64 (m, 1H), 2.83 (m, 1H), 3.17 (m, 1H), 3.56-3.80 (m, 4H), 4.14-4.34 (m, 2H), 4.48 (m, 1H), 4.66 (m, 1H), 6.62 (d, J = 8.9Hz, 1H), 7.22-7.27 (m, 1H), 7.29-7.33 (m, 1H), 7.65 (dd, J = 7.9, 1.0Hz, 1H), 7.90 (dd , J = 8.9, 2.3Hz, 1H), 8.49 (d, J = 2.3Hz, 1H).

Example 229

(S) -2-((7-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [ d) imidazol-1-yl) methyl) morpholin

Add TFA (2 mL, 26.0 mmol) to (R) -2-((7-chloro-2- (6-((2S, 5S) -2,5-dimethyl) in CH ₂ Cl ₂ (5 ml)) Pyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-1-yl) methyl) morpholin-4-carboxylic acid tert-butyl ester (204 mg, 0.388 mmol), and The reaction mixture was stirred at room temperature for 3 hours. The reaction was concentrated, and the remaining liquid was mixed with ethyl acetate and concentrated again. Saturated NaHCO _3, then saturated Na ₂ CO ₃ and the remaining acid and the resulting mixture was extracted with EtOAc (3 x 25mL). The organic extracts were combined, washed with brine, dried over MgSO _4, filtered, and concentrated. The product was dissolved in DMF and loaded onto a silica gel column for purification. Adjusting column in hexane, then 100% hexane for 2 minutes, then to 100% CH ₂ Cl ₂ for 2 minutes, followed by a gradient of 0-10% CH ₃ OH / CH ₂ Cl ₂ elution. Add 1: 1 water and acetonitrile (1 mL total) and freeze dry the mixture overnight to give (S) -2-((7-chloro-2- (6-((2S, 5S) -2) as a white solid , 5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-1-yl) methyl) morphin (37 mg). LCMS (ES) m / z = 426.3, 428.3 [M + H] ⁺ . ¹ H NMR (400MHz, DMSO- d ₆ ): δ 1.16 (d, J = 6.34Hz, 6H), 1.59-1.71 (m, 2H), 2.18-2.36 (m, 4H), 2.57-2.71 (m, 2H ), 2.58-2.72 (m, 1H), 3.17-3.25 (m, 1H), 3.60 (br d, J = 11.15Hz, 1H), 3, 65-3.79 (m, 1H), 4.17-4.34 (m, 2H), 4.42 (dd, J = 15.21, 8.36Hz, 1H), 4.53-4.59 (m, 1H), 6.62 (d, J = 8.6Hz, 1H), 7.20-7.25 (m, 1H), 7.28-7.32 (m, 1H), 7.62-7.66 (m, 1H), 7.90 (d, J = 8.9Hz, 1H), 8.49 (d, J = 2.0Hz, 1H).

Intermediate 319

(R) -2-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-7-methoxy -5- (methylamine formamyl) -1H-benzo [d] imidazol-1-yl) methyl) morpholin 4-carboxylic acid tert-butyl ester

Add 8N NaOH (3mL) and EtOH (15mL) to (R) -2-((5-cyano-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1- Yl) pyridin-3-yl) -4-fluoro-7-methoxy-1H-benzo [d] imidazol-1-yl) methyl) morpholin 4-carboxylic acid tert-butyl ester (1.3 g, 2.302 mmol), and the reaction mixture was heated to reflux over 20 hours. The reaction was concentrated, then water (10 mL) was added, and the resulting mixture was extracted with EtOAc (3 x 10 mL). The organic extracts were combined and extracted with a 1 N NaOH solution (10 mL). The aqueous layer was then acidified by adding 6N HCl solution and freeze-dried overnight. Add EDC (0.441 g, 2.302 mmol), HOBt (0.353 g, 2.302 mmol), methylamine hydrochloride (0.233 g, 3.45 mmol), DMSO (5 mL), and N-methylmorpholine (2.53 mL, 23.02) mmol) was added to the resulting light brown solid, and the reaction mixture was stirred overnight. The reaction was quenched with water (10 mL) and extracted with EtOAc (4 x 5 mL). The organic extracts were combined, washed with brine, dried over MgSO _4, filtered, and concentrated. The resulting material was dissolved in DMSO (1.5 mL) and purified by reverse-phase HPLC (50-99% CH ₃ CN in (0.1% NH ₄ OH in water)) to give (R) -2-(( 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-7-methoxy-5- (methylamine methyl Fluorenyl) -1H-benzo [d] imidazol-1-yl) methyl) morpholin-4-carboxylic acid tert-butyl ester (24 mg), lyophilized to a very light gray solid. LC-MS (ES) m / z = 597 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 1.15 (d, J = 6.1 Hz, 6 H), 1.40 (s, 9 H), 1.66 (d, J = 5.8 Hz, 2 H), 2.24 (br.s. , 2H), 2.46-2.48 (m, 2H), 2.82 (d, J = 4.6Hz, 3H), 3.18-3.26 (m, 1H), 3.63-3.81 (m, 4H), 3.96 (s, 3H), 4.17-4.38 (m, 3H), 4.50 (d, J = 12.7Hz, 1H), 6.62 (d, J = 9.1Hz, 1H), 7.00 (d, J = 4.6Hz, 1H), 7.93 (dd, J = 9.0, 2.4Hz, 1H), 8.14-8.19 (m, 1H), 8.54 (d, J = 2.3Hz, 1H).

Example 230

2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-7-methoxy-N-methyl-1- (((S) -4-methylmorpholin-2-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide

TFA (600 μl, 7.79 mmol) was added to (R) -2-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidine- in CH ₂ Cl ₂ (1 mL)) 1-yl) pyridin-3-yl) -4-fluoro-7-methoxy-5- (methylaminomethylmethyl) -1H-benzo [d] imidazol-1-yl) methyl) morph Lin-4-carboxylic acid tert-butyl ester (24 mg, 0.040 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The reaction was concentrated and then with a saturated aqueous solution of NaHCO ₃ until basic, followed by addition of saturated aqueous Na ₂ CO ₃ (2mL). The resulting mixture was extracted with EtOAc (3 x 10mL), and then the organic extracts were combined, washed with brine, dried over MgSO _4, filtered, and concentrated. The obtained transparent oil was dissolved in 1,2-dichloroethane (1000 μl), 36% of formaldehyde (15.39 μl, 0.201 mmol) and acetic acid (6.91 μl, 0.121 mmol) in water were added, and the resulting mixture was at room temperature Stir for 15 minutes. Then NaBH (OAc) ₃ (29.8 mg, 0.141 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction was concentrated and followed by quenched with saturated aqueous NaHCO ₃ until basic, followed by addition of saturated aqueous Na ₂ CO ₃ (2mL). The resulting mixture was extracted with EtOAc (3 x 10mL), and then the organic extracts were combined, washed with brine, dried over MgSO _4, filtered, and concentrated. Purification by chromatography on SiO ₂ (gradient: 0 to 50% (80:20 CH ₂ Cl ₂ : CH ₃ OH) / CH ₂ Cl ₂ ) provides 2- (6- ((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-7-methoxy-N-methyl-1-(((S) 4-methylmorpholin-2-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide (14.6 mg). LC-MS (ES) m / z = 511 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 1.15 (d, J = 6.1 Hz, 6H), 1.63-1.74 (m, 3H), 1.90-1.98 (m, 1H), 2.15 (s, 3H), 2.25 (br.s., 2H), 2.60 (d, J = 10.4Hz, 1H), 2.82 (d, J = 4.6Hz, 3H), 3.25-3.31 (m, 2H), 3.66 (d, J = 10.4 Hz, 1H), 3.75-3.83 (m, 1H), 3.96 (s, 3H), 4.21-4.38 (m, 3H), 4.43-4.50 (m, 1H), 6.62 (d, J = 8.9 Hz, 1H) , 6.99 (d, J = 4.6 Hz, 1H), 7.93 (dd, J = 9.0, 2.4 Hz, 1H), 8.13-8.19 (m, 1H), 8.52 (d, J = 2.3 Hz, 1H).

Example 231-Capsule composition

The oral dosage form for administration of the present invention is prepared by filling a standard two-piece hard gelatin capsule with the ingredients in the proportions shown in Table I below.

Example 232-Injectable parenteral composition

The injectable form for administration of the present invention is 5- (1-((1-ethyl-1H-pyrazol-3-yl) methyl) by stirring 1.7% by weight in 10 vol% propylene glycol in water ) -1H-benzo [d] imidazol-2-yl) -N, N-dipropylpyridin-2-amine (the compound of Example 2).

Example 233-Lozenge composition

Sucrose, calcium sulfate dihydrate and the compound of the present invention as shown in Table II below were mixed and granulated with a 10% gelatin solution in the proportions shown. The wet granules are screened, dried, mixed with starch, talc and stearic acid, screened and compressed into lozenges.

Example 234: c-MYC cell-based analysis

C-MYC detection and analysis

Human c-MYC homogeneous time-resolved fluorescence (HTRF) analysis kit (Cisbio, Cat # 63ADK053PEC) was used to measure MYC content in COLO320HSR cells (ATCC, Cat # CCL-220.1) according to the manufacturer's instructions. Briefly, a 1536-well plate pre-labeled compound plate was inoculated with COLO320HSR cells (4000 cells / well) in a medium containing 0.01% CHAPS (RPMI medium w / L-glutamine + 10% FBS). The plate was incubated at 37 ° C overnight. After incubation, the cells were lysed at room temperature for 1 h using a cell kinase lysis buffer (CisBio, Cat # 64KL1FDF) supplemented with a protease inhibitor (Sigma, Cat # P8340-5ml). Donor and acceptor antibodies were added to the plate and incubated for another 4 hours at room temperature. The plates were read using BMG PHERAstar FS (BMG LABTECH Inc., Cary, NC) in HTRF mode (320nm excitation and 665nm and 620nm emission). The 665/620 ratio is measured as an analysis signal. This analysis produces a positive signal for the presence of MYC.

The compounds of the invention were tested for their activity against c-MYC in the above analysis.

The compounds of the examples are generally tested according to the c-MYC cell-based analysis described above and exhibit plC50 values in at least one set of experimental runs, or in two or more experimental run groups: The average plC50 value of 5.7.

The compound of Example 5 was generally tested according to the c-MYC cell-based analysis described above and exhibited an average plC50 value of 5.7 for c-MYC in at least one set of experimental runs.

The compound of Example 9 was generally tested according to the c-MYC cell-based analysis described above and exhibited an average plC50 value of 7 for c-MYC in at least one set of experimental runs.

The compound of Example 20 was generally tested according to the c-MYC cell-based analysis described above and exhibited an average plC ₅₀ value of 6.5 for c-MYC in at least one set of experimental runs.

The compound of Example 25 was generally tested according to the c-MYC cell-based analysis described above and exhibited an average plC50 value of 6.4 for c-MYC in at least one set of experimental runs.

The compound of Example 44 was generally tested according to the c-MYC cell-based analysis described above and exhibited an average plC50 value of 6.8 for c-MYC in at least one set of experimental runs.

The compound of Example 51 was generally tested according to the c-MYC cell-based analysis described above and exhibited an average plC50 value of 6.5 for c-MYC in at least one set of experimental runs.

The compound of Example 61 was generally tested according to the c-MYC cell-based analysis described above and exhibited an average plC50 value of 6.2 for c-MYC in at least one set of experimental runs.

The compound of Example 68 was generally tested according to the c-MYC cell-based analysis described above and exhibited an average plC50 value of 7.3 for c-MYC in at least one set of experimental runs.

The compound of Example 75 was generally tested according to the c-MYC cell-based analysis described above and exhibited an average plC50 value of 6.3 for c-MYC in at least one set of experimental runs.

