RNA-binding molecules with small core scaffolds (R-scores) and uses thereof

Abstract

The present invention relates to novel RNA-binding azetidine compounds of general formula (I), as well as stereoisomers, hydrates, solvates, and pharmaceutically acceptable salts of the azetidine compounds, and pharmaceutical compositions comprising the azetidine compounds together with at least one pharmaceutically acceptable carrier, excipient, and / or diluent. The azetidine compounds are particularly useful for the treatment and / or prevention of diseases caused by and / or associated with microRNA expression or microRNA misexpression, particularly cancer, tumor, viral infection, immune-related disease, inflammatory disease, diabetes, cardiovascular disease, metabolic disease, and neurodegenerative disease. [Formula 1] JPEG2025535433000198.jpg34162

Description

Detailed Description of the Invention

[0001] [detail] The present invention relates to novel RNA-binding azetidine compounds of general formula (I), as well as stereoisomers, hydrates, solvates, and pharmaceutically acceptable salts of the azetidine compounds, and pharmaceutical compositions comprising the azetidine compounds together with at least one pharmaceutically acceptable carrier, excipient, and / or diluent. The azetidine compounds are particularly useful for the treatment and / or prevention of diseases caused by and / or associated with microRNA expression or microRNA misexpression, particularly cancer, tumor, viral infection, immune-related disease, inflammatory disease, diabetes, cardiovascular disease, metabolic disease, and neurodegenerative disease.

[0002] [Background of the invention] RNA plays a crucial role in gene expression, and dysregulation of RNA metabolism and biology is associated with the progression of various human diseases. Targeting the human transcriptome represents a new perspective in drug discovery. Both coding and non-coding RNAs have become promising targets for therapeutic drug development in various modalities. MicroRNAs (miRNAs) are a type of small non-coding RNA, approximately 17 to 25 nucleotides in length, that regulate gene expression and influence many biological processes, including inflammation, cell cycle regulation, and stress response. MicroRNAs are transcribed by RNA polymerase II, and the primary transcript, the primary miRNA (pri-miRNA), contains the miRNA sequence in the arm of the local stem. It is then processed by the microprocessor complex (Drosha and DGCR8) to release a stem-loop intermediate, i.e., precursor miRNA (pre-miRNA), containing approximately 85 nucleotides. The pre-miRNA is then transported to the cytoplasm and further cleaved by Dicer to generate the mature miRNA (Michlewski G, et al. RNA 2019, 25, 1-16).

[0003] Dysregulation of oncogenic miRNAs, such as miR-17 and miR-21, has been found in various types of cancer. When comparing B-cell lymphoma samples and cell lines with normal tissues, elevated levels of primary or mature miRNAs from the miR17-92 cluster are often observed. In a murine B-cell lymphoma model, forced expression of the miR-17-92 cluster, along with c-myc expression, accelerates tumor progression (He L, et al. Nature 2005, 435, 828-833). In the development of lung cancer, particularly small cell lung cancer, the miR-17-92 cluster is significantly and frequently overexpressed, promoting lung cancer cell proliferation (Yoji H, et al. Cancer Res. 2005, 65, 9628-9632). miR-17 promotes gastric cancer cell proliferation and inhibits cell apoptosis through post-transcriptional regulation of p21 and TP53INP1 (Mei W. et al., Eur. J. Cancer 2013, 49, 2010-2021). Consistently, miR-17 has been found to be overexpressed in breast, colon, pancreatic, and prostate cancers, and high expression of the miR-17-92 cluster has been associated with poor overall survival in many cancers (Volinia S. et al., Proc. Natl. Acad. Sci. 2006, 103, 2257-2261; Feifei L. et al., Oncotarget. 2017, 8, 69125-69138). Similar to miR-17, miR-21 has been identified as an oncogenic miRNA (Mridul B. et al., Cell Signal. 2021, 83, 109995). Overexpression of miR-21 has been observed in breast cancer, colon cancer, liver cancer, brain cancer, pancreatic cancer, prostate cancer, and other human cancers (Leigh-Ann M, et al., Current genomics. 11(7), 537-561 (201 0) Anti-miR-21 oligonucleotides can suppress cancer cell proliferation in vitro and in vivo, suggesting that miR-21 may function as a novel therapeutic target (ML S, et al., Oncogene. 2007, 26, 2799-2803).

[0004] The development of small molecules targeting miR-17 and miR-21 could lead to the discovery of novel therapeutics for many related diseases. In addition to screening for such small molecule compounds, the sequence-based design of structure-specific small molecule binders for miRNAs exists in the literature (Disney M, et al. ACS Chem. Biol. 2016, 11, 1720-1728; Disney M, et al. J. Am. Chem. Soc. 2020, 142, 6970-6802). A series of currently available RNA-binding small molecules contain aromatic hydrophobic groups as core scaffolds that mimic nucleobases. However, aromatic core scaffolds limit the chemical space of potential RNA-binding molecules. Therefore, there is a strong need to discover RNA-binding small molecules encompassing new chemical domains, aiming to identify molecules with distinct physicochemical properties and biological performance for RNA binding.

[0005] WO2020 / 041384A1 discloses a method and small molecule for inhibiting the nuclease activity of an RNA-guided endonuclease, such as Cas9, in a CRISPR system by contacting the endonuclease-guided complex with a 2-cyanoazetidine derivative. Compounds BRD7608 and BRD9822 have demonstrated inhibitory activity against a wide range of CRISPR proteins. The 2-cyanoazetidine compounds are described as being useful for treating various diseases, including liver disease, autoimmune diseases, central nervous system diseases, cancer, and other proliferative diseases.

[0006] Nobutaka Kato et al. (Nature 2016, 538(7625)344-349) and Micah Maetani et al. (ACS Med Chem Lett 2017, 8(4), 438-442) discovered bicyclic azetidine compounds with the potential to cure and prevent malaria with a single oral dose and protect at-risk populations by high-throughput screening of a compound library derived from diversity-oriented synthesis against a multidrug-resistant strain (P. falciparum) using a phenotypic blood-stage growth inhibition assay that models human blood-stage infection. This screening yielded novel compound scaffolds, including 2-cyano-4-hydroxymethylazetidine, against known targets.

[0007] WO2014 / 028946A2 relates to 2-cyano-4-hydroxymethylazetidine compounds that are useful for regulating hepatic cholesterol metabolism in animals by increasing LDL uptake levels or LDL receptor levels. These compounds are further described as inducers or upregulators of TRIB1 expression, and are useful for the treatment and / or prevention of various diseases, disorders, and conditions of the cardiovascular system, including, for example, myocardial infarction, coronary heart disease, atherosclerosis, and dyslipidemia.

[0008] It is an object of the present invention to provide small RNA-binding compounds and / or pharmaceutically acceptable salts thereof that can be used as pharmaceutically active agents, in particular for the treatment of diseases caused by and / or associated with microRNA expression or microRNA misexpression, as well as compositions comprising at least one of these compounds as pharmaceutically active agent.

[0009] The object of the present invention is solved by the teaching of the independent claims. Further advantageous features, aspects and details of the invention are evident from the dependent claims, the description, the drawings and the examples of the present application.

[0010] [Description of the Invention] The present invention relates to novel RNA-binding small molecules with an azetidine core scaffold. The small molecules, which have a rigid core (also referred to herein as "R-score"), encompass new and unexplored chemical space associated with the small azetidine core with sterically rigid features, and will enable the systematic construction of RNA-binding azetidine compounds by appending RNA-binding fragments as substituents.

[0011] The inventors have shown that the RNA-binding azetidine compounds of the present invention bind to tumorigenic miRNAs, inhibit colony formation, and inhibit the growth of human cancer cells expressing oncogenic miRNAs, thereby demonstrating the potential application of R-Score molecules as a general strategy for targeting structural elements on RNA targets.

[0012] Accordingly, the present invention relates to a compound of general formula (I) or a regioisomer, diastereomer, enantiomer, mixture of regioisomers, mixture of diastereomers, mixture of enantiomers, solvate, hydrate, or pharmaceutically acceptable salt thereof of a compound of general formula (I):

[0013] [ka]

[0014] During the ceremony, R 1 is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -(CH2)3CH3, -(CH2)4CH3, -(CH2)5CH3, -CH2CH(CH3)2, -(CH2)2CH(CH3 )2, -CH(CH2CH3)CH3, -CH(CH2CH3)2, -C(CH3)3, -CH2CH=CH2, -(CH2)2CH=CH2, -(CH2)3CH=CH2, -(CH2)4CH=CH2, -L 1 -A 1 , or -B 1 represents; R 2 -H, -CN, -NR4 R 5 , -L 2 -A 2 , -B 2 , or -C 2 represents; R 3 -A 3 or -B 3 where R 2 If is -CN, R 3 -A 3 and; L 1 represents -CO- or -SO2-; L 2 is -CH2-NR 6 -CO-, -CH2-NR 6 -SO2-, or

[0015] [ka] represents;

[0016] R 4 and R 5 are, independently of one another, -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6H 11 , -CH2- Cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-C5H9, -CH2-cyclo-C6H 11 , -CH2-Ph, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, or -CH2CH2SCH3; A 1 and A 2 are independent of each other,

[0017] [ka]

[0018] [ka] Selected from;

[0019] A 3 teeth,

[0020] [ka] represents;

[0021] [ka] having C selected from:

[0022] B 1 -H 1 , -P 1 -H 1 , or -P 1 -Y 1 -H 1 represents; B 2 -H 2 , -P 2 -H 2 , or -P 2 -Y 2 -H 2 represents; B 3 -H 3 , -P 3 -H 3 , or -P 3 -Y 3 -H 3 represents; C 2 teeth,

[0023] [ka] Selected from;

[0024] Y 1 , Y 2 , and Y 3 are, independently of each other, -O-, -NR 22 -, -CO-NR 22 -, -NR 22 -CO-, -SO2-NR22 -, -NR 22 -SO2-, or -NR 22 -CO-NR 23 -Selected from; P 1 , P 2 , and P 3 are independent of each other,

[0025] [ka] Selected from;

[0026] H 1 , H 2 , and H 3 are independent of each other,

[0027] [ka]

[0028] [ka]

[0029] [ka]

[0030] [ka]

[0031] [ka] Selected from;

[0032] R 17 ~R 20 and R 28 ~R 32are, independently of each other, -H, -F, -Cl, -Br, -I, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -CH2-CH2I, -OCH3, -OC2H5, -OC3H7, -OCH(CH3)2, -OC(CH3)3, -OC4H9, -OCHF2, -OCF3, -OCH2CF3, -OC2F5, -OCH2OCH3, -O-cyclo-C3H5, -OCH2-cyclo-C3H5, -O-C2H for cyclo-C3H5, -CHO, -COCH3, -COCF3, -COC2H5, -COC3H7, -COCH(CH3)2, -COC(CH3)3, -COOH, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -OOC-CH3, -OOC-CF3, -OOC-C2H5, -OOC-C3H7, -OOC-CH(CH3)2, -OOC-C(CH3)3, -NH2, -NHCH3, -NHC2H5, -NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC2H5, -NHCOC3H7, -NHCOCH(CH3)2, -NHCOC(CH3)3, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONHCH(CH3)2, -CONH-cyclo-C3H5, -CONHC(CH3)3, -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -SO2NH2, -SO2NHCH3, -SO2NHC2H5, -SO2NHC3H7, -SO2NHCH(CH3)2, -SO2NH-cyclo-C3H5, -SO2NHC(CH3)3, -SO2N(CH3)2, -SO2N(C2H5)2, -SO2N(C3H7)2, -SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2, -NHSO2CH3, -NHSO2CF3, -NHSO2C2H5, -NHSO2C3H7, -NHSO2CH(CH3)2, -NHSO2C(CH3)3 , -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -C≡CH, -C≡C-CH3, -CH2-C≡CH, -Ph, -O-Ph, -O-CH2-Ph, -C(=NH)NH2, or

[0033] [ka] represents;

[0034] R 6 , R 11 , R 12 , R 21 ~R 23 , R 33 ~R 35 , R 40 , R 41 , R 46 , and R 47 are, independently of one another, -H, -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6H 11 , -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-C5H9, -CH2-cyclo-C6H 11 , -CH2-Ph, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -COO-C(CH3)3, -COO-CH2Ph, or -CH2CH2SCH3; R 24 ~R 27 , R 36a ~R 39a , R 36b ~R 39b , R 42a ~R 45a , and R 42b ~R 45bare, independently of one another, -H, -F, -Cl, -Br, -I, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2F, -CHF2, -CF 3、-CH2Cl、-CH2Br、-CH2I、-CH2-CH2F、-CH2-CHF2、-CH2-CF3、-CH2-CH2Cl、 -CH2-CH2Br、-CH2-CH2I、-OCH3、-OC2H5、-OC3H7、-OCH(CH3)2、-OC(CH3)3、 -OC4H9、-OCHF2、-OCF3、-OCH2CF3、-OC2F5、-OCH2OCH3、-O-シクロ-C3H5、-OCH 2-シクロ-C3H5、-O-C2H4-シクロ-C3H5、-CHO、-COCH3、-COCF3、-COC2H5、-COC3H7 、-COCH(CH3)2、-COC(CH3)3、-COOH、-COOCH3、-COOC2H5、-COOC3H7、-COOCH (CH3)2、-COOC(CH3)3、-OOC-CH3、-OOC-CF3、-OOC-C2H5、-OOC-C3H7、-OOC- CH(CH3)2、-OOC-C(CH3)3、-NH2、-NHCH3、-NHC2H5、-NHC3H7、-NHCH(CH3)2、-NHC(CH3)3、-N(CH3)2、-N(C2H5)2、-N(C3H7)2、-N[CH(CH3)2]2、-N[C(CH3) 3]2、-NHCOCH3、-NHCOCF3、-NHCOC2H5、-NHCOC3H7、-NHCOCH(CH3)2、-NHCOC (CH3)3、-CONH2、-CONHCH3、-CONHC2H5、-CONHC3H7、-CONHCH(CH3)2、-CONH -シクロ-C3H5、-CONHC(CH3)3、-CON(CH3)2、-CON(C2H5)2、-CON(C3H7)2、-CON [CH(CH3)2]2、-CON[C(CH3)3]2、-SO2NH2、-SO2NHCH3、-SO2NHC2H5、-SO2NHC 3H7、-SO2NHCH(CH3)2、-SO2NH-シクロ-C3H5、-SO2NHC(CH3)3、-SO2N(CH3)2、-SO2N(C2H5)2、-SO2N(C3H7)2、-SO2N[CH(CH3)2]2、-SO2N[C(CH3)3]2、-NHS O2CH3、-NHSO2CF3、-NHSO2C2H5、-NHSO2C3H7、-NHSO2CH(CH3)2、-NHSO2C(C) H3)3、-CH=CH2、-CH2-CH=CH2、-C(CH3)=CH2、-CH=CH-CH3、-C≡CH、-C≡C-CH3、-CH2-C≡CH, -Ph, -O-Ph, or -O-CH2-Ph; X represents -CN, -NH2, or -CH2OH; preferably -CN or -NH2; However, X and R 2 cannot be simultaneously -CN.

[0035] Preferably, L 1 represents -CO-. Preferably, L 2 is -CH2-NH-CO-, or

[0036] [ka] represents;

[0037] Preferably, R 4 and R 5 are each independently -CH3, -CH2CH3, or -CH(CH3)2. More preferably, R 4 and R 5 represents -CH3, -CH2CH3, or -CH(CH3)2. In a preferred embodiment, R 4 and R 5 represents -CH3.

[0038] Preferably, B 1 -H 1 , or -P 1 -H 1 Represents B 2 -H 2 , or -P 2 -H 2 Represents B 3 -H 3 , or -P 3 -H 3 Represents. Preferably, Y 1 , Y 2 , and Y 3 are, independently of each other, -O-, -NR 22 -, -CO-NR 22 -, -NR 22In a preferred embodiment, Y 1 , Y 2 , and Y 3 is -NR 22 In a preferred embodiment, Y 1 is -NH-CO-.

[0039] Preferably, P 1 , P 2 , and P 3 are independent of each other,

[0040] [ka] is selected from

[0041] where R 24 ~R 27 has the meaning defined herein. More preferably, P 1 , P 2 , and P 3 teeth:

[0042] [ka] Represents.

[0043] A preferred embodiment of the present invention relates to compounds of formula (I) wherein R 1 -L 1 -A 1 , or -B 1 represents;R 2 -L 2 -A 2 , -B 2 , or -C 2 represents; and R 3 -A 3 or -B 3 where R 2 If is -CN, R 3 -A 3 where A 1 , A 2 , A 3 , B1 , B 2 , B 3 , C 2 , L 1 , L 2 , R 2 and X has the meaning defined herein.

[0044] Preferably, R 17 ~R 20 and R 28 ~R 32 are, independently of one another, -H, -F, -Cl, -Br, -OH, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C(CH3)3, -NH2, -NHCH3, -NHC2H5, -N(CH3)2, -N(C2H5)2, -OCH3, -OC2H5, or

[0045] [ka] Represents.

[0046] More preferably, R 17 ~R 20 represents -H, and R 28 ~R 32 are, independently of one another, -H, -F, -Br, -OH, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C(CH3)3, -NH2, -N(CH3)2-, -OCH3, or

[0047] [ka] Represents.

[0048] Preferably, R 6 , R 11 , R 12 , R 21 ~R 23 , R 33 ~R 35 , R 40 , R 41 , R 46 , and R 47are each independently -H, -CH3, -COO-C(CH3)3, or -COO-CH2Ph. Most preferably, R 6 , R 11 , R 12 , R 21 ~R 23 , R 33 ~R 35 , R 40 , R 41 , R 46 , and R 47 are each independently -H, -CH3, or -COO-C(CH3)3. In a preferred embodiment, R 40 represents -CH3 or -COO-C(CH3)3.

[0049] Preferably, R 24 ~R 27 , R 36a ~R 39a , R 36b ~R 39b , R 42a ~R 45a , and R 42b ~R 45b are each independently H, -F, -Cl, -Br, -OH, -CH, -C2H, -C3H, -CH(CH3), -C(CH3), -NH, -NHCH, -NHC2H, -N(CH3), -N(C2H)2, -OCH, or -OC2H. 24 ~R 27 represents -H. More preferably, R 36a ~R 39a , R 36b ~R 39b , R 42a ~R 45a , and R 42b ~R 45b represents -H. More preferably, R 24 ~R 27 , R 36a ~R 39a , R 36b ~R 39b , R 42a ~R 45a , and R 42b ~R 45b represents -H.

[0050] In a preferred embodiment of the present invention, R 1 are -CH2CH2CH3, -CH2CH=CH2,

[0051] [ka]

[0052] [ka] represents;

[0053] where R 7 , R 8 , R 11 , and R 24 ~R 32 has the meaning defined herein. In an even more preferred embodiment of the present invention, R 1 are -CH2CH2CH3, -CH2CH=CH2,

[0054] [ka] Represents.

[0055] In a preferred embodiment of the present invention, R 2 -H, -CN,

[0056] [ka] represents;

[0057] where R 11 , R 24 ~R 32 , R 36a ~R 39a , and R 36b ~R 39b has the meaning defined herein. In a further preferred embodiment of the present invention, R 2 -H, -CN,

[0058] [ka] Represents.

[0059] In a preferred embodiment of the present invention, R 3 teeth,

[0060] [ka] represents;

[0061] where R 24 ~R 32 has the meaning defined herein. In an even more preferred embodiment of the present invention, R 3 teeth,

[0062] [ka] Represents.

[0063] Another embodiment of the present invention relates to a compound of general formula (I), or a regioisomer, diastereomer, enantiomer, mixture of regioisomers, mixture of diastereomers, mixture of enantiomers, solvate, hydrate, or pharmaceutically acceptable salt thereof of a compound of general formula (I):

[0064] [ka]

[0065] During the ceremony, R 1is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -(CH2)3CH3, -(CH2)4CH3, -(CH2)5CH3, -CH2CH(CH3)2, -(CH2)2CH(CH3 )2, -CH(CH2CH3)CH3, -CH(CH2CH3)2, -C(CH3)3, -CH2CH=CH2, -(CH2)2CH=CH2, -(CH2)3CH=CH2, -(CH2)4CH=CH2, -L 1 -A 1 , or -B 1 represents; R 2 -H, -CN, -NR 4 R 5 , -L 2 -A 2 , -B 2 , or -C 2 represents; R 3 -A 3 or -B 3 where R 2 If is -CN, R 3 -A 3 and; L 1 represents -CO- or -SO2-; L 2 is -CH2-NR 6 -CO-, -CH2-NR 6 -SO2-, or

[0066] [ka] represents;

[0067] R 4 and R 5 are, independently of one another, -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6H 11 , -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-C5H9, -CH2-cyclo-C6H 11, -CH2-Ph, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, or -CH2CH2SCH3; A 1 and A 2 are independent of each other,

[0068] [ka]

[0069] [ka] Selected from;

[0070] A 3 teeth,

[0071] [ka] represents;

[0072] [ka] having C selected from:

[0073] B 1 -H 1 , -P 1 -H 1 , or -P 1 -Y 1 -H 1 represents; B 2 -H 2 , -P 2 -H 2 , or -P 2 -Y 2 -H 2 represents; B 3 -H 3 , -P 3 -H 3 , or -P 3 -Y 3 -H 3 represents; C2 teeth,

[0074] [ka] Selected from;

[0075] Y 1 , Y 2 , and Y 3 are, independently of each other, -O-, -NR 22 -, -CO-NR 22 -, -NR 22 -CO-, -SO2-NR 22 -, -NR 22 -SO2-, or -NR 22 -CO-NR 23 -Selected from; P 1 , P 2 , and P 3 are independent of each other,

[0076] [ka] Selected from;

[0077] H 1 , H 2 , and H 3 are, independently of each other:

[0078] [ka]

[0079] [ka]

[0080] [ka]

[0081] [ka]

[0082] [ka] Selected from;

[0083] R 17 ~R 20 and R 28 ~R 32are, independently of each other, -H, -F, -Cl, -Br, -I, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -CH2-CH2I, -OCH3, -OC2H5, -OC3H7, -OCH(CH3)2, -OC(CH3)3, -OC4H9, -OCHF2, -OCF3, -OCH2CF3, -OC2F5, -OCH2OCH3, -O-cyclo-C3H5, -OCH2-cyclo-C3H5, -O-C2H4-cyclo-C3H5, -CHO, -COCH3, -COCF3, -COC2H5, -COC3H7, -COCH(CH3)2, -COC(CH3)3, -COOH, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -OOC-CH3, -OOC-CF3, -OOC-C2H5, -OOC-C3H7, -OOC-CH(CH3)2, -OOC-C(CH3)3, -NH2, -NHCH3, -NHC2H5, -NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC2H5, -NHCOC3H7, -NHCOCH(CH3)2, -NHCOC(CH3)3, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONHCH(CH3)2, -CONH-cyclo-C3H5, -CONHC(CH3)3, -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -SO2NH2, -SO2NHCH3, -SO2NHC2H5, -SO2NHC3H7, -SO2NHCH(CH3)2, -SO2NH-cyclo-C3H5, -SO2NHC(CH3)3, -SO2N(CH3)2, -SO2N(C2H5)2, -SO2N(C3H7)2, -SO2N[CH(CH3)2]2,-SO2N[C(CH3)3]2, -NHSO2C, H3, -NHSO2CF3, -NHSO2C2H5, -NHSO2C3H7, -NHSO2CH(CH3)2, -NHSO2C(CH3)3, -CH=CH2, -CH2-CH=CH2 , -C(CH3)=CH2, -CH=CH-CH3, -C≡CH, -C≡C-CH3, -CH2-C≡CH, -Ph, -O-Ph, -O-CH2-Ph, -C(=NH)NH2, or

[0084] [ka] represents;

[0085] R 6 , R 11 , R 12 , R 21 ~R 23 , R 33 ~R 35 , R 40 , R 41 , R 46 , and R 47 are, independently of one another, -H, -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6H 11 , -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-C5H9, -CH2-cyclo-C6H 11 , -CH2-Ph, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -COO-C(CH3)3, -COO-CH2Ph, or -CH2CH2SCH3; R 24 ~R 27 , R 36a ~R 39a , R 36b ~R 39b , R 42a ~R 45a , and R 42b ~R 45bare, independently of one another, -H, -F, -Cl, -Br, -I, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -CH2-CH 2I, -OCH3, -OC2H5, -OC3H7, -OCH(CH3)2, -OC(CH3)3, -OC4H9, -OCHF2, -OCF3, -OCH2CF3, -OC2F5, -OCH2OCH3, -O-cyclo-C3H5, -OCH2-cyclo-C3H5, -O-C2H4-cyclo-C3H5, -CHO, -COCH3, -COCF3, -COC2H5, -COC3H7, -COCH(CH3)2, -COC(CH3)3, -COOH, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -OOC-CH3, -OOC-CF3, -OOC-C2H5, -OOC-C3H7, -OOC-CH(CH3)2, -OOC-C(CH3)3, -NH2, -NHCH3, -NHC2H5, -NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC2H5, -NHCOC3H7, -NHCOCH(CH3)2, -NHCOC(CH3)3, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONHCH(CH3)2, -CONH-cyclo-C3H5, -CONHC(CH3)3, -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -SO2NH2, -SO2NHCH3, -SO2NHC2H5, -SO2NHC3H7, -SO2NHCH(CH3)2, -SO2NH-cyclo-C3H5, -SO2NHC(CH3)3, -SO2N(CH3)2, -SO2N(C2H5)2, -SO2N(C3H7)2, -SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2, -NHSO2CH3, -NHSO2CF3, -NHSO2C2H5, -NHSO2C3H7, -NHSO2CH(CH3)2, -NHSO2C(CH3)3, -CH=CH2, -CH^2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -C≡CH, -C≡C-CH3, -CH2-C≡CH, -Ph, -O-Ph, or -O-CH2-Ph; X represents -CN, or -NH2; However, X and R 2 cannot be simultaneously -CN.

[0086] Preferably, L 1 represents -CO-. Preferably, L 2 is -CH2-NH-CO-, or

[0087] [ka] represents;

[0088] Preferably, R 4 and R 5 are each independently -CH3, -CH2CH3, or -CH(CH3)2. More preferably, R 4 and R 5 represents -CH3, -CH2CH3, or -CH(CH3)2. In a preferred embodiment, R 4 and R 5 represents -CH3.

[0089] Preferably, B 1 -H 1 , or -P 1 -H 1 Represents B 2 -H 2 , or -P 2 -H 2 Represents B 3 -H 3 , or -P 3 -H 3 Represents. Preferably, Y 1 , Y 2 , and Y 3 are, independently of each other, -O-, -NR 22 -, -CO-NR 22 -, -NR 22 In a preferred embodiment, Y 1 , Y 2 , and Y 3 is -NR 22 In a preferred embodiment, Y1 is -NH-CO-.

[0090] Preferably, P 1 , P 2 , and P 3 are independent of each other,

[0091] [ka] is selected from

[0092] where R 24 ~R 27 has the meaning defined herein. More preferably, P 1 , P 2 , and P 3 teeth,

[0093] [ka] Represents.

[0094] A preferred embodiment of the present invention relates to compounds of formula (I) wherein R 1 -L 1 -A 1 , or -B 1 represents;R 2 -L 2 -A 2 , -B 2 , or -C 2 represents; and R 3 -A 3 or -B 3 where R 2 If is -CN, R 3 -A 3 where X represents -CN or -NH2, and A 1 , A 2 , A 3 , B 1 , B 2 , B 3 , C 2 , L 1 , L 2 , and R 2has the meaning defined herein.

[0095] Preferably, R 17 ~R 20 and R 28 ~R 32 are, independently of one another, -H, -F, -Cl, -Br, -OH, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C(CH3)3, -NH2, -NHCH3, -NHC2H5, -N(CH3)2, -N(C2H5)2, -OCH3, -OC2H5, or

[0096] [ka] Represents.

[0097] More preferably, R 17 ~R 20 represents -H, and R 28 ~R 32 are, independently of one another, -H, -F, -Br, -OH, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C(CH3)3, -NH2, -N(CH3)2-, -OCH3, or

[0098] [ka] Represents.

[0099] Preferably, R 6 , R 11 , R 12 , R 21 ~R 23 , R 33 ~R 35 , R 40 , R 4 1 , R 46 , and R 47 are each independently -H, -CH3, -COO-C(CH3)3, or -COO-CH2Ph. Most preferably, R 6 , R 11 , R 12 , R 21 ~R23 , R 33 ~R 35 , R 40 , R 41 , R 46 , and R 47 are each independently -H, -CH3, or -COO-C(CH3)3. In a preferred embodiment, R 40 represents -CH3 or -COO-C(CH3)3.

[0100] Preferably, R 24 ~R 27 , R 36a ~R 39a , R 36b ~R 39b , R 42a ~R 45a , and R 42b ~R 45b are each independently H, -F, -Cl, -Br, -OH, -CH, -C2H, -C3H, -CH(CH3), -C(CH3), -NH, -NHCH, -NHC2H, -N(CH3), -N(C2H)2, -OCH, or -OC2H. 24 ~R 27 represents -H. More preferably, R 36a ~R 39a , R 36b ~R 39b , R 42a ~R 45a , and R 42b ~R 45b represents -H. More preferably, R 24 ~R 27 , R 36a ~R 39a , R 36b ~R 39b , R 42a ~R 45a , and R 42b ~R 45b represents -H.

[0101] In a preferred embodiment of the present invention, R 1 are -CH2CH2CH3, -CH2CH=CH2,

[0102] [ka]

[0103] [ka] represents;

[0104] where R 7 , R 8 , R 11 , and R 24 ~R 32 has the meaning defined herein. In an even more preferred embodiment of the present invention, R 1 are -CH2CH2CH3, -CH2CH=CH2,

[0105] [ka] Represents.

[0106] In a preferred embodiment of the present invention, R 2 are -H, -CN, -N(CH3)2,

[0107] [ka] represents;

[0108] where R 11 , R 24 ~R 32 , R 36a ~R 39a , and R 36b ~R 39b has the meaning defined herein. In a further preferred embodiment of the present invention, R 2 -H, -CN,

[0109] [ka] Represents.

[0110] In a preferred embodiment of the present invention, R 3 teeth,

[0111] [ka] represents;

[0112] where R 24 ~R 32 has the meaning defined herein. In an even more preferred embodiment of the present invention, R 3 teeth,

[0113] [ka] Represents.

[0114] A further aspect of the invention relates to compounds of formula (Ia), (Ib), (Ic), and (Id):

[0115] [ka]

[0116] In the formula, X represents -CN, -NH2, or -CH2OH, and R 1 , R 2 , and R 3 has the meaning defined herein. Preferably, X represents -CN or -NH2.

[0117] Preferably, in all formulas (Ia), (Ib), (Ic), and (Id) disclosed herein, R 1 Ha-L 1 -A 1 represents -CO-, and L 1 It has.

