Sulfonamide-based compounds and use thereof as FTO inhibitors

Abstract

The present invention is directed to compound(s) and methods for use thereof, such as for the treatment and prevention of a disease / disorders related with FTO activity in a subject.

Description

SULFONAMIDE-BASED COMPOUNDS AND USE THEREOF AS FTP INHIBITORSCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority under 35 U.S.C. § 119(e) of IL Patent Application No. 315854 filed September 23, 2024 and U.S. Provisional Patent Application No. 63 / 753,491, filed February 4, 2025. The contents of the above applications are all incorporated by reference as if fully set forth herein in their entirety.FIELD OF THE INVENTION

[0002] The invention relates generally to the field of compositions comprising one or more sulfonamide-based compounds and methods of using same such as for treating of a Fat Mass and Obesity associated protein (FTO) related diseases.BACKGROUND

[0003] Current research in cancer treatment has identified the Fat Mass and Obesity associated protein (FTO) as a significant factor in mRNA stabilization and cancer cell proliferation. FTO is an m6A demethylase that plays a crucial role in the regulation of mRNA stability, and its overexpression has been linked to various cancers, including acute myeloid leukemia (AML), renal cell carcinoma, melanoma and pancreatic cancer. Studies have shown that specific knockdown techniques targeting FTO can lead to a substantial reduction in FTO mRNA and protein levels, resulting in decreased cancer cell proliferation.

[0004] To this end, the need for more effective and targeted treatments remains critical. The development of new FTO inhibitors that can selectively target and inhibit FTO activity in cancer cells is essential to address this unmet need and improve therapeutic outcomes for patients with FTO-related cancers.

[0005] The foregoing examples of the related art and limitations related therewith are intended to be illustrative and not exclusive. Other limitations of the related art will become apparent to those of skill in the art upon a reading of the specification.SUMMARY

[0006] In one aspect of the invention, there is provided a compound represented by or comprising Formula I:including any salt thereof, wherein: each B and C independently represents an aromatic or aliphatic heterocyclic ring; each X comprises -N- or -(CH)-; R2represents any one of: an optionally substituted heterocyclic ring, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl; each R1and R independently represents hydrogen or a substituent selected from halo, -NO2, -CN, -OH, -OR”, -CONH2, -CONR”2, -CNNR”2, -CSNR’2, -CONH-OH, -CONH-NH2, oxo, -NHCOR”, -NHCSR”, -NHCNR”, -NC(=O)OR”, -NC(=O)NR”, - NC(=S)OR”, -NC(=S)NR”, -SO2R”, -SOR”, -SR”, -SO2OR”, -SO2N(R”)2, -NHNR”2, - NNR”, C1-C6haloalkyl, optionally substituted C1-C6alkyl, -NR”2, -NH(C1-C6 alkyl), - N(C1-C6 alkyl)2, C1-C6alkoxy, C1-C6haloalkoxy, hydroxy(C1-C6alkyl), hydroxy(C1-C6alkoxy), alkoxy(C1-C6alkyl), alkoxy(C1-C6alkoxy), C1-C6alkyl-NR”2, C1-C6alkyl-SR”, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, -CO2H, -CO2R”, -OCOR”, -OCOR”, - OC(=O)OR”, -OC(=O)NR”, -OC(=S)OR”, -OC(=S)NR”, or a combination thereof; each R” independently represents hydrogen, or is selected from the group comprising optionally substituted C1-C10 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, or a combination thereof; and wherein R3 is H.

[0007] In one embodiment, the compound is represented by Formula 1 :

[0008] In one embodiment, B is selected from piperidine, pyridine, pyridazine, pyrimidine, pyrazine, pyrazole, imidazole, pyrrole and pyrrolidine.

[0009] In one embodiment, C is a Cs-C6heterocyclic aliphatic or Cs-C6heteroaromatic ring; and wherein R1represents one or more substituents, each independently selected from O-R’, halogen, nitro, cyano, thiol, -NR”2and C1-C6alkyl, wherein R’ comprises any one of an optionally substituted alkyl, an optionally substituted cycloalkyl, substituted cycloalkyl and an optionally substituted aryl.

[0010] In one embodiment, C is a Cs heteroaromatic ring.

[0011] In one embodiment, the compound is represented by Formula IA

[0012] In one embodiment, R1is attached to ring A at a position 1, 2, 3, 4 or any combination thereof.

[0013] In one embodiment, the compound is represented by Formula II:

[0014] In one embodiment, R is hydrogen or a C1-C6alkyl.

[0015] In one embodiment, R1is selected from -H, -OH, Cl, F, Br, I, NH2, NHR’, NR’ 2, C1-C6alkyl, and -O-R’.

[0016] In one embodiment, R2is an optionally substituted heterocyclic ring.

[0017] In one embodiment, R2is Pyrazole-Rx and wherein Rx represents any one of H, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted aryl, (C1-C6alkyl)-aryl and an optionally substituted heteroaryl.

[0018] In one embodiment, the compound is represented by Formula III:

[0019] In one embodiment, the compound comprises any one of:including any salt thereof.

[0020] In one embodiment, the compound is represented by Formula (IV):

[0021] In one embodiment, R is hydrogen.

[0022] In one embodiment, each R1independently represents -H, -OH, Cl, F, Br, I2, NH2, NHR’, NR’ 2, Ci-C6alkyl, or -O-R’, and wherein R’ comprises an optionally substituted C1-C6alkyl, or an optionally substituted cycloalkyl.

[0023] In one embodiment, the compound is represented by Formula (V):

[0024] In one embodiment, R2is an optionally substituted C3-C6 cycloalkyl, an optionally substituted aryl or an optionally substituted heteroaryl.

[0025] In one embodiment, the compound is any one of:including any salt thereof.

[0026] In another aspect, there is provided a pharmaceutical composition comprising the compound of the invention and a pharmaceutically acceptable carrier.

[0027] In one embodiment, the pharmaceutical composition comprising a therapeutically effective amount of the compound.

[0028] In one embodiment, the pharmaceutical composition is for use in the inhibition of FTO activity within a cell.

[0029] In one embodiment, the pharmaceutical composition is for use in the treatment of a cancer in a subject.

[0030] In one embodiment, the cancer is an FTO related cancer.

[0031] In some embodiments, the cancer comprises centrosome amplification.

[0032] In one embodiment, the FTO related cancer is selected from osteosarcoma, skin cancer, bladder cancer, pancreatic cancer, kidney cancer, cervical cancer, lung cancer, breast cancer, prostate cancer, liver cancer, ovarian cancer, head and neck cancer and hematopoietic cancer.

