C-MYC mRNA translation modulators and uses thereof in the treatment of cancer

Description

[0001] The present invention relates to c-Myc mRNA translation modulators, compositions and methods of preparation thereof, and uses thereof in the treatment of cancer.BACKGROUND OF THE INVENTION

[0002] Cancer is the second most common cause of death in the United States, exceeded only by heart disease. In the United States, cancer accounts for 1 of every 4 deaths. The 5-year relative survival rate for all cancer patients diagnosed in 1996-2003 is 66%, up from 50% in 1975-1977 (Cancer Facts & Figures American Cancer Society: Atlanta, GA (2008)). The rate of new cancer cases decreased by an average 0.6% per year among men between 2000 and 2009 and stayed the same for women. From 2000 through 2009, death rates from all cancers combined decreased on average 1.8% per year among men and 1.4% per year among women. This improvement in survival reflects progress in diagnosing at an earlier stage and improvements in treatment. Discovering highly effective anticancer agents with low toxicity is a primary goal of cancer research.

[0003] The Myc family includes three major members, the proto-oncogene c-Myc (cellular Myelocytomatosis, short Myc), as well as L-Myc and N-Myc. These three Myc homologs are involved in the early stages of carcinogenesis and metastatic spread in most human cancers. In most types of tumors Myc gene is not mutated or duplicated, but its mRNA and / or protein levels are increased, indicating that in cancer Myc overexpression is induced at the level of transcription, mRNA steady state levels and translation. Indeed, Myc gene expression normally depends on growth factor signaling and both Myc mRNA and Myc protein have very short half-lives (of 30 and 20 min respectively) [Dang, C. V. (2012). Myc on the path to cancer. Cell 149, 22-35]. In tumor cells however, the cellular levels of Myc become independent from such signaling and regulation, and the resulting exacerbated Myc function drives intracellular and extracellular transcription programs that allow tumors to grow and thrive. However, Myc does not necessarily need to be overexpressed in order for a cancer to be highly dependent upon its activity. A study from Soucek et al. (Nature (2008) 455(7213):679-83) shows that tumors that express c-Myc at endogenous levels exhibit tumor regression upon Myc inhibition via a genetically engineered system. Therefore, treatment with a Myc inhibitor is not necessarily limited to cancers that overexpress Myc. Compounds according to this invention may also be used to regulate the translation of Myc mRNA, wherein the direct target for the compounds is a protein or RNA which regulate Myc mRNA translation, and as such any tumor which is Myc dependent will benefit from the therapeutic utility if these compounds.

[0004] Due to its extensive pathogenic significance, Myc is an important anticancer target. Deregulated Myc gene is found in a wide range of human hematological malignancies and solid tumors, especially in breast cancer, ovarian carcinoma, acute myeloid leukemia, chronic myelogenous leukemia, Hodgkin's and Burkitt's lymphoma, diffuse large Bcell lymphoma, prostate cancer, colon cancer, gastric cancer, primary central nervous system lymphoma, glioblastoma, medulloblastoma, melanoma, non-small cell lung carcinoma, germinal center-derived lymphomas, esophageal squamous cell carcinoma, osteosarcoma, bladder cancer, pancreatic cancer and lung adenocarcinoma. Recent studies also indicate that deregulation of c-Myc is related to the occurrence of BRAF V600E thyroid cancers, choroid plexus carcinoma, and colitis-associated cancer. In addition, amplification of the Myc gene was found in a significant number of epithelial ovarian cancer cases. In TCGA datasets, the amplification of Myc occurs in several cancer types, including breast, colorectal, pancreatic, gastric, and uterine cancers.

[0005] Although Myc gene is a very important oncogene and considered as a driver in carcinogenesis and Myc protein is a key transcription factor broadly targeting various genes, rational designing a direct Myc inhibitor is still challenging. This is mainly because Myc protein lacks structural regions amenable to therapeutic inhibition by small molecules and is considered an undruggable target [BioDrugs (2019) 33:539-553].

[0006] Designing and developing Myc modulators is challenging, primarily because the Myc protein has a disordered structure which lacks a pocket or groove that can act as a binding site for modulators. Interfering with the Myc transcription, blocking the protein-protein interaction (PPI) of Myc and its cofactors, and influencing on signaling pathways related to Myc were used in the past as potential modulatory targets, but failed to be developed as drug candidates. Myc PPI inhibitors failed to show sufficient efficacy in cell-based assays and animal models due to the requirement of high target occupancy to drive efficacy. Modulators of signaling pathways upstream to Myc, for example mTOR modulators, failed due lack of target specificity.

[0007] Nevertheless, a therapeutic approach to target c-Myc has remained elusive. The absence of a clear ligand-binding domain establishes a formidable obstacle toward direct inhibition, which is a challenging feature shared among many compelling transcriptional targets in cancer. Thus, alternative modalities that target Myc are required, as outlined herein, namely compounds which regulate Myc mRNA translation.

[0008] Muraglia et al. discloses N-(2-alkylaminoethyl)-4-(1,2,4-oxadiazol-5-yl)piperazine-1-carboxamides as highly potent, smoothened antagonists for the treatment of neoplasias with aberrantly reactivated hedgehog (Hh) signaling pathway (Bioorganic and Medicinal Chemistry Letters, Elsevier, Amsterdam, NL, vol. 21, no. 18, pages 5283-5288, DOI: 10.1016 / J.BMCL.2011.07.030).SUMMARY OF THE INVENTION

[0009] The present invention provides a compound represented by the structure of formula (I(a(ii))): wherein R 1< is F, Cl, Br, I, OH, CF 3 , OCH 3 , CN, NO 2 , -CH 2 CN, C 1 -C 5 linear or branched, substituted or unsubstituted alkyl, C 1 -C 5 linear or branched, or C 3 -C 8 cyclic haloalkyl, substituted or unsubstituted C 1 -C 5 linear or branched, or C 3 -C 8 cyclic alkoxy, C 1 -C 5 linear or branched haloalkoxy, NH-C(O)-R 7< , C 1 -C 5 linear or branched alkoxyalkyl; wherein R 7< is H, C 1 -C 5 substituted or unsubstituted linear or branched alkyl, C 1 -C 5 linear or branched alkoxy, C(O)R, or S(O) 2 R; wherein R is H, F, Cl, Br, I, OH, CF 3 , CN, NO 2 , C 1 -C 5 linear or branched, substituted or unsubstituted alkyl, C 1 -C 5 linear or branched alkoxy, C 1 -C 5 linear or branched haloalkyl, R 6< -N(alkyl) 2 , R 6< -NH(alkyl), R 6< -NH(cycloalkyl), R 6< -NH(aryl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic ring, R 6< -(substituted or unsubstituted heterocycle) or C(O)-(alkyl); R 6< is [CH 2 ] p , [CH 2 ] pa -O-[CH 2 ] pb , or [CH 2 ] p -O; wherein p is 1, 2 or 3; and each pa and pb is independently an integer between 1 and 5; R 4< is H, F, Cl, Br, I, OH, CF 3 , CN, NO 2 , C 1 -C 5 linear or branched, substituted or unsubstituted alkyl, C 1 -C 5 linear or branched, or C 3 -C 8 cyclic haloalkyl; R 6b< is absent or O, C=O, [CH 2 ] p ; R 8< is H, F, Cl, Br, I, OH, CF 3 , CN, NO 2 , C 1 -C 5 linear or branched, substituted or unsubstituted alkyl, C 1 -C 5 linear or branched, or C 3 -C 8 cyclic haloalkyl; R 9< is substituted or unsubstituted saturated C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkenyl, substituted or unsubstituted saturated or unsaturated 3-8 membered heterocyclic ring or R 20< , wherein R 20< is represented by the following structure: B ring is a single or fused 3-12 membered heterocyclic ring, C 3 -C 8 saturated or unsaturated cycloalkyl or a spiro ring system; X 6< is N; X 7< is CH or N; l and q are each independently an integer between 0 and 4; or its pharmaceutically acceptable salt, optical isomer, tautomer, hydrate, N-oxide, or any combination thereof.

[0010] In an embodiment, R 1< is Cl, O-R 20< , OCH 3 , -R 6< CN, C 1 -C 5 linear or branched, or C 3 -C 8 cyclic haloalkyl, CF 3 , C 1 -C 5 linear or branched haloalkoxy, OCF 3 , OCHF 2 , CHF 2 , CF 3 , or NHC(O)-CH 3 ; R 7< is methyl, ethyl, CH 2 -CH 2 -O-CH 3 , or O-CH 3 ; R 6< is CH 2 -CH 2 -CH 2 ; R 6b< is CH 2 ; R 9< is cyclohexyl, cyclopentyl, cyclopropyl, cyclohexenyl, methyl piperidine, tetrahydrofuran or tetrahydrothiopyran; or the B ring is piperidine or pyrrolidine, or any combination thereof.

[0011] In an embodiment, R 6b< is absent, O, C=O, [CH 2 ] p or CH 2.

[0012] In an embodiment, R 9< is R 20< , substituted or unsubstituted heteroaryl, pyridine, 3-methyl-pyridine, thiazolyl, oxazolyl thiophenyl, furanyl, substituted or unsubstituted saturated C 3 -C 8 cycloalkyl, cyclohexyl, cyclopentyl, cyclopropyl, substituted or unsubstituted C 3 -C 8 cycloalkenyl, cyclohexenyl, substituted or unsubstituted 3-8 membered heterocyclic ring, tetrahydropyran, or tetrahydrothiopyran.

[0013] In some embodiments, the compound is represented by the structure of formula (I (a (iii ))):

[0014] In some embodiments, the compound of formula I(a(ii)) is represented by the structure of formula (II): wherein R 1< is H, F, Cl, Br, I, OH, CF 3 , OCH 3 , CN, NO 2 , C 1 -C 5 linear or branched, substituted or unsubstituted alkyl, C 1 -C 5 linear or branched, or C 3 -C 8 cyclic haloalkyl, C 1 -C 5 substituted or unsubstituted, linear or branched, or C 3 -C 8 cyclic alkoxy, C 1 -C 5 linear or branched haloalkoxy, NH-C(O)-R 7< , or C 1 -C 5 linear or branched alkoxyalkyl; wherein R 7< is H, C 1 -C 5 substituted or unsubstituted linear or branched alkyl, C 1 -C 5 linear or branched alkoxy, C(O)R, or S(O) 2 R; R 6< is [CH 2 ] p , [CH 2 ] pa -O-[CH 2 ] pb , or [CH 2 ] p -O; R 6b< is absent or O, C=O, or [CH 2 ] p ; wherein p is an integer between 1 and 3; and each pa and pb is independently an integer between 1 and 5; B ring is a single or fused 3-12 membered heterocyclic ring or C 3 -C 8 saturated or unsaturated spiro or cycloalkyl ring; D ring is a saturated or unsaturated single, fused or spiro, heterocyclic 3-12 membered ring or a saturated, unsaturated, single, fused or spiro, aliphatic carbocyclic 3-12 membered ring; R 11< and R 12< are each independently H, F, Cl, Br, I, OH, CF 3 , OCH 3 , CN, NO 2 , C 1 -C 5 linear or branched, substituted or unsubstituted alkyl, C 1 -C 5 linear or branched, or C 3 -C 8 cyclic haloalkyl, C 1 -C 5 substituted or unsubstituted, linear or branched, or C 3 -C 8 cyclic alkoxy, C 1 -C 5 linear or branched haloalkoxy, C 1 -C 5 linear or branched alkoxyalkyl, R 20< , NH 2 , NHR, NR 2 ; wherein R is H, F, Cl, Br, I, OH, CF 3 , CN, NO 2 , C 1 -C 5 linear or branched, substituted or unsubstituted alkyl, C 1 -C 5 linear or branched alkoxy, C 1 -C 5 linear or branched haloalkyl, R 6< -aryl, R 6< -N(alkyl) 2 , R 6< -NH(alkyl), R 6< -NH(cycloalkyl), R 6< -NH(aryl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic ring, R 6< -(substituted or unsubstituted heterocycle) or C(O)-(alkyl); X 7< is CH or N; R 20< is represented by the following structure: or its pharmaceutically acceptable salt, optical isomer, tautomer, hydrate, N-oxide, pharmaceutical product or any combination thereof.

[0015] In an embodiment, the heterocyclic 3-12 membered D ring is tetrahydrofuran, piperidine, azepane, oxepane, azetidine, tetrahydrothiopyran, tetrahydropyran, pyrrolidine, oxetane or diazirine. In an embodiment, the aliphatic carbocyclic 3-12 membered D ring is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclohexenyl. In an embodiment, R 11< and R 12< are each independently methyl, ethyl, ethylacetylene, 1-butyne, CHF 2 , methoxy, O-(CH 2 ) 2 -OH, OCF 3 or OCHF 2 In some embodiments, R 6< is absent or is [CH 2 ] p , CH 2 , or CH 2 CH 2- CH 2 .

[0016] The present invention also provides a pharmaceutical composition comprising the compound of this invention and a pharmaceutically acceptable carrier.

[0017] The present invention also provides a compound as described herein above, for use in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting cancer in a subject suffering from cancer.

[0018] In some embodiments, the cancer is selected from: breast cancer, ovarian carcinoma, acute myeloid leukemia, chronic myelogenous leukemia, Hodgkin's and Burkitt's lymphoma, diffuse large Bcell lymphoma, prostate cancer, colon cancer, gastric cancer, primary central nervous system lymphoma, glioblastoma, medulloblastoma, melanoma, non-small cell lung carcinoma, germinal center-derived lymphomas, esophageal squamous cell carcinoma, osteosarcoma, bladder cancer, pancreatic cancer, lung adenocarcinoma, BRAF V600E thyroid cancer, choroid plexus carcinoma, colitis-associated cancer, epithelial ovarian cancer, colorectal cancer, pancreatic cancer or uterine cancer.

[0019] In some embodiments, the cancer is early cancer, advanced cancer, invasive cancer, metastatic cancer, drug resistant cancer or any combination thereof.

[0020] In some embodiments, the subject has been previously treated with chemotherapy, immunotherapy, radiotherapy, biological therapy, surgical intervention, or any combination thereof.

[0021] In some embodiments, the compound is administered in combination with an anti-cancer therapy.

[0022] In some embodiments, the anti-cancer therapy is chemotherapy, immunotherapy, radiotherapy, biological therapy, surgical intervention, or any combination thereof.

[0023] The present invention also provides a compound as described herein above, for use in suppressing, reducing or inhibiting tumor growth in a subject suffering from cancer.

[0024] The present invention also provides an in vitro method of modulating c-Myc mRNA translation in a cell, comprising contacting a compound according to this invention as described hereinabove, with a cell, thereby modulating c-Myc mRNA translation in said cell.

[0025] The present invention also provides an in vitro method of regulating c-Myc mRNA transcription in a cell, comprising contacting a compound according to this invention as described hereinabove, with a cell, thereby regulating c-Myc mRNA transcription in said cell.

[0026] In some embodiments, the in vitro method is carried out: (a) by regulating c-Myc mRNA splicing (inclusion or exclusion of untranslated region or alternative usage of exons); (b) by regulation of c-Myc mRNA modifications; (c) by regulation of the interaction of RNA binding protein with c-Myc mRNA thereby changing mRNA localization; (d) by regulating c-Myc mRNA localization in the cytoplasm; (e) by regulating ribosomes or ribosome accessory factor to c-Myc mRNA; (f) by reducing the amount of c-Myc protein in the cell; or any combination thereof.BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 demonstrates how protein synthesis monitoring (PSM) specifically monitors c-Myc synthesis. The assay system comprises human non-small cell lung carcinoma cell line A549, which is expressing high level of c-Myc. Two tRNAs (di-tRNA) which decode one specific glutamine codon and one specific serine codon were transfected with control RNAi or an RNAi directed to c-Myc. The FRET signal specifically monitors c-Myc translation, as the FRET signal in c-Myc siRNA treated cells was inhibited. Cell nuclei stained with DAPI and FRET signals from tRNA pair which decodes glutamine-serine di-codons are signed on the images. Figure 2 depicts selective regulation of c-Myc translation. The panel demonstrates metabolic labeling in A549 cells, treated with vehicle, general translation inhibitor cycloheximide or anti-c-Myc compound. Treatment with cycloheximide resulted in total inhibition of global protein synthesis, while treatment with tested compound showed no significant effect. Cell nuclei stained with DAPI and AHA metabolic labeling are signed on the images. Figure 3 demonstrates that compounds act at the level of translation. A549 cells were exposed to vehicle, general transcription inhibitor actinomycin D or anti-c-Myc compound. In the upper panel, significant decrease in c-Myc protein level was observed after treatment with either actinomycin D or tested compound. Lower panel shows complete reduction in c-Myc mRNA level as well as transcription sites after treatment with actinomycin D. Treatment with tested compound showed no effect on either c-Myc mRNA level or transcription sites. Cell nuclei stained with DAPI, c-Myc protein, c-Myc mRNA and transcription sites are signed on the images. Figures 4A-4B demonstrate the efficacy and toxicity window of compounds. Figure 4A depicts representative images from compound 207. Images were taken with x20 objective in Operetta machine (Perkin-Elmer). Cell nuclei stained with DAPI and c-Myc protein are signed on the images. Figure 4B depicts pIC50 of toxicity in A549 cells plotted against pIC 50 of toxicity in SK-N-F1 cells expressing very low c-Myc protein level. Dashed lines represent x10 or x100 toxicity window between two cell types. DETAILED DESCRIPTION OF THE INVENTION

[0028] The present invention provides a compound represented by the structure of formula (I(a(ii))): wherein B ring is a single or fused 3-12 membered heteroaromatic ring (e.g. pyrimidine, 2-, 3- or 4-pyridine, pyridazine, pyrazine, isothiazole, thiadiazole, imidazole, triazole, thiazole, oxazole, isoxazole, 1-methylimidazole, pyrrole, furan, thiophene, oxadiazole, indole, indane, benzodihydrofuran, tetrahydroquinoline, or pyrazole), a 3-8 membered saturated or unsaturated heterocyclic ring (e.g. tetrahydropyran, tetrahydrofuran, pyrrolidine, piperidine, piperazine, 2-oxopyrrolidine, 2,5-dioxopyrrolidine, 2,5-dioxoimidazolidine, oxetane, chromane), a C 3 -C 8 cycloalkyl ring (e.g. cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl) or a spiro ring system (e.g. ); R 1< is H, F, Cl, Br, I, OH, O-R 20< , CF 3 , OCH 3 , CN, NO 2 , -CH 2 CN, -R 6< CN, C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C 1 -C 5 linear or branched, or C 3 -C 8 cyclic haloalkyl (e.g., CHF 2 ), C 1 -C 5 substituted or unsubstituted, linear or branched, or C 3 -C 8 cyclic alkoxy (e.g. methoxy, O-(CH 2 ) 2 -OH), C 1 -C 5 linear or branched haloalkoxy (e.g., OCF 3 , OCHF 2 ), NH-C(O)-R 7< (e.g., NHC(O)-CH 3 ), C 1 -C 5 linear or branched alkoxyalkyl; wherein R 7< is H, C 1 -C 5 substituted or unsubstituted linear or branched alkyl (e.g., methyl, ethyl, CH 2 -CH 2 -O-CH 3 ), C 1 -C 5 linear or branched alkoxy (e.g., O-CH 3 ), C(O)R, or S(O) 2 R; wherein R is H, F, Cl, Br, I, OH, CF 3 , CN, NO 2 , C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, propyl, isopropyl, isobutyl), C 1 -C 5 linear or branched alkoxy (e.g. methoxy), C 1 -C 5 linear or branched haloalkyl (e.g., CHF 2 , CF 3 , , R 6< -aryl (e.g., CH 2 -Ph, CH 2 -Ph-ethyl), R 6< -N(alkyl) 2 , R 6< -NH(alkyl), (R 6< -NH(cycloalkyl), (R 6< -NH(aryl), substituted or unsubstituted aryl (e.g., phenyl, ethylphenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine) or benzimidazole), substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., piperidine, pyrrolidine), R 6< -(substituted or unsubstituted heterocycle) (e.g., (CH 2 ) 3 -piperidine, CH 2 -benzoxazole, CH 2 -benzimidazole, CH 2 -indole) or C(O)-(alkyl) (e.g. C(O)-CH 3 ); R 20< is represented by the following structure: R 4< and R 8< are each independently H, F, Cl, Br, I, OH, CF 3 , CN, NO 2 , C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, tert-butyl, CH 2 CH 2 CH(CH 3 ) 2 , CH 2 -C(CH 3 ) 3 ), C 1 -Cs linear or branched, or C 3 -C 8 cyclic haloalkyl; R 6< is [CH 2 ] p (e.g., CH 2 -CH 2 -CH 2 ), [CH 2 ] pa -O-[CH 2 ] pb , or [CH 2 ] p -O; wherein p is 1, 2 or 3; and each pa and pb is independently an integer between 1 and 5; R 6b< is absent or O, C=O, or [CH 2 ] p (e.g. CH 2 , CH 2 CH 2 , or CH 2 CH 2 CH 2 );R 9< is substituted or unsubstituted saturated C 3 -C 8 cycloalkyl (e.g., cyclohexyl, cyclopentyl, cyclopropyl), substituted or unsubstituted C 3 -C 8 cycloalkenyl (e.g., cyclohexenyl), substituted or unsubstituted saturated or unsaturated 3-8 membered heterocyclic ring (e.g., methyl-piperidine, tetrahydropyran, tetrahydrothiopyran) or R 20< , wherein R 20< is represented by the following structure: X 6< is N; X 7< is CH or N; l and q are each independently an integer between 0 and 4 (e.g., 0, 1 or 2); or its pharmaceutically acceptable salt, optical isomer, tautomer, hydrate, N-oxide, pharmaceutical product or any combination thereof.

[0029] In various embodiments, the compound is represented by the structure of formula (I(a(iii))): wherein R 1< is H, F, Cl, Br, I, OH, O-R 20< , CF 3 , OCH 3 , CN, NO 2 , -CH 2 CN, -R 6< CN, C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C 1 -C 5 linear or branched, or C 3 -C 8 cyclic haloalkyl (e.g., CHF 2 ), C 1 -C 5 substituted or unsubstituted, linear or branched, or C 3 -C 8 cyclic alkoxy (e.g. methoxy, O-(CH 2 ) 2 -OH), C 1 -C 5 linear or branched haloalkoxy (e.g., OCF 3 , OCHF 2 ), NH-C(O)-R 7< (e.g., NHC(O)-CH 3 ), C 1 -C 5 linear or branched alkoxyalkyl; wherein R 6< [CH 2 ] p (e.g. CH 2 , CH 2 CH 2 , CH 2 CH 2 CH 2 ), [CH 2 ] pa -O-[CH 2 ] pb (e.g. CH 2 OCH 2 ), or [CH 2 ] p -O (e.g., CH 2 CH 2 O); wherein p is an integer between 1 and 3; and each pa and pb is independently an integer between 1 and 5; R 7< is H, C 1 -C 5 substituted or unsubstituted linear or branched alkyl (e.g., methyl, ethyl, CH 2 -CH 2 -O-CH 3 ), C 1 -C 5 linear or branched alkoxy (e.g., O-CH 3 ), C(O)R, or S(O) 2 R; wherein R is H, F, Cl, Br, I, OH, CF 3 , CN, NO 2 , C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, propyl, isopropyl, isobutyl), C 1 -C 5 linear or branched alkoxy (e.g. methoxy), C 1 -C 5 linear or branched haloalkyl (e.g., CHF 2 , CF 3 , R 6< -aryl (e.g., CH 2 -Ph, CH 2 -Ph-ethyl), R 6< -N(alkyl) 2 , R 6< -NH(alkyl), (R 6< -NH(cycloalkyl), (R 6< -NH(aryl), substituted or unsubstituted aryl (e.g., phenyl, ethylphenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine) or benzimidazole), substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., piperidine, pyrrolidine), R 6< -(substituted or unsubstituted heterocycle) (e.g., (CH 2 ) 3 -piperidine, CH 2 -benzoxazole, CH 2 -benzimidazole, CH 2 -indole) or C(O)-(alkyl) (e.g. C(O)-CH 3 ); R 9< is substituted or unsubstituted saturated C 3 -C 8 cycloalkyl (e.g., cyclohexyl, cyclopentyl, cyclopropyl), substituted or unsubstituted C 3 -C 8 cycloalkenyl (e.g., cyclohexenyl), substituted or unsubstituted saturated or unsaturated 3-8 membered heterocyclic ring (e.g., methyl-piperidine, tetrahydropyran, tetrahydrothiopyran) or R 20< , wherein R 20< is represented by the following structure: R 4< is H, F, Cl, Br, I, OH, CF 3 , CN, NO 2 , C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, tert-butyl, CH 2 CH 2 CH(CH 3 ) 2 , CH 2 -C(CH 3 ) 3 ), C 1 -C 5 linear or branched, or C 3 -C 8 cyclic haloalkyl; X 6< is N; X 7< is CH or N; l is an integer between 0 and 4 (e.g., 0, 1 or 2); or its pharmaceutically acceptable salt, optical isomer, tautomer, hydrate, N-oxide, pharmaceutical product or any combination thereof.

[0030] In various embodiments, the compound is represented by the structure of formula (II): wherein R 1< is H, F, Cl, Br, I, OH, CF 3 , OCH 3 , CN, NO 2 , C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C 1 -C 5 linear or branched, or C 3 -C 8 cyclic haloalkyl (e.g., CHF 2 ), C 1 -C 5 substituted or unsubstituted, linear or branched, or C 3 -C 8 cyclic alkoxy (e.g. methoxy, O-(CH 2 ) 2 -OH), C 1 -C 5 linear or branched haloalkoxy (e.g., OCF 3 , OCHF 2 ), NH-C(O)-R 7< (e.g., NHC(O)-CH 3 ), C 1 -C 5 linear or branched alkoxyalkyl; wherein R 7< is H, C 1 -C 5 substituted or unsubstituted linear or branched alkyl (e.g., methyl, ethyl, CH 2 -CH 2 -O-CH 3 ), C 1 -C 5 linear or branched alkoxy (e.g., O-CH 3 ), C(O)R, or S(O) 2 R; R 6< is [CH 2 ] p (e.g., CH 2 -CH 2 -CH 2 ), [CH 2 ] pa -O-[CH 2 ] pb , or [CH 2 ] p -O; R 6b< is absent or O, C=O, [CH 2 ] p (e.g. CH 2 ; wherein p is an integer between 1 and 3; and each pa and pb is independently an integer between 1 and 5;B ring is a single or fused heterocyclic 3-12 membered ring (e.g., piperidine, pyrrolidine, 2-pyrrolidone, indole), C 3 -C 8 saturated or unsaturated cycloalkyl or a spiro ring system; D ring is a saturated or unsaturated, single, fused or spiro, heterocyclic 3-12 membered ring (e.g., tetrahydrofuran, piperidine, azepane, oxepane, 2-oxaspiro[3.3]heptane, tetrahydro-2H-thiopyran 1,1-dioxide, tetrahydrothiopyran, tetrahydropyran, pyrrolidine, oxetane, diazirine); R 11< and R 12< are each independently H, F, Cl, Br, I, OH, CF 3 , OCH 3 , CN, NO 2 , C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C 1 -C 5 linear or branched, or C 3 -C 8 cyclic haloalkyl (e.g., CHF 2 ), C 1 -C 5 substituted or unsubstituted, linear or branched, or C 3 -C 8 cyclic alkoxy (e.g. methoxy, O-(CH 2 ) 2 -OH), C 1 -C 5 linear or branched haloalkoxy (e.g., OCF 3 , OCHF 2 ), C 1 -C 5 linear or branched alkoxyalkyl, R 20< , NH 2 , NHR, NR 2 ; wherein R is H, F, Cl, Br, I, OH, CF 3 , CN, NO 2 , C 1 -C 5 linear or branched, substituted or unsubstituted alkyl, C 1 -C 5 linear or branched alkoxy, C 1 -C 5 linear or branched haloalkyl, R 6< -aryl, R 6< -N(alkyl) 2 , R 6< -NH(alkyl), (R 6< -NH(cycloalkyl), (R 6< -NH(aryl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic ring, R 6< -(substituted or unsubstituted heterocycle) or C(O)-(alkyl); X 7< is CH or N; R 20< is represented by the following structure: or its pharmaceutically acceptable salt, optical isomer, tautomer, hydrate, N-oxide, pharmaceutical product or any combination thereof.

[0031] In some embodiments, D ring is saturated or unsaturated single, fused or spiro, heterocyclic 3-12 membered ring. In some embodiments, D ring is tetrahydrofuran, piperidine, azepane, oxepane, 2-oxaspiro[3.3]heptane, azetidine, tetrahydro-2H-thiopyran 1,1-dioxide, tetrahydrothiopyran, tetrahydropyran, pyrrolidine, oxetane or diazirine. In some embodiments, D ring is a saturated or unsaturated, single, fused or spiro, aliphatic carbocyclic 3-12 membered ring. In some embodiments, D ring is a saturated, single, 3-8 membered cycloalkyl ring. In some embodiments, D ring is an unsaturated, single, 3-8 membered cycloalkenyl ring. In some embodiments, D ring is a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclohexenyl. In some embodiments, D ring is saturated or unsaturated, single, fused or spiro, aliphatic carbocyclic 3-12 membered ring. In some embodiments, D ring is C 3 -C 8 cycloalkyl. In some embodiments, D ring is cyclopropyl, methylcyclopropyl, cyclobutyl, cyclohexyl, cyclohexenyl, cyclopentyl. In some embodiments, D ring is oxetane, azetidine, tetrahydrofuran, tetrahydropyran, pyrrolidine, tetrahydrothiopyran, piperidine, azepane, oxepane, 2H-thiopyran-tetrahydro-1,1-dioxide.

[0032] In some embodiments, B of formula I(a(ii)) is a single or fused heterocyclic 3-12 membered ring. In other embodiments, B is piperidine, pyrrolidine, or piperazine In some embodiments, B is an unsaturated, single, 3-12 membered heterocyclic ring. In some embodiments, B is 2-pyrrolidone or indole. In other embodiments, B is pyridinyl. In other embodiments, B is 2-pyridinyl. In other embodiments, B is 3-pyridinyl. In other embodiments, B is 4-pyridinyl. In other embodiments, B is pyrimidine. In other embodiments, B is pyridazine. In other embodiments, B is pyrazine. In other embodiments, B is pyrazole. In other embodiments, B is thiazole. In other embodiments, B is imidazole. In other embodiments, B is 1-methylimidazole. In other embodiments, B is thiophene. In other embodiments, B is isothiazolyl. In other embodiments, B is thiadiazolyl. In other embodiments, B is triazolyl. In other embodiments, B is thiazolyl. In other embodiments, B is oxazolyl. In other embodiments, B is isoxazolyl. In other embodiments, B is pyrrolyl. In other embodiments, B is furanyl. In other embodiments, B is indole. In other embodiments, B is benzodihydrofuran. In other embodiments, B is tetrahydroquinoline. In other embodiments, B is tetrahydropyran. In other embodiments, B is tetrahydrofuran. In other embodiments, B is 1,2,3-, 1,2,4-, 1,2,5- or 1,3,4-oxadiazolyl. In other embodiments, B is oxadiazolyl. In other embodiments, B is pyrrolidine. In other embodiments, B is piperazine. In other embodiments, B is. In other embodiments, B is 2-oxopyrrolidine. In other embodiments, B is 2-pyrrolidone. In other embodiments, B is 2,5-dioxopyrrolidine. In other embodiments, B is 2,5-dioxoimidazolidine. In other embodiments, B is 2,5-dihydrothiazole. In other embodiments, B is oxetane. In other embodiments, B is chromane. In other embodiments, B is piperidine. In other embodiments, B is cyclohexyl. In other embodiments, B is cyclooctyl. In other embodiments, B is cyclopropyl. In other embodiments, B is cyclopentyl. In other embodiments, B is cyclobutyl. In other embodiments, B is a spiro ring system. In other embodiments, B is In other embodiments, B is In other embodiments, B is In other embodiments, B is In other embodiments, B is In some embodiments, B ring is a single or fused 3-8 membered heterocyclic ring (e.g., piperidine), C 3 -C 8 saturated or unsaturated cycloalkyl or a spiro ring system. In some embodiments, B ring is a single or fused 3-12 membered heteroaromatic ring (e.g. pyrimidine, 2-, 3- or 4-pyridine, pyridazine, pyrazine, isothiazole, thiadiazole, imidazole, triazole, thiazole, oxazole, isoxazole, 1-methylimidazole, pyrrole, furan, thiophene, oxadiazole, indole, benzodihydrofuran, tetrahydroquinoline, or pyrazole). In some embodiments, B ring is a 3-8 membered saturated or unsaturated heterocyclic ring (e.g. tetrahydropyran, tetrahydrofuran, pyrrolidine, piperidine, piperazine, 2-oxopyrrolidine, 2,5-dioxopyrrolidine, 2,5-dioxoimidazolidine, oxetane, chromane). In some embodiments, B ring is a C 3 -C 8 cycloalkyl ring (e.g. cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl). In some embodiments, B ring is a C 3 -C 8 cycloalkenyl ring. In some embodiments, B ring is a spiro ring system.

[0033] In some embodiments, D ring of formula II is a saturated or unsaturated, single, fused or spiro, carbocyclic or heterocyclic 3-12 membered ring. In some embodiments, D ring is not an aromatic carbocyclic ring. In some embodiments, D ring is not an aryl. In some embodiments, D ring is a saturated or unsaturated, single, fused or spiro, heterocyclic 3-12 membered ring. In some embodiments, D ring is tetrahydrofuran, piperidine, azepane, oxepane, 2-oxaspiro[3.3]heptane, azetidine, tetrahydro-2H-thiopyran 1,1-dioxide, tetrahydrothiopyran, tetrahydropyran, pyrrolidine, oxetane or diazirine. In some embodiments, D ring is a saturated or unsaturated, single, fused or spiro, aliphatic carbocyclic 3-12 membered ring. In some embodiments, D ring is a saturated, single, 3-8 membered cycloalkyl ring. In some embodiments, D ring is an unsaturated, single, 3-8 membered cycloalkenyl ring. In some embodiments, D ring is a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclohexenyl. In some embodiments, D ring is a saturated, single, 3-12 membered carbocyclic ring. In some embodiments, D ring is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. In some embodiments, D ring is an unsaturated, single, 3-12 membered carbocyclic ring. In some embodiments, D ring is cyclohexenyl. In some embodiments, D ring is a saturated, single, 3-12 membered heterocyclic ring. In some embodiments, D ring is tetrahydrofuran, piperidine, azepane, oxepane, 2-oxaspiro[3.3]heptane, azetidine, tetrahydro-2H-thiopyran 1,1-dioxide, tetrahydrothiopyran, tetrahydropyran, pyrrolidine, oxetane. In some embodiments, D ring is cyclopropyl. In some embodiments, D ring is cyclobutyl. In some embodiments, D ring is cyclopentyl. In some embodiments, D ring is cyclohexyl. In some embodiments, D ring is cyclohexenyl. In some embodiments, D ring is tetrahydrofuran. In some embodiments, D ring is piperidine. In some embodiments, D ring is azepane. In some embodiments, D ring is oxepane. In some embodiments, D ring is 2-oxaspiro[3.3]heptane. In some embodiments, D ring is azetidine. In some embodiments, D ring is tetrahydro-2H-thiopyran 1,1-dioxide. In some embodiments, D ring is tetrahydrothiopyran. In some embodiments, D ring is tetrahydropyran. In some embodiments, D ring is pyrrolidine. In some embodiments, D ring is oxetane. In some embodiments, D ring is diazirine.

[0034] In some embodiments, X 7< of compound of formula I(a(ii)), I(a(iii) and / or II is CH. In other embodiments, X 7< is N.

[0035] In some embodiments, both of X 6< and X 7< are N. In some embodiments, X 6< is N and X 7< is CH.

[0036] In some embodiments, R 1< of formula I(a(ii)), I(a(iii) and / or II is H. In some embodiments, R 1< is C 1 -C 5 linear or branched, substituted or unsubstituted alkyl. In other embodiments, R 1< is methyl. In other embodiments, R 1< is ethyl. In other embodiments, R 1< is iso-propyl. In other embodiments, R 1< is t-Bu. In other embodiments, R 1< is iso-butyl. In other embodiments, R 1< is pentyl. In other embodiments, R 1< is propyl. In other embodiments, R 1< is O-R 20< . In other embodiments, R 1< is F. In other embodiments, R 1< is Cl. In other embodiments, R 1< is Br. In other embodiments, R 1< is I. In other embodiments, R 1< is benzyl. In other embodiments, R 1< is in the ortho position. In other embodiments, R 1< is an ortho-methyl. In other embodiments, R 1< is OH. In other embodiments, R 1< is OCH 3 . In other embodiments, R 1< is CN. In other embodiments, R 1< is NO 2 . In other embodiments, R 1< is CH 2 CN. In other embodiments, R 1< is R 6 CN. In other embodiments, R 1< is C 1 -C 5 linear or branched, or C 3 -C 8 cyclic haloalkyl. In other embodiments, R 1< is CF 3 . In other embodiments, R 1< is CHF 2 . In other embodiments, R 1< is C 1 -C 5 substituted or unsubstituted, linear or branched, or C 3 -C 8 cyclic alkoxy. In other embodiments, R 1< is methoxy. In other embodiments, R 1< is O-(CH 2 ) 2 -OH. In other embodiments, R 1< is C 1 -C 5 linear or branched haloalkoxy. In other embodiments, R 1< is OCF 3 . In other embodiments, R 1< is OCHF 2 . In other embodiments, R 1< is NH-C(O)-R 7< . In other embodiments, R 1< is NHC(O)-CH 3 . In other embodiments, R 1< is C 1 -C 5 linear or branched alkoxyalkyl. In some embodiments, R 1< of compound of formula (I(a(ii))) or (I(a(iii))) is in the para position. In some embodiments, R 1< is in the ortho position. In some embodiments, R 1< is in the meta position. In some embodiments, R 1< is F, Cl, Br, I, OH, CF 3 , OCH 3 , CN, NO 2 , -CH 2 CN, C 1 -C 5 linear or branched, substituted or unsubstituted alkyl, C 1 -C 5 linear or branched, or C 3 -C 8 cyclic haloalkyl (e.g., CHF 2 , CF 3 ), substituted or unsubstituted C 1 -C 5 linear or branched, or C 3 -C 8 cyclic alkoxy, C 1 -C 5 linear or branched haloalkoxy, NH-C(O)-R 7< , NHC(O)-CH 3 or C 1 -C 5 linear or branched alkoxyalkyl. In some embodiments, R 1< is Cl, O-R 20< , OCH 3 , -R 6< CN, C 1 -C 5 linear or branched, or C 3 -C 8 cyclic haloalkyl, CF 3 , C 1 -C 5 linear or branched haloalkoxy, OCF 3 , or OCHF 2 . In some embodiments, R 1< is F, Cl, Br, I, CF 3 , OCH 3 , CN, C 1 -C 5 linear or branched, or C 3 -C 8 cyclic haloalkyl, CHF 2 , substituted or unsubstituted C 1 -C 5 linear or branched, or C 3 -C 8 cyclic alkoxy, C 1 -C 5 linear or branched haloalkoxy, OCF 3 , or OCHF 2 .

[0037] In some embodiments, R 4< of formula I(a(ii)) or I(a(iii) is H. In other embodiments, R 4< is Cl. In other embodiments, R 4< is I. In other embodiments, R 4< is F. In other embodiments, R 4< is Br. In other embodiments, R 4< is OH. In other embodiments, R 4< is C 1 -C 5 linear or branched, substituted or unsubstituted alkyl. In other embodiments, R 4< is methyl. In other embodiments, R 4< is ethyl. In other embodiments, R 4< is propyl. In other embodiments, R 4< is iso-propyl. In other embodiments, R 4< is t-Bu. In other embodiments, R 4< is iso-butyl. In other embodiments, R 4< is pentyl. In other embodiments, R 4< is CH 2 -C(CH 3 ) 3 . In other embodiments, R 4< is CH 2 CH 2 CH(CH 3 ) 2 . In other embodiments, R 4< is C 1 -C 5 linear or branched, or C 3 -C 8 cyclic haloalkyl. In other embodiments, R 4< is CF 2 CH 3 . In other embodiments, R 4< is CF 2 -cyclobutyl. In other embodiments, R 4< is CH 2 CF 3 . In other embodiments, R 4< is CF 2 CH 2 CH 3 . In other embodiments, R 4< is CF 3 . In other embodiments, R 4< is CF 2 CH 2 CH 3 . In other embodiments, R 4< is CH 2 CH 2 CF 3 . In other embodiments, R 4< is CF 2 CH(CH 3 ) 2 . In other embodiments, R 4< is CF(CH 3 )-CH(CH 3 ) 2 .

[0038] In some embodiments, R 6< of formula I(a(ii)), I(a(iii) and / or II is [CH 2 ] p wherein p is an integer between 1 and 3. In other embodiments, R 6< is [CH 2 ] p -O. In other embodiments, R 6< is CH 2 CH 2 O. In other embodiments, R 6< is CH 2. In other embodiments, R 6< is CH 2 CH 2 . In other embodiments, R 6< is CH 2 CH 2 CH 2 . In other embodiments, each R 6< is independently [CH 2 ] pa -O-[CH 2 ] pb , wherein each pa and pb is independently an integer between 1 and 5. In other embodiments, R 6< is CH 2 OCH 2 . In some embodiments, R 6< is [CH 2 ] p (e.g., CH 2 -CH 2 -CH 2 ), [CH 2 ] pa -O-[CH 2 ] pb , or [CH 2 ] p -O. In some embodiments, R 6< is [CH 2 ] p (e.g., CH 2 -CH 2 -CH 2 ), [CH 2 ] pa -O-[CH 2 ] pb , or [CH 2 ] p -O, wherein p is 1, 2 or 3; and each pa and pb is independently an integer between 1 and 5.

[0039] In some embodiments, R 6b< of formula I(a(ii)), I(a(iii), and / or II is absent. In other embodiments, R 6b< is [CH 2 ] p wherein p is an integer between 1 and 3. In other embodiments, R 6b< is O. In other embodiments, R 6b< is C=O. In other embodiments, R 6b< is CH 2. In other embodiments, R 6b< is CH 2 CH 2 . In other embodiments, R 6b< is CH 2 CH 2 CH 2 . In some embodiments, R 6b< is absent or is O, C=O, or [CH 2 ] p (e.g., CH 2 ).

[0040] In some embodiments, R 7< of formula I(a(ii)) or I(a(iii), is H. C 1 -C 5 substituted or unsubstituted linear or branched alkyl. In other embodiments, R 7< is methyl. In other embodiments, R 7< is ethyl. In other embodiments, R 7< is CH 2 CH 2 OCH 3 . In other embodiments, R 7< is C(O)R. In other embodiments, R 7< is C 1 -C 5 linear or branched alkoxy. In other embodiments, R 7< is methoxy. In other embodiments, R 7< is S(O) 2 R.

