KR20230081459A - Novel 3-pyridine and 4-phenylpyridine derivatives substituted with heterocyclics and uses thereof - Google Patents

Abstract

The present invention relates to novel heterocyclic substituted 3-phenylpyridine and 4-phenylpyridine derivatives and uses thereof, and compositions containing the 3-phenylpyridine and 4-phenylpyridine derivatives as active ingredients can treat cancer It can be used for various medicinal purposes such as myelofibrosis, acquired immune deficiency syndrome, graft-versus-host disease, Weaver syndrome, psoriasis and liver fibrosis.

Description

Novel 3-phenylpyridine and 4-phenylpyridine derivatives substituted with heterocyclics and uses thereof

The present invention relates to novel heterocyclic substituted 3-phenylpyridine and 4-phenylpyridine derivatives and their medicinal uses.

Epigenetics is a phenomenon in which gene expression patterns and activity of gene expression are changed according to the structure of chromatin without DNA sequence change, and this is inherited to the next generation. There are several forms such as DNA acetylation, methylation, ubiquitylation, and phosphorylation, among which DNA methylation is the best known (Waddington, CH. 1959; Waddington, CH. 2012). Histone methyltransferases (HMTs) are a family of enzymes that control selective methylation at specific amino acid sites in histones, and covalent modifications of histones, such as methylation, control changes in the chromatin structure of eukaryotic DNA, resulting in genetic changes in gene expression. causes It is known that histone modifications play an important role in epigenetic transcription control and induce cancer by regulating the expression of cancer-inducing genes and cancer-suppressing genes as well as disease development and progression. As a result, it can be used for the treatment of diseases such as cancer through selective inhibition of related enzymes (Lai, W. et al. 2017).

Polycomb group (PcG) proteins are known as proteins that change the structure of histones by methylating or attaching ubiquitin to specific histone parts that make up the chromatin structure, and as a result, transcription of specific genes. is known as a transcriptional repressor because it is not disclosed (Morey, L. et al. 2010; Schuettengruber, B. et al. 2007). PcG proteins form two well-conserved complexes in eukaryotes, and are divided into polycomb repressive complex 1 (PRC1) and polycomb repressive complex 2 (PRC2). In PRC1, BMI-1, CBX2, RING1A/B, and EDR1 (PHC1) form a complex, and in PRC2, EZH1 or EZH2, EED, SUZ12 and RbAP46/48 form a complex (Sparmann, A. et al. 2006; Nakayama , T. et al. 2009). The PRC2 complex catalyzes mono-trimethylation of H3K27, resulting in chromatin compaction and gene repression. PRC2 is an epigenetic regulator of transcription and plays a role in various biological processes such as stem cell maintenance, DNA repair, and epithelial-mesenchymal transition (EMT) (Dimou, A. et al. 2017).

EZH2 (Enhancer of zeste homolog 2) is a major catalytic subunit of polycomb repressive complex 2 (PRC2) that promotes the methylation of histone H3 lysine 27 (H3K27) having a SET domain. It is regulated by the EED subunit through an allosteric activation mechanism of EZH2 methyltransferase activity (Simon, JA. et al. 2008). It is known that the mammalian genome encodes EZH1 and EZH2, PRC2-EZH1 has low histone methyltransferase activity, but PRC2-EZH2 has high H3K27 methyltransferase activity (Yamagishi, M. et al. 2019 ; Shen, X. et al. 2008; Margueron, R. et al. 2008). In addition to PRC-2-dependent H3K27 methylation, EZH2 methylates non-histone protein substrates, including the transcription factor GATA4, and methylates non-histone targets or directly interacts with other proteins to regulate downstream genes in a PRC2-independent manner. (He, A. et al. 2012; Kim, E. et al. 2013; Xu, K. et al. 2012)

In this way, EZH2 acts as a key regulator of cell cycle progression, autophagy and apoptosis, promotes DNA damage repair, inhibits cellular senescence, and plays important roles in cell lineage determination and relative signaling pathways. (Nutt, SL. et al. 2020; Yao, Y. et al. 2016; Ito, T. et al. 2018). EZH2 is phosphorylated at the 21st serine by Akt, and the phosphorylated EzH2 methylates STAT3 to activate the STAT3 signaling pathway (Kim, E. et al. Cancer Cell 2013; 23(6):839-852 ). Because EZH2 functions in these diverse biological processes, it is implicated in many diseases, including cancer.

EZH2 overexpression is also known to be associated with myelofibrosis, acquired immune deficiency syndrome (HIV), graft-versus-host disease (GVHD), Weaver Syndrome, psoriasis vulgaris, and liver fibrosis (Aljubran, SA et al. 2012; Barosi G. 2012; He, S. et al. 2012; Zhang, P. et al. 2011). Mutations altering EZH2 tyrosine 641 (e.g., Y641C, Y641F, Y641N, Y641S and Y641H) were observed in up to 22% of diffuse large B-cell lymphomas and 7% of follicular lymphomas (FL) (Morin, RD et al. 2010), mutations in alanine 677 (A677) and alanine 687 (A687) have also been reported (McCabe, M. et al. 2012; Majer, C. et al. 2012). EZH2 activating mutations alter substrate specificity, leading to H3K27 trimethylation.

EZH2 is involved in prostate cancer (Varambally, S. et al. 2002), breast cancer (Bachmann, IM. et al. 2006; Kleer, CG. et al. 2003) esophageal cancer (Qiu, BQ. et al. 2020), and anaplastic thyroid cancer. (Pellecchia, S. et al. 2020), nasopharyngeal cancer (Fan, DC. et al. 2020), gastric cancer (Gan, L. et al. 2018), bladder cancer (Tang, SH. et al. 2014), lung cancer ( Murai, F. et al. 2015), liver cancer (Kondo, Y. et al. 2007), ovarian cancer (Lu, C. et al. 2007), endometrial cancer (Krill, L. et al. 2020; Zhou, J. et al. 2013), melanoma (Bachmann, IM. et al. 2006), renal cancer (Wagener, N et al. 2010), and myeloma (Tremblay-LeMay, R. et. al. 2018; Li, B et al. 2019) and lymphoma (McCabe, M. et al. 2012), and is overexpressed in a wide range of cancers, and plays a role as an oncogene. High expression of EZH2 is associated with poor cancer prognosis.

EZH2 overexpression is known to promote cancer metastasis by inducing epithelial to mesenchymal transition (EMT) and inducing angiogenesis by increasing vimentin, a mesenchymal cell marker, and decreasing E-cadherin, an epithelial cell marker. (Ma, J. et al. 2018; Lu C. et al. 2010).

EZH2 is expressed in both cancer cells and immune cells, and expression of EZH2 in cancer cells can suppress cancer immunity. EZH2 expression has been reported to negatively interact with CD8+ T cells in ovarian cancer, and it has been reported that inhibition of EZH2 increases anticancer immune responses in glioblastoma (GBM) (Peng, D. et al. 2015; Yin, Y. et al. 2017).

Many cancer patients develop drug resistance after treatment with various drugs, including chemotherapy, resulting in poor treatment efficacy. One of the various drug resistance mechanisms is EZH2 overexpression. It has been reported that drug resistance by platinum treatment, Cisplatin, lung cancer treatment Gefitinib, and breast cancer treatment Tamoxifen, which are used as primary treatment for ovarian cancer, are related to EZH2 expression (Sun, J et al. 2019; Liu, X. et al. 2019; Wu, Y. et al. 2018).

Therefore, pharmacological inhibition of EZH2 can be applied as a targeted therapy for treating various diseases as well as cancer, and therapeutic effects can be expected through combination therapy with previously developed chemotherapy, targeted anticancer agents, or immunotherapeutic agents.

International Patent Publication WO 2012-142504 A1 (published on 2012.10.18.)