[0033] In another aspect, there is provided a method for preventing or treating a disease in a subject, comprising administering to the subject the pharmaceutical composition of the invention, thereby preventing or treating a disease or a disorder in a subject.

[0034] In one embodiment, the disease is a proliferative disease.

[0035] In one embodiment, the proliferative disease is associated with FTO overexpression in the subject.

[0036] In some embodiments, the proliferative disease comprises centrosome amplification.

[0037] In one embodiment, the method comprises administering a therapeutically effective amount of the pharmaceutical composition to the subject.

[0038] In one embodiment, administering comprises any one of: oral administration, rectal administration, vaginal administration, transdermal administration, ophthalmic administration, subcutaneous administration, intramuscular administration, intravenous administration, topical administration, nasal administration, sublingual administration, buccal administration, systemic administration, or any combination thereof.

[0039] In another aspect, there is provided a method for treating a cancer with centrosome amplification in a subject, comprising administering to the subject a therapeutically effective amount of an FTO inhibitor, thereby preventing or treating the cancer with centrosome amplification in the subject.

[0040] In one embodiment, the FTO inhibitor comprises one or more of: nucleic acid molecule, small molecule, polypeptide or protein, including any combination thereof.

[0041] In one embodiment, the FTO inhibitor is a compound of Formula I:including any salt thereof, wherein each of B and C independently represents a heterocyclic ring (i.e. an aromatic or aliphatic heterocyclyl); X represents -N- or -(CH)-; R2represents any one of: an optionally substituted cyclyl, an optionally substituted alkyl, an optionally substituted heterocyclic ring, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl; each R1and R independently represents hydrogen or a substituent selected from halo, thioxo, carbonyl, imino, amino, -NO2, -CN, -OH, -OR”, -CONH2, -C0NR”2, -CNNR”2, -CSNR’2, -CONH-OH, -C0NH-NH2, oxo, -NHCOR”, -NHCSR”, -NHCNR”, - NC(=0)0R”, -NC(=0)NR”, -NC(=S)OR”, -NC(=S)NR”, -SO2R”, -SOR”, -SR”, - SO2OR”, -SO2N(R”)2, -NHNR”2, -NNR”, C1-C6haloalkyl, optionally substituted C1-C6alkyl, -NR”2, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, Ci-C6alkoxy, Ci-C6haloalkoxy, hydroxy(C1-C6alkyl), hydroxy(C1-C6alkoxy), alkoxy(C1-C6alkyl), alkoxy(C1-C6alkoxy), C1-C6alkyl-NR”2, C1-C6alkyl-SR”, -CONH(C1-C6 alkyl), - CON(C1-C6 alkyl)2, -C02H, -C02R”, -0C0R”, -0C(=0)0R”, -0C(=0)NR”, - OC(=S)OR”, -OC(=S)NR”, C1-C6alkyl-OR” and R” or a combination thereof; each R” independently represents hydrogen, or is selected from the group comprising optionally substituted C1-C10 alkyl, optionally substituted C1-C10 alkenyl, optionally substituted Ci- C10 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C1-C10 alkyl- C3-C10 cycloalkyl, optionally substituted C3-C10 heterocyclyl, optionally substituted C1-C10 alkyl-C3-C10heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted C1-C10 alkyl-aryl / heteroaryl, hydroxy, -OR”, amino, -NH2, -NR”2, - NR”(C1-C6alkyl), -N(C1-C6alkyl)2, C1-C6alkoxy, C1-C6haloalkoxy, hydroxy(C1-C6alkyl), hydroxy(C1-C6alkoxy), alkoxy(C1-C6alkyl), alkoxy(C1-C6alkoxy), C1-C6alkyl- NR”2, C1-C6alkyl-SR”, C1-C6alkyl-OR” or a combination thereof.

[0042] In one embodiment, the cancer comprising centrosome amplification is selected from the group consisting of an osteosarcoma, a skin cancer, a bladder cancer, a pancreaticcancer, a kidney cancer, a cervical cancer, a lung cancer, a breast cancer, a prostate cancer, a liver cancer, an ovarian cancer, a head and neck cancer and a hematopoietic cancer comprising centrosome amplification.

[0043] In one embodiment, the method further comprises selecting a subject confirmed to suffer from a cancer comprising centrosome amplification.

[0044] The following embodiments and aspects thereof are described and illustrated in conjunction with systems, tools and methods which are meant to be exemplary and illustrative, not limiting in scope.

[0045] In addition to the exemplary aspects and embodiments described above, further aspects and embodiments will become apparent by study of the following detailed description.BRIEF DESCRIPTION OF THE DRAWINGS

[0046] Fig. 1 is a graph presenting analysis of the cell viability of A375 melanoma cells upon incubation with the exemplary compounds of the invention (RNB-675 and RNB 637).

[0047] Fig. 2 is a graph presenting analysis of the cell viability of MV411 AML cancer cells upon incubation with the exemplary compounds of the invention (RNB-557, RNB 637 and RNB-631) and cell viability was measured using the C6llTiter-Glo assay (Pr omega).

[0048] Figures 3A-3C. (3A)_AML cell lines were treated with an exemplary compound of the invention (RNB-557) at the indicated concentrations for 96 hours, and cell viability was assessed using the C6llTiter-Glo assay (Promega). (3B) C6llTiter-Glo assay results comparing the viability of Thp-1 AML cells and normal PBMCs from a healthy donor, 96 hours after treatment with the indicated compounds. Blue dashed square represents exemplary compounds of the invention (RNB-557, 675 and 637), while all other compounds are approved first-line treatments for AML. (3C) Table summarizing the IC50 values for the molecules shown in panel C.

[0049] Fig. 4 is a bar graph presenting the effect of 120 H treating with RNB-557 (3pM) on cancer cells proliferation.

[0050] Fig. 5 is a graph presenting analysis of the cell viability experiment which was performed for AML cell lines (Kasumi-1, THP-1, NKM-1 MV411) and normal PBMCs(Peripheral blood mononuclear cells) which were treated for 96 hours with RNB-557 at the indicated concentrations before measuring the cell viability using C6ll Titer Glow assay.