[0118] Preferably, in all formulas (Ia), (Ib), (Ic), and (Id), R 2 Ha-L2 -A 2 represents where L 2 is -CH2-NH-CO-, or

[0119] [ka] represents;

[0120] Preferably, in all formulas (Ia), (Ib), (Ic), and (Id), R 2 Ha-NR 4 R 5 where R 4 and R 5 are each independently -CH3, -CH2CH3, or -CH(CH3)2. More preferably, R 4 and R 5 represents -CH3, -CH2CH3, or -CH(CH3)2. In a preferred embodiment, R 4 and R 5 represents -CH3.

[0121] Preferably, in all of formulae (Ia), (Ib), (Ic) and (Id), Te, R 1 -P 1 -Y 1 -H 1 where Y 1 -O-, -NR 22 -, -CO-NR 22 -, -NR 22 In a preferred embodiment, Y 1 is -NR 22 In a preferred embodiment, Y 1 is -NH-CO-.

[0122] Preferably, in all formulas (Ia), (Ib), (Ic), and (Id), R 2 -P 2 -Y 2 -H 2 where Y2 -O-, -NR 22 -, -CO-NR 22 -, -NR 22 In a preferred embodiment, Y 2 is -NR 22 represents -CO-.

[0123] Preferably, in all formulas (Ia), (Ib), (Ic), and (Id), R 3 -P 3 -Y 3 -H 3 where Y 3 -O-, -NR 22 -, -CO-NR 22 -, -NR 22 In a preferred embodiment, Y 3 is -NR 22 represents -CO-.

[0124] Preferably, in all formulas (Ia), (Ib), (Ic), and (Id), R 1 -P 1 -H 1 , or -P 1 -Y 1 -H 1 where P 1 teeth,

[0125] [ka] is selected from

[0126] where H 1 , Y 1 , R 24 ~R 27 has the meaning defined herein. More preferably, P 1 teeth,

[0127] [ka] Represents.

[0128] Preferably, in all formulas (Ia), (Ib), (Ic), and (Id), R 2 -P 2 -H 2 , or -P 2 -Y 2 -H 2 where P 2 teeth,

[0129] [ka] is selected from

[0130] where H 2 , Y 2 , and R 24 ~R 27 has the meaning defined herein. More preferably, P 2 teeth:

[0131] [ka] Represents.

[0132] Preferably, in all formulas (Ia), (Ib), (Ic), and (Id), R 3 -P 3 -H 3 , or -P 3 -Y 3 -H 3 where P 3 teeth,

[0133] [ka] is selected from

[0134] where H 3 , Y 3 , and R 24 ~R 27 has the meaning defined herein. More preferably, P3 teeth,

[0135] [ka] Represents.

[0136] Preferably, in all formulas (Ia), (Ib), (Ic), and (Id), R 17 ~R 20 , and R 28 ~R 32 are, independently of one another, -H, -F, -Cl, -Br, -OH, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C(CH3)3, -NH2, -NHCH3, -NHC2H5, -N(CH3)2, -N(C2H5)2, -OCH3, -OC2H5, or

[0137] [ka] Represents.

[0138] More preferably, in all formulas (Ia), (Ib), (Ic), and (Id), R 17 ~R 20 represents -H, and R 28 ~R 32 are, independently of each other, -H, -F, -Br, -OH, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C(CH3)3, -NH2, -N(CH3)2, -, -OCH3,

[0139] [ka] Represents.

[0140] Preferably, in all formulas (Ia), (Ib), (Ic), and (Id), R 6 , R 11 , R 12 , R 21 ~R 23 , R 33 ~R 35 , R 40 , R41 , R 46 , and R 47 are each independently -H, -CH3, -COO-C(CH3)3, or -COO-CH2Ph. Most preferably, R 6 , R 11 , R 12 , R 21 ~R 23 , R 33 ~R 35 , R 40 , R 41 , R 46 , and R 47 are each independently -H, -CH3, or -COO-C(CH3)3. In a preferred embodiment, R 40 represents -CH3 or -COO-C(CH3)3.

[0141] Preferably, in all formulae (Ia), (Ib), (Ic) and (Id), R 24 ~R 27 , R 36a ~R 39a , R 36b ~R 39b , R 42a ~R 45a , and R 42b ~R 45b represent, independently of one another, H, -F, -Cl, -Br, -OH, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C(CH3)3, -NH2, -NHCH3, -NHC2H5, -N(CH3)2, -N(C2H5)2, -OCH3, or -OC2H5.

[0142] More preferably, R 24 ~R 27 represents -H. More preferably, R 36a ~R 39a , R 36b ~R 39b , R 42a ~R 45a , and R 42b ~R 45b represents -H. More preferably, R 24 ~R 27 , R 36a ~R 39a , R36b ~R 39b , R 42a ~R 45a , and R 42b ~R 45b represents -H.

[0143] Preferably, in all formulas (Ia), (Ib), (Ic), and (Id) disclosed herein, R 1 are -CH2CH2CH3, -CH2CH=CH2,

[0144] [ka]

[0145] [ka] represents;

[0146] where R 7 , R 8 , R 11 , and R 24 ~R 32 has the meaning defined herein. More preferably, in all formulas (Ia), (Ib), (Ic), and (Id) disclosed herein, R 1 are -CH2CH2CH3, -CH2CH=CH2,

[0147] [ka] Represents.

[0148] Preferably, in all formulas (Ia), (Ib), (Ic), and (Id) disclosed herein: R 2 are -H, -CN, -N(CH3)2,

[0149] [ka] represents;

[0150] where R 11 , R 24 ~R 32 , R 36a ~R 39a , and R 36b ~R 39b has the meaning defined herein. More preferably, in all formulas (Ia), (Ib), (Ic), and (Id) disclosed herein, R 2 -H, -CN,

[0151] [ka] Represents.

[0152] Preferably, in all formulas (Ia), (Ib), (Ic), and (Id) disclosed herein: R 3 teeth,

[0153] [ka] represents;

[0154] where R 24 ~R 32 has the meaning defined herein. More preferably, in all formulas (Ia), (Ib), (Ic), and (Id) disclosed herein, R 3 teeth

[0155] [ka] Represents.

[0156] A further aspect of the present invention relates to RNA-binding azetidine compounds of the following formulae (II-1) to (II-6):

[0157] [ka]

[0158] In the formula, R 1 , R 3 , A 2 , A 3 , B 1 and B 2 has the meaning defined herein. A further aspect of the present invention relates to RNA-binding azetidine compounds of the following formulae (II-2) to (II-6):

[0159] [ka]

[0160] In the formula, R 1 , R 3 , A 2 , B 1 and B 2 has the meaning defined herein. Thus, in a preferred embodiment, the present invention relates to compounds of formula (II-1), wherein R 1 and A 3 has the meaning defined herein.

[0161] Preferably, in formula (II-1) disclosed herein, R 1 are -CH2CH2CH3, -CH2CH=CH2,

[0162] [ka]

[0163] [ka] represents;

[0164] where R 7 , R 8 , R 11 , and R 24 ~R32 has the meaning defined herein. More preferably, in formula (II-1) disclosed herein, R 1 are -CH2CH2CH3, -CH2CH=CH2,

[0165] [ka] Represents.

[0166] Preferably, in formula (II-1) disclosed herein, A 3 teeth,

[0167] [ka] represents

[0168] where R 24 ~R 32 has the meaning defined herein. More preferably, in the formula (II-1) disclosed herein, A 3 teeth,

[0169] [ka] Represents.

[0170] Thus, in a preferred embodiment, the present invention relates to compounds of formula (II-2):

[0171] [ka]

[0172] In the formula, R 1 , R 3 and A 2 has the meaning defined herein. Preferably, in formula (II-2) disclosed herein, R 1are -CH2CH2CH3, -CH2CH=CH2,

[0173] [ka] JPEG2025535433000080.jpg39170

[0174] where R 7 , R 8 , R 11 and R 24 ~R 32 has the meaning defined herein. More preferably, in formula (II-2) disclosed herein, R 1 are -CH2CH2CH3, -CH2CH=CH2,

[0175] [ka] Represents.

[0176] Preferably, in formula (II-2) disclosed herein, A 2 teeth,

[0177] [ka] represents

[0178] where R 7 ~R 11 has the meaning defined herein. More preferably, in formula (II-2) disclosed herein, A 2 teeth,

[0179] [ka] Represents.

[0180] Preferably, in formula (II-2) disclosed herein, R 3teeth,

[0181] [ka] represents;

[0182] where R 24 ~R 32 has the meaning defined herein. More preferably, in formula (II-2) disclosed herein, R 3 teeth,

[0183] [ka] Represents.

[0184] Thus, in a preferred embodiment, the present invention relates to compounds of formula (II-3):

[0185] [ka]

[0186] In the formula, R 1 and R 3 has the meaning defined herein. Preferably, in formula (II-3) disclosed herein, R 1 are -CH2CH2CH3, -CH2CH=CH2,

[0187] [ka] JPEG2025535433000088.jpg39169;

[0188] where R 7 , R 8 , R 11 and R 24 ~R 32 has the meaning defined herein. More preferably, in formula (II-3) disclosed herein, R 1 are -CH2CH2CH3, -CH2CH=CH2,

[0189] [ka] Represents.

[0190] Preferably, in formula (II-3) disclosed herein, R 3 teeth,

[0191] [ka] represents;

[0192] where R 24 ~R 32 has the meaning defined herein. More preferably, in formula (II-3) disclosed herein, R 3 teeth,

[0193] [ka] Represents.

[0194] Thus, in a preferred embodiment, the present invention relates to compounds of formula (II-4):

[0195] [ka]

[0196] In the formula, R 1 , R 3 and A 2 has the meaning defined herein. Preferably, in formula (II-4), R 1 are -CH2CH2CH3, -CH2CH=CH2,

[0197] [ka]

[0198] [ka] represents;

[0199] where R 7 , R 8 , R 11 and R 24 ~R 32 has the meaning defined herein. More preferably, in formula (II-4), R 1 are -CH2CH2CH3, -CH2CH=CH2,

[0200] [ka] Represents.

[0201] Preferably, in formula (II-4), A 2 teeth

[0202] [ka] represents

[0203] where R 7 ~R 10 has the meaning defined herein. More preferably, in formula (II-4), A 2 teeth

[0204] [ka] Represents.

[0205] Preferably, in formula (II-4) disclosed herein, R3 teeth

[0206] [ka] represents;

[0207] where R 24 ~R 32 has the meaning defined herein. More preferably, in formula (II-4) disclosed herein, R 3 teeth,

[0208] [ka] Represents.

[0209] Thus, in a preferred embodiment, the present invention relates to compounds of formula (II-5):

[0210] [ka]

[0211] In the formula, R 1 , R 3 , and C 2 has the meaning defined herein. Preferably, in formula (II-5), R 1 are -CH2CH2CH3, -CH2CH=CH2,

[0212] [ka]

[0213] [ka] represents;

[0214] where R 7 , R 8 , R11 , and R 24 ~R 32 has the meaning defined herein. More preferably, in formula (II-5) disclosed herein, R 1 are -CH2CH2CH3, -CH2CH=CH2,

[0215] [ka] Represents.

[0216] Preferably, in formula (II-5) disclosed herein, R 3 teeth,

[0217] [ka] represents;

[0218] where R 24 ~R 32 has the meaning defined herein. More preferably, in formula (II-5) disclosed herein, R 3 teeth,

[0219] [ka] Represents.

[0220] Preferably, in formula (II-5) disclosed herein, C 2 teeth

[0221] [ka] represents;

[0222] where R 28 ~R 32 , R 36a ~R 39a , and R 36b ~R 39bhas the meaning defined herein. More preferably, in formula (II-5) disclosed herein, C 2 teeth,

[0223] [ka] Represents.

[0224] Thus, in a preferred embodiment, the present invention relates to compounds of formula (II-6):

[0225] [ka]

[0226] In the formula, R 3 , B 1 and B 2 has the meaning defined herein. Preferably, in formula (II-6) disclosed herein, B 1 teeth,

[0227] [ka] represents

[0228] where R 24 ~R 32 has the meaning defined herein. More preferably, in formula (II-6) disclosed herein, B 1 teeth,

[0229] [ka] Represents.

[0230] Preferably, in formula (II-6) disclosed herein, B 2 teeth,

[0231] [ka] represents

[0232] where R 24 ~R 32 , R 36a ~R 39a , and R 36b ~R 39b has the meaning defined herein. More preferably, in formula (II-6) disclosed herein, B 2 teeth,

[0233] [ka] Represents.

[0234] Preferably, in formula (II-6) disclosed herein, B 3 teeth

[0235] [ka] represents;

[0236] where R 24 ~R 32 has the meaning defined herein. More preferably, in formula (II-6) disclosed herein, B 3 teeth,

[0237] [ka] Represents.

[0238] Preferably, the compounds of the present invention are selected from the following list: 1-(1-amino-(3-aminothieno[2,3-b]pyridine-2-carbonyl)phenyl-4-carbonyl)-4-(hydroxymethyl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile; 1-(3-aminothieno[2,3-b]pyridine-2-carbonyl)-4-(hydroxymethyl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile; 3-amino-N-((4-(hydroxymethyl)-1-propyl-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidin-2-yl)methyl)thieno[2,3-b]pyridine-2-carboxamide; 1-Allyl-4-((4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile; 3-(4-(1H-benzo[d]imidazol-6-yl)phenyl)-1-(3-aminothieno[2,3-b]pyridine-2-carbonyl)-4-(hydroxymethyl)azetidine-2-carbonitrile; N-((3-(4-(1H-benzo[d]imidazol-6-yl)phenyl)-4-(hydroxymethyl)-1-propylazetidin-2-yl)methyl)-3-aminothieno[2,3-b]pyridine-2-carboxamide; 1-Allyl-4-((4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile; 4-(hydroxymethyl)-1-(4-methylthiazole-2-carbonyl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile; 3-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(4-(methylamino)quinazolin-2-yl)azetidine-2-carbonitrile; 3-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(4-(methylamino)quinazolin-2-yl)azetidine-2-carbonitrile; 1-(3-aminothieno[2,3-b]pyridine-2-carbonyl)-3-(4-(3,5-dimethylisoxazol-4-yl)phenyl)azetidine-2-carbonitrile; 1-(4-(methylamino)quinazolin-2-yl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile; 1-(3-aminothieno[2,3-b]pyridine-2-carbonyl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile; 3-(4-(1H-benzo[d]imidazol-6-yl)phenyl)-1-(4-(methylamino)quinazolin-2-yl)azetidine-2-carbonitrile; tert-butyl 4-(2-amino-4-(4-bromophenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)azetidin-1-yl)piperidine-1-carboxylate; tert-butyl 4-(2-amino-4-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-(4-fluorophenyl)azetidin-1-yl)piperidine-1-carboxylate; Di-tert-butyl 4,4'-(4-amino-3-(4-fluorophenyl)azetidine-1,2-diyl)bis(piperidine-1-carboxylate); Di-tert-butyl 4,4'-(4-amino-3-(4-(4-methylpiperazin-1-yl)phenyl)azetidine-1,2-diyl)bis(piperidine-1-carboxylate); tert-Butyl 4-(2-amino-4-(4-bromophenyl)-3-(4-fluorophenyl)azetidin-1-yl)piperidine-1-carboxylate; tert-butyl 4-(2-amino-4-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-3-(4-fluorophenyl)azetidin-1-yl)piperidine-1-carboxylate; 4-(benzo[d]thiazol-2-yl)-3-(1-methylpiperidin-4-yl)-1-(quinazolin-4-yl)azetidin-2-amine; 4-(benzo[d]thiazol-2-yl)-3-(1-methylpiperidin-4-yl)-1-(pyrimidin-2-yl)azetidin-2-amine; 4-(1H-benzo[d]imidazol-2-yl)-1,3-bis(1-methylpiperidin-4-yl)azetidin-2-amine; 4-(1H-benzo[d]imidazol-2-yl)-3-(3,5-dimethoxyphenyl)-1-(1H-indol-3-yl)azetidin-2-amine; 3-(1-methylpiperidin-4-yl)-1-(9H-purin-6-yl)-4-(4-(trifluoromethyl)phenyl)azetidin-2-amine; 3-(3,5-dimethoxyphenyl)-1-(1-methylpiperidin-4-yl)-4-(4-(thiazol-4-yl)phenyl)azetidin-2-amine; 1-(benzo[d]oxazol-2-yl)-3-(4-(4,5-dihydro-1H-imidazol-2-yl)phenyl)-4-(4-(4-methylpiperazin-1-yl)phenyl)azetidin-2-amine; 3-(3,5-dimethoxyphenyl)-1-(1-methylpiperidin-4-yl)-4-morpholinoazetidin-2-amine; 1-(4,6-dimethoxypyrimidin-2-yl)-4-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-(thiazol-4-yl)phenyl)azetidin-2-amine; 4-(9H-carbazol-9-yl)-1-(1-methylpiperidin-4-yl)-3-(4-(thiazol-4-yl)phenyl)azetidin-2-amine; 1-(1H-benzo[d]imidazol-2-yl)-3-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-4-(4-methylpiperazin-1-yl)azetidin-2-amine; 3-(3,5-dimethoxyphenyl)-4-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(1-methylpiperidin-4-yl)azetidin-2-amine; and 4-(Benzo[d]thiazol-2-yl)-3-(3,5-dimethoxyphenyl)-1-(1-methylpiperidin-4-yl)azetidin-2-amine.

[0239] More preferably, the compound of the present invention is selected from the following list: 3-amino-N-((4-(hydroxymethyl)-1-propyl-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidin-2-yl)methyl)thieno[2,3-b]pyridine-2-carboxamide; 1-Allyl-4-((4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile; N-((3-(4-(1H-benzo[d]imidazol-6-yl)phenyl)-4-(hydroxymethyl)-1-propylazetidin-2-yl)methyl)-3-aminothieno[2,3-b]pyridine-2-carboxamide; 1-Allyl-4-((4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile; 3-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(4- (Methylamino)quinazolin-2-yl)azetidine-2-carbonitrile; 3-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(4-(methylamino)quinazolin-2-yl)azetidine-2-carbonitrile; 1-(3-aminothieno[2,3-b]pyridine-2-carbonyl)-3-(4-(3,5-dimethylisoxazol-4-yl)phenyl)azetidine-2-carbonitrile; 1-(4-(methylamino)quinazolin-2-yl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile; 1-(3-aminothieno[2,3-b]pyridine-2-carbonyl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile; 3-(4-(1H-benzo[d]imidazol-6-yl)phenyl)-1-(4-(methylamino)quinazolin-2-yl)azetidine-2-carbonitrile; tert-butyl 4-(2-amino-4-(4-bromophenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)azetidin-1-yl)piperidine-1-carboxylate; tert-butyl 4-(2-amino-4-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-(4-fluorophenyl)azetidin-1-yl)piperidine-1-carboxylate; Di-tert-butyl 4,4'-(4-amino-3-(4-fluorophenyl)azetidine-1,2-diyl)bis(piperidine-1-carboxylate); Di-tert-butyl 4,4'-(4-amino-3-(4-(4-methylpiperazin-1-yl)phenyl)azetidine-1,2-diyl)bis(piperidine-1-carboxylate); tert-Butyl 4-(2-amino-4-(4-bromophenyl)-3-(4-fluorophenyl)azetidin-1-yl)piperidine-1-carboxylate; tert-butyl 4-(2-amino-4-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-3-(4-fluorophenyl)azetidin-1-yl)piperidine-1-carboxylate; 4-(benzo[d]thiazol-2-yl)-3-(1-methylpiperidin-4-yl)-1-(quinazolin-4-yl)azetidin-2-amine; 4-(benzo[d]thiazol-2-yl)-3-(1-methylpiperidin-4-yl)-1-(pyrimidin-2-yl)azetidin-2-amine; 4-(1H-benzo[d]imidazol-2-yl)-1,3-bis(1-methylpiperidin-4-yl)azetidin-2-amine; 4-(1H-benzo[d]imidazol-2-yl)-3-(3,5-dimethoxyphenyl)-1-(1H-indol-3-yl)azetidin-2-amine; 3-(1-methylpiperidin-4-yl)-1-(9H-purin-6-yl)-4-(4-(trifluoromethyl)phenyl)azetidin-2-amine; 3-(3,5-dimethoxyphenyl)-1-(1-methylpiperidin-4-yl)-4-(4-(thiazol-4-yl)phenyl)azetidin-2-amine; 1-(benzo[d]oxazol-2-yl)-3-(4-(4,5-dihydro-1H-imidazol-2-yl)phenyl)-4-(4-(4-methylpiperazin-1-yl)phenyl)azetidin-2-amine; 3-(3,5-dimethoxyphenyl)-1-(1-methylpiperidin-4-yl)-4-morpholinoazetidin-2-amine; 1-(4,6-dimethoxypyrimidin-2-yl)-4-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-(thiazol-4-yl)phenyl)azetidin-2-amine; 4-(9H-carbazol-9-yl)-1-(1-methylpiperidin-4-yl)- 3-(4-(thiazol-4-yl)phenyl)azetidin-2-amine; 1-(1H-benzo[d]imidazol-2-yl)-3-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-4-(4-methylpiperazin-1-yl)azetidin-2-amine; 3-(3,5-dimethoxyphenyl)-4-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(1-methylpiperidin-4-yl)azetidin-2-amine; and 4-(Benzo[d]thiazol-2-yl)-3-(3,5-dimethoxyphenyl)-1-(1-methylpiperidin-4-yl)azetidin-2-amine.

[0240] More preferably, the compound of the present invention is selected from the following list: 1-(3-aminothieno[2,3-b]pyridine-2-carbonyl)-4-(hydroxymethyl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile; 3-(4-(1H-benzo[d]imidazol-6-yl)phenyl)-1-(3-aminothieno[2,3-b]pyridine-2-carbonyl)-4-(hydroxymethyl)azetidine-2-carbonitrile; cis-N-((3-(4-(1H-benzo[d]imidazol-6-yl)phenyl)-4-(hydroxymethyl)-1-propylazetidin-2-yl)methyl)-3-aminothieno[2,3-b]pyridine-2-carboxamide; trans-N-((3-(4-(1H-benzo[d]imidazol-6-yl)phenyl)-4-(hydroxymethyl)-1-propylazetidin-2-yl)methyl)-3-aminothieno[2,3-b]pyridine-2-carboxamide; 1-Allyl-4-((4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile; cis-4-(hydroxymethyl)-1-(4-methylthiazole-2-carbonyl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile; trans-4-(hydroxymethyl)-1-(5-methyloxazole-2-carbonyl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile; 3-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(4-(methylamino)quinazolin-2-yl)azetidine-2-carbonitrile; cis-1-(3-aminothieno[2,3-b]pyridine-2-carbonyl)-3-(4-(3,5-dimethylisoxazol-4-yl)phenyl)azetidine-2-carbonitrile; trans-1-(3-aminothieno[2,3-b]pyridine-2-carbonyl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile; and 3-(4-(1H-benzo[d]imidazol-6-yl)phenyl)-1-(4-(methylamino)quinazolin-2-yl)azetidine-2-carbonitrile.

[0241] More preferably, the compound of the present invention is selected from the following list: cis-N-((3-(4-(1H-benzo[d]imidazol-6-yl)phenyl)-4-(hydroxymethyl)-1-propylazetidin-2-yl)methyl)-3-aminothieno[2,3-b]pyridine-2-carboxamide; trans-N-((3-(4-(1H-benzo[d]imidazol-6-yl)phenyl)-4-(hydroxymethyl)-1-propylazetidin-2-yl)methyl)-3-aminothieno[2,3-b]pyridine-2-carboxamide; 1-Allyl-4-((4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile; 3-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(4-(methylamino)quinazolin-2-yl)azetidine-2-carbonitrile; cis-1-(3-aminothieno[2,3-b]pyridine-2-carbonyl)-3-(4-(3,5-dimethylisoxazol-4-yl)phenyl)azetidine-2-carbonitrile; trans-1-(3-aminothieno[2,3-b]pyridine-2-carbonyl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile; and 3-(4-(1H-benzo[d]imidazol-6-yl)phenyl)-1-(4-(methylamino)quinazolin-2-yl)azetidine-2-carbonitrile.

[0242] The compounds of general formulae (I), (Ia), (Ib), (Ic), (Id), (II-1), (II-2), (II-3), (II-4), (II-5), and (II-6) may exist in the form of optical isomers, i.e., diastereomers, enantiomers, and mixtures of said isomers in all ratios, for example, racemic mixtures. The present invention includes all such forms, in particular pure diastereomeric or enantiomeric forms. The different isomers may be separated or resolved one from the other by conventional methods, or any isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric synthesis.

[0243] medical use Another aspect of the present invention relates to the use of the inventive RNA-binding azetidine compounds of general formulae (I), (Ia), (Ib), (Ic), (Id), (II-1), (II-2), (II-3), (II-4), (II-5), and (II-6) as pharmaceuticals, i.e., pharmaceutically active agents applicable in medicines.

[0244] As shown by melting temperature curves measured by differential scanning fluorimetry (DSF), compounds of general formulas (Ia), (Ib), (Ic), (Id), (II-1), (II-2), (II-3), (II-4), (II-5), and (II-6) contain a stem-loop (hairpin) structural motif and exhibit high binding ability to microRNAs. Surprisingly, it has been found that compounds according to general formulas (Ia), (Ib), (Ic), (Id), (II-1), (II-2), (II-3), (II-4), (II-5), and (II-6), as well as their pharmaceutically acceptable salts, exhibit antiproliferative and anticancer activity, thereby modulating the function and / or activity of microRNAs. Thus, compounds according to general formulas (Ia), (Ib), (Ic), (Id), (II-1), (II-2), (II-3), (II-4), (II-5), and (II-6), as well as pharmaceutically acceptable salts thereof, are useful as microRNA binding agents.

[0245] As used herein, the term "microRNA binder" refers to a small molecule compound that binds to one or more structural motifs in an RNA molecule, including stem-loops, internal loops, bulges, three-stem junctions, tetraloops, and pseudoknots.

[0246] As used herein, "misexpression" refers to a non-wild-type gene expression pattern. Misexpression includes: expression at a non-wild-type level, i.e., overexpression or underexpression; an expression pattern that differs from the wild-type in terms of the time or stage at which the microRNA is expressed, such as increased or decreased expression (compared to the wild-type) during a given developmental period or stage; a difference from the wild-type in terms of decreased expression (compared to the wild-type) in a given cell type or tissue type. Differential expression pattern: An expression pattern that differs from the wild type in terms of the effect of environmental or extracellular stimuli on microRNA expression, such as an increased or decreased pattern of expression (compared to the wild type) in the presence of increased or decreased stimulus strength.

[0247] Thus, the present invention relates to the use of the compounds of the invention of formula (I) or regioisomers, diastereomers, enantiomers, mixtures of regioisomers, mixtures of diastereomers, mixtures of enantiomers, solvates, hydrates or pharmaceutically acceptable salts thereof in the treatment and / or prevention of diseases caused by and / or associated with microRNA expression or microRNA misexpression.

[0248] [ka]

[0249] During the ceremony, R 1 is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -(CH2)3CH3, -(CH2)4CH3, -(CH2)5CH3, -CH2CH(CH3)2, -(CH2)2CH(CH3 )2, -CH(CH2CH3)CH3, -CH(CH2CH3)2, -C(CH3)3, -CH2CH=CH2, -(CH2)2CH=CH2, -(CH2)3CH=CH2, -(CH2)4CH=CH2, -L 1 -A 1 , or -B 1 represents; R 2 -H, -CN, -NR 4 R 5 , -L 2 -A 2 , -B 2 , or -C 2 represents; R 3 -A 3 or -B 3 where R 2 If is -CN, R 3 A-A 3 and; L 1 represents -CO- or -SO2-; L 2 is -CH2-NR 6 -CO-, -CH2-NR6 -SO2-, or

[0250] [ka] represents;

[0251] R 4 and R 5 are, independently of one another, -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6H 11 , -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-C5H9, -CH2-cyclo-C6H 11 , -CH2-Ph, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, or -CH2CH2SCH3; A 1 and A 2 are independent of each other,

[0252] [ka]

[0253] [ka] Selected from;

[0254] A 3 teeth,

[0255] [ka] represents;

[0256] [ka] having C selected from:

[0257] B 1 -H1 , -P 1 -H 1 , or -P 1 -Y 1 -H 1 represents; B 2 -H 2 , -P 2 -H 2 , or -P 2 -Y 2 -H 2 represents; B 3 -H 3 , -P 3 -H 3 , or -P 3 -Y 3 -H 3 represents; C 2 teeth:

[0258] [ka] Selected from;

[0259] Y 1 , Y 2 , and Y 3 are independently: -O-, -NR 22 -, -CO-NR 22 -, -NR 22 -CO-, -SO2-NR 22 -, -NR 22 -SO2- or -NR 22 -CO-NR 23 -Selected from; P 1 , P 2 , and P 3 are independent of each other,

[0260] [ka] Selected from;

[0261] H 1 , H 2 , and H 3 are independent of each other,

[0262] [ka]

[0263] [ka]

[0264] [ka]

[0265] [ka]

[0266] [ka] Selected from;

[0267] R 17 ~R 20 and R 28 ~R 32are, independently of each other, -H, -F, -Cl, -Br, -I, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -CH2-CH2I, -OCH3, -OC2H5, -OC3H7, -OCH(CH3)2, -OC(CH3)3, -OC4H9, -OCHF2, -OCF3, -OCH2CF3, -OC2F5, -OCH2OCH3, -O-cyclo-C3H5, -OCH2-cyclo-C3H5, -O-C2H4-cyclo-C3H5, -CHO, -COCH3, -COCF3, -COC2H5, -COC3H7, -COCH(CH3)2, -COC(CH3)3, -COOH, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -OOC-CH3, -OOC-CF3, -OOC-C2H5, -OOC-C3H7, -OOC-CH(CH3)2, -OOC-C(CH3)3, -NH2, -NHCH3, -NHC2H5, -NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC2H5, -NHCOC3H7, -NHCOCH(CH3)2, -NHCOC(CH3)3, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONHCH(CH3)2, -CONH-cyclo-C3H5, -CONHC(CH3)3, -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -SO2NH2, -SO2NHCH3, -SO2NHC2H5, -SO2NHC3H7, -SO2NHCH(CH3)?? It seems there is an incomplete part in the original text after "-SO2NHCH(CH3)2, -SO2NH-cyclo-C3H5, -SO2NHC(CH3)3, -SO2N(CH3)2, -SO2N(C2H5)2, -SO2N(C3H7)2, -SO2N[CH(CH3)2]2,". Please check and provide the complete text if needed for a more accurate translation.-SO2N[C(CH3)3]2, -NHSO2C, H3, -NHSO2CF3, -NHSO2C2H5, -NHSO2C3H7, -NHSO2CH(CH3)2, -NHSO2C(CH3)3, -CH=CH2, -CH2-CH=CH2 , -C(CH3)=CH2, -CH=CH-CH3, -C≡CH, -C≡C-CH3, -CH2-C≡CH, -Ph, -O-Ph, -O-CH2-Ph, -C(=NH)NH2, or

[0268] [ka] represents;

[0269] R 6 , R 11 , R 12 , R 21 ~R 23 , R 33 ~R 35 , R 40 , R 41 , R 46 , and R 47 are, independently of one another, -H, -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6H 11 , -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-C5H9, -CH2-cyclo-C6H 11 , -CH2-Ph, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -COO-C(CH3)3, -COO-CH2Ph, or -CH2CH2SCH3; R 24 ~R 27 , R 36a ~R 39a , R 36b ~R 39b , R 42a ~R 45a , and R 42b ~R 45bare, independently of one another, -H, -F, -Cl, -Br, -I, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF 2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -CH2-CH2I, -OCH3, -OC2H5, -OC3H7, -OCH(CH3)2, -OC(CH3)3, -OC4H9, -OCHF2, -OCF3, -OCH2CF3, -OC2F5, -OCH2OCH3, -O-cyclo-C3H5, -OCH2-cyclo-C3H5, -O-C2H4-cyclo-C3H5, -CHO, -COCH3, -COCF3, -COC2H5, -COC3H7, -COCH(CH3)2, -COC(CH3)3, -COOH, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -OOC-CH3, -OOC-CF3, -OOC-C2H5, -OOC-C3H7, -OOC-CH(CH3)2, -OOC-C(CH3)3, -NH2, -NHCH3, -NHC2H5, -NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC2H5, -NHCOC3H7, -NHCOCH(CH3)2, -NHCOC(CH3)3, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONHCH(CH3)2, -CONH-cyclo-C3H5, -CONHC(CH3)3, -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -SO2NH2, -SO2NHCH3, -SO2NHC2H5, -SO2NHC3H7, -SO2NHCH(CH3)2, -SO2NH-cyclo-C3H5, -SO2NHC(CH3)3, -SO2N(CH3)2, -SO2N(C2H5)2, -SO2N(C3H7)2, -SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2, -NHSO2CH3, -NHSO2CF3, -NHSO2C2H5, -NHSO2C3H7, -NHSO2CH(CH3)2, -NHSO2C(CH3)3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -C≡CH, -C≡C-CH3, -CH2-C≡CH, -Ph, -O-Ph, or -O-CH2-Ph; X represents -CN, -NH2, or -CH2OH; preferably, it represents -CN or -NH2.