The compound of Example 86 was generally tested according to the c-MYC cell-based analysis described above and exhibited an average plC50 value of 5.9 for c-MYC in at least one set of experimental runs.

The compound of Example 99 was generally tested according to the c-MYC cell-based analysis described above and exhibited an average plC50 value of 7.2 for c-MYC in at least one set of experimental runs.

The compound of Example 116 was generally tested according to the c-MYC cell-based analysis described above and exhibited an average plC50 value of 5.8 for c-MYC in at least one set of experimental runs.

The compound of Example 121 was generally tested according to the c-MYC cell-based analysis described above and exhibited an average plC50 value of 6.4 for c-MYC in at least one set of experimental runs.

The compound of Example 132 was generally tested according to the c-MYC cell-based analysis described above and exhibited an average plC50 value of 6.6 for c-MYC in at least one set of experimental runs.

The compound of Example 136 was generally tested according to the c-MYC cell-based analysis described above and exhibited an average plC50 value of 6.7 for c-MYC in at least one set of experimental runs.

The compound of Example 145 was generally tested according to the c-MYC cell-based analysis described above and exhibited an average plC50 value of 6.3 for c-MYC in at least one set of experimental runs.

The compound of Example 158 was generally tested according to the c-MYC cell-based analysis described above and exhibited an average plC50 value of 5.9 for c-MYC in at least one set of experimental runs.

The compound of Example 164 was generally tested according to the c-MYC cell-based analysis described above and exhibited an average plC50 value of 6.8 for c-MYC in at least one set of experimental runs.

The compound of Example 174 was generally tested according to the c-MYC cell-based analysis described above and exhibited an average plC50 value of 7.4 for c-MYC in at least one set of experimental runs.

The compound of Example 180 was generally tested according to the c-MYC cell-based analysis described above and exhibited an average plC50 value of 7.2 for c-MYC in at least one set of experimental runs.

The compound of Example 191 was generally tested according to the c-MYC cell-based analysis described above and exhibited an average plC50 value of 6.6 for c-MYC in at least one set of experimental runs.

The compound of Example 195 was generally tested according to the c-MYC cell-based analysis described above and presented an average plC50 value of 7.5 for c-MYC in at least one set of experimental runs.

The compound of Example 210 was generally tested according to the c-MYC cell-based analysis described above and exhibited an average plC50 value of 6.8 for c-MYC in at least one set of experimental runs.

The compound of Example 223 was generally tested according to the c-MYC cell-based analysis described above and exhibited an average plC50 value of 7.3 for c-MYC in at least one set of experimental runs.

The compound of Example 226 was generally tested according to the c-MYC cell-based analysis described above and exhibited an average plC50 value of 7.7 for c-MYC in at least one set of experimental runs.

The compound of Example 229 was generally tested according to the c-MYC cell-based analysis described above and exhibited an average plC50 value of 6.8 for c-MYC in at least one set of experimental runs.

The compound of Example 230 was generally tested according to the c-MYC cell-based analysis described above and exhibited an average plC50 value of 7.7 for c-MYC in at least one set of experimental runs.

Examples 2, 3, 4, 5, 8, 10, 12, 14, 16, 17, 22, 28 to 41, 48, 58, 61, 63, 64, 77 to 80, 82, 83, 85 to 87, 89, 90, 93, 94, 95, 104, 108, 110, 112, 114 to 117, 122, 124, 130, 133, 134, 138, 140, 142, 143, 146 to 148, 157 to 159, 161, Compounds of 167, 176, 179, 181, 227, and 228 are usually tested according to the c-MYC cell-based analysis described above and present an average pIC50 value for c-MYC in at least one set of experimental runs: 5.7 and 6.2.

Examples 1, 7, 11, 13, 15, 18 to 21, 23 to 27, 42 to 45, 47, 49 to 55, 57, 59, 60, 65 to 67, 69, 70, 72 to 75, 81, 84, 91, 92, 96 to 98, 101 to 103, 105 to 107, 109, 111, 114 to 117, 120, 121, 123, 125, 127, 128, 131, 132, 135, 136, 141, 144, 145, 149, 150, 152 to 156, 160, 164 to 172, 175, 183, 184, 186, 189 to 193, 196, 197, 200, 202, 205, 206, 208 to 218, 220, 222, 224, and The compound of 229 is usually tested according to the above c-MYC cell-based analysis and presents an average pIC50 value for c-MYC in at least one set of experimental runs: 6.3 and 6.8.

Examples 6, 9, 46, 56, 68, 71, 76, 88, 99, 100, 113, 118, 119, 126, 129, 137, 139, 151, 162, 163, 173, 174, 177, 178, 180, 182, 185, 187, 188, 194, 195, 198, 199, 201, 203, 204, 207, 211, 219, 221, 223, 225, 226, and 230 compounds are usually cell-based based on the above c-MYC The analysis was tested and presented an average pIC50 value for c-MYC in at least one set of experimental runs: 6.9.

Example 235: p300 Acetyltransferase Radioactivity / SPA-pIC50 Analysis

Biochemical measurements of p300 acetamidine transferase activity were analyzed in a radioactive SPA analysis. A 96-well plate (Corning 3884) was labeled with 500 nL of compound in each well (11 points, 3-fold serial dilution in DMSO), and positive and negative control wells were labeled with 500 nL DMSO (Sigma D8418). 8 μL of 1.5x matrix mixture was added to each well. The negative control wells were then pre-quenched with the addition of 12 μL of formic acid (12.5% JT Baker 0129-01), followed by the addition of 4 μL of the 3x enzyme mixture to initiate the reaction in all wells. After incubating for 30 minutes and shaking, the reaction wells were quenched with 12 μL of formic acid (12.5% JT Baker 0129-01). Then add SPA beads (12 μL per well, 3mg / mL Perkin Elmer RPNQ0007) and incubate and shake for 30 minutes. in The plates were read on a MicroBeta2 (Perkin Elmer) after a 200 minute delay. The analysis conditions before quenching were as follows, 0.8 nM full-length wild-type p300 (Active Motif 31124), 1 μM acetamidine coenzyme A (Sigma A2056), 1 μM ³ H-acetamidine coenzyme A (Perkin Elmer NET2902250UC), 0.2 μM H3- 21 peptide (Anaspec AS-61702), 50mM Tris pH 8.0 (Invitrogen 1566025), 1mM DTT (Invitrogen P2325), 0.1mM EDTA (Gibco 15575-038), 0.04% pluronic acid F127 (Life Technologies P6866 ) And 10% glycerol (Em Science GX0185-6).

Representative samples of the compounds described in this application were tested in the p300 acetamidine transferase radioactive / SPA analysis described above, and were found to inhibit p300 / CBP tissue protein acetamidine transferase activity.

The compound of Example 6 was generally tested according to the p300 acetamyltransferase radioactivity / SPA analysis described above and exhibited an average pIC50 value of 7.29 for p300 / CBP tissue protein acetamyl transferase activity in at least one set of experimental runs. .

The compound of Example 21 was generally tested according to the p300 acetamyltransferase radioactivity / SPA analysis described above and exhibited an average pIC50 value of 6.4 for p300 / CBP tissue protein acetamyl transferase activity in at least one set of experimental runs. .

The compound of Example 39 was generally tested according to the p300 acetamyltransferase radioactivity / SPA analysis described above and exhibited an average pIC50 value of 6.9 for p300 / CBP tissue protein acetamyl transferase activity in at least one set of experimental runs. .

The compound of Example 57 is generally tested according to the p300 acetamyltransferase radioactivity / SPA analysis described above and exhibits an average pIC50 value of 7.4 for p300 / CBP tissue protein acetamyl transferase activity in at least one set of experimental runs. .

The compound of Example 69 was generally tested according to the p300 acetamyltransferase radioactivity / SPA analysis described above and exhibited an average pIC50 value of 7.3 for p300 / CBP tissue protein acetamyl transferase activity in at least one set of experimental runs. .

The compound of Example 76 was generally tested according to the p300 acetamyltransferase radioactivity / SPA analysis described above and exhibited an average pIC50 value of 6.3 for p300 / CBP tissue protein acetamyl transferase activity in at least one set of experimental runs. .

The compound of Example 82 is generally tested according to the p300 acetamyltransferase radioactivity / SPA analysis described above and exhibits an average pIC50 value of 6.8 for p300 / CBP tissue protein acetamyl transferase activity in at least one set of experimental runs. .

The compound of Example 126 is generally tested according to the p300 acetamyltransferase radioactivity / SPA analysis described above and exhibits an average pIC50 value of 6.8 for p300 / CBP tissue protein acetamyl transferase activity in at least one set of experimental runs. .

The compound of Example 133 is generally tested according to the p300 acetamyltransferase radioactivity / SPA analysis described above and exhibits an average pIC50 value of 6.2 for p300 / CBP tissue protein acetamyl transferase activity in at least one set of experimental runs. .

The compound of Example 141 is generally tested according to the p300 acetamyltransferase radioactivity / SPA analysis described above and exhibits an average pIC50 value of 6.3 for p300 / CBP tissue protein acetamyl transferase activity in at least one set of experimental runs. .

The compound of Example 149 was generally tested according to the p300 acetamyltransferase radioactivity / SPA analysis described above and exhibited an average pIC50 value of 6.2 for p300 / CBP tissue protein acetamyl transferase activity in at least one set of experimental runs. .

The compound of Example 164 is generally tested according to the p300 acetamyltransferase radioactivity / SPA analysis described above and exhibits an average pIC50 value of 6.3 for p300 / CBP tissue protein acetamyl transferase activity in at least one set of experimental runs .

The compound of Example 167 is generally tested according to the p300 acetamyltransferase radioactivity / SPA analysis described above and exhibits an average pIC50 value of 6.1 for p300 / CBP tissue protein acetamyl transferase activity in at least one set of experimental runs. .

Although the preferred specific examples of the present invention are explained by the above, it should be understood that the present invention is not limited to the precise indications disclosed herein and reserves all the right to modify within the scope of the following patent applications.