Waddington CH. Canalization of development and genetic assimilation of acquired characters. Nature 1959;183:1654-1655. Waddington CH. The epigenotype 1942. Int J Epidemiol 2012;41:10-13. Lai W, Pugh B. Understanding Nucleosome Dynamics and their Links to Gene Expression and DNA Replication. Nat Rev Mol Cell Biol. 2017;18:548-562. Morey L, Helin K. Polycomb group protein-mediated repression of transcription. Trends Biochem Sci 2010;35:323-332. Schuettengruber B, Chourrout D, Vervoort M, Leblanc B, Cavalli G. Genome regulation by polycomb and trithorax proteins. Cell 2007;128:735-745. Sparmann A, van Lohuizen M. Polycomb silencers control cell fate, development and cancer. Nat Rev Cancer 2006;6:846-856. Nakayama T, Yamashita M. Critical role of the polycomb and trithorax complexes in the maintenance of CD4 T cell memory. Semin Immunol 2009;21:78-83. Dimou A, Dincmana T, Evannob E, Gemmilla R, Rochec J, Drabkin H. Epigenetics during EMT in lung cancer: EZH2 as a potential therapeutic target. Cancer Treat Res Commun 2017;12:40-48. Simon JA, Lange CA. Roles of the EZH2 histone methyltransferase in cancer epigenetics. Mutat Res 2008;647(1-2):21-29. Yamagishi M, Hori M, Fujikawa D, Ohsugi T, Honma D, Adachi N, et al. Targeting excessive EZH1 and EZH2 activities for abnormal histone methylation and transcription network in malignant lymphomas. Cell Rep 2019;29: 2321-2337. Shen X, Liu Y, Hsu YJ, Fujiwara Y, Kim J, Mao X, et al. EZH1 mediates methylation on histone H3 lysine 27 and complements EZH2 in maintaining stem cell identity and executing pluripotency. Mol Cell 2008;32:491-502. Margueron R, Li G, Sarma K, Blais A, Zavadil J, Woodcock CL, et al. Ezh1 and Ezh2 maintain repressive chromatin through different mechanisms. Mol Cell 2008;32:503-518. He A, Shen X, Ma Q, Cao J, von Gise A, Zhou P, et al. PRC2 directly methylates GATA4 and represses its transcriptional activity. Genes Dev 2012;26(1):37-42. Kim E, Kim M, Woo DH, Shin Y, Shin J, Chang N, et al. Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells. Cancer Cell 2013;23(6):839-852. Xu K, Wu ZJ, Groner AC, He HH, Cai C, Lis RT, et al. EZH2 oncogenic activity in castration-resistant prostate cancer cells is Polycomb independent. Science 2012;338(6113):1465-1469. Nutt SL, Keenan C, Chopin M, Allan RS. EZH2 function in immune cell development. Biol Chem 2020;401(8):933-943. Yao Y, Hu H, Yang Y, Zhou G, Shang Z, Yang X, et al. Downregulation of enhancer of zeste homolog 2 (EZH2) is essential for the induction of autophagy and apoptosis in colorectal cancer cells. Genes (Basel) 2016;7:10. Ito T, Teo YV, Evans SA, Neretti N, Sedivy JM. Regulation of cellular senescence by Polycomb chromatin modifiers through distinct DNA damage-and histone methylation-dependent pathways. Cell Rep 2018;22(13):3480-3492. Aljubran SA, Ruan C, Parthasarathy PT, Ramanathan GK, Rajanbabu V, Bao H, et al. Enhancer of Zeste Homolog 2 Induces Pulmonary Artery Smooth Muscle Cell Proliferation. PLoS One 2012;7(5):e37712. Barosi G. Emerging targeted therapies in myelofibrosis. Expert Rev Hematol 2012 Jun;5(3):313-324. He S, Wang J, Kato K, Xie F, Varambally S, Mineishi S, et al. Inhibition of histone methylation arrests ongoing graft-versus-host disease in mice by selectively inducing apoptosis of alloreactive effector T cells. Blood. 2012;119(5):1274-1282. Zhang P, Su Y, Zhao M, Huang W, Lu Q. Abnormal histone modifications in PBMCs from patients with psoriasis vulgaris. Eur J Dermatol 2011;21(4):552-557. Morin RD, Johnson NA, Severson T, Mungall A, An J, Goya R, et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet 2010;42(2):181-185. McCabe M, Graves A, Ganji G, Diaz E, Halsey W, Jiang Y, et al. Mutation of A677 in histone methyltransferase EZH2 in human B-cell lymphoma promotes hypertrimethylation of histone H3 on lysine 27 (H3K27). Proc Natl Acad Sci USA 2012;109(8):2989-2994. Majer C, Jin L, Scott M, Knutson S, Kuntz K, Keilhack H, et al. A687V EZH2 is a gain-of-function mutation found in lymphoma patients. FEBS Lett 2012;586(19):3448-3451. Varambally S, Dhanasekaran SM, Zhou M, Barrette TR, Kumar-Sinha C, Sanda MG, et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 2002;419(6907):624-629. Bachmann IM, Halvorsen OJ, Collett K, Stefansson IM, Straume O, Haukaas SA, et al. EZH2 expression is associated with high proliferation rate and aggressive tumor subgroups in cutaneous melanoma and cancers of the endometrium, prostate, and breast. J Clin Oncol 2006;24(2):268-273. Kleer CG, Cao Q, Varambally S, Shen R, Ota I, Tomlins SA, et al. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc Natl Acad Sci USA 2003;100:11606-11611. Qiu BQ, Lin XH, Ye XD, Huang W, Pei X, Xiong D, et al. Long non-coding RNA PSMA3-AS1 promotes malignant phenotypes of esophageal cancer by modulating the miR-101/EZH2 axis as a ceRNA. Aging (Albany NY). 2020;12(2):1843-1856. Pellecchia S, Sepe R, Decaussin-Petrucci M, Ivan C, Shimizu M, Coppolaet C, et al. The long non-coding RNA Prader Willi/Angelman Region RNA5 (PAR5) is downregulated in anaplastic thyroid carcinomas where it acts as a tumor suppressor by reducing EZH2 activity. Cancers (Basel) 2020;12(1):E235. Fan DC, Zhao YR, Qi H, Hou JX, Zhang TH. MiRNA-506 presents multiple tumor suppressor activities by targeting EZH2 in nasopharyngeal carcinoma. Auris Nasus Larynx 2020;47(4):632-642. Gan L, Xu M, Hua R, Tan C, Zhang J, Gong Y, et al. The polycomb group protein EZH2 induces epithelial-mesenchymal transition and pluripotent phenotype of gastric cancer cells by binding to PTEN promoter. J Hematol Oncol 2018;11(1):9. Tang SH, Huang HS, WuHU, Tsai YT, Chuang MJ, Yu CP, et al. Pharmacologic down-regulation of EZH2 suppresses bladder cancer in vitro and in vivo. Oncotarget 2014;5:10342-10355. Murai F, Koinuma D, Shinozaki-Ushiku A, Fukayama M, Miyaozono K, Ehata S. EZH2 promotes progression of small cell lung cancer by suppressing the TGF-β-Smad-ASCL1 pathway. Cell Discov 2015;1:15026. Kondo Y, Shen L, Suzuki S, Kurokawa T, Masuko K, Tanaka Y, et al. Alterations of DNA methylation and histone modifications contribute to gene silencing in hepatocellular carcinomas. Hepatol Res 2007;37:974-983. Lu C, Bonome T, Li Y, Kamat AA, Han LY, Schmandt R, et al. Gene alterations identified by expression profiling in tumor-associated endothelial cells from invasive ovarian carcinoma. Cancer Res 2007;67:1757-1768. Krill L, Deng W, Eskander R, Mutch D, Zweizig S, Hoang B, et al. Overexpression of enhance of Zeste homolog 2 (EZH2) in endometrial carcinoma: An NRG Oncology/ Gynecologic Oncology Group Study. Gynecol Oncol 2020;156(2):423-429. Zhou J, Roh JW, Bandyopadhyay S, Chen Z, Munkarah AR, Hussein Y, et al. Overexpression of enhancer of zeste homolog 2 (EZH2) and focal adhesion kinase (FAK) in high grade endometrial carcinoma. Gynecol Oncol 2013;128:344-348. Wagener N, Macher-Goeppinger S, Pritsch M, Husing J, Hoppe-Seyler K, Schirmacher P, et al. Enhancer of zeste homolog 2 (EZH2) expression is an independent prognostic factor in renal cell carcinoma. BMC Cancer 2010;10:524. Tremblay-LeMay R, Rastgoo N, Pourabdollah M, Chang H. EZH2 as a therapeutic target for multiple myeloma and other haematological malignancies. Biomark Res 2018;6:34. Li B, Chng WJ. EZH2 abnormalities in lymphoid malignancies: underlying mechanisms and therapeutic implications. J Hematol Oncol 2019;12(1):118. McCabe M, Ott H, Ganji G, Korenchuk S, Thompson C, Aller G. et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 2012;492(7427):108-112. Ma J, Zhang J, Weng YC, Wang JC. EZH2-mediated microRNA-139-5p regulates epithelial-mesenchymal transition and lymph node metastasis of pancreatic cancer. Mol Cell 2018;41(9):868-880. Lu C, Han HD, Mangala LS, Ali-Fehmi R, Newton CS, Ozbun L, et al. Regulation of tumor angiogenesis by EZH2. Cancer Cell 2010;18(2):185-197. Peng D, Kryczek I, Nagarsheth N, Zhao L, Wei S, Wang W, et al. Epigenetic silencing of TH1-type chemokines shapes tumor immunity and immunotherapy. Nature. 2015; 527(7577):249-253. Yin Y, Qiu S, Li X, Huang B, Xu Y, Peng Y. EZH2 suppression in glioblastoma shifts microglia toward M1 phenotype in tumor microenvironment. J Neuroinflammation 2017;14(1):220. Sun J, Cai X, Yung MM, Zhou W, Li J, Zhang Y, et al. miR-137 mediates the functional link between c-Myc and EZH2 that regulates cisplatin resistance in ovarian cancer. Oncogene 2019;38(4):564-580. Liu X, Lu X, Zhen F, Jin S, Yu T, Zhu Q, et al. LINC00665 induces acquired resistance to Gefitinib through recruiting EZH2 and activating PI3K/AKT pathway in NSCLC. Mol Ther Nucleic Acids 2019;16:155-161. Wu Y, Zhang Z, Cenciarini ME, Proietti CJ, Amasino M, Hong T, et al. Tamoxifen resistance in breast cancer is regulated by the EZH2-ERα-GREB1 transcriptional axis. Cancer Res. 2018; 78(3):671-684.

An object of the present invention is to provide novel heterocyclic substituted 3-phenylpyridine and 4-phenylpyridine derivatives and uses thereof.

The present invention relates to compounds of formula 1 consisting of 3-phenylpyridine and 4-phenylpyridine derivatives, or their enantiomers, diastereomers, stereoisomers, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof. .

[Formula 1]

In the above formula,

A is a bond, -CH ₂ -, or -C(O)-;

,

,

,

또는

이며;B is

,

,

,

or

is;

또는

이며;C is

or

is;

D is independently CH or N;

E is independently CH or N;

R ₁ is independently hydrogen or (C ₁ -C ₆ )alkyl;

R ₂ is hydrogen or (C ₁ -C ₆ )alkyl;

R ₃ , R ₄ are independently hydrogen, substituted or unsubstituted (C ₁ -C ₆ )alkyl, substituted or unsubstituted (C ₃ -C ₁₀ )cycloalkyl, substituted or unsubstituted (C ₃ -C ₁₀ )heterocycloalkyl, substituted or unsubstituted (C ₃ -C ₁₀ )aryl, or substituted or unsubstituted (C ₃ -C ₁₀ )heteroaryl,

The substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl means that one or more hydrogens in the chain or ring are independently halogen, amino, -Boc, (C ₁ -C ₆ )alkyl, halo(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy or halo(C ₁ -C ₆ )alkoxy;

R ₅ is independently substituted or unsubstituted phenyl;

the substituted phenyl is substituted with hydrogen, halogen, halo(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy;

R ₆ is hydrogen, halogen, halo(C ₁ -C ₆ )alkyl, or (C ₁ -C ₆ )alkoxy;

R ₇ is hydrogen, (C ₁ -C ₆ )alkyl or benzyl;

m is an integer of 0 or 1;

n is an integer from 0 to 2; and

p is an integer from 0 to 4;

In the present invention, in Formula 1, R ₃ and R ₄ are substituted or unsubstituted (C ₃ -C ₁₀ )heterocycloalkyl,

The substituted heterocycloalkyl is such that at least one hydrogen in the ring is independently halogen, amino, -Boc, (C ₁ -C ₆ )alkyl, halo(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy or A compound that is an enantiomer, diastereomer, stereoisomer, hydrate, solvate, prodrug or pharmaceutically acceptable salt thereof, characterized by being substituted with halo(C ₁ -C ₆ )alkoxy.

The 3-phenylpyridine and 4-phenylpyridine derivative compounds of the present invention were prepared by the same methods as in Scheme 1 to Scheme 5 below.

[Scheme 1]

[Scheme 2]

[Scheme 3]

[Scheme 4]

[Scheme 5]

In addition, in the present invention, the compound represented by Formula 1 is a compound characterized in that it is any one selected from the group of compounds or its enantiomer, diastereomer or stereoisomer, hydrate, solvate, prodrug or pharmaceutical thereof. It relates to acceptable salts.

tert-Butyl 4-(5-(3-(2-(2-(benzyloxy)-4,6-dimethylpyridin-3-yl)-4-(4-fluorophenyl)-1H-imidazole-1 -carbonyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (Compound 1-3);

tert-Butyl 4-(5-(3-(2-(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-4-(4-fluorophenyl)-1H- Imidazole-1-carbonyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (Compound 1- 5);

3-(1-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methyl-5-(6-(piperazin-1-yl)pyridin-3-yl)benzoyl) -4-(4-fluorophenyl)-1H-imidazol-2-yl)-4,6-dimethylpyridin-2(1H)-one hydrochloride (Compound 1-7);

tert-Butyl 4-(5-(3-(2-(2-(benzyloxy)-4,6-dimethylpyridin-3-yl)-1H-benzo[d]imidazole-1-carbonyl)-5 -(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (Compound 1-4);

tert-Butyl 4-(5-(3-(2-(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-1H-benzo[d]imidazole-1-car Bornyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (Compound 1-6);

3-(1-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methyl-5-(6-(piperazin-1-yl)pyridin-3-yl)benzoyl) -1H-benzo[d]imidazol-2-yl)-4,6-dimethylpyridin-2(1H)-one hydrochloride (Compound 1-8);

tert-Butyl 4-(5-(3-((2-(2-(benzyloxy)-4,6-dimethylpyridin-3-yl)-4-(4-fluorophenyl)-1H-imidazole- 1-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (Compound 2-7) ;

tert-Butyl 4-(5-(3-((2-(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-4-(4-fluorophenyl)-1H -imidazol-1-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (compound 2-11);