[0041] In some embodiments, R 8< of compound of formula I(a(ii)) or I(a(iii) is H. In other embodiments, R 8< is Cl. In other embodiments, R 8< is I. In other embodiments, R 8< is F. In other embodiments, R 8< is Br. In other embodiments, R 8< is OH. In other embodiments, R 8< is C 1 -C 5 linear or branched, substituted or unsubstituted alkyl. In other embodiments, R 8< is methyl. In other embodiments, R 8< is ethyl. In other embodiments, R 8< is propyl. In other embodiments, R 8< is iso-propyl. In other embodiments, R 8< is t-Bu. In other embodiments, R 8< is iso-butyl. In other embodiments, R 4< is pentyl. In other embodiments, R 8< is CH 2 -C(CH 3 ) 3 . In other embodiments, R 8< is CH 2 CH 2 CH(CH 3 ) 2 . In other embodiments, R 8< is C 1 -C 5 linear or branched, or C 3 -C 8 cyclic haloalkyl. In other embodiments, R 8< is CF 2 CH 3 . In other embodiments, R 8< is CF 2 -cyclobutyl. In other embodiments, R 8< is CH 2 CF 3 . In other embodiments, R 8< is CF 2 CH 2 CH 3 . In other embodiments, R 8< is CF 3 . In other embodiments, R 8< is CF 2 CH 2 CH 3 . In other embodiments, R 8< is CH 2 CH 2 CF 3 . In other embodiments, R 8< is CF 2 CH(CH 3 ) 2 . In other embodiments, R 8< is CF(CH 3 )-CH(CH 3 ) 2 . In some embodiments, R 8< is H, F, Cl, Br, I, OH, CF 3 , CN, NO 2 , C 1 -C 5 linear or branched, substituted or unsubstituted alkyl, C 1 -C 5 linear or branched, or C 3 -C 8 cyclic haloalkyl.

[0042] In some embodiments, R 9< of formula I(a(ii)) or I(a(iii) is 2, 3 or 4 pyridine. In other embodiments, R 9< is methyl-pyridine. In other embodiments, R 9< is fluoro-pyridine. In other embodiments, R 9< is furan. In other embodiments, R 9< is pyrrole. In other embodiments, R 9< is methyl-pyrrole. In other embodiments, R 9< is thiazole. In other embodiments, R 9< is isothiazole. In other embodiments, R 9< is thiophene. In other embodiments, R 9< is methylthiophene. In other embodiments, R 9< is methylfuran. In other embodiments, R 9< is methylpyridine. In other embodiments, R 9< is methylthiazole. In other embodiments, R 9< is substituted or unsubstituted C 3 -C 8 cycloalkyl. In other embodiments, R 9< is cyclopropyl. In other embodiments, R 9< is methylcyclopropyl. In other embodiments, R 9< is dimethylcyclopropyl. In other embodiments, R 9< is cyclobutyl. In other embodiments, R 9< is cyclohexyl. In other embodiments, R 9< is cyclopentyl. In other embodiments, R 9< is substituted or unsubstituted unsaturated C 3 -C 8 cycloalkyl. In other embodiments, R 9< is substituted or unsubstituted C 3 -C 8 cycloalkenyl. In other embodiments, R 9< is cyclohexenyl. In other embodiments, R 9< is substituted or unsubstituted, saturated or unsaturated 3-8 membered heterocyclic ring. In other embodiments, R 9< is substituted or unsubstituted, saturated 3-8 membered heterocyclic ring. In other embodiments, R 9< is oxetane. In other embodiments, R 9< is azetidine. In other embodiments, R 9< is methyloxetane. In other embodiments, R 9< is tetrahydrofuran. In other embodiments, R 9< is methyltetrahydropyran. In other embodiments, R 9< is pyrrolidine. In other embodiments, R 9< is methylpyrrolidine. In other embodiments, R 9< is tetrahydropyran. In other embodiments, R 9< is tetrahydrothiopyran. In other embodiments, R 9< is piperidine. In other embodiments, R 9< is methylpiperidine. In other embodiments, R 9< is azepane. In other embodiments, R 9< is oxepane. In other embodiments, R 9< is 2H-thiopyran- tetrahydro-1,1-dioxide. In other embodiments, R 9< is substituted or unsubstituted, unsaturated 3-8 membered heterocyclic ring. In other embodiments, R 9< is C 1 -C 5 linear or branched, or C 3 -C 8 cyclic haloalkyl. In some embodiments, R 9< is pyridine, 3-methyl-pyridine, thiazolyl, oxazolyl thiophenyl, furanyl, substituted or unsubstituted saturated C 3 -C 8 cycloalkyl, cyclohexyl, cyclopentyl, cyclopropyl, substituted or unsubstituted C 3 -C 8 cycloalkenyl, cyclohexenyl, substituted or unsubstituted 3-8 membered heterocyclic ring, tetrahydropyran, or tetrahydrothiopyran. In some embodiments, R 9< is substituted or unsubstituted saturated C 3 -C 8 cycloalkyl (e.g., cyclohexyl, cyclopentyl, cyclopropyl), substituted or unsubstituted C 3 -C 8 cycloalkenyl (e.g., cyclohexenyl), or substituted or unsubstituted saturated or unsaturated 3-8 membered heterocyclic ring (e.g., methyl-piperidine, tetrahydropyran, tetrahydrothiopyran). In some embodiments, R 9< is R 20< . In some embodiments, R 9< may be further substituted with at least one substitution selected from: F, Cl, Br, I, OH, SH, C 1 -C 5 linear alkyne (e.g., acetylene), diazirine, C 1 -C 5 linear, cyclic or branched alkyl (e.g. methyl, ethyl, propyl, isopropyl or cyclopropyl), substituted or unsubstituted benzyl (e.g., benzyl, methylbenzyl), substituted or unsubstituted aryl (e.g., phenyl, fluorophenyl), heteroaryl (e.g., indole, tetrahydropyran, pyridine (2, 3, and 4-pyridine)), C 3 -C 8 cycloalkyl (e.g., cyclopropyl), C 1 -C 5 linear or branched alkyl-OH (e.g., C(CH 3 ) 2 CH 2 -OH, CH 2 CH 2 -OH), 3-8 membered heterocyclic ring (e.g., piperidine), alkoxy (e.g. methoxy, ethoxy, propyloxy, isopropyloxy), NH 2 , N(alkyl) 2 (e.g. N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 , N(CH 3 )(CH 2 CH 3 )), NH(alkyl) (e.g. NHCH 3 , NHCH 2 CH 3 , NHCH 2 CH 2 CH 3 ) NH(cycloalkyl) (e.g. NH(cyclohexyl), NH(cyclopentyl)), NH(aryl) (e.g. NH(phenyl), NH(pyridinyl)), NH(benzyl), N(cycloalkyl) 2 (e.g. N(cyclohexyl) 2 , N(cylopentyl) 2 ), N(aryl) 2 (e.g. N(phenyl) 2 , N(pyridinyl) 2 ), N(alkyl)(aryl) (e.g. N(methyl)(phenyl), N(methyl)(pyridinyl)), N(alkyl)(cycloalkyl) (e.g. N(methyl)(cyclopropyl), N(methyl)(cyclohexyl), N(methyl)(cyclopentyl)), N(aryl)(cycloalkyl) (e.g. N(phenyl)(cyclohexyl), N(pyridinyl)(cyclohexyl)), NHC(O)(alkyl) (e.g. NHC(O)CH 3 ), CF 3 , aryl, phenyl, heteroaryl, C 3 -C 8 cycloalkyl, halophenyl, (benzyloxy)phenyl, CN and NO 2 .

[0043] In some embodiments, R of compound of formula I(a(ii)), I(a(iii) and / or II is H. In other embodiments, R is F. In other embodiments, R is Cl. In other embodiments, R is Br. In other embodiments, R is I. In other embodiments, R is OH. In other embodiments, R is CF 3 . In other embodiments, R is CN. In other embodiments, R is NO 2 . In other embodiments, R is N(R a< )(R b< ). In other embodiments, R is C 1 -C 5 linear or branched, substituted or unsubstituted alkyl. In other embodiments, R is methyl. In other embodiments, R is ethyl. In other embodiments, R is propyl. In other embodiments, R is isobutyl. In other embodiments, R is isopropyl. In other embodiments, R is C 1 -C 5 linear or branched alkoxy. In other embodiments, R is methoxy. In other embodiments, R is C 1 -C 5 linear or branched haloalkyl. In other embodiments, R is CHF 2 . In other embodiments, R is CF 3 . In other embodiments, R is R 6< -aryl. In other embodiments, R is CH 2 -Ph. In other embodiments, R is CH 2 -Ph-ethyl. In other embodiments, R is R 6< -N(alkyl) 2 . In other embodiments, R is R 6< -NH(alkyl). In other embodiments, R is (R 6< -NH(cycloalkyl). In other embodiments, R is (R 6< -NH(aryl). In other embodiments, R is substituted or unsubstituted aryl. In other embodiments, R is phenyl. In other embodiments, R is ethylphenyl. In other embodiments, R is substituted or unsubstituted heteroaryl. In other embodiments, R is 2, 3, or 4 pyridine. In other embodiments, R is benzimidazole. In other embodiments, R is substituted or unsubstituted C 3 -C 8 cycloalkyl. In other embodiments, R is cyclopropyl. In other embodiments, R is substituted or unsubstituted 3-8 membered heterocyclic ring. In other embodiments, R is piperidine. In other embodiments, R is pyrrolidine. In other embodiments, R is R 6< -(substituted or unsubstituted heterocycle). In other embodiments, R is (CH 2 ) 3 -piperidine. In other embodiments, R is C(O)-(alkyl). In other embodiments, R is C(O)-(CH 3 ). In other embodiments, R is F, Cl, Br, I, OH, CF 3 , CN, NO 2 , C 1 -C 5 linear or branched, substituted or unsubstituted alkyl, C 1 -C 5 linear or branched alkoxy, C 1 -C 5 linear or branched haloalkyl, R 6< -aryl, R 6< -N(alkyl) 2 , R 6< -NH(alkyl), (R 6< -NH(cycloalkyl), (R 6< -NH(aryl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic ring, R 6< -(substituted or unsubstituted heterocycle) or C(O)-(alkyl).

[0044] In some embodiments, l of formula I(a(ii)) and / or I(a(iii) is an integer between 0 and 4. In other embodiments, l is between 0 and 3. In other embodiments, l is between 1 and 4. In other embodiments, l is 0. In other embodiments, l is 1. In other embodiments, l is 2. In other embodiments, l is 3. In other embodiments, l is 4.

[0045] In some embodiments, q of formula I(a(ii)) is an integer between 0 and 4. In other embodiments, q is between 0 and 3. In other embodiments, q is between 1 and 4. In other embodiments, q is 0. In other embodiments, q is 1. In other embodiments, q is 2. In other embodiments, q is 3. In other embodiments, q is 4.

[0046] In some embodiments, p of formula I(a(ii)), I(a(iii) and / or II is 1. In other embodiments, p is 2. In other embodiments, p is 3. In other embodiments, p is between 1 and 3.

[0047] In some embodiments, p a< of formula I(a(ii)) and / or II is 1. In other embodiments, p a< is 2. In other embodiments, p a< is 3. In other embodiments, p a< is 4. In other embodiments, p a< is 5.

[0048] In some embodiments, p b< of formula I(a(ii)) and / or II is 1. In other embodiments, p b< is 2. In other embodiments, p b< is 3. In other embodiments, p b< is 4. In other embodiments, p b< is 5.

[0049] In various embodiments, the compounds is presented in Table 1, pharmaceutical compositions and / or uses thereof: Table 1: Compound number Compound Name 220 N-((1-(cyclopropylmethyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide221 N-((1-(cyclopropylmethyl)pyrrolidin-3-yl)methyl)-4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperazine-1-carboxamide223 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((5-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide243 1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((5-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide244 1-(3-(4-cyanophenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((5-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide248 4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-(3-(4-(pyridin-2-ylmethyl)piperidin-1-yl)propyl)piperazine-1-carboxamide286 N-((1-(2-(3-(but-3-yn-1-yl)-3H-diazirin-3-yl)ethyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide320 N-((1-(furan-2-ylmethyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide322 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(pyridin-4-ylmethyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide323 N-((1-(cyclopentylmethyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide325 N-((1-((1H-pyrrol-3-yl)methyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide326 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((4-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide329 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((4-methylpyridin-3-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide330 N-((1-(furan-3-ylmethyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide333 N-((1-((5-fluoropyridin-3-yl)methyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide334 N-((1-((3-fluoropyridin-2-yl)methyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide335 N-((1-((5-fluoropyridin-2-yl)methyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide336 N-((1-(cyclobutylmethyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide337 N-((1-((2,2-dimethylcyclopropyl)methyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide338 N-((1-(cyclohexylmethyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide340 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(pyridin-2-ylmethyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide341 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(thiazol-5-ylmethyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide347 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((tetrahydrofuran-3-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide348 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((3-methylpyridin-4-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide350 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((3-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide351 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((6-methylpyridin-3-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide352 N+((1-(isothiazol-5-ylmethyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide353 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((1-methylpiperidin-4-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide354 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((tetrahydro-2H-thiopyran-4-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide355 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((tetrahydro-2H-pyran-4-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide356 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(pyridin-3-ylmethyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide357 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(thiophen-3-ylmethyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide359 N-((1-((3-fluoropyridin-4-yl]methyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide360 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(thiazol-4-ylmethyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide361 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((tetrahydro-2H-pyran-2-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide363 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((1-methyl-1H-pyrrol-2-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide364 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(thiazol-2-ylmethyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide365 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((5-methylpyridin-3-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide368 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((2-methylcyclopropyl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide369 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(((S)-1-methylpyrrolidin-2-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide370 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(tetrahydrofuran-3-yl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide371 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((3-methyloxetan-3-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide372 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(thiophen-2-ylmethyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide373 N-((1-(isothiazol-4-ylmethyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide375 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((tetrahydro-2H-pyran-3-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide377 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((4-methyltetrahydro-2H-pyran-4-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide379 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((5-methylfuran-2-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide380 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((2-methylpyridin-3-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide381 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((3-methylthiophen-2-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide382 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((4-methylfuran-2-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide383 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((2-methylthiazol-4-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide384 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((4-methylthiazol-2-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide385 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((5-methylthiophen-2-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide387 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((6-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide388 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((2-methylthiazol-5-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide389 N-((1-((1H-pyrrol-2-yl)methyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide391 N-((1-(azepan-4-ylmethyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide392 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(((S)-pyrrolidin-2-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide393 N-((1-((3,3-difluorocyclobutyl)methyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide394 N-((1-(((1s,3s)-3-aminocyclobutyl)methyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide395 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(oxetan-2-ylmethyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide396 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(tetrahydro-2H-pyran-3-yl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide398 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide399 N-((1-(2-oxaspiro[3.3]heptan-6-yl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide400 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(oxepan-4-yl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide401 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(oxetan-3-yl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide402 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(2-methyltetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide404 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((4-methylthiazol-5-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide405 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((tetrahydrofuran-2-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide406 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((3-methylfuran-2-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide407 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((5-methylthiazol-2-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide408 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(oxetan-3-ylmethyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide409 N-((1-(cyclohex-1-en-1-ylmethyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide412 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(((R)-piperidin-3-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide413 N-((1-(((R)-azetidin-2-yl)methyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide414 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(((R)-1-methylpiperidin-2-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide415 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(((R)-piperidin-2-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide416 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide421 N-((1-(cyclohexylmethyl)pyrrolidin-3-yl)methyl)-4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperazine-1-carboxamide422 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(((S)-1-methylpiperidin-3-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide423 N-((1-(((1s,4s)-4-aminocyclohexyl)methyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide425 N-((1-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl)pyrrolidin-3-yl)methyl)-4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperazine-1-carboxamide430 4-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-N-(3-(4-(pyridin-2-ylmethyl)piperidin-1-yl)propyl)piperazine-1-carboxamide431 4-(3-(4-cyanophenyl)-1,2,4-oxadiazol-5-yl)-N-(3-(4-(pyridin-2-ylmethyl)piperidin-1-yl)propyl)piperazine-1-carboxamide432 4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((tetrahydro-2H-pyran-4-yl)methyl)pyrrolidin-3-yl)methyl)piperazine-1-carboxamide433 (R)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((1-methylpiperidin-4-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide434 (S)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((1-methylpiperidin-4-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide435 N-(3-(4-(pyridin-2-ylmethyl)piperidin-1-yl)propyl)-1-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide436 N-(3-(4-(pyridin-2-ylmethyl)piperidin-1-yl)propyl)-4-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)piperazine-1-carboxamide437 4-(3-(4-(difluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-N-(3-(4-(pyridin-2-ylmethyl)piperidin-1-yl)propyl)piperazine-1-carboxamide440 N-(3-(4-fluoro-4-(pyridin-2-yl)piperidin-1-yl)propyl)-4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperazine-1-carboxamide441 4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-(3-(4-(pyridin-2-ylmethyl)piperazin-1-yl)propyl)piperazine-1-carboxamide451 N-(((4-(pyridin-2-ylmethyl)piperidin-1-yl)methoxy)methyl)-4-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)piperazine-1-carboxamide452 N-(((4-(pyridin-2-yloxy)piperidin-1-yl)methoxymethyl)-4-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)piperazine-1-carboxamide453 1-(3-(4-(difluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-N-(3-(4-(pyridin-2-ylmethyl)piperidin-1-yl)propyl)piperidine-4-carboxamide456 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-(2-((1-(pyridin-2-ylmethyl)piperidin-4-yl)oxy)ethyl)piperidine-4-carboxamide457 4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-(2-((1-(pyridin-2-ylmethyl)piperidin-4-yl)oxy)ethyl)piperazine-1-carboxamide458 4-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)-N-(3-(4-(pyridin-2-ylmethyl)piperidin-1-yl)propyl)piperazine-1-carboxamide459 N-(3-(4-(pyridin-2-ylmethyl)piperidin-1-yl)propyl)-4-(3-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)piperazine-1-carboxamide460 4-(3-(4-(difluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-N-(3-(4-(pyridin-2-ylmethyl)piperidin-1-yl)propyl)piperazine-1-carboxamide461 N-(3-(4-fluoro-4-(pyridin-2-ylmethyl)piperidin-1-yl)propyl)-4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperazine-1-carboxamide464 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(((R)-1-methylpiperidin-3-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide465 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-(((R)-1-(((S)-1-methylpiperidin-3-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide466 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-(((S)-1-(((S)-1-methylpiperidin-3-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide467 1-(3-(4-cyanophenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(((S)-1-methylpiperidin-3-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide468 1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(((S)-1-methylpiperidin-3-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide470 1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)-N-(((S)-1-(((S)-1-methylpiperidin-3-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide471 1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)-N-(((R)-1-(((S)-1-methylpiperidin-3-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide474 1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)-N-(((S)-1-(((R)-1-methylpiperidin-3-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide475 1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)-N-(((R)-1-(((R)-1-methylpiperidin-3-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide

[0050] It is well understood that in structures presented in this invention wherein the carbon atom has less than 4 bonds, H atoms are present to complete the valence of the carbon. It is well understood that in structures presented in this invention wherein the nitrogen atom has less than 3 bonds, H atoms are present to complete the valence of the nitrogen.

[0051] In some embodiments, this invention is directed to the compounds listed hereinabove, pharmaceutical compositions and / or uses thereof, wherein the compound is pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, pharmaceutical product or any combination thereof.

[0052] In various embodiments, B of formula I(a(ii)) and / or II is a single or fused C 3 -C 12 heterocyclic (e.g. tetrahydropyran, tetrahydrofuran, pyrrolidine, piperidine, piperazine, 2-oxopyrrolidine, 2,5-dioxopyrrolidine, 2,5-dioxoimidazolidine, oxetane, chromane), C 3 -C 8 saturated or unsaturated cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl) ring or a spiro ring system (e.g. ).

[0053] In various embodiments, D ring of formula II is a saturated or unsaturated, single, fused or spiro, carbocyclic or heterocyclic 3-12 membered ring. In various embodiments, D ring is saturated, single, 3-8 membered carbocyclic ring. In various embodiments, D ring is C 3 -C 8 cycloalkyl. In various embodiments, D ring is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. In various embodiments, D ring is unsaturated, single, 3-8 membered carbocyclic ring. In various embodiments, D ring is C 3 -C 8 cycloalkenyl. In various embodiments, D ring is cyclohexenyl. In various embodiments, D ring is saturated, unsaturated or aromatic, single, 3-8 membered heterocyclic ring. In various embodiments, D ring is unsaturated, single, heterocyclic 3-8 membered ring. In various embodiments, D ring is saturated, single, 3-8 membered heterocyclic ring. In various embodiments, D ring is tetrahydrofuran, piperidine, azepane, oxepane, 2-oxaspiro[3.3]heptane, tetrahydro-2H-thiopyran 1,1-dioxide, tetrahydropyran, tetrahydrothiopyran, pyrrolidine, or oxetane. In some embodiments, D ring is not an aromatic carbocyclic ring. In some embodiments, D ring is not an aryl. In some embodiments, D ring is a saturated or unsaturated, single, fused or spiro, heterocyclic 3-12 membered ring. In some embodiments, D ring is tetrahydrofuran, piperidine, azepane, oxepane, 2-oxaspiro[3.3]heptane, azetidine, tetrahydro-2H-thiopyran 1,1-dioxide, tetrahydrothiopyran, tetrahydropyran, pyrrolidine, oxetane or diazirine. In some embodiments, D ring is a saturated or unsaturated, single, fused or spiro, aliphatic carbocyclic 3-12 membered ring. In some embodiments, D ring is a saturated, single, 3-8 membered cycloalkyl ring. In some embodiments, D ring is an unsaturated, single, 3-8 membered cycloalkenyl ring. In some embodiments, D ring is a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclohexenyl.

[0054] In various embodiments, R 1 of I(a(ii)), I(a(iii) and / or II are each independently F, Cl, Br, I, OH, O-R 20< , CF 3 , OCH 3 , CN, NO 2 , -CH 2 CN, -R 6< CN, C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C 1 -C 5 linear or branched, or C 3 -C 8 cyclic haloalkyl (e.g., CHF 2 ), C 1 -C 5 substituted or unsubstituted, linear or branched, or C 3 -C 8 cyclic alkoxy (e.g. methoxy, O-(CH 2 ) 2 -OH), C 1 -C 5 linear or branched haloalkoxy (e.g., OCF 3 , OCHF 2 ), C 1 -C 5 linear or branched alkoxyalkyl (wherein substitutions include: F, Cl, Br, I, C 1 -C 5 linear alkyne, diazirine, C 1 -C 5 linear, cyclic or branched alkyl (e.g. methyl, ethyl, propyl, isopropyl or cyclopropyl), OH, alkoxy, NH 2 , N(alkyl) 2 (e.g. N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 , N(CH 3 )(CH 2 CH 3 )), NH(alkyl) (e.g. NHCH 3 , NHCH 2 CH 3 , NHCH 2 CH 2 CH 3 ) NH(cycloalkyl) (e.g. NH(cyclohexyl), NH(cylopentyl)), NH(aryl) (e.g. NH(phenyl), NH(pyridinyl)), NH(benzyl), N(cycloalkyl) 2 (e.g. N(cyclohexyl) 2 , N(cylopentyl) 2 ), N(aryl) 2 (e.g. N(phenyl) 2 , N(pyridinyl) 2 ), N(alkyl)(aryl) (e.g. N(methyl)(phenyl), N(methyl)(pyridinyl)), N(alkyl)(cycloalkyl) (e.g. N(methyl)(cyclopropyl), N(methyl)(cyclohexyl), N(methyl)(cyclopentyl)), N(aryl)(cycloalkyl) (e.g. N(phenyl)(cyclohexyl), N(pyridinyl)(cyclohexyl)) NHC(O)(alkyl) (e.g. NHC(O)CH 3 ), CF 3 , aryl, phenyl, heteroaryl, C 3 -C 8 cycloalkyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 or any combination thereof).

[0055] In various embodiments, R 4 of formula I(a(ii)) and / or I(a(iii) is each independently H, F, Cl, Br, I, OH, CF 3 , CN, NO 2 , C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, tert-butyl, CH 2 CH 2 CH(CH 3 ) 2 , CH 2 -C(CH 3 ) 3 ), C 1 -C 5 linear or branched, or C 3 -C 8 cyclic haloalkyl (wherein substitutions include: F, Cl, Br, I, C 1 -C 5 linear, cyclic or branched alkyl (e.g. methyl, ethyl, propyl, isopropyl or cyclopropyl), OH, alkoxy, NH 2 , N(alkyl) 2 (e.g. N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 , N(CH 3 )(CH 2 CH 3 )) NH(alkyl) (e.g. NHCH 3 , NHCH 2 CH 3 , NHCH 2 CH 2 CH 3 ) NH(cycloalkyl) (e.g. NH(cyclohexyl), NH(cylopentyl)), NH(aryl) (e.g. NH(phenyl), NH(pyridinyl)), NH(benzyl), N(cycloalkyl) 2 (e.g. N(cyclohexyl) 2 , N(cylopentyl) 2 ), N(aryl) 2 (e.g. N(phenyl) 2 , N(pyridinyl) 2 ), N(alkyl)(aryl) (e.g. N(methyl)(phenyl), N(methyl)(pyridinyl)), N(alkyl)(cycloalkyl) (e.g. N(methyl)(cyclopropyl), N(methyl)(cyclohexyl), N(methyl)(cyclopentyl)), N(aryl)(cycloalkyl) (e.g. N(phenyl)(cyclohexyl), N(pyridinyl)(cyclohexyl)), CF 3 , aryl, phenyl, heteroaryl, C 3 -C 8 cycloalkyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 or any combination thereof).

[0056] In various embodiments, R 6< of formula I(a(ii)), I(a(iii) and / or II is [CH 2 ] p (e.g. CH 2 , CH 2 CH 2 , or CH 2 CH 2 CH 2 ), [CH 2 ] pa -O-[CH 2 ] pb (e.g. CH 2 OCH 2 ), or [CH 2 ] p -O (e.g., CH 2 CH 2 O). In other embodiments, R 6< is CH 2 . In other embodiments, R 6< is CH 2 CH 2 . In other embodiments, R 6< is CH 2 CH 2 CH 2 .

[0057] In various embodiments, R 6b< of formula I(a(ii)), I(a(iii) and / or II is absent or O, C=O, [CH 2 ] p (e.g. CH 2 , CH 2 CH 2 , or CH 2 CH 2 CH 2 ). In other embodiments, R 6b< is CH 2 . In other embodiments, R 6b< is CH 2 CH 2 . In other embodiments, R 6b< is CH 2 CH 2 CH 2 .

[0058] In some embodiments, both R 6< and R 6b< are CH 2 . In other embodiments, R 6< is CH 2 and R 6b< is absent. In other embodiments, R 6< is CH 2 CH 2 CH 2 and R 6b< is absent. In other embodiments, R 6< is CH 2 CH 2 CH 2 and R 6b< is CH 2 . In other embodiments, R 6b< is CH 2 CH 2 CH 2 and R 6< is CH 2 . In other embodiments, R 6< is CH 2 OCH 2 and R 6b< is CH 2 . In other embodiments, R 6< is CH 2 OCH 2 and R 6b< is O.

[0059] In various embodiments, R 7< of I(a(ii)) and / or I(a(iii) is H, C 1 -C 5 substituted or unsubstituted linear or branched alkyl (e.g., methyl, ethyl, CH 2 -CH 2 -O-CH 3 ), C 1 -C 5 linear or branched alkoxy (e.g., O-CH 3 ), C(O)R, or S(O) 2 R (wherein substitutions include: F, Cl, Br, I, OH, C 1 -C 5 linear, cyclic or branched alkyl (e.g. methyl, ethyl, propyl, isopropyl or cyclopropyl), C 1 -C 5 linear or branched alkyl-OH (e.g., C(CH 3 ) 2 CH 2 -OH, CH 2 CH 2 -OH), 3-8 membered heterocyclic ring (e.g., piperidine), alkoxy, NH 2 , N(alkyl) 2 (e.g. N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 , N(CH 3 )(CH 2 CH 3 )) NH(alkyl) (e.g. NHCH 3 , NHCH 2 CH 3 , NHCH 2 CH 2 CH 3 ) NH(cycloalkyl) (e.g. NH(cyclohexyl), NH(cylopentyl)), NH(aryl) (e.g. NH(phenyl), NH(pyridinyl)), NH(benzyl), N(cycloalkyl) 2 (e.g. N(cyclohexyl) 2 , N(cylopentyl) 2 ), N(aryl) 2 (e.g. N(phenyl) 2 , N(pyridinyl) 2 ), N(alkyl)(aryl) (e.g. N(methyl)(phenyl), N(methyl)(pyridinyl)), N(alkyl)(cycloalkyl) (e.g. N(methyl)(cyclopropyl), N(methyl)(cyclohexyl), N(methyl)(cyclopentyl)), N(aryl)(cycloalkyl) (e.g. N(phenyl)(cyclohexyl), N(pyridinyl)(cyclohexyl)), CF 3 , aryl, phenyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 or any combination thereof). In various embodiments, R 8< of formula I(a(ii)) and / or I(a(iii) is H, F, Cl, Br, I, OH, CF 3 , CN, NO 2 , C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, t-Bu, CH 2 -C(CH 3 ) 3 , CH 2 CH 2 CH(CH 3 ) 2 ), C 1 -C 5 linear or branched, or C 3 -C 8 cyclic haloalkyl (wherein substitutions include: F, Cl, Br, I, C 1 -C 5 linear, cyclic or branched alkyl (e.g. methyl, ethyl, propyl, isopropyl or cyclopropyl), OH, alkoxy, (e.g. methoxy, ethoxy, propyloxy, isopropyloxy), NH 2 , N(alkyl) 2 (e.g. N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 , N(CH 3 )(CH 2 CH 3 )) NH(alkyl) (e.g. NHCH 3 , NHCH 2 CH 3 , NHCH 2 CH 2 CH 3 ), NH(cycloalkyl) (e.g. NH(cyclohexyl), NH(cylopentyl)), NH(aryl) (e.g. NH(phenyl), NH(pyridinyl)), NH(benzyl), N(cycloalkyl) 2 (e.g. N(cyclohexyl) 2 , N(cylopentyl) 2 ), N(aryl) 2 (e.g. N(phenyl) 2 , N(pyridinyl) 2 ), N(alkyl)(aryl) (e.g. N(methyl)(phenyl), N(methyl)(pyridinyl)), N(alkyl)(cycloalkyl) (e.g. N(methyl)(cyclopropyl), N(methyl)(cyclohexyl), N(methyl)(cyclopentyl)), N(aryl)(cycloalkyl) (e.g. N(phenyl)(cyclohexyl), N(pyridinyl)(cyclohexyl)),CF 3 , aryl, phenyl, heteroaryl, C 3 -C 8 cycloalkyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 or any combination thereof).

[0060] In various embodiments, R 9< of formula I I(a(ii)) and / or I(a(iii) is substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine), furan, thiazole, isothiazole, thiophene, pyrrole, methylthiophene, methylfuran, methylpyridine, methylthiazole, indole, benzimidazole, pyrrolopyridine, benzoxazole), substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g., cyclopropyl, methylcyclopropyl, cyclobutyl, cyclohexyl, cyclohexenyl, cyclopentyl), C 1 -C 5 linear or branched, or C 3 -C 8 cyclic haloalkyl (e.g. CF 3 , CHF 2 ), NH 2 , N(alkyl) 2 (e.g. N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 , N(CH 3 )(CH 2 CH 3 )), NH(alkyl) (e.g. NHCH 3 , NHCH 2 CH 3 , NHCH 2 CH 2 CH 3 ) or substituted or unsubstituted 3-8 membered heterocyclic ring (e.g. oxetane, azetidine, methyloxetane, tetrahydrofuran, methyltetrahydropyran, pyrrolidine, methylpyrrolidine, tetrahydropyran, tetrahydrothiopyran, piperidine, methylpiperidine, azepane, oxepane, 2H-Thiopyran- tetrahydro-1,1-dioxide) (wherein substitutions include: F, Cl, Br, I, OH, SH, diazirine, C 1 -C 5 linear alkyne, C 1 -C 5 linear, cyclic or branched alkyl (e.g. methyl, ethyl, propyl, isopropyl or cyclopropyl), aryl (e.g., phenyl), heteroaryl (e.g., pyridine (2, 3, and 4-pyridine)), C 3 -C 8 cycloalkyl (e.g., cyclopropyl), C 1 -C 5 linear alkyne, diazirine, 3-8 membered heterocyclic ring, alkoxy, NH 2 , N(alkyl) 2 (e.g. N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 , N(CH 3 )(CH 2 CH 3 )) NH(alkyl) (e.g. NHCH 3 , NHCH 2 CH 3 , NHCH 2 CH 2 CH 3 ) NH(cycloalkyl) (e.g. NH(cyclohexyl), NH(cylopentyl)), NH(aryl) (e.g. NH(phenyl), NH(pyridinyl)), NH(benzyl), N(cycloalkyl) 2 (e.g. N(cyclohexyl) 2 , N(cylopentyl) 2 ), N(aryl) 2 (e.g. N(phenyl) 2 , N(pyridinyl) 2 ), N(alkyl)(aryl) (e.g. N(methyl)(phenyl), N(methyl)(pyridinyl)), N(alkyl)(cycloalkyl) (e.g. N(methyl)(cyclopropyl), N(methyl)(cyclohexyl), N(methyl)(cyclopentyl)), N(aryl)(cycloalkyl) (e.g. N(phenyl)(cyclohexyl), N(pyridinyl)(cyclohexyl)), CF 3 , phenyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 or any combination thereof).

[0061] In various embodiments, R 11< of formula II is H, F, Cl, Br, I, OH, CF 3 , OCH 3 , CN, NO 2 , -CH 2 CN, C 1 -C 5 linear or branched, substituted or unsubstituted alkyl, methyl, ethyl, C 1 -C 5 linear or branched, or C 3 -C 8 cyclic haloalkyl, CHF 2 , C 1 -C 5 substituted or unsubstituted, linear or branched, or C 3 -C 8 cyclic alkoxy, methoxy, O-(CH 2 ) 2 -OH, C 1 -C 5 linear or branched haloalkoxy, OCF 3 , OCHF 2 , C 1 -C 5 linear or branched alkoxyalkyl, R 20< , NH 2 , NHR, or NR 2 . In various embodiments, R 11< is H. In various embodiments, R 11< is alkyl. In various embodiments, R 11< is methyl. In various embodiments, R 11< is ethyl. In various embodiments, R 11< is ethylacetylene. In various embodiments, R 11< is 1-butyne. In various embodiments, R 11< is NH 2 . In various embodiments, R 11< is F. In various embodiments, R 11< is Cl. In various embodiments, R 11< is Br. In various embodiments, R 11< is I.

[0062] In various embodiments, R 12< of formula II is H, F, Cl, Br, I, OH, CF 3 , OCH 3 , CN, NO 2 , -CH 2 CN, C 1 -C 5 linear or branched, substituted or unsubstituted alkyl, methyl, ethyl, C 1 -C 5 linear or branched, or C 3 -C 8 cyclic haloalkyl, CHF 2 , C 1 -C 5 substituted or unsubstituted, linear or branched, or C 3 -C 8 cyclic alkoxy, methoxy, O-(CH 2 ) 2 -OH, C 1 -C 5 linear or branched haloalkoxy, OCF 3 , OCHF 2 , C 1 -C 5 linear or branched alkoxyalkyl, R 20< , NH 2 , NHR, or NR 2 . In various embodiments, R 12< is H. In various embodiments, R 12< is alkyl. In various embodiments, R 12< is methyl. In various embodiments, R 12< is ethyl. In various embodiments, R 12< is ethylacetylene. In various embodiments, R 12< is 1-butyne. In various embodiments, R 12< is NH 2 . In various embodiments, R 12< is F. In various embodiments, R 12< is Cl. In various embodiments, R 12< is Br. In various embodiments, R 12< is I.

[0063] In various embodiments, R of formula I(a(ii)), I(a(iii) and / or II is H, F, Cl, Br, I, OH, CF 3 , CN, NO 2 , C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, propyl, isopropyl, isobutyl or cyclopropyl), C 1 -C 5 linear or branched alkoxy(e.g. methoxy), C 1 -C 5 linear or branched haloalkyl (e.g., CHF 2 , CF 3 , R 6< -aryl (e.g., CH 2 -Ph, CH 2 -Ph-ethyl), R 6< -N(alkyl) 2 , R 6< -NH(alkyl), (R 6< -NH(cycloalkyl), (R 6< -NH(aryl), substituted or unsubstituted aryl (e.g., phenyl, ethylphenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine), benzimidazole), substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted 3-8 membered heterocyclic ring, R 6< -(substituted or unsubstituted heterocycle) (e.g. (CH 2 ) 3 -piperidine), or C(O)-(alkyl) (e.g. C(O)(CH 3 ) (wherein substitutions include: F, Cl, Br, I, OH, SH, diazirine, C 1 -C 5 linear alkyne, C 1 -Cs linear, cyclic or branched alkyl (e.g. methyl, ethyl, propyl, isopropyl, isobutyl or cyclopropyl), substituted or unsubstituted benzyl (e.g., benzyl, methylbenzyl), aryl (e.g., phenyl, fluorophenyl), heteroaryl (e.g., pyridine (2, 3, and 4-pyridine), indole, tetrahydropyran), C 3 -C 8 cycloalkyl (e.g., cyclopropyl), 3-8 membered heterocyclic ring (e.g. piperidine, pyrrolidine), alkoxy, NH 2 , N(alkyl) 2 (e.g. N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 , N(CH 3 )(CH 2 CH 3 )) NH(alkyl) (e.g. NHCH 3 , NHCH 2 CH 3 , NHCH 2 CH 2 CH 3 ) NH(cycloalkyl) (e.g. NH(cyclohexyl), NH(cylopentyl)), NH(aryl) (e.g. NH(phenyl), NH(pyridinyl)), NH(benzyl), N(cycloalkyl) 2 (e.g. N(cyclohexyl) 2 , N(cylopentyl) 2 ), N(aryl) 2 (e.g. N(phenyl) 2 , N(pyridinyl) 2 ), N(alkyl)(aryl) (e.g. N(methyl)(phenyl), N(methyl)(pyridinyl)), N(alkyl)(cycloalkyl) (e.g. N(methyl)(cyclopropyl), N(methyl)(cyclohexyl), N(methyl)(cyclopentyl)), N(aryl)(cycloalkyl) (e.g. N(phenyl)(cyclohexyl), N(pyridinyl)(cyclohexyl)), CF 3 , phenyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 or any combination thereof).

[0064] In various embodiments, X 7< of formula I(a(ii)), I(a(iii) and / or II are each independently CH or N.

[0065] In some embodiments, l of formula I(a(ii)) and / or I(a(iii) is 0. In other embodiments, l is 1. In other embodiments, l is 2. In other embodiments, l is 3. In other embodiments, l is 4. In other embodiments, l is between 1 and 3. In other embodiments, l is between 0 and 3. In other embodiments, l is between 0 and 4. In other embodiments, l is between 2 and 4. In other embodiments, l is between 1 and 4.

[0066] In some embodiments, q of formula I(a(ii)) is 0. In other embodiments, q is 1. In other embodiments, q is 2. In other embodiments, q is 3. In other embodiments, q is 4. In other embodiments, q is between 1 and 3. In other embodiments, q is between 0 and 3. In other embodiments, q is between 0 and 4. In other embodiments, q is between 2 and 4. In other embodiments, q is between q and 4.

[0067] In some embodiments, p of formula I(a(ii)) and / or I(a(iii) is 1. In other embodiments, p is 2. In other embodiments, p is 3. In other embodiments, p is between 1 and 3.

[0068] In some embodiments, p a< of formula I(a(ii)), I(a(iii) and / or II is 1. In other embodiments, p a< is 2. In other embodiments, p a< is 3. In other embodiments, p a< is 4. In other embodiments, p a< is 5.

[0069] In some embodiments, p b< of formula I(a(ii)), I(a(iii) and / or II is 1. In other embodiments, p b< is 2. In other embodiments, p b< is 3. In other embodiments, p b< is 4. In other embodiments, p b< is 5.

[0070] It is understood that for heterocyclic, aryl or cycloalkyl rings, l is limited to the number of available positions for substitution, i.e. to the number of CH or NH groups minus one.

[0071] As used herein, "single aromatic or heteroaromatic ring" can be any such ring, including phenyl, pyridinyl, (2-, 3-, and 4-pyridinyl), pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, 1-methylimidazole, pyrazolyl, pyrrolyl, furanyl, thiophene-yl, triazolyl, thiadiazolyl, 1,2,3-, 1,2,4-, 1,2,5- or 1,3,4- oxadiazolyl, 3-methyl-4H-1,2,4-triazole, 5-methyl-1,2,4-oxadiazole etc. As used herein, "single or fused aliphatic or aromatic heterocyclic ring" can be any such ring, including: phenyl, naphthyl, pyridinyl, (2-, 3-, and 4-pyridinyl), quinolinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, 1-methylimidazole, pyrazolyl, pyrrolyl, furanyl, thiophene-yl, quinolinyl, isoquinolinyl, 2,3-dihydroindenyl, indenyl, tetrahydronaphthyl, 3,4-dihydro-2H-benzo[b][1,4]dioxepine, benzodioxolyl, benzo[d][1,3]dioxole, tetrahydronaphthyl, indolyl, 1H-indole, isoindolyl, anthracenyl, benzimidazolyl, 2,3-dihydro-1H-benzo[d]imidazolyl, indazolyl, 2H-indazole, triazolyl, 4,5,6,7-tetrahydro-2H-indazole, 3H-indol-3-one, purinyl, benzoxazolyl, 1,3-benzoxazolyl, benzisoxazolyl, benzothiazolyl, 1,3-benzothiazole, 4,5,6,7-tetrahydro-1,3-benzothiazole, quinazolinyl, quinoxalinyl, 1,2,3,4-tetrahydroquinoxaline, 1-(pyridin-1(2H)-yl)ethanone, cinnolinyl, phthalazinyl, quinolinyl, isoquinolinyl, acridinyl, benzofuranyl, 1-benzofuran, isobenzofuranyl, benzofuran-2(3H)-one, benzothiophenyl, benzoxadiazole, benzo[c][1,2,5]oxadiazolyl, benzo[c]thiophenyl, benzodioxolyl, thiadiazolyl, [1,3]oxazolo[4,5-b]pyridine, 1,2,3-, 1,2,4-, 1,2,5- or 1,3,4- oxadiazolyl, imidazo[2,1-b][1,3]thiazole, 4H,5H,6H-cyclopenta[d][1,3]thiazole, 5H,6H,7H,8H-imidazo[1,2-a]pyridine, 7-oxo-6H,7H-[1,3]thiazolo[4,5-d]pyrimidine, [1,3]thiazolo[5,4-b]pyridine, 2H,3H-imidazo[2,1-b][1,3]thiazole, thieno[3,2-d]pyrimidin-4(3H)-one, 4-oxo-4H-thieno[3,2-d][1,3]thiazin, imidazo[1,2-a]pyridine, 1H-imidazo[4,5-b]pyridine, 1H-imidazo[4,5-c]pyridine, 3H-imidazo[4,5-c]pyridine, pyrazolo[1,5-a]pyridine, imidazo[1,2-a]pyrazine, imidazo[1,2-a]pyrimidine, 1H-pyrrolo[2,3-b]pyridine, pyrido[2,3-b]pyrazine, pyrido[2,3-b]pyrazin-3(4H)-one, 4H-thieno[3,2-b]pyrrole, quinoxalin-2(1H)-one, 1H-pyrrolo[3,2-b]pyridine, 7H-pyrrolo[2,3-d]pyrimidine, oxazolo[5,4-b]pyridine, thiazolo[5,4-b]pyridine, thieno[3,2-c]pyridine, 3-methyl-4H-1,2,4-triazole, 5-methyl-1,2,4-oxadiazole, methylthiophene, methylfuran, methylpyridine, methylthiazole, indole, indane, benzimidazole, pyrrolopyridine, benzoxazole, oxetane, azetidine, methyloxetane, tetrahydrofuran, methyltetrahydropyran, pyrrolidine, methylpyrrolidine, tetrahydropyran, tetrahydrothiopyran, methylpiperidine, azepane, oxepane, 2H-thiopyran-tetrahydro-1,1-dioxide, 1-methylimidazole, pyrrole, furan, thiophene, oxadiazole, indole, indane, benzodihydrofuran, tetrahydroquinoline, tetrahydrofuran, piperidine, morpholine, thiomorpholine-1,1-dioxide, benzopyrrolidine, piperazine, 2-oxopyrrolidine, 2,5-dioxopyrrolidine, 2,5-dioxoimidazolidine, chromane, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl etc. or a spiro ring system (e.g. ).