Claims (31)

A compound according to formula Ib: Wherein: R ′ is a C _1-6 alkyl group, substituted with 1 to 3 substituents independently selected from the group consisting of a fluoro group, a pendant oxygen group, an aryl group substituted with a heteroaryl group, a heterocyclic group, and 4 heterocyclic groups independently substituted with the following substituents: fluoro, chloro, bromo, pendant, -OH, heteroaryl, C _1-6 alkyl, and 1 to 5 independently C _1-6 alkyl substituted with a substituent selected from the group consisting of fluoro, chloro, bromo, iodo, pendant, -CN, -OH, and -NH ₂ , heteroaryl, 1 to 4 Heteroaryl substituted with independently selected from the group consisting of fluoro, chloro, bromo, -OH, heteroaryl, _C1-6 alkyl, and 1 to 5 independently selected from C _1-6 alkyl substituted with substituents: fluoro, chloro, bromo, iodo, pendant, -CN, -OH, and -NH ₂ , C _1-6 alkoxy, 1 to 9 C _1-6 alkoxy substituted with independently selected from the group consisting of: fluoro, chloro, pendant, -OH, -NH ₂ , -NHCH ₃ , and -N (CH ₃ ) ₂ , -O Cycloalkyl, and -O cycloalkyl substituted with 1 to 4 substituents independently selected from: fluoro, chloro, pendant oxy, -OH, -NH ₂ , -NHCH ₃ , and -N (CH ₃ ) ₂ ; X ^{1 ′} is selected from: CR ^{1 ′} and N, wherein R ^{1 ′} is selected from: hydrogen, fluoro, chloro, bromo, iodo, -OH, -NH ₂ ,- _{NHCH 3, -N (CH 3)} 2, -CN, C 1-4 alkoxy, 1-7 independently selected substituents of the C _1-4 alkoxy: fluoro, chloro , Pendant oxy, -OH, -NH ₂ , -NHCH ₃ , and -N (CH ₃ ) ₂ , C _1-6 alkyl, C _1- substituted with 1 to 7 substituents independently selected from ₆ alkyl: fluoro, chloro, bromo, iodo, pendant oxy, -CN, -OH, -OC _1-5 alkyl, heterocyclyl, -COOH, -S (O) ₂ H,- S (O) ₂ R ^x, wherein R ^X is selected from fluorine and C _1-3 alkyl, heterocyclyl, and -NR ^a R ^b substituted by 1 to 3 C _1-3 alkyl, followed, where R ^a and R ^b are independently selected from: hydrogen, C _1-5 alkoxy, one to four substituents independently selected from the group C _1-5 alkoxy substituted with: fluoro, oxo, -OH, -OC _1-5 alkyl, cycloalkyl, cycloalkyl substituted with -OH, -COOH, -NH ₂ , -S (O) ₂ H, and -S (O) ₂ CH ₃ , C _1-5 alkyl, one to four substituents independently selected from the group consisting of C _1-5 alkyl substituents: fluoro, oxo, -OH, -OC _{1 -5} alkyl, cycloalkyl, cycloalkyl substituted with -OH, -COOH, -NH ₂ , -S (O) ₂ H, and -S (O) ₂ R ^x , where R ^x is selected C _1-3 alkyl, and from fluorine-substituted 1-3 followed by C _1-3 alkyl, cycloalkyl, and with 1 to 4 substituents independently selected from the group consisting of cycloalkyl substituents selected from: Fluoro, pendant oxy, -OH, -O _1-5 alkyl, -COOH, and -NH ₂ , heteroaryl, and heteroaryl substituted with 1 to 4 substituents independently selected from: fluoro, chloro, C _1-6 alkyl, and with 1 to 5 substituents independently selected from the group consisting of substituted C _1-6 alkyl substituents: fluoro, chloro, bromo, iodo, an oxygen side , -CN, -OH, and -NH ₂ ; R ^{2 ′} , R ^{3 ′} , and R ^{4 ′} are independently selected from: hydrogen, fluoro, chloro, bromo, iodo, -OH boronic acid, 1, 3,6,2-dioxazaborocane-4,8-dione, -CN, -NR ^c R ^d , wherein R ^c and R ^d are independently selected from: hydrogen, C _1-5 alkyl, C _1-5 alkyl substituted with 1 to 4 substituents independently selected from: fluoro, pendant oxy, -OH, -OC _1-5 alkyl, cycloalkyl, -COOH, -NH ₂ , -N (H) C _1-4 alkyl, -N (C _1-4 alkyl) ₂ , -N (H ) C _1-4 alkyl, wherein alkyl is substituted by fluoro group 1 to 3 times, N (C _1-4 alkyl) ₂ , wherein each alkyl is substituted by fluoro group 1 to 3 times, -S (O ) ₂ H, and -S (O) ₂ R ^x, wherein R ^x is selected from fluoro and C _1-3 alkyl group substituted with 1 to 3 C _1-3 alkyl followed, -S (O) ₂ H ^{_{, -S (O) 2 R x}} ', wherein R ^x' is selected from fluoro and C _1-3 alkyl group substituted with 1 to 3 followed by C _1-3 alkyl, an aryl group, an aryl group, with 1 to 4 substituents independently selected from fluoro, pendant oxy, -OH, -O _1-5 alkyl, -COOH, and -NH ₂ , heteroaryl, heteroaryl, via 1 to 4 Independently substituted with a substituent selected from the group consisting of fluoro, pendant oxy, -OH, -O _1-5 alkyl, -COOH, and -NH ₂ , heterocyclyl, heterocyclyl, 1 to 4 Independently selected from the group consisting of fluoro, pendant oxy, -OH, -O _1-5 alkyl, -COOH, and -NH ₂ , cycloalkyl, and independently selected from 1 to 4 Cycloalkyl substituted with the following substituents: fluoro, pendant oxy, -OH, -O _1-5 alkyl, -COOH, and -NH ₂ , heterocyclyl, C _1-4 alkoxy, via 1 to 7 are independently selected from the following substituents of the C ₁ - ₄ alkoxy group: fluoro, chloro, side _{Group, -OH, -NH 2, -NHCH 3} , and _{-N (CH 3) 2, C} 1-6 alkyl, 1-7 substituents independently selected from the group C _1-6 alkyl substituents : Fluoro, chloro, bromo, iodo, pendant oxy, -CN, -OH, -OC _1-5 alkyl, heterocyclyl, -COOH, -S (O) ₂ H, -S (O ) ₂ R ^x, wherein R ^x is selected from fluoro and C _1-3 alkyl group substituted with 1 to 3 C _1-3 alkyl followed, and -NR ^a R ^b, wherein R ^a and R ^b are independently lines selected from: hydrogen, C _1-5 alkyl, one to four substituents independently selected from the group consisting of C _1-5 alkyl substituents: fluoro, oxo, -OH, -OC _1-5 alkyl Group, cycloalkyl, -COOH, -NH ₂ , -S (O) ₂ H, and -S (O) ₂ R ^x , where R ^x is selected from C _1-3 alkyl and substituted with 1 to 5 by fluoro 3 times C _1-3 alkyl, aryl, aryl, substituted with 1 to 4 substituents independently selected from: fluoro, pendant oxy, -OH, -O _1-5 alkyl,- COOH, and -NH ₂ , heteroalkyl, heteroalkyl, substituted with 1 to 4 substituents independently selected from: fluoro, pendant oxy, -OH, -O _1-5 alkyl, -COOH and -NH _2, heterocycloalkyl, heteroalkyl, 1-4 independently selected substituents: fluoro, side Groups, -OH, -O _1-5 alkyl, -COOH, and -NH _2, cycloalkyl, and with 1 to 4 substituents independently selected from the group consisting of cycloalkyl substituents: fluoro, oxygen-side , -OH, -O _1-5 alkyl, -COOH, and -NH ₂ , aryl, aryl substituted with 1 to 4 substituents independently selected from fluoro, chloro, C _{1 -6} alkyl, and C _1-6 alkyl substituted with 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, pendant oxy, -CN, -OH, and -NH ₂ , cycloalkyl, cycloalkyl substituted with 1 to 4 substituents independently selected from fluoro, chloro, C _1-6 alkyl, and independently selected from 1 to 5 C _1-6 alkyl substituted with the following substituents: fluoro, chloro, bromo, iodo, pendant oxy, -CN, -OH, and -NH ₂ , heterocyclic, independently selected from 1 to 4 from the group consisting of heterocyclyl substituents: fluoro, chloro, C _1-6 alkyl, and with 1 to 5 substituents independently selected from the group consisting of substituents of the C _1-6 alkyl group: fluoro, chloro , Bromo, iodo, pendant oxy, -CN, -OH, and -NH ₂ , heteroaryl, and heteroaryl substituted with 1 to 4 substituents independently selected from : Fluoro, chloro, C _1-6 alkyl, and with 1 to 5 substituents independently selected from the group consisting of substituted C _1-6 alkyl substituents: fluoro, chloro, bromo, iodo, side Oxy, -CN, -OH and -NH ₂ or 2 adjacent members of R ^{1 '} , R ^2' , R ^{3 '} , and R ^4' together form a group containing 3 to 6 independently selected from the following Non-aromatic rings of member atoms: carbon, nitrogen, sulfur, oxygen, and boron to form oxaborolyl, heterocyclyl, cycloalkyl, or heteroaryl, wherein the oxa Boracyclopentadienyl, heterocyclyl, cycloalkyl, and heteroaryl are each optionally substituted with 1 to 3 substituents independently selected from the group consisting of fluoro, chloro, -OH, Oxy, C _1-6 alkyl, and -NH ₂ ; R ^{5 ′} and R ^{6 ′} are independently selected from: C _1-4 alkyl, substituted with 1 to 6 substituents independently selected from C _1-4 alkyl: fluoro, pendant oxy, -NH ₂ , C _1-4 alkoxy, and -OH, cycloalkyl, ring substituted with 1 to 5 substituents independently selected from alkyl group: fluoro, chloro, -OH, and C _1-6 alkyl, R ^{5 'and} R ^6' are connected to the nitrogen together with their, and optionally the amount of 1 to 3 Hetero atom to form a heterocyclic group, which is optionally substituted with 1-5 independently selected substituents: fluoro, chloro, C _1-6 alkyl, 1-9 independently selected C _1-6 alkyl substituted with the following substituents: fluoro, chloro, C _1-4 alkoxy, pendant oxy, -OH, -NH ₂ , -N (H) C _1-4 alkyl, -N (C _1-4 alkyl) _2, and -CN, C _1-4 alkoxy, with 1 to 4 substituents independently selected from the group consisting of substituents C _1-4 alkoxy: fluoro group, Pendant oxygen, -OH, -COOH, -NH ₂ , and -CN, pendant oxygen, -NH ₂ , -N (H) C _1-4 alkyl, and -N (C _1-4 alkyl) ₂ , Or one of R ^{5 ′} and R ^{6 ′} together with R ^{7 ′} , and optionally 1 to 3 additional heteroatoms to form a heterocyclic group, optionally 1 to 5 independently selected from The following substituents are substituted: fluoro, chloro, -OH, pendant oxy, C _1-4 alkyl, C _1-4 alkoxy, and -NH ₂ ; and R ^{7 '} is selected from: hydrogen and fluorine Group, or one of R ^{5 ′} and R ^{6 ′} together with R ^{7 ′} , and optionally 1 to 3 additional heteroatoms to form a heterocyclic group, optionally selected from 1 to 5 independently Substituted from the following substituents: fluoro, chloro, -OH, pendant Oxy, C _1-4 alkyl, C _1-4 alkoxy, and -NH ₂ ; or a pharmaceutically acceptable salt thereof. For example, the compound in the scope of patent application No. 1 is represented by the following formula (IIb): Wherein: R ^10b is C _1-4 alkyl, substituted with 1 to 3 substituents independently selected from the group consisting of pendant oxygen, phenyl substituted with pyrimidinyl, heterocyclyl, independently substituted with 1 to 4 Heterocyclyl substituted with a substituent selected from the group consisting of fluoro, chloro, bromo, pendant oxy, heteroaryl, C _1-6 alkyl, and 1 to 5 substituents independently selected from Substituted C _1-6 alkyl: fluoro, chloro, bromo, iodo, pendant oxy, -CN, -OH, and -NH ₂ , heteroaryl, independently selected from 1 to 4 substituted aryl of heteroaryl groups: fluoro, chloro, bromo, heteroaryl, C _1-6 alkyl, and with 1 to 5 substituents independently selected from the group consisting of substituents of C _1-6 alkyl : Fluoro, chloro, bromo, iodo, pendant, -CN, -OH, and -NH ₂ , C _1-6 alkoxy, substituted with 1 to 9 substituents independently selected from the following C _1-6 alkoxy: fluoro, chloro, pendant, -OH, -NH ₂ , -NHCH ₃ , and -N (CH ₃ ) ₂ , -O cycloalkyl, and 1 to 4 -O cycloalkyl substituted independently with