3-(1-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methyl-5-(6-(piperazin-1-yl)pyridin-3-yl)benzyl) -4-(4-fluorophenyl)-1H-imidazol-2-yl)-4,6-dimethylpyridin-2(1H)-one hydrochloride (Compound 2-14);

tert-Butyl 4-(5-(3-((2-(2-(benzyloxy)-4,6-dimethylpyridin-3-yl)-1H-imidazo[4,5-c]pyridin-1- yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (Compound 2-8);

tert-Butyl 4-(5-(3-((2-(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-1H-imidazo[4,5-c] Pyridin-1-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (Compound 2- 12);

tert-butyl 4-(5-(3-((2-(2-(benzyloxy)-4,6-dimethylpyridin-3-yl)-1H-benzo[d]imidazol-1-yl)methyl) -5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (Compound 2-9);

tert-Butyl 4-(5-(3-((2-(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-1H-benzo[d]imidazole-1- yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (Compound 2-13);

3-(1-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methyl-5-(6-(piperazin-1-yl)pyridin-3-yl)benzyl) -1H-benzo[d]imidazol-2-yl)-4,6-dimethylpyridin-2(1H)-one hydrochloride (Compound 2-15);

tert-Butyl 4-(5-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-5-((2-(methylthio)-4-(4-(tri) Fluoromethyl)phenyl)-1H-imidazol-1-yl)methyl)phenyl)pyridin-2-yl)piperazine-1-carboxylate (Compound 2-10);

tert-butyl 4-(5-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(4-(4-fluorophenyl)-1H-imidazol-2-yl) -4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (Compound 3-8);

tert-Butyl 4-(5-(3-(1-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-4-(4-fluorophenyl)-1H-imi Dazol-2-yl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (Compound 3-9) ;

tert-Butyl 4-(5-(3-(1-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-(4-fluorophenyl) -1H-imidazol-2-yl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (compound 3-10);

3-((2-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methyl-5-(6-(piperazin-1-yl)pyridin-3-yl)phenyl )-4-(4-fluorophenyl)-1H-imidazol-1-yl)methyl)-4,6-dimethylpyridin-2(1H)-one hydrochloride (Compound 3-11);

tert-Butyl 4-(5-(3-((2-(2-(benzyloxy)-4,6-dimethylpyridin-3-yl)-4,4-dimethyl-4,5-dihydroimidazole- 1-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (Compound 5-5) ; and

tert-Butyl 4-(5-(3-((2-(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-4,4-dimethyl-4,5-di Hydroimidazol-1-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (Compound 5-6).

In addition, the following terms in the present invention have the following meanings unless otherwise indicated. Any term not defined has an art-understood meaning.

The term “alkyl” refers to a single-bonded straight or branched hydrocarbon group having 1 to 20 carbon atoms and preferably 1 to 6 carbon atoms, and includes methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, tert-butyl, 1-methylpropyl, pentyl and hexyl.

The term “alkoxy” refers to an oxygen group to which a single bonded straight or branched saturated hydrocarbon having 1 to 20 carbon atoms and preferably 1 to 6 carbon atoms is bonded, and includes methoxy, ethoxy, propoxy, n-butoxy, tert-butoxy, and 1-methylpropoxy.

The term “Boc” means tert-butoxycarbonyl.

The terms “halo” and “halogen” are used in their conventional sense to refer to fluoro, chloro, bromo or iodo substituents.

The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms of the alkyl group have been replaced with a halo group, and the alkyl and halo groups are as defined above.

The term “haloalkoxy” refers to an alkoxy group in which one or more hydrogen atoms of the alkoxy group have been replaced with a halo group, and halo and alkoxy are as defined above.

The terms "cycle" and "ring" refer to a substituted or aromatic group which may be substituted or unsubstituted and/or may or may not contain heteroatoms, and may be a monocycle, bicycle, polycycle, or spirocycle. refers to the

The term “cycloalkyl” refers to a saturated hydrocarbon group having a single bond in a ring shape. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[3.1.1]heptyl, spiro[4.5]decyl, spiro[5.5]undecyl, adamantyl, nor Bonil etc. are mentioned.

The term “aryl” refers to an aromatic substituent having at least one ring having a covalent pi electron system, and includes phenyl, benzyl, naphthyl, anthryl, indanyl, biphenyl, triphenyl, and the like.

The term "heterocycloalkyl" refers to a ring-shaped single-bond saturated hydrocarbon group containing one or more heteroatoms such as N, O, or S, and depends on the number and type of heteroatoms included in the ring and the number of carbon atoms. Ridinyl, pyrrolidinyl, piperidinyl, oxopiperidinyl, morpholinyl, piperazinil, oxopiperazinyl, morpholinyl, thiomorpholinyl, azepanil, diazepanil, oxazepanil, thia Zephanil, dioxothiazepanil, azetidinyl, azocanyl, tetrahydrofuranil, tetrahydroisoquinolinyl, tetrahydropyranil, tetrahydrobenzo[b]thiophenyl, oxazolidinyl, dioxanil, dioxolanil, azaspiro[5.5]undecanyl, azaspiro[3,3]heptanyl, or azaspiro[3.5]nonanyl; and the like.

The term "heteroaryl" refers to an aromatic ring compound containing one or more heteroatoms such as N, O, or S, and depending on the number and type of heteroatoms included in the ring and the number of carbon atoms, pyridyl, pyrrolyl, Rolidinyl, pyridinyl, furanyl, quinolidinyl, indolyl, pyrimidinyl, imidazolyl, 1,2,4-triazolyl, tetrazolyl, pyranyl, thiophenyl, thiazolyl, dibenzothiophenyl , dibenzofuranyl, dibenzoselenophene, thiophene, benzofuran, benzothiophenyl, benzoselenophenyl, carbazolyl, indolocarbazolyl, pyridylindolyl, pyrrolodipyridinyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, oxatriazolyl, dioxazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, triazinyl, oxazinyl, oxathiazinyl, Oxadiazinyl, indolyl, benzimidazolyl, indazolyl, indoxazolinyl, benzoxazolinyl, benzisoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cinolinyl, quinazolinyl, quinoxalinyl , naphthyridinyl, phthalazinyl, pteridinyl, xanthenyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, benzofuropyridinyl, furodipyridinyl, benzothienopyridinyl, thie nordipyridinyl, benzoselenophenopyridinyl and selenophenodipyridinyl; and the like.

Furthermore, the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All such compounds and diastereomers are included within the scope of the present invention.

In the present invention, the pharmaceutically acceptable salt means a salt or complex of Formula 1 having a desired biological activity. Examples of such salts include, but are not limited to, acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), and acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid , salts formed with organic acids such as benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, naphthalene disulfonic acid, and poly-galacturonic acid. The compounds may also be administered as pharmaceutically acceptable quaternary salts known to those skilled in the art, in particular chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxyl rates (e.g., benzoates, succinates, acetates, glycolates, maleates, malates, fumarates, citrates, tartrates, ascorbates, cinamoates, mandeloates and diphenylacetate). The compound of Formula 1 of the present invention may include not only pharmaceutically acceptable salts, but also all salts, hydrates, solvates, and prodrugs that can be prepared by conventional methods.

The acid addition salt according to the present invention can be prepared by a conventional method, for example, a precipitate formed by dissolving a derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile, etc., and adding an organic or inorganic acid thereto It may be prepared by filtering and drying, or by distilling the solvent and excess acid under reduced pressure, drying it, and crystallizing it in an organic solvent.

In addition, a pharmaceutically acceptable metal salt may be prepared using a base. An alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare a sodium, potassium or calcium salt as the metal salt. Corresponding salts are also obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).

The present invention provides a therapeutically effective amount of the compound represented by Formula 1, or an enantiomer, diastereomer, stereoisomer, hydrate, solvate, prodrug or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier thereof. It relates to a pharmaceutical composition for inhibiting EZH2 (Enhancer of zeste homolog 2) comprising.

In addition, the composition for inhibiting EZH2 (Enhancer of zeste homolog 2) relates to a pharmaceutical composition characterized in that for preventing or treating cancer, myelofibrosis, acquired immune deficiency syndrome, graft-versus-host disease, Weaver syndrome, psoriasis and liver fibrosis.

The cancer means solid cancer or blood cancer, and the solid cancer means brain cancer, brain tumor, benign astrocytoma, malignant astrocytoma, pituitary adenoma, meningioma, brain lymphoma, oligodendroglioma, intracranial race, ependymoma, brainstem tumor, head and neck tumor, Glioma, glioblastoma, laryngeal cancer, oropharyngeal cancer, nasal cancer, nasopharyngeal cancer, salivary gland cancer, hypopharynx cancer, tonsil cancer, thyroid cancer, oral cancer, esophageal cancer, eye cancer, chest tumor, small cell lung cancer, non-small cell lung cancer, thymus cancer, lung adenocarcinoma , lung cancer, lung squamous cell carcinoma, pleural cancer, mediastinal tumor, breast cancer, male breast cancer, abdominal tumor, stomach cancer, gastric mastoid, liver cancer, hepatoblastoma, gallbladder cancer, biliary tract cancer, pancreatic cancer, small intestine cancer, colorectal cancer, colon cancer, rectal cancer, Duodenal cancer, anal cancer, bladder cancer, kidney cancer, renal pelvic cancer, heart cancer, peritoneal cancer, adrenal cancer, spinal cord cancer, bone cancer, sexual genital tumor, penile cancer, prostate cancer, female genital tract tumor, cervical cancer, endometrial cancer, ovarian cancer , uterine sarcoma, vaginal cancer, female external genital cancer, female urethral cancer, or skin cancer, but is not particularly limited thereto. In addition, the blood cancer may be selected from the group consisting of acute myelogenous leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, childhood lymphoma, malignant lymphoma, multiple myeloma, or aplastic anemia, but is not particularly limited thereto.

The pharmaceutical composition according to the present invention may be formulated in a suitable form together with a generally used pharmaceutically acceptable carrier. "Pharmaceutically acceptable" refers to a composition that is physiologically acceptable and does not usually cause allergic reactions such as gastrointestinal disorders, dizziness, etc., or similar reactions when administered to humans. In addition, the composition may be formulated and used in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories and sterile injection solutions according to conventional methods.

Carriers, excipients and diluents that may be included in the composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl paraoxybenzoate, propyl paraoxybenzoate, talc, magnesium stearate, and mineral oil, but is not limited thereto. When formulated, it is prepared using diluents or excipients such as commonly used fillers, stabilizers, binders, disintegrants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations include at least one excipient in the compound of the present invention, for example, starch, microcrystalline cellulose, sucrose or lactose, It is prepared by mixing low-substituted hydroxypropyl cellulose, hypromellose, and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, solutions for oral use, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, aromatics, and preservatives may be included. . Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried formulations, and suppositories. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending agents. As a base for suppositories, witepsol, macrogol, tween 61, cacao butter, laurin paper, glycerol, gelatin, and the like may be used. In order to formulate a formulation for parenteral administration, the 3-phenylpyridine and 4-phenylpyridine derivative compounds of Formula 1 or their pharmaceutically acceptable salts are sterilized or used as preservatives, stabilizers, hydration agents or emulsifiers, or salts for osmotic pressure control. Alternatively, it may be mixed in water with adjuvants such as buffers and other therapeutically useful substances to prepare a solution or suspension, which may be prepared in an ampoule or vial unit dosage form.

A pharmaceutical composition comprising the compound of Formula 1 disclosed in the present invention as an active ingredient may be administered to mammals such as rats, livestock, and humans through various routes. All modes of administration are contemplated, eg oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine intrathecal or intracerebrovascular injection. The dose depends on the age, sex, and weight of the subject to be treated, the specific disease or pathological condition to be treated, the severity of the disease or pathological condition, the time of administration, the route of administration, the absorption, distribution and excretion rate of the drug, the type of other drug used, and the prescription It will depend on judgment, etc. Determination of dosage based on these factors is within the level of those skilled in the art, and generally dosages range from 0.01 mg/kg/day to approximately 2000 mg/kg/day. A more preferred dosage is 1 mg/kg/day to 500 mg/kg/day. Administration may be administered once a day, or may be administered in several divided doses. The dosage is not intended to limit the scope of the present invention in any way.