[0072] As used herein, the term "alkyl" can be any straight- or branched-chain alkyl group containing up to about 30 carbons unless otherwise specified. In various embodiments, an alkyl includes C 1 -C 5 carbons. In some embodiments, an alkyl includes C 1 -C 6 carbons. In some embodiments, an alkyl includes C 1 -C 8 carbons. In some embodiments, an alkyl includes C 1 -C 10 carbons. In some embodiments, an alkyl is a C 1 -C 12 carbons. In some embodiments, an alkyl is a C 1 -C 20 carbons. In some embodiments, branched alkyl is an alkyl substituted by alkyl side chains of 1 to 5 carbons. In various embodiments, the alkyl group may be unsubstituted. In some embodiments, the alkyl group may be substituted by a heteroaryl, aryl, cycloalkyl, heterocyclic ring, halogen, haloalkyl, hydroxyl, alkoxy, carbonyl, amido, alkylamido, dialkylamido, cyano, nitro, CO 2 H, amino, alkylamino, dialkylamino, carboxyl, thio, thioalkyl, C 1 -C 5 linear or branched haloalkoxy, CF 3 , phenyl, halophenyl, (benzyloxy)phenyl, -CH 2 CN, NH 2 , NH-alkyl, N(alkyl) 2 , -OC(O)CF 3 , -OCH 2 Ph, -NHCO-alkyl, -C(O)Ph, C(O)O-alkyl, C(O)H, - C(O)NH 2 or any combination thereof. In some embodiments, 1-3 carbon atoms of the alkyl chain / backbone form a heterocyclic, aromatic, heteroaryl or a cycloalkyl ring, e.g. with cyclopropyl the alkyl is for example -CH 2 -CH 2 -CH(CH 2 )CH-CH 3 (2 carbon atoms of cyclopropyl within the alkyl backbone) or -CH 2 -CH 2 -C(CH 2 ) 2 -CH 3 (1 carbon atom of cyclopropyl within the alkyl backbone).

[0073] The alkyl group can be a sole substituent, or it can be a component of a larger substituent, such as in an alkoxy, alkoxyalkyl, haloalkyl, arylalkyl, alkylamino, dialkylamino, alkylamido, alkylurea, etc. Preferred alkyl groups are methyl, ethyl, and propyl, and thus halomethyl, dihalomethyl, trihalomethyl, haloethyl, dihaloethyl, trihaloethyl, halopropyl, dihalopropyl, trihalopropyl, methoxy, ethoxy, propoxy, arylmethyl, arylethyl, arylpropyl, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, methylamido, acetamido, propylamido, halomethylamido, haloethylamido, halopropylamido, methyl-urea, ethyl-urea, propyl-urea, 2, 3, or 4-CH 2 -C 6 H 4 -Cl, C(OH)(CH 3 )(Ph), etc.

[0074] As used herein, the term "aryl" refers to any aromatic ring that is directly bonded to another group and can be either substituted or unsubstituted. The aryl group can be a sole substituent, or the aryl group can be a component of a larger substituent, such as in an arylalkyl, arylamino, arylamido, etc. In some embodiments, the term aryl according to this invention, includes also heteroaryl. Exemplary aryl groups include phenyl, tolyl, xylyl, furanyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, thiazolyl, oxazolyl, isooxazolyl, pyrazolyl, imidazolyl, thiophene-yl, pyrrolyl, indolyl, benzimidazolyl, phenylmethyl, phenylethyl, indane, phenylamino, phenylamido, 3-methyl-4H-1,2,4-triazolyl, oxadiazolyl, 5-methyl-1,2,4-oxadiazolyl, isothiazolyl, thiadiazolyl, triazolyl, methylthiophene, methylfuran, methylpyridine, methylthiazole, indole, indane, benzimidazole, pyrrolopyridine, benzoxazole, 1-methylimidazole, pyrrole, furan, thiophene, oxadiazole, indane, benzodihydrofuran, tetrahydroquinoline, benzopyrrolidine, chromane, etc. Substitutions include : heteroaryl, aryl, cycloalkyl, heterocyclic ring, F, Cl, Br, I, C 1 -C 5 linear or branched alkyl, heterocyclyl, C 1 -C 5 linear or branched haloalkyl, C 1 -C 5 linear or branched alkoxy, C 1 -C 5 linear or branched haloalkoxy, CF 3 , phenyl, halophenyl, CN, NO 2 , -CH 2 CN, NH 2 , NH-alkyl, N(alkyl) 2 , hydroxyl, - OC(O)CF 3 , -OCH 2 Ph, -NHCO-alkyl, COOH, -C(O)Ph, C(O)O-alkyl, C(O)H, -C(O)NH 2 or any combination thereof. The term "arylene" or a "heteroarylene" refers to "aryl" or "heteroaryl" as described hereinabove, where the aryl or heteroaryl is directly bonded to at least two other groups, e.g. phenyl connected at the left hand side to an alkyl backbone and to halide at the left hand side, when the alkyl and halide are for example para to each other (i.e. the compound is 1-alkyl-4-halophenyl).

[0075] As used herein, the term "alkoxy" refers to an ether group substituted by an alkyl group as defined above. Alkoxy refers both to linear and to branched alkoxy groups. Examples of alkoxy groups are methoxy, ethoxy, propoxy, iso-propoxy, tert-butoxy. In some embodiments, the alkoxy may be substituted, unsubstituted, linear, branched or cyclic. In some embodiments, the alkoxy is a linear or branched C 1 -C 5 alkoxy. In some embodiments, the alkoxy is a linear or branched C 2 -C 7 alkoxy. In some embodiments, the alkoxy is a linear or branched C 2 -C 5 alkoxy. In some embodiments, the alkoxy is a cyclic C 3 -C 8 alkoxy. In some embodiments, the alkoxy is a cyclic C 5 -C 7 alkoxy.

[0076] As used herein, the term "aminoalkyl" refers to an amine group substituted by an alkyl group as defined above. Aminoalkyl refers to monoalkylamine, dialkylamine or trialkylamine. Examples of aminoalkyl groups are -N(Me) 2 , -NHMe, -NH 3 .

[0077] A "haloalkyl" group refers, in some embodiments, to an alkyl group as defined above, which is substituted by one or more halogen atoms, e.g. by F, Cl, Br or I. The term "haloalkyl" include fluoroalkyl, i.e., to an alkyl group bearing at least one fluorine atom. Examples of haloalkyl groups are CF 3 , CF 2 CF 3 , CF 2 CH 3 , CH 2 CF 3 , CF 2 CH 2 CH 3 , CH 2 CH 2 CF 3 , CF 2 CH(CH 3 ) 2 and CF(CH 3 )-CH(CH 3 ) 2 . In some embodiments, the haloalkyl may be linear, branched or cyclic. In some embodiments, the haloalkyl is a linear or branched C 1 -C 5 haloalkyl. In some embodiments, the haloalkyl is a linear or branched C 2 -C 7 haloalkyl. In some embodiments, the haloalkyl is a linear or branched C 2 -C 5 haloalkyl. In some embodiments, the haloalkyl is a cyclic C 3 -C 8 haloalkyl. In some embodiments, the haloalkyl is a cyclic C 5 -C 7 haloalkyl.

[0078] A "halophenyl" group refers, in some embodiments, to a phenyl substituent which is substituted by one or more halogen atoms, e.g. by F, Cl, Br or I. In one embodiment, the halophenyl is 4-chlorophenyl.

[0079] A "haloalkoxy" group refers, in some embodiments, to an alkoxy group as defined above, which is substituted by one or more halogen atoms, e.g. by F, Cl, Br or I. The term "haloalkoxy" include fluoroalkoxy, i.e., to an alkoxy group bearing at least one fluorine atom. Examples of haloalkoxy groups are OCF 3 , OCF 2 CF 3 , OCF 2 CH 3 , OCH 2 CF 3 , OCF 2 CH 2 CH 3 , OCH 2 CH 2 CF 3 , OCF 2 CH(CH 3 ) 2 and OCF(CH 3 )-CH(CH 3 ) 2 . In some embodiments, the haloalkoxy may be substituted, unsubstituted, linear, branched or cyclic. In some embodiments, the haloalkoxy is a linear or branched C 1 -C 5 haloalkoxy. In some embodiments, the haloalkoxy is a linear or branched C 2 -C 7 haloalkoxy. In some embodiments, the haloalkoxy is a linear or branched C 2 -C 5 haloalkoxy. In some embodiments, the haloalkoxy is a cyclic C 3 -C 8 haloalkoxy. In some embodiments, the haloalkoxy is a cyclic C 5 -C 7 haloalkoxy.

[0080] An "alkoxyalkyl" group refers, in some embodiments, to an alkyl group as defined above, which is substituted by alkoxy group as defined above, e.g. by methoxy, ethoxy, propoxy, i-propoxy, t-butoxy etc. Examples of alkoxyalkyl groups are -CH 2 -O-CH 3 , -CH 2 -O-CH(CH 3 ) 2 , -CH 2 -O-C(CH 3 ) 3 , -CH 2 -CH 2 -O-CH 3 , -CH 2 -CH 2 -O-CH(CH 3 ) 2 , -CH 2 -CH 2 -O-C(CH 3 ) 3 . In some embodiments, the alkoxyalkyl may be substituted, unsubstituted, linear, branched or cyclic. In some embodiments, the alkoxyalkyl is a linear or branched C 1 -C 5 alkoxyalkyl. In some embodiments, the alkoxyalkyl is a linear or branched C 2 -C 7 alkoxyalkyl. In some embodiments, the alkoxyalkyl is a linear or branched C 2 -C 5 alkoxyalkyl. In some embodiments, the alkoxyalkyl is a cyclic C 3 -C 8 alkoxyalkyl. In some embodiments, the alkoxyalkyl is a cyclic C 5 -C 7 alkoxyalkyl.

[0081] A "cycloalkyl" or "carbocyclic" group refers, in various embodiments, to a ring structure comprising carbon atoms as ring atoms, which may be either saturated or unsaturated, substituted or unsubstituted, single or fused. In some embodiments, the cycloalkyl is saturated. In some embodiments, the cycloalkyl is unsaturated. In some embodiments, the cycloalkyl is substituted. In some embodiments, the cycloalkyl is unsubstituted. In some embodiments, the cycloalkyl is a single ring. In some embodiments, the cycloalkyl is a fused ring system. In some embodiments, the cycloalkyl is a 3-10 membered ring. In some embodiments, the cycloalkyl is a 3-12 membered ring. In some embodiments, the cycloalkyl is a 6 membered ring. In some embodiments, the cycloalkyl is a 5-7 membered ring. In some embodiments, the cycloalkyl is a 3-8 membered ring. In some embodiments, the cycloalkyl group may be unsubstituted or substituted by a heteroaryl, aryl, cycloalkyl, heterocyclic ring, halogen, alkyl, haloalkyl, hydroxyl, alkoxy, carbonyl, amido, alkylamido, dialkylamido, cyano, nitro, CO 2 H, amino, alkylamino, dialkylamino, carboxyl, thio, thioalkyl, C 1 -C 5 linear or branched haloalkoxy, CF 3 , phenyl, halophenyl, (benzyloxy)phenyl, -CH 2 CN, NH 2 , NH-alkyl, N(alkyl) 2 , - OC(O)CF 3 , -OCH 2 Ph, -NHCO-alkyl, -C(O)Ph, C(O)O-alkyl, C(O)H, -C(O)NH 2 or any combination thereof. In some embodiments, the cycloalkyl ring may be fused to another saturated or unsaturated cycloalkyl or heterocyclic 3-8 membered ring. In some embodiments, the cycloalkyl ring is a saturated ring. In some embodiments, the cycloalkyl ring is an unsaturated ring. Examples of a cycloalkyl group comprise cyclohexyl, cyclohexenyl, cyclopropyl, cyclopropenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclobutyl, cyclobutenyl, cycloctyl, cycloctadienyl (COD), cycloctaene (COE) etc. The term "cycloalkylene" refers to "cycloalkyl" as described here on above, where the cycloalkyl is directly bonded to at least two other groups, e.g. cyclohexyl connected at the left hand side to an alkyl backbone and to halide at the left hand side, when the alkyl and halide are for example connected at the 1,4 positions.

[0082] A "heterocycle" or "heterocyclic" group refers, in various embodiments, to a ring structure comprising in addition to carbon atoms, sulfur, oxygen, nitrogen or any combination thereof, as part of the ring. A "heteroaromatic ring" refers in various embodiments, to an aromatic ring structure comprising in addition to carbon atoms, sulfur, oxygen, nitrogen or any combination thereof, as part of the ring. In some embodiments, the heterocycle or heteroaromatic ring is a 3-10 membered ring. In some embodiments, the heterocycle or heteroaromatic ring is a 3-12 membered ring. In some embodiments, the heterocycle or heteroaromatic ring is a 6 membered ring. In some embodiments, the heterocycle or heteroaromatic ring is a 5-7 membered ring. In some embodiments, the heterocycle or heteroaromatic ring is a 3-8 membered ring. In some embodiments, the heterocycle group or heteroaromatic ring may be unsubstituted or substituted by an aryl, heteroaryl, heterocyclic ring, cycloalkyl, halogen, alkyl, haloalkyl, hydroxyl, alkoxy, carbonyl, amido, alkylamido, dialkylamido, cyano, nitro, CO 2 H, amino, alkylamino, dialkylamino, carboxyl, thio, thioalkyl, C 1 -C 5 linear or branched haloalkoxy, CF 3 , phenyl, halophenyl, (benzyloxy)phenyl, -CH 2 CN, NH 2 , NH-alkyl, N(alkyl) 2 , -OC(O)CF 3 , -OCH 2 Ph, -NHCO-alkyl, -C(O)Ph, C(O)O-alkyl, C(O)H, -C(O)NH 2 or any combination thereof. In some embodiments, the heterocycle ring or heteroaromatic ring may be fused to another saturated or unsaturated cycloalkyl or heterocyclic 3-8 membered ring. In some embodiments, the heterocyclic ring is a saturated ring. In some embodiments, the heterocyclic ring is an unsaturated ring. Examples of a heterocyclic ring or heteroaromatic ring systems comprise pyridine, piperidine, morpholine, piperazine, thiophene, pyrrole, benzodioxole, benzofuran-2(3H)-one, benzo[d][1,3]dioxole, indole, oxazole, isoxazole, imidazole and 1-methylimidazole, furan, triazole, pyrimidine, pyrazine, oxacyclobutane (1 or 2-oxacyclobutane), naphthalene, tetrahydrothiophene 1,1-dioxide, thiazole, benzimidazole, piperidine, 1-methylpiperidine, isoquinoline, 1,3-dihydroisobenzofuran, benzofuran, 3-methyl-4H-1,2,4-triazole, oxadiazolyl, 5-methyl-1,2,4-oxadiazole, pyrazole, isothiazole, thiadiazole, tetrahydrofuran, oxazolone, oxazolidone, thiazolone, isothiazolinone, isoxazolidinone, imidazolidinone, pyrazolone, 2H-pyrrol-2-one, furanone, thiophenone, thiane 1,1-dioxide, triazolopyrimidine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, methylthiophene, methylfuran, methylpyridine, methylthiazole, indole, benzimidazole, pyrrolopyridine, benzoxazole, oxetane, azetidine, methyloxetane, tetrahydrofuran, methyltetrahydropyran, pyrrolidine, methylpyrrolidine, tetrahydropyran, tetrahydrothiopyran, piperidine, methylpiperidine, azepane, oxepane, 2H-Thiopyran-tetrahydro-1,1-dioxide, 1-methylimidazole, furan, thiophene, oxadiazole, indole, benzodihydrofuran, tetrahydroquinoline, tetrahydrofuran, morpholine, thiomorpholine-1,1-dioxide, piperazine, benzopyrrolidine, 2-oxopyrrolidine, 2,5-dioxopyrrolidine, 2,5-dioxoimidazolidine, chromane, or indole. The term "heterocycloalkylene" refers to "heterocyclic ring" as described here on above, where the heterocyclic ring is directly bonded to at least two other groups, e.g. piperazine connected at the left hand side to an alkyl backbone and to halide at the left hand side, when the alkyl and halide are for example connected at the 1,4 or 2,5 positions.

[0083] In some embodiments, "heterocyclic ring" according to this invention refers to substituted or unsubstituted, 3 to 12 membered, saturated, unsaturated, aliphatic or aromatic, single, fused or spiro rings, which comprise at least one heteroatom selected from: N, O or S. In some embodiments, the heterocyclic ring may be substituted, unsubstituted, saturated, unsaturated, aliphatic, aromatic, single, fused or spiro ring. In some embodiments, the heterocyclic ring may be substituted. In some embodiments, the heterocyclic ring may be unsubstituted. In some embodiments, the heterocyclic ring may be saturated. In some embodiments, the heterocyclic ring may be unsaturated. In some embodiments, the heterocyclic ring may be aliphatic. In some embodiments, the heterocyclic ring may be aromatic. In some embodiments, the heterocyclic ring may be single ring. In some embodiments, the heterocyclic ring may be fused ring. In some embodiments, the heterocyclic ring may be spiro ring. In some embodiments, the heterocyclic ring may be any combination of: substituted, unsubstituted, saturated, unsaturated, aliphatic, aromatic, single, fused or spiro ring. The heterocyclic ring(s) may be 3-12; 3-10; 3-9; 3-8; 3-7; 3-6; 3-5; 4-6; 4-7; 4-8; 4-9; 5-6; 5-7; 5-8; 5-10 or 5-9 membered ring(s). Examples of heterocyclic rings include: pyran, tetrahydropyran, pyrrazole, imidazole, furan, tetrahydrofuran, dioxane, oxetane, azetidine, pyridine, pyridazine, pyrimidine, piperidine, piperazine, triazole, oxadiazole, tetrahydrofuran (THF), piperidine, tetrahydrofurane, morpholine, thiomorpholine 1,1-dioxide, oxa-azaspirodecane, azaspiroheptane, 5-azaspiro[2.4]heptane, 2-azaspiro[3.3]heptane, oxa-azaspiroheptane, 2-oxa-6-azaspiro[3.3]heptane pyrrole, pyrrolidine, pyrrolidine-2-one, 2-oxo-pyrrolidine, pyrrolidinone, quinuclidine, oxetane, azepane, azepan-2-one, azabicyclohexane, 2-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.1.0]hexane, 1-oxa-8-azaspiro[4.5]decane, diazabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.1]heptane, thiomorpholine 1,1-dioxide. In some embodiments, the heterocyclic ring may be further substituted with at least one group selected from: F, Cl, Br, I, CF 3 , C 1 -C 5 linear or branched alkyl (e.g., methyl, ethyl, propyl), alkyleneamine (e.g., CH 2 -NH 2 ), C 1 -C 5 linear or branched haloalkyl, OH, alkoxy (e.g., OCH 3 ), alkylene-OH (e.g., CH 2 -OH), amide, alkylene-amide (e.g., CH 2 -C(O)NH 2 ), C(O)-heterocyclic ring, amine (e.g., NH 2 ), alkylamine (e.g., NH(CH 3 )), dialkylamine (e.g., N(CH 3 ) 2 ), CF 3 , aryl, phenyl, halophenyl, heteroaryl, C 3 -C 8 cycloalkyl (e.g., cyclopropyl), saturated, unsaturated, aromatic, single fused or spiral 3-8 membered heterocyclic ring, CN, and NO 2 .

[0084] In some embodiments, "single or fused saturated, unsaturated or aromatic heterocyclic ring" or "saturated, unsaturated, aromatic, single, fused or spiro heterocyclic ring" can be any such ring(s), which comprise at least one heteroatom selected from: N, O or S. The heterocyclic ring may be 3-12; 3-10; 3-9; 3-8; 3-7; 3-6; 3-5; 4-6; 4-7; 4-8; 4-9; 5-6; 5-7; 5-8; 5-10 or 5-9 membered ring(s). In some embodiments, the heterocyclic ring may be substituted. In some embodiments, the heterocyclic ring may be unsubstituted. In some embodiments, the heterocyclic ring may be saturated. In some embodiments, the heterocyclic ring may be unsaturated. In some embodiments, the heterocyclic ring may be aliphatic. In some embodiments, the heterocyclic ring may be aromatic. In some embodiments, the heterocyclic ring may be single ring. In some embodiments, the heterocyclic ring may be fused ring. In some embodiments, the heterocyclic ring may be spiro ring. In some embodiments, the heterocyclic ring may be any combination of: substituted, unsubstituted, saturated, unsaturated, aromatic, single, fused or spiro ring. Examples of such heterocyclic rings according to this invention include: pyridinyl, (2-, 3-, and 4-pyridinyl), quinolinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, 1-methylimidazole, pyrazolyl, pyrrolyl, furanyl, thiophene-yl, quinolinyl, isoquinolinyl, 2,3-dihydroindenyl, indenyl, tetrahydronaphthyl, 3,4-dihydro-2H-benzo[b][1,4]dioxepine, benzodioxolyl, benzo[d][1,3]dioxole, tetrahydronaphthyl, indolyl, 1H-indole, isoindolyl, anthracenyl, benzimidazolyl, 2,3-dihydro-1H-benzo[d]imidazolyl, indazolyl, 2H-indazole, triazolyl, 4,5,6,7-tetrahydro-2H-indazole, 3H-indol-3-one, purinyl, benzoxazolyl, 1,3-benzoxazolyl, benzisoxazolyl, benzothiazolyl, 1,3-benzothiazole, 4,5,6,7-tetrahydro-1,3-benzothiazole, quinazolinyl, quinoxalinyl, 1,2,3,4-tetrahydroquinoxaline, 1-(pyridin-1(2H)-yl)ethanone, cinnolinyl, phthalazinyl, quinolinyl, isoquinolinyl, acridinyl, benzofuranyl, 1-benzofuran, isobenzofuranyl, benzofuran-2(3H)-one, benzothiophenyl, benzoxadiazole, benzo[c][1,2,5]oxadiazolyl, benzo[c]thiophenyl, benzodioxolyl, thiadiazolyl, [1,3]oxazolo[4,5-b]pyridine, 1,2,3-, 1,2,4-, 1,2,5- or 1,3,4- oxadiazolyl, imidazo[2,1-b][1,3]thiazole, 4H,5H,6H-cyclopenta[d][1,3]thiazole, SH,6H,7H,8H-imidazo[1,2-a]pyridine, 7-oxo-6H,7H-[1,3]thiazolo[4,5-d]pyrimidine, [1,3]thiazolo[5,4-b]pyridine, 2H,3H-imidazo[2,1-b][1,3]thiazole, thieno[3,2-d]pyrimidin-4(3H)-one, 4-oxo-4H-thieno[3,2-d][1,3]thiazin, imidazo[1,2-a]pyridine, 1H-imidazo[4,5-b]pyridine, 1H-imidazo[4,5-c]pyridine, 3H-imidazo[4,5-c]pyridine, pyrazolo[1,5-a]pyridine, imidazo[1,2-a]pyrazine, imidazo[1,2-a]pyrimidine, 1H-pyrrolo[2,3-blpyridine, pyrido[2,3-b]pyrazine, pyrido[2,3-b]pyrazin-3(4H)-one, 4H-thieno[3,2-b]pyrrole, quinoxalin-2(1H)-one, 1H-pyrrolo[3,2-b]pyridine, 7H-pyrrolo[2,3-d]pyrimidine, oxazolo[5,4-b]pyridine, thiazolo[5,4-b]pyridine, thieno[3,2-c]pyridine, 3-methyl-4H-1,2,4-triazole, 5-methyl-1,2,4-oxadiazole etc. In some embodiments, the heterocyclic ring according to this invention includes: pyran, tetrahydropyran, pyrrazole, imidazole, furan, tetrahydrofuran, dioxane, oxetane, azetidine, pyridine, pyridazine, pyrimidine, piperidine, piperazine, triazole, oxadiazole, tetrahydrofuran (THF), piperidine, tetrahydrofurane, morpholine, thiomorpholine 1,1-dioxide, oxa-azaspirodecane, azaspiroheptane, 5-azaspiro[2.4]heptane, 2-azaspiro[3.3]heptane, oxa-azaspiroheptane, pyrrol, pyrrolidine, pyrrolidine-2-one, 2-oxo-pyrrolidine, pyrrolidinone, quinuclidine, oxetane, azepane, azepan-2-one, azabicyclohexane, 2-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.1.0]hexane, 1-oxa-8-azaspiro[4.5]decane, and / or diazabicyclo[2.2.1]heptane. In some embodiments, the heterocyclic ring may be further substituted with at least one group selected from: F, Cl, Br, I, CF 3 , C 1 -C 5 linear or branched alkyl (e.g., methyl, ethyl, propyl), alkyleneamine (e.g., CH 2 -NH 2 ), C 1 -C 5 linear or branched haloalkyl, OH, alkoxy (e.g., OCH 3 ), alkylene-OH (e.g., CH 2 -OH), amide, alkylene-amide (e.g., CH 2 -C(O)NH 2 ), C(O)-heterocyclic ring, amine (e.g., NH 2 ), alkylamine (e.g., NH(CH 3 )), dialkylamine (e.g., N(CH 3 ) 2 ), CF 3 , aryl, phenyl, halophenyl, heteroaryl, C 3 -C 8 cycloalkyl (e.g., cyclopropyl), saturated, unsaturated, aromatic, single fused or spiral 3-8 membered heterocyclic ring, CN, and NO 2 .

[0085] In some embodiments, when a chemical term / group (e.g. alkyl, aryl, heteroaryl, cycloalkyl, amino, alkoxy, etc.) is said to be substituted, examples of the substituent or substituents include the following: F, Cl, Br, I, OH, SH, diazirine, C 1 -C 5 linear alkyne, C 1 -C 5 linear or branched alkyl, aryl (e.g., phenyl, fluorophenyl), heteroaryl (e.g., pyridine (2, 3, and 4-pyridine), thiophene, indole, tetrahydropyran), cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl), heterocyclic ring, alkoxy (e.g. methoxy, ethoxy, propyloxy, isopropyloxy), C 1 -C 5 linear, cyclic or branched alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl or cyclopropyl), OH, alkoxy, NH 2 , N(alkyl) 2 (e.g. N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 , N(CH 3 )(CH 2 CH 3 )), NH(alkyl) (e.g. NHCH 3 , NHCH 2 CH 3 , NHCH 2 CH 2 CH 3 ) NH(cycloalkyl) (e.g. NH(cyclohexyl), NH(cyclopentyl)), NH(aryl) (e.g. NH(phenyl), NH(pyridinyl)), NH(benzyl), N(cycloalkyl) 2 (e.g. N(cyclohexyl) 2 , N(cyclopentyl) 2 ), N(aryl) 2 (e.g. N(phenyl) 2 , N(pyridinyl) 2 ), N(alkyl)(aryl) (e.g. N(methyl)(phenyl), N(methyl)(pyridinyl)), N(alkyl)(cycloalkyl) (e.g. N(methyl)(cyclopropyl), N(methyl)(cyclohexyl), N(methyl)(cyclopentyl)), N(aryl)(cycloalkyl) (e.g. N(phenyl)(cyclohexyl), N(pyridinyl)(cyclohexyl)) NHC(O)(alkyl) (e.g. NHC(O)CH 3 ), CF 3 , phenyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 , haloalkyl, carbonyl, amido, alkylamido, dialkylamido, CO 2 H, carboxyl, thio, thioalkyl, C 1 -C 5 linear or branched haloalkoxy, CF 3 , phenyl, (benzyloxy)phenyl, -CH 2 CN, -OC(O)CF 3 , -OCH 2 Ph, -NHCO-alkyl, -C(O)Ph, C(O)O-alkyl, C(O)H, -C(O)NH 2 , substituted or unsubstituted benzyl (e.g., benzyl, methylbenzyl), oxo (i.e. =O, forming with the substituted carbon a carbonyl), haloalkyl (e.g. CF 3 , CH 2 CF 3 ), cycloalkyl (e.g. cyclopropyl), C 1 -C 5 linear or branched haloalkoxy (e.g., OCF 3 , OCHF 2 ), 3-8 membered heterocyclic ring (e.g., piperidine), C 1 -C 5 linear or branched alkoxyalkyl (e.g. CH 3 OCH 2 ), C 1 -C 5 linear or branched alkyl-OH (e.g., C(CH 3 ) 2 CH 2 -OH, CH 2 CH 2 -OH), or any combination thereof

[0086] In various embodiments, this invention provides a compound of this invention or its optical isomer, pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, N-oxide, or crystal or combinations thereof. In various embodiments, this invention provides an optical isomer of the compound of this invention. In some embodiments, this invention provides a pharmaceutically acceptable salt of the compound of this invention. In some embodiments, this invention provides a pharmaceutical product of the compound of this invention. In some embodiments, this invention provides a tautomer of the compound of this invention. In some embodiments, this invention provides a hydrate of the compound of this invention. In some embodiments, this invention provides an N-oxide of the compound of this invention. In some embodiments, this invention provides a crystal of the compound of this invention. In some embodiments, the composition is a combination of an optical isomer, pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, N-oxide, or crystal of the compound of this invention.

[0087] In various embodiments, this invention encompasses the use of various stereoisomers of the compounds of the invention. It will be appreciated by those skilled in the art that the compounds of the present invention may contain at least one chiral center. Accordingly, the compounds used in the present invention may exist in, and be isolated in, optically-active or racemic forms. The compounds according to this invention may further exist as stereoisomers which may be also optically-active isomers (e.g., enantiomers such as (R) or (S)), as enantiomerically enriched mixtures, racemic mixtures, or as single diastereomers, diastereomeric mixtures, or any other stereoisomers: (R)(R), (R)(S), (S)(S), (S)(R), (R)(R)(R), (R)(R)(S), (R)(S)(R), (S)(R)(R), (R)(S)(S), (S)(R)(S), (S)(S)(R) or (S)(S)(S) stereoisomers. It is to be understood that the present invention encompasses any racemic, optically-active, or stereoisomeric form, or mixtures thereof, which form possesses properties useful in the treatment of the various conditions described herein.

[0088] It is well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase).

[0089] The compounds of the present invention can also be present in the form of a racemic mixture, containing substantially equivalent amounts of stereoisomers. In some embodiments, the compounds of the present invention can be prepared or otherwise isolated, using known procedures, to obtain a stereoisomer substantially free of its corresponding stereoisomer (i.e., substantially pure). By substantially pure, it is intended that a stereoisomer is at least about 90% pure, more preferably at least about 95% pure, even more preferably at least about 98% pure, most preferably at least about 99% pure. In various embodiments, the compound according to the invention comprises a substantially pure stereoisomer. In some embodiments, the substantially pure stereoisomer is at least 70%; 75%; 80%; 85%; 90%; 93%; 95%; 97%; 98%; 99%; 99.5% pure.

[0090] In various embodiments, the compound comprises a single stereoisomer in a purity of >80%; >85%; >90%; >91%; >92%; >93%; >94%; >95%; >96%; >97%; >98%; >99%; >99.5% enantiomeric excess (ee). In various embodiments, the compound comprises a single stereoisomer in a purity >80%; >85%; >90%; >91%; >92%; >93%; >94%; >95%; >96%; >97%; >98%; >99%; >99.5% enantiomeric ratio (er). In various embodiments, the compound comprises a single stereoisomer in a purity higher than 80%; 85%; 90%; 91%; 92%; 93%; 94%; 95%; 96%; 97%; 98%; 99%; 99.5%. In some embodiments, the compound is compound 369, 392, 412, 413, 414, 415, 422, 433, 434, 464, 465, 466, 467, 468, 470, 471, 474 or 475.

[0091] In various embodiments, the compound is a substantially pure single enantiomer. In various embodiments, the compound comprises a mixture of enantiomers. In various embodiments, the compound is a racemate.

[0092] In various embodiments, the compound has two chiral centers. In various embodiments, the compound comprises a mixture of stereoisomers. In various embodiments, the compound comprises a mixture of 2, 3, or 4 stereoisomers. In various embodiments, the compound is a single stereoisomer. In various embodiments, the compound is a substantially pure single stereoisomer. In various embodiments, the substantially pure stereoisomer has at least 80%, 85%, 90%, 95%, 97%, 98%, 99% purity. In various embodiments, the compound is the substantially pure RR stereoisomer. In various embodiments, the compound is the substantially pure SS stereoisomer. In various embodiments, the compound is the substantially pure RS stereoisomer. In various embodiments, the compound is the substantially pure SR stereoisomer.

[0093] Compounds of the present invention can also be in the form of a hydrate, which means that the compound further includes a stoichiometric or non-stoichiometric amount of water bound by noncovalent intermolecular forces.

[0094] As used herein, when some chemical functional group (e.g., alkyl or aryl) is said to be "substituted", it is herein defined that one or more substitutions are possible.

[0095] Compounds of the present invention may exist in the form of one or more of the possible tautomers and depending on the conditions it may be possible to separate some or all of the tautomers into individual and distinct entities. It is to be understood that all of the possible tautomers, including all additional enol and keto tautomers and / or isomers are hereby covered. For example, the following tautomers are included: Tautomerization of the imidazole ring Tautomerization of the pyrazolone ring:

[0096] The invention includes "pharmaceutically acceptable salts" of the compounds of this invention, which may be produced, by reaction of a compound of this invention with an acid or base. Certain compounds, particularly those possessing acid or basic groups, can also be in the form of a salt, preferably a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" refers to those salts that retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxylic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine and the like. Other salts are known to those of skill in the art and can readily be adapted for use in accordance with the present invention.

[0097] Suitable pharmaceutically acceptable salts of amines of compounds the compounds of this invention may be prepared from an inorganic acid or from an organic acid. In various embodiments, examples of inorganic salts of amines are bisulfates, borates, bromides, chlorides, hemisulfates, hydrobromates, hydrochlorates, 2-hydroxyethylsulfonates (hydroxyethanesulfonates), iodates, iodides, isothionates, nitrates, persulfates, phosphate, sulfates, sulfamates, sulfanilates, sulfonic acids (alkylsulfonates, arylsulfonates, halogen substituted alkylsulfonates, halogen substituted arylsulfonates), sulfonates and thiocyanates.

[0098] In various embodiments, examples of organic salts of amines may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are acetates, arginines, aspartates, ascorbates, adipates, anthranilates, algenates, alkane carboxylates, substituted alkane carboxylates, alginates, benzenesulfonates, benzoates, bisulfates, butyrates, bicarbonates, bitartrates, citrates, camphorates, camphorsulfonates, cyclohexylsulfamates, cyclopentanepropionates, calcium edetates, camsylates, carbonates, clavulanates, cinnamates, dicarboxylates, digluconates, dodecylsulfonates, dihydrochlorides, decanoates, enanthuates, ethanesulfonates, edetates, edisylates, estolates, esylates, fumarates, formates, fluorides, galacturonates gluconates, glutamates, glycolates, glucorate, glucoheptanoates, glycerophosphates, gluceptates, glycollylarsanilates, glutarates, glutamate, heptanoates, hexanoates, hydroxymaleates, hydroxycarboxlic acids, hexylresorcinates, hydroxybenzoates, hydroxynaphthoates, hydrofluorates, lactates, lactobionates, laurates, malates, maleates, methylenebis(beta-oxynaphthoate), malonates, mandelates, mesylates, methane sulfonates, methylbromides, methylnitrates, methylsulfonates, monopotassium maleates, mucates, monocarboxylates, naphthalenesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, napsylates, N-methylglucamines, oxalates, octanoates, oleates, pamoates, phenylacetates, picrates, phenylbenzoates, pivalates, propionates, phthalates, phenylacetate, pectinates, phenylpropionates, palmitates, pantothenates, polygalacturates, pyruvates, quinates, salicylates, succinates, stearates, sulfanilate, subacetates, tartrates, theophyllineacetates, p-toluenesulfonates (tosylates), trifluoroacetates, terephthalates, tannates, teoclates, trihaloacetates, triethiodide, tricarboxylates, undecanoates and valerates.

[0099] In various embodiments, examples of inorganic salts of carboxylic acids or hydroxyls may be selected from ammonium, alkali metals to include lithium, sodium, potassium, cesium; alkaline earth metals to include calcium, magnesium, aluminium; zinc, barium, cholines, quaternary ammoniums.

[0100] In some embodiments, examples of organic salts of carboxylic acids or hydroxyl may be selected from arginine, organic amines to include aliphatic organic amines, alicyclic organic amines, aromatic organic amines, benzathines, t-butylamines, benethamines (N-benzylphenethylamine), dicyclohexylamines, dimethylamines, diethanolamines, ethanolamines, ethylenediamines, hydrabamines, imidazoles, lysines, methylamines, meglamines, N-methyl-D-glucamines, N,N'-dibenzylethylenediamines, nicotinamides, organic amines, ornithines, pyridines, picolies, piperazines, procain, tris(hydroxymethyl)methylamines, triethylamines, triethanolamines, trimethylamines, tromethamines and ureas.

[0101] In various embodiments, the salts may be formed by conventional means, such as by reacting the free base or free acid form of the product with one or more equivalents of the appropriate acid or base in a solvent or medium in which the salt is insoluble or in a solvent such as water, which is removed in vacuo or by freeze drying or by exchanging the ions of an existing salt for another ion or suitable ionexchange resin.Pharmaceutical composition

[0102] The present invention provides a pharmaceutical composition including a pharmaceutically acceptable carrier and a compound according to the aspects of the present invention. The pharmaceutical composition can contain one or more of the above-identified compounds of the present invention. Typically, the pharmaceutical composition of the present invention will include a compound of the present invention or its pharmaceutically acceptable salt, as well as a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" refers to any suitable adjuvants, carriers, excipients, or stabilizers, and can be in solid or liquid form such as, tablets, capsules, powders, solutions, suspensions, or emulsions.

[0103] Typically, the composition will contain from about 0.01 to 99 percent, preferably from about 20 to 75 percent of active compound(s), together with the adjuvants, carriers and / or excipients. While individual needs may vary, determination of optimal ranges of effective amounts of each component is within the skill of the art. Typical dosages comprise about 0.01 to about 100 mg / kg body wt. The preferred dosages comprise about 0.1 to about 100 mg / kg body wt. The most preferred dosages comprise about 1 to about 100 mg / kg body wt. Treatment regimen for the administration of the compounds of the present invention can also be determined readily by those with ordinary skill in art. That is, the frequency of administration and size of the dose can be established by routine optimization, preferably while minimizing any side effects.

[0104] The solid unit dosage forms can be of the conventional type. The solid form can be a capsule and the like, such as an ordinary gelatin type containing the compounds of the present invention and a carrier, for example, lubricants and inert fillers such as, lactose, sucrose, or cornstarch. In some embodiments, these compounds are tabulated with conventional tablet bases such as lactose, sucrose, or cornstarch in combination with binders like acacia, cornstarch, or gelatin, disintegrating agents, such as cornstarch, potato starch, or alginic acid, and a lubricant, like stearic acid or magnesium stearate.

[0105] The tablets, capsules, and the like can also contain a binder such as gum tragacanth, acacia, corn starch, or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose, or saccharin. When the dosage unit form is a capsule, it can contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

[0106] Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets can be coated with shellac, sugar, or both. A syrup can contain, in addition to active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye, and flavoring such as cherry or orange flavor.

[0107] For oral therapeutic administration, these active compounds can be incorporated with excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compound in these compositions can, of course, be varied and can conveniently be between about 2% to about 60% of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained. Preferred compositions according to the present invention are prepared so that an oral dosage unit contains between about 1 mg and 800 mg of active compound.

[0108] The active compounds of the present invention may be orally administered, for example, with an inert diluent, or with an assimilable edible carrier, or they can be enclosed in hard- or soft-shell capsules, or they can be compressed into tablets, or they can be incorporated directly with the food of the diet.

[0109] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form should be sterile and should be fluid to the extent that easy syringability exists. It should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0110] The compounds or pharmaceutical compositions of the present invention may also be administered in injectable dosages by solution or suspension of these materials in a physiologically acceptable diluent with a pharmaceutical adjuvant, carrier or excipient. Such adjuvants, carriers and / or excipients include sterile liquids, such as water and oils, with or without the addition of a surfactant and other pharmaceutically and physiologically acceptable components. Illustrative oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, or mineral oil. In general, water, saline, aqueous dextrose and related sugar solution, and glycols, such as propylene glycol or polyethylene glycol, are preferred liquid carriers, particularly for injectable solutions.

[0111] These active compounds may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Illustrative oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, or mineral oil. In general, water, saline, aqueous dextrose and related sugar solution, and glycols such as, propylene glycol or polyethylene glycol, are preferred liquid carriers, particularly for injectable solutions. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

[0112] For use as aerosols, the compounds of the present invention in solution or suspension may be packaged in a pressurized aerosol container together with suitable propellants, for example, hydrocarbon propellants like propane, butane, or isobutane with conventional adjuvants. The materials of the present invention also may be administered in a non-pressurized form such as in a nebulizer or atomizer.

[0113] In various embodiments, the compounds of this invention are administered in combination with an anti-cancer therapy. Examples of such therapies include: chemotherapy, immunotherapy, radiotherapy, biological therapy, surgical intervention, and combinations thereof. In various embodiments, the compound is administered in combination with an anti-cancer agent by administering the compounds as herein described, alone or in combination with other agents.

[0114] When administering the compounds of the present invention, they can be administered systemically or, alternatively, they can be administered directly to a specific site where cancer is present. Thus, administering can be accomplished in any manner effective for delivering the compounds or the pharmaceutical compositions to the cancerous cells. Exemplary modes of administration include administering the compounds or compositions orally, topically, transdermally, parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, intraocularly, intraarterially, intralesionally, or by application to mucous membranes, such as, that of the nose, throat, and bronchial tubes.Biological Activity

[0115] In various embodiments, the invention provides compounds and compositions, including any embodiment described herein, for use as a medicament. In various embodiments, use of a compound of this invention or a composition comprising the same, will have utility in inhibiting, suppressing, enhancing, or stimulating a desired response in a subject, as will be understood by one skilled in the art. In some embodiments, the compositions may further comprise additional active ingredients, whose activity is useful for the particular application for which the compound of this invention is being administered.

[0116] The invention relates to the treatment, inhibition, and reduction of cancer, employing the use of a compound according to this invention or a pharmaceutically acceptable salt thereof. Accordingly, in various embodiments, the compounds of this invention are useful in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting cancer in a subject. In some embodiments, the compound is a c-Myc mRNA translation modulator. In some embodiments, the compound is a c-Myc mRNA translation inhibitor. In some embodiments, the compound is a c-Myc inhibitor. In some embodiments, the compound is a c-Myc mRNA transcription regulator. In some embodiments, the compound is any combination of a c-Myc mRNA transcription regulator, a c-Myc mRNA transcription regulator and a c-Myc inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1. In some embodiments, the cancer is early cancer. In some embodiments, the cancer is advanced cancer. In some embodiments, the cancer is invasive cancer. In some embodiments, the cancer is metastatic cancer. In some embodiments, the cancer is drug resistant cancer.