[0051] Figures 6A-6G. (6A) Schematic representation of m6A ELISA method principles: biotinylated-ssRNA oligos are uploaded to a strepavidin-coated plate. Following adherence of the RNA, m6A levels are detected by anti-m6A antibody. This assays allows the determination of FTO activity based on the presence of m6A-ssRNA after incubation with recombinant FTO. (6B) m6A RNA oligo vs non m6A RNA oligo detection calibration with different concentrations of primary (Anti m6A) and secondary (2nd) antibodies. (6C) Recombinant FTO western blot analysis. Recombinant FTO produced in E.coli was detected by the anti-human FTO antibody. (6D) Enzymatic reaction calibration of different FTO and ssRNA concentrations. (6E) FTO concentration calibration for 12.5nM ssRNA. (6F) FTO activity was also validated by m6A dot blot. ssRNA-m6A and FTO / BSA were incubated at 37c for 0, 2h or 4h before uploading to the membrane. (6G) Assay layout of screening assay measuring FTO inhibition. 7 compounds and control FTO inhibitors FB23 and MA, lOpM, are shown. Technical controls; ssRNA- m6A (No-FTO) and no ssRNA-m6A. Compounds 2 and 5 were detected as FTO inhibitors.

[0052] Figures 7A-7B are graphs showing an average inhibition of tumor volume growth (7A) and average mice body weight (7B) after in-vivo administration of RNB-557 (red) compared to a control group (black).

[0053] Figures 8A-8D are bar graphs, images and microscope images showing A549 cells transfected with either FTO siRNA or non-targeting siRNA at lOOnM with RNAiMAX reagent (Thermo Fisher). 72 hours post transfection cells were either harvested for RNA purification followed by RT-qPCR (8A), protein purification for Western Blot (WB) (8C and 8D) or fixed for Immunofluorescence (IF) (8B). FTO in both WB and IF was detected by an anti FTO antibody (Several antibodies were screened and anti FTO ab 126605 by Abeam gave the best signal to noise ratio in both WB and IF).

[0054] Figures 9A-9B are graphs showing cell cycle analysis using Hoechst DNA staining followed by flow cytometry. Data shows accumulation of cells at G2 / M phase after treatment with 557 (9A) and 637 (9B) in different concentrations as indicated.

[0055] Figures 10A-10B are graphs and microscope images showing cell cycle analysis using Hoechst DNA staining followed by flow cytometry (10A) and microscopy (10B).Flow cytometry data (10A) show accumulation of cells at G2 / M phase after treatment with RNB-557 (Left) andRNB-637 (Right) at different concentrations as indicated. Microscope images (X40) show high DNA content of cells with aberrant mitotic process (10B).

[0056] Figures 11A-11B are microscope images (X60) of treated (11A) BxPC-3cells with DMSO or RNB-637 at a concentration of 3pM. (11B) C6lls were stained for DNA content using Hoechst (Blue or teal) and alpha-Tubulin (green).

[0057] Figures 12A-12B are microscope images (X60) taken in BxPC3 prostate cancer cells with an (12A) anti-FTO antibody (Abeam: abl 36605), an anti-pericentrin antibody (Abeam: ab28144), and (12B) an anti-KIFCl antibody showing FTO enrichment at centromeres and KIFC1 mislocalization.

[0058] Figures 12C-12D are (12C) microscope images and bar graphs quantifying KIFC1 localization between centrosomes and (12D) the distance between centrosomes during mitosis.

[0059] Figures 13A-13C are (13A) microscope images (X40) taken 144 hours post double siRNA transfection showing FTO expression, pericentrin expression and the nucleus. Yellow arrows depict mitotic cells. Bar graphs quantify (13B) the number of cells with 2 centromeres and (13C) the number of mitotic cells with chromosome misalignment. Chromosome misalignment refers to a mitotic defect in which chromosomes fail to properly align at the metaphase plate (midzone) during mitosis.

[0060] Figures 14A-14C: are (14A-14B) microscope images (X40) and (14C) bar graphs of cancer cells treated with various concentrations of RNB-637 and then imaged to identify centrosome clustering and chromosome misalignment and measured to quantify apoptosis.

[0061] Figures 15A-15F: (15A) Bar graph of centromere number in cell lines with and without CA. (15B) Bar graph of the percentage of mitotic cells that show multipolar mitosis in cell lines with and without CA. (15C) Microscope images of centromeres (as seen by pericentrin staining) in cell lines with and without CA. (15D) A line graph of relative cell number in CA+ and CA- cells with increasing concentrations of an inhibitor of the invention (RNB-637). (15E) A line graph of relative cell number of cancer cells with CA and normal cells without CA upon administration of RNB-637. (15F) Table summarizing the killing ability of the FTO inhibitor RNB-637 in cells with and without CA.

[0062] Fig. 16 is a bar graph presenting the effect of treatment with RNB-637 (1 pM) on cancer cell proliferation.DETAILED DESCRIPTION

[0063] In one aspect of the invention disclosed herein, there is a compound or a salt thereof, wherein the compound is represented by Formula I:, including any salt thereof, wherein: each of B and C independently represents a heterocyclic ring (i.e. an aromatic or aliphatic heterocyclyl); X represents -N- or -(CH)-; R2represents any one of: an optionally substituted cyclyl, an optionally substituted alkyl, an optionally substituted heterocyclic ring, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl; each R1and R independently represents hydrogen or a substituent selected from halo, thioxo, carbonyl, imino, -NO2, -CN, -OH, -OR”, -CONH2, -CONR”2, -CNNR”2, -CSNR’2, -CONH-OH, -CONH-NH2, oxo, -NHCOR”, -NHCSR”, -NHCNR”, -NC(=O)OR”, -NC(=O)NR”, -NC(=S)OR”, -NC(=S)NR”, -SO2R”, -SOR”, -SR”, - SO2OR”, -SO2N(R”)2, -NHNR’b, -NNR”, C1-C6haloalkyl, an optionally substituted alkyl, optionally substituted C1-C6alkyl, -NR”2, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, Ci- C6alkoxy, C1-C6haloalkoxy, hydroxy(C1-C6alkyl), hydroxy(C1-C6alkoxy), alkoxy(C1-C6alkyl), alkoxy(Ci-C6alkoxy), Ci-C6alkyl-NR”2, Ci-C6alkyl-SR”, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, -CO2H, -CO2R”, -OCOR”, -OC(=O)OR”, -OC(=O)NR”, - OC(=S)OR”, -OC(=S)NR”, C1-C6alkyl-OR” and R” or a combination thereof; each R” independently represents hydrogen, or is selected from the group comprising optionally substituted C1-C10 alkyl, optionally substituted cycloalkyl, optionally substituted C1-C10 alkenyl, optionally substituted C1-C10 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, an optionally substituted cyclyl, , hydroxy, -OR”, amino, -NH2, -NR”2, -NR”(C1-C6 alkyl), -N(C1-C6alkyl)2, C1-C6alkoxy, C1-C6haloalkoxy, hydroxy(C1-C6alkyl), hydroxy(C1-C6alkoxy), alkoxy(C1-C6alkyl), alkoxy(C1-C6alkoxy), C1-C6alkyl- NR”2, C1-C6alkyl-SR”, C1-C6alkyl-OR” or a combination thereof.