In addition, the pharmaceutical composition of the present invention can be used alone or in combination with methods using surgery, hormone therapy, chemotherapy, and biological response modifiers for the prevention or treatment of cancer.

The present invention relates to novel heterocyclic substituted 3-phenylpyridine and 4-phenylpyridine derivatives and their medicinal uses. It can be used as a composition for prevention or treatment of myelofibrosis, acquired immune deficiency syndrome, graft-versus-host disease, Weaver's syndrome, psoriasis, and liver fibrosis.

Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the embodiments described herein and may be embodied in other forms. Rather, the disclosure herein is provided so that it will be thorough and complete, and will fully convey the spirit of the invention to those skilled in the art.

<Example 1. Synthesis of compound and confirmation of physical and chemical properties>

The synthesis process of the compounds 1-1 to 5-6 of the present invention is as follows.

Prior to the above, compounds 1-1 to 1-8 were prepared according to Scheme 1 above.

tert-Butyl 4-(5-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(methoxycarbonyl)-4-methylphenyl)pyridin-2-yl)piperazin- Preparation of 1-carboxylate (Compound 1-1)

Compound 1-1 was prepared according to a known patent method (WO2012142504A1).

5-(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-3-yl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2 -Preparation of methylbenzoic acid (Compound 1-2)

Compound 1-2 was prepared according to a known patent method (WO2012142504A1).

tert-Butyl 4-(5-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(methoxycarbonyl)- in MeOH/THF (1:2=7:12 mL) A solution of 4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (1000 mg, 1.856 mmol) and 3N-NaOH (6.19 mL, 18.56 mmol) was stirred at 55 °C for 21 h. The reaction mixture was cooled to 0° C., concentrated under reduced pressure, and the pH was adjusted to a range of 3-4 by adding 1N HCl solution. The reaction mixture was diluted with ethyl acetate and water, extracted with ethyl acetate (x3), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatogram (DCM: MeOH = 30:1) to give compound 1-2 (428 mg, 25.6%).

tert-Butyl 4-(5-(3-(2-(2-(benzyloxy)-4,6-dimethylpyridin-3-yl)-4-(4-fluorophenyl)-1H-imidazole-1 Preparation of -carbonyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (Compound 1-3)

5-(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-3-yl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2 - A solution of methylbenzoic acid (100 mg, 0.190 mmol) in DCM (2 ml) was cooled to 0 °C. Oxalyl chloride (25 uL, 0.285 mmol), DMF (1 drop) were added and stirred for 3.5 hours. The reaction mixture was concentrated at low temperature under reduced pressure and evaporated in vacuo. To the remaining solution in DCM (1 ml) and Et3N (80 uL, 0.570 mmol) was added 2-(benzyloxy)-3-(4-(4-fluorophenyl)-1H-imine in DCM (1 ml) at 0 °C. A solution of dazol-2-yl)-4,6-dimethylpyridine (71 mg, 0.190 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with H ₂ O, NaHCO ₃ and ethyl acetate at 0 °C, extracted with ethyl acetate (x3), washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatogram (DCM: MeOH = 40:1) to give compound 1-3 (98 mg, 58.6%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.23 (m, 1H), 7.81 (m, 2H), 7.63 (s, 1H), 7.43 (m, 1H), 7.13 - 7.04 (m, 9H), 6.63 ( d, J = 8.5 Hz, 1H), 6.51 (s, 1H), 5.31 (m, 1H), 5.09 (m, 1H), 3.97 (m, 1H), 3.58 (s, 8H), 3.33 (m, 2H) ), 3.08 (m, 2H), 2.96 (m, 1H), 2.31 (s, 3H), 2.22 (s, 3H), 2.16 (s, 3H), 1.67 (m, 4H), 1.49 (s, 9H) , 0.89 (t, J = 6.9 Hz, 3H)

tert-Butyl 4-(5-(3-(2-(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-4-(4-fluorophenyl)-1H- Imidazole-1-carbonyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (Compound 1- 5) Manufacture of

tert-Butyl 4-(5-(3-(2-(2-(benzyloxy)-4,6-dimethylpyridin-3-yl)-4-(4-fluorophenyl)- in MeOH (1 ml) 1H-imidazole-1-carbonyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (88 mg 0.1 mmol) and 10% Pd/C (10 mg, 0.01 mmol) was charged with N ₂ . A balloon filled with H ₂ was then fitted. The mixture was stirred at room temperature (25° C.) for 17 hours. Pd/C was removed with a Celite filter. The solvent was evaporated in vacuo and the residue was separated by flash column chromatogram (DCM:MeOH = 40:1) to give compounds 1-5 (48 mg, 58%).

¹ H NMR (600 MHz, CDCl ₃ ) δ 8.26 (s, 1H), 7.79 (m, 2H), 7.56 (m, 2H), 7.30 (m, 2H), 7.07 (t, J = 8.4 Hz, 2H) , 6.64 (d, J = 8.4 Hz, 1H), 5.77 (s, 1H), 3.93 (m, 2H), 3.54 (s, 8H), 3.29 (t, J = 10.8 Hz, 2H), 3.04 (m, 2H), 2.97 (m, 1H), 2.36 (s, 3H), 2.17 (s, 3H), 1.98 (s, 3H), 1.63 (m, 4H), 1.48 (s, 9H), 0.81 (m, 3H) )

3-(1-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methyl-5-(6-(piperazin-1-yl)pyridin-3-yl)benzoyl) Preparation of -4-(4-fluorophenyl)-1H-imidazol-2-yl)-4,6-dimethylpyridin-2(1H)-one hydrochloride (Compound 1-7)

tert-Butyl 4-(5-(3-(2-(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-4- in anhydrous CH ₂ Cl 2 (2 _mL ) (4-fluorophenyl)-1H-imidazole-1-carbonyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine To a solution of -1-carboxylate (21.4 mg, 0.027 mmol) was added dropwise 4M HC in dioxane (0.4 mL)l at 0 °C. The resulting mixture was stirred at room temperature for 4.5 hours. The reaction mixture was concentrated under reduced pressure. The resulting solid was filtered, rinsed with diethyl ether (2 mL x 8), and concentrated in vacuo to give HCl salt compound 1-7 (14.2 mg, 72%).

¹ H NMR (600 MHz, CD ₃ OD) δ 8.61 (m, 2H), 8.33 (m, 2H), 7.96 (s, 1H), 7.90 (m, 2H), 7.59 (m, 1H), 7.29 (m , 2H), 6.33 (s, 1H), 4.30 (s, 1H), 4.10 (s, 5H), 3.98 (m, 3H), 3.62 (s, 3H), 3.51 (m, 7H), 2.72 (s, 3H), 2.36 (s, 3H), 2.29 (s, 3H), 1.07 (m, 3H)

tert-Butyl 4-(5-(3-(2-(2-(benzyloxy)-4,6-dimethylpyridin-3-yl)-1H-benzo[d]imidazole-1-carbonyl)-5 Preparation of -(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (Compound 1-4)

5-(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-3-yl)-3-(ethyl(tetrahydro-2H-pyran-4-) in DCM (2 ml) A solution of yl)amino)-2-methylbenzoic acid (80 mg, 0.1525 mmol) was cooled to 0°C. Add oxalyl chloride (20 uL, 0.2287 mmol), DMF (2 drops via syringe) and stir for 3.5 hours. The reaction mixture was concentrated at low temperature under reduced pressure and evaporated in vacuo. The remaining solution in DCM (1 ml) and Et ₃ N (64 uL, 0.4575 mmol) was 2-(2-(benzyloxy)-4,6-dimethylpyridin-3-yl) in DCM (1 ml) at 0 °C. -1H-benzo[d]imidazole (50 mg, 0.1525 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with H ₂ O, NaHCO ₃ and ethyl acetate at 0 °C, extracted with ethyl acetate (x3), washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatogram (DCM:MeOH = 40:1) to give compound 1-4 (32 mg, 25%).

^1H NMR (600 MHz, CDCl ₃ ) δ 8.39 (d, J = 2.4 Hz, 1H), 8.17 (d, J = 2.4 Hz, 2H), 8.90 (d, J = 1.8 Hz, 1H), 7.81 (d , J = 7.8 Hz, 1H), 7.68 (dd, J = 9.0, 2.4 Hz, 1H), 7.48 (d, J = 2.4 Hz, 1H), 7.39 (m, 1H), 7.25 (m, 1H), 7.12 (m, 3H) 7.05 (s, 1H), 6.69 (d, J = 9.0 Hz, 1H), 6.59 (brs, 1H), 6.42 (brs, 1H), 3.96 (m, 2H), 3.55 (s, 8H) ), 3.33 (m, 2H), 3.13 (m, 2H), 3.05 (m, 1H), 2.65 (s, 3H), 2.25 (s, 3H), 2.21 (s, 3H), 1.75 - 1.60 (m, 4H), 1.49 (s, 9H), 0.87 (t, J = 7.2 Hz, 3H).

tert-Butyl 4-(5-(3-(2-(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-1H-benzo[d]imidazole-1-car Preparation of bornyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (Compound 1-6)

tert-Butyl 4-(5-(3-(2-(2-(benzyloxy)-4,6-dimethylpyridin-3-yl)-1H-benzo[d]imidazole-1 in MeOH (3 ml) -carbonyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (26 mg 0.031 mmol) and 10 A solution of % Pd/C (3.3 mg, 0.003 mmol) was charged with N ₂ . A balloon filled with H ₂ was then fitted. The mixture was stirred at room temperature (25° C.) for 20 hours. Pd/C was removed with a Celite filter. The solvent was evaporated in vacuo and the residue was separated by flash column chromatogram (DCM:MeOH = 40:1) to give compound 1-6 (12.5mg, 54%).

¹ H NMR (600 MHz, CDCl ₃ ) δ 8.2 (s, 2H), 7.81 (d, J = 7.2 Hz, 2H), 7.47 (d, J = 9.0 Hz, 2H), 7.37-7.25 (m, 6H) , 6.56 (s, 1H), 3.90 (s, 4H), 3.51 (s, 8H), 3.26 (s, 4H), 3.01 (s, 2H), 2.92 (s, 1H), 2.00 (s, 3H), 1.27 (s, 6H), 1.26 (s, 9H).

3-(1-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methyl-5-(6-(piperazin-1-yl)pyridin-3-yl)benzoyl) Preparation of -1H-benzo[d]imidazol-2-yl)-4,6-dimethylpyridin-2(1H)-one hydrochloride (Compound 1-8)

tert-Butyl 4-(5-(3-(2-(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-1H- in anhydrous CH ₂ Cl 2 (2 _mL ) Benzo[d]imidazole-1-carbonyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (3.4 mg, 4.5 umol) was added 4M HCl in dioxane (0.3 mL) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The resulting solid was filtered, rinsed with diethyl ether (2 mL x 8), and concentrated in vacuo to give HCl salt compound 1-8 (2.3 mg).

Compounds 2-1 to 2-16 were prepared according to Scheme 2 above.

Preparation of 2-(benzyloxy)-3-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-4,6-dimethylpyridine (Compound 2-16)

2-(4-fluorophenyl)-2-oxoacetaldehyde hydrate (320 mg, 2.1 mmol), 2-(benzyloxy)-4,6 _- dimethylnicotinaldehyde (482 mg, 2.0 mmol) was added NH ₄ OAc (771 mg, 10 mmol) at room temperature. The resulting mixture was stirred at 50° C. for 20 hours. After cooling to room temperature, it was concentrated under reduced pressure. The resulting mixture was diluted with H ₂ O and CH ₂ Cl ₂ , extracted with CH ₂ Cl ₂ (X2), washed with saturated NaHCO ₃ , dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (CH ₂ Cl ₂ :CH ₃ OH = 19:1) to give compound 2-16 (392 mg, 52.5%).