[0117] In some embodiments, the cancer is selected from: bladder cancer (urothelial carcinoma), myelodysplasia, breast cancer, cervix cancer, endometrium cancer, esophagus cancer, head and neck cancer (squamous cell carcinoma), kidney cancer (e.g., renal cell carcinoma, clear cell renal cell carcinoma), liver cancer (hepatocellular carcinoma), lung cancer (e.g., metastatic, non-small cell, NSCLC, squamous cell carcinoma, small cell (SCLC)), metastatic cancer (e.g., to brain), nasopharynx cancer, solid tumor cancer, stomach cancer, adrenocortical carcinoma, Glioblastoma multiforme, acute myeloid leukemia, chronic lymphocytic leukemia, lymphoma (e.g., Hodgkin's (classical), diffuse large B-cell, primary central nervous system), malignant melanoma, uveal melanoma, meningioma, multiple myeloma, breast cancer, metastatic breast cancer, anus cancer (e.g. squamous cell), biliary cancer, bladder cancer, muscle invasive urothelial carcinoma, colorectal cancer, metastatic colorectal cancer, fallopian tube cancer, gastroesophageal junction cancer (e.g., adenocarcinoma), larynx cancer (e.g., squamous cell), Merkel cell cancer, mouth cancer, ovary cancer (e.g., epithelial), pancreas cancer (e.g., adenocarcinoma, metastatic), penis cancer (e.g., squamous cell carcinoma), peritoneum cancer, prostate cancer (e.g., castration-resistant, metastatic), rectum cancer, skin cancer (e.g., basal cell carcinoma, squamous cell carcinoma), small intestine cancer (e.g., adenocarcinoma), testicular cancer, thymus cancer, anaplastic thyroid cancer, cholangiocarcinoma, chordoma, cutaneous T-cell lymphoma, digestive-gastrointestinal cancer, familial pheochromocytoma-paraganglioma, Glioma, HTLV-1-associated adult T-cell leukemia-lymphoma, hematologic-blood cancer, hepatitis C (HCV), papillomaviral respiratory Infection, uterine leiomyosarcoma, acute lymphocytic leukemia, chronic myeloid leukemia, T-cell Lymphoma, follicular lymphoma, primary mediastinal large B-cell lymphoma, diffuse large B-cell testicular lymphoma, melanoma, malignant mesothelioma, pleural mesothelioma, mycosis fungoides, neuroendocrine cancer, oral epithelial dysplasia, Sarcoma, severe sepsis, sezary syndrome, smoldering myeloma, soft tissue sarcoma, nasal natural killer (NK) cell T-cell lymphoma, peripheral T-cell lymphoma.

[0118] In some embodiments, the cancer is selected from: breast cancer, ovarian carcinoma, acute myeloid leukemia, chronic myelogenous leukemia, Hodgkin's and Burkitt's lymphoma, diffuse large Bcell lymphoma, prostate cancer, colon cancer, gastric cancer, primary central nervous system lymphoma, glioblastoma, medulloblastoma, melanoma, non-small cell lung carcinoma, germinal center-derived lymphomas, esophageal squamous cell carcinoma, osteosarcoma, bladder cancer, pancreatic cancer, lung adenocarcinoma, BRAF V600E thyroid cancer, choroid plexus carcinoma, colitis-associated cancer, epithelial ovarian cancer, colorectal cancer, pancreatic cancer or uterine cancer.

[0119] In some embodiments, the cancer may be selected from solid tumors and non-solid tumors.

[0120] In various embodiments, the compounds of this invention are useful in suppressing, reducing or inhibiting tumor growth in a subject.

[0121] In some embodiments, the tumor may be a solid tumor or a non-solid tumor.

[0122] In some embodiments, the solid tumor cancer is selected from : breast cancer, ovarian carcinoma, prostate cancer, colon cancer, gastric cancer, glioblastoma, medulloblastoma, melanoma, non-small cell lung carcinoma, esophageal squamous cell carcinoma, osteosarcoma, bladder cancer, pancreatic cancer, lung adenocarcinoma, BRAF V600E thyroid cancer, choroid plexus carcinoma, colitis-associated cancer, epithelial ovarian cancer, colorectal cancer, pancreatic cancer or uterine cancer.

[0123] In some embodiments, the non-solid tumors include: hematological malignancies including leukemia, lymphoma or myeloma and inherited cancers such as retinoblastoma and Wilm's tumor.

[0124] In some embodiments, the non-solid tumor cancer is selected from : acute myeloid leukemia, chronic myelogenous leukemia, Hodgkin's and Burkitt's lymphoma, diffuse large Bcell lymphoma, primary central nervous system lymphoma, glioblastoma, medulloblastoma, germinal center-derived lymphomas, myeloma, retinoblastoma or Wilm's tumor.

[0125] Therefore, and in various embodiments, the compounds of this invention are useful in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting cancer. In some embodiments, the cancer is early cancer. In some embodiments, the cancer is advanced cancer. In some embodiments, the cancer is invasive cancer. In some embodiments, the cancer is metastatic cancer. In some embodiments, the cancer is drug resistant cancer. In some embodiments, the compound is a c-Myc mRNA translation modulator. In some embodiments, the compound is a c-Myc mRNA translation inhibitor. In some embodiments, the compound is a c-Myc mRNA transcription regulator. In some embodiments, the compound is selective to c-Myc. In some embodiments, the compound reduces the amount of c-Myc protein in a cell. In some embodiments, the compound is any one of the compounds listed in Table 1.

[0126] In various embodiments, the compounds of this invention are useful in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting breast cancer. In some embodiments, the breast cancer is early breast cancer. In some embodiments, the breast cancer is advanced breast cancer. In some embodiments, the breast cancer is invasive breast cancer. In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, the breast cancer is drug resistant breast cancer. In some embodiments, the compound is a c-Myc mRNA translation modulator. In some embodiments, the compound is a c-Myc mRNA translation inhibitor. In some embodiments, the compound is a c-Myc mRNA transcription regulator. In some embodiments, the compound is selective to c-Myc. In some embodiments, the compound reduces the amount of c-Myc protein in a cell. In some embodiments, the compound is any one of the compounds listed in Table 1.

[0127] In various embodiments, the compounds of this invention are useful in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting ovarian carcinoma. In some embodiments, the ovarian carcinoma is advanced ovarian carcinoma. In some embodiments, the ovarian carcinoma is invasive ovarian carcinoma. In some embodiments, the ovarian carcinoma is metastatic ovarian carcinoma. In some embodiments, the ovarian carcinoma is drug resistant ovarian carcinoma. In some embodiments, the compound is a c-Myc mRNA translation modulator. In some embodiments, the compound is a c-Myc mRNA translation inhibitor. In some embodiments, the compound is a c-Myc mRNA transcription regulator. In some embodiments, the compound is selective to c-Myc. In some embodiments, the compound reduces the amount of c-Myc protein in a cell. In some embodiments, the compound is any one of the compounds listed in Table 1.

[0128] In various embodiments, the compounds of this invention are useful in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting acute myeloid leukemia. In some embodiments, the acute myeloid leukemia is early acute myeloid leukemia. In some embodiments, the acute myeloid leukemia is advanced acute myeloid leukemia. In some embodiments, the acute myeloid leukemia is invasive acute myeloid leukemia. In some embodiments, the acute myeloid leukemia is metastatic acute myeloid leukemia. In some embodiments, the acute myeloid leukemia is drug resistant acute myeloid leukemia. In some embodiments, the compound is a c-Myc mRNA translation modulator. In some embodiments, the compound is a c-Myc mRNA translation inhibitor. In some embodiments, the compound is a c-Myc mRNA transcription regulator. In some embodiments, the compound is selective to c-Myc. In some embodiments, the compound reduces the amount of c-Myc protein in a cell. In some embodiments, the compound is any one of the compounds listed in Table 1.

[0129] In various embodiments, the compounds of this invention are useful in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting chronic myelogenous leukemia. In some embodiments, the chronic myelogenous leukemia is early chronic myelogenous leukemia. In some embodiments, the chronic myelogenous leukemia is advanced chronic myelogenous leukemia. In some embodiments, the chronic myelogenous leukemia is invasive chronic myelogenous leukemia. In some embodiments, the chronic myelogenous leukemia is metastatic chronic myelogenous leukemia. In some embodiments, the chronic myelogenous leukemia is drug resistant chronic myelogenous leukemia. In some embodiments, the compound is a c-Myc mRNA translation modulator. In some embodiments, the compound is a c-Myc mRNA translation inhibitor. In some embodiments, the compound is a c-Myc mRNA transcription regulator. In some embodiments, the compound is selective to c-Myc. In some embodiments, the compound reduces the amount of c-Myc protein in a cell. In some embodiments, the compound is any one of the compounds listed in Table 1.

[0130] In various embodiments, the compounds of this invention are useful in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting Hodgkin's and / or Burkitt's lymphoma. In some embodiments, the Hodgkin's and / or Burkitt's lymphoma is early Hodgkin's and / or Burkitt's lymphoma. In some embodiments, the Hodgkin's and / or Burkitt's lymphoma is advanced Hodgkin's and / or Burkitt's lymphoma. In some embodiments, the Hodgkin's and / or Burkitt's lymphoma is invasive Hodgkin's and / or Burkitt's lymphoma. In some embodiments, the cancer is metastatic Hodgkin's and / or Burkitt's lymphoma. In some embodiments, the Hodgkin's and / or Burkitt's lymphoma is drug resistant Hodgkin's and / or Burkitt's lymphoma. In some embodiments, the compound is a c-Myc mRNA translation modulator. In some embodiments, the compound is a c-Myc mRNA translation inhibitor. In some embodiments, the compound is a c-Myc mRNA transcription regulator. In some embodiments, the compound is selective to c-Myc. In some embodiments, the compound reduces the amount of c-Myc protein in a cell. In some embodiments, the compound is any one of the compounds listed in Table 1.

[0131] In various embodiments, the compounds of this invention are useful in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting diffuse large Bcell lymphoma. In some embodiments, the diffuse large Bcell lymphoma is early diffuse large Bcell lymphoma. In some embodiments, the diffuse large Bcell lymphoma is advanced diffuse large Bcell lymphoma. In some embodiments, the diffuse large Bcell lymphoma is invasive diffuse large Bcell lymphoma. In some embodiments, the diffuse large Bcell lymphoma is metastatic diffuse large Bcell lymphoma. In some embodiments, the diffuse large Bcell lymphoma is drug resistant diffuse large Bcell lymphoma. In some embodiments, the compound is a c-Myc mRNA translation modulator. In some embodiments, the compound is a c-Myc mRNA translation inhibitor. In some embodiments, the compound is a c-Myc mRNA transcription regulator. In some embodiments, the compound is selective to c-Myc. In some embodiments, the compound reduces the amount of c-Myc protein in a cell. In some embodiments, the compound is any one of the compounds listed in Table 1.

[0132] In various embodiments, the compounds of this invention are useful in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting prostate cancer. In some embodiments, the prostate cancer is early prostate cancer. In some embodiments, the prostate cancer is advanced prostate cancer. In some embodiments, the prostate cancer is invasive prostate cancer. In some embodiments, the prostate cancer is metastatic prostate cancer. In some embodiments, the prostate cancer is drug resistant prostate cancer. In some embodiments, the compound is a c-Myc mRNA translation modulator. In some embodiments, the compound is a c-Myc mRNA translation inhibitor. In some embodiments, the compound is a c-Myc mRNA transcription regulator. In some embodiments, the compound is selective to c-Myc. In some embodiments, the compound reduces the amount of c-Myc protein in a cell. In some embodiments, the compound is any one of the compounds listed in Table 1.

[0133] In various embodiments, the compounds of this invention are useful in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting colon cancer. In some embodiments, the colon cancer is early colon cancer. In some embodiments, the colon cancer is advanced colon cancer. In some embodiments, the colon cancer is invasive colon cancer. In some embodiments, the colon cancer is metastatic colon cancer. In some embodiments, the colon cancer is drug resistant colon cancer. In some embodiments, the compound is a c-Myc mRNA translation modulator. In some embodiments, the compound is a c-Myc mRNA translation inhibitor. In some embodiments, the compound is a c-Myc mRNA transcription regulator. In some embodiments, the compound is selective to c-Myc. In some embodiments, the compound reduces the amount of c-Myc protein in a cell. In some embodiments, the compound is any one of the compounds listed in Table 1.

[0134] In various embodiments, the compounds of this invention are useful in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting gastric cancer. In some embodiments, the gastric cancer is early gastric cancer. In some embodiments, the gastric cancer is advanced gastric cancer. In some embodiments, the gastric cancer is invasive gastric cancer. In some embodiments, the gastric cancer is metastatic gastric cancer. In some embodiments, the gastric cancer is drug resistant gastric cancer. In some embodiments, the compound is a c-Myc mRNA translation modulator. In some embodiments, the compound is a c-Myc mRNA translation inhibitor. In some embodiments, the compound is a c-Myc mRNA transcription regulator. In some embodiments, the compound is selective to c-Myc. In some embodiments, the compound reduces the amount of c-Myc protein in a cell. In some embodiments, the compound is any one of the compounds listed in Table 1.

[0135] In various embodiments, the compounds of this invention are useful in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting lymphoma. In some embodiments, the lymphoma is early lymphoma. In some embodiments, the lymphoma is advanced lymphoma. In some embodiments, the lymphoma is invasive lymphoma. In some embodiments, the lymphoma is metastatic lymphoma. In some embodiments, the lymphoma is drug resistant lymphoma. In some embodiments, the lymphoma is primary central nervous system lymphoma. In some embodiments, the lymphoma is germinal center-derived lymphoma. In some embodiments, the lymphoma is Hodgkin's lymphoma. In some embodiments, the lymphoma is Burkitt's lymphoma. In some embodiments, the lymphoma is diffuse large B-cell lymphoma. In some embodiments, the compound is a c-Myc mRNA translation modulator. In some embodiments, the compound is a c-Myc mRNA translation inhibitor. In some embodiments, the compound is a c-Myc mRNA transcription regulator. In some embodiments, the compound is selective to c-Myc. In some embodiments, the compound reduces the amount of c-Myc protein in a cell. In some embodiments, the compound is any one of the compounds listed in Table 1.

[0136] In various embodiments, the compounds of this invention are useful in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting glioblastoma. In some embodiments, the glioblastoma is early glioblastoma. In some embodiments, the glioblastoma is advanced glioblastoma. In some embodiments, the glioblastoma is invasive glioblastoma. In some embodiments, the glioblastoma is metastatic glioblastoma. In some embodiments, the glioblastoma is drug resistant glioblastoma. In some embodiments, the compound is a c-Myc mRNA translation modulator. In some embodiments, the compound is a c-Myc mRNA translation inhibitor. In some embodiments, the compound is a c-Myc mRNA transcription regulator. In some embodiments, the compound is selective to c-Myc. In some embodiments, the compound reduces the amount of c-Myc protein in a cell. In some embodiments, the compound is any one of the compounds listed in Table 1.

[0137] In various embodiments, the compounds of this invention are useful in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting medulloblastoma. In some embodiments, the medulloblastoma is early medulloblastoma. In some embodiments, the medulloblastoma is advanced medulloblastoma. In some embodiments, the medulloblastoma is invasive medulloblastoma. In some embodiments, the medulloblastoma is metastatic medulloblastoma. In some embodiments, the medulloblastoma is drug resistant medulloblastoma. In some embodiments, the compound is a c-Myc mRNA translation modulator. In some embodiments, the compound is a c-Myc mRNA translation inhibitor. In some embodiments, the compound is a c-Myc mRNA transcription regulator. In some embodiments, the compound is selective to c-Myc. In some embodiments, the compound reduces the amount of c-Myc protein in a cell. In some embodiments, the compound is any one of the compounds listed in Table 1.

[0138] In various embodiments, the compounds of this invention are useful in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting melanoma. In some embodiments, the melanoma is early melanoma. In some embodiments, the melanoma is advanced melanoma. In some embodiments, the melanoma is invasive melanoma. In some embodiments, the melanoma is metastatic melanoma. In some embodiments, the melanoma is drug resistant melanoma. In some embodiments, the compound is a c-Myc mRNA translation modulator. In some embodiments, the compound is a c-Myc mRNA translation inhibitor. In some embodiments, the compound is a c-Myc mRNA transcription regulator. In some embodiments, the compound is selective to c-Myc. In some embodiments, the compound reduces the amount of c-Myc protein in a cell. In some embodiments, the compound is any one of the compounds listed in Table 1.

[0139] In various embodiments, the compounds of this invention are useful in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting non-small cell lung carcinoma. In some embodiments, the non-small cell lung carcinoma is early non-small cell lung carcinoma. In some embodiments, the non-small cell lung carcinoma is advanced non-small cell lung carcinoma. In some embodiments, the non-small cell lung carcinoma is invasive non-small cell lung carcinoma. In some embodiments, the non-small cell lung carcinoma is metastatic non-small cell lung carcinoma. In some embodiments, the non-small cell lung carcinoma is drug resistant non-small cell lung carcinoma. In some embodiments, the compound is a c-Myc mRNA translation modulator. In some embodiments, the compound is a c-Myc mRNA translation inhibitor. In some embodiments, the compound is a c-Myc mRNA transcription regulator. In some embodiments, the compound is selective to c-Myc. In some embodiments, the compound reduces the amount of c-Myc protein in a cell. In some embodiments, the compound is any one of the compounds listed in Table 1.

[0140] In various embodiments, the compounds of this invention are useful in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting esophageal squamous cell carcinoma. In some embodiments, the esophageal squamous cell carcinoma is early esophageal squamous cell carcinoma. In some embodiments, the esophageal squamous cell carcinoma is advanced esophageal squamous cell carcinoma. In some embodiments, the esophageal squamous cell carcinoma is invasive esophageal squamous cell carcinoma. In some embodiments, the esophageal squamous cell carcinoma is metastatic esophageal squamous cell carcinoma. In some embodiments, the esophageal squamous cell carcinoma is drug resistant esophageal squamous cell carcinoma. In some embodiments, the compound is a c-Myc mRNA translation modulator. In some embodiments, the compound is a c-Myc mRNA translation inhibitor. In some embodiments, the compound is a c-Myc mRNA transcription regulator. In some embodiments, the compound is selective to c-Myc. In some embodiments, the compound reduces the amount of c-Myc protein in a cell. In some embodiments, the compound is any one of the compounds listed in Table 1.

[0141] In various embodiments, the compounds of this invention are useful in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting osteosarcoma a. In some embodiments, the osteosarcoma is early osteosarcoma. In some embodiments, the osteosarcoma is advanced osteosarcoma. In some embodiments, the osteosarcoma is invasive osteosarcoma. In some embodiments, the osteosarcoma is metastatic osteosarcoma. In some embodiments, the osteosarcoma is drug resistant osteosarcoma. In some embodiments, the compound is a c-Myc mRNA translation modulator. In some embodiments, the compound is a c-Myc mRNA translation inhibitor. In some embodiments, the compound is a c-Myc mRNA transcription regulator. In some embodiments, the compound is selective to c-Myc. In some embodiments, the compound reduces the amount of c-Myc protein in a cell. In some embodiments, the compound is any one of the compounds listed in Table 1.

[0142] In various embodiments, the compounds of this invention are useful in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting bladder cancer. In some embodiments, the bladder cancer is early bladder cancer. In some embodiments, the bladder cancer is advanced bladder cancer. In some embodiments, the bladder cancer is invasive bladder cancer. In some embodiments, the bladder cancer is metastatic bladder cancer. In some embodiments, the bladder cancer is drug resistant bladder cancer. In some embodiments, the compound is a c-Myc mRNA translation modulator. In some embodiments, the compound is a c-Myc mRNA translation inhibitor. In some embodiments, the compound is a c-Myc mRNA transcription regulator. In some embodiments, the compound is selective to c-Myc. In some embodiments, the compound reduces the amount of c-Myc protein in a cell. In some embodiments, the compound is any one of the compounds listed in Table 1.

[0143] In various embodiments, the compounds of this invention are useful in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting pancreatic cancer. In some embodiments, the pancreatic cancer is early pancreatic cancer. In some embodiments, the pancreatic cancer is advanced pancreatic cancer. In some embodiments, the pancreatic cancer is invasive pancreatic cancer. In some embodiments, the pancreatic cancer is metastatic pancreatic cancer. In some embodiments, the pancreatic cancer is drug resistant pancreatic cancer. In some embodiments, the compound is a c-Myc mRNA translation modulator. In some embodiments, the compound is a c-Myc mRNA translation inhibitor. In some embodiments, the compound is a c-Myc mRNA transcription regulator. In some embodiments, the compound is selective to c-Myc. In some embodiments, the compound reduces the amount of c-Myc protein in a cell. In some embodiments, the compound is any one of the compounds listed in Table 1.

[0144] In various embodiments, the compounds of this invention are useful in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting lung adenocarcinoma. In some embodiments, the lung adenocarcinoma is early lung adenocarcinoma. In some embodiments, the lung adenocarcinoma is advanced lung adenocarcinoma. In some embodiments, the lung adenocarcinoma is invasive lung adenocarcinoma. In some embodiments, the lung adenocarcinoma is metastatic lung adenocarcinoma. In some embodiments, the lung adenocarcinoma is drug resistant lung adenocarcinoma. In some embodiments, the compound is a c-Myc mRNA translation modulator. In some embodiments, the compound is a c-Myc mRNA translation inhibitor. In some embodiments, the compound is a c-Myc mRNA transcription regulator. In some embodiments, the compound is selective to c-Myc. In some embodiments, the compound reduces the amount of c-Myc protein in a cell. In some embodiments, the compound is any one of the compounds listed in Table 1.

[0145] In various embodiments, the compounds of this invention are useful in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting thyroid cancer. In some embodiments, the thyroid cancer is early thyroid cancer. In some embodiments, the thyroid cancer is advanced thyroid cancer. In some embodiments, the thyroid cancer is invasive thyroid cancer. In some embodiments, the thyroid cancer is metastatic thyroid cancer. In some embodiments, the thyroid cancer is drug resistant thyroid cancer. In some embodiments, the thyroid cancer is BRAF V600E thyroid cancer. In some embodiments, the compound is a c-Myc mRNA translation modulator. In some embodiments, the compound is a c-Myc mRNA translation inhibitor. In some embodiments, the compound is a c-Myc mRNA transcription regulator. In some embodiments, the compound is selective to c-Myc. In some embodiments, the compound reduces the amount of c-Myc protein in a cell. In some embodiments, the compound is any one of the compounds listed in Table 1.

[0146] In various embodiments, the compounds of this invention are useful in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting choroid plexus carcinoma. In some embodiments, the choroid plexus carcinoma is early choroid plexus carcinoma. In some embodiments, the choroid plexus carcinoma is advanced choroid plexus carcinoma. In some embodiments, the choroid plexus carcinoma is invasive choroid plexus carcinoma. In some embodiments, the choroid plexus carcinoma is metastatic choroid plexus carcinoma. In some embodiments, the choroid plexus carcinoma is drug resistant choroid plexus carcinoma. In some embodiments, the compound is a c-Myc mRNA translation modulator. In some embodiments, the compound is a c-Myc mRNA translation inhibitor. In some embodiments, the compound is a c-Myc mRNA transcription regulator. In some embodiments, the compound is selective to c-Myc. In some embodiments, the compound reduces the amount of c-Myc protein in a cell. In some embodiments, the compound is any one of the compounds listed in Table 1.

[0147] In various embodiments, the compounds of this invention are useful in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting colitis-associated cancer. In some embodiments, the colitis-associated cancer is early colitis-associated cancer. In some embodiments, the colitis-associated cancer is advanced colitis-associated cancer. In some embodiments, the colitis-associated cancer is invasive colitis-associated cancer. In some embodiments, the colitis-associated cancer is metastatic colitis-associated cancer. In some embodiments, the cancer is drug resistant colitis-associated cancer. In some embodiments, the compound is a c-Myc mRNA translation modulator. In some embodiments, the compound is a c-Myc mRNA translation inhibitor. In some embodiments, the compound is a c-Myc mRNA transcription regulator. In some embodiments, the compound is selective to c-Myc. In some embodiments, the compound reduces the amount of c-Myc protein in a cell. In some embodiments, the compound is any one of the compounds listed in Table 1.

[0148] In various embodiments, the compounds of this invention are useful in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting ovarian cancer. In some embodiments, the ovarian cancer is early ovarian cancer. In some embodiments, the ovarian cancer is advanced ovarian cancer . In some embodiments, the ovarian cancer is invasive ovarian cancer. In some embodiments, the ovarian cancer is metastatic ovarian cancer. In some embodiments, the ovarian cancer is drug resistant ovarian cancer. In some embodiments, the ovarian cancer is epithelial ovarian cancer. In some embodiments, the compound is a c-Myc mRNA translation modulator. In some embodiments, the compound is a c-Myc mRNA translation inhibitor. In some embodiments, the compound is a c-Myc mRNA transcription regulator. In some embodiments, the compound is selective to c-Myc. In some embodiments, the compound reduces the amount of c-Myc protein in a cell. In some embodiments, the compound is any one of the compounds listed in Table 1.

[0149] In various embodiments, the compounds of this invention are useful in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting colorectal cancer. In some embodiments, the colorectal cancer is early colorectal cancer. In some embodiments, the colorectal cancer is advanced colorectal cancer. In some embodiments, the colorectal cancer is invasive colorectal cancer. In some embodiments, the colorectal cancer is metastatic colorectal cancer. In some embodiments, the colorectal cancer is drug resistant colorectal cancer. In some embodiments, the compound is a c-Myc mRNA translation modulator. In some embodiments, the compound is a c-Myc mRNA translation inhibitor. In some embodiments, the compound is a c-Myc mRNA transcription regulator. In some embodiments, the compound is selective to c-Myc. In some embodiments, the compound reduces the amount of c-Myc protein in a cell. In some embodiments, the compound is any one of the compounds listed in Table 1.

[0150] In various embodiments, the compounds of this invention are useful in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting uterine cancer. In some embodiments, the uterine cancer is early uterine cancer. In some embodiments, the uterine cancer is advanced uterine cancer. In some embodiments, the uterine cancer is invasive uterine cancer. In some embodiments, the uterine cancer is metastatic uterine cancer. In some embodiments, the uterine cancer is drug resistant uterine cancer. In some embodiments, the compound is a c-Myc mRNA translation modulator. In some embodiments, the compound is a c-Myc mRNA translation inhibitor. In some embodiments, the compound is a c-Myc mRNA transcription regulator. In some embodiments, the compound is selective to c-Myc. In some embodiments, the compound reduces the amount of c-Myc protein in a cell. In some embodiments, the compound is any one of the compounds listed in Table 1.

[0151] In various embodiments, the compounds of this invention are useful in increasing the survival of a subject suffering from metastatic cancer. In some embodiments, the compound is a c-Myc mRNA translation modulator. In some embodiments, the compound is a c-Myc mRNA translation inhibitor. In some embodiments, the compound is a c-Myc mRNA transcription regulator. In some embodiments, the compound is selective to c-Myc. In some embodiments, the compound reduces the amount of c-Myc protein in a cell. In some embodiments, the cancer is breast cancer, ovarian carcinoma, acute myeloid leukemia, chronic myelogenous leukemia, Hodgkin's and Burkitt's lymphoma, diffuse large Bcell lymphoma, prostate cancer, colon cancer, gastric cancer, primary central nervous system lymphoma, glioblastoma, medulloblastoma, melanoma, non-small cell lung carcinoma, germinal center-derived lymphomas, esophageal squamous cell carcinoma, osteosarcoma, bladder cancer, pancreatic cancer, lung adenocarcinoma, thyroid cancer, choroid plexus carcinoma, colitis-associated cancer, colorectal cancer, or uterine cancer.

[0152] In various embodiments, the compounds of this invention are useful in treating, suppressing, reducing the severity, reducing the risk, or inhibiting advanced cancer. In some embodiments, the compound is a c-Myc mRNA translation modulator. In some embodiments, the compound is a c-Myc mRNA translation inhibitor. In some embodiments, the compound is a c-Myc mRNA transcription regulator. In some embodiments, the compound is selective to c-Myc. In some embodiments, the compound reduces the amount of c-Myc protein in a cell. In some embodiments, the cancer is breast cancer, ovarian carcinoma, acute myeloid leukemia, chronic myelogenous leukemia, Hodgkin's and Burkitt's lymphoma, diffuse large Bcell lymphoma, prostate cancer, colon cancer, gastric cancer, primary central nervous system lymphoma, glioblastoma, medulloblastoma, melanoma, non-small cell lung carcinoma, germinal center-derived lymphomas, esophageal squamous cell carcinoma, osteosarcoma, bladder cancer, pancreatic cancer, lung adenocarcinoma, thyroid cancer, choroid plexus carcinoma, colitis-associated cancer, colorectal cancer, or uterine cancer.

[0153] The compounds of the present invention are useful in the treatment, reducing the severity, reducing the risk, or inhibition of cancer, metastatic cancer, advanced cancer, drug resistant cancer, and various forms of cancer. In a preferred embodiment, the cancer is breast cancer, ovarian carcinoma, acute myeloid leukemia, chronic myelogenous leukemia, Hodgkin's and Burkitt's lymphoma, diffuse large Bcell lymphoma, prostate cancer, colon cancer, gastric cancer, primary central nervous system lymphoma, glioblastoma, medulloblastoma, melanoma, non-small cell lung carcinoma, germinal center-derived lymphomas, esophageal squamous cell carcinoma, osteosarcoma, bladder cancer, pancreatic cancer, lung adenocarcinoma, thyroid cancer, choroid plexus carcinoma, colitis-associated cancer, colorectal cancer, or uterine cancer. Based upon their believed mode of action, it is believed that other forms of cancer will likewise be treatable or preventable upon administration of the compounds or compositions of the present invention to a patient. Preferred compounds of the present invention are selectively disruptive to cancer cells, causing ablation of cancer cells but preferably not normal cells. Significantly, harm to normal cells is minimized because the cancer cells are susceptible to disruption at much lower concentrations of the compounds of the present invention.

[0154] In various embodiments, other types of cancers that may be treatable with the c-Myc mRNA translation modulators according to this invention include: adrenocortical carcinoma, anal cancer, bladder cancer, brain tumor, brain stem tumor, breast cancer, glioma, cerebellar astrocytoma, cerebral astrocytoma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal, pineal tumors, hypothalamic glioma, carcinoid tumor, carcinoma, cervical cancer, colon cancer, central nervous system (CNS) cancer, endometrial cancer, esophageal cancer, extrahepatic bile duct cancer, Ewing's family of tumors (Pnet), extracranial germ cell tumor, eye cancer, intraocular melanoma, gallbladder cancer, gastric cancer, germ cell tumor, extragonadal, gestational trophoblastic tumor, head and neck cancer, hypopharyngeal cancer, islet cell carcinoma, laryngeal cancer, leukemia, acute lymphoblastic, leukemia, oral cavity cancer, liver cancer, lung cancer, non-small cell lung cancer, small cell, lymphoma, AIDS-related lymphoma, central nervous system (primary), lymphoma, cutaneous T-cell, lymphoma, Hodgkin's disease, non-Hodgkin's disease, malignant mesothelioma, melanoma, Merkel cell carcinoma, metastatic squamous carcinoma, multiple myeloma, plasma cell neoplasms, Mycosis fungoides, myelodysplastic syndrome, myeloproliferative disorders, nasopharyngeal cancer, neuroblastoma, oropharyngeal cancer, osteosarcoma, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, exocrine, pancreatic cancer, islet cell carcinoma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pheochromocytoma cancer, pituitary cancer, plasma cell neoplasm, prostate cancer, rhabdomyosarcoma, rectal cancer, renal cancer, renal cell cancer, salivary gland cancer, Sezary syndrome, skin cancer, cutaneous T-cell lymphoma, skin cancer, Kaposi's sarcoma, skin cancer, melanoma, small intestine cancer, soft tissue sarcoma, soft tissue sarcoma, testicular cancer, thymoma, malignant, thyroid cancer, urethral cancer, uterine cancer, sarcoma, unusual cancer of childhood, vaginal cancer, vulvar cancer, Wilms' tumor, hepatocellular cancer, hematological cancer or any combination thereof. In some embodiments, the cancer is invasive. In some embodiments, the cancer is metastatic cancer. In some embodiments, the cancer is advanced cancer. In some embodiments, the cancer is drug resistant cancer.

[0155] In various embodiments, "metastatic cancer" refers to a cancer that spread (metastasized) from its original site to another area of the body. Virtually all cancers have the potential to spread. Whether metastases develop depends on the complex interaction of many tumor cell factors, including the type of cancer, the degree of maturity (differentiation) of the tumor cells, the location and how long the cancer has been present, as well as other incompletely understood factors. Metastases spread in three ways - by local extension from the tumor to the surrounding tissues, through the bloodstream to distant sites or through the lymphatic system to neighboring or distant lymph nodes. Each kind of cancer may have a typical route of spread. The tumor is called by the primary site (ex. breast cancer that has spread to the brain is called metastatic breast cancer to the brain).

[0156] In various embodiments, "drug-resistant cancer" refers to cancer cells that acquire resistance to chemotherapy. Cancer cells can acquire resistance to chemotherapy by a range of mechanisms, including the mutation or overexpression of the drug target, inactivation of the drug, or elimination of the drug from the cell. Tumors that recur after an initial response to chemotherapy may be resistant to multiple drugs (they are multidrug resistant). In the conventional view of drug resistance, one or several cells in the tumor population acquire genetic changes that confer drug resistance. Accordingly, the reasons for drug resistance, inter alia, are: a) some of the cells that are not killed by the chemotherapy mutate (change) and become resistant to the drug. Once they multiply, there may be more resistant cells than cells that are sensitive to the chemotherapy; b) Gene amplification. A cancer cell may produce hundreds of copies of a particular gene. This gene triggers an overproduction of protein that renders the anticancer drug ineffective; c) cancer cells may pump the drug out of the cell as fast as it is going in using a molecule called p-glycoprotein; d) cancer cells may stop taking in the drugs because the protein that transports the drug across the cell wall stops working; e) the cancer cells may learn how to repair the DNA breaks caused by some anti-cancer drugs; f) cancer cells may develop a mechanism that inactivates the drug. One major contributor to multidrug resistance is overexpression of P-glycoprotein (P-gp). This protein is a clinically important transporter protein belonging to the ATP-binding cassette family of cell membrane transporters. It can pump substrates including anticancer drugs out of tumor cells through an ATP-dependent mechanism; g) Cells and tumors with activating RAS mutations are relatively resistant to most anti-cancer agents. Thus, the resistance to anticancer agents used in chemotherapy is the main cause of treatment failure in malignant disorders, provoking tumors to become resistant. Drug resistance is the major cause of cancer chemotherapy failure.

[0157] In various embodiments, "resistant cancer" refers to drug-resistant cancer as described herein above. In some embodiments, "resistant cancer" refers to cancer cells that acquire resistance to any treatment such as chemotherapy, radiotherapy or biological therapy.

[0158] In various embodiments, this invention is directed to treating, suppressing, reducing the severity, reducing the risk, or inhibiting cancer in a subject, wherein the subject has been previously treated with chemotherapy, radiotherapy or biological therapy.

[0159] In various embodiments, "Chemotherapy" refers to chemical treatment for cancer such as drugs that kill cancer cells directly. Such drugs are referred as "anti-cancer" drugs or "antineoplastics." Today's therapy uses more than 100 drugs to treat cancer. To cure a specific cancer. Chemotherapy is used to control tumor growth when cure is not possible; to shrink tumors before surgery or radiation therapy; to relieve symptoms (such as pain); and to destroy microscopic cancer cells that may be present after the known tumor is removed by surgery (called adjuvant therapy). Adjuvant therapy is given to prevent a possible cancer reoccurrence.

[0160] In various embodiments, "Radiotherapy" (also referred herein as "Radiation therapy") refers to high energy x-rays and similar rays (such as electrons) to treat disease. Many people with cancer will have radiotherapy as part of their treatment. This can be given either as external radiotherapy from outside the body using x-rays or from within the body as internal radiotherapy. Radiotherapy works by destroying the cancer cells in the treated area. Although normal cells can also be damaged by the radiotherapy, they can usually repair themselves. Radiotherapy treatment can cure some cancers and can also reduce the chance of a cancer coming back after surgery. It may be used to reduce cancer symptoms.

[0161] In various embodiments, "Biological therapy" refers to substances that occur naturally in the body to destroy cancer cells. There are several types of treatment including: monoclonal antibodies, cancer growth inhibitors, vaccines and gene therapy. Biological therapy is also known as immunotherapy.

[0162] When the compounds or pharmaceutical compositions of the present invention are administered to treat, suppress, reduce the severity, reduce the risk, or inhibit a cancerous condition, the pharmaceutical composition can also contain, or can be administered in conjunction with, other therapeutic agents or treatment regimen presently known or hereafter developed for the treatment of various types of cancer. Examples of other therapeutic agents or treatment regimen include radiation therapy, immunotherapy, chemotherapy, surgical intervention, and combinations thereof.

[0163] In various embodiments, the compound according to this invention, is administered in combination with an anti-cancer therapy. Examples of such therapies include: chemotherapy, immunotherapy, radiotherapy, biological therapy, surgical intervention, and combinations thereof.

[0164] In various embodiments, the compound is administered in combination with an anti-cancer agent by administering the compounds as herein described, alone or in combination with other agents.

[0165] In various embodiments, the composition for cancer treatment of the present invention can be used together with existing chemotherapy drugs or be made as a mixture with them. Such a chemotherapy drug includes, for example, alkylating agents, nitrosourea agents, antimetabolites, antitumor antibiotics, alkaloids derived from plant, topoisomerase inhibitors, hormone therapy medicines, hormone antagonists, aromatase inhibitors, P-glycoprotein inhibitors, platinum complex derivatives, other immunotherapeutic drugs, and other anticancer agents. Further, they can be used together with hypoleukocytosis (neutrophil) medicines that are cancer treatment adjuvant, thrombopenia medicines, antiemetic drugs, and cancer pain medicines for patient's QOL recovery or be made as a mixture with them.

[0166] The present invention provides an in vitro method of modulating c-Myc mRNA translation in a cell, comprising contacting a compound represented by the structure of formula I(a(ii)), I(a(iii), II and / or by the structures listed in Table 1, as defined herein above. In some embodiments, the in vitro method is carried out by regulating c-Myc mRNA splicing. In some embodiments, the in vitro method is carried out by inclusion or exclusion of untranslated region or alternative usage of exons. In some embodiments, the in vitro method is carried out by regulation of c-Myc mRNA modifications. In some embodiments, the in vitro method is carried out by regulation of the interaction of RNA binding protein with c-Myc mRNA thereby changing mRNA localization. In some embodiments, the in vitro method is carried out by regulating c-Myc mRNA localization in the cytoplasm. In some embodiments, the in vitro method is carried out by regulating ribosomes or ribosome accessory factor to c-Myc mRNA. In some embodiments, the in vitro method is carried out by reducing the amount of c-Myc protein in the cell.

[0167] The present invention further provides an in vitro method of regulating c-Myc mRNA transcription in a cell, comprising contacting a compound represented by the structure of formula I(a(ii)), I(a(iii), II and / or by the structures listed in Table 1, as defined herein above, with a cell. In some embodiments, the in vitro method is carried out by regulating c-Myc mRNA splicing. In some embodiments, the in vitro method is carried out by inclusion or exclusion of untranslated region or alternative usage of exons. In some embodiments, the in vitro method is carried out by regulation of c-Myc mRNA modifications. In some embodiments, the in vitro method is carried out by regulation of the interaction of RNA binding protein with c-Myc mRNA thereby changing mRNA localization. In some embodiments, the in vitro method is carried out by regulating c-Myc mRNA localization in the cytoplasm. In some embodiments, the in vitro method is carried out by regulating ribosomes or ribosome accessory factor to c-Myc mRNA. In some embodiments, the in vitro method is carried out by reducing the amount of c-Myc protein in the cell.

[0168] The present invention provides a compound for use in destroying a cancerous cell and contacting the cancerous cell with the compound under conditions effective to destroy the contacted cancerous cell. According to various embodiments of destroying the cancerous cells, the cells to be destroyed can be located either in vivo or ex vivo (i.e., in culture).

[0169] In an embodiment, the compound of the present invention is useful in treating or preventing a cancerous condition.

[0170] According to one embodiment, the patient to be treated is characterized by the presence of a precancerous condition, and the administering of the compound is effective to prevent development of the precancerous condition into the cancerous condition. This can occur by destroying the precancerous cell prior to or concurrent with its further development into a cancerous state.

[0171] According to other embodiments, the patient to be treated is characterized by the presence of a cancerous condition, and the administering of the compound is effective either to cause regression of the cancerous condition or to inhibit growth of the cancerous condition, i.e., stopping its growth altogether or reducing its rate of growth. This preferably occurs by destroying cancer cells, regardless of their location in the patient body. That is, whether the cancer cells are located at a primary tumor site or whether the cancer cells have metastasized and created secondary tumors within the patient body.

[0172] As used herein, subject or patient refers to any mammalian patient humans and other primates, dogs, cats, horses, cows, sheep, pigs, rats, mice, and other rodents. In various embodiments, the subject is male. In some embodiments, the subject is female. In some embodiments, while the compounds as described herein may be useful for treating either males or females.

[0173] When administering the compounds of the present invention, they can be administered systemically or, alternatively, they can be administered directly to a specific site where cancer cells or precancerous cells are present. Thus, administering can be accomplished in any manner effective for delivering the compounds or the pharmaceutical compositions to the cancer cells or precancerous cells. Exemplary modes of administration include administering the compounds or compositions orally, topically, transdermally, parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, intraocularly, intraarterially, intralesionally, or by application to mucous membranes, such as, that of the nose, throat, and bronchial tubes.

[0174] The following examples are presented in order to more fully illustrate the preferred embodiments of the invention.EXAMPLES EXAMPLE 1 Synthetic Details for Compounds of the Invention (Schemes 1-2) General Methods

[0175] All reagents were commercial grade and were used as received without further purification, unless otherwise specified. Reagent grade solvents were used in all cases, unless otherwise specified. Thin layer chromatography was carried out using pre-coated silica gel F-254 plates (thickness 0.25 mm). 1< H-NMR and 19< F-NMR spectra were recorded on a Bruker Avance 400MHz or Bruker Avance III 400MHz spectrometer. The chemical shifts are expressed in ppm using the residual solvent as internal standard. Splitting patterns are designated as s (singlet), d (doublet), dd (doublet of doublets), t (triplet), dt (doublet of triplets), q (quartet), m (multiplet) and br s (broad singlet).Abbreviations

[0176] AcOHAcetic acid amphosBis(di-tert-butyl(4-dimethylaminophenyl)phosphine Boctert-Butyloxycarbonyl BuLin-butyl lithium t-BuLitert-butyl lithium BOP(Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate CDI1,1'-Carbonyldiimidazole DBU1,8-Diazabicyclo[5.4.0]undec-7-ene dppb1,4-Bis(diphenylphosphino)butane dppf1,1'-Bis(diphenylphosphino)ferrocene DCMDichloromethane DCE1,2-Dichloroethane DIBAL-HDiisobutylaluminum hydride DIPEAN,N-Diisopropylethylamine DMFN,N-Dimethylformamide DMADimethylacetamide DMAP4-Dimethylaminopyridine DME1,2-Dimethoxyethane DMSODimethyl sulfoxide EDC.HClN-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride HATUN-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide HBTUN,N,N',N'-Tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate HPLCHigh performance liquid chromatography KIPotassium iodide K 2 CO 3 Potassium carbonate MsClMethanesulfonyl chloride Na 2 SO 4 Sodium sulfate NBSN-Bromosuccinimide rtRoom temperature SEM2-(Trimethylsilyl)ethoxymethyl T3PPropylphosphonic anhydride TBAFTetrabutylammonium fluoride TCFHN,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate THFTetrahydrofuran TMS-OTfTrimethylsilyl trifluoromethanesulfonate General synthesis of compounds of the invention

[0177]

[0178] The first step of the synthesis involves base-mediated reaction of hydroxylamine hydrochloride with substituted benzonitrile 1 to afford substituted benzamidoxime intermediate 2. Intermediate 2 then undergoes cyclization with CDI in the presence of DBU in DMF to afford substituted 1,2,4-oxadiazol-5(2H)-one intermediate 3. In the third step, methyl 4-piperidinecarboxylate reacts with intermediate 3 via a direct amination reaction mediated by BOP and DBU in acetonitrile to provide intermediate 4. The ester moiety of intermediate 4 is hydrolyzed to the corresponding carboxylic acid 5, using lithium hydroxide in a mixture of water / THF at room temperature. The final step involves amide coupling reaction of carboxylic acid intermediate 5 using HATU as the coupling reagent, with a variety of primary and secondary amines, to provide substituted 1,2,4-oxadiazol-5-yl-piperidine amides, Structure I.