[0064] In some embodiments, the compound is represented by Formula I, with the proviso that the compound is not-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-lHpyrrolo[2,3-c]pyridin-4-yl)phenyl]cyclopropane- sulfonamide; N-[3-(4-Amino-pyrazolo[3,4-d]pyrimidin-l-yl)-phenyl]-4-chloro- benzenesulfonamide; N- [3 -(4-amino-pyrazolo [3 ,4-d]pyrimidin- 1 -y l)-phenyl] -4- methoxybenzenesulfonamide; N-[4-(4-Amino-pyrazolo[3,4-d]pyrimidin-l-yl)-phenyl]-4- chloro-benzenesulfonamide; N-[4-(4-Amino-pyrazoIo[3,4-d]pyrimidin-l-yl)-phenyl]-4- methoxybenzenesulfonamide; N-[3-(6,7-dihydro-5H-pyrrolo[2,l-c][l,2,4]triazol-3- yl)phenyl]benzenesulfonamide; N-[3-(6,7-dihydro-5H-pyrrolo[l,2-a]imidazol-3- yl)phenyl]cyclohexanesulfonamide; N-[3-(6,7-dihydro-5H-pyrrolo[l,2-a]imidazol-3- yl)phenyl]cyclopropanesulfonamide; N-[3-(6,7-dihydro-5H-pyrrolo[l,2-a]imidazol-3- yl)phenyl]-2-fluorobenzenesulfonamide; N-[3-(6,7-dihydro-5H-pyrrolo[l,2-a]imidazol-3- yl)phenyl]-2,4-difluoro-benzenesulfonamide.

[0065] In some embodiments, the compound is of Formula I, wherein R1is H or represents one or more substituents each independently selected hydroxy, halo, nitro, cyano, SR”, -N ”2, alkyl (e.g. C1-C6alkyl), and -OR”.

[0066] In some embodiments, the compound is of Formula I, wherein R2represents any one of: an optionally substituted cyclyl, an optionally substituted heterocyclic ring, an optionally substituted pyrazole, an optionally substituted cycloalkyl, an optionally substituted aryl, or an optionally substituted heteroaryl.

[0067] In some embodiments, B comprises a C3-C6 heterocyclic ring or a C5-C6 heteroaromatic ring. In some embodiments, B is selected from piperidine, pyridine, pyridazine, pyrimidine, pyrazine, pyrazole, imidazole, pyrrole, and pyrrolidine.

[0068] In some embodiments, B is a C6aryl or heteroaryl. In some embodiments, B is pyridine. In some embodiments, B is pyridazine. In some embodiments, B is pyrimidine. In some embodiments, B is pyrazine.

[0069] In some embodiments, C is a Cs-C6heterocyclic aliphatic or Cs-C6heteroaromatic ring. In some embodiments, C is a C5 heterocyclic aliphatic or C5 heteroaromatic ring. In some embodiments, C is selected from pyrazole, imidazole, pyrrole, pyrrolidine. In some embodiments, C is imidazole.

[0070] In some embodiments, the compound is of Formula I, wherein B is pyridine and C is imidazole. In some embodiments, the compound is of Formula I, wherein B is pyridine and C is imidazole; R3 is H and R2is an optionally substituted heterocyclic ring (e.g. optionally substituted pyrazole). In some embodiments, the compound is of Formula I, wherein B is pyridine and C is imidazole; R3 is H and R2is a is an optionally substituted heterocyclic ring (e.g. optionally substituted pyrazole); wherein R1is H or represents one or more substituents each independently selected hydroxy, halo, nitro, cyano, SR”, -NR”2, alkyl (e.g. C1-C6alkyl), C1-C6alkyl-OR”, R” and -OR”, optionally wherein R is H. In some embodiments, the compound is of Formula I, wherein B and C are as disclosed above and wherein X is positioned at the position 3.

[0071] In some embodiments, the compound is represented by Formula I’:, wherein XI is N or CH; and wherein X, R, Rl and R2are as described hereinabove.

[0072] In some embodiments, the compound is represented by Formula IA:described hereinabove.

[0073] In some embodiments, the compound is represented by any one of Formulae above wherein R1represents one or more substituent(s) attached to ring A at a position 1, 2, 3 or 4. In some embodiments, the compound is represented by Formula any one of Formulae above wherein R2is a is an optionally substituted heterocyclic ring (e.g. optionally substituted pyrazole) or an optionally substituted cycloalkyl (e.g. C5-C6 cycloalkyl). In some embodiments, the compound is of any one of Formulae above, wherein R2is an optionally substituted heterocyclic ring (e.g. optionally substituted pyrazole); wherein R1is H or represents one or more substituents each independently selected hydroxy, halo, nitro, cyano, SR”, -NR”2, alkyl (e.g. C1-C6alkyl), and -OR”. ). In some embodiments, the compound is of any one of Formulae above, wherein XI is CH, X is N, wherein R2is an optionally substituted heterocyclic ring (e.g. optionally substituted pyrazole); wherein R1is H or represents one or more substituents each independently selected hydroxy, halo, nitro, cyano, SR”, -NR”2, alkyl (e.g. C1-C6alkyl), and -OR”.

[0074] In some embodiments, the compound is represented by any one of Formulae above wherein one or more R represents one or more substituent(s) attached to ring B at a position 11, 12 or 14. In some embodiments, the compound is represented by any one of Formulae above wherein one or more R represents one or more substituent(s) attached to ring B at a position 11, 12 or 14, wherein R is selected from hydrogen, C1-C6alkyl and halo.

[0075] In some embodiments, the compound is represented by any one of Formulae above wherein R1 is attached to ring A at position 2. In some embodiments, the compound is represented by any one of Formulae above wherein R1 is attached to ring A at position 2 and is selected from -H, -OH, Cl, F, Br, I, NH2, NHR”, NR”2, Ci-C6alkyl, -O-R”, R” and C1-C6alkyl-OR”.

[0076] In some embodiments, the compound is represented by Formula II:X, RI , R2and R are as described hereinabove.

[0077] In some embodiments, the compound is represented by Formula II / IIA, wherein R is hydrogen or C1-C6alkyl. In some embodiments, the compound is represented by Formula II / IIA, wherein R is hydrogen and wherein R1is -OR”.