¹ H NMR (600 MHz, CDCl ₃ ) δ 10.27 (s, 1H), 7.81 (s, 1H), 7.57 - 6.95 (m, 10H), 5.51 (s, 2H), 2.81 (s, 3H), 2.46 ( s, 3H)

tert-Butyl 4-(5-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(methoxycarbonyl)-4-methylphenyl)pyridin-2-yl)piperazin- Preparation of 1-carboxylate (Compound 2-1)

Compound 2-1 was prepared according to a known patent method (WO2012142504A1).

tert-Butyl 4-(5-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(hydroxymethyl)-4-methylphenyl)pyridin-2-yl)piperazine-1 -Preparation of carboxylate (Compound 2-2)

tert-butyl-4-(5-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(methoxycarbonyl)-4-methylphenyl)pyridine in anhydrous THF (4 mL) A solution of -2-yl)piperazine-1-carboxylate (570 mg, 1.058 mmol) was cooled to -78 °C. DIBAL-H (2.65 mL, 2.645 mmol) in THF 1M solution was added dropwise and the mixture was stirred at 0 °C for 3 h. The reaction mixture was quenched with K·Na·tartrate (1000 mg) in H ₂ O (3 mL) at -78 °C and the slurry was stirred at room temperature for 1 hour. The mixture was extracted with ethyl acetate (x3), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CH ₂ Cl ₂ :CH ₃ OH = 19:1) to give compound 2-2 (368 mg, 68%).

^1H NMR (600 MHz, CDCl ₃ ) δ 8.44 (d, J = 2.4 Hz, 1H), 7.73 (dd, J = 9.0, 2.4 Hz, 1H), 7.35 (d, J = 1.2 Hz, 1H), 7.26 (d, J = 1.2 Hz, 1H), 6.73 (d, J = 9.0 Hz, 1H), 4.78 (s, 2H), 3.97 (m, 2H), 3.59 (s, 8H), 3.35 (m, 2H) , 3.12 (m, 2H), 3.03 (m, 1H), 2.35 (s, 3H), 1.58 (s, 4H), 1.51 (s, 9H), 0.92 (t, J = 7.2 Hz, 3H)

tert-Butyl 4-(5-(3-(bromomethyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazin-1 -Preparation of carboxylate (Compound 2-4)

tert-butyl 4-(5-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(hydroxymethyl)-4-methylphenyl) in anhydrous CH ₂ Cl ₂ (7 mL) To a solution of pyridin-2-yl)piperazine-1-carboxylate (340 mg, 0.6658 mmol), triphenylphosphine (192 mg, 0.7324 mmol) and carbon tetrabromide (243 mg, 0.7324 mmol) were added at 0 °C. added. The resulting mixture was stirred overnight (ca. 20 hours) at ambient temperature. After cooling to room temperature, quench with H ₂ O at 0 °C, extract CH ₂ Cl ₂ (X2), dry over MgSO ₄ and concentrate under reduced pressure. The residue was purified by column chromatography (CH ₂ Cl ₂ :CH ₃ OH = 19:1) to give compound 2-4 (248 mg, 65%).

^1H NMR (400 MHz, CDCl ₃ ) δ 8.40 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.24 (s, 1H), 6.70 (d, J = 8.0 Hz, 1H), 4.57 (s, 2H), 3.95 (m, 2H), 3.56 (s, 8H), 3.32 (m, 2H), 3.08 (m, 2H), 2.98 (m, 1H), 2.39 (s, 3H), 1.68 ( m, 4H), 1.48 (s, 9H), 0.89 (t, J = 7.2 Hz, 3H)

tert-Butyl 4-(5-(3-((2-(2-(benzyloxy)-4,6-dimethylpyridin-3-yl)-4-(4-fluorophenyl)-1H-imidazole- 1-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (Compound 2-7) manufacture of

2-(benzyloxy)-3-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-4,6-dimethylpyridine (29 mg, 0.0785 mmol) in DMF (2.5 ml), A solution of CS ₂ CO ₃ (64mg, 0.1962mmol) was stirred at room temperature for 5 minutes. tert-Butyl 4-(5-(3-(bromomethyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1 - A solution of carboxylate (45 mg, 0.0785 mmol) in DMF (1 ml) was added to the reaction solution. The reaction mixture was stirred at 50 °C for 19 hours. After cooling to room temperature, quenched with H ₂ O (5 mL), extracted with EtOAc (X2), dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1 to 10:1) to give compound 2-7 (42 mg, 62%).

tert-Butyl 4-(5-(3-((2-(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-4-(4-fluorophenyl)-1H -imidazol-1-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (compound 2-11) Manufacture

tert-Butyl 4-(5-(3-((2-(2-(benzyloxy)-4,6-dimethylpyridin-3-yl)-4-(4-fluorophenyl)- in MeOH (2 mL) 1H-imidazol-1-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate ( 36 mg 0.0415 mmol) and 10% Pd/C (4.4 mg) was charged with N ₂ . A balloon filled with H ₂ was then fitted. The mixture was stirred at room temperature (25° C.) for 15 hours. Pd/C was removed with a Celite filter. The solvent was evaporated in vacuo and the residue was separated by flash column chromatogram (DCM:MeOH = 20:1) to give compound 2-11 (24.5 mg, 76%).

^1H NMR (600 MHz, CDCl ₃ ) δ 8.32 (s, 1H), 7.73 (t, J = 4.2 Hz, 2H), 7.59 (m, 1H), 7.23 (s, 1H), 7.15 (d, J = 4.2 Hz, 1H), 7.02 (m, 2H), 6.98 (s, 1H), 6.66 (m, 1H), 5.90 (s, 1H), 5.14 (s, 2H), 3.92 (d, J = 9.6 Hz, 2H), 3.53 (s, 8H), 3.30 (t, J = 11.4 Hz, 2H), 3.04 (m, 2H), 2.95 (m, 1H), 2.19 (s, 3H), 2.16 (s, 3H), 2.03 (s, 3H), 1.69 (m, 2H), 1.59 (m, 2H), 1.49 (s, 9H), 0.84 (m, 3H)

3-(1-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methyl-5-(6-(piperazin-1-yl)pyridin-3-yl)benzyl) Preparation of -4-(4-fluorophenyl)-1H-imidazol-2-yl)-4,6-dimethylpyridin-2(1H)-one hydrochloride (Compound 2-14)

tert-Butyl 4-(5-(3-((2-(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-4 in anhydrous CH ₂ Cl 2 ₍ 1.5 mL) -(4-fluorophenyl)-1H-imidazol-1-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl) To a solution of piperazine-1-carboxylate (13 mg, 0.01675 mmol) was added dropwise 4M HCl in dioxane (0.3 mL) at 0 °C. The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. The resulting solid was filtered, rinsed with diethyl ether (1 mL x 10), and concentrated in vacuo to give the HCl salt product compound 2-14 (7.6 mg, 64%).

tert-Butyl 4-(5-(3-((2-(2-(benzyloxy)-4,6-dimethylpyridin-3-yl)-1H-imidazo[4,5-c]pyridin-1- Preparation of yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (Compound 2-8)

2-(2-(benzyloxy)-4,6-dimethylpyridin-3-yl)-1H-imidazo[4,5-c]pyridine (33 mg, 0.1 mmol), CS ₂ in DMF (1.5 mL) A solution of CO ₃ (98mg, 0.3mmol) was stirred at room temperature for 5 minutes. tert-butyl 4-(5-(3-(bromomethyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2- in DMF (1 ml) 1) A solution of piperazine-1-carboxylate (57 mg, 0.1 mmol) was added to the reaction solution. The reaction mixture was stirred at 100 °C for 3 hours and at 80 °C for 16 hours. After cooling to room temperature, quenched with H ₂ O (10 mL) at 0 °C, extracted with EtOAc(X2), dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1 to 10:1) to give compound 2-8 (28.5 mg, 34.6%).

¹ H NMR (600 MHz, CDCl ₃ ) δ 8.55 (s, 1H), 8.34 (d,, J = 2.4 Hz 2H), 7.79 (d, J = 7.2 Hz, 1H), 7.70 (m, 1H), 7.59 (m, 1H), 7.36 (m, 1H), 7.29 (m, 2H), 7.15 (m, 1H), 7.10 (m, 1H) 6.99 (s, 1H), 6.64 (s, 1H), 6.65 (d) , J = 9.6 Hz, 1H), 5.53 (s, 2H), 5.45 (s, 2H), 3.96 (m, 2H), 3.56 (s, 8H), 3.33 (m, 2H), 3.10 (m, 2H) , 2.95 (m, 1H), 2.43 (s, 3H), 2.28 (s, 3H), 2.22 (s, 3H), 1.73 (m, 2H), 1.66 (m, 2H), 1.49 (s, 9H), 0.89 (t, J = 7.2 Hz, 3H)

tert-Butyl 4-(5-(3-((2-(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-1H-imidazo[4,5-c] Pyridin-1-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (Compound 2- 12) Manufacturing

tert-Butyl 4-(5-(3-((2-(2-(benzyloxy))-4,6-dimethylpyridin-3-yl)-1H-imidazo[4,5- in MeOH (2 ml) c] pyridin-1-yl) methyl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methylphenyl) pyridin-2-yl) piperazine-1-carboxylate (15 mg, 0.0182 mmol) and 10% Pd/C (5 mg) was charged with N ₂ . A balloon filled with H ₂ was then fitted. The mixture was stirred at room temperature (25° C.) for 21 hours. Pd/C was removed with a Celite filter. The solvent was evaporated in vacuo and the residue was separated by flash column chromatogram (DCM:MeOH = 10:1) to give compound 2-12 (6.5 mg, 48%).

^1H NMR (600 MHz, CD ₃ OD) δ 9.22 (s, 1H), 8.53 (d, J = 7.2 Hz 1H), 8.33 (d, J = 7.4 Hz, 1H), 8.08 (d, J = 7.4 Hz , 1H), 7.81 (dd, J = 9.0, 2.4 Hz, 1H), 7.51 (s, 1H), 7.26 (s, 1H), 6.90 (d, J = 9.0 Hz, 1H), 6.36 (s, 1H) , 5.96 (s, 2H), 3.90 (m, 2H), 3.51 (m, 8H), 3.35 (m, 2H), 3.30 (m, 2H), 3.09 (m, 1H), 2.74 (s, 3H), 2.37 (s, 3H), 2.31 (s, 3H), 1.75 (m, 2H), 1.57 (m, 2H), 1.49 (s, 9H), 0.89 (t, J = 7.2 Hz, 3H)

tert-butyl 4-(5-(3-((2-(2-(benzyloxy)-4,6-dimethylpyridin-3-yl)-1H-benzo[d]imidazol-1-yl)methyl) Preparation of -5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (Compound 2-9)

2-(2-(benzyloxy)-4,6-dimethylpyridin-3-yl)-1H-benzo[d]imidazole (30 mg, 0.091 mmol) in DMF (2 ml), CS ₂ CO ₃ (71 mg, 0.218 mmol) was stirred at room temperature for 5 minutes. tert-butyl 4-(5-(3-(bromomethyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2- in DMF (1 ml) 1) A solution of piperazine-1-carboxylate (50 mg, 0.087 mmol) was added to the reaction solution. The reaction mixture was stirred at 50 °C for 16 hours. After cooling to room temperature, quenched with H ₂ O (5 mL) at 0 °C, extracted with EtOAc(X2), dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1 to 10:1) to give compound 2-9 (62 mg, 87%).