substituents selected from the group consisting of fluoro, chloro, pendant, -OH, -NH ₂ , -NHCH ₃ , and -N (CH ₃ ) ₂ ; R ^{11 b} is selected from the group consisting of: hydrogen, fluoro, chloro, bromo, iodo, -OH, -NH ₂ , -CN, C _1-4 alkoxy, and 1 to 7 substituents independently selected from the following Substituted C _1-4 alkoxy: fluoro, chloro, pendant oxy, -OH, -NH ₂ , -NHCH ₃ , and -N (CH ₃ ) ₂ , C _1-6 alkyl, via 1 to C _1-6 alkyl substituted with 7 substituents independently selected from: fluoro, chloro, bromo, iodo, pendant oxy, -CN, -OH, -OC _1-5 alkyl, hetero cycloalkyl _{group, -COOH, -S (O) 2} H, -S (O) 2 R x1 ', where R ^x1' is selected from fluoro and C _1-3 alkyl substituted with 1 to 3 C _1-3 followed Alkyl, and -NR ^{a1 '} R ^b1' , wherein R ^{a1 '} and R ^b1' are independently selected from: hydrogen, C _1-5 alkoxy, C _1-5 alkyl, independently from 1 to 4 C _1-5 alkyl substituted with substituents selected from: fluoro, pendant oxy, -OH, -OC _1-5 alkyl, cycloalkyl, cycloalkyl substituted with -OH, -COOH , -NH ₂ , -S (O) ₂ H, and -S (O) ₂ CH ₃ , cycloalkyl, and cycloalkyl substituted with 1 to 4 substituents independently selected from the following: fluoro, Pendant oxygen, -OH, -O _1-5 alkyl, -COOH, and -NH ₂ , heteroaryl, and independently selected from 1 to 4 Substituent groups consisting of a substituted heteroaryl group: fluoro, chloro, C _1-6 alkyl, and with 1 to 5 substituents independently selected from the group consisting of substituted C _1-6 alkyl substituents: fluoro, chloro group, bromo, iodo, oxo, -CN, -OH and ^{_{-NH 2; R 12b, R 13b}} , and R ^14b are independently selected from: hydrogen, fluoro, chloro, bromo, iodo , -OH, boric acid, 1,3,6,2-dioxazepine-octane-4,8-dione, -CN, -NR ^{c1 '} R ^d1' , where R ^{c1 '} and R ^d1' are independently selected from: hydrogen, C _1-5 alkyl, one to four substituents independently selected from the group consisting of C _1-5 alkyl substituents: fluoro, oxo, -OH, -OC _{1 -5} alkyl, cycloalkyl, -COOH, -NH ₂ , -N (H) C _1-4 alkyl, -N (H) C _1-4 alkyl, in which alkyl is substituted by 1 to 5 3 times, and -S (O) ₂ H, -S (O) ₂ H, -S (O) ₂ C _1-3 alkyl, heterocyclyl, C _1-4 alkoxy, 1 to 7 C _1-4 alkoxy substituted with independently selected from the group consisting of fluoro, chloro, pendant, -OH, -NH ₂ , -NHCH ₃ , and -N (CH ₃ ) ₂ , C _{1 -6} alkyl, C _1-6 alkyl substituted with 1 to 7 substituents independently selected from: fluoro, chloro, bromo, iodo , Pendant oxygen, -CN, -OH, -OC _1-5 alkyl, heterocyclyl, -COOH, -S (O) ₂ H, -S (O) ₂ R ^{x1 '} , where R ^x1' is selected C _1-3 alkyl, and from fluorine-substituted with 1 to 3 C _1-3 alkyl followed, and -NR ^{a1 'R b1',} wherein R ^{a1 'and} R ^b1' are independently selected: hydrogen, C _{1 -5} alkoxy, C _1-5 alkyl, with 1 to 4 substituents independently selected from the group consisting of substituents of C _1-5 alkyl: fluoro, oxo, -OH, -OC _1-5 Alkyl, cycloalkyl, -COOH, -NH ₂ , -S (O) ₂ H, and -S (O) ₂ R ^{x1 '} , where R ^x1 is selected from C _1-3 alkyl and substituted with fluoro 1 to 3 times C _1-3 alkyl; cycloalkyl, and cycloalkyl substituted with 1 to 4 substituents independently selected from the group consisting of fluoro, pendant oxy, -OH, -O _{1- 5} alkyl, -COOH, and -NH ₂ , heteroaryl, and heteroaryl substituted with 1 to 3 substituents independently selected from: fluoro, chloro, C _1-6 alkyl, and C _1-6 alkyl substituted with 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, pendant oxy, -CN, -OH and -NH ₂ , or R ^12b, R ^13b, and two adjacent members of R ^14b together form a containing 3 to 6 are independently selected from the group consisting of Non-aromatic rings of member atoms: carbon, nitrogen, sulfur, oxygen, and boron to form oxaborolyl, heterocyclyl, cycloalkyl, or heteroaryl, wherein the oxa Boracyclopentadienyl, heterocyclyl, cycloalkyl, and heteroaryl are each optionally substituted with 1 to 3 substituents independently selected from the group consisting of fluoro, chloro, -OH, Oxy, C _1-6 alkyl, and -NH ₂ ; R ^15b and R ^16b are independently selected from C _1-4 alkyl, C ₁ substituted with 1 to 6 substituents independently selected from _-4 alkyl: fluoro, pendant oxy, -NH ₂ , C _1-4 alkoxy, and -OH, cycloalkyl, and cycloalkane substituted with 1 to 5 substituents independently selected from : Fluoro, chloro, -OH, and C _1-6 alkyl, R ^15b and R ^16b together with the nitrogen to which they are attached, and optionally 1 to 3 additional heteroatoms to form a heterocyclyl , Optionally substituted with 1 to 5 substituents independently selected from the following: fluoro, chloro, C _1-6 alkyl, C ₁ substituted with 1 to 9 substituents independently selected from _-6 alkyl: fluoro, chloro, C _1-4 alkoxy, pendant oxy, -OH, -NH ₂ , -N (H) C _1-4 Alkyl, -N (C _1-4 alkyl) _2, and -CN, C _1-4 alkoxy, with 1 to 4 substituents independently selected from the group consisting of substituents C _1-4 alkoxy: Fluoro, pendant oxy, -OH, -COOH, -NH ₂ , and -CN, pendant oxy, -NH ₂ , -N (H) C _1-4 alkyl, and -N (C _1-4 alkane ₂ ), or one of R ^15b and R ^16b together with R ^17b , and optionally 1 to 3 additional heteroatoms to form a heterocyclyl, optionally 1 to 3 independently selected from The following substituents are substituted: fluoro, -OH, C _1-4 alkyl, and C _1-4 alkoxy; and R ^17b is selected from: hydrogen and fluoro, or one of R ^15b and R ^16b With R ^17b , and optionally 1 to 3 additional heteroatoms to form a heterocyclyl, optionally substituted with 1 to 3 substituents independently selected from the group: fluoro, -OH, C _{1 -4} alkyl, and C _1-4 alkoxy; or a pharmaceutically acceptable salt thereof. For example, the compound in the scope of patent application No. 1 is represented by the following formula (IIb '): Wherein: R ^{10b ′} is a C _1-4 alkyl group, which is substituted with 1 to 3 substituents independently selected from the group consisting of a pendant oxygen group, a phenyl group substituted with a pyrimidinyl group, a heterocyclic group, and 1 to 4 independent groups. Heterocyclyl substituted with a substituent selected from the group consisting of fluoro, chloro, bromo, pendant, heteroaryl, C _1-6 alkyl, and substituted with 1 to 5 independently selected from -Substituted C _1-6 alkyl: fluoro, chloro, bromo, iodo, pendant, -CN, -OH, and -NH ₂ , heteroaryl, independently selected from 1 to 4 the substituent of the substituted heteroaryl group: 1 to 5 substituents selected from fluoro, chloro, bromo, heteroaryl, C _1-6 alkyl, and the substituted independently by C _1-6 alkoxy group Group: fluoro, chloro, bromo, iodo, pendant, -CN, -OH, and -NH ₂ , C _1-6 alkoxy, substituted with 1 to 9 substituents independently selected from C _1-6 alkoxy: fluoro, chloro, pendant, -OH, -NH ₂ , -NHCH ₃ , and -N (CH ₃ ) ₂ , -O cycloalkyl, and 1 to 4 -O cycloalkyl substituted with independently selected substituents: fluoro, chloro, pendant, -OH, -NH ₂ , -NHCH ₃ , and -N (CH ₃ ) ₂ ; R ^{12b '} , ^R13b' , and ^{R14b '} are independently selected from the group consisting of: hydrogen, fluoro, chloro, bromo, iodo, -OH, boric acid, 1,3,6,2-dioxazepine Cyclooctane-4,8-dione, -CN, -NR ^c1b R ^d1b , wherein R ^c1b and R ^d1b are independently selected from: hydrogen, C _1-5 alkyl, independently selected from 1 to 4 C _1-5 alkyl substituted with the following substituents: fluoro, pendant oxy, -OH, -OC _1-5 alkyl, cycloalkyl, -COOH, -NH ₂ , -N (H) C _{1- 4-} alkyl, -N (H) C _1-4 alkyl, wherein alkyl is substituted 1 to 3 times with fluoro, and -S (O) ₂ H, -S (O) ₂ H, -S (O ) ₂ C _1-3 alkyl, heterocyclyl, C _1-4 alkoxy, by 1-7 substituents independently selected from the group C _1-4 alkoxy substituted with: fluoro, chloro, _{oxo, -OH, -NH 2, -NHCH 3} , and _{-N (CH 3) 2, C} 1-6 alkyl, substituted with 1-7 substituents independently selected from the group consisting of C _1-6 Alkyl: fluoro, chloro, bromo, iodo, pendant oxy, -CN, -OH, -OC _1-5 alkyl, heterocyclyl, -COOH, -S (O) ₂ H, -S (O) ₂ R ^x1a, wherein R ^x1a selected from fluoro and C _1-3 alkyl group substituted with 1 to 3 C _1-3 alkyl followed, and -NR ^a1b R ^b1b, wherein R ^a1b lines and R ^b1b Site selected from: hydrogen, C _1-5 alkoxy, C _1-5 alkyl, with 1 to 4 substituents independently selected from the group consisting of substituents of C _1-5 alkyl: fluoro, oxo, -OH, -OC _1-5 alkyl, cycloalkyl, -COOH, -NH ₂ , -S (O) ₂ H, and -S (O) ₂ R ^x1b , wherein R ^x1b is selected from C _1-3 Alkyl and C _1-3 alkyl substituted 1 to 3 times with fluoro; cycloalkyl, and cycloalkyl substituted with 1 to 4 substituents independently selected from: fluoro, pendant oxy, -OH, -O _1-5 alkyl, -COOH, and -NH ₂ , heteroaryl, and heteroaryl substituted with 1 to 3 substituents independently selected from: fluoro, chloro, C _1-6 alkyl, and C _1-6 alkyl substituted with 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, pendant oxy, -CN, -OH And -NH ₂ , or 2 adjacent members of R ^{12b ′} , R ^{13b ′} , and R ^{14b ′} form a non-aromatic ring containing 3 to 6 member atoms independently selected from the group consisting of carbon, nitrogen, Sulfur, oxygen, and boron to form an oxaborolyl, heterocyclyl, cycloalkyl, or heteroaryl group, wherein the oxaborylcyclopentadienyl, heterocyclyl, Alkyl, aryl and heteroaryl groups are each based visual needs substituted with 1 to 3 substituents independently selected from the following substituents: fluoro, chloro, -OH, oxo, C _1-6 alkyl, and -NH _2; R ^{15b 'and} R ^16b' are independently selected: C _1-4 alkyl, substituted with the following one to six substituents independently selected from C _1-4 alkyl: fluoro, oxo, -NH ₂ , C _1-4 alkoxy, and -OH, cycloalkyl, and cycloalkyl substituted with 1 to 5 substituents independently selected from: fluoro, chloro, -OH, and C _1-6 alkyl, R ^{15b ′} and R ^{16b ′} together with the nitrogen to which they are attached, and optionally 1 to 3 additional heteroatoms to form a heterocyclic group, which optionally passes 1 to 5 is independently selected from the following substituents: fluoro, chloro, C _1-6 alkyl, 1-9 substituents independently selected from the group C _1-6 alkyl substituents: fluoro, chloro , C _1-4 alkoxy, pendant oxy, -OH, -NH ₂ , -N (H) C _1-4 alkyl, -N (C _1-4 alkyl) ₂ , and -CN, C _{1 -4} alkoxy, C _1-4 alkoxy substituted with 1 to 4 substituents independently selected from: fluoro, pendant, -OH, -COOH, -NH ₂ , and -CN, Pendant oxygen, -NH ₂ ,- N (H) C _1-4 alkyl, and -N (C _1-4 alkyl) ₂ , or one of R ^{15b ′} and R ^{16b ′} together with R ^{17b ′} , and optionally 1 to 3 Additional heteroatoms to form a heterocyclyl, optionally substituted with 1 to 3 substituents independently selected