[0078] In some embodiments, the compound is represented by Formula II / IIA wherein R1represents one or more substituents, each independently selected from -H, -OH, Cl, F, Br, I2, SH, -S-R’, NO2, CN, NH2, NHR’, NR’2, Ci-C6alkyl, -OR”, Ci-C6alkyl-OR” and R” In some embodiments, the compound is represented by Formula II / IIA, wherein Ri represents a single substituent attached to the phenyl ring at a position 2. ”. In some embodiments, the compound is represented by Formula II / IIA, wherein R1represents a single substituent attached to the phenyl ring at a position 2, and wherein RI represents - OR”, C1-C6alkyl or C1-C6alkyl-OR”.

[0079] In some embodiments, the compound is of Formula II / IIA, wherein R2is an optionally substituted heterocyclic ring. In some embodiments, R2is an optionally substituted pyrazole, wherein substituted is as described herein.

[0080] In some embodiments, R2is Pyrazole-Rx; wherein Rx represents any one of H, an optionally substituted alkyl, an optionally substituted cycloalkyl, R’, Y-R’, an optionally substituted aryl, an optionally substituted (C1-C6hetereoalkyl)-aryl, an optionally substituted (C1-C6hetereoalkyl)-cycloalkyl, an optionally substituted (C1-C6hetereoalkyl)- heterocyclyl, an optionally substituted (C1-C6alkyl)-aryl, an optionally substituted (C1-C6alkyl)-cycloalkyl, an optionally substituted (C1-C6alkyl)-heterocyclyl, an optionally substituted (C1-C6alkyl)-Y-aryl, an optionally substituted (C1-C6alkyl)-Y-cycloalkyl, an optionally substituted (C1-C6alkyl)-Y-heterocyclyl and an optionally substituted heteroaryl, wherein Y represents a heteroatom (i.e., S, O, N, or NH) or any one of: - CONR”, -CNNR”, -CSNR”, -CONH-O, -CONH-NH, carbonyl, -NHCOR”, -NHCSR”, - NHCNR”, -NHC(=O)O, -NHC(=O)NH, -NHC(=S)O, -NHC(=S)NH, -SO2, -SO, -SO2O, - SO2NR”, -NHNR”, -NN, -NR”, -CO2, -OCO, -OC(=O)O, -OC(=O)NR”, -OC(=S)O, - OC(=S)NR”, wherein R’ is H, R”, absent or is as described herein.

[0081] The term “cycloalkyl” encompasses any one of: 3-10 or 3-14 membered cycloalkyl, 3-10 or 3-14 membered aliphatic cycloalkyl, 3-10 or 3-14 membered aliphatic heterocyclyl, (C3-C14) cycloalkyl, (C3-C12) cycloalkyl, (C3-C10) cycloalkyl, (C3-C8) cycloalkyl, and C6-C12 ring. This term encompasses any one of: a mono-cyclic, a bicyclic and a polycyclic ring, as disclosed herein.

[0082] In some embodiments, R2is Pyrazole-Rx, wherein Rx is an optionally substituted C1-C6alkyl. In some embodiments, Rx is an optionally substituted cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl). In some embodiments, the Rx is a C1-C6alkyl.

[0083] In some embodiments, the compound is represented by Formula III:wherein R1 is as described hereinabove; and wherein Rx represents any one of H, alkyl, cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl), and phenyl, (C1-C6alkyl)-phenyl, an optionally substituted aryl, an optionally substituted heteroaryl. In some embodiments, the compound is represented by Formula III / IIIA, wherein R1 is -OR”. In some embodiments, the compound is represented by Formula III / IIIA, wherein R1 is -OR”, Ci- C6alkyl-OR” or is absent; and wherein Rx is an alkyl. In some embodiments, the compound is represented by Formula III, wherein X is C-H. In some embodiments, the compound is represented by Formula IIIA, wherein at least one X is N.

[0084] In some embodiments, the compound is represented by Formula III / IIIA, wherein R1is -OR”, C1-C6alkyl-OR” or is absent, and wherein R” comprises any one of C1-C6alkyl, a substituted alkyl, an optionally substituted cycloalkyl (e.g., cyclopropyl, cyclobutyl). In some embodiments, the compound is represented by Formula III / IIIA, wherein R1is -OR”, and wherein R” is C1-C3 alkyl (e.g. methyl or ethyl).

[0085] In some embodiments, Rx is C1-C6alkyl (linear or cyclic). In some embodiment, Rx is methyl. In some embodiments, Rx is ethyl. In some embodiments, Rx is propyl. In some embodiments, Rx is butyl. In some embodiments, Rx is hexyl.

[0086] In some embodiments, the compound is represented by Formula IIIB:, wherein Rl, X, XI and Rx are as described hereinabove. In some embodiments, the compound is represented by Formula IIIB, wherein at least one X is N. In some embodiments, the compound is represented by Formula IIIB1 :wherein Rl, X, XI and Rx are as described hereinabove. In some embodiments, the compound is represented by any one of Formulae IIIA-IIIB2, wherein XI is CH.

[0087] In some embodiments, the compound of the present invention is represented by any one of RNB-557 / 637 / 631 / 675 / 1705 / 476 / 1701 / 1702 / 1703 / 1710 / 1720 / 1729 / 1734 / 1735 / 683 / 691 / 698:including any salt thereof.

[0088] In some embodiments, the compound of the present invention is represented byFormula (IV):, wherein Ri, R and R2are as disclosed hereinabove. In some embodiments, the compound is represented by Formula IV, wherein Rl represents one or more substituents, each independently selected from -OH, Cl, F, Br, H, NH2, NHR”, NR”2, C1-C6alkyl, and -OR”, wherein R” is as disclosed hereinabove. In some embodiments, the compound of the present invention is represented by Formula (IV) with the proviso that the compound is not N-[3-(6,7-dihydro-5H-pyrrolo[2,l-c][l,2,4]triazol-3- yl)phenyl]benzenesulfonamide; N-[3-(6,7-dihydro-5H-pyrrolo[l,2-a]imidazol-3- yl)phenyl]cyclohexanesulfonamide; N-[3-(6,7-dihydro-5H-pyrrolo[l,2-a]imidazol-3- yl)phenyl]cyclopropanesulfonamide; N-[3-(6,7-dihydro-5H-pyrrolo[l,2-a]imidazol-3- yl)phenyl]-2-fluorobenzenesulfonamide or N-[3-(6,7-dihydro-5H-pyrrolo[l,2-a]imidazol- 3-yl)phenyl]-2,4-difluoro-benzenesulfonamide. In some embodiments, the compound of the present invention is represented by Formula (IV), wherein Rl is not H and / or wherein R2is not phenyl, cyclohexane or cyclopropane (substituted or unsubstituted). In some embodiments, the compound of the present invention is not RNB-515 or RNB-512.