[0270] Preferably, X represents -CN or -NH2. Furthermore, the present invention relates to the use of compounds according to general formulas (I), (Ia), (Ib), (Ic), (Id), (II-1), (II-2), (II-3), (II-4), (II-5), and (II-6), and pharmaceutically acceptable salts thereof, for the prevention and / or treatment of diseases caused by and / or associated with microRNA expression or microRNA misexpression. In one embodiment, the compounds of the present invention according to general formulas (I), (Ia), (Ib), (Ic), (Id), (II-1), (II-2), (II-3), (II-4), (II-5), and (II-6), and pharmaceutically acceptable salts thereof, can be used for the prevention and / or treatment of diseases caused by and / or associated with microRNA expression or microRNA misexpression, wherein the compounds modulate the function and / or activity of microRNA.

[0271] In a preferred embodiment, the present invention relates to compounds according to general formulas (I), (Ia), (Ib), (Ic), (Id), (II-2), (II-3), (II-4), (II-5), and (II-6), and pharmaceutically acceptable salts thereof, for the prevention and / or treatment of diseases caused by and / or associated with microRNA expression or microRNA misexpression. In one embodiment, the compounds of the present invention according to general formulas (I), (Ia), (Ib), (Ic), (Id), (II-2), (II-3), (II-4), (II-5), and (II-6), and pharmaceutically acceptable salts thereof, inhibit microRNA expression or microRNA misexpression. The compounds can be used for the prevention and / or treatment of diseases caused by and / or associated with microRNA expression or microRNA misexpression, wherein the compounds modulate the function and / or activity of a microRNA.

[0272] In one embodiment, the compounds of the present invention according to general formula (I), (Ia), (Ib), (Ic), (Id), (II-1), (II-2), (II-3), (II-4), (II-5), and (II-6), as well as pharmaceutically acceptable salts thereof, can be used for the prevention and / or treatment of diseases caused by and / or associated with microRNA expression or microRNA misexpression, wherein said disease is selected from cancer, tumor, metastasis, viral infection, immune disease, autoimmune disease, inflammatory disease, diabetes, cardiovascular disease, metabolic disease, and neurodegenerative disease.

[0273] In other embodiments, the compounds of the present invention according to general formula (I), (Ia), (Ib), (Ic), (Id), (II-2), (II-3), (II-4), (II-5), and (II-6), as well as their pharmaceutically acceptable salts, can be used for the prevention and / or treatment of diseases caused by and / or associated with microRNA expression or microRNA misexpression, wherein said disease is selected from cancer, tumor, metastasis, viral infection, immune disease, autoimmune disease, inflammatory disease, diabetes, cardiovascular disease, metabolic disease, and neurodegenerative disease.

[0274] Thus, the compounds of the present invention can be used for the prevention and / or treatment of cancer, tumors, metastasis, viral infections, immune diseases, autoimmune diseases, inflammatory diseases, diabetes, cardiovascular diseases, metabolic diseases, and neurodegenerative diseases.

[0275] More specifically, tumors, cancers or metastases that can be treated and / or prevented by the compounds of the present invention include adenocarcinoma, choroidal melanoma, acute leukemia, acoustic neurinoma, ampullary carcinoma, anal carcinoma, astrocytoma, basal cell carcinoma, pancreatic cancer, desmoid tumor, bladder cancer, bronchial carcinoma, estrogen-dependent and -independent breast cancer, Burkitt's lymphoma, endometrial cancer, CUP syndrome (cancer of unknown primary), colon cancer, small intestine cancer, small intestine tumors, ovarian cancer, endometrial cancer, ependymoma, epithelial cancer types, Ewing's tumor, digestive system tumors, stomach cancer, gallbladder ... carcinomas), uterine cancer, cervical cancer, glioblastoma, gynecological tumors, ear, nose, and throat tumors, blood tumors, hairy cell leukemia, urethral cancer, skin cancer, skin-testicular cancer, brain tumors (gliomas), brain metastases, testicular cancer, pituitary tumors, carcinoid, Kaposi's sarcoma, laryngeal cancer, germ cell tumors, bone cancer, colorectal cancer, head and neck tumors (tumors of the ENT region), colon cancer, craniopharyngioma, oral cancer (tumors of the oral region and Cancer of the lip), cancer of the central nervous system, liver cancer, liver metastasis, leukemia, eyelid tumors, lung cancer, lymph node cancer (Hodgkin's / non-Hodgkin's lymphoma), lymphoma, gastric cancer, malignant melanoma, malignant tumors, malignant tumors of the digestive tract, breast cancer, rectal cancer, medulloblastoma, melanoma, meningioma, Hodgkin's disease, mycosis fungoides, nasal cancer, schwannoma, neuroblastoma, kidney cancer, renal cell carcinoma, non-Hodgkin's lymphoma, oligodendroglioma, esophageal cancer, osteolytic and osteogenic cancer, Osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, plasmacytoma, prostate cancer, pharyngeal cancer, rectal cancer, retinoblastoma, vaginal cancer, thyroid cancer, Schneeberger's disease, esophageal cancer, spinaliomas, T-cell lymphoma (mycosis fungoides), thymoma, ductal carcinoma, eye tumors, urethral cancer, urinary tract tumors, urothelial carcinoma, vulvar cancer, appearance of warts, soft tissue tumors, soft tissue sarcoma, Wilms' tumor, cervical cancer, tongue cancer, Invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, lobular carcinoma in situ, small cell lung cancer, non-small cell lung cancer, bronchial adenoma, pleuropulmonary blastoma, mesothelioma, brainstem glioma, hypothalamic glioma, cerebellar astrocytoma, cerebral astrocytoma, neuroectodermal tumor, pineal tumor, uterine sarcoma, salivary gland cancer, anal gland adenocarcinoma, mast cell tumor, pelvic tumor, ureteral tumor, hereditary papillary renal carcinoma, sporadic papillary renal carcinoma, intraocular melanoma, hepatocellular carcinoma (fibroid) Hepatocellular carcinoma (hepatocellular carcinoma with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic cholangiocarcinoma), mixed hepatocellular-cholangiocarcinoma, squamous cell carcinoma, malignant melanoma, Merkel cell skin cancer, non-melanoma skin cancer, hypopharyngeal carcinoma, nasopharyngeal carcinoma, oropharyngeal carcinoma, oral carcinoma, squamous cell carcinoma, oral melanoma, AIDS-related lymphoma, cutaneous T-cell lymphoma, central nervous system lymphoma, malignant fibrous histiocytoma, lymphosarcoma, rhabdomyosarcoma, malignant histiocytosis, fibrosarcoma, hemangiosarcoma, hemangiopericytoma, leiomyosarcoma, canine mammary carcinoma, and feline mammary carcinoma.

[0276] In preferred embodiments, the cancer is selected from breast cancer, colon cancer, pancreatic cancer, and prostate cancer. Furthermore, the compounds of general formula (I), (Ia), (Ib), (Ic), (Id), (II-1), (II-2), (II-3), (II-4), (II-5), and (II-6) are useful for the treatment and / or prevention of immune disorders and / or autoimmune diseases, wherein the immune disorders and / or autoimmune diseases include asthma, diabetes, rheumatic diseases, AIDS, rejection of transplanted organs and tissues, rhinitis, chronic obstructive pulmonary disease, osteoporosis, ulcerative colitis, sinusitis, systemic lupus erythematosus, recurrent infections, atopic dermatitis / eczema and occupational allergies, food allergies, drug allergies, severe anaphylactic reactions, anaphylaxis, symptoms of allergic diseases, primary immunodeficiency diseases, antibody deficiency states, or selected from the group consisting of: cellular immunodeficiency, severe combined immunodeficiency, DiGeorge syndrome, hyper-IgE syndrome, Wiskott-Aldrich syndrome, ataxia-telangiectasia, immune-mediated cancer, white blood cell deficiency, autoimmune disease, systemic lupus erythematosus, rheumatoid arthritis (RA), multiple sclerosis (MS), immune-mediated or type 1 diabetes, immune-mediated glomerulonephritis, scleroderma, pernicious anemia, alopecia, pemphigus, pemphigus vulgaris, myasthenia gravis, inflammatory bowel disease, Crohn's disease, psoriasis, autoimmune thyroid disease, Hashimoto's disease, dermatomyositis, Goodpasture's syndrome, myasthenia gravis pseudoparalysis, sympathetic ophthalmia, phacogenic uveitis, chronic invasive hepatitis, primary biliary cirrhosis, autoimmune hemolytic anemia, and Weroff's disease.

[0277] The compounds of general formula (I), (Ia), (Ib), (Ic), (Id), (II-1), (II-2), (II-3), (II-4), (II-5), and (II-6) are useful in treating adenovirus, Ebola virus, Epstein-Barr virus, flavivirus, FSME-virus, influenza virus, hantavirus, human immunodeficiency virus ("HIV"), herpes simplex virus ("HSV", type 1 or 2), human herpes virus 6 (HHV-6), human papillomavirus ("HPV", type 16 or 17), human erythrocyte sequestration virus ("ECV"), ... 8), human cytomegalovirus ("HCMV"), human hepatitis B or C virus ("HBV", type B; "HCV", type C), Lassa virus, Lyssavirus (EBL1 or EBL2), Marburg virus, norovirus, parvovirus B19, pestivirus, poliovirus, respiratory syncytial virus, rhinovirus, rotavirus, SARS-associated coronavirus, and varicella-zoster virus.

[0278] Furthermore, the compounds of the present invention of general formula (I), (Ia), (Ib), (Ic), (Id), (II-1), (II-2), (II-3), (II-4), (II-5), and (II-6) are useful for the treatment and / or prevention of inflammatory diseases, wherein the inflammatory diseases are abscess formation, acanthamoeba, acanthamoebiasis, acne vulgaris, actinomycosis, acute inflammatory skin diseases, acute laryngeal infections in adults, acute multifocal macular pigment epitheliopathy, acute (thermal) injury, acute retinal necrosis, acute suppurative otitis media, algal disease, and the like. disorders), allergic contact dermatitis, amyloidosis angioedema, ankylosing spondylitis, aspergillosis, atopic dermatitis, Aujeszky's disease, autoantibodies in vasculitis, babesiosis, bacterial diseases, bacterial laryngitis, bacterial meningitis, Behçet's disease, birdshot choroidopathy, blastomycosis, Borna disease, brucellosis, bullous tympanocytosis, bursitis, candidiasis, canine distemper encephalomyelitis, canine distemper encephalomyelitis in young animals, canine ehrlichiosis, canine herpesvirus Encephalomyelitis, cholesteatomatous otitis media, chronic (granulomatous) disease, chronic inflammatory skin disease, chronic relapsing encephalomyelitis, chronic suppurative otitis media, cicatricial pemphigoid, coccidiomycosis, coccidioidomycosis, common upper respiratory tract infections, contact ulcers and granulomas, Crohn's disease, cryptococcosis, cysticercosis, dermatomyositis, diphtheria, discoid lupus erythematosus, drug-induced vasculitis, drug or hypersensitivity reactions, encephalitozoonosis, eosinophilic meningoencephalitis, erythema multiforme (EM minor), feline leukemia virus, feline immunodeficiency Whole viruses, feline infectious peritonitis, feline polioencephalomyelitis, feline spongiform encephalopathy, fibromyositis, Fuchs' heterochromic iritis, gastroesophageal (laryngopharyngeal) reflux disease, giant cell arteritis, glanders, glaucoma ciliary body disease, gonococcal granular myringitis, granulomatous meningoencephalomyelitis, herpes simplex, histoplasmosis, idiopathic diseases, idiopathic inflammatory diseases, immune and idiopathic diseases, infections in immunocompromised hosts, canine infectious hepatitis, inhalation laryngitis, interstitial nephritis, irritant contact dermatitis, juvenile rheumatoid arthritis, Kawasaki disease, La Crosse virus encephalitis, laryngeal abscess, laryngotracheitis (croup), leishmaniasis, lens-induced uveitis, leprosy, leprosy Ptospirosis, Leukemia, Lichen Planus, Lupus, Lyme Disease, Lymphoma, Meningitis, Greyhound Meningoencephalitis, Miscellaneous Meningitis / Meningoencephalitis, Microscopic Polyangiitis, Multifocal Choroiditis, Multifocal Distemper Encephalomyelitis in Adult Animals, Multiple Sclerosis, Myotonic Dysphonia, Mycotic (Fungal) Diseases, Fungal Diseases of the CNS, Necrotizing Encephalitis, Neosporosis, Geriatric Encephalitis, Onchocerciasis, Parasitic Encephalomyelitis, Parasitic Infections, Pars Planitis, Parvoviral Encephalitis, Pediatric Laryngitis, Pollutant and Inhalant Allergies, Polymyositis, Post-Vaccination Canine Distemper Encephalitis , post-vaccination rabies, prion protein-induced disease, protothecosis, protozoal encephalitis-encephalomyelitis, psoriasis, psoriatic arthritis, pug encephalitis, pyogenic granulomatous meningomyeloencephalitis, rabies, radiation injury, radiation laryngitis, radiation necrosis, relapsing polychondritis, Reiter's syndrome, retinitis pigmentosa, retinoblastoma, rheumatoid arthritis, rickettsial infections, Rocky Mountain spotted fever, salmon poisoning, sarcocystis, sarcoidosis, schistosomiasis, scleroderma, serpiginous choroiditis, Shaker dog disease, Sjogren's syndrome, spastic croup, spirochetal (syphilitic) disease, spongiotic dermatitis,Sporotrichosis, steroid-responsive meningitis-arteritis, Stevens-Johnson syndrome (SJS, EM major), supraglottitis (epiglottitis), sympathetic ophthalmia, syngamus laryngeus, syphilis, systemic lupus erythematosus, systemic vasculitis in sarcoidosis, Takayasu's arteritis, tendinitis (tendonitis), thromboangiitis obliterans (Buerger's disease), canine tick-borne encephalitis, toxic epidermal necrolysis (TEN), toxocariasis, toxoplasmosis, trauma, traumatic laryngitis, trichinosis, trypanosomiasis, tuberculosis, tularemia, ulcerative colitis, urticaria (urticaria) measles (hives), vasculitis, vasculitis and malignant tumors, vasculitis and rheumatoid arthritis, vasculitis in systemic lupus erythematosus, vasculitis in idiopathic inflammatory myopathies, vasculitis of the central nervous system, vasculitis secondary to bacterial, fungal, and parasitic infections, viral diseases, viral laryngitis, vitiligo, vocal overuse, vocal cord hemorrhage, Vogt-Koyanagi-Harada syndrome, Wegener's granulomatosis, and Whipple's disease,

[0279] Furthermore, the compounds of the present invention of general formula (I), (Ia), (Ib), (Ic), (Id), (II-1), (II-2), (II-3), (II-4), (II-5), and (II-6) are useful for the treatment and / or prevention of cardiovascular diseases, wherein cardiovascular diseases include hypercholesterolemia, diabetic dyslipidemia, hypertension, arteriosclerosis, atherosclerosis, myocardial infarction, acute coronary syndrome, angina pectoris, congestive heart failure, aortic aneurysm, aortic dissection, iliac or femoral aneurysm, pulmonary embolism, primary hypertension, atrial fibrillation, stroke, transient ischemic attack, systolic dysfunction, diastolic dysfunction, myocarditis, atrial tachycardia, ventricular fibrillation, endocarditis, arteriopathy, vasculitis, atherosclerotic plaque, vulnerable plaque, acute coronary syndrome, acute ischemic attack, sudden cardiac death, peripheral vascular disease, coronary artery disease (CAD), peripheral arterial disease (PAD), and cerebrovascular disease.

[0280] Furthermore, the compounds of the present invention of general formula (I), (Ia), (Ib), (Ic), (Id), (II-1), (II-2), (II-3), (II-4), (II-5), and (II-6) are useful for the treatment and / or prevention of metabolic diseases, wherein the metabolic diseases are selected from the group including or consisting of acid-base imbalances, metabolic bone diseases, metabolic brain diseases, calcium metabolism disorders, DNA repair deficiencies, glucose metabolism disorders, hyperlactatemia, iron metabolism disorders, lipid metabolism disorders, malabsorption syndromes, metabolic syndromes, metabolic, inborn errors, mitochondrial diseases, phosphorus metabolism disorders, porphyrias, protein homeostasis deficiencies, skin diseases, metabolic, wasting syndromes, and water-electrolyte imbalances.

[0281] Furthermore, the compounds of the present invention of general formula (I), (Ia), (Ib), (Ic), (Id), (II-1), (II-2), (II-3), (II-4), (II-5), and (II-6) are useful for the treatment and / or prevention of neurodegenerative diseases, wherein the neurodegenerative diseases are ADHD, AIDS-neurological complications, septum pellucidum defect, acquired epileptic aphasia, acute disseminated encephalomyelitis, adrenoleukodystrophy, agenesis of the corpus callosum, agnosia, Aicardi syndrome, Alexander disease, Alpers disease, alternating hemiplegia, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and the like. ), anencephaly, aneurysm, Angelman syndrome, angiomatosis, anoxia, aphasia, apraxia, arachnoid cyst, arachnoiditis, Arnold-Chiari malformation, cerebral arteriovenous malformation, aspartame, Asperger's syndrome, ataxia-telangiectasia, ataxia, attention-deficit hyperactivity disorder, autism, autonomic dysfunction, low back pain, Barth syndrome, Batten disease, Behçet's disease, Bell's palsy, benign essential blepharospasm, benign focal muscular atrophy, benign intracranial hypertension, Bernhard-Ross syndrome, Binswanger's disease, blepharospasm, Bloch-Sulzberger syndrome, brachial plexus birth trauma, arm Plexus injury, Bradbury-Eggleston syndrome, cerebral aneurysm, brain injury, brain and spinal cord tumor, Brown-Séquard syndrome, spinal and bulbar muscular atrophy, Canavan disease, carpal tunnel syndrome, causalgia, cavernoma, cavernous hemangioma, cavernous vascular malformation, central cervical spinal cord injury, central spinal cord injury, central pain syndrome, craniopathy, cerebellar degeneration, cerebellar hypoplasia, cerebral aneurysm, cerebral arteriosclerosis, cerebral atrophy, cerebral beriberi, cerebral gigantism, cerebral hypoxia, cerebral palsy, cerebro-oculofacial skeletal syndrome, Charcot-Marie-Tooth disease, Chiari malformation, chorea, chorea, acanthocytosis, chronic inflammatory demyelinating polyposis Radicular neuropathy (CIDP), chronic orthostatic intolerance, chronic pain, Cockayne syndrome type II, Coffin-Lowry syndrome, coma, persistent vegetative state (PSV), complex regional pain syndrome, congenital facial diplegia, congenital myasthenia, congenital myopathy, congenital vascular cavernous malformations, corticobasal degeneration, cranial arteritis, craniosynostosis, Creutzfeldt-Jakob disease, cumulative trauma disorder, Cushing's syndrome, cytomegalovirus infection, dancing eyes-dancing feet syndrome, Dandy-Walker syndrome, Dawson's disease,Morsier syndrome, Degerines-Kramcke palsy, multi-infarct dementia, subcortical dementia, dementia with Lewy bodies, dermatomyositis, developmental coordination disorder, Devic's syndrome, diabetic neuropathy, diffuse sclerosis, Dravet syndrome, autonomic neuropathy, dysgraphia, dyslexia, dysphagia, dyspraxia, dystonia, early infantile epileptic encephalopathy, empty sella syndrome, encephalitis lethargic, encephalitis and meningitis, encephalocele, encephalopathy, trigeminal angiomatosis, epilepsy, Erb's palsy, Erb's-Duchenne and Degerines-Kramcke palsy, Fabry disease, Fahr's syndrome, syncope, familial dysautonomia, familial hemangiomas, familial idiopathic basal ganglia calcification, familial spastic paraparesis, febrile seizures (e.g., GEFS and GEFS plus), Fisher's syndrome syndrome, floppy baby syndrome, Friedreich's ataxia, Gaucher's disease, Gerstmann's syndrome, Gerstmann-Straussler-Scheinker disease, giant cell arteritis, giant cell inclusion body disease, spherical cell leukodystrophy, glossopharyngeal neuralgia, Guillain-Barré syndrome, HTLV-1-associated myelopathy, Hallervorden-Spatz disease, head trauma, headache, persistent migraine, hemifacial spasm, alternating hemiplegia, hereditary neuropathy, hereditary spastic paraplegia, hereditary ataxia polyneuritis, herpes zoster oticus, herpes zoster, Hirayama syndrome, holoprosencephaly, Huntington's disease, hydranencephaly, normal pressure hydrocephalus, hydrocephalus (especially TGF-β-induced hydrocephalus), hydromyelia, hypercortisolism, hypersomnia, hypertonia, hypotonia, hypoxia, immune-mediated encephalomyelitis, inclusion body myositis, incontinentia pigmenti, infantile myelopathy Hypotonia, infantile phytanic acid storage disease, infantile Refsum's disease, infantile spasms, inflammatory myopathy, intestinal lipodystrophy, intracranial cyst, intracranial hypertension, Isaac's syndrome, Joubert's syndrome, Kearns-Sayre's syndrome, Kennedy's disease, Kinsborn's syndrome, Klein-Levin's syndrome, Klippel-Feil's syndrome, Klippel-Trenaunay's syndrome (KTS), Klüver-Bucy's syndrome, Korsakoff's amnesic syndrome, Krabbe's disease, Kugelberg-Welander's disease, kuru, Lambert-Eaton myasthenic syndrome, Landau-Kleffner's syndrome, lateral thigh Cutaneous nerve entrapment, Lateral bulbar syndrome, Learning disability, Leigh's disease, Lennox-Gastaut syndrome, Lesch-Nyhan syndrome, Leukodystrophy, Levin-Critchley syndrome, Dementia with Lewy bodies, Lissencephaly, Locked-in syndrome, Lou Gehrig's disease, Lupus - neurological sequelae, Lyme disease - neurological complications, Machado-Joseph disease, Megalencephaly, Megalencephaly, Melkerson-Rosenthal syndrome, Meningitis, Menkes disease, Dysesthesias femoral neuralgia, Metachromatic leukodystrophy, Microcephaly, Migraine, Miller-Fisher syndrome, Minor stroke, Mitochondrial myopathy, Möbius syndrome syndrome, monolimb muscular atrophy, motor neuron disease, moyamoya disease, mucolipidosis, mucopolysaccharidosis, multi-infarct dementia, multifocal motor neuropathy, multiple sclerosis (MS), multiple system atrophy (MSA-C and MSA-P), multiple system atrophy with orthostatic hypotension, muscular dystrophy, congenital myasthenia, myasthenia gravis, myelinolytic diffuse sclerosis, infantile myoclonic encephalopathy, myoclonus, congenital myopathy, thyrotoxic myopathy, myopathy, myotonia congenita, myotonia, narcolepsy, neuroacanthocytosis, neurodegeneration with cerebral iron accumulation, neurofibromatosis, nephropathy Neuroleptic malignant syndrome, neurological complications of AIDS, neurological manifestations of Pompe disease, neuromyelitis optica, neuromyotonia, neuronal ceroid lipofuscinosis, neuronal migration disorders, hereditary neuropathies, neurosarcoidosis, neurotoxicity, cavernous nevus, Niemann-Pick disease, O'Sullivan-McLeod syndrome, occipital neuralgia, subclinical spinal dysraphism, Ohtahara syndrome, olivopontocerebellar atrophy, opsoclonus myoclonus, orthostatic hypotension, overuse syndrome, chronic pain, paraneoplastic syndromes, paresthesia, Parkinson's disease, congenital palmyotonia, paroxysmal choreoathetosis,Paroxysmal migraine, Parry-Romberg disease, Pelizaeus-Merzbach disease, Pena-Shokeir II syndrome, radicular cyst, periodic paralysis, peripheral neuropathy, periventricular leukomalacia, persistent vegetative state, pervasive developmental disorder, phytanic acid storage disease, Pick's disease, piriformis syndrome, pituitary tumor, polymyositis, Pompe disease, porencephaly, post-polio syndrome, post-herpetic neuralgia, post-infectious encephalomyelitis, orthostatic hypotension, postural orthostatic tachycardia syndrome, orthostatic tachycardia syndrome, primary lateral sclerosis, prion disease, progressive facial hemifacial atrophy, progressive ataxia, progressive multifocal leukoencephalopathy, progressive sclerosing polio-dystrophy Pfeiffer's disease, progressive supranuclear palsy, pseudotumor cerebri, pyridoxine-dependent and pyridoxine-responsive seizure disorders, Ramsay Hunt syndrome type I, Ramsay Hunt syndrome type II, Rasmussen's encephalitis and other autoimmune epilepsies, reflex sympathetic dystrophy syndrome, infantile Refsum's disease, Refsum's disease, repetitive movement disorder, repetitive stress disorder, restless legs syndrome, retroviral-associated myelopathy, Rett's syndrome, Reye's syndrome, Riley-Day syndrome, SUNCT headache, sacral nerve root cyst, chorea, salivary gland disease, Sandhoff's disease, Schilder's disease, schizencephaly, seizure disorders, septo-optic dysplasia syndrome, severe myoclonic epilepsy in infants (SMEI), shaken baby syndrome, shingles, Shy-Drager syndrome, Sjögren's syndrome, sleep apnea syndrome, sleeping sickness, Soto syndrome, spasticity, spina bifida, spinal cord infarction, spinal cord injury, spinal cord tumor, spinal muscular atrophy, spinocerebellar atrophy, Steele-Richardson-Olszewski syndrome, stiff-person syndrome, striatonigral degeneration, stroke, Sturge-Weber syndrome, subacute sclerosing panencephalitis, subcortical arteriosclerotic encephalopathy, dysphagia, Sydenham chorea, syncope, syphilitic spinal sclerosis, spinal hydromyelopathy, syringomyelia, systemic Lupus erythematosus, tabes dorsalis, tardive dyskinesia, Tarlov cyst, Tay-Sachs disease, temporal arteritis, tethered spinal cord syndrome, Thomsen's disease, thoracic outlet syndrome, thyrotoxic myopathy, painful tics, Todd's palsy, Tourette's syndrome, transient ischemic attack, transmissible spongiform encephalopathy, transverse myelitis, traumatic brain injury, tremor, trigeminal neuralgia, tropical spastic paraplegia, tuberous sclerosis, vascular erectile tumors, vasculitis including temporal arteritis, von Economo disease, von Hippel-Lindau disease (VHL), von Recklinghausen disease, Wallenberg syndrome, Werdnig-Hoffmann disease,Wernicke-Ko, and selected from the group consisting of: Russakoff syndrome, West syndrome, Whipple disease, Williams syndrome, Wilson disease, X-linked spinal-bulbar muscular atrophy, and Zellweger syndrome.

[0282] Furthermore, the compounds according to general formula (I), (Ia), (Ib), (Ic), (Id), (II-1), (II-2), (II-3), (II-4), (II-5), and (II-6), as well as pharmaceutically acceptable salts thereof, are useful for the prevention and / or treatment of diseases caused by and / or associated with microRNA expression or microRNA misexpression, wherein the microRNA comprises a stem-loop (hairpin) structure.

[0283] Furthermore, the compounds according to general formula (I), (Ia), (Ib), (Ic), (Id), (II-1), (II-2), (II-3), (II-4), (II-5), and (II-6), as well as pharmaceutically acceptable salts thereof, are useful for the prevention and / or treatment of diseases caused by and / or associated with microRNA expression or microRNA misexpression, wherein the microRNA is selected from the group consisting of hsa-miR, ... -153-1, hsa-miR-153-2, hsa-miR-18a, hsa-miR-19b-2, hsa-miR-20a, hsa-miR-222, hsa-miR-3180-4, hsa-miR-4267, hsa-miR -487a, hsa-miR-539, hsa-miR-571, hsa-miR-106a, hsa-miR-1197, hsa-miR-1324, hsa-miR-27b, hsa-miR-3178, hsa-miR-548a- 2, hsa-miR-658, hsa-miR-662, hsa-miR-93, hsa-miR-1307, hsa-miR-3147, hsa-miR-375, hsa-miR-378f, hsa-miR-378h, hsa-m iR-422a, hsa-miR-423, hsa-miR-4673, hsa-miR-4761, hsa-let-7e, hsa-miR-150, hsa-miR-181b-2, hsa-miR-186, hsa-miR-25, The human microRNA is selected from hsa-miR-27a, hsa-miR-3130-2, hsa-miR-3616, hsa-miR-381, hsa-miR-382, hsa-miR-449a, hsa-miR-4739, hsa-miR-495, hsa-miR-501, hsa-miR-548g, hsa-miR-548j, hsa-miR-555, hsa-miR-660, hsa-miR-7-1, and hsa-miR-92a-1.

[0284] Furthermore, the compounds according to general formula (I), (Ia), (Ib), (Ic), (Id), (II-1), (II-2), (II-3), (II-4), (II-5), and (II-6), as well as pharmaceutically acceptable salts thereof, are useful for the prevention and / or treatment of diseases caused by and / or associated with microRNA expression or microRNA misexpression, wherein the microRNA comprises a stem-loop region having a sequence set forth in SEQ ID No. 3 to SEQ ID No. 53.