from: fluoro, -OH, C _1-4 alkyl, and C _1-4 alkoxy And R ^{17b ′} is selected from: hydrogen and fluoro, or one of R ^{15b ′} and R ^{16b ′} together with R ^{17b ′} , and optionally 1 to 3 additional heteroatoms to form a heterocyclic group, It is optionally substituted with 1 to 3 substituents independently selected from the group consisting of a fluoro group, —OH, a C _1-4 alkyl group, and a C _1-4 alkoxy group; or a pharmaceutically acceptable salt thereof. For example, the compound in the scope of patent application No. 1 or 2 is represented by the following formula (IVb): Where: R ^20b is C _1-2 alkyl substituted with: phenyl substituted with pyrimidinyl, pyrazolyl, pyrazolyl substituted with C _1-3 alkyl, pyr _Pyridyl substituted with C _1-3 alkyl Base Phenyl _Ci, substituted with C _1-3 alkyl base, Oxazolyl, substituted with C _1-3 alkyl Azolyl, imidazolyl, imidazolyl substituted with C _1-3 alkyl, morpholinyl, morpholinyl substituted 1 or 2 times with C _1-3 alkyl, morpholin substituted with pendant oxy Base, two Alkyl, substituted by C _1-3 alkyl Alkyl, 4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine ; Triazolyl, triazolyl substituted with C _1-3 alkyl, thiazolyl, thiazolyl substituted with C _1-3 alkyl, -O cyclopentyl, C _1-6 alkoxy, fluoro substituted with 1-6 followed by C _1-6 alkoxy, unsubstituted of substituted hydroxyl groups of C _1-6 alkoxy, tetrahydrofuranyl, pyridinyl, substituted by bromo group of pyridinyl, pyrimidinyl, or pyridinyl; R ^21b Is selected from: hydrogen, fluoro, chloro, bromo, -OH, -CN, -NH ₂ , -C (O) NHCH ₃ , -C (O) NHCH ₂ CH ₂ OH, -C (O) NHCH ₂ CH ₂ SO ₂ CH ₃ , -C (O) NHOCH ₃ , -C (O) NH ₂ , -C (O) OCH ₃ , -C (O) NHCH ₂ cyclopropyl, -C (O) NH ring Butyl, optionally substituted with hydroxy, -CH ₂ morpholinyl, -CH ₂ OH, -CH ₂ NHCH ₂ CF ₃ , -CH ₂ NHCH ₂ CH ₂ SO ₂ CH ₃ , -CH ₂ SO ₂ CH ₃ , -CH (OH) CF ₃ , -CH ₃ , -CF ₃ , -OCH ₃ , methoxy-d3, pyrazolyl, Oxazolyl, and substituted once or twice with methyl Oxazolyl; R ^22b , R ^23b , and R ^24b are independently selected from: hydrogen, fluoro, chloro, bromo, -OH, boric acid, 1,3,6,2-dioxazepine Alkane-4,8-dione, -CN, -C (O) NHCH ₃ , -C (O) NHCH ₂ CH ₃ , -C (O) NHCH ₂ CF ₂ H, -C (O) NHCH ₂ CH ₂ OH, -C (O) NHCH ₂ CH ₂ SO ₂ CH ₃ , -C (O) NHOCH ₃ , -C (O) NH ₂ , -C (O) OCH ₃ , -C (O) NHCH ₂ cyclopropyl , -C (O) NH cyclobutyl, optionally substituted with a hydroxyl group, -CH ₂ morpholinyl, -CH ₂ OH, -CH ₂ NHCH ₂ CF ₃ , -CH ₂ NHCH ₂ CH ₂ SO ₂ CH ₃ , -CH ₂ SO ₂ CH ₃ , -CH (OH) CF ₃ , -CH ₃ , -CF ₃ , -OCH ₃ , methoxy -d ₃ , -NHC (O) CH ₃ , -NH ₂ , -NHSO ₂ CH ₃ , morpholinyl pyrazolyl, Oxazolyl, and substituted once or twice with methyl Oxazolyl, or R ^23b and R ^24b together with the carbon atom to which they are attached to form oxaborolyl, optionally substituted with a hydroxyl group; R ^25b and R ^26b are independently selected from : C _1-3 alkyl, fluoro substituted with 1 to 3 followed by C _1-3 alkyl, and cyclopropyl, R ^25b and R ^26b together with the nitrogen of their attached together to form: a nitrogen Ta, pyrrolyl piperidinyl, their respective lines or two optionally substituted by one of the following: C _1-3 alkyl or fluorine substituted with 1 to 3 followed by C _1-3 alkyl, or R ^25b and R ^26b one of Together with R ^27b , and optionally one additional heteroatom to form: pyrrolidinyl, or morpholinyl, each of which is optionally substituted with C _1-3 alkyl groups 1 to 4 times; and R ^27b is selected from: hydrogen and fluorine; or one of R ^25b and R ^26b together with R ^27b , and optionally an additional heteroatom to form: pyrrolidinyl, or morpholinyl, etc. Each is optionally substituted 1 to 4 times with a C _1-3 alkyl group; or a pharmaceutically acceptable salt thereof. For example, the compound in the scope of patent application No. 1 or 3 is represented by the following formula (IVb '): Wherein: R ^{20b ′} is a C _1-2 alkyl group substituted with: phenyl substituted with pyrimidinyl, pyrazolyl, pyrazolyl substituted with C _1-3 alkyl, pyr _Pyridyl substituted with C _1-3 alkyl Base Phenyl _Ci, substituted with C _1-3 alkyl base, Oxazolyl, substituted with C _1-3 alkyl Oxazolyl, imidazolyl, imidazolyl substituted with C _1-3 alkyl, morpholinyl, morpholinyl substituted 1 or 2 times with C _1-3 alkyl, morpholin substituted with pendant oxy Base, two Alkyl, substituted by C _1-3 alkyl Alkyl, 4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine ; Triazolyl, triazolyl substituted with C _1-3 alkyl, thiazolyl, thiazolyl substituted with C _1-3 alkyl, -O cyclopentyl, C _1-6 alkoxy, fluoro substituted with 1-6 followed by C _1-6 alkoxy, unsubstituted of substituted hydroxyl groups of C _1-6 alkoxy, tetrahydrofuranyl, pyridinyl, substituted by bromo group of pyridinyl, pyrimidinyl, or pyridinyl; R ^{22b '} , R ^23b' , and R ^{24b '} are independently selected from: hydrogen, fluoro, chloro, bromo, -OH, boric acid, 1,3,6,2-dioxazepine- 4,8-dione, -CN, -C (O) NHCH ₃ , -C (O) NHCH ₂ CH ₃ , -C (O) NHCH ₂ CF ₂ H, -C (O) NHCH ₂ CH ₂ OH, -C (O) NHCH ₂ CH ₂ SO ₂ CH ₃ , -C (O) NHOCH ₃ , -C (O) NH ₂ , -C (O) OCH ₃ , -C (O) NHCH ₂ cyclopropyl,- C (O) NH cyclobutyl, optionally substituted with hydroxy, -CH ₂ morpholinyl, -CH ₂ OH, -CH ₂ NHCH ₂ CF ₃ , -CH ₂ NHCH ₂ CH ₂ SO ₂ CH ₃ ,- CH ₂ SO ₂ CH ₃ , -CH (OH) CF ₃ , -CH ₃ , -CF ₃ , -OCH ₃ , methoxy -d ₃ , -NHC (O) CH ₃ , -NH ₂ , -NHSO ₂ CH ₃ , morpholinyl pyrazolyl, Oxazolyl, and substituted once or twice with methyl An oxazolyl group, or R ^{23b '} and R ^24b' together with the carbon atom to which they are attached to form an oxaborolyl, optionally substituted with a hydroxyl group; R ^{25b '} and R ^26b' are is independently selected from: C _1-3 alkyl, fluoro substituted with 1 to 3 followed by C _1-3 alkyl, and cyclopropyl, R ^{25b 'and} R ^26b' are connected to the nitrogen to form, together with their : Da nitrogen group, pyrrolidinyl, their respective lines of the following optionally substituted with one or two substituted: C _1-3 alkyl or fluorine substituted with 1 to 3 followed by C _1-3 alkyl, or R ^{25b One of '} and R ^26b' together with R ^{27b '} , and optionally one additional heteroatom to form: pyrrolidinyl, or morpholinyl, each of them is optionally passed C _1-3 Alkyl substitution 1 to 4 times; and R ^{27b '} is selected from: hydrogen and fluorine; or one of R ^25b' and R ^{26b '} together with R ^27b' , and optionally one additional heteroatom to form : Pyrrolidinyl, or morpholinyl, each of which is optionally substituted with C _1-3 alkyl groups 1 to 4 times; or a pharmaceutically acceptable salt thereof. For example, the compound in the first scope of the patent application is selected from: N, N-diethyl-5- (1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H- Benzo [d] imidazol-2-yl) pyridin-2-amine; 5- (1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole -2-yl) -N, N-dipropylpyridine-2-amine; N-ethyl-5- (1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H -Benzo [d] imidazol-2-yl) -N-propylpyridin-2-amine; 1-((1-ethyl-1H-pyrazol-3-yl) methyl) -2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole; N-ethyl-5- (1-((1-ethyl-1H-pyrazole- 3-yl) methyl) -1H-benzo [d] imidazol-2-yl) -N-isopropylpyridin-2-amine; 2- (6- (diethylamino) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -N-methyl-1H-benzo [d] imidazole-5-carboxamide; (S) -1- ( (1-ethyl-1H-pyrazol-3-yl) methyl) -N-methyl-2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H- Benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5R) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-(( 1-ethyl-1H-pyrazol-3-yl) methyl) -N-methyl-1H-benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5S)- 2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyridine -3-yl) methyl) -N-methyl-1H-benzo [d] imidazole-5-carboxamide; 2- (6- (cyclopropyl (ethyl) amino) pyridin-3-yl ) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -N-methyl-1H-benzo [d] imidazole-5-carboxamide; 2- (6- ( Diethylamino) -5-fluoropyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -N-methyl-1H-benzo [d] Imidazol-5-carboxamide; (S) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -2- (5-fluoro-6- (2-methylpyrrolidine -1-yl) pyridin-3-yl) -N-methyl-1H-benzo [d] imidazol-5-carboxamide; 2- (6-((2S, 5S) -2,5-dimethyl Pyrrolidin-1-yl) -5-fluoropyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -N-methyl-1H-benzo [d] Imidazole-5-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1- Ethyl-1H-pyrazol-3-yl) methyl) -N- (2-hydroxyethyl) -1H-benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide; (S) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -2- (6- (2-methylpyrrolidine- 1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5R) -2,5-dimethylpyrrolidine-1 -Yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide; 5- ( 4-chloro-1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridine-2 -Amine; N, N-diethyl-5- (1-((1-ethyl-1H-pyraol-3-yl) methyl) -4-methyl-1H-benzo [d ] Imidazol-2-yl) pyridin-2-amine; 4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl)- 1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole; 5- (7-chloro-1-((1-ethyl-1H-pyridine Azole-3-yl) methyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine; 5-bromo-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole; (2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H- Pyrazol-3-yl) methyl) -1H-benzo [d] imidazol-5-yl) boronic acid; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1- Yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -5- (1H-pyrazol-3-yl) -1H-benzo [d ] Imidazole; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazole- 3-yl) methyl) -5- (1H-pyrazol-4-yl) -1H-benzo [d] imidazole; 5- (4,5-dichloro-1-((1-ethyl-1H-pyrazol-3-yl ) Methyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine; 2- (6-((2S, 5S) -2,5-dimethyl Pyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl) methyl) -5-fluoro-1H-benzo [d] imidazole; N, N-diethyl-5- (1-((1-ethyl-1H-pyrazol-3-yl) methyl) -5-methoxy-1H-benzo [d] imidazole-2- ) Pyridin-2-amine; N, N-diethyl-5- (1-((1-ethyl-1H-pyrazol-3-yl) methyl) -6-methyl-1H-benzo [d] Imidazol-2-yl) pyridin-2-amine; 2- (6- (diethylamino) pyridin-3-yl) -1-((1-ethyl-1H-pyrazol-3-yl ) Methyl) -1H-benzo [d] imidazole-7-carbonitrile; 2- (6- (diethylamino) pyridin-3-yl) -1-((1-ethyl-1H-pyrazole -3-yl) methyl) -1H-benzo [d] imidazole-5-carbonitrile; 2- (6- (diethylamino) pyridin-3-yl) -1-((1-ethyl- 1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-4-carbonitrile; 2- (6- (diethylamino) pyridin-3-yl) -1-((1 -Ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-4-carboxamide; N, N-diethyl-5- (1-((1-ethyl -1H-pyrazol-3-yl) methyl) -5-methyl-1H-benzo [d] imidazol-2-yl) pyridin-2-amine; 5- (5-chloro-1-(( 1- 1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine; N, N-diethyl- 5- (1-((1-ethyl-1H-pyrazol-3-yl) methyl) -7-methyl-1H-benzo [d] imidazol-2-yl) pyridin-2-amine; N , N-diethyl-5- (1-((1-ethyl-1H-pyrazol-3-yl) methyl) -4-methoxy-1H-benzo [d] imidazol-2-yl ) Pyridine-2-amine; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-ethyl-1H -Pyrazol-3-yl) methyl) -4- (trifluoromethyl) -1H-benzo [d] imidazole; (2- (6- (diethylamino) pyridin-3-yl) -1 -((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazol-5-yl) boronic acid; (S) -1- (2- (tertiary butoxy ) Ethyl) -2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole; 1- (2- (tertiary butoxy ) Ethyl) -2- (6-((2S, 5R) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole; 1- ( 2- (tertiary butoxy) ethyl) -2- (6- (diethylamino) pyridin-3-yl) -1H-benzo [d] imidazole-5-carboxylic acid methyl ester; 1- (2 -(Tertiary butoxy) ethyl) -2- (6- (diethylamino) pyridin-3-yl) -1H-benzo [d] imidazole-5-carboxamide; 1- (2- (Tertiary butoxy) ethyl) -N- (cyclopropylmethyl) -2- (6- (diethylamino) ) Pyridin-3-yl) -1H-benzo [d] imidazol-5-carboxamide; 1- (2- (tertiary butoxy) ethyl) -2- (6- (diethylamino) Pyridine-3-yl) -N- (2-hydroxyethyl) -1H-benzo [d] imidazol-5-carboxamide; 5- (1- (2- (tertiary butoxy) ethyl) 4-Chloro-1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine; 5- (1- (2- (tertiary butoxy) ethyl) -4- (trifluoromethyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine; 5- (5-bromo-1- (2- ( Tertiary butoxy) ethyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine; (1- (2- (tertiary butoxy) Ethyl) -2- (6- (diethylamino) pyridin-3-yl) -1H-benzo [d] imidazol-5-yl) boronic acid; 5- (1- (2- (tertiary butoxy (Yl) ethyl) -5- (1H-pyrazol-3-yl) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine; 5- (1 -(2- (tertiary butoxy) ethyl) -5-fluoro-1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine; 5- (1 -(2- (tertiary butoxy) ethyl) -4-fluoro-1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridine-2-amine; 1- (2 -(Tertiary butoxy) ethyl) -2- (6- (diethylamino) pyridin-3-yl) -1H-benzo [d] imidazole-4-carbonitrile; 1- (2- ( Tertiary butoxy) ethyl) -2- (6- (diethylamino) pyridin-3-yl) -1H- Benzo [d] imidazole-4-carboxamide; N, N-diethyl-5- (1- (2-isopropoxyethyl) -1H-benzo [d] imidazol-2-yl) Pyridine-2-amine; 5- (4-chloro-1- (2-isopropoxyethyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridine-2 -Amine; 2- (6- (diethylamino) pyridin-3-yl) -1- (2-isopropoxyethyl) -1H-benzo [d] imidazole-5-carboxamide; ( S) -1- (2-isopropoxyethyl) -2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-5 -Formamidine; (S) -1- (2-isopropoxyethyl) -2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] Imidazole-5-carboxamide; 4-chloro-2- (6- (diethylamino) pyridin-3-yl) -1- (2-isopropoxyethyl) -1H-benzo [d] Imidazole-5-carboxamide; 5- (4-chloro-1- (2-isopropoxyethyl) -5- (morpholinylmethyl) -1H-benzo [d] imidazole -2-yl) -N, N-diethylpyridin-2-amine; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl ) -1- (2-ethoxyethyl) -1H-benzo [d] imidazole; 2- (6-((2S, 5R) -2,5-dimethylpyrrolidin-1-yl) pyridine -3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] imidazole; (S) -1- (2-ethoxyethyl) -2- (6- (2 -Methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole 1- (2-ethoxyethyl) -2- (1-ethyl-2,2-dimethyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridine-5- Yl) -1H-benzo [d] imidazole; 7- (1- (2-ethoxyethyl) -1H-benzo [d] imidazol-2-yl) -4-ethyl-3-methyl -3,4-dihydro-2H-pyrido [3,2-b] [1,4] ; 5- (1- (2-ethoxyethyl) -1H-benzo [d] imidazol-2-yl) -N-ethyl-N- (2,2,2-trifluoroethyl) pyridine -2-amine; 5- (4-chloro-1- (2-ethoxyethyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridine-2-amine ; (2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -4-methyl -1H-benzo [d] imidazol-5-yl) boronic acid; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl)- 3- (2-ethoxyethyl) -3H- [1,2] oxaborolo [4 ', 3': 3,4] benzo [1,2-d ] Imidazole-6 (8H) -alcohol; 4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- ( 2-ethoxyethyl) -1H-benzo [d] imidazole; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -5-fluoro-1H-benzo [d] imidazole; 5- (5-bromo-4-chloro-1- (2-ethoxyethyl) -1H -Benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine; (4-chloro-2- (6- (diethylamino) pyridin-3-yl) -1 -(2-ethoxyethyl) -1H-benzo [d] imidazol-5-yl) boronic acid; 5-bromo-4-chloro-2- (6-((2S, 5S) -2,5- Dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] imidazole; (4-chloro-2- (6 -((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] imidazole- 5-yl) boronic acid; 5- (5-bromo-4-chloro-1- (2-ethoxyethyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethyl -3-fluoropyridine-2-amine; (4-chloro-2- (6- (diethylamino) -5-fluoropyridin-3-yl) -1- (2-ethoxyethyl) -1H -Benzo [d] imidazol-5-yl) boronic acid; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- ( 2-ethoxyethyl) -4- (trifluoromethyl) -1H-benzo [d] imidazole; 5- (5-bromo-1- (2-ethoxyethyl) -1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridin-2-amine; (2- (6- (diethylamino) pyridin-3-yl) -1- (2-ethoxy Ethyl) -1H-benzo [d] imidazol-5-yl) boronic acid; (S)-(1- (2-ethoxyethyl) -2- (6- (2-methylpyrrolidine-1) -Yl) pyridin-3-yl) -1H-benzo [d] imidazol-5-yl) boronic acid; 5-bromo-2- (6-((2S, 5S) -2,5-dimethylpyrrolidine -1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] imidazole; (2- (6-((2S, 5S) -2,5- Dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] imidazol-5-yl) boronic acid; 2- (6- ( (2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl ) -5,6-difluoro-1H-benzo [d] imidazole; (S) -1- (2-ethoxyethyl) -4-fluoro-2- (6- (2-methylpyrrole) Pyridin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridine- 3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] imidazole-5-carboxylic acid methyl ester; 2- (6-((2S, 5S) -2,5-dimethyl Pyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -N-methyl-1H-benzo [d] imidazole-5-carboxamide; (S) -1- (2-ethoxyethyl) -6-fluoro-2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole; 5- (3- (2-ethoxyethyl) -3H-imidazo [4,5-b] pyridin-2-yl) -N, N-diethylpyridin-2-amine; 2- (6 -((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3- (2-ethoxyethyl) -N-methyl-3H-imidazo [4,5-b] pyridine-6-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3- (2-ethoxyethyl) -7-methyl-3H-imidazo [4,5-b] pyridine; (2- (6- (diethylamino) pyridin-3-yl) -3- ( 2-ethoxyethyl) -3H-imidazo [4,5-b] pyridin-6-yl) boronic acid; (2- (6-((2S, 5S) -2,5-dimethylpyrrole -1-yl) pyridin-3-yl) -3- (2-ethoxyethyl) -3H-imidazo [4,5-b] pyridine- 6-yl) boronic acid; (2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3- (2-ethoxyethyl ) -7-methyl-3H-imidazo [4,5-b] pyridin-6-yl) boronic acid; 5- (4-chloro-1- (2-propoxyethyl) -1H-benzo [ d] imidazol-2-yl) -N, N-diethylpyridine-2-amine; 5- (4-chloro-1- (2- (cyclopentyloxy) ethyl) -1H-benzo [d ] Imidazol-2-yl) -N, N-diethylpyridine-2-amine; 5-bromo-4-chloro-1- (2- (2,2-difluoroethoxy) ethyl) -2 -(6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole; (4-chloro-1- (2 -(2,2-difluoroethoxy) ethyl) -2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H -Benzo [d] imidazol-5-yl) boronic acid; 4-chloro-1- (2- (2,2-difluoroethoxy) ethyl) -2- (6-((2S, 5S)- 2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole; N, N-diethyl-5- (1-((2-ethyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-2-yl) pyridin-2-amine; 4-ethyl-7- (1-((2-ethyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-2-yl) -3-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1, 4] ; 4-ethyl-7- (1-((2-ethyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-2-yl) -3,3-dimethyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] ; 2-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-1-yl ) Methyl) -4-ethyl Azole; 4-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-1- (Methyl) methyl) -2-ethyl Azole; 2- (4-ethyl-3-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] -7-yl) -1-((2-ethyl Azole-4-yl) methyl) -N-methyl-1H-benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrole Pyridin-1-yl) pyridin-3-yl) -1-((2-ethyl Azole-4-yl) methyl) -N-methyl-1H-benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrole Pyridin-1-yl) pyridin-3-yl) -1-((2-ethyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-5-carboxamide; (2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1- Yl) pyridin-3-yl) -1-((2-ethyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-5-yl) metanol; N-((2- (6-((2S, 5S) -2,5-dimethyl Pyrrolidin-1-yl) pyridin-3-yl) -1-((2-ethyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-5-yl) methyl) -2,2,2-trifluoroethylamine; (S) -1-((1-methyl -1H-pyrazol-3-yl) methyl) -2- (6- (2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole; N, N -Diethyl-5- (1-((2-ethyl-1H-imidazol-4-yl) methyl) -1H-benzo [d] imidazol-2-yl) pyridin-2-amine; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((2-ethyl-1H-imidazol-4-yl) methyl ) -1H-benzo [d] imidazole; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((4- Ethyl-1H-imidazol-2-yl) methyl) -1H-benzo [d] imidazole; N, N-diethyl-5- (1-((3-ethyl-1H-1,2, 4-triazol-5-yl) methyl) -1H-benzo [d] imidazol-2-yl) pyridin-2-amine; N, N-diethyl-5- (1-((2-ethyl Thiazol-4-yl) methyl) -1H-benzo [d] imidazol-2-yl) pyridin-2-amine; N, N-diethyl-5- (1- ( Azol-2-ylmethyl) -1H-benzo [d] imidazol-2-yl) pyridin-2-amine; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidine- 1-yl) pyridin-3-yl) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole; 2- (6-((2S , 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -N-methyl-1-((1-methyl-1H-pyrazol-3-yl) methyl ) -1H-benzo [d] imidazole-5-carboxamide; 2- (4-ethyl-3,3-dimethyl-3,4-dihydro-2H-pyrido [3,2-b ] [1,4] -7-yl) -N-methyl-1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((1-methyl-1H-pyrazol-3-yl) methyl Yl) -1H-benzo [d] imidazole-5-carboxamide; 2- (4-ethyl-3,3-dimethyl-3,4-dihydro-2H-pyrido [3,2- b] [1,4] -7-yl) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazol-5-carboxamide; 2- (1-ethyl -2,2-dimethyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-5-yl) -N-methyl-1-((1-methyl-1H- Pyrazol-3-yl) methyl) -1H-benzo [d] imidazol-5-carboxamide; 2- (1-ethyl-2,2-dimethyl-2,3-dihydro-1H -Pyrrolo [2,3-b] pyridin-5-yl) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5- Formamidine; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -N-methyl-1-((2-methyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-5-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl ) Pyridin-3-yl) -4-fluoro-N-methyl-1-((2-methyl Azole-4-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl ) Pyridin-3-yl) -4-fluoro-1-((2-methyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-5-carboxamide; 5-bromo-2- (6-((2S, 5S) -2,5-dimethylpyrrolidine -1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -4-fluoro-1H-benzo [d] imidazole; 2- (6-((2S, 5S) -2 , 5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -4-fluoro-N-methyl-1H-benzo [d] imidazole- 5-formamidine; (2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl ) -1H-benzo [d] imidazol-5-yl) methanol; 2- (6- (diethylamino) pyridin-3-yl) -N-methyl-3-((1-methyl-1H -Pyrazol-3-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-carboxamide; 2- (6-((2S, 5S) -2,5-dimethyl Pyrrolidin-1-yl) pyridin-3-yl) -N-methyl-3-((1-methyl-1H-pyrazol-3-yl) methyl) -3H-imidazo [4,5- b) pyridine-6-formamidine; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3-((1-methyl -1H-pyrazol-3-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-carboxamide; 2- (1-ethyl-2,2-dimethyl- 2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-5-yl) -N-methyl-3-((1-methyl-1H-pyrazol-3-yl) methyl ) -3H-imidazo [4,5-b] pyridine-6-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) Pyridin-3-yl) -1-((3-ethyl-1H-1,2,4-triazol-5-yl) methyl) -1H-benzo [d] imidazole; 4-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -5-((methylsulfonyl) methyl) -1H-benzo (d ] Imidazol-1-yl) methyl) -2-ethyl Azole; 2- (4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxy (Ethyl) -1H-benzo [d] imidazol-5-yl) -6-methyl-1,3,6,2-dioxazepine-4,8-dione; 1- (2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((2-ethyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-5-yl) -2,2,2-trifluoroethanol; N- (2- (6-((2S, 5S) -2 , 5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] imidazol-5-yl) acetamidinium; R) -2- (4-ethyl-3-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] -7-yl) -N-methyl-3-((2-methyl Azole-4-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidine -1-yl) pyridin-3-yl) -N-methyl-3-((2-methyl Azole-4-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-carboxamide; (4-chloro-2- (6-((2S, 5S) -2,5- Dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((2-methyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-5-yl) boronic acid; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl ) Pyridin-3-yl) -1- (2-ethoxyethyl) -N-((1r, 3S) -3-hydroxycyclobutyl) -1H-benzo [d] imidazole-5-carboxamidine Amine; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -N-methyl Oxy-1H-benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -N- (2-hydroxyethyl) -1H-benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5S)- 2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -N- (2- (methylsulfonyl) ethyl) -1H- Benzo [d] imidazole-5-carboxamide; N-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl)- 1- (2-ethoxyethyl) -1H-benzo [d] imidazol-5-yl) methyl) -2- (methylsulfonyl) ethylamine; 4-((2- (6- ( (2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] imidazole-5- (Yl) methyl) morpholin; (4-chloro-1- (2-ethoxyethyl) -2- (4-ethyl-3,3-dimethyl-3,4-dihydro-2H -Pyrido [3,2-b] [1,4] -7-yl) -1H-benzo [d] imidazol-5-yl) boronic acid; 5- (1- (2-ethoxyethyl) -1H-benzo [d] imidazol-2-yl)- N, N-diethylpyridine-2-amine; 5- (1- (2-ethoxyethyl) -7-methoxy-1H-benzo [d] imidazol-2-yl) -N, N-diethylpyridine-2-amine; N, N-diethyl-5- (1-((2-methyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-2-yl) pyridin-2-amine; 2- (6-((2S, 5S) -2,5-dimethylpyrrole -1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] imidazol-5-amine; N- (2- (6-((2S, 5S ) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1- (2-ethoxyethyl) -1H-benzo [d] imidazol-5-yl) methanesulfonate Amidoamine; 4- (2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -3-((1-methyl-1H- Pyrazol-3-yl) methyl) -3H-imidazo [4,5-b] pyridin-6-yl) morpholin; (R) -2- (4-ethyl-3-methyl-3 , 4-dihydro-2H-pyrido [3,2-b] [1,4] -7-yl) -N-methyl-3-((1-methyl-1H-pyrazol-3-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-formamidine Amine; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((2-methyl Azole-4-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl ) Pyridin-3-yl) -3-((2-methyl Azole-4-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-carboxamide; 2- (4-ethyl-3,3-dimethyl-3,4-di Hydrogen-2H-pyrido [3,2-b] [1,4] -7-yl) -N-methyl-3-((1-methyl-1H-pyrazol-3-yl) methyl) -3H-imidazo [4,5-b] pyridine-6-formamidine Amine; (4-chloro-2- (4-ethyl-3,3-dimethyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] -7-yl) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazol-5-yl) boronic acid; (4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-((2-ethyl Azole-4-yl) methyl) -1H-benzo [d] imidazol-5-yl) boronic acid; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl ) Pyridin-3-yl) -4-fluoro-N-methyl-1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5- Formamidine; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-1-((1-methyl- 1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidine- 1-yl) pyridin-3-yl) -3-((2-methyl-1H-imidazol-4-yl) methyl) -3H-imidazo [4,5-b] pyridine; 2- (6- ((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -6-fluoro-3-((1-methyl-1H-pyrazol-3-yl) (Methyl) -3H-imidazo [4,5-b] pyridine; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl)- 3-((1-methyl-1H-pyrazol-3-yl) methyl) -3H-imidazo [4,5-b] pyridine; 2- (6- (diethylamino) pyridine-3- Yl) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide; 2- (6- (diethylamino) ) Pyridin-3-yl) -N-methyl-1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide; N, N-diethyl-5- (1-((tetrahydrofuran-2-yl) methyl) -1H-benzo [d] imidazol-2-yl) pyridin-2-amine (S) -N, N-diethyl-5- (1-((tetrahydrofuran-2-yl) methyl) -1H-benzo [d] imidazol-2-yl) pyridin-2-amine; N, N-diethyl-5- (1- (3- (pyrimidin-5-yl) benzyl) -1H-benzo [d] imidazol-2-yl) pyridin-2-amine; 2- (6- (Diethylamino) pyridin-3-yl) -N-methyl-1- (3- (pyrimidin-5-yl) benzyl) -1H-benzo [d] imidazole-5-carboxamide; (S) -2-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-7-methoxy -1H-benzo [d] imidazol-1-yl) methyl) morpholin; (S) -2-((2- (6-((2S, 5S) -2,5-dimethylpyrrole -1-yl) pyridin-3-yl) -4-fluoro-7-methoxy-1H-benzo [d] imidazol-1-yl) methyl) -4-methylmorpholin; (S) -2-((4-fluoro-7-methoxy-2- (6-((S) -2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] Imidazol-1-yl) methyl) morpholin; (S) -2-((2- (6-((2S, 4S) -2,4-dimethylazepine-1-yl) pyridine-3 -Yl) -4-fluoro-7-methoxy-1H-benzo [d] imidazol-1-yl) methyl) morpholin; 2- (6-((2S, 5S) -2,5- Dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1-((((S) -4-methylmorpholin-2-yl) methyl) -1H-benzene Benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy -N-methyl-1-(((S) -4-methylmorpholin-2-yl) methyl) -1H-benzo [d] imidazole-5-carboxamide; 2- (6- ((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -N-ethyl-7-methoxy-1-((((S) -morpholin 2-yl) methyl) -1H-benzo [d] imidazol-5-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) Pyridine-3-yl) -N-ethyl-7-methoxy-1-((((S) -4-methylmorpholin-2-yl) methyl) -1H-benzo [d] imidazole 5-formamidine; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-1-(((S ) -Morpholin-2-yl) methyl) -1H-benzo [d] imidazol-7-ol; (S) -2-((4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-1-yl) methyl) morpholin; (S) -2-(( 4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-1-yl) (Methyl) -4-methylmorpholin; (S) -2-((7-methoxy-2- (6-((S) -2-methylpyrrolidin-1-yl) pyridine-3 -Yl) -1H-benzo [d] imidazol-1-yl) methyl); (S) -2-((2- (6-((2S, 5S) -2,5-dimethylpyrrole -1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [d] imidazol-1-yl) methyl) morpholin; (2S, 6S) -2-((2- (6-((2S, 5S) -2,5-dimethyl Pyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [d] imidazol-1-yl) methyl) -6-methylmorpholine; (2S, 6S ) -2-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [ d) imidazol-1-yl) methyl) -4,6-dimethylmorpholin; 1-(((22,6S) -4,6-dimethylmorpholin-2-yl) methyl ) -2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-N-methyl-1H-benzo (d) Imidazole-5-carboxamide; 1-((((2S, 6S) -4,6-dimethylmorpholin-2-yl) methyl) -2- (6-((2S, 5S ) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [d] imidazol-5-carboxamide; (S) -2- ((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-fluoro-1H-benzo [d] imidazole-1- (Methyl) methyl) morpholin; (S) -2-((2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl)- 7-fluoro-1H-benzo [d] imidazol-1-yl) methyl) -4-methylmorpholine; (S) -2-((4-chloro-2- (6-((S) 2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-1-yl) methyl) morpholin; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -N-ethyl-3-((1-methyl-1H-pyrazol-3-yl) methyl) -3H - Zolo [4,5-b] pyridine-6-carboxamide; N- (2,2-difluoroethyl) -2- (6-((2S, 5S) -2,5-dimethylpyrrole Pyridin-1-yl) pyridin-3-yl) -3-((1-methyl-1H-pyrazol-3-yl) methyl) -3H-imidazo [4,5-b] pyridine-6- Formamidine; 1-(((R) -1,4-di Alk-2-yl) methyl) -2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7- (methoxy- d3) -1H-benzo [d] imidazole; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7- (methoxy -D3) -1- (pyridine 2-ylmethyl) -1H-benzo [d] imidazole; N-ethyl-7-methoxy-1-((((S) -4-methylmorpholin-2-yl) methyl ) -2- (6-((S) -2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-5-carboxamide; 1- (2- Ethoxyethyl) -2- (6- (ethyl (2,2,2-trifluoroethyl) amino) pyridin-3-yl) -7-methoxy-1H-benzo [d] Imidazole-5-carboxamide; 1- (2-ethoxyethyl) -2- (6- (ethyl (2,2,2-trifluoroethyl) amino) pyridin-3-yl)- 7-methoxy-N-methyl-1H-benzo [d] imidazole-5-carboxamide; 1- (2-ethoxyethyl) -2- (6- (ethyl (2,2 , 2-trifluoroethyl) amino) pyridin-3-yl) -7-hydroxy-1H-benzo [d] imidazole-5-carboxamide; 1- (2-ethoxyethyl) -2 -(6- (ethyl (2,2,2-trifluoroethyl) amino) pyridin-3-yl) -7-hydroxy-N-methyl-1H-benzo [d] imidazole-5-methyl Fluorenamine; N, N-diethyl-5- (5-methoxy-1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole 2-yl) pyridine-2-amine; 2- (6- (diethylamino) pyridin-3-yl) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazol-5-ol; 4- (2- (2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridine-3- ) -4-fluoro-7-methoxy-1H-benzo [d] imidazol-1-yl) ethyl) piperyl -2-one; 4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -1-(((S)- Morpholin-2-yl) methyl) -1H-benzo [d] imidazol-7-ol; (R) -6-((2- (6-((2S, 5S) -2,5-di Methylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [d] imidazol-1-yl) methyl) morpholin-3-one; 2-(( 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [d] imidazole-1- (Methyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine ; (R) -7-methoxy-1-((1-methyl-1H-pyrazol-3-yl) methyl) -2- (6- (2- (trifluoromethyl) pyrrolidine- 1-yl) pyridin-3-yl) -1H-benzo [d] imidazole; (R) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -2- (6 -(2- (trifluoromethyl) pyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-7-ol; 2- (6-((2S, 5S) -2 , 5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -N-ethyl-4-fluoro-7-methoxy-1-(((S) -morpholin-2-yl ) Methyl) -1H-benzo [d] imidazole-5-carboxamide; N-ethyl-4-fluoro-7-methoxy-1-(((S) -4-methylmorpholin 2-yl) methyl) -2- (6-((S) -2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-5-carboxamidine Amine; 1-(((R) -1,4-di Alk-2-yl) methyl) -2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -N-methyl-1H- Benzo [d] imidazole-5-carboxamide; 4- (2- (4-chloro-2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridine -3-yl) -1H-benzo [d] imidazol-1-yl) ethyl) piper -2-one; N-ethyl-4-fluoro-7-methoxy-2- (6-((S) -2-methylpyrrolidin-1-yl) pyridin-3-yl) -1- ((((S) -morpholin-2-yl) methyl) -1H-benzo [d] imidazol-5-carboxamide; 3-((2- (6-((2S, 5S) -2 , 5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [d] imidazol-1-yl) methyl) morpholin; (R)- 7-methoxy-N-methyl-1-((1-methyl-1H-pyrazol-3-yl) methyl) -2- (6- (2- (trifluoromethyl) pyrrolidine- 1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-5-carboxamide; (S) -2- (6- (4,4-difluoro-2-methylpyrrolidine- 1-yl) pyridin-3-yl) -7-methoxy-1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole; 2- (6-((2S, 4S) -4-fluoro-2-methylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1-((1-methyl-1H-pyridine Azole-3-yl) methyl) -1H-benzo [d] imidazole; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl ) -7-methoxy-1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazole; 4- (2- (2- (6- ( ((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H-benzo [d] imidazol-1-yl) ethyl) Morpholin; 2- (2- (2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -7-methoxy-1H -benzene [d] Imidazol-1-yl) ethoxy) eth-1-ol; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl ) -1-((1-methyl-1H-pyrazol-3-yl) methyl) -1H-benzo [d] imidazol-7-amine; 4-fluoro-7-methoxy-1- ( ((S) -4-methylmorpholin-2-yl) methyl) -2- (6-((S) -2-methylpyrrolidin-1-yl) pyridin-3-yl) -1H -Benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro -7-methoxy-1- (2-morpholinylethyl) -1H-benzo [d] imidazole-5-carboxamide; 2- (6-((2S, 5S) -2,5 -Dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-7-methoxy-N-methyl-1- (2-morpholinylethyl) -1H-benzo [d] Imidazole-5-carboxamide; 2- (6-((2S, 5S) -2,5-dimethylpyrrolidin-1-yl) pyridin-3-yl) -4-fluoro-7- Methoxy-1-(((S) -4-methylmorpholin-2-yl) methyl) -1H-benzo [d] imidazol-5-carboxamide; and N, N-diethyl 5- (1-((6- (pyrimidin-5-yl) pyridin-2-yl) methyl) -1H-benzo [d] imidazol-2-yl) pyridin-2-amine; or a pharmaceutical thereof Acceptable salt.     A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.         A therapeutically effective amount of a compound as described in any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating cancer and precancerous syndrome in a mammal in need thereof Of its purpose.         For example, the application in the scope of patent application No. 8 wherein the mammal is a human.         According to the application of the scope of the patent application, the cancer is selected from the group consisting of: brain cancer (glioma), glioblastoma, astrocytoma, pleomorphic glioblastoma, Bannayan-Zonana syndrome , Cowden disease, Lhermitte-Duclos disease, breast cancer, colorectal cancer, head and neck cancer, kidney cancer, lung cancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, Glucagonoma, insulinoma, metastatic melanoma, prostate cancer, sarcoma, and thyroid cancer.         A use of a compound of formula (Ib) or a pharmaceutically acceptable salt thereof as described in item 1 of the scope of patent application for the manufacture of a medicament for treating cancer.         A therapeutically effective amount of a compound of formula Ib, or a pharmaceutically acceptable salt thereof, as described in item 1 of the scope of the patent application for the manufacture of reduced MYC protein (c-MYC) and / or cells in mammals in need thereof Use of a medicament for inhibiting p300 / CBP tissue protein acetamyl transferase.         For example, the application of the scope of patent application No. 12 wherein the mammal is a human.         An effective amount of a) a compound of formula (Ib) or a pharmaceutically acceptable salt thereof as described in item 1 of the scope of the patent application; and b) at least one antitumor agent for manufacture in a mammal in need thereof Use of medicaments for treating cancer.         The use according to item 14 of the scope of patent application, wherein the at least one antitumor agent is selected from the group consisting of: anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomers Enzyme II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormone analogs, signaling pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeutics; pro-apoptosis Agents (proapoptotic agents); inhibitors of cell cycle messaging; proteasome inhibitors; and cancer metabolism inhibitors.         A pharmaceutical combination according to item 14 of the scope of patent application, which is used for treatment.         The use of a pharmaceutical combination as described in item 14 of the scope of patent application is for the preparation of a medicament for treating cancer.         According to the application of the scope of patent application No. 8, wherein the cancer is selected from the group consisting of: brain cancer (glioma), glioblastoma, astrocytoma, glioblastoma multiforme, Bannayan-Zonana syndrome , Cowden disease, Lhermitte-Duclos disease, breast cancer, inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma, rhabdomyosarcoma, ependymal tumor, neurotubular tumor, colorectal cancer, head and neck cancer, kidney cancer, lung cancer, liver cancer , Melanoma, ovarian cancer, pancreatic cancer, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, metastatic melanoma, prostate cancer, sarcoma, osteosarcoma, giant bone cells Tumor, thyroid cancer, lymphocytic T-cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy cell leukemia, acute lymphocytic leukemia, acute myeloid leukemia, chronic neutrophilic leukemia, acute lymphoblastic T-cell leukemia, Plasmacytoma, immunoblastic large cell leukemia, adventitial cell leukemia, multiple myeloma megakaryoblastic leukemia (Multiple my eloma Megakaryoblastic leukemia), multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, red blood cell leukemia, malignant lymphoma, hodgkins lymphoma, non-Hodgkin's lymph Tumor, lymphoblast T-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urinary epithelial cancer, lung cancer, vulvar cancer, cervical cancer, endometrial cancer, kidney cancer, Mesothelioma, esophageal cancer, salivary adenocarcinoma, hepatocellular carcinoma, gastric cancer, nasopharyngeal cancer, buccal cancer, oral cancer, GIST (Gastrointestinal Stromal Tumor), and testicular cancer.         For example, the application in the scope of patent application No. 18, wherein the mammal is a human.         A method for preparing a pharmaceutical composition containing a pharmaceutically acceptable excipient and an effective amount of a compound of formula (Ib) or a pharmaceutically acceptable salt thereof as described in item 1 of the patent application scope. Comprising incorporating a compound of formula (Ib) or a pharmaceutically acceptable salt thereof into a pharmaceutically acceptable excipient.         According to the application of the scope of application patent No. 8, wherein the precancerous syndrome is selected from the group consisting of cervical intraepithelial neoplasia, unidentified single gamma globulin (MGUS), myelodysplastic syndrome, aplastic anemia, Cervical lesions, skin moles (pre-melanoma), prostate intraepithelial tumors (intraductal) neoplasia (PIN), ductal carcinoma in situ (DCIS), colon polyps, and severe hepatitis or cirrhosis.         For example, the use of item 14 of the patent application scope, wherein the at least one antitumor agent is pazopanib.         Use of a therapeutically effective amount of a compound of formula Ib or a pharmaceutically acceptable salt thereof as described in item 1 of the scope of the patent application for the manufacture of a medicament for the treatment of ocular nitrile disease in a human in need thereof.         A pharmaceutical composition comprising 0.5 to 1,000 mg of a compound or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 4 of the patent application scope, and 0.5 to 1,000 mg of a pharmaceutically acceptable excipient Shape agent.         A therapeutically effective amount of a compound of formula Ib or a pharmaceutically acceptable salt thereof as described in item 1 of the scope of the patent application for the manufacture of a p300 / CBP tissue protein acetamyltransferase inhibitor in a mammal in need thereof Use of active medicaments.         For example, the application of the scope of the patent application No. 25, wherein the mammal is a human.         A therapeutically effective amount of a compound as described in any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for treating a disease selected from the following disease states in a mammal in need thereof Uses: cardiac hypertrophy, diabetes, obesity and non-alcoholic fatty liver disease, HIV, polycystic kidney disease, inflammatory diseases, joint adhesion spondylitis, psoriasis, psoriasis arthritis, rheumatoid arthritis, Crohn's disease , And multiple sclerosis.         For example, the application of the scope of patent application No. 27, wherein the mammal is a human.         An effective amount of a) a compound of formula (Ib) or a pharmaceutically acceptable salt thereof as described in item 1 of the scope of the patent application; and b) at least one other active compound for use in the manufacture of a treatment in a subject in need thereof Use of a medicament selected from the following disease states: cardiac hypertrophy, diabetes, obesity and non-alcoholic fatty liver disease, HIV, polycystic kidney disease, inflammatory disease, joint adhesion spondylitis, psoriasis, psoriasis arthritis, quasi Rheumatoid arthritis, Crohn's disease, and multiple sclerosis.         A therapeutically effective amount of a compound of formula Ib or a pharmaceutically acceptable salt thereof as described in item 1 of the scope of patent application for the manufacture of a medicament for reducing MYC protein (c-MYC) in cells in mammals in need thereof Of its purpose.         For example, the application of the scope of the patent application No. 25, wherein the mammal is a human.