[0089] In some embodiments, R1is hydrogen. In some embodiments, R1is halogen (Cl, F, Br, I2). In some embodiments, R1is hydroxy (OH). In some embodiments, R1is C1-C6alkyl. In some embodiments, R1is -OR”, wherein R’ comprises any one of C1-C6alkyl, a substituted alkyl, cycloalkyl (e.g., cyclopropyl, cyclobutyl).

[0090] In some embodiments, the compound is represented by Formula IV, wherein R is hydrogen, or wherein both R and R1are hydrogen.

[0091] In some embodiments, the compound is represented by Formula (V):wherein R2is selected from an optionally substituted cycloalkyl (e.g., C3-C6 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl), an optionally substituted aryl or an optionally substituted heteroaryl. In some embodiments, R2is an optionally substituted pyrazole. In some embodiments, R2is a pyrazole substituted by Rx, wherein Rx is as disclosed above.

[0092] In some embodiments, R2is a cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl). In some embodiments, R2is a substituted phenyl. In some embodiments, R2is mono, di or tri substituted phenyl. In some embodiments, phenyl is substituted by one or more halo. In some embodiments, R2is a phenyl substituted by any one of F, CL, Br, I.

[0093] In some embodiments, the compound of the present invention is any one of:, including any salt thereof.

[0094] In some embodiments, the compound of invention is selected from:0095] As used herein, the term “substituted” or the term “substituent” encompasses one or more (e.g. 2, 3, 4, 5, or 6) substituents, wherein each of the one or more substituent(s) is independently selected from hydrogen, halogen, -NO2, -CN, -OH, oxo, amino, thioxo, carbonyl, imino, -(C=O)NH2, -CONR’2, -CNNR’2, -CSNR’2, -CONH-OH, -CONH-NH2, NHCOR’, -NHCSR’, -NHCNR’, , -NC(=O)OR, -NC(=O)NR’, -NC(=S)OR’, -NC(=S)NR’, -SO2R’, -SOR’, -SR’, -SO2OR’, -SO2N(R’)2, -NHNR’2, -NNR’, Ci-C6haloalkyl, optionally substituted C1-C6alkyl, -NH2, -NR’ 2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, C1-C6alkoxy, C1-C6haloalkoxy, hydroxy(C1-C6alkyl), hydroxy(C1-C6alkoxy), alkoxy(C1-C6alkyl), alkoxy(C1-C6alkoxy), C1-C6alkyl-NR’2, C1-C6alkyl-SR’, - CONH(C1-C6alkyl), -CON( C1-C6alkyl)2, -CO2H, -CO2R’, -OCOR, -OCOR’, - OC(=O)OR’, -OC(=O)NR’, -OC(=S)OR’, -OC(=S)NR’, or a combination thereof; wherein each R’ independently represents hydrogen, or is selected from the group comprising optionally substituted C1-C10 alkyl, optionally substituted C1-C30 alkyl, optionally substituted C1-C30 alkenyl, optionally substituted C1-C30 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, hydroxy, amino, -NH2, -NR’2-NH(C1-C6alkyl), -N(C1-C6alkyl)2, C1-C6alkoxy, C1-C6haloalkoxy, hydroxy(C1-C6alkyl), hydroxy(C1-C6alkoxy), alkoxy(C1-C6alkyl), alkoxy(C1-C6alkoxy), C1-C6alkyl-NR’2, Ci-C6alkyl-SR’, or a combination thereof, a skilled artisan will appreciate that the substituent is bound to the scaffold via a single or a double bond, as allowed by valency.

[0096] As used herein, the term “1-6 ring” is referred to a cyclic aliphatic or aromatic compound comprising between 1 and 6 carbon atoms. In some embodiments, 1-6 Comprises between 1 and 4, between 1 and 5, between 1 and 6 carbon atoms including any value therebetween.

[0097] As used herein the term “C1-C6alkyl” including any C1-C6alkyl related compounds, is referred to any linear or branched alkyl chain comprising between 1 and 6, between 1 and 2, between 2 and 3, between 3 and 4, between 4 and 5, between 5 and 6, carbon atoms, including any range therebetween. In some embodiments, C1-C6alkyl comprises any of methyl, ethyl, propyl, butyl, pentyl, iso-pentyl, hexyl, and tert-butyl or any combination thereof. In some embodiments, C1-C6alkyl as described herein further comprises an unsaturated bond, wherein the unsaturated bond is located at 1st, 2nd, 3rd, 4th, 5th- or 6thposition of the C1-C6alkyl.

[0098] As used herein the term “(C3-C10) cycloalkyl” is referred to an optionally substituted C3, C4, C5, C6, C7, C8, C9 or CIO ring. In some embodiments, (C3-C10) Comprises optionally substituted cyclopropane, cyclobutene, cyclopentane, cyclohexane, or cycloheptane.

[0099] As used herein the term “(Cs-Cs) cycloalkyl” is referred to an optionally substituted C3, C4, C5, C6, C7, or C8 ring. In some embodiments, (C3-C10) Comprises optionally substituted cyclopropane, cyclobutene, cyclopentane, cyclohexane, or cycloheptane.

[0100] As used herein the term “(C6-C12) ring” is referred to an optionally substituted C6, C7, C8, C9, CIO, Cll, or C12 ring. In some embodiments, (C6-C12) ring is referred to a bicyclic ring (e.g. fused ring, spirocyclic ring, biaryl ring).

[0101] As used herein the term “bicyclic heteroaryl” referred to (C6-C12) a bicyclic heteroaryl ring, wherein bicyclic (C6-Cio) ring is as described herein.

[0102] As used herein the term “bicyclic aryl” referred to (C6-C12) a bicyclic aryl ring, wherein bicyclic (C6-C12) ring is as described herein.

[0103] As used herein the term “bicyclic heterocyclyl” referred to (C6-C12) a bicyclic heterocyclic ring, wherein (bicyclic C6-C12) ring is as described herein.

[0104] As used herein the term “bicyclic cycloalkyl” referred to (C6-C12) a bicyclic cycloalkyl ring, wherein bicyclic (C6-C12) ring is as described herein.

[0105] In some embodiments, the compounds described herein are pharmaceutical grade compounds, having a chemical purity above 95%, above 97%, or above 99%, including any range between.

[0106] In some embodiments, the compound of the invention comprises any one of the compounds disclosed herein, including any salt thereof. In some embodiments, the salt of the compound is a pharmaceutically acceptable salt.