[0285] Pharmaceutical Composition Another aspect of the present invention relates to pharmaceutical compositions comprising at least one compound of the present invention as an active agent, together with at least one pharmaceutically acceptable carrier, excipient, and / or diluent.The pharmaceutical compositions of the present invention can be prepared in a known manner with conventional solid or liquid carriers or conventional solid or liquid diluents, and conventional pharmaceutically prepared adjuvants, at appropriate dosage levels.Preferred formulations are suitable for oral administration.These dosage forms include, for example, pills, tablets, film tablets, coated tablets, capsules, powders, and depots.

[0286] Furthermore, the present invention also includes pharmaceutical formulations for parenteral administration, including dermal, intradermal, intragastric, intracutan, intravascular, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, buccal, percutan, rectal, subcutaneous, sublingual, topical, or transdermal administration, which formulations comprise, in addition to typical excipients and / or diluents, at least one compound according to the present invention.

[0287] Pharmaceutical compositions of the present invention containing at least one compound of the present invention as an active agent will typically be administered with a suitable carrier material selected according to the intended dosage form, i.e., for oral administration, in the form of tablets, capsules (either solid-filled, semi-solid-filled, or liquid-filled), powders for formulation, extrudates, deposits, gels, elixirs, dispersible granules, syrups, suspensions, etc., and in accordance with conventional pharmaceutical practice. For example, when administered orally in the form of tablets or capsules, the active drug component may be combined with any oral non-toxic pharmaceutically acceptable carrier, preferably with an inert carrier such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid-filled capsules), etc. Furthermore, suitable binders, lubricants, disintegrants, and coloring agents may be incorporated into the tablets or capsules. The powders and tablets may contain from about 5% to about 95% by weight of the compounds of the present invention of general formula (I), (Ia), (Ib), (Ic), (Id), (II-1), (II-2), (II-3), (II-4), (II-5), and (II-6) as the active agent.

[0288] Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol, and waxes. Suitable lubricants may include boric acid, sodium benzoate, sodium acetate, sodium chloride, etc. Suitable disintegrants include starch, methylcellulose, guar gum, etc. Sweeteners, flavoring agents, and preservatives may be included as needed. Disintegrants, diluents, lubricants, binders, etc. are described in more detail below.

[0289] Furthermore, the pharmaceutical compositions of the present invention may be formulated in sustained release formulations that provide rate-controlled release of one or more of the components or active ingredients to optimize therapeutic effects such as antihistamine activity. Suitable dosage forms for sustained release include tablets with layers of different disintegration rates, or controlled-release polymer matrices impregnated with the active ingredient and formed into tablets, or capsules containing such impregnated or encapsulated porous polymer matrices.

[0290] Liquid form preparations include solutions, suspensions, and emulsions. Examples include water or water / propylene glycol solutions for parenteral injection, or the addition of sweeteners or opacifiers for oral solutions, suspensions, and emulsions. Liquid form preparations may also include solutions for intranasal administration. Aerosol preparations suitable for inhalation may include solutions and powdered solids, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g., nitrogen. To prepare suppositories, a low-melting fat or wax, such as a mixture of fatty acid glycerides such as cocoa butter, is first melted, and the active ingredient is then dispersed homogeneously therein, for example, by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby solidify.

[0291] Also included are solid preparations which are intended to be converted, shortly before use, to liquid preparations for either oral or parenteral administration, including solutions, suspensions, and emulsions.

[0292] The compounds of the present invention may also be delivered transdermally. The transdermal compositions may take the form of creams, lotions, aerosols, and / or emulsions and may be included in a transdermal patch of the matrix or reservoir type as are known in the art for this purpose.

[0293] The term "capsule" as used herein refers to a specific container or enclosure made of, for example, methylcellulose, polyvinyl alcohol, or modified gelatin or starch for holding or containing a composition containing an active ingredient. Hard-shelled capsules are typically made by blending relatively high-gel-strength gelatin from bone or pigskin. The capsule itself may contain small amounts of colorants, opacifiers, plasticizers, and / or preservatives. By tablet, we mean a compressed or molded solid dosage form, which contains the active ingredient together with a suitable diluent. Tablets may be prepared by compressing mixtures or granulations obtained by wet granulation, dry granulation, or by compression methods well known to those skilled in the art.

[0294] Oral gel refers to the active ingredient dispersed or solubilized in a hydrophilic semi-solid matrix. Constitutional powder refers to a powder blend containing the active ingredient, which can be suspended in, for example, water or juice, and a suitable diluent.

[0295] Suitable diluents are usually substances that make up the majority of the composition or dosage form.Suitable diluents include sugars such as lactose, sucrose, mannitol, and sorbitol, starches derived from wheat, corn, rice, and potato, and celluloses such as microcrystalline cellulose.The amount of diluent in the composition can range from about 5% to about 95% by weight, preferably from about 25% to about 75% by weight, more preferably from about 30% to about 60% by weight of the total composition.

[0296] The term disintegrant refers to a material added to the composition to aid in the disintegration (disintegration) and release of the pharmacologically active ingredients of the drug.Suitable disintegrants include starch, "cold water soluble" modified starch, such as sodium carboxymethyl starch, natural and synthetic gums, such as locust bean, karaya, guar, tragacanth, and agar, cellulose derivatives, such as methylcellulose and sodium carboxymethylcellulose, microcrystalline cellulose, and cross-linked microcrystalline cellulose, such as sodium croscarmellose, alginates, such as alginic acid and sodium alginate, clays, such as bentonite, and effervescent mixtures.The amount of disintegrant in the composition can range from about 2% to about 20% by weight of the composition, more preferably from about 5% to about 10% by weight.

[0297] Binders are substances that bind or "glue" powder particles together, clumping them together by forming granules, thus acting as the "adhesive" in the formulation. Binders add cohesive strength to that already provided by the diluent or bulking agent. Suitable binders include sugars such as sucrose; starches derived from wheat, corn, rice, and potato; natural gums such as acacia, gelatin, and tragacanth; seaweed derivatives such as alginic acid, sodium alginate, and calcium ammonium alginate; cellulose materials such as methylcellulose, sodium carboxymethylcellulose, and hydroxypropylmethylcellulose; polyvinylpyrrolidone; and inorganic compounds such as magnesium aluminum silicate. The amount of binder in the composition may range from about 2% to about 20% by weight of the composition, preferably from about 3% to about 10% by weight, and more preferably from about 3% to about 6% by weight.

[0298] Lubricants reduce friction and wear, helping tablet granules to hold together in the mold after compression. "Lubricant" refers to the type of material added to a dosage form to facilitate its removal from a mold or die. Suitable lubricants include metallic stearates, such as magnesium stearate, calcium stearate, or potassium stearate, stearic acid, high-melting point waxes, and other water-soluble lubricants, such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycol, and D,L-leucine. Because lubricants must be present on the surface of the granules, they are usually added at the very last step before compression. The amount of lubricant in the composition may range from about 0.2% to about 5% by weight of the composition, preferably from about 0.5% to about 2% by weight of the composition, and more preferably from about 0.3% to about 1.5% by weight of the composition.

[0299] Glidants are materials that prevent the components of pharmaceutical compositions from solidifying and improve the flow properties of granules, thus making them flow smoothly and uniformly.Suitable glidants include silicon dioxide and talc.The amount of glidant in the composition can be in the range of about 0.1% to about 5% by weight, preferably about 0.5% to about 2% by weight of the final composition.

[0300] A colorant is an excipient that provides color to a composition or dosage form. Such excipients can include food-grade dyes adsorbed onto a suitable adsorbent, such as clay or aluminum oxide. The amount of colorant can vary from about 0.1% to about 5% by weight of the composition, preferably from about 0.1% to about 1% by weight.

[0301] The pharmaceutical compositions of the present invention are suitable for the treatment and / or prevention of proliferative diseases, tumors, cancers, metastases, immune diseases, autoimmune diseases, and inflammatory diseases. Another aspect of the present invention relates to drug combinations and pharmaceutical compositions comprising at least one compound of general formula (I), (Ia), (Ib), (Ic), (Id), (II-1), (II-2), (II-3), (II-4), (II-5), and (II-6) as an active agent, together with at least one pharmaceutically acceptable carrier, excipient, and / or diluent, and one or more other antitumor or antiretroviral agents. As used herein, the term "drug combination" refers to a combination of at least two pharmaceutically active agents or therapeutic agents, with or without additional components, carriers, diluents, and / or solvents.

[0302] The compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II-1), (II-2), (II-3), (II-4), (II-5), and (II-6) may be administered as the sole pharmaceutical agent or in combination with one or more additional therapeutic agents, where the drug combination does not cause unacceptable side effects. This combination therapy includes the administration of a single pharmaceutical dosage formulation comprising a compound of any one of Formulas (I), (Ia), (Ib), (Ic), (Id), (II-1), (II-2), (II-3), (II-4), (II-5), and (II-6) and one or more additional therapeutic agents in the form of a single pharmaceutical composition, as well as the administration of a compound of Formulas (I), (Ia), (Ib), (Ic), (Id), (II-1), (II-2), (II-3), (II-4), (II-5), and (II-6) and each additional therapeutic agent in their own separate pharmaceutical dosage formulations, i.e., their own separate pharmaceutical compositions. For example, a compound of any one of Formulas (I), (Ia), (Ib), (Ic), (Id), (II-1), (II-2), (II-3), (II-4), (II-5), and (II-6) and a therapeutic agent may be administered to a patient together in a single oral administration composition, such as a tablet or capsule, or each agent may be administered in a separate pharmaceutical composition.

[0303] When separate pharmaceutical compositions are used, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II-1), (II-2), (II-3), (II-4), (II-5), and (II-6) and the one or more additional therapeutic agents may be administered substantially simultaneously (e.g., simultaneously) or separately at staggered times (e.g., sequentially).

[0304] The compounds of the invention may also be used in the treatment of cancer in combination with radiation therapy and / or surgical intervention. Additionally, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II-1), (II-2), (II-3), (II-4), (II-5), and (II-6) may be utilized per se or in compositions in research and diagnostics, or as analytical reference standards, etc., as is well known in the art. [Drawing Description] [Brief explanation of the drawings]

[0305] [Figure 1-1] The melting temperature shift of precursor microRNA-17 hairpins treated with the indicated compounds (A:A1, B:A3, C:A2, D:A4, E:A11) is shown relative to the melting temperature shift of the DMSO control. [Figure 1-2] : Melting temperature shift of precursor microRNA-17 hairpins treated with the indicated compounds (A:A1, B:A3, C:A2, D:A4, E:A11) compared to the melting temperature shift of the DMSO control. [Figure 2-1] The melting temperature shift of precursor microRNA-21 hairpins treated with the indicated compounds (A:A1, B:A3, C:A2, D:A4, E:A11) is shown relative to the melting temperature shift of the DMSO control. [Figure 2-2] : Melting temperature shift of precursor microRNA-21 hairpin treated with the indicated compounds (A:A1, B:A3, C:A2, D:A4, E:A11) compared to that of the DMSO control. [Figure 3]The colony formation results for compounds A10, A11, B2, B5, B8, and B9 are shown compared to DMSO. Compounds A10, A11, B2, B5, B8, and B9 can inhibit MDA-MB-231 cell proliferation, with B2 and B8 having superior antiproliferative potential compared to other selected compounds. [Figure 4-1] The anti-cancer activities of the compounds of the present invention in different cancer cell lines are shown using IC50 curves. Most of the tested compounds showed strong anti-cancer effects in the selected cancer cell lines. [Figure 4-2] The anti-cancer activities of the compounds of the present invention in different cancer cell lines are shown using IC50 curves. Most of the tested compounds showed strong anti-cancer effects in the selected cancer cell lines. [Figure 4-3] The anti-cancer activities of the compounds of the present invention in different cancer cell lines are shown using IC50 curves. Most of the tested compounds showed strong anti-cancer effects in the selected cancer cell lines. [Figure 4-4] The anti-cancer activities of the compounds of the present invention in different cancer cell lines are shown using IC50 curves. Most of the tested compounds showed strong anti-cancer effects in the selected cancer cell lines. [Figure 4-5] The anti-cancer activities of the compounds of the present invention in different cancer cell lines are shown using IC50 curves. Most of the tested compounds showed strong anti-cancer effects in the selected cancer cell lines. [Figure 4-6] The anti-cancer activities of the compounds of the present invention in different cancer cell lines are shown using IC50 curves. Most of the tested compounds showed strong anti-cancer effects in the selected cancer cell lines. [Figure 4-7] The anti-cancer activities of the compounds of the present invention in different cancer cell lines are shown using IC50 curves. Most of the tested compounds showed strong anti-cancer effects in the selected cancer cell lines. [Figure 4-8] The anti-cancer activities of the compounds of the present invention in different cancer cell lines are shown using IC50 curves. Most of the tested compounds showed strong anti-cancer effects in the selected cancer cell lines. [Figure 4-9] The anti-cancer activities of the compounds of the present invention in different cancer cell lines are shown using IC50 curves. Most of the tested compounds showed strong anti-cancer effects in the selected cancer cell lines. [Figure 4-10] The anti-cancer activities of the compounds of the present invention in different cancer cell lines are shown using IC50 curves. Most of the tested compounds showed strong anti-cancer effects in the selected cancer cell lines. [Figure 4-11] The anti-cancer activities of the compounds of the present invention in different cancer cell lines are shown using IC50 curves. Most of the tested compounds showed strong anti-cancer effects in the selected cancer cell lines. [Figure 4-12] The anti-cancer activities of the compounds of the present invention in different cancer cell lines are shown using IC50 curves. Most of the tested compounds showed strong anti-cancer effects in the selected cancer cell lines. [Figure 4-13] The anti-cancer activities of the compounds of the present invention in different cancer cell lines are shown using IC50 curves. Most of the tested compounds showed strong anti-cancer effects in the selected cancer cell lines. [Figure 4-14] The anti-cancer activities of the compounds of the present invention in different cancer cell lines are shown using IC50 curves. Most of the tested compounds showed strong anti-cancer effects in the selected cancer cell lines. [Figure 4-15] The anti-cancer activities of the compounds of the present invention in different cancer cell lines are shown using IC50 curves. Most of the tested compounds showed strong anti-cancer effects in the selected cancer cell lines. [Figure 4-16] The anti-cancer activities of the compounds of the present invention in different cancer cell lines are shown using IC50 curves. Most of the tested compounds showed strong anti-cancer effects in the selected cancer cell lines. [Figure 4-17] The anti-cancer activities of the compounds of the present invention in different cancer cell lines are shown using IC50 curves. Most of the tested compounds showed strong anti-cancer effects in the selected cancer cell lines. [Figure 4-18]The anti-cancer activities of the compounds of the present invention in different cancer cell lines are shown using IC50 curves. Most of the tested compounds showed strong anti-cancer effects in the selected cancer cell lines. [Figure 4-19] The anti-cancer activities of the compounds of the present invention in different cancer cell lines are shown using IC50 curves. Most of the tested compounds showed strong anti-cancer effects in the selected cancer cell lines. [Figure 4-20] The anti-cancer activities of the compounds of the present invention in different cancer cell lines are shown using IC50 curves. Most of the tested compounds showed strong anti-cancer effects in the selected cancer cell lines. [Figure 4-21] The anti-cancer activities of the compounds of the present invention in different cancer cell lines are shown using IC50 curves. Most of the tested compounds showed strong anti-cancer effects in the selected cancer cell lines. [Figure 4-22] The anti-cancer activities of the compounds of the present invention in different cancer cell lines are shown using IC50 curves. Most of the tested compounds showed strong anti-cancer effects in the selected cancer cell lines. [Figure 4-23] The anti-cancer activities of the compounds of the present invention in different cancer cell lines are shown using IC50 curves. Most of the tested compounds showed strong anti-cancer effects in the selected cancer cell lines. [Figure 4-24] The anti-cancer activities of the compounds of the present invention in different cancer cell lines are shown using IC50 curves. Most of the tested compounds showed strong anti-cancer effects in the selected cancer cell lines. [Figure 4-25] The anti-cancer activities of the compounds of the present invention in different cancer cell lines are shown using IC50 curves. Most of the tested compounds showed strong anti-cancer effects in the selected cancer cell lines. [Figure 4-26] The anti-cancer activities of the compounds of the present invention in different cancer cell lines are shown using IC50 curves. Most of the tested compounds showed strong anti-cancer effects in the selected cancer cell lines. [Figure 4-27]The anti-cancer activities of the compounds of the present invention in different cancer cell lines are shown using IC50 curves. Most of the tested compounds showed strong anti-cancer effects in the selected cancer cell lines. [Figure 4-28] The anti-cancer activities of the compounds of the present invention in different cancer cell lines are shown using IC50 curves. Most of the tested compounds showed strong anti-cancer effects in the selected cancer cell lines. [Figure 4-29] The anti-cancer activities of the compounds of the present invention in different cancer cell lines are shown using IC50 curves. Most of the tested compounds showed strong anti-cancer effects in the selected cancer cell lines. [Figure 4-30] The anti-cancer activities of the compounds of the present invention in different cancer cell lines are shown using IC50 curves. Most of the tested compounds showed strong anti-cancer effects in the selected cancer cell lines. [Figure 4-31] The anti-cancer activities of the compounds of the present invention in different cancer cell lines are shown using IC50 curves. Most of the tested compounds showed strong anti-cancer effects in the selected cancer cell lines. [Figure 4-32] The anti-cancer activities of the compounds of the present invention in different cancer cell lines are shown using IC50 curves. Most of the tested compounds showed strong anti-cancer effects in the selected cancer cell lines. DETAILED DESCRIPTION OF THE INVENTION

[0306] The following examples are included to demonstrate preferred embodiments of the invention. It should be understood by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventors to function well in the practice of the invention, and can therefore be considered to constitute preferred modes for such practice. However, those of skill in the art should, in light of the present disclosure, understand that many changes can be made to the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.

[0307] Further modifications and alternative embodiments of various aspects of the invention will be apparent to those skilled in the art upon consideration of this specification. Accordingly, this specification is to be construed as illustrative only, and is for the purpose of teaching those skilled in the art the general manner of carrying out the invention. It is to be understood that the forms of the invention shown and described herein are to be construed as examples of embodiments. Elements and materials may be substituted for those shown and described herein, parts and steps may be reversed, and certain features of the invention may be utilized independently, all of which will become apparent to those skilled in the art after having the benefit of this specification of the invention. Changes may be made in the elements described herein without departing from the spirit and scope of the invention, as set forth in the following claims.

[0308] [Example] A. Chemical synthesis Abbreviations and acronyms: DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; DCM: dichloromethane; DIBAL: diisobutylaluminum hydride; DIPEA: N,N-diisopropylethylamine; DMF: dimethylformamide; Et2O: diethyl ether; EtOAc: ethyl acetate; Et3N: triethylamine; EtOH: ethanol; h: hour min: minute; HOBt: 1-hydroxybenzotriazole; HPLC: high performance liquid chromatography; MeOH: methanol; min: minute; MS: molecular sieves; Ms: methanesulfonyl; MW: microwave; NIS: N-iodosuccinimide; Ns: p-nitrobenzenesulfonyl; PE: petroleum benzine; pH: hydrogen ion index; PyBOP: benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate; RM: reaction mixture; rt: room temperature; TFA: trifluoroacetic acid; TfOH: triflic acid; THF: tetrahydrofuran; TMS: trimethylsilyl; TLC: thin layer chromatography.

[0309] General information about chemical synthesis: Commercially available reagents purchased from Sigma-Aldrich, BLD Pharmatech GmbH, and TCI Deutschland GmbH were used without further purification unless otherwise noted. Solvents were routinely dried and redistilled before use. All reactions were carried out in oven-dried glassware under an inert atmosphere unless otherwise noted. Analytical thin-layer chromatography (TLC) was performed on Kieselgel 60F254 aluminum plates precoated with 0.25 mm thick silica gel. TLC plates were visualized using ultraviolet light and by staining with Hanessian solution (cerium sulfate and ammonium molybdate in aqueous sulfuric acid) or sulfuric acid-ethanol solution.

[0310] Analytical UHPLC-MS and LC-MS were performed on an Agilent 1290 Infinity system equipped with a mass detector. An appropriate gradient system was applied by mixing water (+0.1% TFA) and acetonitrile (+0.1%). Purification of the product was carried out either by column chromatography using Fluka Kieselgel 60 (230-400 mesh) or by a preparative Agilent 1100 HPLC system equipped with a mass detector. 1 H and 13 C NMR spectra were measured on a Varian 400-MR or Varian 700 spectrometer using Me4Si as an internal standard. NMR chemical shifts (δ) are reported in ppm and coupling constants (J) are reported in Hz. High-resolution mass spectra (HRMS) were recorded at the Max-Planck Institute for Molecular Physiology using an Agilent 6210 ESI-TOF mass spectrometer.

[0311] General Procedure 1: The aryl bromide analog was dissolved in 1,4-dioxane. (4-Trifluoromethylphenyl)boronic acid and KPO were added to the solution under N protection. The mixture was heated to 90°C overnight. The solvent was removed in vacuo. The residue was purified by HPLC to give the corresponding title compound.

[0312] General procedure 2 for the synthesis of imines. Rigorous dried 4 Å molecular sieves (1.0 g / mmol) were added to a solution of amine in DCM (5 mL / mmol) at room temperature under N2. After 5 min, the carbonyl compound (1.0 equiv.) was added to the reaction mixture, which was left stirring at room temperature overnight, then filtered through Celite, and the solvent was removed in vacuo to give the crude imine. The imine was then 1 It was judged to be greater than 95% pure by 1 H NMR and was used in the next step without further purification.

[0313] General procedure 3 for the synthesis of sulfonyl azetidinimines. A solution of sulfonyl azide (1.0 mmol) in DCM (2 mL) was treated sequentially with EtN (2.0 mmol), alkyne (1.0 mmol), imine (1.2 mmol), and CuI (0.1 mmol) at room temperature. The reaction mixture was then heated at room temperature for 1 hour. After stirring at room temperature under N2 for 3-5 hours, the solvent was removed in vacuo, and the product was purified by silica gel column chromatography or preparative HPLC to give a pair of diastereomers that could be isolated separately (diastereomeric ratios ranging from 7:1 to 10:1).

[0314] General procedure 4 for deprotection of the Ns functionality from sulfonylazetidinimines. To a solution of p-nitrobenzenesulfonylazetidinimine (0.1 mmol) in DMF was added K2CO3 (0.5 mmol, 5.0 equiv.), followed by benzenethiol (0.25 mmol, 2.5 equiv.). The resulting suspension was stirred at room temperature for 3 hours, after which the solvent was removed in vacuo. The crude product was purified by silica gel column chromatography or preparative HPLC to give the pure product.

[0315] Example A.1: Synthesis of 1-(1-amino-(3-aminothieno[2,3-b]pyridine-2-carbonyl)phenyl-4-carbonyl)-4-(hydroxymethyl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile (A1)

[0316] [ka]

[0317] [ka]

[0318] Intermediate 1: Synthesis of 2-amino-3-(4-bromophenyl)-3-hydroxypropanoic acid 4-Bromobenzaldehyde (100.0 g, 0.54 mol) was dissolved in ethanol (EtOH) in a 2 L round-bottom flask. To the solvent glycine (20.3 g, 0.27 mol) was added KOH (30.3 g, 0.54 mol) in an ice bath. It is essential that the KOH be added in one portion. After about 15 minutes, a thick white precipitate began to form. The reaction mixture was then cooled to 100°C. The mixture was stirred for 2 hours at room temperature under N2. 2N aqueous HCl (400 mL) was added to adjust the pH of the solution to approximately 4. The mixture was then stirred at 60 °C until a homogeneous yellow solution was obtained. The solvent was removed in vacuo to give a suspension with a white precipitate. The precipitate was filtered, and the remaining aqueous solution was washed three times with EtOAc (200 mL). The pH of the aqueous solution was then basified to 9 with concentrated aqueous ammonia, and excess ammonia was removed in vacuo. When the formation of a precipitate was first observed, the reaction mixture was evaporated to one-quarter of its volume. The mixture was filtered, and the resulting filter cake was dried in vacuo to give Intermediate 1 (51.3 g, 0.20 mol). 1HNMR (400MHz, CD3OD): δ3.64(d,1H,J=3.6Hz),5.25(d,1H,J=3.6Hz),7.41(d,2H,J=8.4Hz),7.53(d,2H,J=8.4Hz).

[0319] Intermediate 2: Synthesis of 3-(4-bromophenyl)-2-((tert-butoxycarbonyl)amino)-3-hydroxypropanoic acid Intermediate 1 (32.6 g, 12.5 mmol) was dissolved in 10% aqueous KCO (10% w / v; 500 mL). Di-tert-butyl dicarbonate (34.2 g, 157.0 mmol) was dissolved in 1,4-dioxane (500 mL) and added to the aqueous solution, and the mixture was then stirred at room temperature for 48 hours. The mixture was concentrated in vacuo, taken up in 1N aqueous NaOH (100 mL), and washed twice with EtO (100 mL). The aqueous layer was acidified with 1N aqueous HCl, and the product was extracted three times with EtOAc (200 mL). The organic phase was dried over anhydrous MgSO, filtered, and concentrated in vacuo to give Intermediate 2 (26.7 g, 74.0 mmol), which was isolated and used in the next step without further purification. 1 HNMR (400MHz, CD3OD): δ1.32(s,9H),4.37(d,1H,J=2.7Hz),5.23(d,1H,J=2.7Hz),7.32(d,2H,8.4Hz),7.46(d,2H,J=8.4Hz).

[0320] Intermediate 3: Synthesis of tert-butyl (1-(4-bromophenyl)-1,3-dihydroxypropan-2-yl)carbamate Intermediate 2 (5.29 g, 14.7 mmol) and N-hydroxy-succinimide (1.69 g, 14.7 mmol) were dissolved in EtOAc (200 mL), and the mixture was cooled to 0 °C. N,N'-Dicyclohexyl-carbodiimide (3.00 g, 14.7 mmol) was added, and the reaction mixture was stirred for 30 minutes, warmed to room temperature, and stirred for an additional 30 minutes. It was then cooled to 0 °C and filtered to remove the precipitated by-product, N,N'-dicyclo-hexylurea. The filtrate was concentrated in vacuo, and the residue was dissolved in THF (100 mL). The solution was cooled to 0 °C, and NaBH (5.60 g, 150.0 mmol) was added. The mixture was stirred for 2 minutes, after which water was added dropwise to the mixture until bubbling ceased, followed by the addition of an equal volume of THF over 30 minutes. The mixture was warmed to room temperature and stirred for 5 hours. The dioxane was removed in vacuo, and EtOAc (200 mL) was added. The aqueous layer was then slowly acidified with 1N aqueous HCl. The EtOAc layer was washed with brine and dried over anhydrous MgSO. The mixture was filtered, and the filtrate was concentrated in vacuo to give the crude product (4.56 g, 12.7 mmol). The crude product was purified by silica gel column chromatography eluting with EtOAc / PE (1:4) to give intermediate 3 as a white solid (4.31 g, 12.4 mmol). 1 HNMR (400MHz, CD3OD): δ1.32(s,9H),3.46-3.51(m,1H),3.63-3.73(m,2H),4.88(brs,1H),7.29(d,2H,J=8.3Hz),7.45(d,2H,J=8.3Hz).

[0321] Intermediate 4: Synthesis of 2-amino-1-(4-bromophenyl)propane-1,3-diol Intermediate 3 (4.31 g, 12.4 mmol) was dissolved in 4 M HCl in dioxane. The HCl salt was partitioned between 50 mL of 2N aqueous NaOH and an equal volume of ethyl acetate. The aqueous layer was washed with EtOAc (50 mL). The combined EtOAc fractions were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo to give a waxy solid (2.72 g, 11.1 mmol), which was used without further purification. 1 HNMR(400MHz,CD3OD):δ2.83-2.90(m,1H),3.30-3.35(m,1H),3.46(dd,1H,J=10. 8Hz,4.8Hz),4.56(d,1H,J=6.6Hz),7.29(d,2H,J=8.6Hz),7.49(d,2H,J=8.6Hz).

[0322] Intermediate 5: Synthesis of 2-(allylamino)-1-(4-bromophenyl)propane-1,3-diol Intermediate 4 (2.72 g, 11.1 mmol) was dissolved in PhMe (50 mL). DBU (1.68 g, 11.1 mmol) was added to the reaction mixture, which was stirred for 10 minutes at room temperature. Then, 3-bromoprop-1-ene (1.34 g, 11.1 mmol) was added to the reaction mixture, which was then stirred at 40° C. for 2 hours. Then, water (100 mL) was added to the reaction solution, followed by EtOAc (50 mL). The aqueous phase was extracted three times with EtOAc (100 mL). The combined organic phase was washed with brine and dried over MgSO. The mixture was filtered, and the filtrate was concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography to give Intermediate 5 (1.59 g, 5.60 mmol).

[0323] Intermediates 6a and 6b: Synthesis of 2-(allyl(1-(4-bromophenyl)-1,3-dihydroxypropan-2-yl)amino)acetonitrile Intermediate 5 (1.59 g, 5.60 mmol) was dissolved in acetonitrile (50 mL). To this solution was added potassium carbonate (1.54 g, 11.1 mmol) and 2-bromoacetonitrile (2.00 g, 16.7 mmol), and the resulting heterogeneous mixture was heated to 85 °C. After stirring the mixture for 3 hours, the reaction mixture was concentrated in vacuo. The resulting residue was dissolved in water and EtOAc. The aqueous layer was extracted twice with EtOAc. The combined organic phases were washed with brine and dried over MgSO4, filtered, and the filtrate was concentrated in vacuo to give the crude product, which was purified by silica gel chromatography to give Intermediate 6a (0.76 g, 2.30 mmol) and 6b (0.72 g, 2.20 mmol) as diastereomers.

[0324] Intermediate 7a: Synthesis of 2-(allyl(1-(4-bromophenyl)-1-hydroxy-3-(trityloxy)propan-2-yl)amino)acetonitrile Intermediate 6a (0.72 g, 2.20 mmol) was dissolved in DCM (50 mL), followed by the addition of triethylamine (0.67 g, 6.60 mmol). The reaction mixture was cooled to 0 °C with the addition of trityl chloride (0.93 g, 3.30 mmol). The mixture was stirred overnight and allowed to warm slowly to room temperature. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted twice with DCM. The combined organic phases were dried over MgSO4, filtered, and the filtrate was concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography eluting with EtOAc / PE (gradient: 1:1) to give Intermediate 7a (0.78 g, 1.37 mmol).