^1H NMR (400 MHz, CDCl ₃ ) δ 8.11 (s, 1H), 8.02 (s, 2H), 7.87 (d, J = 8.0 Hz, 1H), 7.36 (m, 4H), 7.28 (m, 3H) , 7.12 (s, 1H), 6.58 (m, 1H), 6.54 (s, 1H), 6.47 (m, 1H), 5.60 (d, J = 12.0 Hz, 1H), 5.25 (d, J = 12.0 Hz 1H) ), 5.12 (m, 2H), 3.95 (m, 2H), 3.55 (s, 8H), 3.31 (m, 2H), 3.02 (m, 1H), 2.39 (s, 3H), 1.96 (s, 3H) , 1.90 (s, 3H), 1.64 (m, 4H), 1.49 (s, 9H), 0.84 (t, J = 7.2 Hz, 3H)

tert-Butyl 4-(5-(3-((2-(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-1H-benzo[d]imidazole-1- Preparation of yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (Compound 2-13)

tert-Butyl 4-(5-(3-((2-(2-(benzyloxy)-4,6-dimethylpyridin-3-yl)-1H-benzo[d]imidazole- in MeOH (3 mL) 1-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (50 mg 0.0608 mmol) and 10% Pd/C (7 mg) was charged with N ₂ . A balloon filled with H ₂ was then fitted. The mixture was stirred at room temperature (25° C.) for 15 hours. Pd/C was removed with a Celite filter. The solvent was evaporated in vacuo and the residue was separated by flash column chromatogram (DCM:MeOH = 20:1) to give compound 2-13 (28.6 mg, 64%).

^1H NMR (600 MHz, CDCl ₃ ) δ 8.14 (d, J = 2.4 Hz, 1H), 8.02 (s, 2H), 7.83 (d, J = 7.8 Hz, 1H), 7.45 (dd, J = 9.0, 2.4 Hz, 1H), 7.28 (m, 3H), 7.15 (s, 1H), 6.78 (s, 1H), 6.56 (d, J = 9.0 Hz, 1H), 5.80 (s, 1H), 5.40 (s, 2H), 3.91 (m, 2H), 3.47 (m, 8H), 3.28 (m, 2H), 3.01 (m, 2H), 3.90 (m, 1H), 2.12 (s, 3H), 2.07 (s, 3H) ), 1.88 (s, 3H), 1.66 (m, 2H), 1.58 (m, 2H), 1.49 (s, 9H), 0.81 (t, J = 7.2 Hz, 3H)

3-(1-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methyl-5-(6-(piperazin-1-yl)pyridin-3-yl)benzyl) Preparation of -1H-benzo[d]imidazol-2-yl)-4,6-dimethylpyridin-2(1H)-one hydrochloride (Compound 2-15)

tert-Butyl 4-(5-(3-((2-(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-1H in anhydrous CH _{2 Cl} 2 ₍ 1.5 mL) -Benzo[d]imidazol-1-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-car To a solution of the boxylate (16 mg, 0.02186 mmol) was added 4M HCl in dioxane (0.3 mL) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. The resulting solid was filtered, rinsed with diethyl ether (2 mL x 8), and concentrated in vacuo to give the HCl salt product compound 2-15 (13.4 mg, 91.7%).

¹ H NMR (600 MHz, CD ₃ OD) δ 8.44 - 8.38 (m, 2H), 8.12 (m, 2H), 7.92 (d, J = 8.4 Hz, 1H), 7.77 (m, 1H), 7.71 (t , J = 7.8 Hz, 1H), 7.64 (m, 1H), 7.46 (m, 2H), 6.34 (s, 1H), 5.99 (m, 1H), 5.72 (m, 1H), 4.24 (m, 1H) , 4.05 - 3.89 (m, 8H), 3.65 (m, 3H), 3.46 (m, 7H), 2.51 (s, 3H), 2.22 (s, 3H), 2.20 (s, 3H), 1.17 (t, J = 7.2 Hz, 3H)

tert-Butyl 4-(5-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-5-((2-(methylthio)-4-(4-(tri) Preparation of fluoromethyl) phenyl) -1H-imidazol-1-yl) methyl) phenyl) pyridin-2-yl) piperazine-1-carboxylate (Compound 2-10)

2-(methylthio)-4-(4-(trifluoromethyl)phenyl)-1H-imidazole (21 mg, 0.0882 mmol), CS ₂ CO ₃ (64 mg, 0.195 mmol) in DMF (2.55 ml) The solution was stirred at room temperature for 5 minutes. tert-butyl 4-(5-(3-(bromomethyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2- in DMF (1 ml) 1) A solution of piperazine-1-carboxylate (45 mg, 0.078 mmol) was added to the reaction solution. The reaction mixture was stirred at 55 °C for 15 hours. After cooling to room temperature, quenched with H ₂ O at 0 °C, extracted with EtOAc(X2), dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1) to give compound 2-10 (42 mg, 72%).

^1H NMR (600 MHz, CDCl ₃ ) δ 8.00 (s, 1H), 7.82 (d, J = 7.8 Hz, 2H), 7.59 (d, J = 9.0 Hz, 1H), 7.56 (d, J = 7.8 Hz) , 1H), 7.21 (s, 1H), 7.18 (s, 1H), 6.86 (s, 1H), 6.65 (d, J = 9.0 Hz, 1H), 3.94 (m, 2H), 3.53 (s, 8H) , 3.32 (t, J = 11.4 Hz, 2H), 3.08 (m, 2H), 2.98 (m, 1H), 2.65 (s, 3H), 2.28 (s, 3H), 2.73 (m, 2H), 1.64 ( m, 2H), 1.47 (s, 9H), 0.89 (t, J = 7.2 Hz, 3H)

Compounds 3-1 to 3-11 were prepared according to Scheme 3 above.

tert-Butyl 4-(5-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(methoxycarbonyl)-4-methylphenyl)pyridin-2-yl)piperazin- Preparation of 1-carboxylate (Compound 3-1)

Compound 3-1 was prepared according to a known patent method (WO2012142504A1).

tert-Butyl 4-(5-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(hydroxymethyl)-4-methylphenyl)pyridin-2-yl)piperazine-1 -Preparation of carboxylate (compound 3-2)

tert-Butyl 4-(5-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(methoxycarbonyl)-4-methylphenyl)pyridine- in anhydrous THF (4 mL) A solution of 2-yl)piperazine-1-carboxylate (570 mg, 1.058 mmol) was cooled to -78 °C. DIBAL-H (2.65 mL, 2.645 mmol) in THF 1M solution was added dropwise and the mixture was stirred at 0 °C for 3 h. The reaction mixture was quenched with K·Na·tartrate (1000 mg) in H ₂ O (3 mL) at -78 °C and the slurry was stirred at room temperature for 1 hour. The mixture was extracted with ethyl acetate (x3), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CH ₂ Cl ₂ :CH ₃ OH = 19:1) to give compound 3-2 (368 mg, 68%).

^1H NMR (600 MHz, CDCl ₃ ) δ 8.44 (d, J = 2.4 Hz, 1H), 7.73 (dd, J = 9.0, 2.4 Hz, 1H), 7.35 (d, J = 1.2 Hz, 1H), 7.26 (d, J = 1.2 Hz, 1H), 6.73 (d, J = 9.0 Hz, 1H), 4.78 (s, 2H), 3.97 (m, 2H), 3.59 (s, 8H), 3.35 (m, 2H) , 3.12 (m, 2H), 3.03 (m, 1H), 2.35 (s, 3H), 1.58 (s, 4H), 1.51 (s, 9H), 0.92 (t, J = 7.2 Hz, 3H)

tert-Butyl 4-(5-(3-(bromomethyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazin-1 -Preparation of carboxylate (Compound 3-4)

tert-butyl 4-(5-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(hydroxymethyl)-4-methylphenyl) in anhydrous CH ₂ Cl ₂ (7 mL) To a solution of pyridin-2-yl)piperazine-1-carboxylate (340 mg, 0.6658 mmol), triphenylphosphine (192 mg, 0.7324 mmol) and carbon tetrabromide (243 mg, 0.7324 mmol) were added at 0 °C. added. The resulting mixture was stirred overnight (ca. 20 hours) at ambient temperature. After cooling to room temperature, quenched with H ₂ O at 0 °C, extracted CH ₂ Cl ₂ (X2), dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (CH ₂ Cl ₂ :CH ₃ OH = 19:1) to give compound 3-4 (248 mg, 65%).

^1H NMR (400 MHz, CDCl ₃ ) δ 8.40 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.24 (s, 1H), 6.70 (d, J = 8.0 Hz, 1H), 4.57 (s, 2H), 3.95 (m, 2H), 3.56 (s, 8H), 3.32 (m, 2H), 3.08 (m, 2H), 2.98 (m, 1H), 2.39 (s, 3H), 1.68 ( m, 4H), 1.48 (s, 9H), 0.89 (t, J = 7.2 Hz, 3H)

tert-Butyl 4-(5-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-formyl-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxyl Preparation of rate (compounds 3-7)

tert-Butyl 4-(5-(3-(bromomethyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2- in DMSO (3.5 mL) 1) To a solution of piperazine-1-carboxylate (500 mg, 0.8717mmol) was added NaHCO ₃ (146 mg, 1.7380 mmol) at room temperature. The resulting mixture was stirred at 95° C. for 3 hours. After cooling to room temperature, diluted with H ₂ O and EtOAC, EtOAC(X2) was extracted, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (CH ₂ Cl ₂ :CH ₃ OH = 19:1) to give compound 3-7 (278 mg, 62.7%).

^1H NMR (600 MHz, CDCl ₃ ) δ 10.38 (s, 1H), 8.43 (s, 1H), 7.73 (m, 2H), 7.51 (s, 1H), 6.72 (d, J = 8.4 Hz, 1H) , 3.96 (m, 2H), 3.57 (s, 8H), 3.33 (m, 2H), 3.11 (m, 2H), 3.10 (m, 1H), 2.64 (s, 3H), 1.73 (m, 2H), 1.65 (m, 2H), 1.48 (s, 9H), 0.90 (t, J = 7.2 Hz, 3H)

tert-butyl 4-(5-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(4-(4-fluorophenyl)-1H-imidazol-2-yl) Preparation of -4-methylphenyl) pyridin-2-yl) piperazine-1-carboxylate (Compound 3-8)

tert-butyl 4-(5-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-formyl-4-methylphenyl)pyridin-2-yl in CH ₃ OH (5 mL) ) To a solution of piperazine-1-carboxylate (130 mg, 0.255 mmol) and 2-(4-fluorophenyl)-2-oxoacetaldehyde (41 mg, 0.268 mmol) was added NH ₄ OAc (98 mg, 1.275 mmol). ) was added at room temperature. The resulting mixture was stirred at 50° C. for 19 hours. After cooling to room temperature, it was concentrated under reduced pressure. The resulting mixture was diluted with H ₂ O and CH ₂ Cl ₂ , extracted with CH ₂ Cl ₂ (X2), washed with saturated NaHCO ₃ , dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (CH ₂ Cl ₂ :CH ₃ OH = 19:1) to give compound 3-8 (43 mg, 87.5%).