[0179] The first step involves a direct amination reaction between 1,2,4-oxadiazol-5(2H)-one intermediate 3 (previously described in Scheme 1 ) and N-Boc-piperazine, using BOP and DBU in acetonitrile to deliver intermediate 6. The N-Boc protecting group is removed under acidic conditions, using hydrogen chloride in dioxane to generate substituted 1,2,4-oxadiazol-5-yl-piperazine intermediate 7. The final urea formation step uses triphosgene to activate carboxylic acid intermediate 5. The activated piperazinecarbonyl chloride reacts with a number of primary and secondary amines, to provide the final substituted 1,2,4-oxadiazol-5-yl-piperazine ureas, Structure II. EXAMPLE 2 Synthetic Details for Intermediates and Compounds of the Invention (Schemes 3-25) Intermediate Preparation4-(Aminomethyl)-1-(4-methylbenzyl)pyrrolidin-2-one (Intermediate A )

[0180] Step 1: 4-(Azidomethyl)-1-(4-methylbenzyl)pyrrolidin-2-one

[0181] To a stirred solution of 4-(hydroxymethyl)-1-(4-methylbenzyl)pyrrolidin-2-one (1.50 g, 6.84 mmol) in DMF (25 mL), was added triethylamine (2.08 g, 20.56 mmol) and methanesulfonyl chloride (1.18 g, 10.30 mmol) at 0°C. The resulting mixture was stirred for 1 h at room temperature. Sodium azide (0.89 g, 13.69 mmol), was then added to the stirred reaction mixture at room temperature. The resulting solution was stirred for an additional 3 h at room temperature. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with water (3 × 20 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: Column: Spherical C18, 20 - 40 µm, 330 g; Mobile Phase A: water (plus 10 mM NH 4 HCO 3 ); Mobile Phase B: acetonitrile; Flow rate: 80 mL / min; Gradient: 50% B - 75% B in 20 min; Detector: UV 220 / 254 nm. The fractions containing the desired product were collected and concentrated under reduced pressure to afford 4-(azidomethyl)-1-(4-methylbenzyl)pyrrolidin-2-one as a light yellow oil.

[0182] Yield: 1.20 g (72%). 1< HNMR (400 MHz, CDCl 3 ) δ 7.17-7.08 (m, 4H), 4.38 (s, 2H), 3.40-3.32 (m, 2H), 3.30-3.23 (m, 1H), 3.03-2.97 (m, 1H), 2.63-2.46 (m, 2H), 2.32 (s, 3H), 2.25-2.18 (m, 1H). m / z: [ESI +< ] 245 (M+H) +< .Step 2 : 4-(Aminomethyl)-1-(4-methylbenzyl)pyrrolidin-2-one

[0183] To a stirred solution of 4-(azidomethyl)-1-(4-methylbenzyl)pyrrolidin-2-one (1.30 g, 5.32 mmol) in methanol (15 mL) and water (9 mL), was added tributyl phosphine (3.23 g, 15.96 mmol) dropwise at room temperature. The resulting mixture was stirred for 3 h at room temperature. The resulting mixture was filtered and the residue was washed with methanol (3 × 10 mL). The filtrate was then concentrated under reduced pressure. The resulting residue was purified by reverse phase flash chromatography with the following conditions: Column: Spherical C18, 20 - 40 µm, 330 g; Mobile Phase A: water (plus 10 mM NH 4 HCO 3 ); Mobile Phase B: acetonitrile; Flow rate: 80 mL / min; Gradient: 50% B - 75% B in 20 min; Detector: UV 220 / 254 nm. The fractions containing the desired product were collected and concentrated under reduced pressure to afford 4-(aminomethyl)-1-(4-methylbenzyl)pyrrolidin-2-one as a light yellow oil.

[0184] Yield: 0.70 g (60%). 1< H NMR (400 MHz, CDCl 3 ) δ 7.13 (s, 4H), 4.40 (s, 2H), 3.37 (dd, J = 8.0, 10.0 Hz, 1H), 3.00 (dd, J = 5.6, 10.0 Hz, 1H), 2.79-2.55 (m, 3H), 2.36-2.34 (m, 1H), 2.34 (s, 3H), 2.20 (dd, J = 6.4, 16.8 Hz,1H). NH 2 protons not observed. m / z: [ESI +< ] 219 (M+H) +< .Tert-butyl (3-(4-phenoxypiperidin-1-yl)propyl)carbamate (Intermediate B )

[0185]

[0186] To a stirred solution of 4-phenoxypiperidine (0.60 g, 3.39mmol) and tert-butyl (3-bromopropyl)carbamate (3.22 g, 13.52 mmol), in 1,4-dioxane (15 mL), were added KI (0.28 g, 1.69 mmol) and K 2 CO 3 (1.87 g, 13.53 mmol) portion-wise at room temperature. The resulting mixture was stirred for overnight at 100°C. Upon completion, the resulting mixture was cooled to room temperature and filtered. The filtered residue was washed with acetonitrile (3 × 10 mL). The combined filtrate was then concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: Column: Spherical C18, 20 - 40 µm, 330 g; Mobile Phase A: water (plus 10 mM NH 4 HCO 3 ); Mobile Phase B: acetonitrile; Flow rate: 80 mL / min; Gradient: 50% B - 75% B in 20 min; Detector: 220 / 254 nm. The fractions containing the desired product were collected and concentrated under reduced pressure to afford tert-butyl (3-(4-phenoxypiperidin-1-yl)propyl)carbamate as a light yellow oil.

[0187] Yield: 0.60 g (53%). 1< H NMR (400 MHz, CDCl 3 ) δ 7.35-7.25 (m, 2H), 7.00-6.89 (m, 3H), 5.52 (br s, 1H), 4.39-4.33 (m, 1H), 3.25-3.20 (m, 2H), 2.75 (d, J = 11.2 Hz, 2H), 2.51-2.42 (m, 2H), 2.32 (s, 2H), 2.05-2.00 (m, 2H), 1.90-1.85 (m, 2H), 1.74-1.66 (m, 2H), 1.47 (s, 9H). m / z: [ESI +< ] 335 (M+H) +< .

[0188] The intermediates below were prepared according to the procedure described for Intermediate B. Tert-butyl (3-(4-(pyridin-2-ylmethyl)piperidin-1-yl)propyl)carbamate.

[0189] The compound was synthesized according to the procedure described for Intermediate B, using 2-(piperidin-4-ylmethyl)pyridine (0.40 g, 2.27 mmol) and tert-butyl (3-bromopropyl)carbamate (2.16 g, 9.08 mmol) as the starting material.

[0190] Yield 0.25 g (33%), as a light yellow oil. 1< H NMR (400 MHz, CDCl 3 ) δ 8.57 (dd, J = 2.0, 4.8 Hz, 1H), 7.63 (dd, J = 2.0, 7.6 Hz, 1H), 7.20-7.10 (m, 2H), 5.32 (br s, 1H), 3.52-3.47 (m, 2H), 3.25-3.16 (m, 2H), 2.97-2.90 (m, 2H), 2.81-2.75 (m, 2H), 2.60-2.45 (m, 2H), 2.09-2.00 (m, 1H), 1.94 (td, J = 6.4, 13.2 Hz, 2H), 1.82-1.73 (m, 4H), 1.45 (s, 9H). m / z: [ESI +< ] 334 (M+H) +< .Tert-butyl 2-(1-(pyridin-2-ylmethyl)piperidin-4-yloxy)ethylcarbamate.

[0191] The compound was synthesized according to the procedure described for Intermediate B, using tert-butyl 2-(piperidin-4-yloxy)ethylcarbamate (0.30 g, 1.23 mmol) and 2-(bromomethyl)pyridine (0.25 g, 1.45 mmol) as the starting material.

[0192] Yield 0.35 g (85%), as an off-white solid. 1< H NMR (400 MHz, CDCl 3 ) δ 8.59-8.57 (m, 1H), 7.68 (dd, J = 2.0, 7.6 Hz, 1H), 7.44 (d, J = 7.6 Hz, 1H), 7.22-7.15 (m, 1H), 4.90 (br s, 1H), 3.67 (s, 2H), 3.53-3.51 (m, 2H), 3.37-3.31 (m, 2H), 2.85-2.77 (m, 2H), 2.55-2.48 (m, 1H), 2.30-2.20 (m, 2H), 1.98-1.85 (m, 2H), 1.66-1.58 (m, 2H), 1.47 (s, 9H). m / z: [ESI +< ] 336 (M+H) +< .Tert-butyl 3-[3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl]azetidine-1-carboxylate (Intermediate C )

[0193]

[0194] To a stirred solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (3.00 g, 14.91 mmol) and N'-hydroxy-4-methoxybenzimidamide (3.00 g, 18.05 mmol) in DMF (50 mL), was added HBTU (8.50 g, 22.41 mmol) and triethylamine (3.00 g, 29.65 mmol), at room temperature. The mixture was stirred for 16 h at 100°C. After cooling to room temperature, the resulting mixture was purified by reverse phase flash chromatography with the following conditions: Column: Spherical C18, 20 - 40 µm, 330 g; Mobile Phase A: water (plus 10 mM NH 4 HCO 3 ); Mobile Phase B: acetonitrile; Flow rate: 80 mL / min; Gradient: 60% B - 80% B in 20 min; Detector: UV 254 / 215 nm. The fractions containing desired product were collected and concentrated under reduced pressure to afford tert-butyl 3-[3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl]azetidine-1-carboxylate as a brown oil.

[0195] Yield: 3.20 g (65%). 1< H NMR (400 MHz, CDCl 3 ) δ 7.97 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 8.8 Hz, 2H), 4.35-4.26 (m, 2H), 4.25-4.16 (m, 1H), 4.15-4.08 (m, 2H), 3.85 (s, 3H), 1.41 (s, 9H). m / z: [ESI +< ] 276 (M+H-56) +< . The intermediates below were prepared according the procedure described for Intermediate C. Methyl (1r,4r)-4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)cyclohexane-1-carboxylate.

[0196] The compound was synthesized according to the procedure described for Intermediate C, using N-hydroxy-4-methoxybenzimidamide (4.02 g, 24.19 mmol) and (1r,4r)-4-(methoxycarbonyl)cyclohexane-1-carboxylic acid (4.51 g, 24.22 mmol) as the starting material.

[0197] Yield 4.00 g (52%), as an off-white solid. 1< H NMR (400 MHz, DMSO) δ 7.93 (d, J = 9.0 Hz, 2H), 7.09 (d, J = 9.0 Hz, 2H), 3.83 (s, 3H), 3.61 (s, 3H), 3.07 (dt, J = 3.2, 11.6 Hz, 1H), 2.42 (dt, J = 6.6, 11.2 Hz, 1H), 2.16 (dd, J = 3.6, 12.8 Hz, 2H), 2.01 (dd, J = 3.6, 13.6 Hz, 2H), 1.70-1.57 (m, 2H), 1.55-1.47 (m, 2H). m / z: [ESI +< ] 317 (M+H) +< .Methyl (1s,4s)-4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)cyclohexane-1-carboxylate

[0198] The compound was synthesized according to the procedure described for Intermediate C, using N-hydroxy-4-methoxybenzimidamide (2.00 g, 12.04 mmol) and (1s,4s)-4-(methoxycarbonyl)cyclohexane-1-carboxylic acid (2.25 g, 12.08 mmol) as the starting material.

[0199] Yield 3.00 g (79%), as a yellow solid. 1< H NMR (400 MHz, DMSO) δ 7.93 (d, J = 9.0 Hz, 2H), 7.09 (d, J = 9.0 Hz, 2H), 3.83 (s, 3H), 3.60 (s, 3H), 3.27 (q, J = 5.6 Hz, 1H), 2.62 (td, J = 4.4, 8.2 Hz, 1H), 1.92 (t, J = 5.6 Hz, 4H), 1.85-1.65 (m, 4H). m / z: [ESI +< ] 317 (M+H) +< .Tert-butyl 1-[4-methoxy-[1,1-biphenyl]-3-yl]piperidine-4-carboxylate (Intermediate D )

[0200] Step1: Tert-butyl 1-(3-bromophenyl)piperidine-4-carboxylate

[0201] To a stirred solution of (3-bromophenyl)boronic acid (5.00 g, 24.90 mmol) and tert-butyl piperidine-4-carboxylate (4.61 g, 24.90 mmol) in DCM (120 mL), were added copper(II) acetate(6.78 g, 37.33 mmol) and triethylamine (7.56 g, 74.71 mmol) at room temperature under an oxygen atmosphere (1.5 atm.). The resulting mixture was stirred at room temperature under an oxygen atmosphere for 16 h. The resulting mixture was diluted with water (100 mL) and extracted with DCM (3 × 100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 5% ethyl acetate in petroleum ether to afford tert-butyl 1-(3-bromophenyl)piperidine-4-carboxylate as a light brown oil.

[0202] Yield: 0.96 g (11%). 1< H NMR (400 MHz, DMSO) δ 7.16-7.10 (m, 1H), 7.06 (t, J = 2.0 Hz, 1H), 6.95-6.86 (m, 2H), 3.64 (td, J = 3.6, 12.4 Hz, 2H), 2.86-2.73 (m, 2H), 2.45-2.35 (m, 1H), 1.89-1.80 (m, 2H), 1.64-1.51 (m, 2H), 1.41 (s, 9H). m / z: [ESI +< ] 340, 342 (M+H) +< .Step 2: Tert-butyl 1-[4'-methoxy-[1,1'-biphenyl]-3-yl]piperidine-4-carboxylate

[0203] To a stirred solution of tert-butyl 1-(3-bromophenyl)piperidine-4-carboxylate (0.95 g, 2.79 mmol) and (4-methoxyphenyl)boronic acid (0.85 g, 5.59 mmol) in 1,4-dioxane (8 mL) and water (2 mL), were added K 2 CO 3 (1.12 g, 8.10 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.32 g, 0.28 mmol). The resulting mixture was then purged with nitrogen gas. The reaction mixture was then stirred for 2 h at 90°C. The resulting mixture was cooled to room temperature, diluted with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with brine (50 mL), dried with anhydrous Na 2 SO 4 and filtered. The filtrate was then concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: Column, Spherical C18, 20 - 40 µm, 330 g; Mobile Phase A: water (plus 10 mM formic acid); Mobile Phase B; acetonitrile; Flow rate: 80 mL / min; Gradient: 45% B - 65% B in 20 min; Detector: UV 220 / 254 nm. The fractions containing the desired product were collected and concentrated under reduced pressure to afford tert-butyl 1-[4-methoxy-[1,1-biphenyl]-3-yl]piperidine-4-carboxylate as a dark yellow solid.

[0204] Yield: 1.00 g (97%). 1< H NMR (400 MHz, DMSO) δ 7.57 (d, J = 8.8 Hz, 2H), 7.25 (t, J = 8.0 Hz, 1H), 7.11-7.07 (m, 1H), 7.03-6.95 (m, 3H), 6.91-6.86 (m, 1H), 3.79 (s, 3H), 3.73-3.66 (m, 2H), 2.86-2.73 (m, 2H), 2.43-2.34 (m, 1H), 1.92-1.82 (m, 2H), 1.71-1.55 (m, 2H), 1.41 (s, 9H). m / z: [ESI +< ] 368 (M+H) +< .Methyl 1-(4-(4-methoxyphenyl)thiazol-2-yl)piperidine-4-carboxylate (Intermediate E )

[0205]

[0206] To a stirred solution of methyl 1-carbamothioylpiperidine-4-carboxylate (1.00 g, 4.94 mmol) and 2-bromo-1-(4-methoxyphenyl)ethan-1-one (1.25 g, 5.46 mmol) in ethanol (20 mL) was added triethylamine (1.50 g, 14.82 mmol) at room temperature under a nitrogen atmosphere. The resulting solution was stirred for 16 h at reflux. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 25% ethyl acetate in petroleum ether to afford methyl 1-(4-(4-methoxyphenyl)thiazol-2-yl)piperidine-4-carboxylate as an off-white solid.

[0207] Yield: 1.20 g (73%). 1< H NMR (400 MHz, DMSO) δ 7.81-7.75 (m, 2H), 7.09 (s, 1H), 6.97-6.91 (m, 2H), 3.94-3.86 (m, 2H), 3.78 (s, 3H), 3.64 (s, 3H), 3.18-3.08 (m, 2H), 2.70-2.60 (m, 1H), 2.00-1.90 (m, 2H), 1.72-1.58 (m, 2H). m / z: [ESI +< ] 333 (M+H) +< .1-[3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5-yl]piperidine-4-carboxylic acid (Intermediate F ) and 1-[3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5-yl]-N-(pyrrolidin-3-ylmethyl)piperidine-4-carboxamide hydrochloride (Intermediate G )

[0208] Step 1: N-hydroxy-4-methoxybenzimidamide

[0209] To a stirred solution of 4-methoxybenzonitrile (100.00 g, 0.751 mol) in ethanol (1.50 L) were added hydroxylamine hydrochloride (78.29 g, 1.127 mol) and triethylamine (91.20 g, 0.901 mol) at room temperature. The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was then concentrated under reduced pressure. The residue was dissolved in water (1.5 L) and extracted with ethyl acetate (3 × 1.5 L). The combined organic layers were washed with brine (2 L), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure to afford N'-hydroxy-4-methoxybenzimidamide as a light blue solid.

[0210] Yield 120.00 g (96%). 1< H NMR (400 MHz, DMSO) δ 9.45 (br s, 1H), 7.62 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 5.72 (br s, 2H), 3.78 (s, 3H). m / z: [ESI +< ] 167 (M+H) +< .

[0211] The intermediates were prepared according to the procedure described above.

[0212] N'-hydroxy-5-methoxypyrazine-2-carboximidamide. The compound was synthesized according to the procedure described above, using 5-methoxypyrazine-2-carbonitrile (0.20 g, 1.48 mmol) as the starting material.

[0213] Yield 0.20 g (80%), as an off-white solid. 1< H NMR (400 MHz, CD 3 OD) δ 8.64 (d, J = 1.4 Hz, 1H), 8.21 (d, J = 1.4 Hz, 1H), 4.02 (s, 3H). NH 2 and OH protons not observed. m / z: [ESI +< ] 169 (M+H) +< .

[0214] N'-hydroxy-5-methoxypyrimidine-2-carboximidamide. The compound was synthesized according to the procedure described above, using 5-methoxypyrimidine-2-carbonitrile (3.60 g, 26.64 mmol) as the starting material.

[0215] Yield 3.50 g (78%), as an off-white solid. 1< H NMR (400 MHz, DMSO) δ 9.99 (br s, 1H), 8.56 (s, 2H), 5.75 (br s, 2H), 3.95 (s, 3H). m / z: [ESI +< ] 169 (M+H) +< .

[0216] 4-(Difluoromethyl)-N'-hydroxybenzimidamide. The compound was synthesized according to the procedure described above, using 4-(difluoromethyl)benzonitrile (5.00 g, 32.65 mmol) as the starting material.

[0217] Yield 6.00 g (99%), as a light blue solid. 1< H NMR (400 MHz, DMSO) δ 9.82 (br s, 1H), 7.81 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 8.0 Hz, 2H), 7.05 (t, J = 56.0 Hz, 1H), 5.93 (br s, 2H). m / z: [ESI +< ] 187 (M+H) +< .Step 2: 3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5(4H)-one

[0218] To a stirred solution of N-hydroxy-4-methoxybenzimidamide (80.00 g, 0.481 mol) in 1,4-dioxane (1.20 L) were added DBU (80.62 g, 0.530 mol) and CDI (117.09 g, 0.722 mol), portion-wise at room temperature. The reaction mixture was stirred for 16 h at 100°C. The mixture was cooled to room temperature and diluted with water (1 L). The resulting mixture was acidified to pH 2 with 3M HCl and extracted with ethyl acetate (3 × 1 L). The combined organic layers were washed with brine (1 L) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was triturated with cold chloroform (800 mL) for 1 h. After filtration, the filter cake was washed with cold chloroform (3 × 100 mL) and air dried to afford 3-(4-methoxyphenyl)-1,2,4-oxadiazol-5(4H)-one as a light yellow solid.

[0219] Yield 80.00 g (86%). 1< H NMR (400 MHz, DMSO) δ 12.81 (s, 1H), 7.77 (d, J = 8.8 Hz, 2H), 7.14 (d, J = 8.8 Hz, 2H), 3.84 (s, 3H). m / z: [ESI +< ] 193 (M+H) +< .

[0220] The intermediates below were prepared according to the procedure described above.

[0221] 3-(6-Methoxypyridin-3-yl)-1,2,4-oxadiazol-5(4H)-one. The compound was synthesized according to the procedure described above, using N-hydroxy-6-methoxynicotinimidamide (12.00 g, 71.78 mmol) as the starting material.

[0222] Yield 12.00 g (87%), as a light yellow solid. 1< H NMR (400 MHz, DMSO) δ 13.00 (s, 1H), 8.65-8.55 (m, 1H), 8.12-8.02 (m, 1H), 7.03 (dd, J = 1.2, 8.8 Hz, 1H), 3.94 (s, 3H). m / z: [ESI +< ] 194 (M+H) +< .

[0223] N-(4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)acetamide. The compound was synthesized according to the procedure described above, using N-(4-(N-hydroxycarbamimidoyl)phenyl)acetamide (4.50 g, 23.29 mmol) as the starting material.

[0224] Yield 4.00 g (78%), as a grey solid. 1< H NMR (400 MHz, DMSO) δ 13.03 (br s, 1H), 10.52 (s, 1H), 7.85-7.73 (m, 4H), 1.99 (s, 3H). m / z: [ESI +< ] 220 (M+H) +< .

[0225] 3-(5-Methoxypyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one. The compound was synthesized according to the procedure described above, using N-hydroxy-5-methoxypicolinimidamide (10.00 g, 59.82 mmol) as the starting material.

[0226] Yield 9.00 g (78%), as a light yellow solid. 1< H NMR (400 MHz, DMSO) δ 13.00 (br s, 1H), 8.44 (d, J = 2.8 Hz, 1H), 7.95 (dd, J = 0.8, 8.8 Hz, 1H), 7.61 (dd, J = 2.8, 8.8 Hz, 1H), 3.93 (s, 3H). m / z: [ESI +< ] 194 (M+H) +< .

[0227] 3-(5-Oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)benzonitrile. The compound was synthesized according to the procedure described above, using 3-cyano-N-hydroxybenzimidamide (15.00 g, 93.08 mmol) as the starting material.

[0228] Yield 14.80 g (85%), as a yellow solid. 1< H NMR (400 MHz, DMSO) δ 13.14 (br s, 1H), 8.21 (t, J = 1.6 Hz, 1H), 8.15-8.08 (m, 2H), 7.81 (d, J = 8.0 Hz, 1H). m / z: [ESI +< ] 188 (M+H) +< .

[0229] N-(3-(5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl)phenyl)acetamide. The compound was synthesized according to the procedure described above, using N-(3-(N-hydroxycarbamimidoyl)phenyl)acetamide (8.00 g, 41.41 mmol) as the starting material.

[0230] Yield 6.50 g (72%), as a yellow solid. 1< H NMR (400 MHz, DMSO) δ 13.02 (br s, 1H), 10.23 (br s, 1H), 8.17 (s, 1H), 7.78-7.70 (m, 1H), 7.55-7.46 (m, 1H), 7.46-7.40 (m, 1H), 2.08 (s, 3H). m / z: [ESI +< ] 220 (M+H) +< .

[0231] 3-(4-(Trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5(4H)-one. The compound was synthesized according to the procedure described above, using N-hydroxy-4-(trifluoromethoxy)benzimidamide (15.00 g, 68.14 mmol) as the starting material.

[0232] Yield 10.50 g (63%), as an off-white solid. 1< H NMR (400 MHz, DMSO) δ 13.12 (br s, 1H), 7.95 (d, J = 8.8 Hz, 2H), 7.61 (dd, J = 1.2, 8.8 Hz, 2H). m / z: [ESI +< ] 247 (M+H) +< .

[0233] 3-(4-(Difluoromethoxy)phenyl)-1,2,4-oxadiazol-5(4H)-one. The compound was synthesized according to the procedure described above, using 4-(difluoromethoxy)-N-hydroxybenzimidamide (10.00 g, 49.47 mmol) as the starting material.

[0234] Yield 8.00 g (71%), as a light yellow solid. 1< H NMR (400 MHz, DMSO) δ 13.00 (br s, 1H), 7.90-7.83 (m, 2H), 7.42-7.36 (m, 2H), 7.40 (t, J = 74.0 Hz, 1H). m / z: [ESI +< ] 229 (M+H) +< .

[0235] 3-(2-Chloro-4-methoxyphenyl)-1,2,4-oxadiazol-5(4H)-one. The compound was synthesized according to the procedure described above, using 2-chloro-N-hydroxy-4-methoxybenzimidamide (15.00 g, 74.77 mmol) as the starting material.

[0236] Yield 10.00 g (59%), as a light yellow solid. 1< H NMR (400 MHz, CDCl 3 ) δ 9.26 (br s, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.05 (d, J = 2.6 Hz, 1H), 6.98 (dd, J = 2.6, 8.8 Hz, 1H), 3.91 (s, 3H). m / z: [ESI +< ] 227, 229 (M+H) +< .

[0237] 3-(2-Methoxypyrimidin-5-yl)-1,2,4-oxadiazol-5(4H)-one. The compound was synthesized according to the procedure described above, using N-hydroxy-2-methoxypyrimidine-5-carboximidamide (4.40 g, 26.17 mmol) as the starting material.

[0238] Yield 4.00 g (79%), as a light yellow solid. 1< H NMR (400 MHz, CD 3 OD) δ 8.96 (s, 2H), 4.11 (s, 3H). NH proton not observed. m / z: [ESI +< ] 195 (M+H) +< .

[0239] 3-(5-Methoxypyrazin-2-yl)-1,2,4-oxadiazol-5(4H)-one. The compound was synthesized according to the procedure described above, using N-hydroxy-5-methoxypyrazine-2-carboximidamide (9.00 g, 53.52 mmol) as the starting material.

[0240] Yield 7.60 g (73%), as a light yellow solid. 1< HNMR (400 MHz, CD 3 OD) δ 8.79 (d, J = 1.4 Hz, 1H), 8.33 (d, J = 1.4 Hz, 1H), 4.08 (s, 3H). NH proton not observed. m / z: [ESI +< ] 195 (M+H) +< .

[0241] 3-(5-Methoxypyrimidin-2-yl)-1,2,4-oxadiazol-5(4H)-one. The compound was synthesized according to the procedure described above, using N-hydroxy-5-methoxypyrimidine-2-carboximidamide (3.50 g, 20.81 mmol) as the starting material.

[0242] Yield 2.50 g (62%), as a light yellow solid. 1< H NMR (400 MHz, DMSO) δ 13.15 (br s, 1H), 8.75 (s, 2H), 4.03 (s, 3H). m / z: [ESI +< ] 195 (M+H) +< .

[0243] 3-(4-(Difluoromethyl)phenyl)-1,2,4-oxadiazol-5(4H)-one. The compound was synthesized according to the procedure described above, using 4-(difluoromethyl)-N'-hydroxybenzimidamide (6.00 g, 32.23 mmol) as the starting material.

[0244] Yield 6.10 g (89%), as a light yellow solid. 1< H NMR (400 MHz, DMSO) δ 13.11 (br s, 1H), 7.95 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 8.0 Hz, 2H), 7.13 (t, J = 55.6 Hz, 1H). m / z: [ESI +< ] 211 (M-H) -< .

[0245] 3-(4-(Allyloxy)phenyl)-1,2,4-oxadiazol-5(4H)-one. The compound was synthesized according to the procedure described above, using 4-(allyloxy)-N-hydroxybenzimidamide (38.00 g, 197.69 mmol) as the starting material.

[0246] Yield 38 g (88%), as an off-white solid. 1< H NMR (400 MHz, DMSO) δ 12.83 (br s, 1H), 7.78-7.72 (m, 2H), 7.18-7.12 (m, 2H), 6.13-5.99 (m, 1H), 5.47-5.37 (m, 1H), 5.33-5.26 (m, 1H), 4.70-4.63 (m, 2H). m / z: [ESI +< ] 219 (M+H) +< .Step 3: Methyl 1-[3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl]piperidine-4-carboxylate

[0247] To a stirred solution of 3-(4-methoxyphenyl)-1,2,4-oxadiazol-5(4H)-one (15.00 g, 78.05 mmol) in acetonitrile (225 mL) were added methyl piperidine-4-carboxylate (16.76 g, 117.05 mmol), DBU (17.82 g, 117.05) mmol) and BOP (44.88 g, 101.47 mmol) portion-wise at room temperature. The reaction mixture was then stirred for 16 h at 60°C. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 45%-60% ethyl acetate in petroleum ether to afford methyl 1-[3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl]piperidine-4-carboxylate as a light yellow solid.

[0248] Yield 14.00 g (57%). 1< H NMR (400 MHz, CDCl 3 ) δ 7.94 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 4.20-4.12 (m, 2H), 3.86 (s, 3H), 3.73 (s, 3H), 3.30-3.25 (m, 2H), 2.63-2.56 (m, 1H), 2.09-1.99 (m, 2H), 1.93-1.76 (m, 2H). m / z: [ESI +< ] 318 (M+H) +< .

[0249] The intermediates below were prepared according to the procedure described above.

[0250] Tert-butyl 4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperazine-1-carboxylate. The compound was synthesized according to the procedure described above, using 3-(4-methoxyphenyl)-1,2,4-oxadiazol-5(4H)-one (10.00 g, 52.04 mmol) and tert-butyl piperazine-1-carboxylate (19.39 g, 104.08 mmol) as the starting material.

[0251] Yield 8.00 g (43%), as a light yellow solid. 1< H NMR (400 MHz, DMSO) δ 7.85 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 3.83 (s, 3H), 3.69-3.56 (m, 4H), 3.53-3.46 (m, 4H), 1.44 (s, 9H). m / z: [ESI +< ] 361 (M+H) +< .

[0252] Tert-butyl 4-(3-(4-cyanophenyl)-1,2,4-oxadiazol-5-yl)piperazine-1-carboxylate. The compound was synthesized according to the procedure described above, using 4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)benzonitrile (5.00 g, 26.72 mmol) and tert-butyl piperazine-1-carboxylate(7.46 g, 40.05 mmol) as the starting material.

[0253] Yield 2.50 g (26%), as a light yellow solid. 1< H NMR (400 MHz, CDCl 3 ) δ 8.12 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 8.4 Hz, 2H), 3.70 (dd, J = 3.8, 6.6 Hz, 4H), 3.60 (dd, J = 3.8, 6.6 Hz, 4H), 1.51 (s, 9H). m / z: [ESI +< ] 356 (M+H) +< .

[0254] Tert-butyl 4-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)piperazine-1-carboxylate. The compound was synthesized according to the procedure described above, using 3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5(4H)-one (10.00 g, 40.63 mmol) and tert-butyl piperazine-1-carboxylate (11.35 g, 60.95 mmol) as the starting material.

[0255] Yield 4.25 g (25%), as an off-white solid. 1< H NMR (400 MHz, CDCl 3 ) δ 8.05 (d, J = 8.8 Hz, 2H), 7.29 (d, J = 8.8 Hz, 2H), 3.69 (dd, J = 4.0, 6.8 Hz, 4H), 3.60 (dd, J = 4.0, 6.8 Hz, 4H), 1.51 (s, 9H). m / z: [ESI +< ] 415 (M+H) +< .

[0256] Tert-butyl 4-(3-(4-(difluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)piperazine-1-carboxylate. The compound was synthesized according to the procedure described above, using 3-(4-(difluoromethoxy)phenyl)-1,2,4-oxadiazol-5(4H)-one (12.00 g, 52.60 mmol) and tert-butyl piperazine-1-carboxylate (29.39 g, 157.80 mmol) as the starting material.

[0257] Yield 3.10 g (15%), as a light yellow solid. 1< H NMR (400 MHz, DMSO) δ 7.99-7.92 (m, 2H), 7.36 (t, J = 72.0 Hz, 1H), 7.34-7.28 (m, 2H), 3.64-3.56 (m, 4H), 3.53-3.45 (m, 4H), 1.43 (s, 9H). m / z: [ESI +< ] 397 (M+H) +< .

[0258] Tert-butyl 4-(3-(4-(difluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)piperazine-1-carboxylate. The compound was synthesized according to the procedure described above, using 3-(4-(difluoromethyl)phenyl)-1,2,4-oxadiazol-5(4H)-one (12.00 g, 56.56 mmol) and tert-butyl piperazine-1-carboxylate (29.13 g, 156.42 mmol) as the starting material.

[0259] Yield 6.00 g (28%), as an off-white solid. m / z: [ESI +< ] 381 (M+H) +< . The crude material was used in the next step without further purification.

[0260] Tert-butyl 4-(3-(4-(allyloxy)phenyl)-1,2,4-oxadiazol-5-yl)piperazine-1-carboxylate. The compound was synthesized according to the procedure described above, using 3-(4-(allyloxy)phenyl)-1,2,4-oxadiazol-5(4H)-one (5.00 g, 22.91 mmol) and tert-butyl piperazine-1-carboxylate (8.54 g, 45.82 mmol) as the starting material.

[0261] Yield 6.00 g (68%), as a yellow oil. 1< H NMR (400 MHz, DMSO) δ 7.86-7.80 (m, 2H), 7.10-7.04 (m, 2H), 6.13-5.99 (m, 1H), 5.47-5.37 (m, 1H), 5.32-5.25 (m, 1H), 4.66-4.61 (m, 2H), 3.62-3.54 (m, 4H), 3.52-3.44 (m, 4H), 1.43 (s, 9H). m / z: [ESI +< ] 387 (M+H) +< .

[0262] Methyl 1-(3-(4-(allyloxy)phenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate. The compound was synthesized according to the procedure described above, using 3-(4-(allyloxy)phenyl)-1,2,4-oxadiazol-5(4H)-one (5.00 g, 22.91 mmol) and methyl piperidine-4-carboxylate (4.27 g, 29.82 mmol) as the starting material.

[0263] Yield 4.00 g (51%), as an off-white solid. 1< H NMR (400 MHz, CDCl 3 ) δ 7.99-7.92 (m, 2H), 7.01-6.95 (m, 2H), 6.16-6.01 (m, 1H), 5.50-5.41 (m, 1H), 5.37-5.29 (m, 1H), 4.64-4.57 (m, 2H), 4.24-4.15 (m, 2H), 3.74 (s, 3H), 3.35-3.24 (m, 2H), 2.65-2.55 (m, 1H), 2.12-2.01 (m, 2H), 1.94-1.79 (m, 2H). m / z: [ESI +< ] 344 (M+H) +< .

[0264] Methyl 1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate. The compound was synthesized according to the procedure described above, using 3-(4-chlorophenyl)-1,2,4-oxadiazol-5(4H)-one (8.00 g, 40.69 mmol) and methyl piperidine-4-carboxylate (11.65 g, 81.38 mmol) as the starting material.

[0265] Yield 2.50 g (19%), as a yellow solid. 1< H NMR (400 MHz, CDCl 3 ) δ 7.99-7.92 (m, 2H), 7.45-7.41 (m, 2H), 4.22-4.12 (m, 2H), 3.74 (s, 3H), 3.35-3.24 (m, 2H), 2.68-2.55 (m, 1H), 2.12-2.00 (m, 2H), 1.92-1.82 (m, 2H). m / z: [ESI +< ] 322, 324 (M+H) +< .

[0266] Methyl 1-(3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate. The compound was synthesized according to the procedure described above, using 3-(3-chlorophenyl)-1,2,4-oxadiazol-5(4H)-one (8.00 g, 40.69 mmol) and methyl piperidine-4-carboxylate (11.65 g, 81.38 mmol) as the starting material.

[0267] Yield 1.00 g (8%), as a yellow solid. 1< H NMR (400 MHz, CDCl 3 ) δ 8.02-7.99 (m, 1H), 7.92-7.87 (m, 1H), 7.47-7.42 (m, 1H), 7.41-7.35 (m, 1H), 4.25-4.13 (m, 2H), 3.74 (s, 3H), 3.36-3.24 (m, 2H), 2.68-2.55 (m, 1H), 2.13-2.01 (m, 2H), 1.92-1.80 (m, 2H). m / z: [ESI +< ] 322, 324 (M+H) +< .

[0268] Methyl 1-(3-(2-chlorophenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate. The compound was synthesized according to the procedure described above, using 3-(2-chlorophenyl)-1,2,4-oxadiazol-5(4H)-one (8.00 g, 40.69 mmol) and methyl piperidine-4-carboxylate (11.65 g, 81.38 mmol) as the starting material.

[0269] Yield 0.65 g (5%), as a yellow solid. 1< H NMR (400 MHz, CDCl 3 ) δ 7.88-7.82 (m, 1H), 7.55-7.48 (m, 1H), 7.43-7.33 (m, 2H), 4.24-4.10 (m, 2H), 3.74 (s, 3H), 3.36-3.23 (m, 2H), 2.67-2.55 (m, 1H), 2.11-2.03 (m, 2H), 1.94-1.80 (m, 2H). m / z: [ESI +< ] 322, 324 (M+H) +< .

[0270] Methyl 1-(3-(4-cyanophenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate. The compound was synthesized according to the procedure described above, using 4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)benzonitrile (10.00 g, 53.43 mmol) and methyl piperidine-4-carboxylate (15.30 g, 106.86 mmol) as the starting material.

[0271] Yield 1.87 g (11%), as a yellow solid. 1< H NMR (400 MHz, CDCl 3 ) δ 8.17-8.10 (m, 2H), 7.78-7.73 (m, 2H), 4.23-4.13 (m, 2H), 3.75 (s, 3H), 3.37-3.27 (m, 2H), 2.68-2.58 (m, 1H), 2.13-2.03 (m, 2H), 1.93-1.80 (m, 2H). m / z: [ESI +< ] 313 (M+H) +< .

[0272] Methyl 1-(3-(6-methoxypyridin-3-yl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate. The compound was synthesized according to the procedure described above, using 3-(6-methoxypyridin-3-yl)-1,2,4-oxadiazol-5(4H)-one (12.00 g, 62.12 mmol) and methyl piperidine-4-carboxylate (17.79 g, 124.24 mmol) as the starting material.

[0273] Yield 3.80 g (19%), as a light yellow solid. 1< H NMR (400 MHz, CDCl 3 ) δ 8.80 (dd, J = 0.8, 2.4 Hz, 1H), 8.14 (dd, J = 2.4, 8.6 Hz, 1H), 6.81 (dd, J = 0.8, 8.6 Hz, 1H), 4.17 (td, J = 4.4, 13.8 Hz, 2H), 4.01 (s, 3H), 3.74 (s, 3H), 3.34-3.24 (m, 2H), 2.67-2.56 (m, 1H), 2.11-2.02 (m, 2H), 1.92-1.79 (m, 2H). m / z: [ESI +< ] 319 (M+H) +< .

[0274] Tert-butyl 1-(3-(4-methoxyphenyl)isoxazol-5-yl)piperidine-4-carboxylate. The compound was synthesized according to the procedure described above, using 3-(4-methoxyphenyl)isoxazol-5(4H)-one (4.60 g, 24.06 mmol) and tert-butyl piperidine-4-carboxylate (6.69 g, 36.09 mmol) as the starting material.

[0275] Yield 3.30 g (38%), as a brown solid. 1< H NMR (400 MHz, DMSO) δ 7.71-7.65 (m, 2H), 7.05-6.99 (m, 2H), 5.79 (s, 1H), 3.80 (s, 3H), 3.72-3.63 (m, 2H), 3.09-2.99 (m, 2H), 2.49-2.40 (m, 1H), 1.92-1.84 (m, 2H), 1.65-1.53 (m, 2H), 1.41 (s, 9H). m / z: [ESI +< ] 359 (M+H) +< .

[0276] Tert-butyl 1-(3-(2-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate. The compound was synthesized according to the procedure described above, using 3-(2-methoxyphenyl)-1,2,4-oxadiazol-5(4H)-one (10.00 g, 52.04 mmol) and tert-butyl piperidine-4-carboxylate (14.46 g, 78.06 mmol) as the starting material.

[0277] Yield 3.20 g (17%), as a light yellow solid. 1< H NMR (400 MHz, DMSO) δ 7.72 (dd, J = 1.8, 7.6 Hz, 1H), 7.53-7.46 (m, 1H), 7.16 (dd, J = 1.0, 8.4 Hz, 1H), 7.05 (dd, J = 1.0, 7.6 Hz, 1H), 4.00-3.92 (m, 2H), 3.83 (s, 3H), 3.30-3.20 (m, 2H), 2.59-2.51 (m, 1H), 1.96-1.87 (m, 2H), 1.64-1.52 (m, 2H), 1.42 (s, 9H). m / z: [ESI +< ] 360 (M+H) +< .

[0278] Tert-butyl 1-(3-(4-acetamidophenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate. The compound was synthesized according to the procedure described above, using N-(4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)acetamide (4.00 g, 18.25 mmol) and tert-butyl piperidine-4-carboxylate (5.07 g, 27.37 mmol) as the starting material.

[0279] Yield 2.79 g (40%), as a light yellow solid. 1< H NMR (400 MHz, DMSO) δ 10.19 (br s, 1H), 7.85-7.80 (m, 2H), 7.73-7.68 (m, 2H), 4.01-3.93 (m, 2H), 3.30-3.20 (m, 2H), 2.60-2.52 (m, 1H), 2.08 (s, 3H), 1.97-1.88 (m, 2H), 1.64-1.53 (m, 2H), 1.41 (s, 9H). m / z: [ESI +< ] 387 (M+H) +< .

[0280] Tert-butyl 1-(3-(5-methoxypyridin-2-yl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate. The compound was synthesized according to the procedure described above, using 3-(5-methoxypyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one (8.00 g, 41.42 mmol) and tert-butyl piperidine-4-carboxylate (11.51 g, 62.13 mmol) as the starting material.

[0281] Yield 3.00 g (20%), as a light yellow solid. 1< H NMR (400 MHz, CD 3 OD) δ 8.35 (dd, J = 0.6, 2.8 Hz, 1H), 8.02 (dd, J = 0.6, 8.8 Hz, 1H), 7.52 (dd, J = 2.8, 8.8 Hz, 1H), 4.19-4.14 (m, 2H), 3.96 (s, 3H), 3.33-3.27 (m, 2H), 2.63-2.52 (m, 1H), 2.07-1.98 (m, 2H), 1.80-1.67 (m, 2H), 1.49 (s, 9H). m / z: [ESI +< ] 361 (M+H) +< .

[0282] Tert-butyl 1-(3-(3-methylphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate. The compound was synthesized according to the procedure described above, using 3-(3-methylphenyl)-1,2,4-oxadiazol-5(4H)-one (4.70 g, 26.68 mmol) and tert-butyl piperidine-4-carboxylate (6.94 g, 37.46 mmol) as the starting material.