[0325] Intermediate 8a: Synthesis of 2-(allyl(1-(4-bromophenyl)-1-chloro-3-(trityloxy)propan-2-yl)amino)acetonitrile To a solution of pyridine (0.54 g, 6.90 mmol) in DCM (30 mL) was added thionyl chloride (0.33 g, 2.80 mmol) at room temperature. The solution was cooled to 0°C. Intermediate 7a was dissolved in DCM (5 mL) and added dropwise to the reaction solution over 3 minutes. The mixture was further The mixture was stirred at 0° C. for 15 minutes. The mixture was neutralized by adding saturated aqueous sodium bicarbonate solution. The mixture was extracted twice with DCM. The combined organic phases were dried over MgSO4. The volatiles were removed in vacuo to give the crude product. The residue was purified by silica gel column chromatography eluting with EtOAc:PE=9:91 to give Intermediate 8a (0.58 g, 1.01 mmol).

[0326] Intermediate 9a: Synthesis of 1-allyl-3-(4-bromophenyl)-4-((trityloxy)methyl)azetidine-2-carbonitrile Intermediate 8a (0.55 g, 0.98 mmol) was dissolved in THF (30 mL). The solution was stirred and cooled to -78°C. Lithium bis(trimethylsilyl)amide (1M A solution of 1.5 mL of THF (1.5 mmol) was added dropwise over 3 minutes. The resulting reaction mixture was stirred at −78° C. for 1 hour. The reaction mixture was quenched with saturated aqueous NH4Cl. The product was extracted three times with EtOAc (30 mL). The combined organic phases were dried over MgSO4, filtered, and the filtrate was concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography eluting with EtOAc:PE=9:91 to give intermediate 9a (0.45 g, 0.82 mmol).

[0327] Intermediate 10a: Synthesis of 1-allyl-3-(4-bromophenyl)-4-(hydroxymethyl)azetidine-2-carbonitrile Intermediate 9a (0.40 g, 0.73 mmol) was dissolved in DCM (20 mL). The reaction solution was cooled to 0 °C. TFA (0.42 g, 3.65 mmol) was added to the mixture. The mixture was stirred overnight and allowed to warm slowly to room temperature. The reaction mixture was quenched with saturated aqueous Na2CO3. The product was extracted three times with EtOAc (30 mL). The combined organic phase was dried over MgSO4, filtered, and the filtrate was concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography eluting with EtOAc:PE (gradient: 1:4 to 1:1) to give Intermediate 10a (0.21 g, 0.68 mmol).

[0328] Intermediate 11a: Synthesis of 3-(4-bromophenyl)-4-(hydroxymethyl)azetidine-2-carbonitrile Intermediate 10a (100.0 mg, 0.33 mmol) was dissolved in DCM / EtOH (v / v 1:2, 12 mL). To the reaction mixture, 1,3-dimethylbarbituric acid (76.3 mg, 0.49 mmol) and Pd(PPh3)4 (18.8 mg, 0.016 mmol) were added under N2 protection. The mixture was heated at 40 °C overnight. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography eluting with DCM:MeOH (40:1) to give Intermediate 11a (70.2 mg, 0.26 mmol).

[0329] Intermediate 12a: Synthesis of 3-amino-N-(4-(3-(4-bromophenyl)-2-cyano-4-(hydroxymethyl)azetidine-1-carbonyl)phenyl)thieno[2,3-b]pyridine-2-carboxamide 4-(3-aminothieno[2,3-b]pyridine-2-carboxamido)benzoic acid (80.9 mg, 258.2 μmol) was dissolved in DMF (10 mL), and DIPEA (100.0 mg, 770.2 μmol) and PyBOP (147 mg, 386 μmol) were added to the solution. The mixture was stirred at room temperature for 10 minutes. Intermediate 11a (68.8 mg, 257.7 μmol) was dissolved in DMF (1 mL) and added dropwise to the reaction solution. The mixture was stirred at room temperature overnight. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography eluting with DCM:MeOH (40:1) to give Intermediate 12a (118.1 mg, 0.21 mmol).

[0330] Synthesis of A1: 11-(1-amino-(3-aminothieno[2,3-b]pyridine-2- Synthesis of (4-carbonyl)phenyl-4-(hydroxymethyl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile General Procedure 1: Intermediate 12a (12.7 mg, 22.6 μmol) was dissolved in 1,4-dioxane. (4-(trifluoromethyl)phenyl)boronic acid (11.8 mg, 33.8 μmol) and KPO (14.4 mg, 67.7 μmol) were added to the solution under N protection. The mixture was heated at 90° C. overnight. The solvent was removed in vacuo. The residue was purified by HPLC to give A1 (5.60 mg, 9.02 μmol) as a white solid. LC-MS (m / z): Calculated value C 33 H 24 F3N5O3S + [M+H] + ,628.16;Actual value,628.18.

[0331] Example A.2: Synthesis of 1-(3-aminothieno[2,3-b]pyridine-2-carbonyl)-4-(hydroxymethyl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile (A2)

[0332] [ka]

[0333] Intermediate 12b: Synthesis of 1-(3-aminothieno[2,3-b]pyridine-2-carbonyl)-3-(4-bromophenyl)-4-(hydroxymethyl)azetidine-2-carbonitrile 3-Aminothieno[2,3-b]pyridine-2-carboxylic acid (50.0 mg, 258.2 μmol) was dissolved in DMF (10 mL), and DIPEA (100.0 mg, 770.2 μmol) and PyBOP (147.0 mg, 386.0 μmol) were added to the reaction mixture. The mixture was stirred at room temperature for 10 minutes. Intermediate 11b (68.8 mg, 257.70 μmol) was dissolved in DMF (1 mL) and added dropwise to the reaction mixture. The mixture was stirred at room temperature overnight. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography eluting with DCM:MeOH (40:1) to give Intermediate 12b (93.1 mg, 210.3 μmol).

[0334] Synthesis of A2: Synthesis of 1-(3-aminothieno[2,3-b]pyridine-2-carbonyl)-4-(hydroxymethyl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile The corresponding product was obtained following general procedure 1 for A1. The residue was purified by HPLC. Purification gave A2 (2.7 mg, 5.6 μmol). LC-MS (m / z): calculated value C 26 H 19 F3N4O2S + [M+H] + , 509.13; actual value 509.12.

[0335] Example A.3: Synthesis of 1-(3-aminothieno[2,3-b]pyridine-2-carbonyl)-4-(hydroxymethyl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile (A3) Intermediates 7b, 8b, 9b, 10b, 11c, and 12c were obtained following the procedures for intermediates 7a, 8a, 9a, 10a, 11b, and 12b.

[0336] Synthesis of A3: 1-(3-aminothieno[2,3-b]pyridine-2-carbonyl)-4-(hydroxymethyl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile The corresponding product was obtained following General Procedure 1 for A1. The residue was purified by HPLC to give A3 (3.56 mg, 7.42 μmol). LC-MS (m / z): calculated C 26 H 19 F3N4O2S + [M+H] + ,509.13;Actual value 509.16.

[0337] Compounds A2 and A3 are different diastereomers obtained from different starting materials. Example A.4: Synthesis of 3-amino-N-((4-(hydroxymethyl)-1-propyl-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidin-2-yl)methyl)thieno[2,3-b]pyridine-2-carboxamide (A5)

[0338] [ka]

[0339] Intermediate 11c: Synthesis of 3-(4-bromophenyl)-4-(hydroxymethyl)-1-propylazetidine-2-carbonitrile Intermediate 10b (100.0 mg, 325.7 μmol) was dissolved in MeOH (10 mL) and Pd / C (10.0 mg) was added under an H atmosphere. The mixture was stirred at room temperature for 15 minutes. The Pd / C was filtered off through diatomaceous earth. The filtrate was concentrated in vacuo to give crude intermediate 11c (96.0 mg, 321.5 μmol), which was used in the next step without further purification.

[0340] Intermediate 12c: Synthesis of (4-(aminomethyl)-3-(4-bromophenyl)-1-propylazetidin-2-yl)methanol Intermediate 11c (96.0 mg, 321.5 μmol) was dissolved in DCM (20 mL) and the reaction mixture was cooled to 0° C. DIBAL (1.3 mL, 1.9 mmol, 2.5 M in toluene) was added to the reaction mixture over 3 minutes, and the reaction mixture was slowly warmed to room temperature and stirred for 1 hour. The reaction mixture was quenched by slowly adding methanol until gas evolution ceased. A saturated solution of sodium potassium tartrate was added to the mixture. The gel-like solution was then stirred until it separated into two layers. The aqueous layer was extracted with DCM (10 mL). The combined organic phase was dried over MgSO4, and the filtrate was concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography eluting with DCM:MeOH (20:1) to give Intermediate 12c (73.0 mg, 234.7 μmol).

[0341] Intermediate 13c: Synthesis of 3-amino-N-((3-(4-bromophenyl)-4-(hydroxymethyl)-1-propylazetidin-2-yl)methyl)thieno[2,3-b]pyridine-2-carboxamide 3-Aminothieno[2,3-b]pyridine-2-carboxylic acid (40.0 mg, 206.6 μmol) was dissolved in DMF (10 mL), and DIPEA (100.0 mg, 770.2 μmol) and PyBOP (147.0 mg, 386.0 μmol) were added to the reaction mixture, which was stirred at room temperature for 10 minutes. Intermediate 12c (64.7 mg, 206.6 μmol) dissolved in DMF (1 mL) was added dropwise to the reaction mixture, which was stirred at room temperature overnight. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography, eluting with DCM:MeOH (40:1), to give Intermediate 13c (56.3 mg, 115.0 μmol).

[0342] A5: Synthesis of 3-amino-N-((4-(hydroxymethyl)-1-propyl-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidin-2-yl)methyl)thieno[2,3-b]pyridine-2-carboxamide The corresponding product was obtained following general procedure 1 for A1. The residue was purified by HPLC to give A5 (3.86 mg, 6.92 μmol). 1 HNMR(700MHz,DMSO-d6)δ9.90-9.73(m,1H),8.65(ddd,J=11.7,4.6,1.7Hz,1H),8.44(ddd,J=20.0,8.1,1.6Hz,1H),7.92(dd,J=23.3,8.2H z,2H),7.86-7.79(m,4H),7.63-7.58(m,2H),7.46(ddd,J=14.8,8.2,4.5Hz,1H),7.21(s,2H),5.72(d,J=51.7Hz,1H),5.12-5.07(m,1H),4. 67(tt,J=9.7,4.5Hz,1H),4.45(t,J=9.4Hz,1H),4.30(t,J=9.8Hz,1H),4.01(dd,J=13.9,6.4Hz,1H),3.87-3.80(m,2H),3.57-3.53(m,1H), 3.39-3.35(m,1H),3.16(dtt,J=18.2,6.7,3.7Hz,2H),1.78-1.61(m,1H),1.56(tdt,J=10.5,7.5,5.2Hz,1H),0.91(dt,J=10.3,7.3Hz,3H).

[0343] LC-MS (m / z): Calculated value C 29 H 29 F3N4O2S + [M+H] + ,555.20;Actual value 555.21. Compounds A4 and A5 are different diastereomers obtained from different starting materials.

[0344] A6: Synthesis of 1-allyl-4-((4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile A7: Synthesis of 3-(4-(1H-benzo[d]imidazol-6-yl)phenyl)-1-(3-aminothieno[2,3-b]pyridine-2-carbonyl)-4-(hydroxymethyl)azetidine-2-carbonitrile Compound A7 was prepared according to the synthetic procedures for compounds A2 and A3 starting from intermediate 12b and intermediate 12c, followed by general procedure 1 using bromobenzimidazole.

[0345] Example A.5: Synthesis of N-((3-(4-(1H-benzo[d]imidazol-6-yl)phenyl)-4-(hydroxymethyl)-1-propylazetidin-2-yl)methyl)-3-aminothieno[2,3-b]pyridine-2-carboxamide (A9)

[0346] [ka]

[0347] A9: Synthesis of N-((3-(4-(1H-benzo[d]imidazol-6-yl)phenyl)-4-(hydroxymethyl)-1-propylazetidin-2-yl)methyl)-3-aminothieno[2,3-b]pyridine-2-carboxamide Intermediate 13c (100.0 mg, 0.2 mmol) was dissolved in 1,4-dioxane (10 mL), and the corresponding product was obtained according to general procedure 1 for A1. The residue was purified by silica gel column chromatography eluting with DCM:MeOH (10:1) to give 14c (58.2 mg, 0.09 mmol). 14c was then dissolved in DCM (15 mL), followed by the addition of 1 mL of TFA and stirring at room temperature for 3 hours. The solvent was removed in vacuo, and the residue was purified by HPLC to give product A9 (8.69 mg, 16.5 μmol). 1HNMR(700MHz,DMSO-d6)δ9.82(d,J=62.7Hz,1H),9.16(s,1H),8.65(ddd,J=11.7,4.6,1.7Hz,1H),8.45(ddd,J=17.5,8.2,1.6Hz,1 H),8.02(dd,J=11.4,1.7Hz,1H),7.89-7.75(m,5H),7.59(dd,J=11.0,8.1Hz,2H),7.46(ddd,J=14.6,8.1,4.5Hz,1H),7.27(d,J=63 .9Hz,2H),5.72(d,J=54.9Hz,1H),5.13~5.08(m,1H),4.89(d,J=13.0Hz,1H),4.67(tt,J=9.8,4.4Hz,1H),4.45(t,J=9.4Hz,1H),4. 30(t,J=9.8Hz,1H),4.05-4.01(m,1H),3.95-3.90(m,1H),3.83(d,J=3.2Hz,1H),3.39~3.34(m,1H),3.15(ddt,J=28.1,14.9,4.2Hz ,2H),1.78-1.51(m,2H),0.91(dt,J=10.1,7.4Hz,3H).

[0348] LC-MS (m / z): Calculated value C 29 H 30 N6O2S + [M+H] + ,528.23;Actual value 528.26. Compound A8 and Compound A9 are different diastereomers derived from different starting materials.

[0349] Example A.6: Synthesis of 1-allyl-4-((4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile (A10)

[0350] [ka]

[0351] Intermediate 11d: Synthesis of 1-allyl-4-(hydroxymethyl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile Intermediate 10b (50.0 mg, 162.9 μmol) was dissolved in 1,4-dioxane. The corresponding product was obtained according to general procedure 1 for A1. The residue was purified by silica gel column chromatography eluting with EtOAc / PE (gradient: 1:6 to 1:4) to give intermediate 11d (46.02 mg, 123.73 μmol).

[0352] Intermediate 12d: Synthesis of (1-allyl-4-cyano-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidin-2-yl)methyl methanesulfonate Intermediate 11d (40.0 mg, 135.0 μmol) was dissolved in DCM (10 mL) and cooled to 0 °C. MsCl (30.9 mg, 270.0 μmol) and EtN (41.0 mg, 405.1 μmol) were added to the reaction mixture, which was then stirred at room temperature for 4 h. The reaction mixture was then quenched with saturated aqueous NaCO solution and diluted with DCM. The organic phase was washed with brine and dried over MgSO. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography eluting with EtOAc:PE (1:9) to give intermediate 12d (48.2 mg, 107.0 μmol).

[0353] Intermediate 13d: Synthesis of 1-allyl-4-(azidomethyl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile Intermediate 12d (45.0 mg, 120.3 μmol) was dissolved in DMF (3 mL). NaN (46.9 mg, 601.5 μmol) was added to the mixture. The mixture was heated to 60° C. for 5 hours. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc / PE (gradient: 1:19) to give intermediate 13d (23.1 mg, 57.9 μmol).

[0354] Synthesis of A10: Synthesis of 1-allyl-4-((4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile Intermediate 13d (4.00 mg, 10.1 μmol) was dissolved in DMF (5 mL). The mixture was stirred at room temperature. 2-Ethynylpyridine (2.10 mg, 20.2 μmol) was added to the solution, followed by CuSO4.5H2O (5.02 mg, 20.2 μmol) and L-(+)-ascorbic acid (3.5 mg, 20.2 μmol). The mixture was stirred at room temperature overnight. The solvent was removed in vacuo. The residue was purified by HPLC to give the final product A10 (2.52 mg, 5.0 μmol). 1 HNMR(500MHz,DMSO-d6)δ8.66(s,1H),8.60(d,J=4.8Hz,1H),8.03(d,J=7.9Hz,1H),7.95-7.86(m,3H),7.80(d,J= 8.3Hz,2H),7.77-7.70(m,2H),7.39(d,J=8.2Hz,2H),7.35(dd,J=7.5,5.0Hz,1H),5.78(dddd,J=17.1,10.3,6.7,5 .1Hz,1H),5.24(dq,J=17.1,1.6Hz,1H),5.16(dt,J=10.4,1.5Hz,1H),4.82(d,J=8.1Hz,1H),4.80-4.69(m,2H),4. 27(dt,J=8.8,4.4Hz,1H),3.77(t,J=8.5Hz,1H),3.42(ddt,J=14.1,5.2,1.7Hz,1H),3.18(dd,J=14.1,6.7Hz,1H). LC-MS (m / z): Calculated value C 28 H 23 F3N6 + [M+H] + :501.53;Actual value:501.49.

[0355] Compounds A6 and A10 are different diastereomers derived from different starting materials. Example A.7: Synthesis of 3-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(4-(methylamino)quinazolin-2-yl)azetidine-2-carbonitrile (B1)

[0356] [ka]

[0357] Intermediate 14: Synthesis of 2-(4-bromophenyl)oxirane A reaction mixture of 4-bromobenzaldehyde (5.0 g, 27.0 mmol), trimethylsulfonium iodide (6.1 g, 29.8 mmol), water (1.26 mL, 70.3 mmol), and potassium hydroxide (3.0 g, 54.1 mmol) in acetonitrile (50 mL) was stirred at 55° C. for 4 hours. The mixture was then partitioned between water and diethyl ether, and the organic phase was washed with water, diluted with hydrochloric acid, washed with brine, and dried over MgSO4. The crude product of Intermediate 14 (5.3 g, 26.5 mmol) was obtained. ol) was obtained by removing the organic phase in vacuo, and the crude product obtained was used in the next step without further purification.

[0358] Intermediate 15: Synthesis of 2-(allylamino)-1-(4-bromophenyl)ethan-1-ol Intermediate 14 (4.4 g, 22.1 mmol) was dissolved in DMF (100 mL). 2-Propen-1-amine (5.1 g, 88.4 mmol) was added to the reaction mixture and stirred at 60° C. overnight. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc:hexane (2:1) to give Intermediate 15 (4.1 g, 16.0 mmol).

[0359] Intermediate 16: Synthesis of 2-(allyl(2-(4-bromophenyl)-2-hydroxyethyl)amino)acetonitrile Intermediate 15 (1.7 g, 6.60 mmol) was dissolved in acetonitrile (20 mL). Potassium carbonate (1.84 g, 13.3 mmol) and 2-bromoacetonitrile (2.38 g, 19.9 mmol) were added to the reaction mixture, which was stirred at 85 °C for 3 hours. Water was added to the residue obtained after evaporation of the solvent in vacuo, and the aqueous layer was extracted twice with EtOAc (30 mL). The combined organic phases were washed with brine and dried over MgSO . The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography eluting with EtOAc / hexane (gradient: 1:1) to give Intermediate 16 (1.62 g, 5.31 mmol).

[0360] Intermediate 17: Synthesis of 2-(allyl(2-(4-bromophenyl)-2-chloroethyl)amino)acetonitrile Thionyl chloride (1.0 g, 8.82 mmol) was added to a solution of pyridine (1.7 g, 22.0 mmol) in DCM (30 mL) at room temperature. The solution was cooled to 0 °C. Intermediate 16 was dissolved in DCM (10 mL) and added dropwise to the reaction mixture over 8 minutes. The mixture was stirred at 0 °C for an additional 15 minutes. The mixture was neutralized by the addition of saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with DCM (50 mL). The combined organic phases were dried over MgSO4, filtered, and the filtrate was concentrated in vacuo to give the crude product. The residue was purified by silica gel column chromatography eluting with EtOAc:PE (9:91) to give Intermediate 17 (1.3 g, 4.1 mmol).

[0361] Intermediate 18a and Intermediate 18b: Synthesis of 1-allyl-3-(4-bromophenyl)azetidine-2-carbonitrile Intermediate 17 (1.0 g, 3.23 mmol) was dissolved in THF (30 mL). The solution was stirred and cooled to −78° C. Lithium bis(trimethylsilyl)amide (1 M in THF, 4.8 mL, 4.8 mmol) was added dropwise to the mixture over 3 minutes.

[0362] The mixture was stirred at -78 °C for an additional 1 h. The reaction mixture was quenched with saturated NH4Cl solution and extracted three times with EtOAc (20 mL). The combined organic phases were dried over MgSO4, filtered, and the filtrate was concentrated in vacuo to give the crude product. The residue was purified by silica gel column chromatography eluting with EtOAc / hexane (gradient: 9:91) to give intermediate 18a (0.43 g, 1.62 mmol) and 18b (0.40 g, 1.43 mmol). The first product collected was intermediate 18a, followed by 18b.

[0363] Intermediate 19a: Synthesis of 3-(4-bromophenyl)azetidine-2-carbonitrile Intermediate 18a (340.0 mg, 1.23 mmol) was dissolved in DCM:EtOH=1:2 (18 mL). 1,3-Dimethylbarbituric acid (287.3 mg, 1.8 mmol) was added. ol), Pd(PPh3)4 (70.9 mg, 61.3 μmol) was added under N2 protection. The mixture was heated to 40 °C and stirred overnight. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography eluting with DCM:MeOH (gradient: 40:1) to give intermediate 19 (286.0 mg, 1.2 mmol).

[0364] Intermediate 20a: Synthesis of 3-(4-bromophenyl)-1-(4-(methylamino)quinazolin-2-yl)azetidine-2-carbonitrile Intermediate 19a (80.0 mg, 337.4 μmol) was dissolved in THF (10 mL) and the solution was stirred at room temperature. 2-Chloro-N-methylquinazolin-4-amine (65.3 mg, 337.4 μmol) was added to the solution. The mixture was stirred and heated at 80° C. overnight. The product precipitated and the reaction mixture was filtered. The residue was washed three times with THF and then dried in vacuo to give Intermediate 20a (89.0 mg, 225.7 μmol).

[0365] Synthesis of B1: Synthesis of 3-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(4-(methylamino)quinazolin-2-yl)azetidine-2-carbonitrile Intermediate 20a (20.0 mg, 50.7 μmol) was dissolved in 1,4-dioxane (10 mL). The corresponding product was obtained according to general procedure 1 for A1. The residue was purified by HPLC to give B1 (10.3 mg, 24.1 μmol). 1 HNMR(500MHz,DMSO-d6)δ12.79(s,1H),9.82(s,1H),8.27(d,J=8.1Hz,1H),7.89(t,J=7.8Hz,1H),7.71-7.66(m,2H),7.63(d,J=8.4 Hz,1H),7.55(t,J=7.8Hz,1H),7.49-7.42(m,2H),5.47(d,J=7.0Hz,1H),4.77(t,J=8.5Hz,1H ),4.62-4.53(m,1H),4.44(t,J=7.8Hz,1H),3.15(d,J=4.5Hz,3H),2.41(s,3H),2.24(s,3H). 13 CNMR(176MHz,DMSO)δ165.8,160.3,158.8,158.6,158.4,158.2,137.0,135.9,130.2,129.7,128.7,125.8,12 4.5,117.8,117.7,116.0,110.7,57.2,55.5,40.5,40.4,40.3,40.1,40.0,39.9,39.8,39.7,28.9,11.8,10.9. LC-MS (m / z): Calculated value C 24 H 22 NO + [M+H] + :411.48; Actual value:411.46.

[0366] Example A.8: Synthesis of 3-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(4-(methylamino)quinazolin-2-yl)azetidine-2-carbonitrile (B2) Intermediates 19b, 20b, and B2 (5.15 mg, 12.1 μmol) were obtained following the procedure for intermediates 19a, 20a, and B1. 1 HNMR(700MHz,DMSO-d6)δ9.73(s,1H),8.24(d,J=8.2Hz,1H),7.86(d,J=8.0Hz,1H),7.70-7.66(m,2H),7.63(d,J=8.4Hz,1H),7.55-7.47( m,3H),5.83(d,J=8.9Hz,1H),4.72(d,J=9.4Hz,1H),4.54(s,1H),4.43(q,J=8.0Hz,1H),3.13(d,J=4.5Hz,3H),2.43(s,3H),2.26(s,3H). 13 CNMR(176MHz,DMSO)δ165.73,160.29,158.58,158.41,158.23,130.20,129.50,129.36,124.41,118.40,115.99,110. 67,56.14,55.82,55.80,40.51,40.39,40.37,40.25,40.13,40.01,39.89,39.77,39.65,37.31,28.80,11.91,11.02. MS + :(C 24 H 22 NO) + Calculated value: 411.48, measured value: 411.46.

[0367] Compounds B1 and B2 are different diastereomers obtained from different starting materials. Example A.9: Synthesis of 1-(3-aminothieno[2,3-b]pyridine-2-carbonyl)-3-(4-(3,5-dimethylisoxazol-4-yl)phenyl)azetidine-2-carbonitrile (B3)

[0368] [ka]

[0369] Intermediate 21a: 3-Aminothieno[2,3-b]pyridine-2-carboxylic acid (100.0 mg, 0.5 mmol) was dissolved in DMF (20 mL), and EtN (156.3 mg, 1.5 mmol) and PyBOP (234.9 mg, 617.9 μmol) were added to the reaction mixture, which was stirred at room temperature for 30 minutes. Intermediate 19a (146.5 mg, 0.6 mmol) was dissolved in DMF (3 mL) and added dropwise to the reaction solution. The mixture was stirred at room temperature overnight. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography eluting with DCM:MeOH (gradient: 40:1) to give Intermediate 21a (185.1 mg, 447.9 μmol).

[0370] Synthesis of B3: 1-(3-aminothieno[2,3-b]pyridine-2-carbonyl)-3-(4-(3,5-dimethylisoxazol-4-yl)phenyl)azetidine-2-carbonitrile Intermediate 21a (20 mg, 48.4 μmol) was dissolved in 1,4-dioxane (10 mL). The corresponding product was obtained according to General Procedure 1. The residue was purified by HPLC-MS to give the title compound B3 (8.36 mg, 19.5 μmol). LC-MS (m / z): Calculated value C 23 H 19 N5O2S + [M+H] + :430.48; Actual value:430.46.

[0371] Example A.10: Synthesis of 1-(3-aminothieno[2,3-b]pyridine-2-carbonyl)-3-(4-(3,5-dimethylisoxazol-4-yl)phenyl)azetidine-2-carbonitrile (B4) Intermediates 19b, 21b, and B4 (5.15 mg, 12.1 μmol) were obtained following the procedure for intermediates 19a, 20a, and B2.

[0372] Compounds B3 and B4 are different diastereomers obtained from different starting materials. Example A.11: Synthesis of 1-(4-(methylamino)quinazolin-2-yl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile (B5)

[0373] [ka]

[0374] Intermediate 20a (20.0 mg, 50.7 μmol) was dissolved in 1,4-dioxane (10 mL). The corresponding product was obtained according to general procedure 1 for A1. The residue was purified by HPLC to give B5 (4.56 mg, 9.90 μmol). 1 HNMR(500MHz,DMSO-d6):δ12.79(s,1H),9.80(s,1H),8.24(d,J=8.0Hz,1H ),7.91(d,J=8.2Hz,2H),7.85-7.78(m,5H),7.70(m,J=7.9Hz,2H),7.60(d, J=8.3Hz,1H),7.51(d,J=7.9Hz,1H),5.44(d,J=8.6Hz,1H),4.74(t,J=8.9H z,1H),4.56(d,J=8.4Hz,1H),4.41(q,J=8.0Hz,1H),3.13(d,J=4.5Hz,3H). LC-MS (m / z): Calculated value C 26 H 20 F3N5 + [M+H] + ,460.17;Actual value 460.23.

[0375] Example A.12: Synthesis of 1-(4-(methylamino)quinazolin-2-yl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile (B6) Intermediate 20b (20.0 mg, 50.7 μmol) was dissolved in 1,4-dioxane (10 mL). The corresponding product was obtained according to general procedure 1 for A1. The residue was purified by HPLC to give B6 (6.89 mg, 15.0 μmol). 1HNMR(500MHz,DMSO-d6):δ12.82(s,1H),9.77(s,1H),8.25(d,J=8.2Hz,1H),7.96(d,J=8.1Hz, 2H),7.92-7.80(m,5H),7.75-7.69(m,2H),7.63(d,J=8.3Hz,1H),7.52(d,J=7.9Hz,1H),5.85(d ,J=8.6Hz,1H),4.72(t,J=8.9Hz,1H),4.55(s,1H),4.44(q,J=8.0Hz,1H),3.12(d,J=4.5Hz,3H). 13 CNMR(176MHz,DMSO)δ160.3,158.4,158.3,144.0,138.7,137.6,129.7,128.6,128.4,128.0,127.7,126.4,126.3,126.3 ,126.3,125.7,124.4,124.1,118.3,110.6,56.1,55.8,55.8,40.5,40.4,40.3,40.1,40.0,39.9,39.8,39.7,37.2,28.8. MS + :(C 26 H 20 F3N5) + Calculated value: 460.17; measured value: 460.26. LC-MS (m / z): Calculated value C 26 H 20 F3N5 + [M+H] + ,460.17;Actual value,460.26.

[0376] Compounds B5 and B6 are different diastereomers obtained from different starting materials. Example A.13: Synthesis of 1-(3-aminothieno[2,3-b]pyridine-2-carbonyl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile (B7)

[0377] [ka]

[0378] Intermediate 21a (20.0 mg, 48.4 μmol) was dissolved in 1,4-dioxane (10 mL). The corresponding product was obtained according to general procedure 1 for A1. The residue was purified by HPLC to give B7 (5.26 mg, 11.0 μmol). 1 HNMR(500MHz,DMSO-d6)δ8.69(dd,J=4.6,1.6Hz,1H),8.56(dd,J=8.1,1.6Hz,1H),7.91(d,J=8.2Hz,2H),7.81(d,J=8.3Hz,2H),7.79-7.75(m,2H),7 .65-7.62(m,2H),7.49(dd,J=8.1,4.6Hz,1H),5.25(d,J=7.0Hz,1H),4.88 (dd,J=8.9,7.3Hz,1H),4.49(t,J=7.2Hz,1H),4.41(dt,J=9.0,7.1Hz,1H). MS + :(C 25 H 17 F3N4OS) + Calculated value: 479.11, measured value: 479.16. LC-MS (m / z): Calculated value C 25 H 17 F3N4OS + [M+H] + ;Actual value: 479.11.