^1H NMR (400 MHz, CDCl ₃ ) δ 8.42 (d, J = 2.4 Hz, 1H), 7.83 (m, 1H), 7.72 (dd, J = 9.4, 2.4 Hz, 1H), 7.51 (s, 1H) , 7.35 (s, 1H), 7.32 (m, 1H), 7.25 (s, 1H), 7.07 (t, J = 8.8 Hz, 2H), 6.69 (d, J = 8.8 Hz, 1H), 3.96 (m, 2H), 3.55 (s, 8H), 3.34 (m, 2H), 3.13 (m, 2H), 3.04 (m, 1H), 2.48 (s, 3H), 1.72 (m, 2H), 1.60 (m, 2H) ), 1.48 (s, 9H), 0.93 (t, J = 7.2 Hz, 3H)

tert-Butyl 4-(5-(3-(1-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-4-(4-fluorophenyl)-1H-imi Dazol-2-yl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (Compound 3-9) manufacture of

tert-Butyl 4-(5-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(4-(4-fluorophenyl)-1H-imi in DMF (2 mL) Cs ₂ CO ₃ (91 mg , 0.280 mmol) was added at room temperature. The resulting mixture was stirred at 80 °C for 20 hours. After cooling to room temperature, diluted with H ₂ O and EtOAc at 0 °C, extracted with EtOAc(X2), washed with saturated NaHCO ₃ , dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (CH ₂ Cl ₂ :CH ₃ OH = 19:1) to give compound 3-9 (86 mg, 88.6%).

^1H NMR (400 MHz, CDCl ₃ ) δ 8.37 (d, J = 2.4 Hz, 1H), 7.60 (m, 3H), 7.37 (m, 3H), 7.30 (m, 3H), 7.20 (d, J = 2.0 Hz, 1H), 7.00 (m, 3H), 6.67 (d, J = 8.8 Hz, 1H), 6.48 (s, 1H), 5.40 (s, 1H), 4.91 (s, 2H), 3.96 (m, 2H), 3.57 (s, 8H), 3.33 (m, 2H), 3.12 (m, 2H), 3.05 (m, 1H), 2.37 (s, 3H), 2.11 (s, 3H), 1.85 (s, 3H) ), 1.73 (m, 2H), 1.61 (m, 2H), 1.49 (s, 9H), 0.94 (t, J = 7.2 Hz, 3H)

tert-Butyl 4-(5-(3-(1-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-(4-fluorophenyl) -1H-imidazol-2-yl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (compound 3-10) Preparation of

tert-Butyl 4-(5-(3-(1-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-4-(4-fluoro in MeOH (5 ml) Phenyl)-1H-imidazol-2-yl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (70 mg 0.0808 mmol) and 10% Pd/C (14 mg) was charged with N ₂ . A balloon filled with H ₂ was then fitted. The mixture was stirred at room temperature (30° C.) for 21 hours. Pd/C was removed with a Celite filter. The solvent was evaporated in vacuo and the residue was separated by flash column chromatogram (DCM:MeOH = 40:1) to give compound 3-10 (39 mg, 62%).

^1H NMR (400 MHz, CDCl ₃ ) δ 8.41 (d, J = 2.4 Hz, 1H), 7.75 (m, 2H), 7.70 (dd, J = 8.8, 2.4 Hz, 1H), 7.45 (s, 1H) , 7.35 (dd, J = 10.4, 1.6 Hz, 2H), 7.01 (t, J = 8.8 Hz, 1H), 6.69 (t, J = 8.8 Hz, 1H), 5.79 (s, 2H), 4.88 (s, 2H), 3.97 (m, 2H), 3.56 (s, 8H), 3.34 (m, 2H), 3.14 (m, 2H), 3.09 (m, 1H), 2.23 (s, 3H) ), 2.20 (s, 3H), 1.74 (m, 2H), 1.64 (m, 2H), 1.49 (s, 9H), 0.94 (t, J = 7.2 Hz, 3H)

3-((2-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methyl-5-(6-(piperazin-1-yl)pyridin-3-yl)phenyl )-4-(4-fluorophenyl)-1H-imidazol-1-yl)methyl)-4,6-dimethylpyridin-2(1H)-one hydrochloride (Compound 3-11)

tert-Butyl 4-(5-(3-(1-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl) in anhydrous CH ₂ Cl 2 (1.5 _mL ) -4-(4-fluorophenyl)-1H-imidazol-2-yl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl) To a solution of piperazine-1-carboxylate (16 mg, 0.0206 mmol) was added 4M HCl in dioxane (0.3 mL) dropwise at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The resulting solid was filtered, rinsed with diethyl ether (2 mL x 8), and concentrated in vacuo to give the HCl salt product compound 3-11 (13.3 mg, 90%).

¹ H NMR (600 MHz, CD ₃ OD) δ 8.51 (s, 1H), 7.99-7.81 (m, 6H), 7.47-7.27 (m, 5H), 6.07 (s, 1H), 5.23 (s, 2H) , 4.05 (s, 6H), 3.57 (s, 8H), 2.44 (s, 3H), 2.21 (s, 6H), 1.09 (brs, 3H).

Compounds 4-1 to 4-7 were prepared according to Scheme 4 above.

Preparation of (E)-N1-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methylene)benzene-1,2-diamine (Compound 4-3)

A solution of diamine (compound 4-2) (44.8 mg, 0.414 mmol) in MeOH (3.5 ml) was cooled to 0 °C. A solution of the aldehyde (compound 4-1) (100 mg, 0.414 mmol) in MeOH (2.2 ml) was added and then stirred at 0 °C for 1.5 h. It was then warmed to room temperature and stirred for 4 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatogram (EtOAc:Hep = 1:5) to give compound 4-3 (60 mg, 44.0%).

^1H NMR (600 MHz, CDCl ₃ ) δ 9.04 (s, 1H), 7.47 (d, J = 7.2 Hz, 2H), 7.36 (t, J = 7.2 Hz, 2H), 7.31 (t, J = 7.2 Hz) , 1H), 7.03 (m, 2H), 6.73 (s, 2H), 6.68 (s, 1H), 5.48 (s, 2H), 4.14 (brs, 2H), 2.69 (s, 3H), 2.45 (s, 3H)

Preparation of 2-(2-(benzyloxy)-4,6-dimethylpyridin-3-yl)-1H-benzo[d]imidazole (Compound 4-4)

A solution of compound 4-1 (100 mg, 0.414 mmol), diamine (45 mg, 0.414 mmol) in MeOH (7 ml) was stirred at room temperature for 5 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatogram (EtOAc:Hep = 1:5) to give compound 4-4 (45 mg, 32.9%).

^1H NMR (600 MHz, CDCl ₃ ) δ 10.20 (brs, 1H), 7.80 (d, J = 9.6 Hz, 1H), 7.41-7.32 (m, 6H), 7.23 (m, 2H), 6.81 (s, H), 5.49 (s, 2H), 2.78 (s, 3H), 2.48 (s, 3H).

tert-Butyl 4-(5-(3-(2-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methylamino)phenylcarbamoyl)-5-(ethyl(tetrahydro Preparation of -2H-pyran-4-yl) amino) -4-methylphenyl) pyridin-2-yl) piperazine-1-carboxylate (Compound 4-6)

A solution of compound 4-5 (105 mg, 0.2 mmol) in DCM (2 ml) was cooled to 0 °C. Oxalyl chloride (51 mg, 0.4 mmol) was added and stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. The remaining solution in DCM (1ml) and Et ₃ N (24.3mg, 0.234mmol) and a solution of amine compound 4-3 (66mg, 0.2mmol) in DCM (1ml) were added. The reaction mixture was stirred at room temperature for 24 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatogram (DCM:MeOH = 40:1) to give compound 4-6 (42.8 mg, 25.6%).

^1H NMR (600 MHz, CDCl ₃ ) δ 9.10 (s, 1H), 9.01 (s, 1H), 8.69 (d, J = 8.4 Hz, 1H), 8.39 (d, J = 2.4 Hz, 1H), 7.65 (dd, J = 8.4, 2.4 Hz, 1H), 7.44–7.28 (m, 8H), 7.20 (m, 1H), 7.16 (m, 1H), 6.53 (s, 1H), 5.45 (s, 2H), 3.96 (d, J = 11.4 Hz, 2H), 3.57 (s, 8H), 3.32 (t, J = 11.4 Hz, 2H), 3.11 (q, J = 7.2 Hz, 2H), 3.02 (m, 1H), 2.43 (s, 3H), 2.40 (s, 3H), 2.39 (s, 3H), 1.72 (m, 4H), 1.49 (s, 9H), 0.91 (t, J = 7.2 Hz, 3H).

tert-Butyl 4-(5-(3-(2-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methylamino)phenylcarbamoyl)-5-( Preparation of ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methylphenyl) pyridin-2-yl) piperazine-1-carboxylate (Compound 4-7)

A solution of compound 4-6 (42mg 0.05mmol) and 10% Pd/C (4.5mg) in MeOH (1.5ml) was charged with N ₂ . A balloon filled with H ₂ was then fitted. The mixture was stirred at room temperature (25° C.) for 15 hours. Pd/C was removed with a Celite filter. The solvent was evaporated in vacuo and the residue was separated by flash column chromatogram (DCM:MeOH = 40:1) to give compound 4-7 (18.9 mg, 50.5%).

^1H NMR (600 MHz, CDCl ₃ ) δ 8.48 (d, J = 2.4 Hz, 1H), 7.84 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.67 (dd, J = 8.4, 2.4 Hz, 1H), 7.45 (s, 1H), 7.28 (s, 1H), 7.13 (t, J=7.8Hz, 1H), 6.92 (m, 2H), 6.69 (d, J = 8.4 Hz, 1H) , 5.83 (s, 1H), 4.82 (brs, 1H), 4.16 (s, 1H), 3.92 (d, J = 11.4 Hz, 2H), 3.55 (s, 8H), 3.29 (t, J = 11.4 Hz, 2H), 3.09 (q, J = 7.2 Hz, 2H), 3.01 (m, 1H), 2.42 (s, 3H), 2.18 (s, 3H), 2.16 (s, 3H), 1.69 (m, 4H), 1.48 (s, 9H), 0.88 (t, J = 7.2 Hz, 3H).

Compounds 5-1 to 5-6 were prepared according to Scheme 5 above.

Preparation of 2-(benzyloxy)-3-(4,4-dimethyl-4,5-dihydro-1H-imidazol-2-yl)-4,6-dimethylpyridine (Compound 5-3)

To a solution of the aldehyde (compound 5-1) (100 mg, 0.414 mmol) in t-BuOH (5 mL) was added the diamine (compound 5-2) (40 mg, 0.456 mmol). The mixture was stirred at room temperature. After standing in N ₂ atmosphere for 20 minutes, NaI (25mg, 0.166mmol) and K ₂ CO ₃ (250mg) were added and the mixture was heated to 80°C. Aq.30% H ₂ O ₂ was slowly added dropwise until the color of I ₂ was not released. After 2 hours, the mixture was sat. Aqueous Na ₂ S ₂ O ₄ (1 mL) was added and extracted with DCM. The organic layer was washed with brine (1 x 20 mL) and dried over MgSO ₄ . After filtration, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 10:1) to give compound 5-3 (50 mg, 39.0%).

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.43 (d, J = 7.2 Hz, 2H), 7.39 (t, J = 7.2 Hz, 2H), 7.31 (t, J = 7.2 Hz, 1H), 6.64 (s , 1H), 5.38 (s, 2H), 3.43 (s, 2H), 2.42 (s, 3H), 2.26 (s, 3H), 1.26 (s, 6H).

tert-Butyl 4-(5-(3-((2-(2-(benzyloxy)-4,6-dimethylpyridin-3-yl)-4,4-dimethyl-4,5-dihydroimidazole- 1-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (Compound 5-5) manufacture of

A solution of imidazole (compound 5-3) (26.6 mg, 0.086 mmol), CS ₂ CO ₃ (70 mg, 0.215 mmol) in DMF (15 ml) was stirred at room temperature for 5 min. A solution of compound 5-4 in DMF (1 ml) was added to the reaction solution. The reaction mixture was stirred at 50 °C for 17 hours. After cooling to room temperature, quenched with H ₂ O, extracted with EtOAc(X2), dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1 to 10:1) to give compound 5-5 (25.1 mg, 35.9%).