[0107] In some embodiments, the compounds described herein are chiral compounds (i.e., possess an asymmetric carbon atom). In some embodiments, diastereomers, geometric isomers and individual isomers are encompassed within the scope of the present invention. In some embodiments, a chiral compound described herein is in the form of a racemic mixture. In some embodiments, a chiral compound is in the form of a single enantiomer, with an asymmetric carbon atom having the R configuration. In some embodiments, a chiral compound is in the form of a single enantiomer, with an asymmetric carbon atom having the S configuration as described hereinabove.

[0108] In some embodiments, a chiral compound is in the form of a single enantiomer with enantiomeric purity of more than 70%. In some embodiments, a chiral compound isin the form of a single enantiomer with enantiomeric purity of more than 80%. In some embodiments, a chiral compound is in a form of a single enantiomer with enantiomeric purity of more than 90%. In some embodiments, a chiral compound is in the form of a single enantiomer with enantiomeric purity of more than 95%.

[0109] In some embodiments, the compound of the invention comprising an unsaturated bond is in a form of a trans-, or cis-isomer. In some embodiments, the composition of the invention comprises a mixture of cis- and trans-isomers, as described hereinabove.

[0110] In some embodiments, the compounds described herein can exist in unsolvated form as well as in solvated form, including hydrated form. In general, the solvated form is equivalent to the unsolvated form and is encompassed within the scope of the present invention. C6rtain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

[0111] The term “solvate” refers to a complex of variable stoichiometry (e.g., di-, tri-, tetra-, penta-, hexa-, and so on), which is formed by a solute (the conjugate described herein) and a solvent, whereby the solvent does not interfere with the biological activity of the solute. Suitable solvents include, for example, ethanol, acetic acid and the like.

[0112] The term “hydrate” refers to a solvate, as defined hereinabove, where the solvent is water.

[0113] Unless otherwise indicated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diaster eomeric, geometric, conformational, and rotational) forms of the structure. For example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers are included in this invention. As would be understood to one skilled in the art, a substituent can freely rotate around any rotatable bond. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, geometric, conformational, and rotational mixtures of the present compounds are within the scope of the invention.

[0114] Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0115] Additionally, unless otherwise indicated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopicallyenriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a hydrogen by 18F, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as imaging probes.

[0116] In some embodiments, the compound of the invention includes any salt, any solvate, any hydrate, any stereoisomer, any isotope (e.g., a deuterated compound), and / or any derivative (e.g., a biologically active derivative) of any of the compounds or of the Formulae disclosed herein.

[0117] In some embodiments, the compound of the invention has a binding affinity to FTO. The binding affinity of the compound of the invention to FTO can be determined by CETSA method, disclosed in the Example section.

[0118] In some embodiments, the compound of the invention inhibits FTO activity. FTO activity inhibition can be determined by Recombinant FTO assay, disclosed in the Examples section. In some embodiments, the compound of the invention is characterized by IC50 of less than 10000 nM, less than 5000 nM, less than 2000 nM, less than 1000 nM, less than 200 nM, less than 100 nM, less than 500 nM, less than 50 nM, less than 10 nM, less than 5 nM, less than 1 nM. IC50 can be determined as disclosed in the Examples section (e.g. in a cell-free biochemical assay).Pharmaceutical composition

[0119] In another aspect of the invention disclosed herein, there is a pharmaceutical composition comprising the compound of the invention, a pharmaceutically acceptable salt thereof or both.

[0120] Non-limiting examples of pharmaceutically acceptable salts include but are not limited to: acetate, aspartate, benzenesulfonate, benzoate, bicarbonate, carbonate, halide (such as bromide, chloride, iodide, fluoride), bitartrate, citrate, salicylate, stearate, succinate, sulfate, tartrate, decanoate, edetate, fumarate, gluconate, and lactate or any combination thereof.

[0121] In some embodiments, the pharmaceutical composition comprises the compound of the invention and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compound of the invention and the pharmaceutically acceptable carrier.

[0122] For example, the term "pharmaceutically acceptable" can mean approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. In some embodiments, the compound of the invention is referred to herein as an active ingredient of a pharmaceutical composition.

[0123] In some embodiments, the pharmaceutical composition as described herein is a topical composition. In some embodiments, the pharmaceutical composition is an oral composition. In some embodiments, the pharmaceutical composition is an injectable composition. In some embodiments, the pharmaceutical composition is for a systemic use.

[0124] In some embodiments, the pharmaceutical composition is any of an emulsion, a liquid solution, a gel, a paste, a suspension, a dispersion, an ointment, a cream, or a foam.

[0125] As used herein, the term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the active ingredient is administered. Such carriers can be sterile liquids, such as water-based and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents.

[0126] Other non-limiting examples of carriers include, but are not limited to: terpenes derived from Cannabis, or total terpene extract from Cannabis plants, terpenes from coffee or cocoa, mint-extract, eucalyptus-extract, citrus-extract, tobacco-extract, anis-extract, any vegetable oil, peppermint oil, d-limonene, b-myrcene, a-pinene, linalool, anethole, a- bisabolol, camphor, b-caryophyllene and caryophyllene oxide, 1,8-cineole, citral, citronella, delta-3-carene, farnesol, geraniol, indomethacin, isopulegol, linalool, unalyl acetate, b-myrcene, myrcenol, 1-menthol, menthone, menthol and neomenthol, oridonin, a- pinene, diclofenac, nepafenac, bromfenac, phytol, terpineol, terpinen-4-ol, thymol, and thymoquinone. One skilled in the art will appreciate that a particular carrier used within the pharmaceutical composition of the invention may vary depending on the route of administration.

[0127] In some embodiments, the carrier improves the stability of the active ingredient in a living organism. In some embodiments, the carrier improves the stability of the active ingredient within the pharmaceutical composition. In some embodiments, the carrier enhances the bioavailability of the active ingredient.

[0128] Water may be used as a carrier such as when the active ingredient has a sufficient aqueous solubility, so as to be administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.

[0129] In some embodiments, the carrier is a liquid carrier. In some embodiments, the carrier is an aqueous carrier.

[0130] Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents such as acetates, citrates, or phosphates. Antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; and agents for the adjustment of tonicity such as sodium chloride or dextrose are also envisioned. The carrier may comprise, in total, from 0.1% to 99.99999% by weight of the composition / s or the pharmaceutical composition / s presented herein.