[0379] Example A.14: Synthesis of 3-(4-(1H-benzo[d]imidazol-6-yl)phenyl)-1-(4-(methylamino)quinazolin-2-yl)azetidine-2-carbonitrile (B9)

[0380] [ka]

[0381] Intermediate 20a (20.0 mg, 50.7 μmol) was dissolved in 1,4-dioxane (10 mL). The corresponding product was obtained according to general procedure 1 for A1. The residue was purified by HPLC to give intermediate 22a (7.89 mg, 14.9 μmol). 22a was dissolved in 20 mL of DCM, 1 mL of TFA was added, and the mixture was stirred at room temperature for 2 hours. The solvent was then removed, and the remaining residue was purified by HPLC to give B9 (3.28 mg, 7.6 μmol). 1 HNMR(700MHz,DMSO-d6)δ9.96(s,1H),8.90(s,1H),8.24(d,J=8.2Hz,1H),7.95(d,J=1.7H z,1H),7.86(t,J=7.8Hz,1H),7.80(d,J=8.5Hz,1H),7.78-7.75(m,2H),7.72-7.68(m,1H) ,7.69-7.66(m,2H),7.61(d,J=8.2Hz,1H),7.51(t,J=7.8Hz,1H),5.43(d,J=7.1Hz,1H),4 .75(t,J=8.5Hz,1H),4.56(q,J=7.4Hz,1H),4.41(t,J=7.7Hz,1H),3.14(d,J=4.5Hz,3H). LC-MS (m / z): Calculated value C 26 H 21 N7 + [M+H] + ,431.19;Actual value 431.19.

[0382] Example A.15: Synthesis of 3-(4-(1H-benzo[d]imidazol-6-yl)phenyl)-1-(4-(methylamino)quinazolin-2-yl)azetidine-2-carbonitrile (B10) Intermediate 20b (20.0 mg, 50.7 μmol) was dissolved in 1,4-dioxane (10 mL). The corresponding product was obtained according to general procedure 1 for A1. The residue was purified by HPLC to give intermediate 22b (8.96 mg, 16.9 μmol). 22b was dissolved in 20 mL of DCM, 1 mL of TFA was added, and the mixture was stirred at room temperature for 2 hours. The solvent was removed, and the residue was purified by HPLC to give B10 (3.89 mg, 9.02 μmol). 1 HNMR(700MHz,DMSO-d6)δ9.72(s,1H),9.06(s, 1H),8.26(d,J=8.7Hz,1H),8.04(d,J=1.6Hz,1H),7.92-7.79(m,5H),7.71(dd,J=8.3,4.5Hz,2H),7.65(d,J=8.2Hz,1H),7.53( t,J=7.7Hz,1H),5.87(d,J=8.8Hz,1H),4.75(t,J=8.8Hz,1H),4.61-4.55(m,1H),4.45(d,J=5.9Hz,1H),3.14(d,J=4.6Hz,3H). LC-MS (m / z): Calculated value C 26 H 21 N7 + [M+H] + ,431.19;Actual value 431.21.

[0383] Compounds B9 and B10 are different diastereomers obtained from different starting materials. Example A.16: Synthesis of tert-butyl 4-(2-amino-4-(4-bromophenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)azetidin-1-yl)piperidine-1-carboxylate (C1) Intermediate C1-01: Synthesis of 4-nitrobenzenesulfonyl azide A reaction solution containing 4-nitrobenzenesulfonyl chloride (5.0 g, 22.56 mmol) in a mixture of acetone (30 mL) and water (30 mL) was cooled on an ice bath for 5 minutes, and then NaN (2.93 g, 45.12 mmol) was added to the reaction solution, followed by stirring at room temperature for 3 hours. The solvent was concentrated in vacuo, and the residue was washed with water and extracted three times with ethyl acetate (50 mL). The combined organic phase was washed with brine, dried over MgSO, filtered, and the resulting solvent was removed in vacuo. The crude product was purified by silica gel column chromatography using PE:EtOAc (8:1) to obtain the title compound (4.56 g, 20.0 mmol) as a yellow solid. 1HNMR (400MHz, CDCl3-d): δ8.44-8.36 (m, 2H), 8.13-8.07 (m, 2H).

[0384] [ka]

[0385] Intermediate C1-02: Synthesis of tert-butyl-4-((4-bromobenzylidene)amino)piperidine-1-carboxylate Intermediate C1-02 was obtained following General Procedure 2 for Imine Synthesis.

[0386] Rigorous dried 4 Å molecular sieves (540.0 g / mmol) were added to a solution of tert-butyl 4-aminopiperidine-1-carboxylate (108.2 mg, 0.54 mmol) in DCM (2.5 mL) at room temperature under N2. After 5 min, the 4-aminopiperidine-1-carboxylate was Bromobenzaldehyde (100.0 mg, 0.54 mmol) was added, and the mixture was stirred at room temperature overnight, filtered through Celite, and the solvent was removed in vacuo to give the crude imine (200.0 mg, 0.54 mmol) as a colorless oil. 1 HNMR(400MHz, CDCl3-d): δ8.22(s,1H),7.54(d,J=7.8Hz,2H),7.47(d,J=8.4Hz,2H),4.00(d,J=13. 3Hz,2H), 3.32(p,J=7.7,6.9Hz,1H),2.93(dt,J=13.3,6.8Hz,2H),1.70-1.62(m,4H),1.41(s,9H).

[0387] Intermediate C1-03: Synthesis of 1-(4-ethynylphenyl)-4-methylpiperazine To a solution of 1-ethynyl-4-fluorobenzene (1.0 g, 8.32 mmol) in DMF (30 mL) was added CsCO (4.07 g, 12.5 mmol, 1.50 equiv.) and 1-methylpiperazine (1.25 g, 12.49 mmol, 1.5 equiv.). The reaction mixture was stirred at 80 °C for 12 h, then diluted with water and extracted three times with EtOAc (50 mL). The organic phases were combined, dried over MgSO, filtered, and the solvent was removed in vacuo. The crude product was purified by silica column chromatography (DCM:methanol = 20:1) to give the title compound (52.0 mg, 0.26 mmol) as a pale yellow solid.

[0388] Intermediate C1-04: Synthesis of tert-butyl 4-(2-(4-bromophenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-4-(((4-nitrophenyl)sulfonyl)imino)azetidin-1-yl)piperidine-1-carboxylate Intermediate C1-04 was obtained following General Procedure 3 for the synthesis of sulfonylazetidinimines.

[0389] A solution of sulfonyl azide (34.18 mg, 0.15 mmol) in DCM (2 mL) was treated sequentially with EtN (23.70 mg, 0.30 mmol), 1-(4-ethynylphenyl)-4-methylpiperazine (30.0 mg, 0.15 mmol), tert-butyl-4-((4-bromobenzylidene)amino)piperidine-1-carboxylate (55.1 mg, 0.15 mmol), and CuI (2.85 mg, 0.015 mmol) at room temperature. The reaction mixture was stirred at room temperature under a N atmosphere for 3–5 h, and the solvent was removed in vacuo. The crude product was purified by HPLC to give the title compound (8.63 mg, 11.24 μmol) as a white solid. 1HNMR (500MHz, chloroform-d) δ8.05(d,J=8.9Hz,2H),7.71(d,J=8.9Hz,2H),6.79(d,J=8.4Hz,2H),6.61(d,J=8.6Hz,2H),6.39(d,J=8 .7Hz,2H),5.27(d,J=5.2Hz,1H),5.09(d,J=5.2Hz,1H),4.21-3.94(m,2H),3.80(tt,J=12.0,3.9Hz,1H),3.58(m,2H),3.47(d,J= 13.6Hz,1H),3.39(d,J=13.5Hz,1H),3.17(q,J=12.3,11.8Hz,2H),2.90(d,J=11.7Hz,2H),2.81(s,3H),2.62(q,J=14.3,13.2Hz, 2H), 1.94(ddd,J=12.4,4.3,2.3Hz,1H),1.87-1.81(m,1H), 1.71-1.59(m,1H),1.48-1.37(m,2H),1.35(s,9H),1.24-1.17(m,1H). LC-MS (m / z): Calculated value C 36 H 43 BrN6O6S + [M+H] + ,769.22;Actual value 769.16.

[0390] Intermediate C1-05: Synthesis of tert-butyl-4-(2-(4-bromophenyl)-4-imino-3-(4-(4-methylpiperazin-1-yl)phenyl)azetidin-1-yl)piperidine-1-carboxylate Intermediate C1-05 was obtained according to general procedure 4.

[0391] To a solution of intermediate C1-04 (8.00 mg, 11.0 μmol) in DMF, K2CO3 (55.0 μmol, 5.0 equiv.) was added, followed by benzenethiol (25.0 μmol, 2.5 equiv.). The resulting suspension was stirred at room temperature for 3 hours, and then the solvent was removed in vacuo. The crude product was purified by HPLC to give the pure compound (3.56 mg, 6.1 μmol) as a white solid.

[0392] Synthesis of C1: Synthesis of tert-butyl-4-(2-amino-4-(4-bromophenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)azetidin-1-yl)piperidine-1-carboxylate To a solution of intermediate C1-05 (3.56 mg, 7.2 μmol) in MeOH (1 mL) was added NaBHCN (0.47 mg, 7.5 μmol, 1.5 equiv). The reaction mixture was stirred at room temperature for 1 hour, and then the solvent was removed in vacuo. The crude product was purified by HPLC to give C1 (2.38 mg, 4.1 μmol) as a white solid. LC-MS (m / z): calculated C 30 H 42 BrN5O2 + [M+H] + ,584.26;Actual value 584.20.

[0393] Example A.17: Synthesis of tert-butyl 4-(2-amino-4-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-(4-fluorophenyl)azetidin-1-yl)piperidine-1-carboxylate (C2) Intermediate C2-01: Synthesis of tert-butyl 4-((3,5-di-tert-butyl-4-hydroxybenzylidene)amino)piperidine-1-carboxylate 3,5-Di-tert-butyl-4-hydroxybenzaldehyde (100.0 mg, 0.43 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (85.4 mg, 0.43 mmol, 1 equiv.) were treated according to general procedure 2 to give the title compound (174.23 mg, 0.42 mmol), which was used in the next step without further purification.

[0394] Intermediate C2-02: Synthesis of tert-butyl 4-(2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-(4-fluorophenyl)-4-(((4-nitrophenyl)sulfonyl)imino)azetidin-1-yl)piperidine-1-carboxylate 1-Ethynyl-4-fluorobenzene (40.84 mg, 0.34 mmol), 4-nitrobenzenesulfonyl azide (77.6 mg, 0.34 mmol, 1.0 equiv), and intermediate C2-01 (170.00 mg, 0.41 mmol, 1.2 equiv) were treated according to general procedure 3 to give the title compound (purified by HPLC, 79.2 mg, 0.11 mmol).

[0395] Intermediate C2-03: Synthesis of tert-butyl 4-(2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-(4-fluorophenyl)-4-iminoazetidin-1-yl)piperidine-1-carboxylate Intermediate C2-02 (70.0 mg, 95.0 μmol) was treated according to general procedure 4 to give the title compound (purified by HPLC, 36.9 mg, 66.8 μmol).

[0396] [ka]

[0397] Synthesis of C2: Synthesis of tert-butyl 4-(2-amino-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-(4-fluorophenyl)azetidin-1-yl)piperidine-1-carboxylate To a solution of intermediate C2-03 (36.86 mg, 66.80 μmol) in MeOH (1 mL) was added NaBHCN (6.30 mg, 100.20 μmol, 1.5 equiv). The reaction mixture was stirred at room temperature for 1 hour, and then the solvent was removed in vacuo. The crude product was purified by HPLC to give C2 (16.5 mg, 29.9 μmol). LC-MS (m / z): calculated C 33 H 48 FN3O3 + [M+H] + ,544.38;Actual value 544.42.

[0398] Example A.18: Synthesis of 3-(4-fluorophenyl)-4-(4-methylpiperazin-1-yl)-1-(1-methylpiperidin-4-yl)azetidin-2-amine (C3) Intermediate C3-01: Synthesis of 1-(4-methylpiperazin-1-yl)-N-(1-methylpiperidin-4-yl)methanimine Intermediate C3-01 was obtained according to general procedure 2.

[0399] 4-methylpiperazine-1-carbaldehyde (100.0 mg, 0.78 mmol), 1-Methylpiperidin-4-amine (89.00 mg, 0.78 mmol, 1.0 equiv) was treated according to general procedure 2 to give the title compound (179.30 mg, 0.80 mmol) which was used in the next step without further purification.

[0400] Intermediate C3-02: Synthesis of N-(3-(4-fluorophenyl)-4-(4-methylpiperazin-1-yl)-1-(1-methylpiperidin-4-yl)azetidin-2-ylidene)-4-nitrobenzenesulfonamide 1-Ethynyl-4-fluorobenzene (80.5 mg, 0.67 mmol), 4-nitrobenzenesulfonyl azide (152.1 mg, 0.67 mmol, 1.0 equiv), and intermediate C3-01 (179.3 mg, 0.80 mmol, 1.2 equiv) were treated according to general procedure 3 to afford the title compound (purified by HPLC, 56.3 mg, 0.10 mmol) as a white solid.

[0401] Synthesis of Intermediate C3-03: 3-(4-fluorophenyl)-4-(4-methylpiperazin-1-yl)-1-(1-methylpiperidin-4-yl)azetidin-2-imine Intermediate C3-02 (56.29 mg, 0.10 mmol) was treated according to general procedure 4 to afford the title compound (purified by HPLC, 26.9 mg, 74.3 μmol) as a pale yellow solid.

[0402] [ka]

[0403] Synthesis of C3: Synthesis of 3-(4-fluorophenyl)-4-(4-methylpiperazin-1-yl)-1-(1-methylpiperidin-4-yl)azetidin-2-amine To a solution of intermediate C3-03 (26.9 mg, 74.7 μmol) in MeOH (1 mL) was added NaBHCN (7.04 mg, 112.0 μmol, 1.5 equiv). The reaction mixture was stirred at room temperature for 1 hour, and then the solvent was removed in vacuo. The crude product was purified by HPLC to give C3 (18.6 mg, 51.4 μmol) as a white solid. LC-MS (m / z): calculated C 20 H 32 FN5 + [M+H] + , 362.27; actual value 362.19.

[0404] Example A.19: Synthesis of di-tert-butyl 4,4'-(4-amino-3-(4-(4-methylpiperazin-1-yl)phenyl)azetidine-1,2-diyl)bis(piperidine-1-carboxylate) (C4)

[0405] [ka]

[0406] Intermediate C4-01: Synthesis of tert-butyl 4-(((1-(tert-butoxycarbonyl)piperidin-4-yl)iminomethyl)piperidine-1-carboxylate Intermediate C4-01 was obtained according to general procedure 2.

[0407] tert-Butyl 4-formylpiperidine-1-carboxylate (100.0 mg, 0.47 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (94.13 mg, 0.47 mmol, 1.0 equiv) were treated according to general procedure 2 to give the title compound (186.6 mg, 0.47 mmol) as a colorless oil which was used without further purification. Used in the next step. 1 HNMR (400MHz, CDCl3-d): δ7.51(d,J=4.9Hz,1H),3.98(s,4H),3.04(dq,J=14.1,7.0Hz,1H),2.90-2.67( m,4H),2.25(tq,J=11.7,4.2Hz,1H),1.73-1.63(m,2H),1.53(dt,J=7.3,4.3Hz,4H),1.45-1.30(m,20H).

[0408] Intermediate C4-02: Synthesis of di-tert-butyl 4,4'-(3-(4-(4-methylpiperazin-1-yl)phenyl)-4-(((4-nitrophenyl)sulfonyl)imino)azetidine-1,2-diyl)bis(piperidine-1-carboxylate) 1-(4-ethynylphenyl)-4-methylpiperazine (68.1 mg, 0.34 mmol), 4-nitrobenzenesulfonyl azide (77.6 mg, 0.34 mmol, 1.0 equiv), and intermediate C4-01 (160.0 mg, 0.40 mmol, 1.2 equiv) were treated according to general procedure 3 to give the title compound (HPLC purified, 46.5 mg, 58.5 μmol).

[0409] Intermediate C4-03: Synthesis of di-tert-butyl 4,4'-(4-imino-3-(4-(4-methylpiperazin-1-yl)phenyl)azetidine-1,2-diyl)bis(piperidine-1-carboxylate) Intermediate C4-02 (40.0 mg, 50.3 μmol) was treated according to general procedure 4 to afford the title compound (purified by HPLC, 18.6 mg, 30.4 μmol) as a light brown solid.

[0410] Synthesis of C4: Synthesis of di-tert-butyl 4,4'-(4-amino-3-(4-(4-methylpiperazin-1-yl)phenyl)azetidine-1,2-diyl)bis(piperidine-1-carboxylate) To a solution of intermediate C4-03 (18.57 mg, 30.40 μmol) in MeOH (1 mL) was added NaBHCN (2.87 mg, 45.60 μmol, 1.5 equiv.). The reaction mixture was stirred at room temperature for 1 hour, and the solvent was removed in vacuo. The crude product was purified by HPLC to give C4 (8.96 mg, 14.6 μmol) as a light brown solid. LC-MS (m / z): Calculated value C 34 H 56 N6O4 + [M+H] + ,613.44;Actual value 613.36.

[0411] Example A.20: Synthesis of di-tert-butyl 4,4'-(4-amino-3-(4-fluorophenyl)azetidine-1,2-diyl)bis(piperidine-1-carboxylate) (C5) Intermediate C5-01: Synthesis of di-tert-butyl 4,4'-(3-(4-fluorophenyl)-4-(((4-nitrophenyl)sulfonyl)imino)azetidine-1,2-diyl)bis(piperidine-1-carboxylate) 1-Ethynyl-4-fluorobenzene (45.7 mg, 0.38 mmol), 4-nitrobenzenesulfonyl azide (86.7 mg, 0.38 mmol, 1.0 equiv), and intermediate C4-01 (synthesized according to Example A.19, 180.0 mg, 0.45 mmol, 1.2 equiv) were treated according to general procedure 3 to give the title compound (purified by HPLC, 72.6 mg, 0.10 mmol) as a pale yellow solid.

[0412] Intermediate C5-02: Synthesis of di-tert-butyl 4,4'-(3-(4-fluorophenyl)-4-iminoazetidine-1,2-diyl)bis(piperidine-1-carboxylate) Intermediate C5-01 (50.0 mg, 69.8 μmol) was treated according to General Procedure 4. , to give the title compound (purified by HPLC, 27.4 mg, 51.7 μmol).

[0413] [ka]

[0414] Synthesis of C5: Synthesis of di-tert-butyl 4,4'-(4-amino-3-(4-fluorophenyl)azetidine-1,2-diyl)bis(piperidine-1-carboxylate) To a solution of intermediate C5-02 (27.4 mg, 51.7 μmol) in methanol (1 mL) was added NaBHCN (4.9 mg, 77.5 μmol, 1.5 equiv.). The reaction mixture was stirred at room temperature for 1 hour, and then the solvent was removed in vacuo. The crude product was purified by HPLC to give C5 (18.6 mg, 34.9 μmol) as a white solid. LC-MS (m / z): calculated C 29 H 45 FN4O4 + [M+H] + ,533.35;Actual value 533.29.

[0415] Example A.21: Synthesis of N-(4-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-(3,5-dimethoxyphenyl)-1-(1-methylpiperidin-4-yl)azetidin-2-ylidene)-4-nitrobenzenesulfonamide (C6)

[0416] [ka]

[0417] Intermediate C6-01: Synthesis of 2,6-di-tert-butyl-4-(((1-methylpiperidin-4-yl)imino)methyl)phenol Intermediate C6-01 was obtained according to general procedure 2.

[0418] 3,5-Di-tert-butyl-4-hydroxybenzaldehyde (150.0 mg, 0.64 mmol) and 1-methylpiperidin-4-amine (73.1 mg, 0.64 mmol, 1.0 equiv) were treated according to general procedure 2 to give the title compound (202.2 mg, 0.61 mmol) as a colorless oil, which was used in the next step without further purification.

[0419] Synthesis of C6: Synthesis of N-(4-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-(3,5-dimethoxyphenyl)-1-(1-methylpiperidin-4-yl)azetidin-2-ylidene)-4-nitrobenzenesulfonamide 1-Ethynyl-3,5-dimethoxybenzene (120.0 mg, 0.74 mmol), 4-nitrobenzenesulfonyl azide (168.8 mg, 0.74 mmol, 1.0 equiv.), and intermediate C6-01 (244.5 mg, 0.74 mmol, 1.0 equiv.) were treated according to general procedure 3 to afford the title compound (purified by HPLC, 159.7 mg, 0.23 mmol) as a white solid. LC-MS (m / z): calculated C 37 H 48 N4O7S + [M+H] + ,693.33;Actual value 693.03.

[0420] C6 was further transformed into the imine intermediate according to general procedure 4. The final aminoazetidine compound was obtained following the synthesis of C1. Example A.22: Synthesis of 3-(3,5-dimethoxyphenyl)-1-(1-methylpiperidin-4-yl)-4-(thiazol-2-yl)azetidin-2-imine (C7)

[0421] [ka]

[0422] Intermediate C7-01: Synthesis of N-(1-methylpiperidin-4-yl)-1-(thiazol-2-yl)methylamine Intermediate C7-01 was obtained according to general procedure 2.

[0423] Thiazole-2-carbaldehyde (100.0 mg, 0.88 mmol) and 1-methylpiperidin-4-amine (100.9 mg, 0.88 mmol, 1.0 equiv) were treated according to general procedure 2 to give the title compound (165.4 mg, 0.79 mmol) as a colorless oil, which was used in the next step without further purification.

[0424] Intermediate C7-02: Synthesis of N-(3-(3,5-dimethoxyphenyl)-1-(1-methylpiperidin-4-yl)-4-(thiazol-2-yl)azetidin-2-ylidene)-4-nitrobenzenesulfonamide 1-Ethynyl-3,5-dimethoxybenzene (135.0 mg, 0.83 mmol), 4-nitrobenzenesulfonyl azide (189.9 mg, 0.83 mmol, 1.0 equiv), and intermediate C7-01 (174.2 mg, 0.83 mmol, 1.0 equiv) were treated according to general procedure 3 to afford the title compound (purified by HPLC, 228.6 mg, 0.40 mmol) as a white solid. 1 HNMR (500MHz, chloroform-d) δ8.07(d,J=8.8Hz,2H),7.61(d,J=8.8Hz,2H),7.58(d,J=3.2H z,1H),7.18(d,J=3.1Hz,1H),6.18(t,J=2.2Hz,1H),6.14(d,J=2.2Hz,1H),5.80(d,J=5 .2Hz,1H),5.21(d,J=5.2Hz,1H),4.15(m,1H),3.54(s,6H),2.85(d,J=27.3Hz,1H),2.7 7(s,3H),2.73(d,J=9.0Hz,2H),2.50(ddd,J=27.0,14.0,4.6Hz,2H),2.42-2.25(m,5H). LC-MS (m / z): Calculated value C 20 H 26 N4O2S + [M+H] + ,387.19;Actual value 387.11.

[0425] Synthesis of C7: 3-(3,5-dimethoxyphenyl)-1-(1-methylpiperidine-4 Synthesis of (-yl)-4-(thiazol-2-yl)azetidin-2-imine Intermediate C7-02 (11.0 mg, 19.2 μmol) was treated according to general procedure 4 to afford the title compound (purified by HPLC, 2.16 mg, 5.59 μmol).

[0426] C7 was further converted to the final aminoazetidine compound according to the synthesis of C1. Example A.23: Synthesis of 4-(benzo[d]thiazol-2-yl)-3-(1-methylpiperidin-4-yl)-1-(pyrimidin-2-yl)azetidin-2-amine (C8)

[0427] [ka]

[0428] Intermediate C8-01: Synthesis of 1-(benzo[d]thiazol-2-yl)-N-(pyrimidin-2-yl)methanimine Benzo[d]thiazole-2-carbaldehyde (100.0 mg, 0.61 mmol) and pyrimidin-2-amine (58.3 mg, 0.61 mmol, 1.0 equiv) were treated according to general procedure 2 to give the title compound (142.3 mg, 0.59 mmol), which was used in the next step without further purification.

[0429] Intermediate C8-02: Synthesis of N-(4-(benzo[d]thiazol-2-yl)-3-(1-methylpiperidin-4-yl)-1-(pyrimidin-2-yl)azetidin-2-ylidene)-4-nitrobenzenesulfonamide 4-Ethynyl-1-methylpiperidine (66.5 mg, 0.54 mmol), 4-nitrilo Isobenzenesulfonyl azide (130.00 mg, 0.54 mmol, 1.0 equiv.) and intermediate C8-01 (147.9 mg, 0.65 mmol, 1.2 equiv.) were treated according to general procedure 3 to give the title compound (purified by HPLC, 35.21 mg, 62.47 μmol) as a pale yellow solid.

[0430] Intermediate C8-03: Synthesis of 4-(benzo[d]thiazol-2-yl)-3-(1-methylpiperidin-4-yl)-1-(pyrimidin-2-yl)azetidin-2-imine Intermediate C8-02 (30.0 mg, 53.2 μmol) was treated according to general procedure 4 to afford the title compound (purified by HPLC, 18.5 mg, 48.9 μmol) as a white solid.

[0431] C8: Synthesis of 4-(benzo[d]thiazol-2-yl)-3-(1-methylpiperidin-4-yl)-1-(pyrimidin-2-yl)azetidin-2-amine To a solution of intermediate C8-03 (18.5 mg, 48.9 μmol) in methanol (1 mL) was added NaBHCN (4.61 mg, 73.4 μmol, 1.5 equiv.), and the reaction mixture was stirred at room temperature for 1 h, after which the solvent was removed in vacuo. The crude product was purified by HPLC to give C8 (12.5 mg, 32.9 μmol) as a white solid. LC-MS (m / z): calculated C 20 H 24 N6S + [M+H] + , 381.19; actual value 381.11.

[0432] Example A.24: Synthesis of 1-(4-(3-(3,5-dimethoxyphenyl)-4-imino-1-(1-methylpiperidin-4-yl)azetidin-2-yl)piperidin-1-yl)ethan-1-one (C9) Intermediate C9-01: Synthesis of 1-(4-(((1-methylpiperidin-4-yl)imino)methyl)piperidin-1-yl)ethan-1-one 1-Acetylpiperidine-4-carbaldehyde (100.0 mg, 0.64 mmol) and 1-methylpiperidin-4-amine (73.6 mg, 0.64 mmol, 1.0 equiv) were treated according to general procedure 2 to give the title compound (134.9 mg, 0.54 mmol) as a white solid, which was used in the next step without further purification.

[0433] Intermediate C9-02: Synthesis of N-(4-(1-acetylpiperidin-4-yl)-3-(3,5-dimethoxyphenyl)-1-(1-methylpiperidin-4-yl)azetidin-2-ylidene)-4-nitrobenzenesulfonamide 1-Ethynyl-3,5-dimethoxybenzene (100.0 mg, 0.62 mmol), 4-nitrobenzenesulfonyl azide (140.7 mg, 0.62 mmol, 1.0 equiv), and intermediate C9-01 (155.0 mg, 0.62 mmol, 1.0 equiv) were treated according to general procedure 3 to afford the title compound (purified by HPLC, 156.9 mg, 0.26 mmol) as a white solid.

[0434] [ka]

[0435] Synthesis of C9: Synthesis of 1-(4-(3-(3,5-dimethoxyphenyl)-4-imino-1-(1-methylpiperidin-4-yl)azetidin-2-yl)piperidin-1-yl)ethan-1-one Intermediate C9-02 (50.0 mg, 81.5 μmol) was treated according to general procedure 4 to give the title compound (purified by HPLC, 4.89 mg, 11.4 μmol) as a light brown solid. LC-MS (m / z): calculated C 24 H 36 N4O3 + [M+H] + ,429.29;Actual value 429.21.

[0436] The final aminoazetidine compound was obtained from C9 following the synthetic procedure in C1. Example A.25: Synthesis of ethyl 2-(2-(benzo[d]thiazol-2-yl)-1-(1-methylpiperidin-4-yl)-4-(((4-nitrophenyl)sulfonyl)imino)azetidin-3-yl)thiazole-4-carboxylate (C10)

[0437] [ka]

[0438] Intermediate C10-01: 1-(benzo[d]thiazol-2-yl)-N-(1-methylpiperidin-4-yl)methanimine Benzo[d]thiazole-2-carbaldehyde (100.0 mg, 0.61 mmol) and 1-methylpiperidin-4-amine (70.0 mg, 0.61 mmol, 1.0 equiv) were treated according to general procedure 2 to give the title compound (107.0 mg, 0.41 mmol) as a yellow oil, which was used in the next step without further purification.

[0439] Synthesis of C10: Ethyl 2-(2-(benzo[d]thiazol-2-yl)-1-(1-methylpiperidin-4-yl)-4-(((4-nitrophenyl)sulfonyl)imino)azetidin-3-yl)thiazole-4-carboxylate Ethyl 2-ethynylthiazole-4-carboxylate (50.0 mg, 0.28 mmol), 4-nitrobenzenesulfonyl azide (63.0 mg, 0.28 mmol, 1.0 equiv.), and intermediate C10-01 (71.6 mg, 0.28 mmol, 1.0 equiv.) were treated according to general procedure 3 to afford the title compound (purified by HPLC, 24.9 mg, 38.8 μmol) as a yellow solid. LC-MS (m / z): calculated C 28 H 28 N6O6S3 + [M+H] + ,641.13;Actual value,641.01.

[0440] The imine intermediate compound was obtained from C10 according to general procedure 4. The final aminoazetidine compound was then obtained according to the synthetic procedure of C1. Example A.26: Synthesis of 1-(4-(3-(3,5-dimethoxyphenyl)-2-imino-4-(4-(4-methylpiperazin-1-yl)phenyl)azetidin-1-yl)piperidin-1-yl)ethan-1-one (C11)

[0441] [ka]

[0442] Intermediate C11-01: Synthesis of 1-(4-(4-methylpiperazin-1-yl)phenyl)-N-(1-methylpiperidin-4-yl)methanimine 4-(4-Methylpiperazin-1-yl)benzaldehyde (100.0 mg, 0.49 mmol) and 1-(4-aminopiperidin-1-yl)ethan-1-one (69.6 mg, 0.49 mmol, 1.0 equiv) were treated according to general procedure 2 to give the title compound (108.5 mg, 0.33 mmol) as a yellow oil, which was used in the next step without further purification.

[0443] Intermediate C11-02: Synthesis of N-(1-(1-acetylpiperidin-4-yl)-3-(3,5-dimethoxyphenyl)-4-(4-(4-methylpiperazin-1-yl)phenyl)azetidin-2-ylidene)-4-nitrobenzenesulfonamide 1-Ethynyl-3,5-dimethoxybenzene (35.0 mg, 0.22 mmol), 4-nitrobenzenesulfonyl azide (41.1 mg, 0.22 mmol, 1.0 equiv), and intermediate C11-01 (49.2 mg, 0.22 mmol, 1.0 equiv) were treated according to general procedure 3 to give the title compound (purified by HPLC, 48.6 mg, 70.3 μmol) as a white solid.

[0444] Synthesis of C11: Synthesis of 1-(4-(3-(3,5-dimethoxyphenyl)-2-imino-4-(4-(4-methylpiperazin-1-yl)phenyl)azetidin-1-yl)piperidin-1-yl)ethan-1-one Intermediate C11-02 (80.2 mg, 116.1 μmol) was treated according to general procedure 4 to give the title compound (purified by HPLC, 28.4 mg, 56.2 μmol) as a light brown solid. LC-MS (m / z): calculated C 29 H 39 N5O3 + [M+H] + ,506.31;Actual value 506.21.