[0283] Yield 2.10 g (23%), as a light yellow solid. 1< H NMR (400 MHz, DMSO) δ 7.75-7.72 (m, 1H), 7.72-7.68 (m, 1H), 7.42-7.36 (m, 1H), 7.36-7.32 (m, 1H), 4.02-3.94 (m, 2H), 3.31-3.21 (m, 2H), 2.58-2.52 (m, 1H), 2.37 (s, 3H), 1.96-1.87 (m, 2H), 1.65-1.52 (m, 2H), 1.41 (s, 9H). m / z: [ESI +< ] 344 (M+H) +< .

[0284] Tert-butyl 1-(3-(3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate. The compound was synthesized according to the procedure described above, using 3-(3-methoxyphenyl)-1,2,4-oxadiazol-5(4H)-one (8.00 g, 41.63 mmol) and tert-butyl piperidine-4-carboxylate (11.57 g, 62.44 mmol) as the starting material.

[0285] Yield 6.00 g (40%), as a yellow solid. 1< H NMR (400 MHz, DMSO) δ 7.52-7.46 (m, 1H), 7.45-7.37 (m, 2H), 7.13-7.08 (m, 1H), 4.03-3.94 (m, 2H), 3.81 (s, 3H), 3.32-3.22 (m, 2H), 2.59-2.51 (m, 1H), 1.97-1.87 (m, 2H), 1.66-1.51 (m, 2H), 1.41 (s, 9H). m / z: [ESI +< ] 360 (M+H) +< .

[0286] Tert-butyl 1-(3-(2-methylphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate. The compound was synthesized according to the procedure described above, using 3-(2-methylphenyl)-1,2,4-oxadiazol-5(4H)-one (6.40 g, 36.33 mmol) and tert-butyl piperidine-4-carboxylate (10.10 g, 54.49 mmol) as the starting material.

[0287] Yield 2.50 g (20%), as a yellow solid. 1< H NMR (400 MHz, DMSO) δ 7.82 (dd, J = 1.6, 7.6 Hz, 1H), 7.41 (dd, J = 1.6, 7.6 Hz, 1H), 7.37-7.29 (m, 2H), 4.05-3.92 (m, 2H), 3.32-3.23 (m, 2H), 2.59-2.51 (m, 1H), 2.51 (s, 3H), 1.97-1.86 (m, 2H), 1.66-1.52 (m, 2H), 1.42 (s, 9H). m / z: [ESI +< ] 344 (M+H) +< .

[0288] Tert-butyl 1-(4-(4-methoxyphenyl)oxazol-2-yl)piperidine-4-carboxylate. The compound was synthesized according to the procedure described above, using 4-(4-methoxyphenyl)oxazol-2(3H)-one (3.50 g, 18.31 mmol) and tert-butyl piperidine-4-carboxylate (5.09 g, 27.46 mmol) as the starting material.

[0289] Yield 0.44 g (7%), as a yellow solid. 1< H NMR (400 MHz, DMSO) δ 7.95 (s, 1H), 7.60 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 3.90 (td, J = 4.0, 12.8 Hz, 2H), 3.76 (s, 3H), 3.06 (dt, J = 2.8, 13.2 Hz, 2H), 2.49-2.40 (m, 1H), 1.87 (dd, J = 4.0, 13.2 Hz, 2H), 1.61-1.48 (m, 2H), 1.41 (s, 9H). m / z: [ESI +< ] 359 (M+H) +< .

[0290] Methyl 1-(3-(3-cyanophenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate. The compound was synthesized according to the procedure described above, using 3-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)benzonitrile (14.00 g, 74.80 mmol) and methyl piperidine-4-carboxylate (16.07 g, 112.21 mmol) as the starting material.

[0291] Yield 5.50 g (24%), as a yellow solid. 1< H NMR (400 MHz, DMSO) δ 8.25-8.22 (m, 1H), 8.22-8.18 (m, 1H), 8.05-8.01 (m, 1H), 7.77-7.71 (m, 1H), 4.09-3.95 (m, 2H), 3.64 (s, 3H), 3.37-3.27 (m, 2H), 2.74-2.64 (m, 1H), 2.04-1.93 (m, 2H), 1.72-1.57 (m, 2H). m / z: [ESI +< ] 313 (M+H) +< .

[0292] Tert-butyl 1-(3-(pyridin-4-yl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate. The compound was synthesized according to the procedure described above, using 3-(pyridin-4-yl)-1,2,4-oxadiazol-5(4H)-one (3.20 g, 19.62 mmol) and tert-butyl piperidine-4-carboxylate (5.45 g, 29.42 mmol) as the starting material.

[0293] Yield 2.40 g (37%), as a yellow solid. 1< H NMR (400 MHz, DMSO) δ 8.74 (d, J = 6.2 Hz, 2H), 7.81 (d, J = 6.2 Hz, 2H), 4.01-3.95 (m, 2H), 3.34-3.22 (m, 2H), 2.57-2.50 (m, 1H), 1.95-1.86 (m, 2H), 1.66-1.51 (m, 2H), 1.39 (s, 9H). m / z: [ESI +< ] 331 (M+H) +< .

[0294] Tert-butyl 1-(3-(3-acetamidophenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate. The compound was synthesized according to the procedure described above, using N-(3-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)acetamide (3.00 g, 13.69 mmol) and tert-butyl piperidine-4-carboxylate(3.80 g, 20.53 mmol) as the starting material.

[0295] Yield 1.68 g (32%), as a yellow solid. 1< H NMR (400 MHz, DMSO) δ 10.13 (br s, 1H), 8.18-8.08 (m, 1H), 7.80-7.74 (m, 1H), 7.59-7.46 (m, 1H), 7.45-7.37 (m, 1H), 4.02-3.95 (m, 2H), 3.33-3.21 (m, 2H), 2.58-2.51 (m, 1H), 2.08 (s, 3H), 1.97-1.88 (m 2H), 1.64-1.56 (m, 2H), 1.41 (s, 9H). m / z: [ESI +< ] 387 (M+H) +< .

[0296] Tert-butyl 1-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate. The compound was synthesized according to the procedure described above, using 3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5(4H)-one (5.00 g, 20.31 mmol) and tert-butyl piperidine-4-carboxylate (5.65 g, 30.47 mmol) as the starting material.

[0297] Yield 0.29 g (3%), as a yellow solid. 1< H NMR (400 MHz, DMSO) δ 7.95 (d, J = 8.8 Hz, 2H), 7.30 (d, J = 8.8 Hz, 2H), 4.04-3.94 (m, 2H), 3.32-3.24 (m, 2H), 2.60-2.50 (m, 1H), 1.98-1.88 (m, 2H), 1.67-1.53 (m, 2H), 1.41 (s, 9H). m / z: [ESI +< ] 414 (M+H) +< .

[0298] Tert-butyl 1-(3-(4-(difluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate. The compound was synthesized according to the procedure described above, using 3-(4-(difluoromethoxy)phenyl)-1,2,4-oxadiazol-5(4H)-one (8.00 g, 35.06 mmol) and tert-butyl piperidine-4-carboxylate (9.74 g, 52.60 mmol) as the starting material.

[0299] Yield 5.00 g (36%), as a yellow solid. 1< H NMR (400 MHz, DMSO) δ 7.95 (d, J = 8.8 Hz, 2H), 7.53 (t, J = 73.4 Hz, 1H), 7.30 (d, J = 8.8 Hz, 2H), 4.03-3.93 (m, 2H), 3.33-3.22 (m, 2H), 2.58-2.51 (m, 1H), 1.97-1.85 (m, 2H), 1.66-1.52 (m, 2H), 1.41 (s, 9H). m / z: [ESI +< ] 396 (M+H) +< .

[0300] Tert-butyl 1-(3-(2-chloro-4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate. The compound was synthesized according to the procedure described above, using 3-(2-chloro-4-methoxyphenyl)-1,2,4-oxadiazol-5(4H)-one (8.00 g, 35.30 mmol) and tert-butyl piperidine-4-carboxylate (9.81 g, 52.95 mmol) as the starting material.

[0301] Yield 2.00 g (14%), as a yellow solid. 1< H NMR (400 MHz, CDCl 3 ) δ 7.82 (d, J = 8.8 Hz, 1H), 7.04 (d, J = 2.4 Hz, 1H), 6.89 (dd, J = 3.6, 8.8 Hz, 1H), 4.33-4.17 (m, 2H), 3.82 (s, 3H), 3.33-3.22 (m, 2H), 2.55-2.43 (m, 1H), 2.07-1.97 (m, 2H), 1.88-1.76 (m, 2H), 1.50 (s, 9H). m / z: [ESI +< ] 394, 396 (M+H) +< .

[0302] Tert-butyl 1-(3-(2-methoxypyrimidin-5-yl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate. The compound was synthesized according to the procedure described above, using 3-(2-methoxypyrimidin-5-yl)-1,2,4-oxadiazol-5(4H)-one (4.00 g, 20.60 mmol) and tert-butyl piperidine-4-carboxylate (4.96 g, 26.78 mmol) as the starting material.

[0303] Yield 1.50 g (20%), as a yellow solid. 1< H NMR (400 MHz, CD 3 OD) δ 9.06 (s, 2H), 4.20-4.10 (m, 2H), 4.10 (s, 3H), 3.37-3.30 (m, 2H), 2.64-2.53 (m, 1H), 2.08-1.97 (m, 2H), 1.80-1.67 (m, 2H), 1.49 (s, 9H). m / z: [ESI +< ] 362 (M+H) +< .

[0304] Tert-butyl 1-(3-(5-methoxypyrazin-2-yl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate. The compound was synthesized according to the procedure described above, using 3-(5-methoxypyrazin-2-yl)-1,2,4-oxadiazol-5(4H)-one (0.20 g, 1.03 mmol) and tert-butyl piperidine-4-carboxylate (0.25 g, 1.34 mmol) as the starting material.

[0305] Yield 0.15 g (40%), as a light yellow solid. 1< H NMR (400 MHz, CD 3 OD) δ 8.78 (d, J = 1.4 Hz, 1H), 8.31 (d, J = 1.4 Hz, 1H), 4.19-4.11 (m, 2H), 4.06 (s, 3H), 3.40-3.28 (m, 2H), 2.64-2.52 (m, 1H), 2.08-1.97 (m, 2H), 1.80-1.67 (m, 2H), 1.49 (s, 9H). m / z: [ESI +< ] 362 (M+H) +< .

[0306] Tert-butyl 1-(3-(5-methoxypyrimidin-2-yl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate. The compound was synthesized according to the procedure described above, using 3-(5-methoxypyrimidin-2-yl)-1,2,4-oxadiazol-5(4H)-one (1.30 g, 6.70 mmol) and tert-butyl piperidine-4-carboxylate (1.61 g, 8.71 mmol) as the starting material.

[0307] Yield 0.70 g (29%), as a yellow solid. 1< H NMR (400 MHz, CD 3 OD) δ 8.65 (s, 2H), 4.06 (s, 3H), 3.43-3.30 (m, 2H), 3.12-3.03 (m, 2H), 2.70-2.60 (m, 1H), 2.18-2.08 (m, 2H), 1.90-1.75 (m, 2H), 1.48 (s, 9H). m / z: [ESI +< ] 362 (M+H) +< .

[0308] 3-(4-Methoxyphenyl)-5-(4-phenoxypiperidin-1-yl)-1,2,4-oxadiazole (Compound 135). Using 3-(4-methoxyphenyl)-1,2,4-oxadiazol-5(4H)-one (0.20 g, 1.04 mmol) and 4-phenoxypiperidine (0.37 g, 2.09 mmol) as the starting material.

[0309] Yield 0.20 g (55%), as a light yellow solid. 1< H NMR (400 MHz, DMSO) δ 7.85 (d, J = 8.8 Hz, 2H), 7.31 (dd, J = 7.2, 8.8 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 7.04-7.00 (m, 2H), 6.98-6.93 (m, 1H), 4.74-4.62 (m, 1H), 3.93-3.82 (m, 2H), 3.82 (s, 3H), 3.63-3.53 (m, 2H), 2.12-2.01 (m, 2H), 1.81-1.68 (m, 2H). m / z: [ESI +< ] 352 (M+H) +< , (C 20 H 21 N 3 O 3 )

[0310] 3-(4-Methoxyphenyl)-5-(4-phenylpiperidin-1-yl)-1,2,4-oxadiazole (Compound 136). Using 3-(4-methoxyphenyl)-1,2,4-oxadiazol-5(4H)-one (0.20 g, 1.04 mmol) and 4-phenylpiperidine (0.34 g, 2.11 mmol) as the starting material.

[0311] Yield 0.24 g (69%), as a light yellow solid. 1< H NMR (400 MHz, DMSO) δ 7.86 (d, J = 8.8 Hz, 2H), 7.35-7.26 (m, 4H), 7.22-7.20 (m, 1H), 7.06 (d, J = 8.8 Hz, 2H), 4.26-4.13 (m, 2H), 3.82 (s, 3H), 3.41-3.27 (m, 2H), 2.89-2.75 (m, 1H), 1.95-1.84 (m, 2H), 1.80-1.65 (m, 2H). m / z: [ESI +< ] 336 (M+H) +< , (C 20 H 21 N 3 O 2 ).

[0312] 5-(4-(1H-Benzo[d]imidazol-2-yl)piperidin-1-yl)-3-(4-methoxyphenyl)-1,2,4-oxadiazole (Compound 214): Using 3-(4-methoxyphenyl)-1,2,4-oxadiazol-5(4H)-one (0.20 g, 1.04 mmol) and 2-(piperidin-4-yl)-1H-1,3-benzodiazole (0.31 g, 1.54 mmol) as the starting material.

[0313] Yield 0.14 g (36%), as a light yellow solid. 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.26 (br s, 1H), 7.86 (d, J = 8.8 Hz, 2H), 7.49 (br s, 2H), 7.13 (dd, J = 3.0, 6.0 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 4.28-4.14 (m, 2H), 3.83 (s, 3H), 3.48-3.30 (m, 2H), 3.27-3.16 (m, 1H), 2.19-2.07 (m, 2H), 1.99-1.82 (m, 2H). m / z: [ESI +< ] 376 (M+H) +< , (C 21 H 21 N 5 O 2 ).

[0314] 5-(4-(1H-benzo[d]imidazol-2-yl)piperazin-1-yl)-3-(4-methoxyphenyl)-1,2,4-oxadiazole hemiformate (Compound 235). Using 3-(4-methoxyphenyl)-1,2,4-oxadiazol-5(4H)-one (0.20 g, 1.04 mmol) and 2-(piperazin-1-yl)-1H-1,3-benzodiazole (0.25 g, 1.24 mmol) as the starting material.

[0315] Yield 60 mg (15%), as a light yellow solid. 1< H NMR (400 MHz, DMSO) δ 11.54 (br s, 1H), 8.14 (s, 0.57H, HCOOH), 7.87 (d, J = 8.8 Hz, 2H), 7.22 (d, J = 5.4 Hz, 2H), 7.07 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 6.4 Hz, 2H), 3.83 (s, 3H), 3.80-3.72 (m, 4H), 3.72-3.63 (m, 4H). m / z: [ESI +< ] 377 (M+H) +< , (C 20 H 20 N 6 O 2 ).Step 4: 1-[3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5-yl]piperidine-4-carboxylic acid

[0316] To a stirred solution of methyl 1-[3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl] piperidine-4-carboxylate (10.00 g, 31.51 mmol) in THF (150 mL) were added water (50 mL) and lithium hydroxide (3.77 g, 0.157 mol) at room temperature. The reaction solution was stirred for 2 h at room temperature. The solvents were then removed under reduced pressure. The resulting residue was dissolved in water (100 mL) and acidified to pH 4-5 with a 1M solution of aqueous hydrochloric acid. The resulting mixture was filtered. The filtered solid was washed with water (150 mL) and air dried to afford 1-[3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl]piperidine-4-carboxylic acid, as a light brown solid.

[0317] Yield: 8.00 g (84%). 1< H NMR (400 MHz, DMSO) δ 12.37 (br s, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 4.10-3.97 (m, 2H), 3.83 (s, 3H), 3.31-3.24 (m, 2H), 2.64-2.52 (m, 1H), 1.99-1.93 (m, 2H), 1.69-1.54 (m, 2H). m / z: [ESI +< ] 304 (M+H) +< .

[0318] The intermediates below were prepared according to the procedure described above.

[0319] 1-(3-(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylic acid. The compound was synthesized according to the procedure described above, using methyl 1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate (0.50 g, 1.55 mmol) as the starting material.

[0320] Yield 0.45 g (94%), as a light yellow solid. 1< H NMR (400 MHz, DMSO) δ 12.36 (br s, 1H), 7.91 (d, J = 8.6 Hz, 2H), 7.59 (d, J = 8.6 Hz, 2H), 4.06-3.97 (m, 2H), 3.31-3.25 (m, 2H), 2.64-2.56 (m, 1H), 1.99-1.93 (m, 2H), 1.65-1.57 (m, 2H). m / z: [ESI +< ] 308, 310 (M+H) +< .

[0321] 1-(3-(3-Chlorophenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylic acid. The compound was synthesized according to the procedure described above, using methyl 1-(3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate (0.50 g, 1.55 mmol) as the starting material.

[0322] Yield 0.34 g (71%), as a light yellow solid. 1< H NMR (400 MHz, DMSO) δ 12.34 (br s, 1H), 7.90-7.84 (m, 2H), 7.66-7.61 (m, 1H), 7.59-7.54 (m, 1H), 4.06-3.97 (m, 2H), 3.31-3.26 (m, 2H), 2.64-2.56 (m, 1H), 2.02-1.89 (m, 2H), 1.70-1.55 (m, 2H). m / z: [ESI +< ] 308, 310 (M+H) +< .

[0323] 1-(3-(2-Chlorophenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylic acid. The compound was synthesized according to the procedure described above, using methyl 1-(3-(2-chlorophenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate (0.50 g, 1.55 mmol) as the starting material.

[0324] Yield 0.27 g (57%), as a light yellow solid. 1< H NMR (400 MHz, DMSO) δ 12.38 (br s, 1H), 7.82 (dd, J = 1.8, 7.6 Hz, 1H), 7.62 (dd, J = 1.4, 8.0 Hz, 1H), 7.57-7.54 (m, 1H), 7.52-7.45 (m, 1H), 4.01-3.94 (m, 2H), 3.30-3.20 (m, 2H), 2.62-2.52 (m, 1H), 2.02-1.89 (m, 2H), 1.70-1.54 (m, 2H). m / z: [ESI +< ] 308, 310 (M+H) +< .

[0325] 1-(3-(4-Cyanophenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylic acid. The compound was synthesized according to the procedure described above, using methyl 1-(3-(4-cyanophenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate (1.00 g, 3.20 mmol) as the starting material.

[0326] Yield 0.85 g (89%), as a light yellow solid. 1< H NMR (400 MHz, CDCl 3 ) δ 8.13 (d, J = 8.6 Hz, 2H), 7.76 (d, J = 8.6 Hz, 2H), 4.22-4.16 (m, 2H), 3.41-3.29 (m, 2H), 2.74-2.63 (m, 1H), 2.18-2.08 (m, 2H), 1.97-1.82 (m, 2H). Carboxylic acid proton not observed. m / z: [ESI +< ] 299 (M+H) +< .

[0327] 1-(3-(3-Cyanophenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylic acid. The compound was synthesized according to the procedure described above, using methyl 1-(3-(3-cyanophenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate (1.00 g, 3.20 mmol) as the starting material.

[0328] Yield 0.70 g (73%), as a yellow solid. 1< H NMR (400 MHz, DMSO) δ 12.37 (br s, 1H), 8.24 (dd, J = 1.7, 2.0 Hz, 1H), 8.23-8.18 (m, 1H), 8.06-8.00 (m, 1H), 7.78-7.71 (m, 1H), 4.06-3.95 (m, 2H), 3.35-3.23 (m, 2H), 2.62-2.52 (m, 1H), 2.02-1.90 (m, 2H), 1.70-1.55 (m, 2H). m / z: [ESI +< ] 299 (M+H) +< .

[0329] 1-(3-(6-Methoxypyridin-3-yl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylic acid. The compound was synthesized according to the procedure described above, using methyl 1-(3-(6-methoxypyridin-3-yl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate (1.00 g, 3.14 mmol) as the starting material.

[0330] Yield 0.80 g (84%), as a light yellow solid. 1< H NMR (400 MHz, CDCl 3 ) δ 8.81 (dd, J = 0.8, 2.4 Hz, 1H), 8.15 (dd, J = 2.4, 8.8 Hz, 1H), 6.83 (dd, J = 0.8, 8.8 Hz, 1H), 4.24-4.16 (m, 2H), 4.02 (s, 3H), 3.38-3.26 (m, 2H), 2.73-2.61 (m, 1H), 2.17-2.06 (m, 2H), 1.97-1.83 (m, 2H). Carboxylic acid proton not observed. m / z: [ESI +< ] 305 (M+H) +< .

[0331] 1-(4-(4-Methoxyphenyl)thiazol-2-yl)piperidine-4-carboxylic acid. The compound was synthesized according to the procedure described above, using methyl 1-(4-(4-methoxyphenyl)thiazol-2-yl)piperidine-4-carboxylate (1.20 g, 3.61 mmol) as the starting material.

[0332] Yield 1.00 g (87%), as an off-white solid. 1< H NMR (400 MHz, DMSO) δ 7.78 (d, J = 8.8 Hz, 2H), 7.07 (s, 1H), 6.94 (d, J = 8.8 Hz, 2H), 3.93-3.85 (m, 2H), 3.78 (s, 3H), 3.16-3.04 (m, 2H), 2.50-2.42 (m, 1H), 1.98-1.87 (m, 2H), 1.70-1.53 (m, 2H). Carboxylic acid proton not observed. m / z: [ESI +< ] 319 (M+H) +< .

[0333] (1r,4r)-4-(3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5-yl)cyclohexane-1-carboxylic acid (Compound 175). The compound was synthesized according to the procedure described above, using methyl (1r,4r)-4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)cyclohexane-1-carboxylate (3.00 g, 9.48 mmol) as the starting material.

[0334] Yield 1.60 g (56%), as an off-white solid. 1< H NMR (400 MHz, DMSO) δ 12.15 (br s, 1H), 7.94 (d, J = 8.8 Hz, 2H), 7.10 (d, J = 8.8 Hz, 2H), 3.84 (s, 3H), 3.13-3.00 (m, 1H), 2.37-2.24 (m 1H), 2.16 (dd, J = 3.6, 13.4 Hz, 2H), 2.02 (dd, J = 3.6, 13.4 Hz, 2H), 1.69-1.56 (m, 2H), 1.56-1.41 (m, 2H). m / z: [ESI +< ] 303 (M+H) +< .

[0335] (1s,4s)-4-(3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5-yl)cyclohexane-1-carboxylic acid (Compound 173). The compound was synthesized according to the procedure described above, using methyl (1s,4s)-4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)cyclohexane-1-carboxylate (3.00 g, 9.48 mmol) as the starting material.

[0336] Yield 2.20 g (77%), as an off-white solid. 1< H NMR (400 MHz, DMSO) δ 7.94 (d, J = 8.8 Hz, 2H), 7.10 (d, J = 8.8 Hz, 2H), 3.84 (s, 3H), 3.12-3.00 (m, 1H), 2.34-2.23 (m, 1H), 2.16 (dd, J = 3.6, 13.4 Hz, 2H), 2.02 (dd, J = 3.6, 13.4 Hz, 2H), 1.69-1.55 (m, 2H), 1.56-1.41 (m, 2H). Carboxylic acid proton not observed. m / z: [ESI +< ] 303 (M+H) +< .

[0337] 1-(3-(4-(Allyloxy)phenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylic acid. The compound was synthesized according to the procedure described above, using methyl 1-(3-(4-(allyloxy)phenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate (2.30 g, 6.70 mmol) as the starting material.

[0338] Yield 2.00 g (91%), as an off-white solid. 1< H NMR (400 MHz, DMSO) δ 12.36 (br s, 1H), 7.83 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 8.8 Hz, 2H), 6.13-6.00 (m, 1H), 5.46-5.36 (m, 1H), 5.34-5.26 (m, 1H), 4.68-4.61 (m, 2H), 4.03-3.95 (m, 2H), 3.29-3.23 (m, 2H), 2.60-2.52 (m, 1H), 1.99-1.92 (m, 2H), 1.71-1.49 (m, 2H). m / z: [ESI +< ] 330 (M+H) +< .Step 5: Tert-butyl 3-((1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamido)methyl)pyrrolidine-1-carboxylate

[0339] To a stirred solution of 1-[3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl]piperidine-4-carboxylic acid (1.00 g, 3.30 mmol) in DMF (5 mL) were added HATU (1.50 g, 3.94 mmol), DIPEA (0.85 g, 6.58 mmol) and tert-butyl 3-(aminomethyl)pyrrolidine-1-carboxylate (0.79 g, 3.94 mmol). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The resulting residue was purified by reverse phase flash chromatography with the following conditions: Column: Spherical C18, 20 - 40 µm, 330 g; Mobile Phase A: water (plus 10 mM NH 4 HCO 3 ); Mobile Phase B: acetonitrile; Flow rate:80 mL / min; Gradient: 50% B - 75% B in 20 min; Detector: UV 220 / 254 nm. The fractions containing the desired product were collected and concentrated under reduced pressure to afford tert-butyl 3-((1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamido)methyl)pyrrolidine-1-carboxylate as a light yellow oil.

[0340] Yield: 1.40 g (87%). 1< H NMR (400 MHz, DMSO) δ 7.99 (t, J = 5.4 Hz, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 8.8 Hz, 2H), 4.06 (d, J = 12.6 Hz, 2H), 3.82 (s, 3H), 3.33-3.25 (m, 2H), 3.25-2.99 (m, 5H), 2.94-2.85 (m, 1H), 2.47-2.38 (m, 1H), 2.32-2.21 (m, 1H), 1.91-1.77 (m, 3H), 1.69-1.47 (m, 3H), 1.39 (s, 9H). m / z: [ESI +< ] 486 (M+H) +< .

[0341] The intermediates below were prepared according to the procedure described above.

[0342] Tert-butyl 4-(((1-(4-methylbenzyl)pyrrolidin-3-yl)methyl)carbamoyl)piperidine-1-carboxylate. The compound was synthesized according to the procedure described above, using 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (1.44 g, 6.28 mmol) and (1-(4-methylbenzyl)pyrrolidin-3-yl)methanamine (1.41 g, 6.91 mmol) as the starting material.

[0343] Yield 1.08 g (41%), as a yellow oil. 1< H NMR (400 MHz, CDCl 3 ) δ 7.22 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 6.79 (br s, 1H), 4.28-4.02 (m, 2H), 3.69-3.53 (m, 2H), 3.34-3.16 (m, 2H), 3.01-2.88 (m, 1H), 2.83-2.70 (m, 2H), 2.68-2.61 (m, 1H), 2.53-2.45 (m, 2H), 2.37 (s, 3H), 2.28-2.17 (m, 1H), 2.10-2.00 (m, 1H), 1.79 (d, J = 13.6 Hz, 2H), 1.73-1.54 (m, 4H), 1.49 (s, 9H). m / z: [ESI +< ] 416 (M+H) +< .

[0344] Tert-butyl 3-(((1s,4s)-4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)cyclohexane-1-carboxamido)methyl)pyrrolidine-1-carboxylate. The compound was synthesized according to the procedure described above, using (1s,4s)-4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)cyclohexane-1-carboxylic acid (0.40 g, 1.32 mmol) and tert-butyl 3-(aminomethyl)pyrrolidine-1-carboxylate (0.32 g, 1.59 mmol) as the starting material.

[0345] Yield 0.40 g (63%), as an off-white solid. 1< H NMR (400 MHz, DMSO) δ 7.94 (d, J = 8.8 Hz, 2H), 7.93 (br s, 1H), 7.10 (d, J = 8.8 Hz, 2H), 3.84 (s, 3H), 3.32-3.25 (m, 1H), 3.23-3.14 (m, 1H), 3.12-2.99 (m, 3H), 2.97-2.85 (m, 1H), 2.31-2.10 (m, 3H), 1.89-1.79(m, 4H), 1.66-1.48 (m, 6H), 1.40 (s, 9H). m / z: [ESI +< ] 485 (M+H) +< .

[0346] Tert-butyl 3-(((1r,4r)-4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)cyclohexane-1-carboxamido)methyl)pyrrolidine-1-carboxylate. The compound was synthesized according to the procedure described above, using (1r,4r)-4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)cyclohexane-1-carboxylic acid (0.50 g, 1.65 mmol) and tert-butyl 3-(aminomethyl)pyrrolidine-1-carboxylate (0.40 g, 2.00 mmol) as the starting material.

[0347] Yield 0.70 g (87%), as an off-white solid. 1< H NMR (400 MHz, DMSO) δ 7.94 (d, J = 8.8 Hz, 2H), 7.93 (br s, 1H), 7.11 (d, J = 8.8 Hz, 2H), 3.84 (s, 3H), 3.34-3.24 (m, 1H), 3.22-3.11 (m, 1H), 3.10-2.96 (m, 3H), 2.97-2.85 (m, 1H), 2.34-2.13 (m, 3H), 1.88-1.80 (m, 4H), 1.66-1.48 (m, 6H), 1.40 (s, 9H). m / z: [ESI +< ] 485 (M+H) +< .

[0348] Tert-butyl 3-(4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperazine-1-carbonyl)piperidine-1-carboxylate. The compound was synthesized according to the procedure described above, using 1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (0.50 g, 2.18 mmol) and 3-(4-methoxyphenyl)-5-(piperazin-1-yl)-1,2,4-oxadiazole (0.68 g, 2.61 mmol) as the starting material.

[0349] Yield 0.60 g (58%), as a light yellow oil. 1< H NMR (400 MHz, DMSO) δ 7.85 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 3.95-3.85 (m, 2H), 3.82 (s, 3H), 3.72-3.53 (m, 8H), 2.81 (m, 1H), 2.76-2.65 (m, 2H), 1.87-1.79 (m, 1H), 1.71-1.60 (m, 1H), 1.58-1.41 (m, 2H), 1.41 (s, 9H). m / z: [ESI +< ] 472 (M+H) +< .

[0350] Tert-butyl 4-(3-(1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamido)propyl)piperazine-1-carboxylate. The compound was synthesized according to the procedure described above, using 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylic acid (0.20 g, 0.66 mmol) and tert-butyl 4-(3-aminopropyl)piperazine-1-carboxylate (0.19 g, 0.78 mmol) as the starting material.

[0351] Yield 0.27 g (77%), as a light yellow solid. 1< H NMR (400 MHz, CDCl 3 ) δ 7.95 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 6.82 (br s, 1H), 4.28 (td, J = 3.6, 12.8 Hz, 2H), 3.87 (s, 3H), 3.49-3.43 (m, 4H), 3.42-3.34 (m, 2H), 3.28-3.16 (m, 2H), 2.49 (t, J = 6.3 Hz, 2H), 2.46-2.41 (m, 4H), 2.36-2.25 (m, 1H), 1.97 (dd, J = 3.6, 13.6 Hz, 2H), 1.92-1.82 (m, 2H), 1.78-1.63 (m, 2H), 1.49 (s, 9H). m / z: [ESI +< ] 529 (M+H) +< .

[0352] Tert-butyl 3-((1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamido)methyl)pyrrolidine-1-carboxylate. The compound was synthesized according to the procedure described above, using 1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylic acid (0.30 g, 0.97 mmol) and tert-butyl 3-(aminomethyl)pyrrolidine-1-carboxylate (0.23 g, 1.15 mmol) as the starting material.

[0353] Yield 0.40 g (85%), as a light yellow solid. 1< H NMR (400 MHz, CDCl 3 ) δ 8.11 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 8.4 Hz, 2H), 5.97 (br s, 1H), 4.38-4.16 (m, 2H), 3.55-3.39 (m, 3H), 3.35-3.28 (m, 2H), 3.27-3.17 (m, 2H), 3.15-3.04 (m, 1H), 2.48-2.35 (m, 2H), 2.01-1.93 (m, 3H), 1.94-1.86 (m, 2H), 1.66-1.55 (m, 1H), 1.47 (s, 9H). m / z: [ESI +< ] 490, 492 (M+H) +< .

[0354] Tert-butyl 3-((1-(3-(4-cyanophenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamido)methyl)pyrrolidine-1-carboxylate. The compound was synthesized according to the procedure described above, using 1-(3-(4-cyanophenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylic acid (0.30 g, 1.01 mmol) and tert-butyl 3-(aminomethyl)pyrrolidine-1-carboxylate (0.24 g, 1.20 mmol) as the starting material.

[0355] Yield 0.40 g (82%), as a light yellow solid. 1< H NMR (400 MHz, CDCl 3 ) δ 7.94 (d, J = 8.6 Hz, 2H), 7.43 (d, J = 8.6 Hz, 2H), 5.77 (br s, 1H), 4.37-4.20 (m, 2H), 3.53-3.40 (m, 2H), 3.35-3.28 (m, 2H), 3.26-3.14 (m, 3H), 3.04 (s, 1H), 2.50-2.28 (m, 2H), 2.00-1.94 (m, 3H), 1.93-1.81 (m, 2H), 1.66-1.57 (m, 1H), 1.47 (s, 9H). m / z: [ESI +< ] 481 (M+H) +< .

[0356] Tert-butyl (1R,5S,6s)-6-(1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamido)-3-azabicyclo[3.1.0]hexane-3-carboxylate. The compound was synthesized according to the procedure described above, using 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylic acid (0.30 g, 0.99 mmol) and tert-butyl (1R,55,6s)-6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.24 g, 1.21 mmol) as the starting material.

[0357] Yield 0.29 g (61%), as a light yellow solid. 1< H NMR (400 MHz, CDCl 3 ) δ 7.94 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 5.72 (d, J = 2.4 Hz, 1H), 4.34-4.22 (m, 2H), 3.87 (s, 3H), 3.77-3.65 (m, 2H), 3.44-3.32 (m, 2H), 3.25-3.11 (m, 2H), 2.50-2.44 (m, 1H), 2.37-2.26 (m, 1H), 1.99-1.89 (m, 2H), 1.89-1.73 (m, 2H), 1.69-1.64 (m, 2H), 1.44 (s, 9H). m / z: [ESI +< ] 484 (M+H) +< .

[0358] Tert-butyl (R)-2-((1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamido)methyl)pyrrolidine-1-carboxylate. The compound was synthesized according to the procedure described above, using 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylic acid (0.10 g, 0.33 mmol) and tert-butyl (2R)-2-(aminomethyl)pyrrolidine-1-carboxylate (79 mg, 0.394 mmol) as the starting material.

[0359] Yield 0.10 g (64%), as a light yellow solid. 1< H NMR (400 MHz, CDCl 3 ) δ 7.95 (d, J = 8.8 Hz, 2H), 7.78 (br s, 1H), 6.97 (d, J = 8.8 Hz, 2H), 4.33-4.21 (m, 2H), 4.12-4.01 (m, 1H), 3.87 (s, 3H), 3.42-3.33 (m, 3H), 3.27-3.15 (m, 3H), 2.42-2.30 (m, 1H), 2.09-1.97 (m, 3H), 1.96-1.76 (m, 4H), 1.73-1.6 (m, 1H), 1.49 (s, 9H). m / z: [ESI +< ] 486 (M+H) +< .

[0360] Tert-butyl (R)-3-((1-(3-(4-methoxyphenyl)-1, 2,4-oxadiazol-5-yl)piperidine-4-carboxamido)methyl)pyrrolidine-1-carboxylate. The compound was synthesized according to the procedure described above, using 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylic acid (0.40 g, 1.32 mmol) and tert-butyl (3R)-3-(aminomethyl)pyrrolidine-1-carboxylate (0.32 g, 1.60 mmol) as the starting material.

[0361] Yield 0.50 g (78%), as a light yellow solid. 1< H NMR (400 MHz, CDCl 3 ) δ 7.94 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 5.73 (br s, 1H), 4.37-4.20 (m, 2H), 3.87 (s, 3H), 3.55-3.39 (m, 3H), 3.32 (d, J = 9.0 Hz, 2H), 3.26-3.12 (m, 2H), 3.12-2.93 (m, 1H), 2.52-2.28 (m, 1H), 2.04-1.92 (m, 3H), 1.92-1.80 (m, 3H), 1.68-1.56 (m, 1H), 1.48 (s, 9H). m / z: [ESI +< ] 486 (M+H) +< .

[0362] Tert-butyl (S)-3-((1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamido)methyl)pyrrolidine-1-carboxylate. The compound was synthesized according to the procedure described above, using 1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylic acid (0.50 g, 1.65 mmol) and tert-butyl (3S)-3-(aminomethyl)pyrrolidine-1-carboxylate (0.40 g, 2.00 mmol).

[0363] Yield 0.34 g (42%), as an off-white solid. 1< H NMR (400 MHz, CDCl 3 ) δ 7.97 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 5.70 (t, J = 5.6 Hz, 1H), 4.33 (d, J = 13.2 Hz, 2H), 3.88 (s, 3H), 3.55-3.28 (m, 3H), 3.28-3.14 (m, 3H), 3.10-3.00 (m, 1H), 2.50-2.30 (m, 2H), 2.04-1.96 (m, 4H), 1.94-1.80 (m, 2H), 1.66-1.56 (m, 1H), 1.48 (s, 9H). m / z: [ESI +< ] 486 (M+H) +< .

[0364] 1-(3-(4-(Allyloxy)phenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(4-methylbenzyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide. The compound was synthesized according to the procedure described above, using 1-(3-(4-(allyloxy)phenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylic acid (0.50 g, 1.52 mmol) and (1-(4-methylbenzyl)pyrrolidin-3-yl)methanamine (0.42 g, 2.06 mmol).

[0365] Yield 0.54 g (69%), as an off-white solid. 1< H NMR (400 MHz, CDCl 3 ) δ 7.95 (d, J = 8.8 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 6.94 (br s, 1H), 6.18-6.01 (m, 1H), 5.51-5.39 (m, 1H), 5.38-5.27 (m, 1H), 4.61 (td, J = 1.6, 5.4 Hz, 2H), 4.36-4.16 (m, 2H), 3.59 (s, 2H), 3.39-3.27 (m, 1H), 3.27-3.13 (m, 3H), 3.00-2.88 (m, 1H), 2.73-2.63 (m, 1H), 2.54-2.43 (m, 2H), 2.37 (s, 3H), 2.32-2.28 (m, 1H), 2.14-2.01 (m, 1H), 2.00-1.88 (m, 2H), 1.85-1.75 (m, 2H), 1.67-1.49 (m, 2H). m / z: [ESI +< ] 516 (M+H) +< .Step 6: 1-[3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5-yl]-N-(pyrrolidin-3-ylmethyl)piperidine-4-carboxamide hydrochloride

[0366] To a solution of tert-butyl 3-((1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamido)methyl)pyrrolidine-1-carboxylate (7.00 g, 14.42 mmol) in DCM (150 mL) was added a 4M solution of HCl in dioxane (70 mL) at room temperature. The resulting solution was stirred for 3 h at room temperature. The mixture was then concentrated under reduced pressure, triturated with diethyl ether (3 × 10 mL) and air dried, to afford 1-[3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl]-N-(pyrrolidin-3-ylmethyl)piperidine-4-carboxamide hydrochloride as a brown solid.

[0367] Yield: 5.00 g (82%). 1< H NMR (400 MHz, CD 3 OD) δ 7.90 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.4 Hz, 2H), 4.36-4.22 (m, 2H), 3.88 (s, 3H), 3.47-3.38 (m, 2H), 3.35-3.26 (m, 5H), 3.04-2.95 (m, 1H), 2.65-2.54 (m, 2H), 2.25-2.15 (m, 1H), 2.01-1.94 (m, 2H), 1.90-1.71 (m, 3H). m / z: [ESI +< ] 386 (M+H) +< .

[0368] The following compounds were synthesized according to the procedure described above. A selection of compounds were treated with trifluoroacetic acid (5 eq.) producing the corresponding trifluoroacetate salt. Purification by reverse phase chromatography with the addition of ammonium bicarbonate produced the parent compound, while the addition of formic acid, produced corresponding formate salt.

[0369] 3-(4-Methoxyphenyl)-5-(piperazin-1-yl)-1,2,4-oxadiazole. The compound was synthesized according to the procedure described above, using tert-butyl 4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperazine-1-carboxylate (1.00 g, 2.77 mmol) as the starting material.

[0370] Yield 0.58 g (81%), as an off-white solid. 1< H NMR (400 MHz, DMSO) δ 7.84 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H), 3.56-3.42 (m, 4H), 2.88-2.71 (m, 4H). m / z: [ESI +< ] 261 (M+H) +< .

[0371] 4-(5-(Piperazin-1-yl)-1,2,4-oxadiazol-3-yl)benzonitrile hydrochloride. The compound was synthesized according to the procedure described above, using tert-butyl 4-(3-(4-cyanophenyl)-1,2,4-oxadiazol-5-yl)piperazine-1-carboxylate (2.50 g, 7.03 mmol) as the starting material.

[0372] Yield 1.70 g (83%), as an off-white solid. 1< H NMR (400 MHz, CD 3 OD) δ 8.15 (d, J = 8.0 Hz, 2H), 7.87 (d, J = 8.0 Hz, 2H), 4.01 (t, J = 5.4 Hz, 4H), 3.44 (t, J = 5.4 Hz, 4H). Aliphatic NH proton not observed. m / z: [ESI +< ] 256 (M+H) +< .

[0373] 5-(Piperazin-1-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole. The compound was synthesized according to the procedure described above, using tert-butyl 4-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)piperazine-1-carboxylate (4.25 g, 10.26 mmol) as the starting material.

[0374] Yield 2.50 g (78%), as an off-white solid. m / z: [ESI +< ] 315 (M+H) +< . Crude material was used in the next step without further purification.

[0375] 3-(4-(Difluoromethoxy)phenyl)-5-(piperazin-1-yl)-1,2,4-oxadiazole. The compound was synthesized according to the procedure described above, using tert-butyl 4-(3-(4-(difluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)piperazine-1-carboxylate (3.10 g, 7.82 mmol) as the starting material.

[0376] Yield 2.00 g (86%), as an off-white solid. 1< H NMR (400 MHz, DMSO) δ 7.96 (d, J = 8.8 Hz, 2H), 7.37 (t, J = 73.6 Hz, 1H), 7.33 (d, J = 8.8 Hz, 2H), 3.89-3.82 (m, 4H), 3.30-3.23 (m, 4H). Aliphatic NH proton not observed. m / z: [ESI +< ] 297 (M+H) +< .

[0377] 3-(4-(Difluoromethyl)phenyl)-5-(piperazin-1-yl)-1,2,4-oxadiazole. The compound was synthesized according to the procedure described above, using tert-butyl 4-(3-(4-(difluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)piperazine-1-carboxylate (6.00 g, 15.77 mmol) as the starting material.

[0378] Yield 4.00 g (90%), as an off-white solid. 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.05 (d, J = 8.0 Hz, 2H), 7.73 (d, J= 8.0 Hz, 2H), 7.13 (t, J = 55.6 Hz, 1H), 3.89 (t, J = 5.2 Hz, 4H), 3.77 (br s, 1H), 3.26 (t, J = 5.2 Hz, 4H). m / z: [ESI +< ] 281 (M+H) +< .

[0379] 3-(4-(Allyloxy)phenyl)-5-(piperazin-1-yl)-1,2,4-oxadiazol hydrochloride. The compound was synthesized according to the procedure described above, using tert-butyl 4-(3-(4-(allyloxy)phenyl)-1,2,4-oxadiazol-5-yl)piperazine-1-carboxylate (4.00 g, 10.35 mmol) as the starting material.