^1H NMR (600 MHz, CDCl3) δ 8.30 (d, J = 2.4 Hz, 1H), 7.55 (dd, J = 8.4, 2.4 Hz, 1H), 7.47 (d, J = 7.2 Hz, 2H), 7.38 ( t, J = 7.2 Hz, 2H), 7.34 (d, J = 7.2 Hz, 1H), 7.21 (s, 1H), 6.82 (s, 1H), 6.68 (d, J = 8.4 Hz, 2H), 5.30 ( s, 2H), 3.92 (m, 2H), 3.58 (s, 10H), 3.29 (t, J = 11.4 Hz, 2H), 3.03 (q, J = 7.2 Hz, 2H), 2.92 (m, 1H), 2.42 (s, 6H), 2.06 (s, 3H), 1.67 (m, 4H), 1.53 (s, 12H), 0.83 (t, J = 7.2 Hz, 3H).

tert-Butyl 4-(5-(3-((2-(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-4,4-dimethyl-4,5-di Hydroimidazol-1-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (Compound 5-6) Manufacture

A solution of compound 5-5 (25 mg, 0.031 mmol) and 10% Pd/C (3 mg) in MeOH (1.5 ml) was charged with N ₂ . A balloon filled with H ₂ was then fitted. The mixture was stirred at room temperature (25° C.) for 20 hours. Pd/C was removed with a Celite filter. The solvent was evaporated in vacuo and the residue was separated by flash column chromatogram (DCM:MeOH = 9:1) to give compound 5-6 (22.2 mg, 70.7%).

^1H NMR (600 MHz, CDCl ₃ ) δ 8.35 (d, J = 2.4 Hz, 1H), 7.66 (m, 1H), 7.27 (s, 1H), 7.06 (s, 1H), 6.74 (d, J = 8.4 Hz, 1H), 5.90 (s, 1H), 3.94 (m, 2H), 3.57 (s, 10H), 3.41 (t, J = 11.4 Hz, 2H), 3.10 (q, J = 7.2 Hz, 2H) , 2.95 (m, 1H), 2.45 (s, 3H), 2.29 (s, 3H), 2.19 (s, 3H), 1.66 (s, 3H), 1.60 (m, 4H), 1.52 (s, 3H), 1.49 (s, 9H), 0.85 (t, J = 7.2 Hz, 3H).

< Experimental Example 1: Analysis of EZH2 IC ₅₀ Value>

As shown in Table 1 below, the EZH2 IC ₅₀ value was measured using the compound according to the present invention, and the activity result was confirmed.

Claims (8)

A compound of Formula 1 below, or an enantiomer, diastereomer, stereoisomer, hydrate, solvate, prodrug or pharmaceutically acceptable salt thereof.
[Formula 1]

In the above formula,
A is a bond, -CH ₂ -, or -C(O)-;
B is

,

,

,

or

is;
C is

or

is;
D is independently CH or N;
E is independently CH or N;
R ₁ is independently hydrogen or (C ₁ -C ₆ )alkyl;
R ₂ is hydrogen or (C ₁ -C ₆ )alkyl;
R ₃ , R ₄ are independently hydrogen, substituted or unsubstituted (C ₁ -C ₆ )alkyl, substituted or unsubstituted (C ₃ -C ₁₀ )cycloalkyl, substituted or unsubstituted (C ₃ -C ₁₀ )heterocycloalkyl, substituted or unsubstituted (C ₃ -C ₁₀ )aryl, or substituted or unsubstituted (C ₃ -C ₁₀ )heteroaryl,
The substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl means that one or more hydrogens in the chain or ring are independently halogen, amino, -Boc, (C ₁ -C ₆ )alkyl, halo(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy or halo(C ₁ -C ₆ )alkoxy;
R ₅ is independently substituted or unsubstituted phenyl;
the substituted phenyl is substituted with hydrogen, halogen, halo(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy;
R ₆ is hydrogen, halogen, halo(C ₁ -C ₆ )alkyl, or (C ₁ -C ₆ )alkoxy;
R ₇ is hydrogen, (C ₁ -C ₆ )alkyl or benzyl;
m is an integer of 0 or 1;
n is an integer from 0 to 2; and
p is an integer from 0 to 4; According to claim 1,
In Formula 1, R ₃ and R ₄ are substituted or unsubstituted (C ₃ -C ₁₀ )heterocycloalkyl,
The substituted heterocycloalkyl is such that at least one hydrogen in the ring is independently halogen, amino, -Boc, (C ₁ -C ₆ )alkyl, halo(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy or A compound that is an enantiomer, diastereomer, stereoisomer, hydrate, solvate, prodrug or pharmaceutically acceptable salt thereof, characterized in that it is substituted with halo(C ₁ -C ₆ )alkoxy. According to claim 1 or 2,
The compound represented by Formula 1 is
tert-Butyl 4-(5-(3-(2-(2-(benzyloxy)-4,6-dimethylpyridin-3-yl)-4-(4-fluorophenyl)-1H-imidazole-1 -carbonyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (Compound 1-3);
tert-Butyl 4-(5-(3-(2-(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-4-(4-fluorophenyl)-1H- Imidazole-1-carbonyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (Compound 1- 5);
3-(1-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methyl-5-(6-(piperazin-1-yl)pyridin-3-yl)benzoyl) -4-(4-fluorophenyl)-1H-imidazol-2-yl)-4,6-dimethylpyridin-2(1H)-one hydrochloride (Compound 1-7);
tert-Butyl 4-(5-(3-(2-(2-(benzyloxy)-4,6-dimethylpyridin-3-yl)-1H-benzo[d]imidazole-1-carbonyl)-5 -(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (Compound 1-4);
tert-Butyl 4-(5-(3-(2-(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-1H-benzo[d]imidazole-1-car Bornyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (Compound 1-6);
3-(1-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methyl-5-(6-(piperazin-1-yl)pyridin-3-yl)benzoyl) -1H-benzo[d]imidazol-2-yl)-4,6-dimethylpyridin-2(1H)-one hydrochloride (Compound 1-8);
tert-Butyl 4-(5-(3-((2-(2-(benzyloxy)-4,6-dimethylpyridin-3-yl)-4-(4-fluorophenyl)-1H-imidazole- 1-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (Compound 2-7) ;
tert-Butyl 4-(5-(3-((2-(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-4-(4-fluorophenyl)-1H -imidazol-1-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (compound 2-11);
3-(1-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methyl-5-(6-(piperazin-1-yl)pyridin-3-yl)benzyl) -4-(4-fluorophenyl)-1H-imidazol-2-yl)-4,6-dimethylpyridin-2(1H)-one hydrochloride (Compound 2-14);
tert-Butyl 4-(5-(3-((2-(2-(benzyloxy)-4,6-dimethylpyridin-3-yl)-1H-imidazo[4,5-c]pyridin-1- yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (Compound 2-8);
tert-Butyl 4-(5-(3-((2-(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-1H-imidazo[4,5-c] Pyridin-1-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (Compound 2- 12);
tert-butyl 4-(5-(3-((2-(2-(benzyloxy)-4,6-dimethylpyridin-3-yl)-1H-benzo[d]imidazol-1-yl)methyl) -5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (Compound 2-9);
tert-Butyl 4-(5-(3-((2-(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-1H-benzo[d]imidazole-1- yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (Compound 2-13);
3-(1-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methyl-5-(6-(piperazin-1-yl)pyridin-3-yl)benzyl) -1H-benzo[d]imidazol-2-yl)-4,6-dimethylpyridin-2(1H)-one hydrochloride (Compound 2-15);
tert-Butyl 4-(5-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-5-((2-(methylthio)-4-(4-(tri) Fluoromethyl)phenyl)-1H-imidazol-1-yl)methyl)phenyl)pyridin-2-yl)piperazine-1-carboxylate (Compound 2-10);
tert-butyl 4-(5-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(4-(4-fluorophenyl)-1H-imidazol-2-yl) -4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (Compound 3-8);
tert-Butyl 4-(5-(3-(1-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-4-(4-fluorophenyl)-1H-imi Dazol-2-yl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (Compound 3-9) ;
tert-Butyl 4-(5-(3-(1-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-(4-fluorophenyl) -1H-imidazol-2-yl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (compound 3-10);
3-((2-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methyl-5-(6-(piperazin-1-yl)pyridin-3-yl)phenyl )-4-(4-fluorophenyl)-1H-imidazol-1-yl)methyl)-4,6-dimethylpyridin-2(1H)-one hydrochloride (Compound 3-11);
tert-Butyl 4-(5-(3-((2-(2-(benzyloxy)-4,6-dimethylpyridin-3-yl)-4,4-dimethyl-4,5-dihydroimidazole- 1-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (Compound 5-5) ; and
tert-Butyl 4-(5-(3-((2-(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-4,4-dimethyl-4,5-di Hydroimidazol-1-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (Compound 5-6);
A compound characterized in that it is selected from the group consisting of, or an optical isomer thereof, an enantiomer thereof, a diastereomer, a stereoisomer, a hydrate, a solvate, a prodrug thereof, or a pharmaceutically acceptable salt thereof. A therapeutically effective amount of a compound of any one of claims 1 to 3, or an enantiomer, diastereomer, stereoisomer, hydrate, solvate, prodrug or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt thereof. A pharmaceutical composition for inhibiting EZH2 (Enhancer of zeste homolog 2) comprising a possible carrier. According to claim 4,
The EZH2 (Enhancer of zeste homolog 2) inhibitory composition is a pharmaceutical composition, characterized in that for preventing or treating cancer, myelofibrosis, acquired immune deficiency syndrome, graft-versus-host disease, Weaver syndrome, psoriasis and liver fibrosis. According to claim 5,
The pharmaceutical composition, characterized in that the cancer is solid cancer or hematological cancer. According to claim 6,
The solid cancers include brain cancer, brain tumor, benign astrocytoma, malignant astrocytoma, pituitary adenoma, meningioma, cerebral lymphoma, oligodendroma, intracranial race, ependymoma, brainstem tumor, head and neck tumor, glioma, glioblastoma, laryngeal cancer, oropharyngeal cancer, nasal cavity Cancer, nasopharyngeal cancer, salivary gland cancer, hypopharyngeal cancer, tonsil cancer, thyroid cancer, oral cancer, esophageal cancer, eye cancer, chest tumor, small cell lung cancer, non-small cell lung cancer, thymus cancer, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, pleural cancer, Mediastinum tumor, breast cancer, male breast cancer, abdominal tumor, stomach cancer, gastric mastoid tumor, liver cancer, hepatoblastoma, gallbladder cancer, biliary tract cancer, pancreatic cancer, small intestine cancer, colorectal cancer, colon cancer, rectal cancer, duodenal cancer, anal cancer, bladder cancer, kidney cancer, renal pelvis cancer , heart cancer, peritoneal cancer, adrenal cancer, spinal cord cancer, bone cancer, sexual genital tumor, penile cancer, prostate cancer, female genital tumor, cervical cancer, endometrial cancer, ovarian cancer, uterine sarcoma, vaginal cancer, female external genital cancer, female A pharmaceutical composition, characterized in that urethral cancer or skin cancer. According to claim 6,
The pharmaceutical composition, characterized in that the blood cancer is acute myelogenous leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, childhood lymphoma, malignant lymphoma, multiple myeloma or aplastic anemia.