[0445] The final aminoazetidine compound was obtained from C11 following the synthetic procedure of C1. Example A.27: N-(4-(1-acetylpiperidin-4-yl)-1-(1-methyl) Synthesis of (piperidin-4-yl)-3-(pyrimidin-2-yl)azetidin-2-ylidene)-4-nitrobenzenesulfonamide (C12)

[0446] [ka]

[0447] Synthesis of C12: Synthesis of N-(4-(1-acetylpiperidin-4-yl)-1-(1-methylpiperidin-4-yl)-3-(pyrimidin-2-yl)azetidin-2-ylidene)-4-nitrobenzenesulfonamide 2-Ethynylpyrimidine (30.0 mg, 0.29 mmol), 4-nitrobenzenesulfonyl azide (65.7 mg, 0.29 mmol, 1.0 equiv), and intermediate C9-01 (72.4 mg, 0.29 mmol, 1.0 equiv) were treated according to general procedure 3 to afford the title compound (purified by HPLC, 24.9 mg, 38.8 μmol) as a white solid. 1HNMR(500MHz,chloroform-d)δ8.38(ddd,J=13.5,4.1,1.9Hz,1H),8.28(d,J=8.8Hz,2H),8.15(dd,J=8.6,5.8Hz,2H),8.1 1-8.04(m,1H),6.52(ddd,J=23.5,6.6,4.0Hz,1H),5.06-4.93(m,1H),4.67(dd,J=41.5,13.5Hz,1H),3.83(dd,J=38.0 ,13.8Hz,1H),3.51(d,J=12.1Hz,1H),3.31(d,J=12.1Hz,1H),3.00-2.82(m,3H),2.80(s,3H),2.63(ddd,J=17.5,12.7 ,4.4Hz,1H),2.48(m,2H),2.41-2.26(m,2H),2.07(d,J=9.2Hz,3H),1.81(dd,J=36.5,12.6Hz,1H),1.45-1.02(m,6H). LC-MS (m / z): Calculated value C 26 H 33 N7O5S + [M+H] + ,556.23;Actual value 556.17.

[0448] The imine intermediate compound was obtained from compound C12 according to general procedure 4. The final aminoazetidine was then obtained according to the synthetic procedure of C1. Example A.28: N-(4-(benzo[d]thiazol-2-yl)-3-(4-(dimethylamino)phenyl)-1-(1-methylpiperidin-4-yl)azetidin-2-ylidene)-4-nitrobenzenesulfonamide (C13)

[0449] [ka]

[0450] Intermediate C13-01: Synthesis of 1-(benzo[d]thiazol-2-yl)-N-(1-(tertbutyloxycarbonyl)piperidin-4-yl)methanimine The synthesis of intermediate C13-01 was obtained according to general procedure 2.

[0451] Benzo[d]thiazole-2-carbaldehyde (100.0 mg, 0.61 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (122.7 mg, 0.61 mmol, 1.0 equiv) were treated according to general procedure 2 to give the title compound (175.0 mg, 0.51 mmol) as a yellow oil, which was used in the next step without further purification.

[0452] Synthesis of C13: N-(4-(benzo[d]thiazol-2-yl)-3-(4-(dimethylamino)phenyl)-1-(1-methylpiperidin-4-yl)azetidin-2-ylidene)-4-nitrobenzenesulfonamide 4-Ethynyl-N,N-dimethylaniline (80.0 mg, 0.55 mmol), 4-nitrobenzenesulfonyl azide (125.7 mg, 0.55 mmol, 1.0 equiv), and intermediate C13-01 (190.3 mg, 0.55 mmol, 1.0 equiv) were treated according to general procedure 3 to give the title compound (purified by HPLC, 24.9 mg, 36.1 μmol) as a dark red solid. 1 HNMR (500MHz, chloroform-d) δ8.10(d,J=8.9Hz,2H),7.90(d,J=8.2Hz,1H),7.73-7.66(m,3H) ,7.43(ddd,J=8.3,7.2,1.2Hz,1H),7.33(ddd,J=8.2,7.2,1.1Hz,1H),6.93(d,J=8.4Hz,2 H),6.57(d,J=8.4Hz,2H),5.79(d,J=5.3Hz,1H),5.32(d,J=5.3Hz,1H),4.16(m,2H),3.98 (m,1H),2.83(s,6H),2.74(m,2H),2.06(m,2H),1.86(td,J=12.3,4.2Hz,1H),1.41(s,9H). LC-MS (m / z): Calculated value C 34 H 38 N6O6S2 + [M+H] + ,691.24;Actual value,691.00.

[0453] The imine intermediate compound was obtained from compound C13 according to general procedure 4. The final aminoazetidine compound was then obtained according to the synthetic procedure of C1. Example A.29: Synthesis of 3-(3,5-dimethoxyphenyl)-4-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(1-methylpiperidin-4-yl)azetidin-2-amine (C14)

[0454] [ka]

[0455] Intermediate C14-01: Synthesis of 4-(3,5-dimethylisoxazol-4-yl)benzaldehyde To a solution of 4-bromobenzaldehyde (200.0 mg, 1.08 mmol) in 1,4-dioxane (10 mL) was added (3,5-dimethylisoxazol-4-yl)boronic acid (182.8 mg, 1.30 mmol, 1.20 equiv.), KPO (344.2 mg, 1.62 mmol, 1.50 equiv.) dissolved in water (1 mL), and PdCl(PPh) (30.0 mg, 54.1 μmol, 5 mol%). The reaction mixture was stirred overnight at 90 °C under N protection. The solvent was removed in vacuo, and the residue was washed with water (20 mL) and extracted three times with EtOAc (30 mL). The combined organic phase was washed with brine and dried over MgSO. The mixture was filtered and the filtrate was removed in vacuo to give the crude product, which was purified by silica gel column chromatography eluting with PE: EtOAc (gradient: 4:1 to 2:1) to give intermediate C. 14-01 (179.3 mg, 0.89 mmol) was obtained.

[0456] Intermediate C14-02: Synthesis of 1-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-N-(1-methylpiperidin-4-yl)methanimine Intermediate C14-02 was obtained according to general procedure 2.

[0457] 1-Methylpiperidin-4-amine (100.0 mg, 0.86 mmol) and intermediate C14-01 (176.22 mg, 0.86 mmol, 1.00 equiv) were treated according to general procedure 2 to give the title compound (226.4 mg, 0.76 mmol) as a pale yellow solid, which was used in the next step without further purification.

[0458] Intermediate C14-03: Synthesis of N-(3-(3,5-dimethoxyphenyl)-4-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(1-methylpiperidin-4-yl)azetidin-2-ylidene)-4-nitrobenzenesulfonamide 1-Ethynyl-3,5-dimethoxybenzene (110.0 mg, 0.68 mmol), 4-nitrobenzenesulfonyl azide (154.8 mg, 0.68 mmol, 1.00 equiv), and intermediate C14-02 (201.7 mg, 0.68 mmol, 1.20 equiv) were treated according to general procedure 3 to give the title compound (purified by HPLC, 126.8 mg, 0.19 mmol).

[0459] Intermediate C14-04: Synthesis of 3-(3,5-dimethoxyphenyl)-4-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(1-methylpiperidin-4-yl)azetidin-2-imine C14-04 was prepared according to the synthesis of C8-03.

[0460] C14: Synthesis of 3-(3,5-dimethoxyphenyl)-4-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(1-methylpiperidin-4-yl)azetidin-2-amine C14 was prepared according to the synthesis of C8.

[0461] Example A.30: Synthesis of 4-(benzo[d]thiazol-2-yl)-3-(3,5-dimethoxyphenyl)-1-(1-methylpiperidin-4-yl)azetidin-2-amine (C15)

[0462] [ka]

[0463] Intermediate C15-01: Synthesis of 1-(benzo[d]thiazol-2-yl)-N-(1-methylpiperidin-4-yl)methanimine Intermediate C15-01 was obtained according to general procedure 2.

[0464] 1-Methylpiperidin-4-amine (70.0 mg, 0.61 mmol) and benzo[d]thiazole-2-carbaldehyde (100.0 mg, 0.61 mmol, 1.00 equiv) were treated according to general procedure 2 to give the title compound (167.9 mg, 0.65 mmol) as a pale yellow solid, which was used in the next step without further purification.

[0465] Intermediate C15-02: Synthesis of N-(4-(benzo[d]thiazol-2-yl)-3-(3,5-dimethoxyphenyl)-1-(1-methylpiperidin-4-yl)azetidin-2-ylidene)-4-nitrobenzenesulfonamide 1-Ethynyl-3,5-dimethoxybenzene (105.0 mg, 0.65 mmol), 4-nitrobenzenesulfonyl azide (147.7 mg, 0.65 mmol, 1.0 equiv), and intermediate C15-01 (167.9 mg, 0.65 mmol, 1.2 equiv) were treated according to general procedure 3 to give the title compound (purified by HPLC, 156.9 mg, 0.25 mmol). 1 HNMR(700MHz,CDCl3-d)δ8.01-7.97(m,2H),7.83(d,J=8.1Hz,1H),7.61(dd,J=8.2,1.2Hz,1H) ,7.54-7.49(m,2H),7.35(ddd,J=8.3,7.1,1.2Hz,1H),7.25(ddd,J=8.0,7 .1,1.1Hz,1H),6.04(t,J=2.3Hz,1H),5.89(s,2H),5.80(d,J=5.3Hz,1H), 5.23(d,J=5.3Hz,1H),4.11(tt,J=11.9,4.1Hz,1H),3.66-3.59(m,2H),3. 38(s,6H),2.73(s,3H),2.63-2.54(m,1H),2.38(tt,J=28.0,12.5Hz,4H). LC-MS (m / z): Calculated value C 30 H 31 N5O6S2 + [M+H] + ,622.18;Actual value 622.24.

[0466] Intermediate C15-03: Synthesis of 4-(benzo[d]thiazol-2-yl)-3-(3,5-dimethoxyphenyl)-1-(1-methylpiperidin-4-yl)azetidin-2-imine C15-03 was prepared according to the synthesis of C8-03. 1 H NMR (600 MHz, chloroform-d): δ 9.73 (s, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.46 (ddd, J = 8.3, 7.2, 1.2 Hz, 1H), 7.37 (ddd, J = 8.2, 7.2, 1.1 Hz, 1H), 6.24-6.14 (m, 3H), 5.10 (m, 1H), 4.65 (m, 1H), 3.71 (q, J = 7.0 Hz, 1H), 3.57 (s, 6H), 3.52 (m, 1H), 3.47-3.40 (m, 1H), 3.03-2.87 (m, 2H), 2.72 (s, 3H), 2.47-2.36 (m, 4H). 13 CNMR(151MHz,CDCl3)δ169.14,162.81,161.99,153.17,135.59,132.85,127.46,126.91,124 .07,122.51,105.65,101.22,65.48,58.63,55.72,55.12,52.72,50.91,43.48,26.72,26.53. LC-MS (m / z): Calculated value C 24 H 28 N4O2S + [M+H] + ,437.20;Actual value ,437.08.

[0467] Synthesis of C15: 4-(benzo[d]thiazol-2-yl)-3-(3,5-dimethoxyphenyl)-1-(1-methylpiperidin-4-yl)azetidin-2-amine C15 was prepared according to the synthesis of C8.

[0468] Example A.31: Synthesis of N-(1-(2,4-dimethoxybenzyl)-3-(3,5-dimethoxyphenyl)-4-(4-(3,5-dimethylisoxazol-4-yl)phenyl)azetidin-2-ylidene)-4-nitrobenzenesulfonamide (C16) Intermediate C16-01: Synthesis of 1-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-N-(2,4-dimethoxybenzyl)methanimine Intermediate C16-01 was obtained according to general procedure 2.

[0469] 4-(3,5-Dimethylisoxazol-4-yl)benzaldehyde (100.0 mg, 0.60 mmol) and (2,4-dimethoxyphenyl)methanamine (120.3 mg, 0.60 mmol, 1.00 equiv) were treated according to general procedure 2 to give the title compound (186.9 mg, 0.53 mmol) as a pale yellow solid, which was used in the next step without further purification.

[0470] Synthesis of C16: N-(1-(2,4-dimethoxybenzyl)-3-(3,5-dimethoxyphenyl)-4-(4-(3,5-dimethylisoxazol-4-yl)phenyl)azetidin-2-ylidene)-4-nitrobenzenesulfonamide

[0471] [ka]

[0472] 1-Ethynyl-3,5-dimethoxybenzene (100.0 mg, 0.62 mmol), 4-nitrobenzenesulfonyl azide (140.7 mg, 0.62 mmol, 1.0 equiv), and intermediate C16-01 (216.1 mg, 0.62 mmol, 1.0 equiv) were treated according to general procedure 3 to give the title compound (purified by HPLC, C16, 148.3 mg, 0.21 mmol, pale yellow solid). 1 HNMR(600MHz,chloroform-d)δ8.10(d,J=8.8Hz,1H),7.74(d,J=8.9Hz,1H),7.11(d,J= 8.9Hz,1H),6.95(s,3H),6.46-6.34(m,1H),6.06(d,J=2.2Hz,1H),5.82(d,J=2.2H) z,1H),5.14(d,J=5.4Hz,1H),5.08(d,J=5.3Hz,1H),5.02(d,J=14.1Hz,1H),4.32( d,J=14.1Hz,1H),3.80(s,2H),3.64(s,2H),3.52(s,2H),2.25(s,2H),2.10(s,2H). 13 CNMR(151MHz, CDCl3)δ169.55,165.35,161.78,160.37,158.97,158.63,149.44,148.37,133.71,132.24,130.27,128.80,128.10,12 7.23,123.54,116.25,114.00,107.70,104.53,98.97,98.70,65.75,60.61,57.89,55.66,55.26,43.22,21.27,14.41,11.54,10.73. LC-MS (m / z): Calculated value C 37 H 36 N4O9S + [M+H] + ,713.23;Actual value,713.17.

[0473] The imine intermediate was obtained from C16 according to general procedure 4. The final aminoazetidine compound was obtained following the synthetic procedure of C1. Example A.32: Synthesis of N-(4-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(1-methylpiperidin-4-yl)-3-(pyrimidin-2-yl)azetidin-2-ylidene)-4-nitrobenzenesulfonamide (C17)

[0474] [ka]

[0475] Synthesis of C17: Synthesis of N-(4-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(1-methylpiperidin-4-yl)-3-(pyrimidin-2-yl)azetidin-2-ylidene)-4-nitrobenzenesulfonamide 2-Ethynylpyrimidine (30.0 mg, 0.29 mmol), 4-nitrobenzenesulfonyl azide (65.8 mg, 0.29 mmol, 1.0 equiv), and intermediate C14-01 (85.7 mg, 0.29 mmol, 1.0 equiv) were treated according to general procedure 3 to give the title compound (purified by HPLC, 42.6 mg, 70.7 μmol) as a yellow solid. 1 HNMR(500MHz,chloroform-d)δ8.31(dd,J=6.6,2.0Hz,1H),8.31-8.25(m,2H),8.25(dd,J=4.0,2.0Hz,1H),8.19-8.13 (m,2H),7.32(d,J=8.2Hz,2H),7.20(d,J=8.4Hz,2H),6.48(dd,J=6.7,4.0Hz,1H),5.36(ddd,J=12.5,7.6,4.8Hz, 1H),3.50-3.40(m,2.5H),2.93(m,2.5H),2.81(s,3H),2.77(dd,J=13.3Hz,1H),2.75-2.69(m,0.5H),2.52-2.44( m,0.5H),2.41(dd,J=13.3,4.5Hz,1H),2.38(s,3H),2.24(s,3H),1.90(d,J=12.7Hz,1H),1.79(d,J=13.8Hz,1H). LC-MS (m / z): Calculated value C 30 H 31N7O5S + [M+H] + ,602.22;Actual value 602.34.

[0476] The imine intermediate was obtained from C17 according to general procedure 4. The final aminoazetidine compound was obtained according to the synthetic procedure of C1. Example A.33: Synthesis of 2-(2-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(1-methylpiperidin-4-yl)-4-(((4-nitrophenyl)sulfonyl)imino)azetidin-3-yl)-N-(2-methoxyphenyl)thiazole-4-carboxamide (C18) Synthesis of C18: 2-(2-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(1-methylpiperidin-4-yl)-4-(((4-nitrophenyl)sulfonyl)imino)azetidin-3-yl)-N-(2-methoxyphenyl)thiazole-4-carboxamide

[0477] [ka]

[0478] 2-Ethynyl-N-(2-methoxyphenyl)thiazole-4-carboxamide (30.0 mg, 0.12 mmol), 4-nitrobenzenesulfonyl azide (34.5 mg, 0.12 mmol, 1.0 equiv), and intermediate C14-01 (34.54 mg, 0.12 mmol, 1.0 equiv) were treated according to general procedure 3 to give the title compound (purified by HPLC, 42.6 mg, 70.7 μmol) as a brown solid. 1HNMR (500MHz, chloroform-d) δ8.50(d,J=8.1Hz,1H),8.32(d,J=8.9Hz,2H),8.14(d,J=8.8Hz,2H),7.78 (s,1H),7.32(d,J=8.3Hz,2H),7.17(d,J=8.2Hz,2H),7.11-7.06(m,1H),6.94(d,J=8.7Hz,2H),5.08 -4.97(m,1H),3.90(s,3H),3.72(d,J=12.0Hz,1H),3.51(d,J=12.1Hz,1H),2.89-2.79(m,2H),2.77( s,3H),2.71(dd,J=13.2,3.9Hz,1H),2.38(s,3H),2.24(s,3H),2.00(t,J=16.0Hz,2H),1.87(m,4H). LC-MS (m / z): Calculated value C 37 H 37 N7O7S2 + [M+H] + ,756.23;Actual value 756.39.

[0479] The imine intermediate was obtained from C18 according to general procedure 4. The final aminoazetidine compound was obtained according to the synthetic procedure of C1. Example B: Binding activity to microRNA Differential Scanning Fluorometry (DSF): To measure the binding of compounds to the precursor microRNA-21 hairpin (pre-miR-21hp) or precursor microRNA-17 hairpin (pre-miR-17hp), DSF with denaturation was performed as previously described (ACS Chem. Biol. 2017, 12, 2, 435-443). Precursor microRNA hairpins were dissolved in PBS and annealed by briefly heating to 95°C for 3 minutes and slowly cooling to room temperature. Analysis was performed in duplicate using white qPCR8-strips (VWR) in a total volume of 10 μL PBS solution. The total reaction solution consisted of 1 μM precursor microRNA hairpin, 1% test compound (diluted in DMSO), and 2x SYBR Green II (Thermo Fisher Scientific). The compounds were incubated with the precursor microRNA hairpins for 10 minutes at room temperature, after which SYBR Green II was added to each well, mixed, and incubated for 10 minutes at room temperature. The strips were spun and loaded into an RT-PCR detection system (Bio-Rad CFX Connect), and the fluorescence intensity was measured at 1°C intervals from 20 to 80°C for 30 seconds.

[0480] Data Analysis: The melting temperature (Tm) was determined by the maximum negative value of the first derivative of the fluorescence versus temperature melting curve. ΔTm was calculated by subtracting the Tm value of the DMSO control from the Tm value of the compound.

[0481] result: Some of the tested compounds exhibited the ability to modulate the melting temperature of the tested microRNAs, suggesting that some of the tested compounds may bind to the tested microRNA hairpins and affect the thermal stability of the RNA, making them small RNA binders.

[0482] The DSF results are summarized in Table 1 (ND, data not shown). Graphical results for selected compounds for pre-miR-17hp are shown in Figures 1A-1E. Graphical results for selected compounds for pre-miR-21hp are shown in Figures 2A-2E.

[0483] [Table 1]

[0484] Example C: Determination of the anticancer activity of compounds of the present invention cell culture MAD-MB-231, MCF-7, and JAR cells were cultured in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum (FBS) and 100 μg / mL penicillin-streptomycin. Jurkat, Molt-4, and Ramos cells were cultured in Roswell Park Memorial Institute (RPMI) 1640 medium with 10% fetal bovine serum (FBS) and 100 μg / mL penicillin-streptomycin. All cell lines were cultured in a humidified 5% CO2 incubator at 37°C.

[0485] Colony formation assay MDA-MB-231 cells were harvested and seeded in a 24-well plate at a density of 1,000 cells per well and cultured overnight. The medium was changed every three days, and different compounds were added at different concentrations. After six days, the cells were washed with PBS and fixed with 4% paraformaldehyde solution. After 15 minutes of fixation, the paraformaldehyde solution was washed with PBS and then stained with 0.1% (w / v) crystal violet. After 15 minutes, the cells were washed and photographed.

[0486] result The selected compounds A10, A11, B2, B5, B8, and B9 exhibited dose-dependent antiproliferative activity against the MDA-MB-231 cell line. Among these selected compounds, B2, B5, and B8 exhibited the most potent antiproliferative activity. At a concentration of 10 μM, B2, B5, and B8 completely inhibited MDA-MB-231 cell proliferation.

[0487] Graphical results for selected compounds are shown in Figures 3A-3B. MTT assay Jurkat, Molt-4, and Ramos cells were harvested and seeded in 96-well plates at densities of 8,000–10,000 cells per well and treated with compounds. MCF-7, MDA-MB-231, and JAR cells were harvested and seeded in 96-well plates at densities of 2,000–3,000 cells per well, cultured overnight to allow adhesion, and then treated with compounds. After 72 hours of exposure to increasing concentrations of compounds, cells in each well were mixed with 20 μL of 5 mg / mL MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) for 2 hours, followed by overnight incubation with 50 μL of 20% SDS / 0.01 M HCl. Absorbance was measured at 570 nm.

[0488] Data Analysis: The inhibition rate was calculated using the equation: Inhibition rate = 100% (control - X) / (control - blank). IC 50 Values ​​were calculated by fitting to a dose-response inhibition equation using GraphPad Prism 9 software.

[0489] result: The majority of the tested compounds showed anticancer effects in selected cancer cell lines, including one Burkitt's lymphoma cell line (Ramos), two acute leukemia cell lines (Molt-4 and Jurkat), two breast cancer cell lines (MCF-7 and MDA-MB-231), and one choriocarcinoma cell line (JAR).

[0490] The anti-cancer results are summarized in the following tables. Results for Ramos, Molt-4, and Jurkat cell lines are shown in Table 2. Results for MCF-7, MDA-MB-231, and JAR cell lines are shown in Table 3 (ND, data none).

[0491] I C 50 The curve is shown in FIG.

[0492] [Table 2]

[0493] [Table 3]

[0494] [Table 4-1]

[0495] [Table 4-2]

Claims

1. Compounds of general formula (I) 【Chemical 1】 During the ceremony, R ２ represents -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , -CH(CH ３ ) ２ , -(CH ２ ) ３ CH ３ , -(CH ２ ) ４ CH ３ , -(CH ２ ) ５ CH ３ , -CH ２ CH(CH ３ ) ２ , -(CH ２ ) ２ CH(CH ３ ) ２ , -CH(CH ２ CH ３ )CH ３ , -CH(CH ２ CH ３ ) ２ , -C(CH ３ ) ３ , -CH ２ CH=CH ２ , -(CH ２ ) ２ CH=CH ２ , -(CH ２ ) ３ CH=CH ２ , -(CH ２ ) ４ CH=CH ２ , -L １ -A １ , or -B １ ; R ２ is -H, -CN, -NR ４ R ５ , -L ２ -A ２ , -B ２ , or -C ２ represents; R ３ Is, -A ３ or -B ３ where R ２ When is -CN, R ３ Ha-A ３ and L １ is -CO- or -SO ２ represents -; L ２ is -CH ２ -NR ６ —CO—, —CH ２ -NR ６ -SO ２ -,or 【Chemistry 2】 represents; R ４ and R ５ are each independently —CH ３ , -CH ２ CH ３ , -CH(CH ３ ) ２ , -CH ２ CH ２ CH ３ , -CH ２ CH (CH ３ ) ２ , -C(CH ３ ) ３ , -cyclo-C ３ H ５ , -cyclo-C ４ H ７ , -cyclo-C ５ H ９ , -cyclo-C ６ H １１ , -CH ２ -cyclo-C ３ H ５ , -CH ２ -cyclo-C ４ H ７ , -CH ２ -cyclo-C ５ H ９ , -CH ２ -cyclo-C ６ H １１ , -CH ２ -Ph, -CH ２ OCH ３ , -CH ２ OCH ２ CH ３ , -CH ２ CH ２ OCH ３ , or -CH ２ CH ２ SCH ３ represents; A １ and A ２ are independent of each other, 【Chemistry 3-1】 【Chemistry 3-2】 Selected from: A ３ teeth, 【Chemistry 4】 represents; 【Chemistry 5】 having C selected from: B １ is -H １ , -P １ -H １ , or -P １ -Y １ -H １ represents; B ２ is -H ２ , -P ２ -H ２ , or -P ２ -Y ２ -H ２ represents; B ３ is -H ３ , -P ３ -H ３ , or -P ３ -Y ３ -H ３ represents; C ２ teeth, 【Chemistry 6】 Selected from: Y １ , Y ２ , and Y ３ are each independently —O—, —NR ２２ --CO-NR ２２ -, -NR ２２ -CO-, -SO ２ -NR ２２ -, -NR ２２ -SO ２ - or -NR ２２ -CO-NR ２３ - selected from; P １ , P ２ , and P ３ are independent of each other, 【Chemistry 7】 Selected from: H １ , H ２ , and H ３ are independent of each other, 【Chemistry 8-1】 【Chemistry 8-2】 【Chemistry 8-3】 【Chemistry 8-4】 【Chemistry 8-5】 Selected from: R １７ ~R ２０ and R ２８ ~R ３２ are each independently —H, —F, —Cl, —Br, —I, —OH, —CN, or —NO ２ , -CH ３ , -C ２ H ５ , -C ３ H ７ , -CH(CH ３ ) ２ , -C ４ H ９ , -CH ２ -CH(CH ３ ) ２ , -CH(CH ３ )-C ２ H ５ , -C(CH ３ ) ３ , -cyclo-C ３ H ５ , -CH ２ -cyclo-C ３ H ５ , -CH ２ F, -CHF ２ , -CF ３ , -CH ２ Cl, —CH ２ Br, —CH ２ I, -CH ２ -CH ２ F, -CH ２ -CHF ２ , -CH ２ -CF ３ , -CH ２ -CH ２ Cl, —CH ２ -CH ２ Br, —CH ２ -CH ２ I, -OCH ３ , -OC ２ H ５ , -OC ３ H ７ , -OCH(CH ３ ) ２ , -OC(CH ３ ) ３ , -OC ４ H ９ , -OCHF ２ , -OCF ３ ,-OCH ２ CF ３ ,-OC ２ F ５ ,-OCH ２ OCH ３ 、-O-シクロ-C ３ H ５ ,-OCH ２ -シクロ-C ３ H ５ ,-O-C ２ H ４ -シクロ-C ３ H ５ 、-CHOO、-COCH ３ ,-COCF ３ ,-COC ２ H ５ ,-COC ３ H ７ , -COCH (CH ３ ) ２ , -COC (CH) ３ ) ３ 、-COOOH、-COOCH ３ ,-COO ２ H ５ ,-COO ３ H ７ 、-COOOCH (CH ３ ) ２ , -COOC (CH ３ ) ３ ,-OO--CH ３ ,-OO-CF- ３ ,---- ２ H ５ ,---- ３ H ７ 、-OOC-CH (CH ３ ) ２ 、-OOC-C (CH ３ ) ３ ,-NH ２ ,-NHCH ３ ,-NHC ２ H ５ ,-NHC ３ H ７ , -NHCH (CH ３ ) ２ , -NHC (CH) ３ ) ３ , -N (CH) ３ ) ２ , -N (C) ２ H ５ ) ２ 、-N(C ３ H ７ ) ２ 、-N[CH(CH ３ ) ２ ] ２ 、-N[C(CH ３ ) ３ ] ２ 、-NHCOCH ３ 、-NHCOCF ３ 、-NHCOC ２ H ５ 、-NHCOC ３ H ７ 、-NHCOCH(CH ３ ) ２ 、-NHCOC(CH ３ ) ３ 、-CONH ２ 、-CONHCH ３ 、-CONHC ２ H ５ 、-CONHC ３ H ７ 、-CONHCH(CH ３ ) ２ 、-CONH-シクロ-C ３ H ５ 、-CONHC(CH ３ ) ３ 、-CON(CH ３ ) ２ 、-CON(C ２ H ５ ) ２ 、-CON(C ３ H ７ ) ２ 、-CON[CH(CH ３ ) ２ ] ２ 、-CON[C(CH ３ ) ３ ] ２ 、-SO ２ NH ２ 、-SO ２ NHCH ３ 、-SO ２ NHC ２ H ５ 、-SO ２ NHC ３ H ７ 、-SO ２ NHCH(CH ３ ) ２ 、-SO ２ NH-シクロ-C ３ H ５ 、-SO ２ NHC(CH ３ ) ３ 、-SO ２ N(CH ３ ) ２ 、-SO ２ N(C ２ H ５ ) ２ 、-SO ２ N(C ３ H ７ ) ２ 、-SO ２ N[CH(CH ３ ) ２ ] ２ 、-SO ２ N[C(CH ３ ) ３ ] ２ 、-NHSO ２ CH ３ 、-NHSO ２ CF ３ 、-NHSO ２ C ２ H ５ 、-NHSO ２ C ３ H ７ 、-NHSO ２ CH(CH ３ ) ２ 、-NHSO ２ C(CH ３ ) ３ 、-CH=CH ２ 、-CH ２ -CH=CH ２ 、-C(CH ３ )=CH ２ 、-CH=CH-CH ３ 、-C≡CH、-C≡C-CH ３ 、-CH ２ -C≡CH、-Ph、-O-Ph、-O-CH ２ -Ph、-C(=NH)NH ２ 、または 【Chemistry 9】 represents; R ６ , R １１ , R １２ , R ２１ ~R ２３ , R ３３ ~R ３５ , R ４０ , R ４１ , R ４６ , and R ４７ are each independently —H, —CH ３ , -CH ２ CH ３ , -CH(CH ３ ) ２ , -CH ２ CH ２ CH ３ , -CH ２ CH (CH ３ ) ２ , -C(CH ３ ) ３ , -cyclo-C ３ H ５ , -cyclo-C ４ H ７ , -cyclo-C ５ H ９ , -cyclo-C ６ H １１ , -CH ２ -cyclo-C ３ H ５ , -CH ２ -cyclo-C ４ H ７ , -CH ２ -cyclo-C ５ H ９ , -CH ２ -cyclo-C ６ H １１ , -CH ２ -Ph, -CH ２ OCH ３ , -CH ２ OCH ２ CH ３ , -CH ２ CH ２ OCH ３ , -COO-C(CH ３ ) ３ , —COO—CH ２ Ph, or -CH ２ CH ２ SCH ３ represents; R ２４ ~R ２７ , R ３６ａ ~R ３９ａ , R ３６ｂ ~R ３９ｂ , R ４２ａ ~R ４５ａ , and R ４２ｂ ~R ４５ｂ are each independently —H, —F, —Cl, —Br, —I, —OH, —CN, or —NO ２ , -CH ３ , -C ２ H ５ , -C ３ H ７ , -CH(CH ３ ) ２ , -C ４ H ９ , -CH ２ -CH(CH ３ ) ２ , -CH(CH ３ )-C ２ H ５ , -C(CH ３ ) ３ , -cyclo-C ３ H ５ , -CH ２ -cyclo-C ３ H ５ , -CH ２ F, -CHF ２ , -CF ３ , -CH ２ Cl, —CH ２ Br, —CH ２ I, -CH ２ -CH ２ F, -CH ２ -CHF ２ , -CH ２ -CF ３ , -CH ２ -CH ２ Cl, —CH ２ -CH ２ Br, —CH ２ -CH ２ I, -OCH ３ , -OC ２ H ５ , -OC ３ H ７ , -OCH(CH ３ ) ２ , -OC(CH ３ ) ３ 、-OC ４ H ９ 、-OCHF ２ 、-OCF ３ ,-OCH ２ CF ３ 、-OC ２ F ５ ,-OCH ２ OCH ３ 、-O-シクロ-C ３ H ５ ,-OCH ２ -シクロ-C ３ H ５ 、-O- C ２ H ４ -シクロ-C ３ H ５ 、-CHO、-COCH ３ 、-COCF ３ 、-COC ２ H ５ 、-COC ３ H ７ 、-COCH(CH ３ ) ２ 、-COC(CH ３ ) ３ 、-COOH、-COOCH ３ 、-COOC ２ H ５ 、-COOC ３ H ７ 、-COOCH(CH ３ ) ２ 、-COOC(CH ３ ) ３ 、-OOC-CH ３ 、-OOC-CF ３ 、-OOC-C ２ H ５ 、-OOC-C ３ H ７ 、-OOC-CH(CH ３ ) ２ 、-OOC-C(CH ３ ) ３ 、-NH ２ 、-NHCH ３ 、-NHC ２ H ５ 、-NHC ３ H ７ 、-NHCH(CH ３ ) ２ 、-NHC(CH ３ ) ３ 、-N(CH ３ ) ２ 、-N(C ２ H ５ ) ２ 、-N(C ３ H ７ ) ２ 、-N[CH(CH ３ ) ２ ] ２ 、-N[C(CH ３ ) ３ ] ２ 、-NHCOCH ３ 、-NHCOCF ３ 、-NHCOC ２ H ５ 、-NHCOC ３ H ７ 、-NHCOCH(CH ３ ) ２ 、-NHCOC(CH ３ ) ３ 、-CONH ２ 、-CONHCH ３ 、-CONHC ２ H ５ 、-CONHC ３ H ７ 、-CONHCH(CH ３ ) ２ 、-CONH-シクロ-C ３ H ５ 、-CONHC(CH ３ ) ３ 、-CON(CH ３ ) ２ 、-CON(C ２ H ５ ) ２ 、-CON(C ３ H ７ ) ２ 、-CON[CH(CH ３ ) ２ ] ２ 、-CON[C(CH ３ ) ３ ] ２ 、-SO ２ NH ２ 、-SO ２ NHCH ３ 、-SO ２ NHC ２ H ５ 、-SO ２ NHC ３ H ７ 、-SO ２ NHCH(CH ３ ) ２ 、-SO ２ NH-シクロ-C ３ H ５ 、-SO ２ NHC(CH ３ ) ３ 、-SO ２ N(CH ３ ) ２ 、-SO ２ N(C ２ H ５ ), -SO ２ N(C ２ H ３ ), -SO ７ N[CH(CH ２ ), -SO ２ N[C(CH ３ ), -NHSO ２ , -NHSO ２ CF ２ ), -NHSO ３ C ３ , -NHSO ２ CH ２ ), -NHSO ３ CH ２ ), -NHSO ３ CH(CH ２ ), -NHSO ２ H ５ ), -NHSO ２ C ３ H ７ [[ID=5l]]), -NHSO ２ CH(CH ３ ), -NHSO ２ C(CH ２ ), -CH=CH ３ ), -CH ３ -CH=CH ２ ), -C(CH ２ )=CH ２ ), -CH=CH-CH ３ ), -C≡CH, -C≡C-CH ２ ), -CH ３ -C≡CH, -Ph, -O-Ph, or -O-CH ３ -Ph represents;​​​ X is -CN, -NH ２ , or -CH ２ represents OH; where X and R ２ cannot be simultaneously -CN; A compound of general formula (I) or a regioisomer, diastereomer, enantiomer, mixture of regioisomers, mixture of diastereomers, mixture of enantiomers, solvate, hydrate, or pharmaceutically acceptable salt thereof:

2. 2. The compound of claim 1, wherein X is —CN or —NH ２ Represents a compound.

3. 3. The compound of claim 1 or claim 2, wherein the compound has the following formula (Ia), (Ib), (Ic), or (Id): 【Chemistry 10】 and In the formula, R １ , R ２ , R ３ and X has the meaning defined in claim 1 or claim 2. have, compound.

4. The compound according to claim 1, wherein the compound is represented by the following formulas (II-1) to (II-6): 【Chemistry 11】 and In the formula, R １ , R ３ , A ２ , A ３ , B １ , and B ２ has the meaning defined in claim 1, compound.

5. The compound according to claim 1, wherein the compound is represented by the following formulas (II-2) to (II-6): 【Chemistry 12】 and In the formula, R １ , R ３ , A ２ , B １ , and B ２ has the meaning defined in claim 1, compound.

6. 6. A compound according to any one of claims 1 to 5, wherein R １ is -CH ２ CH ２ CH ３ , -CH ２ CH=CH ２ , 【Chemistry 13-1】 【Chemistry 13-2】 represents; In the formula, R ７ , R ８ , R １１ , and R ２４ ~R ３２ has the meaning defined in claim 1, compound.

7. 7. A compound according to any one of claims 1 to 6, wherein R ２ is -H, -CN, -N(CH ３ ) ２ , 【Chemistry 14】 represents; In the formula, R １１ , R ２４ ~R ３２ , R ３６ａ ~R ３９ａ , and R ３６ｂ ~R ３９ｂ has the meaning defined in claim 1, compound.

8. 8. A compound according to any one of claims 1 to 7, wherein R ３ teeth 【Chemistry 15】 represents; In the formula, R ２４ ~R ３２ has the meaning defined in claim 1, compound.

9. A compound according to claim 1 selected from the following list: 1-(1-amino-(3-aminothieno[2,3-b]pyridine-2-carbonyl)phenyl-4-carbonyl)-4-(hydroxymethyl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile; 1-(3-aminothieno[2,3-b]pyridine-2-carbonyl)-4-(hydroxymethyl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile; 3-amino-N-((4-(hydroxymethyl)-1-propyl-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidin-2-yl)methyl)thieno[2,3-b]pyridine-2-carboxamide; 1-allyl-4-((4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile; 3-(4-(1H-benzo[d]imidazol-6-yl)phenyl)-1-(3-aminothieno[2,3-b]pyridine-2-carbonyl)-4-(hydroxymethyl)azetidine-2-carbonitrile; N-((3-(4-(1H-benzo[d]imidazol-6-yl)phenyl)-4-(hydroxymethyl)-1-propylazetidin-2-yl)methyl)-3-aminothieno[2,3-b]pyridine-2-carboxamide; 1-allyl-4-((4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile; 4-(hydroxymethyl)-1-(4-methylthiazole-2-carbonyl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile; 3-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(4-(methylamino)quinazolin-2-yl)azetidine-2-carbonitrile; 3-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(4-(methylamino)quinazolin-2-yl)azetidine-2-carbonitrile; 1-(3-aminothieno[2,3-b]pyridine-2-carbonyl)-3-(4-(3,5-dimethylisoxazol-4-yl)phenyl)azetidine-2-carbonitrile; 1-(4-(methylamino)quinazolin-2-yl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile; 1-(3-aminothieno[2,3-b]pyridine-2-carbonyl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile; 3-(4-(1H-benzo[d]imidazol-6-yl)phenyl)-1-(4-(methylamino)quinazolin-2-yl)azetidine-2-carbonitrile; tert-butyl 4-(2-amino-4-(4-bromophenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)azetidin-1-yl)piperidine-1-carboxylate; tert-butyl 4-(2-amino-4-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-(4-fluorophenyl)azetidin-1-yl)piperidine-1-carboxylate; di-tert-butyl 4,4′-(4-amino-3-(4-fluorophenyl)azetidine-1,2-diyl)bis(piperidine-1-carboxylate); di-tert-butyl 4,4'-(4-amino-3-(4-(4-methylpiperazin-1-yl)phenyl)azetidine-1,2-diyl)bis(piperidine-1-carboxylate); tert-butyl 4-(2-amino-4-(4-bromophenyl)-3-(4-fluorophenyl)azetidin-1-yl)piperidine-1-carboxylate; tert-butyl 4-(2-amino-4-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-3-(4-fluorophenyl)azetidin-1-yl)piperidine-1-carboxylate; 4-(benzo[d]thiazol-2-yl)-3-(1-methylpiperidin-4-yl)-1-(quinazolin-4-yl)azetidin-2-amine; 4-(benzo[d]thiazol-2-yl)-3-(1-methylpiperidin-4-yl)-1-(pyrimidin-2-yl)azetidin-2-amine; 4-(1H-benzo[d]imidazol-2-yl)-1,3-bis(1-methylpiperidin-4-yl)azetidin-2-amine; 4-(1H-benzo[d]imidazol-2-yl)-3-(3,5-dimethoxyphenyl)-1-(1H-indol-3-yl)azetidin-2-amine; 3-(1-methylpiperidin-4-yl)-1-(9H-purin-6-yl)-4-(4-(trifluoromethyl)phenyl)azetidin-2-amine; 3-(3,5-dimethoxyphenyl)-1-(1-methylpiperidin-4-yl)-4-(4-(thiazol-4-yl)phenyl)azetidin-2-amine; 1-(benzo[d]oxazol-2-yl)-3-(4-(4,5-dihydro-1H-imidazol-2-yl)phenyl)-4-(4-(4-methylpiperazin-1-yl)phenyl)azetidin-2-amine; 3-(3,5-dimethoxyphenyl)-1-(1-methylpiperidin-4-yl)-4-morpholinoazetidin-2-amine; 1-(4,6-dimethoxypyrimidin-2-yl)-4-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-(thiazol-4-yl)phenyl)azetidin-2-amine; 4-(9H-carbazol-9-yl)-1-(1-methylpiperidin-4-yl)-3-(4-(thiazol-4-yl)phenyl)azetidin-2-amine; 1-(1H-benzo[d]imidazol-2-yl)-3-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-4-(4-methylpiperazin-1-yl)azetidin-2-amine; 3-(3,5-dimethoxyphenyl)-4-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(1-methylpiperidin-4-yl)azetidin-2-amine; and 4-(benzo[d]thiazol-2-yl)-3-(3,5-dimethoxyphenyl)-1-(1-methylpiperidin-4-yl)azetidin-2-amine.

10. A compound according to claim 1 selected from the following list: 3-amino-N-((4-(hydroxymethyl)-1-propyl-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidin-2-yl)methyl)thieno[2,3-b]pyridine-2-carboxamide; 1-allyl-4-((4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile; N-((3-(4-(1H-benzo[d]imidazol-6-yl)phenyl)-4-(hydroxymethyl)-1-propylazetidin-2-yl)methyl)-3-aminothieno[2,3-b]pyridine-2-carboxamide; 1-allyl-4-((4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile; 3-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(4-(methylamino)quinazolin-2-yl)azetidine-2-carbonitrile; 3-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(4-(methylamino)quinazolin-2-yl)azetidine-2-carbonitrile; 1-(3-aminothieno[2,3-b]pyridine-2-carbonyl)-3-(4-(3,5-dimethylisoxazol-4-yl)phenyl)azetidine-2-carbonitrile; 1-(4-(methylamino)quinazolin-2-yl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile; 1-(3-aminothieno[2,3-b]pyridine-2-carbonyl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile; 3-(4-(1H-benzo[d]imidazol-6-yl)phenyl)-1-(4-(methylamino)quinazolin-2-yl)azetidine-2-carbonitrile; tert-butyl 4-(2-amino-4-(4-bromophenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)azetidin-1-yl)piperidine-1-carboxylate; tert-butyl 4-(2-amino-4-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-(4-fluorophenyl)azetidin-1-yl)piperidine-1-carboxylate; di-tert-butyl 4,4′-(4-amino-3-(4-fluorophenyl)azetidine-1,2-diyl)bis(piperidine-1-carboxylate); di-tert-butyl 4,4'-(4-amino-3-(4-(4-methylpiperazin-1-yl)phenyl)azetidine-1,2-diyl)bis(piperidine-1-carboxylate); tert-butyl 4-(2-amino-4-(4-bromophenyl)-3-(4-fluorophenyl)azetidin-1-yl)piperidine-1-carboxylate; tert-butyl 4-(2-amino-4-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-3-(4-fluorophenyl)azetidin-1-yl)piperidine-1-carboxylate; 4-(benzo[d]thiazol-2-yl)-3-(1-methylpiperidin-4-yl)-1-(quinazolin-4-yl)azetidin-2-amine; 4-(benzo[d]thiazol-2-yl)-3-(1-methylpiperidin-4-yl)-1-(pyrimidin-2-yl)azetidin-2-amine; 4-(1H-benzo[d]imidazol-2-yl)-1,3-bis(1-methylpiperidin-4-yl)azetidin-2-amine; 4-(1H-benzo[d]imidazol-2-yl)-3-(3,5-dimethoxyphenyl)-1-(1H-indol-3-yl)azetidin-2-amine; 3-(1-methylpiperidin-4-yl)-1-(9H-purin-6-yl)-4-(4-(trifluoromethyl)phenyl)azetidin-2-amine; 3-(3,5-dimethoxyphenyl)-1-(1-methylpiperidin-4-yl)-4-(4-(thiazol-4-yl)phenyl)azetidin-2-amine; 1-(benzo[d]oxazol-2-yl)-3-(4-(4,5-dihydro-1H-imidazol-2-yl)phenyl)-4-(4-(4-methylpiperazin-1-yl)phenyl)azetidin-2-amine; 3-(3,5-dimethoxyphenyl)-1-(1-methylpiperidin-4-yl)-4-morpholinoazetidin-2-amine; 1-(4,6-dimethoxypyrimidin-2-yl)-4-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-(thiazol-4-yl)phenyl)azetidin-2-amine; 4-(9H-carbazol-9-yl)-1-(1-methylpiperidin-4-yl)-3-(4-(thiazol-4-yl)phenyl)azetidin-2-amine; 1-(1H-benzo[d]imidazol-2-yl)-3-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-4-(4-methylpiperazin-1-yl)azetidin-2-amine; 3-(3,5-dimethoxyphenyl)-4-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(1-methylpiperidin-4-yl)azetidin-2-amine; and 4-(benzo[d]thiazol-2-yl)-3-(3,5-dimethoxyphenyl)-1-(1-methylpiperidin-4-yl)azetidin-2-amine.

11. A compound according to claim 1 selected from the following list: 1-(3-aminothieno[2,3-b]pyridine-2-carbonyl)-4-(hydroxymethyl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl) l) azetidine-2-carbonitrile; 3-(4-(1H-benzo[d]imidazol-6-yl)phenyl)-1-(3-aminothieno[2,3-b]pyridine-2-carbonyl)-4-(hydroxymethyl)azetidine-2-carbonitrile; cis-N-((3-(4-(1H-benzo[d]imidazol-6-yl)phenyl)-4-(hydroxymethyl)-1-propylazetidin-2-yl)methyl)-3-aminothieno[2,3-b]pyridine-2-carboxamide; trans-N-((3-(4-(1H-benzo[d]imidazol-6-yl)phenyl)-4-(hydroxymethyl)-1-propylazetidin-2-yl)methyl)-3-aminothieno[2,3-b]pyridine-2-carboxamide; 1-allyl-4-((4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile; cis-4-(hydroxymethyl)-1-(4-methylthiazole-2-carbonyl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile; trans-4-(hydroxymethyl)-1-(5-methyloxazole-2-carbonyl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile; 3-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(4-(methylamino)quinazolin-2-yl)azetidine-2-carbonitrile; cis-1-(3-aminothieno[2,3-b]pyridine-2-carbonyl)-3-(4-(3,5-dimethylisoxazol-4-yl)phenyl)azetidine-2-carbonitrile; trans-1-(3-aminothieno[2,3-b]pyridine-2-carbonyl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile; and 3-(4-(1H-benzo[d]imidazol-6-yl)phenyl)-1-(4-(methylamino)quinazolin-2-yl)azetidine-2-carbonitrile.

12. A compound according to claim 1 selected from the following list: cis-N-((3-(4-(1H-benzo[d]imidazol-6-yl)phenyl)-4-(hydroxymethyl)-1-propylazetidin-2-yl)methyl)-3-aminothieno[2,3-b]pyridine-2-carboxamide; trans-N-((3-(4-(1H-benzo[d]imidazol-6-yl)phenyl)-4-(hydroxymethyl)-1-propylazetidin-2-yl)methyl)-3-aminothieno[2,3-b]pyridine-2-carboxamide; 1-allyl-4-((4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile; 3-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(4-(methylamino)quinazolin-2-yl)azetidine-2-carbonitrile; cis-1-(3-aminothieno[2,3-b]pyridine-2-carbonyl)-3-(4-(3,5-dimethylisoxazol-4-yl)phenyl)azetidine-2-carbonitrile; trans-1-(3-aminothieno[2,3-b]pyridine-2-carbonyl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-2-carbonitrile; and 3-(4-(1H-benzo[d]imidazol-6-yl)phenyl)-1-(4-(methylamino)quinazolin-2-yl)azetidine-2-carbonitrile.

13. A pharmaceutical composition comprising a carrier and a compound according to any one of claims 1 to 12.

14. 1. Compounds of formula (I) for use in the treatment and / or prevention of diseases caused by and / or associated with microRNA expression or microRNA misexpression, 【Chemistry 16】 During the ceremony, R １ represents -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , -CH(CH ３ ) ２ , -(CH ２ ) ３ CH ３ , -(CH ２ ) ４ CH ３ , -(CH ２ ) ５ CH ３ , -CH ２ CH(CH ３ ) ２ , -(CH ２ ) ２ CH(CH ３ ) ２ , -CH(CH ２ CH ３ )CH ３ , -CH(CH ２ CH ３ ) ２ , -C(CH ３ ) ３ , -CH ２ CH=CH ２ , -(CH ２ ) ２ CH=CH ２ , -(CH ２ ) ３ CH=CH ２ , -(CH ２ ) ４ CH=CH ２ , -L １ -A １ , or -B １ ; R ２ is -H, -CN, -NR ４ R ５ , -L ２ -A ２ , -B ２ , or -C ２ represents; R ３ Is, -A ３ or -B ３ where R ２ When is -CN, R ３ Ha-A ３ and L １ is -CO- or -SO ２ represents -; L ２ is -CH ２ -NR ６ —CO—, —CH ２ -NR ６ -SO ２ -,or 【Chemistry 17】 represents; R ４ and R ５ are each independently —CH ３ , -CH ２ CH ３ , -CH(CH ３ ) ２ , -CH ２ CH ２ CH ３ , -CH ２ CH (CH ３ ) ２ , -C(CH ３ ) ３ , -cyclo-C ３ H ５ , -cyclo-C ４ H ７ , -cyclo-C ５ H ９ , -cyclo-C ６ H １１ , -CH ２ -cyclo-C ３ H ５ , -CH ２ -cyclo-C ４ H ７ , -CH ２ -cyclo-C ５ H ９ , -CH ２ -cyclo-C ６ H １１ , -CH ２ -Ph, -CH ２ OCH ３ , -CH ２ OCH ２ CH ３ , -CH ２ CH ２ OCH ３ , or -CH ２ CH ２ SCH ３ represents; A １ and A ２ are independent of each other, 【Chemistry 18-1】 【Chemistry 18-2】 Selected from: A ３ teeth, 【Chemistry 19】 represents; 【Chemistry 20】 having C selected from: B １ is -H １ , -P １ -H １ , or -P １ -Y １ -H １ represents; B ２ is -H ２ , -P ２ -H ２ , or -P ２ -Y ２ -H ２ represents; B ３ is -H ３ , -P ３ -H ３ , or -P ３ -Y ３ -H ３ represents; C ２ teeth, 【Chemical 21】 Selected from: Y １ , Y ２ , and Y ３ are each independently —O—, —NR ２２ --CO-NR ２２ -, -NR ２２ -CO-, -SO ２ -NR ２２ -, -NR ２２ -SO ２ - or -NR ２２ -CO-NR ２３ - selected from; P １ , P ２ , and P ３ are independent of each other, 【Chemical 22】 Selected from: H １ , H ２ , and H ３ are independent of each other, 【Chemistry 23-1】 【Chemistry 23-2】 【Chemistry 23-3】 【Chemistry 23-4】 【Chemistry 23-5】 Selected from: R １７ ~R ２０ and R ２８ ~R ３２ are each independently —H, —F, —Cl, —Br, —I, —OH, —CN, or —NO ２ , -CH ３ , -C ２ H ５ , -C ３ H ７ , -CH(CH ３ ) ２ , -C ４ H ９ , -CH ２ -CH(CH ３ ) ２ , -CH(CH ３ )-C ２ H ５ , -C(CH ３ ) ３ , -cyclo-C ３ H ５ , -CH ２ -cyclo-C ３ H ５ , -CH ２ F, -CHF ２ , -CF ３ , -CH ２ Cl, —CH ２ Br, —CH ２ I, -CH ２ -CH ２ F, -CH ２ -CHF ２ , -CH ２ -CF ３ , -CH ２ -CH ２ Cl, —CH ２ -CH ２ Br, —CH ２ -CH ２ I, -OCH ３ , -OC ２ H ５ , -OC ３ H ７ , -OCH(CH ３ ) ２ , -OC(CH ３ ) ３ , -OC ４ H ９ , -OCHF ２ , -OCF ３ ,-OCH ２ CF ３ ,-OC ２ F ５ ,-OCH ２ OCH ３ 、-O-シクロ-C ３ H ５ ,-OCH ２ -シクロ-C ３ H ５ ,-O-C ２ H ４ -シクロ-C ３ H ５ 、-CHOO、-COCH ３ ,-COCF ３ ,-COC ２ H ５ ,-COC ３ H ７ , -COCH (CH ３ ) ２ , -COC (CH) ３ ) ３ 、-COOOH、-COOCH ３ ,-COO ２ H ５ ,-COO ３ H ７ 、-COOOCH (CH ３ ) ２ , -COOC (CH ３ ) ３ ,-OO--CH ３ ,-OO-CF- ３ ,---- ２ H ５ ,---- ３ H ７ 、-OOC-CH (CH ３ ) ２ 、-OOC-C (CH ３ ) ３ ,-NH ２ ,-NHCH ３ ,-NHC ２ H ５ ,-NHC ３ H ７ , -NHCH (CH ３ ) ２ , -NHC (CH) ３ ) ３ , -N (CH) ３ ) ２ , -N (C) ２ H ５ ) ２ 、-N(C ３ H ７ ) ２ 、-N[CH(CH ３ ) ２ ] ２ 、-N[C(CH ３ ) ３ ] ２ 、-NHCOCH ３ 、-NHCOCF ３ 、-NHCOC ２ H ５ 、-NHCOC ３ H ７ 、-NHCOCH(CH ３ ) ２ 、-NHCOC(CH ３ ) ３ 、-CONH ２ 、-CONHCH ３ 、-CONHC ２ H ５ 、-CONHC ３ H ７ 、-CONHCH(CH ３ ) ２ 、-CONH-シクロ-C ３ H ５ 、-CONHC(CH ３ ) ３ 、-CON(CH ３ ) ２ 、-CON(C ２ H ５ ) ２ 、-CON(C ３ H ７ ) ２ 、-CON[CH(CH ３ ) ２ ] ２ 、-CON[C(CH ３ ) ３ ] ２ 、-SO ２ NH ２ 、-SO ２ NHCH ３ 、-SO ２ NHC ２ H ５ 、-SO ２ NHC ３ H ７ 、-SO ２ NHCH(CH ３ ) ２ ,-SO ２ NH-シクロ-C ３ H ５ ,-SO ２ NH (CH) ３ ) ３ ,-SO ２ N (CH) ３ ) ２ ,-SO ２ N (C) ２ H ５ ) ２ ,-SO ２ N (C) ３ H ７ ) ２ ,-SO ２ N[CH(CH ３ ) ２ ] ２ ,-E ２ N[C(CH) ３ ) ３ ] ２ ,-NHSO ２ C H ３ 、-NHSO ２ CF ３ 、-NHSO ２ C ２ H ５ 、-NHSO ２ C ３ H ７ 、-NHSO ２ CH(CH ３ ) ２ 、-NHSO ２ C(CH ３ ) ３ 、-CH=CH ２ 、-CH ２ -CH=CH ２ 、-C(CH ３ )=CH ２ 、-CH=CH-CH ３ 、-C≡CH、-C≡C-CH ３ 、-CH ２ -C≡CH、-Ph、-O-Ph、-O-CH ２ -Ph、-C(=NH)NH ２ 、または 【Chemistry 24】 represents; R ６ , R １１ , R １２ , R ２１ ~R ２３ , R ３３ ~R ３５ , R ４０ , R ４１ , R ４６ , and R ４７ are each independently —H, —CH ３ , -CH ２ CH ３ , -CH(CH ３ ) ２ , -CH ２ CH ２ CH ３ , -CH ２ CH (CH ３ ) ２ , -C(CH ３ ) ３ , -cyclo-C ３ H ５ , -cyclo-C ４ H ７ , -cyclo-C ５ H ９ , -cyclo-C ６ H １１ , -CH ２ -cyclo-C ３ H ５ , -CH ２ -cyclo-C ４ H ７ , -CH ２ -cyclo-C ５ H ９ , -CH ２ -cyclo-C ６ H １１ , -CH ２ -Ph, -CH ２ OCH ３ , -CH ２ OCH ２ CH ３ , -CH ２ CH ２ OCH ３ , -COO-C(CH ３ ) ３ , —COO—CH ２ Ph, or -CH ２ CH ２ SCH ３ represents; R ２４ ~R ２７ , R ３６ａ ~R ３９ａ , R ３６ｂ ~R ３９ｂ , R ４２ａ ~R ４５ａ , and R ４２ｂ ~R ４５ｂ are each independently —H, —F, —Cl, —Br, —I, —OH, —CN, or —NO ２ , -CH ３ , -C ２ H ５ , -C ３ H ７ , -CH(CH ３ ) ２ , -C ４ H ９ , -CH ２ -CH(CH ３ ) ２ , -CH(CH ３ )-C ２ H ５ , -C(CH ３ ) ３ , -cyclo-C ３ H ５ , -CH ２ -cyclo-C ３ H ５ , -CH ２ F, -CHF ２ , -CF ３ , -CH ２ Cl, —CH ２ Br, —CH ２ I, -CH ２ -CH ２ F, -CH ２ -CHF ２ , -CH ２ -CF ３ , -CH ２ -CH ２ Cl, —CH ２ -CH ２ Br, —CH ２ -CH ２ I, -OCH ３ , -OC ２ H ５ , -OC ３ H ７ , -OCH(CH ３ ) ２ , -OC(CH ３ ) ３ ,-OC ４ H ９ ,-OCHF ２ ,-OCF ３ ,-OCH ２ CF ３ ,-OC ２ F ５ ,-OCH ２ OCH ３ 、-O-シクロ-C ３ H ５ ,-OCH ２ -シクロ-C ３ H ５ ,-O-C ２ H ４ -シクロ-C ３ H ５ 、-CHOO、-COCH ３ ,-COCF ３ ,-COC ２ H ５ ,-COC ３ H ７ , -COCH (CH ３ ) ２ , -COC (CH) ３ ) ３ 、-COOOH、-COOCH ３ ,-COOC ２ H ５ ,-COOC ３ H ７ 、-COOOCH (CH ３ ) ２ , -COOC (CH ３ ) ３ ,-OO--CH ３ ,-OO-CF ３ ,---- ２ H ５ ,---- ３ H ７ 、-OOC-CH (CH ３ ) ２ 、-OOC-C (CH ３ ) ３ ,-NH ２ ,-NHCH ３ ,-NHC ２ H ５ ,-NHC ３ H ７ , -NHCH (CH ３ ) ２ 、-NHC(CH ３ ) ３ 、-N(CH ３ ) ２ 、-N(C ２ H ５ ) ２ 、-N(C ３ H ７ ) ２ 、-N[CH(CH ３ ) ２ ] ２ 、-N[C(CH ３ ) ３ ] ２ 、-NHCOCH ３ 、-NHCOCF ３ 、-NHCOC ２ H ５ 、-NHCOC ３ H ７ 、-NHCOCH(CH ３ ) ２ 、-NHCOC(CH ３ ) ３ 、-CONH ２ 、-CONHCH ３ 、-CONHC ２ H ５ 、-CONHC ３ H ７ 、-CONHCH(CH ３ ) ２ 、-CONH-シクロ-C ３ H ５ 、-CONHC(CH ３ ) ３ 、-CON(CH ３ ) ２ 、-CON(C ２ H ５ ) ２ 、-CON(C ３ H ７ ) ２ 、-CON[CH(CH ３ ) ２ ] ２ 、-CON[C(CH ３ ) ３ ] ２ 、-SO ２ NH ２ 、-SO ２ NHCH ３ 、-SO ２ NHC ２ H ５ 、 -SO ２ NHCH ３ H ７ 、 -SO ２ NHCH(CH ３ ) ２ 、 -SO ２ NH - cyclo - C ３ H ５ 、 -SO ２ NHCH(CH ３ ) ３ 、 -SO ２ N(CH ３ ) ２ 、 -SO ２ N(C ２ H​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ X is -CN, -NH ２ , or -CH ２ represents OH; A compound of formula (I) or a positional isomer, diastereomer, enantiomer, mixture of positional isomers, mixture of diastereomers, mixture of enantiomers, solvate, hydrate, or pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of a disease caused by and / or associated with microRNA expression or microRNA misexpression.

15. 15. The compound for use according to claim 14, wherein X is -CN or -NH ２ Representing a compound for use.

16. 16. A compound for use according to claim 14 or claim 15, wherein said compound modulates the function and / or activity of a microRNA.

17. 17. A compound for use according to any one of claims 14 to 16, wherein the disease is selected from cancer, tumors, metastasis, viral infections, immune diseases, autoimmune diseases, inflammatory diseases, diabetes, cardiovascular diseases, metabolic diseases, and neurodegenerative diseases.

18. 18. A compound for use according to any one of claims 14 to 17, wherein the cancer is selected from breast cancer, colon cancer, pancreatic cancer, and prostate cancer.

19. 19. The compound for use according to any one of claims 14 to 18, wherein the microRNA comprises a stem-loop region having a sequence set forth in SEQ ID No. 3 to SEQ ID No. 53.

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