[0380] Yield 2.80 g (84%), as an off-white solid. 1< H NMR (400 MHz, DMSO) δ 9.67 (br s, 2H), 7.84 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 8.8 Hz, 2H), 6.06 (tdd, J = 5.4, 10.6, 17.2 Hz, 1H), 5.42 (td, J = 1.6, 17.2 Hz, 1H), 5.28 (td, J = 1.6, 10.6 Hz, 1H), 4.64 (td, J = 1.6, 5.4 Hz, 2H), 3.86 (t, J = 5.4 Hz, 4H), 3.24 (t, J = 5.4 Hz, 4H). m / z: [ESI +< ] 287 (M+H) +< .

[0381] 4-(3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-(pyrrolidin-3-ylmethyl)piperazine-1-carboxamide hydrochloride. The compound was synthesized according to the procedure described above, using tert-butyl 3-((4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperazine-1-carboxamido)methyl)pyrrolidine-1-carboxylate (0.80 g, 1.64 mmol) as the starting material.

[0382] Yield 0.50 g (72%), as a light brown solid. 1< H NMR (400 MHz, DMSO) δ 9.55 (br s, 2H), 7.82 (d, J = 8.8 Hz, 2H), 7.45 (br s, 1H), 7.03 (d, J = 8.8 Hz, 2H), 3.79 (s, 3H), 3.66-3.60 (m, 2H), 3.56-3.52 (m, 4H), 3.51-3.45 (m, 4H), 3.44-3.40 (m, 2H), 3.10-2.98 (m, 2H), 2.48-2.38 (m, 1H), 2.01-1.82 (m, 1H), 1.66-1.55 (m, 1H). m / z: [ESI +< ] 387 (M+H) +< .

[0383] N-((1-(4-methylbenzyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide. The compound was synthesized according to the procedure described above, using tert-butyl 4-(((1-(4-methylbenzyl)pyrrolidin-3-yl)methyl)carbamoyl)piperidine-1-carboxylate (2.58 g, 6.21 mmol) as the starting material.

[0384] Yield 0.86 g (44%), as a light yellow solid. 1< H NMR (400 MHz, CDCl 3 ) δ 7.66 (br s, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 3.41 (d, J = 13.8 Hz, 2H), 3.37-3.31 (m, 1H), 3.31-3.21 (m, 2H), 3.12-3.01 (m, 2H), 3.00-2.83 (m, 3H), 2.76-2.65 (m, 1H), 2.56-2.44 (m, 1H), 2.38 (s, 3H), 2.23-2.09 (m, 2H), 2.06-1.96 (m, 5H), 1.82-1.72 (m, 1H). Aliphatic NH proton not observed. m / z: [ESI +< ] 316 (M+H) +< .

[0385] 3-(4-Phenoxypiperidin-1-yl)propan-1-amine hydrochloride. The compound was synthesized according to the procedure described above, using tert-butyl (3-(4-phenoxypiperidin-1-yl)propyl)carbamate (0.20 g, 0.60 mmol) as the starting material.

[0386] Yield 0.12 g (73%), as a light yellow solid. m / z: [ESI +< ] 235 (M+H) +< .

[0387] 3-(4-(Pyridin-2-ylmethyl)piperidin-1-yl)propan-1-amine hydrochloride. The compound was synthesized according to the procedure described above, using tert-butyl (3-(4-(pyridin-2-ylmethyl)piperidin-1-yl)propyl)carbamate (100 mg, 0.300 mmol) as the starting material.

[0388] Yield 50 mg (62%), as a light yellow solid. m / z: [ESI +< ] 234 (M+H) +< .

[0389] 2-(1-(Pyridin-2-ylmethyl)piperidin-4-yloxy)ethanamine dihydrochloride. The compound was synthesized according to the procedure described above, using tert-butyl 2-(1-(pyridin-2-ylmethyl)piperidin-4-yloxy)ethylcarbamate (0.35 g, 1.04 mmol) as the starting material.

[0390] Yield 0.25 g (78%), as an off-white solid. 1< H NMR (400 MHz, DMSO) δ 10.60 (br s, 1H), 8.69 (dd, J = 1.6, 4.8 Hz, 1H), 8.18 (br s, 3H, NH 3 +< ), 7.96 (dd, J = 6.8, 8.4 Hz, 1H), 7.75-7.68 (m, 1H), 7.50 (dd, J = 4.8, 7.6 Hz, 1H), 4.50 (s, 2H), 3.70-3.64 (m, 1H), 3.61 (t, J = 5.2 Hz, 2H), 3.47-3.41 (m, 2H), 3.16-3.01 (m, 2H), 3.03-2.93 (m, 2H), 2.07-1.97 (m, 2H), 1.96-1.86 (m, 2H). m / z: [ESI +< ] 236 (M+H) +< .

[0391] 3-(4-Fluoro-4-(pyridin-2-ylmethyl)piperidin-1-yl)propan-1-amine. The compound was synthesized according to the procedure described above, using tert-butyl (3-(4-fluoro-4-(pyridin-2-ylmethyl)piperidin-1-yl)propyl)carbamate (0.30 g, 0.85 mmol) as the starting material.

[0392] Yield 0.20 g (93%), as a yellow solid. 1< H NMR (400 MHz, CD 3 OD) δ 8.91-8.79 (m, 1H), 8.65 (dd, J = 6.8, 8.4 Hz, 1H), 8.15-7.98 (m, 2H), 3.96 (d, J = 5.4 Hz, 2H), 3.84-3.59 (m, 2H), 3.41-3.34 (m, 4H), 3.22-3.02 (m, 4H), 2.46-2.40 (m, 1H), 2.28-2.18 (m, 2H), 2.17-2.08 (m, 1H). Aliphatic NH 2 not observed. m / z: [ESI +< ] 252 (M+H) +< .

[0393] 3-(4-(2-Fluorobenzyl)piperidin-1-yl)propan-1-amine. The compound was synthesized according to the procedure described above, using tert-butyl (3-(4-(2-fluorobenzyl)piperidin-1-yl)propyl)carbamate (0.15 g, 0.43 mmol) as the starting material.

[0394] Yield 0.10 g (93%), as a yellow solid. 1< H NMR (400 MHz, DMSO) δ 7.36-7.22 (m, 2H), 7.22-7.08 (m, 2H), 3.46-3.36 (m, 2H), 3.11-3.04 (m, 2H), 2.96-2.77 (m, 4H), 2.61-2.56 (m, 2H), 2.08-1.98 (m, 2H), 1.89-1.53 (m, 5H). Aliphatic NH 2 not observed. m / z: [ESI +< ] 251 (M+H) +< .

[0395] 3-(4-Fluoro-4-(pyridin-2-yl)piperidin-1-yl)propan-1-amine. The compound was synthesized according to the procedure described above, using tert-butyl (3-(4-fluoro-4-(pyridin-2-yl)piperidin-1-yl)propyl)carbamate (1.20 g, 3.56 mmol) as the starting material.

[0396] Yield 0.80 g (95%), as a yellow solid. 1< H NMR (400 MHz, DMSO) δ 8.66-8.59 (m, 1H), 7.94 (dd, J = 1.6, 7.8 Hz, 1H), 7.63 (dd, J = 1.2, 7.8 Hz, 1H), 7.58-40 (m, 1H), 3.61-3.52 (m, 2H), 3.33-3.12 (m, 4H), 2.98-2.93 (m, 2H), 2.84-2.59 (m, 2H), 2.27-2.17 (m, 2H), 2.17-2.06 (m, 2H). Aliphatic NH 2 not observed. m / z: [ESI +< ] 238 (M+H) +< .

[0397] 5-(Azetidin-3-yl)-3-(4-methoxyphenyl)-1,2,4-oxadiazole. The compound was synthesized according to the procedure described above, using tert-butyl 3-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (1.00 g, 3.02 mmol) as the starting material.

[0398] Yield 0.55 g (79%), as a brown oil. 1< H NMR (400 MHz, CDCl 3 ) δ 8.05 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 4.32-4.22 (m, 1H), 4.18 (t, J = 8.1 Hz, 2H), 4.03 (t, J = 8.1 Hz, 2H), 3.90 (s, 3H). Aliphatic NH not observed. m / z: [ESI +< ] 232 (M+H) +< .

[0399] (1s,4s)-4-(3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-(pyrrolidin-3-ylmethyl)cyclohexane-1-carboxamide hydrochloride. The compound was synthesized according to the procedure described above, using tert-butyl 3-(((1s,4s)-4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)cyclohexane-1-carboxamido) methyl)pyrrolidine-1-carboxylate (0.40 g, 0.83 mmol) as the starting material.

[0400] Yield 0.30 g (86%), as an off-white solid. 1< H NMR (400 MHz, DMSO) δ 9.24 (br s, 2H), 8.09 (t, J = 5.6 Hz, 1H), 7.93 (d, J = 8.8 Hz, 1H), 7.10 (d, J = 8.8 Hz, 2H), 3.83 (s, 3H), 3.25-3.03 (m, 6H), 2.80-2.70 (m, 1H), 2.45-2.33 (m, 1H), 2.27-2.15 (m, 3H), 2.02-1.90 (m, 1H), 1.89-1.81 (m, 2H), 1.66-1.46 (m, 5H). [ESI +< ] 385 (M+H) +< .

[0401] (1r,4r)-4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-(pyrrolidin-3-ylmethyl)cyclohexane-1-carboxamide hydrochloride. The compound was synthesized according to the procedure described above, using tert-butyl 3-(((1r,4r)-4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)cyclohexane-1-carboxamido)methyl)pyrrolidine-1-carboxylate (0.70 g, 1.44 mmol) as the starting material.

[0402] Yield 0.40 g (66%), as an off-white solid. 1< H NMR (400 MHz, DMSO) δ 9.08 (br s, 2H), 8.06 (t, J = 5.8 Hz, 1H), 7.94 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 8.8 Hz, 2H), 3.84 (s, 3H), 3.26-3.01 (m, 6H), 2.80-2.70 (m, 1H), 2.45-2.33 (m, 1H), 2.27-2.16 (m, 3H), 2.02-1.90 (m, 1H), 1.91-1.84 (m, 2H), 1.69-1.46 (m, 5H). m / z: [ESI +< ] 385 (M+H) +< .

[0403] (4-(3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperazin-1-yl)(piperidin-3-yl)methanone hydrochloride. The compound was synthesized according to the procedure described above, using tert-butyl 3-(4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperazine-1-carbonyl)piperidine-1-carboxylate (0.80 g, 1.70 mmol) as the starting material.

[0404] Yield 0.60 g (86%), as a light yellow solid. 1< H NMR (400 MHz, DMSO) δ 9.26 (br s, 1H), 9.07 (br s, 1H), 7.85 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H), 3.76-3.58 (m, 8H), 3.28-3.13 (m, 3H), 3.04-2.78 (m, 2H), 1.92-1.83 (m, 1H), 1.83-1.70 (m, 2H), 1.68-1.43 (m, 1H). m / z: [ESI +< ] 372 (M+H) +< .

[0405] 1-(3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-(3-(piperazin-1-yl)propyl)piperidine-4-carboxamide hydrochloride. The compound was synthesized according to the procedure described above, using tert-butyl 4-(3-(1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamido)propyl)piperazine-1-carboxylate (0.20 g, 0.38 mmol) as the starting material.

[0406] Yield 0.15 g (84%), as a light brown solid. m / z: [ESI +< ] 429 (M+H) +< .

[0407] 1-(3-(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl)-N-(pyrrolidin-3-ylmethyl)piperidine-4-carboxamide trifluoroacetate. The compound was synthesized according to the procedure described above, using tert-butyl 3-((1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamido) methyl)pyrrolidine-1-carboxylate (0.20 g, 0.41 mmol) as the starting material.

[0408] Yield 0.12 g (61%), as a light yellow solid. 1< H NMR (400 MHz, CD 3 OD) δ 7.95 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 4.29-4.22 (m, 2H), 3.88-3.82 (m, 1H), 3.64-3.53 (m, 2H), 3.46-3.36 (m, 2H), 3.31-3.22 (m, 2H), 3.05-2.95 (m,1H), 2.62-2.54 (m, 2H), 2.22-2.12 (m, 1H), 2.01-1.90 (m, 2H), 1.89-1.64 (m, 3H). m / z: [ESI +< ] 390, 392 (M+H) +< .

[0409] 1-(3-(4-Cyanophenyl)-1,2,4-oxadiazol-5-yl)-N-(pyrrolidin-3-ylmethyl)piperidine-4-carboxamide trifluoroacetate. The compound was synthesized according to the procedure described above, using tert-butyl 3-((1-(3-(4-cyanophenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamido)methyl)pyrrolidine-1-carboxylate (0.20 g, 0.42 mmol) as the starting material.

[0410] Yield 0.20 g (crude), as a light yellow solid. 1< H NMR (400 MHz, CD 3 OD) δ 8.13 (d, J = 8.0 Hz, 2H), 7.86 (d, J = 8.0 Hz, 2H), 4.27 (dd, J = 4.0, 12.8 Hz, 2H), 3.65-3.51 (m, 1H), 3.47-3.36 (m, 2H), 3.321-3.25 (m, 4H), 3.02-2.96 (m, 1H), 2.64-2.53 (m, 2H), 2.23-2.12 (m, 1H), 1.99-1.89 (m, 2H), 1.87-1.73 (m, 3H). m / z: [ESI +< ] 381 (M+H) +< .

[0411] N-((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide hydrochloride. The compound was synthesized according to the procedure described above, using tert-butyl (1R,5S,6s)-6-(1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamido)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.29 g, 0.60 mmol) as the starting material.

[0412] Yield 0.22 g (87%), as a light yellow solid. 1< H NMR (400 MHz, CD 3 OD) δ 7.89 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 8.8 Hz, 2H), 4.24 (d, J = 13.2 Hz, 2H), 3.87 (s, 3H), 3.53 (s, 4H), 3.25 (ddd, J = 2.8, 10.8, 15.2 Hz, 2H), 2.65 (t, J = 2.8 Hz, 1H), 2.58-2.42 (m, 1H), 2.04-1.99 (m, 2H), 1.95-1.86 (m, 2H), 1.85-1.72 (m, 2H). m / z: [ESI +< ] 384 (M+H) +< .

[0413] (R)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-(pyrrolidin-2-ylmethyl)piperidine-4-carboxamide hydrochloride. The compound was synthesized according to the procedure described above, using tert-butyl (R)-2-((1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamido)methyl)pyrrolidine-1-carboxylate (0.34 g, 0.70 mmol) as the starting material.

[0414] Yield 0.24 g (81%), as a light yellow solid. 1< H NMR (400 MHz, CDCl 3 ) δ 10.00 (br s, 1H), 9.20 (br s, 1H), 7.95 (d, J = 8.0 Hz, 2H), 6.96 (d, J = 8.0 Hz, 2H), 4.38-4.22 (m, 2H), 3.87 (s, 3H), 3.46-3.16 (m, 3H), 2.71-2.51 (m, 1H), 2.30-2.00 (m, 8H), 1.98-1.76 (m, 2H), 1.28 (s, 1H), 1.17 (d, J = 6.4 Hz, 1H). Amide NH proton not observed. m / z: [ESI +< ] 386 (M+H) +< .

[0415] (S)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-(pyrrolidin-3-ylmethyl)piperidine-4-carboxamide hydrochloride. The compound was synthesized according to the procedure described above, using tert-butyl (R)-3-((1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamido)methyl)pyrrolidine-1-carboxylate (0.50 g, 1.03 mmol) as the starting material.

[0416] Yield 0.34 g (79%), as a light yellow solid. m / z: [ESI +< ] 386 (M+H) +< .

[0417] (R)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-(pyrrolidin-3-ylmethyl)piperidine-4-carboxamide. The compound was synthesized according to the procedure described above, using tert-butyl (S)-3-((1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamido)methyl)pyrrolidine-1-carboxylate (0.27 g, 0.56 mmol) as the starting material.

[0418] Yield 0.20 g (93%), as an off-white solid. m / z: [ESI +< ] 386 (M+H) +< . Crude material was used in the next step without further purification.

[0419] 1-(3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(((S)-piperidin-3-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide. The compound was synthesized according to the procedure described above, using tert-butyl (3R)-3-((3-((1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamido)methyl)pyrrolidin-1-yl)methyl)piperidine-1-carboxylate (0.24 g, 0.41 mmol) as the starting material.

[0420] Yield 0.18 g (91%), as a yellow solid. 1< H NMR (400 MHz, CDCl 3 ) δ 7.94 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 6.91-6.86 (m, 1H), 4.33-4.25 (m, 2H), 3.87 (s, 3H), 3.37-3.26 (m, 1H), 3.26-3.09 (m, 5H), 3.08-2.98 (m, 1H), 2.95-2.82 (m, 1H), 2.71-2.49 (m, 2H), 2.49-2.14 (m, 6H), 2.10-1.92 (m, 2H), 1.92-1.39 (m, 9H), 1.13-1.01 (m, 1H). m / z: [ESI +< ] 483 (M+H) +< .

[0421] 1-(3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-(((R)-1-(((S)-piperidin-3-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide. The compound was synthesized according to the procedure described above, using tert-butyl (R)-3-(((R)-3-((1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamido)methyl)pyrrolidin-1-yl)methyl)piperidine-1-carboxylate (0.30 g, 0.51 mmol) as the starting material.

[0422] Yield 0.15 g (60%), as an off-white solid. m / z: [ESI +< ] 483 (M+H) +< . Crude material was used in the next step without further purification.

[0423] 1-(3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-(((S)-1-(((S)-piperidin-3-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide. The compound was synthesized according to the procedure described above, using tert-butyl (R)-3-(((S)-3-((1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamido)methyl)pyrrolidin-1-yl)methyl)piperidine-1-carboxylate (0.30 g, 0.51 mmol) as the starting material.

[0424] Yield 0.15 g (60%), as an off-white solid. 1< H NMR (400 MHz, CD 3 OD) δ 7.89 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 8.8 Hz, 2H), 4.30-4.23 (m, 2H), 3.87 (s, 3H), 3.84-3.73 (m, 1H), 3.70-3.46 (m, 1H), 3.44-3.12 (m, 7H), 3.01-2.66 (m, 5H), 2.63-2.53 (m, 1H), 2.39-2.20 (m, 2H), 2.11-1.72 (m, 9H), 1.48-1.33 (m, 1H). Amide NH and aliphatic NH not observed. m / z: [ESI +< ] 483 (M+H) +< .

[0425] 1-(3-(4-Cyanophenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(((S)-piperidin-3-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide dihydrochloride. The compound was synthesized according to the procedure described above, using tert-butyl (3R)-3-((3-((1-(3-(4-cyanophenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamido)methyl)pyrrolidin-1-yl)methyl)piperidine-1-carboxylate (0.25 g, 0.43 mmol) as the starting material.

[0426] Yield 0.18 g (76%), as an off-white solid. 1< H NMR (400 MHz, DMSO) δ 11.09 (br s, 1H, HCl), 9.32 (br s, 1H), 9.10 (br s, 1H), 8.23 (br s, 1H), 8.07 (d, J = 8.8 Hz, 2H), 7.99 (d, J = 8.8 Hz, 2H), 4.13-4.06 (m, 2H), 3.66-3.50 (m, 2H), 3.37-2.94 (m, 9H), 2.84-2.58 (m, 2H), 2.53-2.45 (m, 4H), 2.31-2.19 (m, 0.5H), 2.15-1.99 (m, 0.5H), 1.95-1.54 (m, 8H), 1.29-1.20 (m, 1H). m / z: [ESI +< ] 478 (M+H) +< .

[0427] 1-(3-(4-Chlorophenyl)-1, 2,4-oxadiazol-5-yl)-N-((1-(((S)-piperidin-3-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide. The compound was synthesized according to the procedure described above, using tert-butyl (3R)-3-((3-((1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamido)methyl)pyrrolidin-1-yl)methyl)piperidine-1-carboxylate (0.35 g, 0.60 mmol) as the starting material.

[0428] Yield 0.26 g (90%), as an off-white solid. m / z: [ESI +< ] 487, 489 (M+H) +< . Crude material was used in the next step without further purification.

[0429] 1-(3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(((R)-piperidin-3-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide: Using tert-butyl (3S)-3-((3-((1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamido)methyl)pyrrolidin-1-yl)methyl)piperidine-1-carboxylate (100 mg, 0.172 mmol) as the starting material.

[0430] Yield 30 mg (36%), as a yellow solid. 1< H NMR (400 MHz, DMSO) δ 7.89 (t, J = 5.6 Hz, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 4.06 (td, J = 3.6, 13.2 Hz, 2H), 3.82 (s, 3H), 3.20 (dt, J = 3.2, 12.8 Hz, 2H), 3.09-2.93 (m, 2.5H), 2.85 (d, J = 11.2 Hz, 0.5H), 2.52-2.30 (m, 7H), 2.28-2.16 (m, 2H), 2.16-2.08 (m, 2H), 1.89-1.69 (m, 4H), 1.67-1.50 (m, 4H), 1.33 (d, J = 13.6 Hz, 2H), 1.04-0.89 (m, 1H). Aliphatic NH not observed. m / z: [ESI +< ] 483 (M+H) +< , (C 26 H 38 N 6 O 3 ).

[0431] N-((1-(azepan-4-ylmethyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide (Compound 391): Using tert-butyl 4-((3-((1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamido)methyl)pyrrolidin-1-yl)methyl)azepane-1-carboxylate (100 mg, 0.168 mmol) as the starting material.

[0432] Yield 19 mg (23%), as an off-white solid. 1< H NMR (400 MHz, DMSO) δ 7.89 (t, J = 5.6 Hz, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 8.8 Hz, 2H), 4.06 (td, J = 3.6, 13.2 Hz, 2H), 3.82 (s, 3H), 3.24-3.14 (m, 2H), 3.08-2.95 (m, 2H), 2.91-2.76 (m, 1H), 2.76-2.62 (m, 1H), 2.50-2.32 (m, 5H), 2.27-2.09 (m, 5H), 1.89-1.71 (m, 7H), 1.62 (dt, J = 4.4, 12.4 Hz, 2H), 1.53-1.28 (m, 2H), 1.21-0.96 (m, 2H). Aliphatic NH not observed. m / z: [ESI +< ] 497 (M+H) +< , (C 27 H 40 N 6 O 3 ).

[0433] 1-(3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(((S)-pyrrolidin-2-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide (Compound 392): Using tert-butyl (2S)-2-((3-((1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamido)methyl)pyrrolidin-1-yl)methyl) pyrrolidine-1-carboxylate (200 mg, 0.352 mmol) as the starting material.

[0434] Yield 87 mg (53%), as an off-white solid. 1H NMR (400 MHz, DMSO) δ 7.93 (t, J = 5.6 Hz, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 8.8 Hz, 2H), 4.06 (d, J = 13.2 Hz, 2H), 3.82 (s, 3H), 3.24-3.14 (m, 2H), 3.02 (d, J = 5.8 Hz, 2H), 2.90-2.75 (m, 1H), 2.61-2.50 (m, 4H), 2.48-2.36 (m, 4H), 2.30-2.18 (m, 2H), 1.90-1.68 (m, 5H), 1.62 (m, 3H), 1.30 (m, 2H). Aliphatic NH not observed. m / z: [ESI+] 469 (M+H)+, (C 25 H 36 N 6 O 3 ).

[0435] N-((1-(((R)-azetidin-2-yl)methyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide (Compound 413): Using tert-butyl (2R)-2-((3-((1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamido)methyl)pyrrolidin-1-yl)methyl)azetidine-1-carboxylate (80 mg, 0.144 mmol) as the starting material.

[0436] Yield 14 mg (21%), as an off-white solid. 1< H NMR (400 MHz, DMSO) δ 7.92 (br s, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 4.06 (d, J = 13.2 Hz, 2H), 3.82 (s, 3H), 3.48-3.30 (m, 2H), 3.25-3.14 (m, 2H), 3.08-2.93 (m, 2H), 2.85-2.55 (m, 1H), 2.50-2.35 (m, 6H), 2.28-2.08 (m, 3H), 1.92-1.75 (m, 4H), 1.68-1.56 (m, 2H), 1.45-1.28 (m, 1H). Aliphatic NH not observed. m / z: [ESI +< ] 455 (M+H) +< , (C 24 H 34 N 6 O 3 ).

[0437] N-((1-(((1s,3s)-3-aminocyclobutyl)methyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide (Compound 394): Using tert-butyl ((1s,3s)-3-((3-((1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamido)methyl)pyrrolidin-1-yl)methyl)cyclobutyl)carbamate (100 mg, 0.176 mmol) as the starting material.

[0438] Yield 40 mg (49%), as an off-white solid. 1< H NMR (400 MHz, DMSO) δ 7.83 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 8.8 Hz, 2H), 4.05 (td, J = 3.6, 13.2 Hz, 2H), 3.81 (s, 3H), 3.19 (dt, J = 3.2, 12.8 Hz, 2H), 3.12-3.03 (m, 1H), 2.99 (t, J = 7.2 Hz, 2H), 2.50-2.42 (m, 1H), 2.41-2.28 (m, 5H), 2.28-2.14 (m, 3H), 2.14-2.07 (m, 1H), 1.95-1.84 (m, 1H), 1.83-1.71 (m, 3H), 1.68-1.54 (m, 2H), 1.39-1.19 (m, 3H). Amide NH and aliphatic NH 2 not observed. m / z: [ESI +< ] 469 (M+H) +< , (C 25 H 36 N 6 O 3 ).

[0439] N-((1-(((1s,4s)-4-aminocyclohexyl)methyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide (Compound 423): Using tert-butyl ((1s,4s)-4-((3-((1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamido)methyl)pyrrolidin-1-yl)methyl)cyclohexyl)carbamate (100 mg, 0.168 mmol) as the starting material.

[0440] Yield 11 mg (13%), as an off-white solid. 1< H NMR (400 MHz, DMSO) δ 7.82 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 4.05 (td, J = 3.6, 13.2 Hz, 2H), 3.80 (s, 3H), 3.18 (dt, J = 3.2, 12.8 Hz, 2H), 3.07-2.93 (m, 2H), 2.90-2.80 (m, 1H), 2.50-2.43 (m, 1H), 2.43-2.34 (m, 3H), 2.30-2.08 (m, 4H), 1.89-1.73 (m, 3H), 1.68-1.54 (m, 2H), 1.52-1.27 (m, 10H). Amide NH and aliphatic NH 2 not observed. m / z: [ESI +< ] 497 (M+H) +< , (C 27 H 40 N 6 O 3 ).

[0441] 1-(3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(((R)-piperidin-2-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide (Compound 415): Using tert-butyl (2R)-2-((3-((1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamido)methyl)pyrrolidin-1-yl)methyl)piperidine-1-carboxylate (100 mg, 0.172 mmol) as the starting material.

[0442] Yield 31 mg (37%), as an off-white solid. 1< H NMR (400 MHz, DMSO) δ 7.91 (t, J = 5.6 Hz, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 4.06 (td, J = 3.6, 13.2 Hz, 2H), 3.82 (s, 3H), 3.25-3.14 (m, 2H), 3.10-2.98 (m, 2H), 2.96-2.89 (m, 1H), 2.53-2.31 (m, 8H), 2.30-2.17 (m, 1H), 2.16-2.02 (m, 2H), 1.86-1.72 (m, 3H), 1.72-1.45 (m, 5H), 1.40-1.16 (m, 3H), 1.01-0.86 (m, 1H). m / z: [ESI +< ] 483 (M+H) +< , (C 26 H 38 N 6 O 3 ).1-(3-(4-Methoxyphenyl)-1H-1,2,4-triazol-5-yl)piperidine-4-carboxylic acid (Intermediate H)

[0443] Step 1: Tert-butyl 1-cyanopiperidine-4-carboxylate

[0444] To a stirred solution of tert-butyl piperidine-4-carboxylate (2.00 g, 10.80 mmol) in DCM (20 mL) were added cyanogen bromide (1.26 g, 11.90 mmol) and DIPEA (3.07 g, 23.75 mmol) at 0°C. The resulting solution was stirred for 2 h at 0°C. The resulting mixture was diluted with water (10 mL) and extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl 1-cyanopiperidine-4-carboxylate as a yellow oil.

[0445] Yield: 1.60 g (70%). 1< H NMR (400 MHz, DMSO) δ 3.38-3.30 (m, 2H), 3.06 (ddd, J = 2.8, 11.4, 12.6 Hz, 2H), 2.44-2.37 (m, 1H), 1.81 (dd, J = 3.6, 13.8 Hz, 2H), 1.62-1.49 (m, 2H), 1.40 (s, 9H). m / z: [ESI +< ] 211 (M+H) +< .Step 2: Tert-butyl 1-(3-(4-methoxyphenyl)-1H-1,2,4-triazol-5-yl)piperidine-4-carboxylate

[0446] To a stirred solution of 4-methoxybenzohydrazide (1.00 g, 6.02 mmol) and tert-butyl 1-cyanopiperidine-4-carboxylate (1.52 g, 7.23 mmol) in ethanol (20 mL) were added a 0.7M solution of zinc chloride in THF (1.70 mL, 1.19 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 16 h at 80°C under a nitrogen atmosphere. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18, 20 - 40 µm, 330 g; Mobile Phase A: water (plus 10 mM formic acid); Mobile Phase B: acetonitrile; Flow rate: 80 mL / min; Gradient: 45% B - 70% B in 25 min; Detector, UV: 220 / 254 nm. The fractions containing desired product were collected and concentrated under reduced pressure to afford tert-butyl 1-(3-(4-methoxyphenyl)-1H-1,2,4-triazol-5-yl)piperidine-4-carboxylate as an off-white solid.

[0447] Yield: 2.00 g (93%). 1< H NMR (400 MHz, DMSO) δ 12.49 (br, s, 1H),7.83 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 3.85 (d, J = 12.0 Hz, 2H), 3.79 (s, 3H), 2.99-2.86 (s, 2H), 2.40 (t, J = 11.0 Hz, 1H), 1.84 (dd, J = 3.8, 13.4 Hz, 2H), 1.63-1.46 (m, 2H), 1.40 (s, 9H). m / z: [ESI +< ] 359 (M+H) +< .Step 3: 1-(3-(4-methoxyphenyl)-1H-1,2,4-triazol-5-yl)piperidine-4-carboxylic acid

[0448] A solution of tert-butyl 1-(3-(4-methoxyphenyl)-1H-1,2,4-triazol-5-yl)piperidine-4-carboxylate (2.00 g, 5.58 mmol) in DCM (20 mL) was treated with trifluoroacetic acid (8 mL) for 16 h at room temperature. The resulting solution was concentrated under reduced pressure. The residue was triturated with diethyl ether (30 mL). The precipitated solids were collected by filtration, washed with diethyl ether (2 × 5 mL) and dried in the air to afford 1-(3-(4-methoxyphenyl)-1H-1,2,4-triazol-5-yl)piperidine-4-carboxylic acid as an off-white solid.

[0449] Yield: 1.60 g (95%). 1< H NMR (400 MHz, DMSO) δ 7.85 (d, J = 8.8 Hz, 2H), 7.04 (d, J = 8.8 Hz, 2H), 3.88 (dd, J = 3.6, 12.4 Hz, 2H), 3.81 (s, 3H), 3.03 (t, J = 12.0 Hz, 2H), 2.48 (t, J = 11.0 Hz, 1H), 1.96-1.85 (m, 2H), 1.72-1.52 (m, 2H). Triazole NH and carboxylic acid protons not observed. m / z: [ESI +< ] 303 (M+H) +< .

[0450] The intermediates below were prepared according to the procedure described above.

[0451] 1-(3-(4-Methoxyphenyl)isoxazol-5-yl)piperidine-4-carboxylic acid. The compound was synthesized according to the procedure described above, using tert-butyl 1-(3-(4-methoxyphenyl)isoxazol-5-yl)piperidine-4-carboxylate (2.40 g, 6.70 mmol) as the starting material.

[0452] Yield 1.83 g (90%), as a brown solid. 1< H NMR (400 MHz, DMSO) δ 12.20 (br s, 1H), 7.68 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 5.78 (s, 1H), 3.81 (s, 3H), 3.69 (td, J = 4.0, 12.8 Hz, 2H), 3.13-2.99 (m, 2H), 2.55-2.46 (m, 1H), 1.97-1.87 (m, 2H), 1.69-1.57 (m, 2H). m / z: [ESI +< ] 303 (M+H) +< .

[0453] 1-(4'-Methoxy-[1,1'-biphenyl)-3-yl)piperidine-4-carboxylic acid. The compound was synthesized according to the procedure described above, using tert-butyl 1-(3-(5-methoxypyridin-2-yl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate (1.00 g, 2.77 mmol) as the starting material.

[0454] Crude yield 0.82 g, as an off-white solid. m / z: [ESI +< ] 312 (M+H) +< .

[0455] 1-(3-(2-Methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylic acid. The compound was synthesized according to the procedure described above, using tert-butyl 1-(3-(2-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate (1.00 g, 2.78 mmol) as the starting material.

[0456] Yield 0.50 g (59%), as a light yellow solid. 1< H NMR (400 MHz, CD 3 OD) δ 7.90 (d, J = 8.8 Hz, 2H), 7.69 (d, J = 8.8 Hz, 2H), 4.15 (td, J = 4.0, 13.6 Hz, 2H), 3.36-3.30 (m, 2H), 2.69-2.55 (m, 1H), 2.17 (s, 3H), 2.07 (td, J = 3.6, 11.6 Hz, 2H), 1.85-1.71 (m, 2H). Carboxylic acid proton not observed. m / z: [ESI +< ] 304 (M+H) +< .

[0457] 1-(3-(4-Acetamidophenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylic acid. The compound was synthesized according to the procedure described above, using tert-butyl 1-(3-(4-acetamidophenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate (1.00 g, 2.59 mmol) as the starting material.

[0458] Yield 0.45 g (53%), as a light yellow solid. 1< H NMR (400 MHz, CD 3 OD) δ 7.90 (d, J = 8.8 Hz, 2H), 7.69 (d, J = 8.8 Hz, 2H), 4.15 (td, J = 4.0, 13.6 Hz, 2H), 3.36-3.30 (m, 2H), 2.69-2.55 (m, 1H), 2.17 (s, 3H), 2.07 (td, J = 3.6, 11.6 Hz, 2H), 1.85-1.71 (m, 2H). Amide NH and carboxylic acid protons not observed. m / z: [ESI +< ] 331 (M+H) +< .

[0459] 1-(3-(5-Methoxypyridin-2-yl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylic acid. The compound was synthesized according to the procedure described above, using tert-butyl 1-(3-(5-methoxypyridin-2-yl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate (2.00 g, 5.55 mmol) as the starting material.

[0460] Crude yield 1.50 g, as a light yellow solid. m / z: [ESI +< ] 305 (M+H) +<

[0461] 1-(3-(3-methylphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylic acid. The compound was synthesized according to the procedure described above, using tert-butyl 1-(3-(3-methylphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate (1.00 g, 2.91 mmol) as the starting material.

[0462] Yield 0.60 g (72%), as a light yellow solid. 1< H NMR (400 MHz, CD 3 OD) δ 7.79 (dd, J = 0.8, 1.6 Hz, 1H), 7.77-7.72 (m, 1H), 7.42-7.29 (m, 2H), 4.16 (td, J = 4.0, 13.6 Hz, 2H), 3.40-3.29 (m, 2H), 2.69-2.55 (m, 1H), 2.42 (s, 3H), 2.07 (td, J = 3.6, 11.8 Hz, 2H), 1.85-1.73 (m, 2H). Carboxylic acid proton not observed. m / z: [ESI +< ] 288 (M+H) +< .

[0463] 1-(3-(3-Methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylic acid. The compound was synthesized according to the procedure described above, using tert-butyl 1-(3-(3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate (1.00 g, 2.78 mmol) as the starting material.

[0464] Yield 0.52 g (62%), as a light yellow solid. 1< H NMR (400 MHz, CD 3 OD) δ 7.54 (dd, J = 1.2, 7.6 Hz, 1H), 7.50 (dd, J = 1.4, 2.8 Hz, 1H), 7.39 (dd, J = 2.0, 8.0 Hz, 1H), 7.08 (ddd, J = 1.0, 2.8, 8.4 Hz, 1H), 4.15 (td, J = 3.6, 13.2 Hz, 2H), 3.86 (s, 3H), 3.40-3.28 (m, 2H), 2.69-2.55 (m, 1H), 2.07 (dd, J = 3.8, 13.8 Hz, 2H), 1.85-1.73 (m, 2H). Carboxylic acid proton not observed. m / z: [ESI +< ] 304 (M+H) +< .

[0465] 1-(3-(2-Methylphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylic acid. The compound was synthesized according to the procedure described above, using tert-butyl 1-(3-(2-methylphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate (2.00 g, 5.82 mmol) as the starting material.

[0466] Yield 0.90 g (54%), as a light yellow solid. 1< H NMR (400 MHz, CD 3 OD) δ 7.79 (dd, J = 1.6, 7.6 Hz, 1H), 7.39 (dd, J = 1.6, 7.6 Hz, 1H), 7.35-7.27 (m, 2H), 4.14 (td, J = 3.6, 13.2 Hz, 2H), 3.42-3.30 (m, 2H), 2.69-2.55 (m, 1H), 2.54 (s, 3H), 2.08 (dd, J = 3.6, 13.8 Hz, 2H), 1.85-1.74 (m, 2H). Carboxylic acid proton not observed. m / z: [ESI +< ] 288 (M+H) +< .

[0467] 1-(4-(4-Methoxyphenyl)oxazol-2-yl)piperidine-4-carboxylic acid. The compound was synthesized according to the procedure described above, using tert-butyl 1-(4-(4-methoxyphenyl)oxazol-2-yl)piperidine-4-carboxylate (0.44 g, 1.23 mmol) as the starting material.

[0468] Yield 0.37 g (99%), as an off-white solid. 1< H NMR (400 MHz, DMSO) δ 7.97 (s, 1H), 7.60 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 3.92 (d, J = 12.8 Hz, 2H), 3.77 (s, 3H), 3.15-3.01 (m, 2H), 2.54-2.44 (m, 1H), 1.96-1.85 (m, 2H), 1.65-1.49 (m, 2H). Carboxylic acid proton not observed. m / z: [ESI +< ] 303 (M+H) +< .

[0469] 1-(3-(Pyridin-4-yl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylic acid. The compound was synthesized according to the procedure described above, using tert-butyl 1-(3-(pyridin-4-yl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate (1.20 g, 3.63 mmol) as the starting material.

[0470] Yield 0.90 g (90%), as a yellow solid. 1< H NMR (400 MHz, CD 3 OD) δ 8.96 (d, J = 6.8 Hz, 2H), 8.49 (d, J = 6.8 Hz, 2H), 4.18 (td, J = 4.0, 13.6 Hz, 2H), 3.39 (ddd, J = 3.2, 11.2, 13.8 Hz, 2H), 2.72-2.63 (m, 1H), 2.08 (ddd, J = 4.6, 9.2, 13.0 Hz, 2H), 1.93-1.82 (m, 2H). Carboxylic acid proton not observed. m / z: [ESI +< ] 275 (M+H) +< .

[0471] 1-(3-(3-Acetamidophenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylic acid. The compound was synthesized according to the procedure described above, using tert-butyl 1-(3-(3-acetamidophenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate (1.00 g, 2.59 mmol) as the starting material.

[0472] Yield 0.15 g (17%), as a yellow solid. 1< H NMR (400 MHz, DMSO) δ 10.14 (br s, 1H), 8.15 (d, J = 2.0 Hz, 1H), 7.77 (dd, J = 2.0, 7.6 Hz, 1H), 7.59-7.53 (m, 1H), 7.41 (d, J = 7.8 Hz, 1H), 3.99 (td, J = 4.2, 13.2 Hz, 2H), 3.35-3.24 (m, 2H), 2.61-2.52 (m, 1H), 2.06 (s, 3H), 1.96 (dd, J = 3.6, 13.6 Hz, 2H), 1.69-1.53 (m, 2H). Carboxylic acid proton not observed . m / z: [ESI +< ] 331 (M+H) +< .

[0473] 1-(3-(4-(Trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylic acid. The compound was synthesized according to the procedure described above, using tert-butyl 1-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate (0.28 g, 0.68 mmol) as the starting material.

[0474] Yield 0.20 g (82%), as a light yellow solid. 1< H NMR (400 MHz, DMSO) δ 12.37 (br s, 1H), 8.02 (d, J = 8.8 Hz, 2H), 7.51 (d, J = 8.8 Hz, 2H), 4.00 (td, J = 4.0, 13.2 Hz, 2H), 3.32-3.22 (m, 2H), 2.68-2.58 (m, 1H), 2.03-1.91 (m, 2H), 1.70-1.58 (m, 2H). m / z: [ESI +< ] 358 (M+H) +< .

[0475] 1-(3-(4-(Difluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylic acid. The compound was synthesized according to the procedure described above, using tert-butyl 1-(3-(4-(difluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate (2.00 g, 5.06 mmol) as the starting material.

[0476] Yield 1.00 g (58%), as a light yellow solid. 1< H NMR (400 MHz, CDCl 3 ) δ 8.02 (d, J = 8.8 Hz, 2H), 7.20 (d, J = 8.8 Hz, 2H), 6.59 (t, J = 73.4 Hz, 1H), 4.19 (td, J = 4.2, 13.6 Hz, 2H), 3.33 (ddd, J = 3.2, 10.8, 13.8 Hz, 2H), 2.72-2.58 (m, 1H), 2.11 (dd, J = 3.8, 13.8 Hz, 2H), 1.90-1.76 (m, 2H). Carboxylic acid proton not observed. m / z: [ESI +< ] 340 (M+H) +< .

[0477] 1-(3-(2-Chloro-4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylic acid. The compound was synthesized according to the procedure described above, using tert-butyl 1-(3-(2-chloro-4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate (2.00 g, 5.08 mmol) as the starting material.

[0478] Yield 0.80 g (47%), as a light yellow solid. 1< H NMR (400 MHz, CDCl 3 ) δ 7.81 (d, J = 8.8 Hz, 1H), 7.04 (d, J = 2.6 Hz, 1H), 6.89 (dd, J = 8.8, 2.6 Hz, 1H), 4.17 (td, J = 4.2, 13.4 Hz, 2H), 3.86 (s, 3H), 3.31 (ddd, J = 3.2, 10.8, 13.8 Hz, 2H), 2.72-2.58 (m, 1H), 2.10 (dd, J = 4.0, 13.8 Hz, 2H), 1.90-1.76 (m, 2H). Carboxylic acid proton not observed. m / z: [ESI +< ] 338, 340 (M+H) +< .

[0479] 1-(3-(2-Methoxypyrimidin-5-yl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylic acid. The compound was synthesized according to the procedure described above, using tert-butyl 1-(3-(2-methoxypyrimidin-5-yl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate (0.20 g, 0.55 mmol) as the starting material.

[0480] Yield 0.11 g (65%), as an off-white solid. 1< H NMR (400 MHz, CD 3 OD) δ 9.07 (s, 2H), 4.17 (td, J = 4.2, 13.6 Hz, 2H), 4.10 (s, 3H), 3.40-3.34 (m, 2H), 2.72-2.58 (m, 1H), 2.08 (dd, J = 3.8, 13.8 Hz, 2H), 1.87-1.71 (m, 2H). Carboxylic acid proton not observed. m / z: [ESI +< ] 306 (M+H) +< .

[0481] 1-(3-(5-Methoxypyrazin-2-yl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylic acid. The compound was synthesized according to the procedure described above, using tert-butyl 1-(3-(5-methoxypyrazin-2-yl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate (140 mg, 0.387 mmol) as the starting material.

[0482] Yield 90 mg (76%), as a light yellow solid. 1< H NMR (400 MHz, DMSO) δ 12.38 (br s, 1H), 8.71 (d, J = 1.4 Hz, 1H), 8.43 (d, J = 1.4 Hz, 1H), 4.00 (td, J = 4.2, 13.6 Hz, 2H), 3.99 (s, 3H), 3.31-3.25 (m, 2H), 2.61-2.54 (m, 1H), 2.02-1.92 (m, 2H), 1.68-1.57 (m, 2H). m / z: [ESI +< ] 306 (M+H) +< .

[0483] 1-(3-(5-Methoxypyrimidin-2-yl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylic acid. The compound was synthesized according to the procedure described above, using tert-butyl 1-(3-(5-methoxypyrimidin-2-yl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate (0.70 g, 1.94 mmol) as the starting material.

[0484] Yield 0.50 g (85%) as a yellow solid. 1< H NMR (400 MHz, CD 3 OD) δ 8.63 (s, 2H), 4.21 (td, J = 3.6, 13.4 Hz, 2H), 4.05 (s, 3H), 3.32-3.23 (m, 2H), 2.48-2.38 (m, 1H), 2.03 (dd, J = 3.6, 13.8 Hz, 2H), 1.88-1.70 (m, 2H). Carboxylic acid proton not observed. m / z: [ESI +< ] 306 (M+H) +< .Tert-butyl 3-((4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperazine-1 carboxamido)methyl)pyrrolidine-1-carboxylate (Intermediate I)

[0485]

[0486] To a stirred solution of 3-(4-methoxyphenyl)-5-(piperazin-1-yl)-1,2,4-oxadiazole (0.50 g, 1.92 mmol) in DCM (8 mL) were added bis(trichloromethyl)carbonate (0.29 g, 0.98 mmol) and triethylamine (0.39 g, 3.85 mmol) at 0°C under a nitrogen atmosphere. The resulting solution was stirred for 0.5 h at 0°C. To the resulting mixture, was added tert-butyl 3-(aminomethyl)pyrrolidine-1-carboxylate (0.39 g, 1.92 mmol) at 0°C under a nitrogen atmosphere and stirring was continued for an additional 0.5 h. The resulting mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: Column: Spherical C18, 20 - 40 µm, 330 g; Mobile Phase A: water (plus 10 mM NH 4 HCO 3 ); Mobile Phase B: acetonitrile; Flow rate:80 mL / min; Gradient: 50% B - 75% B in 20 min; Detector: UV 254 / 215 nm. The fractions containing desired product were collected at 64% B and concentrated under reduced pressure to afford tert-butyl 3-((4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperazine-1-carboxamido)methyl)pyrrolidine-1-carboxylate as a light yellow oil.

[0487] Yield: 0.73 g (78%). 1< H NMR (400 MHz, DMSO) δ 7.85 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 6.79 (t, J = 5.6 Hz, 1H), 3.82 (s, 3H), 3.64-3.53 (m, 4H), 3.47 (m, 4H), 3.37-3.25 (m, 2H), 3.25-3.15 (m, 1H), 3.04 (dd, J = 7.6, 16.8 Hz, 2H), 2.94 (q, J = 7.2 Hz, 1H), 2.38-2.23 (m, 1H), 1.91-1.80 (m, 1H), 1.63-1.49 (m, 1H), 1.39 (s, 9H). m / z: [ESI +< ] 487 (M+H) +< .

[0488] The compounds below were prepared according to the procedure described above.

[0489] 4-(3-(4-(Allyloxy)phenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(4-methylbenzyl)pyrrolidin-3-yl)methyl)piperazine-1-carboxamide. The compound was synthesized according to the procedure described above, using 3-(4-(allyloxy)phenyl)-5-(piperazin-1-yl)-1,2,4-oxadiazole hydrochloride (1.00 g, 3.10 mmol) and (1-(4-methylbenzyl)pyrrolidin-3-yl)methanamine hydrochloride (1.68 g, 6.70 mmol) as the starting material.

[0490] Yield 1.50 g (94%), as a yellow oil. 1< H NMR (400 MHz, DMSO) δ 7.84 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 7.8 Hz, 2H), 7.12 (d, J = 7.8 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H), 6.74 (t, J = 5.6 Hz, 1H), 6.06 (tdd, J = 5.2, 10.6, 17.2 Hz, 1H), 5.48-5.36 (m, 1H), 5.29 (td, J = 1.6, 10.6 Hz, 1H), 4.64 (td, J = 1.6, 5.2 Hz, 2H), 3.57 (s, 2H), 3.54 (dd, J = 4.0, 6.8 Hz, 4H), 3.44 (dd, J = 4.0, 6.8 Hz, 4H), 3.09-2.98 (m, 3H), 2.64-2.54 (m, 2H), 2.37-2.30 (m, 2H), 2.28 (s, 3H), 1.90-1.76 (m, 1H), 1.50-1.40 (m, 1H). m / z: [ESI +< ] 517 (M+H) +< .

[0491] (4-(3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperazin-1-yl)(4-methylpiperidin-1-yl)methanone (Compound 145): Using 3-(4-methoxyphenyl)-5-(piperazin-1-yl)-1,2,4-oxadiazole (200 mg, 0.768 mmol) and 4-methylpiperidine (76 mg, 0.766 mmol) as the starting material.

[0492] Yield 66 mg (22%), as an off-white solid. 1< H NMR (400 MHz, DMSO) δ 7.84 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H), 3.65-3.58 (m, 6H), 3.32-3.23 (m, 4H), 2.74 (dd, J = 1.6, 13.6 Hz, 2H), 1.60 (d, J = 13.2 Hz, 2H), 1.53-1.48 (m, 1H), 1.13-1.02 (m, 2H), 0.92 (d, J = 6.4 Hz, 3H). m / z: [ESI +< ] 386 (M+H) +< , (C 20 H 27 N 5 O 3 ).

[0493] (4-(3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperazin-1-yl)(4-methoxypiperidin-1-yl)methanone (Compound 190): Using 3-(4-methoxyphenyl)-5-(piperazin-1-yl)-1,2,4-oxadiazole (0.20 g, 0.77 mmol) and 4-methoxypiperidine (0.11 g, 0.92 mmol) as the starting material.

[0494] Yield 0.22 g (71%), as a light yellow solid. 1< H NMR (400 MHz, DMSO) δ 7.83 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 8.8 Hz, 2H), 3.81 (s, 3H), 3.60 (dd, J = 3.6, 6.4 Hz, 4H), 3.43 (td, J = 4.4, 13.2 Hz, 2H), 3.33 (s, 2H), 3.27-3.24 (m, 6H), 2.95 (ddd, J = 3.2, 9.2, 13.2 Hz, 2H), 1.88-1.78 (m, 2H), 1.47-1.32 (m, 2H). m / z: [ESI +< ] 402 (M+H) +< , (C 20 H 27 N 5 O 4 ).

[0495] 1-(4-(4-(3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperazine-1-carbonyl)piperazin-1-yl)ethan-1-one (Compound 225): Using 3-(4-methoxyphenyl)-5-(piperazin-1-yl)-1,2,4-oxadiazole (0.20 g, 0.77 mmol) and 1-(piperazin-1-yl)ethan-1-one (0.10 g, 0.77 mmol) as the starting material.

[0496] Yield 0.20 g (62%), as a light yellow solid. 1< H NMR (400 MHz, DMSO) δ 7.84 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H), 3.66-3.58 (m, 4H), 3.51-3.39 (m, 4H), 3.32 (s, 2H), 3.31 (s, 2H), 3.22 (t, J = 5.2 Hz, 2H), 3.16 (t, J = 5.2 Hz, 2H), 2.02 (s, 3H). m / z: [ESI +< ] 415 (M+H) +< , (C 20 H 26 N 6 O 4 ).

[0497] (3-Isobutylpiperidin-1-yl)(4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperazin-1-yl)methanone (Compound 226): Using 3-(4-methoxyphenyl)-5-(piperazin-1-yl)-1,2,4-oxadiazole (0.15 g, 0.58 mmol) and 3-isobutylpiperidine (81 mg, 0.573 mmol) as the starting material.

[0498] Yield 0.20 g (82%), as a light yellow solid. 1< H NMR (400 MHz, DMSO) δ 7.84 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H), 3.68-3.49 (m, 6H), 3.26 (dd, J = 4.0, 6.4 Hz, 4H), 2.81-2.70 (m, 1H), 2.45-2.30 (m, 1H), 1.76 (d, J = 12.8 Hz, 1H), 1.64 (dt, J = 3.6, 13.2 Hz, 2H), 1.57-1.33 (m, 2H), 1.13-0.95 (m, 3H), 0.88 (d, J = 6.4 Hz, 3H), 0.86 (d, J = 6.4 Hz, 3H). m / z: [ESI +< ] 428 (M+H) +< , (C 23 H 33 N 5 O 3 ).

[0499] (4-(3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperazin-1-yl)(4-phenoxypiperidin-1-yl)methanone (Compound 216): Using 3-(4-methoxyphenyl)-5-(piperazin-1-yl)-1,2,4-oxadiazole (0.15 g, 0.58 mmol) and 4-phenoxypiperidine (0.10 g, 0.58 mmol) as the starting material.

[0500] Yield 0.15 g (55%), as a light yellow solid. 1< H NMR (400 MHz, DMSO) δ 7.84 (d, J = 8.8 Hz, 2H), 7.32-7.26 (m, 2H), 7.05 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.0 Hz, 2H), 6.93 (t, J = 7.2 Hz, 1H), 4.62-4.54 (m, 1H), 3.81 (s, 3H), 3.61 (dd, J = 3.6, 6.4 Hz, 4H), 3.49 (d, J = 13.2 Hz, 2H), 3.30 (dd, J = 3.6, 6.4 Hz, 4H), 3.10 (ddd, J = 3.2, 9.2, 12.8 Hz, 2H), 1.95 (d, J = 12.8 Hz, 2H), 1.67-1.53 (m, 2H). m / z: [ESI +< ] 464 (M+H) +< , (C 25 H 29 N 5 O 4 ).

[0501] 4-(3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-methylpiperazine-1-carboxamide (Compound 191): Using 3-(4-methoxyphenyl)-5-(piperazin-1-yl)-1,2,4-oxadiazole (0.20 g, 0.77 mmol) and methanamine hydrochloride (63 mg, 0.933 mmol) as the starting material.

[0502] Yield 0.15 g (62%), as a light yellow solid. 1< H NMR (400 MHz, DMSO) δ 7.84 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 8.8 Hz, 2H), 6.59 (q, J = 4.2 Hz, 1H), 3.81 (s, 3H), 3.56 (dd, J = 3.6, 6.8 Hz, 4H), 3.44 (dd, J = 3.6, 6.8 Hz, 4H), 2.59 (d, J = 4.2 Hz, 3H). m / z: [ESI +< ] 318 (M+H) +< , (C 15 H 19 N 5 O 3 ).

[0503] (3-(3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5-yl)azetidin-1-yl)(4-methylpiperidin-1-yl)methanone (Compound 153): Using 5-(azetidin-3-yl)-3-(4-methoxyphenyl)-1,2,4-oxadiazole (0.20 g, 0.87 mmol) and 4-methylpiperidine (0.17 g, 1.73 mmol) as the starting material.

[0504] Yield 0.16 g (52%), as a light yellow oil. 1< H NMR (400 MHz, DMSO) δ 8.96 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 8.8 Hz, 2H), 4.32 (m, 2H), 4.28-4.18 (m, 1H), 4.16 (m, 2H), 3.85 (s, 3H), 3.78-3.69 (d, J = 13.2 Hz, 2H), 2.77-2.66 (m, 2H), 1.63-1.55 (m, 2H), 1.56-1.46 (m, 1H), 1.06-0.93 (m, 2H), 0.90 (d, J = 6.4 Hz, 3H). m / z: [ESI +< ] 357 (M+H) +< , (C 19 H 24 N 4 O 3 ).

[0505] 4-(3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-methylpyrrolidin-3-yl)methyl)piperazine-1-carboxamide formate (Compound 206): Using 3-(4-methoxyphenyl)-5-(piperazin-1-yl)-1,2,4-oxadiazole (150 mg, 0.576 mmol) and (1-methylpyrrolidin-3-yl)methanamine (66 mg, 0.578 mmol) as the starting material.

[0506] Yield 150 mg (58%), as a light yellow solid. 1< H NMR (400 MHz, DMSO) δ 8.23 (s, 1H, HCOOH), 7.84 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 6.77 (t, J = 5.6 Hz, 1H), 3.82 (s, 3H), 3.57 (dd, J = 3.6, 6.8 Hz, 4H), 3.46 (dd, J = 3.6, 6.8 Hz, 4H), 3.07-3.00 (m, 2H), 2.64 (t, J = 8.8 Hz, 2H), 2.56 (t, J = 7.8 Hz, 1H), 2.43 (dd, J = 5.6, 9.6 Hz, 1H), 2.35 (s, 4H), 1.95-1.80 (m, 1H), 1.52-1.40 (m, 1H). m / z: [ESI +< ] 401 (M+H) +< , (C 20 H 28 N 6 O 3 ).

[0507] 4-(3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-phenylpyrrolidin-3-yl)methyl)piperazine-1-carboxamide (Compound 345): Using 3-(4-methoxyphenyl)-5-(piperazin-1-yl)-1,2,4-oxadiazole (100 mg, 0.384 mmol) and (1-phenylpyrrolidin-3-yl)methanamine (81 mg, 0.460 mmol) as the starting material.

[0508] Yield 10 mg (6%), as an off-white solid. 1< H NMR (400 MHz, DMSO) δ 7.84 (d, J = 8.8 Hz, 2H), 7.15 (dd, J = 7.2, 8.4 Hz, 2H), 7.05 (d, J = 8.8 Hz, 2H), 6.83 (t, J = 5.6 Hz, 1H), 6.57 (dd, J = 1.6, 7.2 Hz, 1H), 6.51 (dd, J = 1.2, 8.4 Hz, 2H), 3.82 (s, 3H), 3.57 (dd, J = 3.6, 6.8 Hz, 4H), 3.51-3.44 (m, 4H), 3.32-3.25 (m, 2H), 3.20 (dd, J = 1.6, 7.2 Hz, 1H), 3.15-3.05 (m, 2H), 3.00 (dd, J = 6.0, 9.6 Hz, 1H), 2.50-2.46 (m, 1H), 2.10-1.97 (m, 1H), 1.80-1.67 (m, 1H). m / z: [ESI +< ] 463 (M+H) +< , (C 25 H 30 N 6 O 3 ).

[0509] N-(3-(4-Benzylpiperidin-1-yl)propyl)-4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperazine-1-carboxamide (Compound 207): Using 3-(4-methoxyphenyl)-5-(piperazin-1-yl)-1,2,4-oxadiazole (150 mg, 0.576 mmol) and 3-(4-benzylpiperidin-1-yl)propan-1-amine (134 mg, 0.577 mmol) as the starting material.

[0510] Yield 0.15 g (50%), as a light yellow solid. 1< H NMR (400 MHz, DMSO) δ 7.84 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 7.4 Hz, 2H), 7.21-7.11 (m, 3H), 7.05 (d, J = 8.8 Hz, 2H), 6.69 (t, J = 5.6 Hz, 1H), 3.81 (s, 3H), 3.55 (dd, J = 3.6, 6.8 Hz, 4H), 3.43 (dd, J = 3.6, 6.8 Hz, 4H), 3.09-3.02 (m, 2H), 2.82 (d, J = 11.0 Hz, 2H), 2.50-2.48 (m, 2H), 2.24 (t, J = 7.2 Hz, 2H), 1.76 (t, J = 11.6 Hz, 2H), 1.60-1.49 (m, 4H), 1.48-1.37 (m, 1H), 1.23-1.08 (m, 2H). m / z: [ESI +< ] 519 (M+H) +< , (C 29 H 38 N 6 O 3 ).

[0511] 4-(3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-(3-(4-methylpiperidin-1-yl)propyl)piperazine-1-carboxamide formate (Compound 208): Using 3-(4-methoxyphenyl)-5-(piperazin-1-yl)-1,2,4-oxadiazole (150 mg, 0.576 mmol) and 3-(4-methylpiperidin-1-yl)propan-1-amine (90 mg, 0.576 mmol) as the starting material.

[0512] Yield 0.15 g (53%), as a light yellow solid. 1< H NMR (400 MHz, DMSO) δ 8.22 (s, 1H, HCOOH), 7.84 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 8.8 Hz, 2H), 6.73 (t, J = 5.6 Hz, 1H), 3.82 (s, 3H), 3.56 (dd, J = 3.6, 6.8 Hz, 4H), 3.45 (dd, J = 3.6, 6.8 Hz, 4H), 3.13-3.02 (m, 2H), 2.91 (d, J = 10.6 Hz, 2H), 2.39 (t, J = 7.2 Hz, 2H), 2.00 (t, J = 11.6 Hz, 2H), 1.68-1.55 (m, 4H), 1.36 (td, J = 5.6, 11.4 Hz, 1H), 1.20-1.08 (m, 2H), 0.89 (d, J = 6.4 Hz, 3H). m / z: [ESI +< ] 443 (M+H) +< , (C 23 H 34 N 6 O 3 ).

[0513] 4-(3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-(3-(4-phenoxypiperidin-1-yl)propyl)piperazine-1-carboxamide formate (Compound 245): Using 3-(4-methoxyphenyl)-5-(piperazin-1-yl)-1,2,4-oxadiazole (0.20 g, 0.77 mmol) and 3-(4-phenoxypiperidin-1-yl)propan-1-amine (0.22 g, 0.92 mmol) as the starting material.

[0514] Yield 0.12 g (28%), as a light yellow solid. 1< H NMR (400 MHz, DMSO) δ 8.17 (s, 1H, HCOOH), 7.85 (d, J = 8.8 Hz, 2H), 7.32-7.23 (m, 2H), 7.05 (d, J = 8.8 Hz, 2H), 6.96 (s, 1H), 6.97-6.87 (m, 2H), 6.70 (t, J = 5.2 Hz, 1H), 4.43-4.34 (m, 1H), 3.83 (s, 3H), 3.57 (dd, J = 3.6, 6.8 Hz, 4H), 3.46 (dd, J = 3.6, 6.8 Hz, 4H), 3.12-3.05 (m, 2H), 2.74 (t, J = 7.6 Hz, 2H), 2.36 (t, J = 7.2 Hz, 2H), 2.26 (t, J = 9.6 Hz, 2H), 1.94 (t, J = 8.0 Hz, 2H), 1.70-1.55 (m, 4H). m / z: [ESI +< ] 521 (M+H) +< , (C 28 H 36 N 6 O 4 ).

[0515] 4-(3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-(3-(4-(pyridin-2-ylmethyl)piperidin-1-yl)propyl)piperazine-1-carboxamide formate (Compound 248): Using 3-(4-methoxyphenyl)-5-(piperazin-1-yl)-1,2,4-oxadiazole (60 mg, 0.231 mmol) and 3-(4-(pyridin-2-ylmethyl)piperidin-1-yl)propan-1-amine (65 mg, 0.279 mmol) as the starting material.

[0516] Yield 20 mg (15%), as a light yellow solid. 1< H NMR (400 MHz, DMSO) δ 8.51-8.45 (m, 1H), 8.19 (s, 1H, HCOOH), 7.85 (d, J = 8.8 Hz, 2H), 7.68 (dd, J = 2.0, 7.6 Hz, 1H), 7.22 (dd, J = 1.2, 7.8 Hz, 1H), 7.20-7.15 (m, 1H), 7.06 (d, J = 8.8 Hz, 2H), 6.71 (t, J = 5.2 Hz, 1H), 3.82 (s, 3H), 3.56 (dd, J = 3.6, 6.8 Hz, 4H), 3.45 (dd, J = 3.6, 6.4 Hz, 4H), 3.12-3.05 (m, 2H), 2.89 (d, J = 11.2 Hz, 2H), 2.65 (d, J = 7.2 Hz, 2H), 2.34 (t, J = 7.2 Hz, 2H), 1.97-1.87 (m, 2H), 1.75 (ddd, J = 4.0, 7.2, 11.2 Hz, 1H), 1.62-1.50 (m, 4H), 1.31-1.13 (m, 2H). m / z: [ESI +< ] 520 (M+H) +< , (C 28 H 37 N 7 O 3 ).

[0517] 4-(3-(4-Cyanophenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(4-methylbenzyl)-5-oxopyrrolidin-3-yl)methyl)piperazine-1-carboxamide (Compound 268): Using 4-(5-(piperazin-1-yl)-1,2,4-oxadiazol-3-yl)benzonitrile (0.20 g, 0.77 mmol) and 4-(aminomethyl)-1-(4-methylbenzyl)pyrrolidin-2-one (0.21 g, 0.94 mmol) as the starting material.

[0518] Yield 0.10 g (26%), as a light yellow solid. 1< H NMR (400 MHz, DMSO) δ 8.07 (d, J = 8.4 Hz, 2H), 8.00 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 8.0 Hz, 2H), 6.81 (t, J = 5.6 Hz, 1H), 4.35-4.25 (m, 2H), 3.57 (dd, J = 3.6, 6.8 Hz, 4H), 3.45 (dd, J = 3.6, 6.8 Hz, 4H), 3.26 (dd, J = 7.6, 10.0 Hz, 1H), 3.06 (t, J = 5.6 Hz, 2H), 2.96 (dd, J =5.2, 10.0 Hz, 1H), 2.47-2.32 (m, 2H), 2.27 (s, 3H), 2.14 (dd, J = 6.0, 16.4 Hz, 1H). m / z: [ESI +< ] 500 (M+H) +< , (C 27 H 29 N 7 O 3 ).

[0519] N-(3-(4-(pyridin-2-ylmethyl)piperidin-1-yl)propyl)-4-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)piperazine-1-carboxamide (Compound 436): Using 5-(piperazin-1-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (80 mg, 0.255 mmol) and 3-(4-(pyridin-2-ylmethyl)piperidin-1-yl)propan-1-amine (60 mg, 0.257 mmol) as the starting material.

[0520] Yield 40 mg (27%), as a light yellow solid. 1< H NMR (400 MHz, DMSO) δ 8.48 (ddd, J = 0.8, 2.0, 4.8 Hz, 1H), 8.03 (d, J = 8.8 Hz, 2H), 7.68 (dd, J = 2.0, 7.6 Hz, 1H), 7.52 (dd, J = 1.0, 8.8 Hz, 2H), 7.21 (dd, J = 1.0, 8.0 Hz, 1H), 7.18 (ddd, J = 1.0, 2.4, 8.0 Hz, 1H), 6.69 (t, J = 5.6 Hz, 1H), 3.58 (dd, J = 3.6, 6.8 Hz, 4H), 3.45 (dd, J = 3.6, 6.8 Hz, 4H), 3.08-3.01 (m, 2H), 2.82 (d, J = 11.2 Hz, 2H), 2.63 (d, J = 7.2 Hz, 2H), 2.24 (t, J = 7.2 Hz, 2H), 1.84-1.62 (m, 3H), 1.62-1.45 (m, 4H), 1.28-1.12 (m, 2H); 19< F NMR (376 MHz, DMSO) δ -56.67. m / z: [ESI +< ] 574 (M+H) +< , (C 28 H 34 F 3 N 7 O 3 ).

[0521] 4-(3-(4-(Difluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-N-(3-(4-(pyridin-2-ylmethyl)piperidin-1-yl)propyl)piperazine-1-carboxamide (Compound 437): Using 3-(4-(difluoromethoxy)phenyl)-5-(piperazin-1-yl)-1,2,4-oxadiazole (100 mg, 0.337 mmol) and 3-(4-(pyridin-2-ylmethyl)piperidin-1-yl)propan-1-amine (79 mg, 0.339 mmol) as the starting material.

[0522] Yield 38 mg (20%), as a light orange solid. 1< H NMR (400 MHz, DMSO) δ 8.51-8.43 (m, 1H), 7.96 (d, J = 8.8 Hz, 2H), 7.68 (dd, J = 2.0, 7.6 Hz, 1H), 7.35 (t, J = 73.6 Hz, 1H), 7.31 (d, J = 8.8 Hz, 2H), 7.23-7.18 (m, 2H), 6.68 (t, J = 5.6 Hz, 1H), 3.58 (t, J = 5.2 Hz, 4H), 3.45 (t, J = 5.2 Hz, 4H), 3.05 (q, J = 6.4 Hz, 2H), 2.82 (d, J = 11.2 Hz, 2H), 2.64 (d, J = 7.2 Hz, 2H), 2.24 (t, J = 7.2 Hz, 2H), 1.86-1.63 (m, 3H), 1.63-1.48 (m, 4H), 1.20 (q, J = 10.8 Hz, 2H); 19< F NMR (376 MHz, DMSO) δ -82.61. m / z: [ESI +< ] 556 (M+H) +< , (C 28 H 35 F 2 N 7 O 3 ).

[0523] 4-(3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-(2-((1-(pyridin-2-ylmethyl)piperidin-4-yl)oxy)ethyl)piperazine-1-carboxamide (Compound 457): Using 3-(4-methoxyphenyl)-5-(piperazin-1-yl)-1,2,4-oxadiazole (100 mg, 0.384 mmol) and 2-((1-(pyridin-2-ylmethyl)piperidin-4-yl)oxy)ethan-1-amine (110 mg, 0.467 mmol) as the starting material.

[0524] Yield 26 mg (13%), as a light yellow solid. 1< H NMR (400 MHz, DMSO) δ 8.50-8.43 (m, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.75 (dd, J = 2.0, 7.6 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.24 (dd, J = 4.8, 7.2 Hz, 1H), 7.06 (d, J = 8.8 Hz, 2H), 6.70 (t, J = 5.6 Hz, 1H), 3.82 (s, 3H), 3.61-3.52 (m, 6H), 3.48-3.42 (m, 4H), 3.40-3.31 (m, 3H), 3.22-2.16 (m, 2H), 2.69 (d, J = 10.4 Hz, 2H), 2.12 (t, J = 10.8 Hz, 2H), 1.83 (d, J = 12.3 Hz, 2H), 1.48-1.38 (m, 2H). m / z: [ESI +< ] 522 (M+H) +< , (C 27 H 35 N 7 O 4 ).

[0525] N-(3-(4-phenoxypiperidin-1-yl)propyl)-4-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)piperazine-1-carboxamide (Compound 428): Using 5-(piperazin-1-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (100 mg, 0.318 mmol) and 3-(4-phenoxypiperidin-1-yl)propan-1-amine (75 mg, 0.320 mmol) as the starting material.

[0526] Yield 48 mg (26%), as an off-white solid. 1< H NMR (400 MHz, DMSO) δ 8.04 (d, J = 8.8 Hz, 2H), 7.59-7.48 (m, 2H), 7.30-7.23 (m, 2H), 6.98-6.86 (m, 3H), 6.70 (t, J = 5.6 Hz, 1H), 4.41-4.33 (m, 1H), 3.59 (t, J = 5.2 Hz, 4H), 3.46 (t, J = 5.2 Hz, 4H), 3.13-3.02 (m, 2H), 2.74-2.63 (m, 2H), 2.30 (t, J = 7.2 Hz, 2H), 2.18 (t, J = 10.4 Hz, 2H), 1.98-1.89 (m, 2H), 1.66-1.55 (m, 4H); 19< F NMR (376 MHz, DMSO) δ -56.67. m / z: [ESI +< ] 575 (M+H) +< , (C 28 H 33 F 3 N 6 O 4 ).

[0527] N-((1-((4-(pyridin-2-ylmethyl)piperidin-1-yl)methyl)cyclopropyl)methyl)-4-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)piperazine-1-carboxamide (Compound 450): Using 5-(piperazin-1-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (90 mg, 0.286 mmol) and (1-((4-(pyridin-2-ylmethyl)piperidin-1-yl)methyl)cyclopropyl)methanamine (80 mg, 0.308 mmol) as the starting material.

[0528] Yield 35 mg (20%), as an off-white solid. 1< H NMR (400 MHz, DMSO) δ 8.52-8.42 (m, 1H), 8.04 (d, J = 8.8 Hz, 2H), 7.68 (dd, J = 2.0, 7.6 Hz, 1H), 7.53 (d, J = 8.8 Hz, 2H...

Claims

1. A compound represented by the structure of formula (I(a(ii))): wherein R1 is F, Cl, Br, I, OH, CF3, OCH3, CN, NO2, -CH2CN, C1-C5 linear or branched, substituted or unsubstituted alkyl, C1-C5 linear or branched, or C3-C8 cyclic haloalkyl, substituted or unsubstituted C1-C5 linear or branched, or C3-C8 cyclic alkoxy, C1-C5 linear or branched haloalkoxy, NH-C(O)-R7, C1-C5 linear or branched alkoxyalkyl; wherein R7 is H, C1-C5 substituted or unsubstituted linear or branched alkyl, C1-C5 linear or branched alkoxy, C(O)R, or S(O)2R; wherein R is H, F, Cl, Br, I, OH, CF3, CN, NO2, C1-C5 linear or branched, substituted or unsubstituted alkyl, C1-C5 linear or branched alkoxy, C1-C5 linear or branched haloalkyl, R6-aryl, R6-N(alkyl)2, R6-NH(alkyl), R6-NH(cycloalkyl), R6-NH(aryl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic ring, R6-(substituted or unsubstituted heterocycle) or C(O)-(alkyl); R6 is [CH2]p, [CH2]pa-O-[CH2]pb, or [CH2]p-O; wherein p is 1, 2 or 3; and each pa and pb is independently an integer between 1 and 5; R4 is H, F, Cl, Br, I, OH, CF3, CN, NO2, C1-C5 linear or branched, substituted or unsubstituted alkyl, C1-C5 linear or branched, or C3-C8 cyclic haloalkyl; R6b is absent or O, C=O, [CH2]p; R8 is H, F, Cl, Br, I, OH, CF3, CN, NO2, C1-C5 linear or branched, substituted or unsubstituted alkyl, C1-C5 linear or branched, or C3-C8 cyclic haloalkyl; R9 is substituted or unsubstituted saturated C3-C8 cycloalkyl , substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted saturated or unsaturated 3-8 membered heterocyclic ring or R20, wherein R20 is represented by the following structure: B ring is a single or fused 3-12 membered heterocyclic ring, C3-C8 saturated or unsaturated cycloalkyl or a spiro ring system; X6 is N; X7 is CH or N; l and q are each independently an integer between 0 and 4; or its pharmaceutically acceptable salt, optical isomer, tautomer, hydrate, N-oxide, or any combination thereof.

2. The compound according to claim 1, wherein R1 is Cl, O-R20, OCH3, -R6CN, C1-C5 linear or branched, or C3-C8 cyclic haloalkyl, CF3, C1-C5 linear or branched haloalkoxy, OCF3, OCHF2, CHF2, CF3, or NHC(O)-CH3, wherein R7 is methyl, ethyl, CH2-CH2-O-CH3, or O-CH3; wherein R6 is CH2-CH2-CH2; wherein R6b is CH2; wherein R9 is cyclohexyl, cyclopentyl, cyclopropyl, cyclohexenyl, methyl piperidine, tetrahydrofuran or tetrahydrothiopyran; or wherein the B ring is piperidine or pyrrolidine, or any combination thereof.

3. The compound according to claims 1 or 2, wherein R6b is absent, O, C=O, [CH2]p or CH2.

4. The compound according to any of the preceding claims, wherein R9 is R20, substituted or unsubstituted heteroaryl, pyridine, 3-methyl-pyridine, thiazolyl, oxazolyl thiophenyl, furanyl, substituted or unsubstituted saturated C3-C8 cycloalkyl, cyclohexyl, cyclopentyl, cyclopropyl, substituted or unsubstituted C3-C8 cycloalkenyl, cyclohexenyl, substituted or unsubstituted 3-8 membered heterocyclic ring, tetrahydropyran, or tetrahydrothiopyran.

5. The compound according to any of claims 1-4, represented by the structure of formula (I(a(iii))):

6. The compound according to any of claims 1-5, represented by the structure of formula (II): wherein D ring is a saturated or unsaturated, single, fused or spiro, heterocyclic 3-12 membered ring or a saturated, unsaturated, single, fused or spiro, aliphatic carbocyclic 3-12 membered ring; and R11 and R12 are each independently H, F, Cl, Br, I, OH, CF3, OCH3, CN, NO2, C1-C5 linear or branched, substituted or unsubstituted alkyl, C1-C5 linear or branched, or C3-C8 cyclic haloalkyl, C1-C5 substituted or unsubstituted, linear or branched, or C3-C8 cyclic alkoxy, C1-C5 linear or branched haloalkoxy, C1-C5 linear or branched alkoxyalkyl, R20, NH2, NHR, NR2.

7. The compound according to claim 6, wherein the heterocyclic 3-12 membered D ring is tetrahydrofuran, piperidine, azepane, oxepane, azetidine, tetrahydrothiopyran, tetrahydropyran, pyrrolidine, oxetane or diazirine, or wherein the aliphatic carbocyclic 3-12 membered D ring is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclohexenyl; or wherein R11 and R12 are each independently methyl, ethyl, ethylacetylene, 1-butyne, CHF2, methoxy, O-(CH2)2-OH, OCF3 or OCHF2.

8. The compound according to any of claims 1 to 7, selected from the following: Compound numberCompound Name220N-((1-(cyclopropylmethyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide221N-((1-(cyclopropylmethyl)pyrrolidin-3-yl)methyl)-4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperazine-1-carboxamide2231-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((5-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide2431-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((5-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide2441-(3-(4-cyanophenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((5-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide2484-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-(3-(4-(pyridin-2-ylmethyl)piperidin-1-yl)propyl)piperazine-1-carboxamide286N-((1-(2-(3-(but-3-yn-1-yl)-3H-diazirin-3-yl)ethyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide320N-((1-(furan-2-ylmethyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide3221-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(pyridin-4-ylmethyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide323N-((1-(cyclopentylmethyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide325N-((1-((1H-pyrrol-3-yl)methyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide3261-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((4-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide3291-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((4-methylpyridin-3-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide330N-((1-(furan-3-ylmethyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide333N-((1-((5-fluoropyridin-3-yl)methyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide334N-((1-((3-fluoropyridin-2-yl)methyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide335N-((1-((5-fluoropyridin-2-yl)methyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide336N-((1-(cyclobutylmethyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide337N-((1-((2,2-dimethylcyclopropyl)methyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide338N-((1-(cyclohexylmethyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide3401-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(pyridin-2-ylmethyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide3411-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(thiazol-5-ylmethyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide3471-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((tetrahydrofuran-3-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide3481-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((3-methylpyridin-4-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide3501-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((3-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide3511-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((6-methylpyridin-3-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide352N-((1-(isothiazol-5-ylmethyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide3531-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((1-methylpiperidin-4-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide3541-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((tetrahydro-2H-thiopyran-4-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide3551-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((tetrahydro-2H-pyran-4-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide3561-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(pyridin-3-ylmethyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide3571-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(thiophen-3-ylmethyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide359N-((1-((3-fluoropyridin-4-yl)methyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide3601-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(thiazol-4-ylmethyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide3611-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((tetrahydro-2H-pyran-2-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide3631-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((1-methyl-1H-pyrrol-2-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide3641-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(thiazol-2-ylmethyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide3651-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((5-methylpyridin-3-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide3681-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((2-methylcyclopropyl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide3691-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(((S)-1-methylpyrrolidin-2-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide3701-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(tetrahydrofuran-3-yl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide3711-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((3-methyloxetan-3-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide3721-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(thiophen-2-ylmethyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide373N-((1-(isothiazol-4-ylmethyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide3751-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((tetrahydro-2H-pyran-3-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide3771-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((4-methyltetrahydro-2H-pyran-4-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide3791-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((5-methylfuran-2-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide3801-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((2-methylpyridin-3-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide3811-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((3-methylthiophen-2-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide3821-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((4-methylfuran-2-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide3831-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((2-methylthiazol-4-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide3841-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((4-methylthiazol-2-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide3851-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((5-methylthiophen-2-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide3871-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((6-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide3881-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((2-methylthiazol-5-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide389N-((1-((1H-pyrrol-2-yl)methyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide391N-((1-(azepan-4-ylmethyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide3921-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(((S)-pyrrolidin-2-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide393N-((1-((3,3-difluorocyclobutyl)methyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide394N-((1-(((1s,3s)-3-aminocyclobutyl)methyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide3951-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(oxetan-2-ylmethyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide3961-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(tetrahydro-2H-pyran-3-yl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide3981-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide399N-((1-(2-oxaspiro[3.3]heptan-6-yl]pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide4001-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(oxepan-4-yl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide4011-(3-(4-methoxyphenyl)-1, 2,4-oxadiazol-5-yl)-N-((1-(oxetan-3-yl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide4021-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(2-methyltetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide4041-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((4-methylthiazol-5-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide4051-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((tetrahydrofuran-2-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide4061-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((3-methylfuran-2-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide4071-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((5-methylthiazol-2-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide4081-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(oxetan-3-ylmethyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide409N-((1-(cyclohex-1-en-1-ylmethyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide4121-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(((R)-piperidin-3-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide413N-((1-(((R)-azetidin-2-yl)methyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide4141-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(((R)-1-methylpiperidin-2-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide4151-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(((R)-piperidin-2-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide4161-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide421N-((1-(cyclohexylmethyl)pyrrolidin-3-yl)methyl)-4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperazine-1-carboxamide4221-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(((S)-1-methylpiperidin-3-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide423N-((1-(((1s,4s)-4-aminocyclohexyl)methyl)pyrrolidin-3-yl)methyl)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide425N-((1-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl)pyrrolidin-3-yl)methyl)-4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperazine-1-carboxamide4304-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-N-(3-(4-(pyridin-2-ylmethyl)piperidin-1-yl)propyl)piperazine-1-carboxamide4314-(3-(4-cyanophenyl)-1,2,4-oxadiazol-5-yl)-N-(3-(4-(pyridin-2-ylmethyl)piperidin-1-yl)propyl)piperazine-1-carboxamide4324-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((tetrahydro-2H-pyran-4-yl)methyl)pyrrolidin-3-yl)methyl)piperazine-1-carboxamide433(R)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((1-methylpiperidin-4-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide434(S)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-((1-methylpiperidin-4-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide435N-(3-(4pyridin-2-yl)methyl)piperidin-1-yl)propyl)-1-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide436N-(3-(4-(pyridin-2-ylmethyl)piperidin-1-yl)propyl)-4-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)piperazine-1-carboxamide4374-(3-(4-(difluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-N-(3-(4-(pyridin-2-ylmethyl)piperidin-1-yl)propyl)piperazine-1-carboxamide440N-(3-(4-fluoro-4-(pyridin-2-yl)piperidin-1-yl)propyl)-4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperazine-1-carboxamide4414-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-(3-(4-(pyridin-2-ylmethyl)piperazin-1-yl)propyl)piperazine-1-carboxamide451N-(((4-(pyridin-2-ylmethyl)piperidin-1-yl)methoxy)methyl)-4-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)piperazine-1-carboxamide452N-(((4-(pyridin-2-yloxy)piperidin-1-yl)methoxy)methyl)-4-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)piperazine-1-carboxamide4531-(3-(4-(difluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-N-(3-(4-(pyridin-2-ylmethyl)piperidin-1-yl)propyl)piperidine-4-carboxamide4561-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-(2-((1-(pyridin-2-ylmethyl)piperidin-4-yl)oxy)ethyl)piperidine-4-carboxamide4574-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-(2-((1-(pyridin-2-ylmethyl)piperidin-4-yl)oxy)ethyl)piperazine-1-carboxamide4584-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)-N-(3-(4-(pyridin-2-ylmethyl)piperidin-1-yl)propyl)piperazine-1-carboxamide459N-(3-(4-(pyridin-2-ylmethyl)piperidin-1-yl)propyl)-4-(3-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)piperazine-1-carboxamide4604-(3-(4-(difluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-N-(3-(4-(pyridin-2-ylmethyl)piperidin-1-yl)propyl)piperazine-1-carboxamide461N-(3-(4-fluoro-4-(pyridin-2-ylmethyl)piperidin-1-yl)propyl)-4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperazine-1-carboxamide4641-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(((R)-1-methylpiperidin-3-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide4651-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-(((R)-1-(((S)-1-methylpiperidin-3-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide4661-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-(((S)-1-(((S)-1-methylpiperidin-3-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide4671-(3-(4-cyanophenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(((S)-1-methylpiperidin-3-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide4681-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)-N-((1-(((S)-1-methylpiperidin-3-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide4701-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)-N-(((S)-1-(((S)-1-methylpiperidin-3-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide4711-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)-N-(((R)-1-(((S)-1-methylpiperidin-3-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide4741-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)-N-(((S)-1-(((R)-1-methylpiperidin-3-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide4751-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)-N-(((R)-1-(((R)-1-methylpiperidin-3-yl)methyl)pyrrolidin-3-yl)methyl)piperidine-4-carboxamide9. A pharmaceutical composition comprising the compound of any of the preceding claims and a pharmaceutically acceptable carrier.

10. The compound according to any of claims 1 to 8, or the pharmaceutical composition according to claim 9, for use in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting cancer in a subject suffering from cancer; for use in suppressing, reducing or inhibiting tumor growth in a subject suffering from cancer; or a combination thereof.

11. The compound for use according to claim 10, wherein the cancer is selected from breast cancer, ovarian carcinoma, acute myeloid leukemia, chronic myelogenous leukemia, Hodgkin's and Burkitt's lymphoma, diffuse large Bcell lymphoma, prostate cancer, colon cancer, gastric cancer, primary central nervous system lymphoma, glioblastoma, medulloblastoma, melanoma, non-small cell lung carcinoma, germinal center-derived lymphomas, esophageal squamous cell carcinoma, osteosarcoma, bladder cancer, pancreatic cancer, lung adenocarcinoma, BRAF V600E thyroid cancer, choroid plexus carcinoma, colitis-associated cancer, epithelial ovarian cancer, colorectal cancer, pancreatic cancer or uterine cancer; and / or wherein the cancer is early cancer, advanced cancer, invasive cancer, metastatic cancer, drug resistant cancer or any combination thereof.

12. The compound for use according to any of claims 10-11, wherein the subject has been previously treated with chemotherapy, immunotherapy, radiotherapy, biological therapy, surgical intervention, or any combination thereof; wherein the compound is administered in combination with an anti-cancer therapy; or a combination thereof.

13. The compound for use according to claim 12, wherein the anti-cancer therapy is chemotherapy, immunotherapy, radiotherapy, biological therapy, surgical intervention, or any combination thereof.

14. An in vitro method of modulating c-Myc mRNA translation in a cell, comprising contacting a compound according to any of claims 1-8 with a cell, thereby modulating c-Myc mRNA translation in said cell.

15. An in vitro method of regulating c-Myc mRNA transcription in a cell, comprising contacting a compound according to any of claims 1-8 with a cell, thereby regulating c-Myc mRNA transcription in said cell.

16. The method of claim 14 or 15, wherein said method is carried out (a) by regulating c-Myc mRNA splicing (inclusion or exclusion of untranslated region or alternative usage of exons); (b) by regulation of c-Myc mRNA modifications; (c) by regulation of the interaction of RNA binding protein with c-Myc mRNA thereby changing mRNA localization; (d) by regulating c-Myc mRNA localization in the cytoplasm; (e) by regulating ribosomes or ribosome accessory factor to c-Myc mRNA; (f) by reducing the amount of c-Myc protein in the cell; or any combination thereof.