[0131] In some embodiments, the pharmaceutical composition includes incorporation of any one of the active ingredients into or onto particulate preparations of polymeric compounds such as polylactic acid, polygly colic acid, hydrogels, etc., or onto liposomes, microemulsions, micelles, unilamellar or multilamellar vesicles, erythrocyte ghosts, or spheroplasts. Such compositions may influence the physical state, solubility, stability, rate of in vivo release, and rate of in vivo clearance.

[0132] In some embodiments, the pharmaceutical composition is a liquid at a temperature between 15 to 45°C. In some embodiments, the pharmaceutical composition is a solid at a temperature between 15 to 45°C. In some embodiments, the pharmaceutical composition is a semi-liquid at a temperature between 15 to 45°C. It should be understood that the term “semi-liquid”, is intended to mean materials which are flowable under pressure and / or shear force. In some embodiments, semi-liquid compositions include creams, ointments, gel-like materials, and other similar materials. In some embodiments, the pharmaceutical composition is a semi-liquid composition, characterized by a viscosity in a range from 31,000-800,000 cps.

[0133] Non-limiting examples of carriers for pharmaceutical compositions being in the form of a cream include but are not limited to: non-ionic surfactants (e.g., glyceryl monolinoleate glyceryl monooleate, glyceryl monostearate lanolin alcohols, lecithin mono- and di-glycerides poloxamer polyoxyethylene 50 stearate, and sorbitan trioleate stearic acid), anionic surfactants (e.g. pharmaceutically acceptable salts of fatty acids such as stearic, oleic, palmitic, and lauric acids), cationic surfactants (e.g. pharmaceutically acceptable quaternary ammonium salts such as benzalkonium chloride, benzethonium chloride, and cetylpyridinium chloride) or any combination thereof.

[0134] In some embodiments, the pharmaceutical composition being in the form of a cream further comprises a thickener.

[0135] Non-limiting examples of thickeners include, but are not limited to microcrystalline cellulose, a starch, a modified starch, gum tragacanth, gelatin, and a polymeric thickener (e.g. polyvinylpyrrolidone) or any combination thereof.

[0136] In some embodiments, the pharmaceutical composition further comprises an additional pharmaceutically active agent. In some embodiments, the additional pharmaceutically active agent is an anti-cancer agent. In some embodiments, the additional pharmaceutically active agent is a small molecule.

[0137] In some embodiments, the pharmaceutical composition comprising the compound of the invention is in a unit dosage form. In some embodiments, the pharmaceutical composition is prepared by any of the methods well known in the art of pharmacy. In some embodiments, the unit dosage form is in the form of a tablet, capsule, lozenge, wafer, patch, ampoule, vial, or pre-filled syringe.

[0138] In addition, in vitro assays may optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the formulation will also depend on the route of administration, and the nature of the disease or disorder, and should be decided according to the judgment of the practitioner and each patient's circumstances. Effective doses can be extrapolated from dose-response curves derived from in-vitro or in-vivo animal model test bioassays or systems. In some embodiments, the effective dose is determined as described hereinabove.

[0139] In another embodiment, the pharmaceutical composition of the invention is administered in any conventional oral, parenteral, or transdermal dosage form.

[0140] As used herein, the terms “administering”, “administration”, and like terms refer to any method which, in sound medical practice, delivers a composition containing an active agent to a subject in such a manner as to provide a therapeutic effect.

[0141] In some embodiments, the pharmaceutical composition is administered via oral (i.e., enteral), rectal, vaginal, topical, sublingual, buccal, nasal, ophthalmic, transdermal, subcutaneous, intramuscular, intramuscular, intrathecal, or intravenous routes of administration. The route of administration of the pharmaceutical composition will depend on the disease or condition to be treated. Suitable routes of administration include, but are not limited to, parenteral injections, e.g., intradermal, intravenous, intramuscular, intralesional, subcutaneous, intrathecal, and any other mode of injection as known in the art. In addition, it may be desirable to introduce the pharmaceutical composition of the invention by any suitable route, including intraventricular and intrathecal injection; intraventricular injection may be facilitated by an intraventricular catheter, for example, attached to a reservoir. Pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer.

[0142] In some embodiments, the pharmaceutical composition is in the form of, for example, and not by way of limitation, an ointment, cream, gel, paste, foam, aerosol, suppository, pad, or gelled stick.

[0143] In some embodiments, for oral applications, the pharmaceutical composition is in the form of a tablet or a capsule, which can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; or a glidant such as colloidal silicon dioxide. When the dosage unit form is a capsule, it can contain, in addition to materials of the above type, a liquid carrier such as fatty oil. In addition, dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or other enteric agents. In some embodiments, the tablet of the invention is further film coated. In some embodiments, oral application of the pharmaceutical composition or of the kit is in a form of a drinkable liquid. In some embodiments, oral application of the pharmaceutical composition or of the kit is in a form of an edible product.

[0144] For purposes of parenteral administration, solutions in sesame or peanut oil or in aqueous propylene glycol can be employed, as well as sterile aqueous solutions of the corresponding water-soluble salts. Such aqueous solutions may be suitably buffered, if necessary, and the liquid diluent first rendered isotonic with sufficient saline or glucose. These aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous, and intraperitoneal injection purposes.

[0145] In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compound of the invention.

[0146] In some embodiments, the pharmaceutical composition is for use in inhibition of FTO activity. In some embodiments, inhibition of FTO comprises inhibition of cellular activity of FTO, wherein the inhibition is as described herein. In some embodiments, inhibition comprises a selective inhibition of FTO activity.

[0147] In some embodiments, the compound / pharmaceutical composition of the invention is characterized by IC50 of less than 10000 nM, less than 5000 nM, less than 2000 nM, less than 1000 nM, less than 200 nM, less than 100 nM, less than 500 nM, less than 50 nM, less than 10 nM, less than 5 nM, less than 1 nM. IC50 can be determined as disclosed in the Examples section (e.g. in a cell-free biochemical assay).

[0148] In some embodiments, the pharmaceutical composition is for use in the prevention or treatment of an FTO-related disease / disorder in a subject. In some embodiments, the subject afflicted with FTO-related disease / disorder is responsive to administration of a therapeutically effective amount of the pharmaceutical composition. As used herein, the terms “responsive” encompasses alleviation of at least one symptom thereof, a reduction in the severity thereof, or inhibition of the progression thereof in the subject. In some embodiments, the therapeutically effective amount of the pharmaceutical composition is sufficient for inducing inhibition or reduction of FTO activity in a subject. In some embodiments, the disease or disorder is obesity. In some embodiments, the pharmaceutical composition is for use in producing weight loss in a subject in need thereof.

[0149] In some embodiments, there is provided a pharmaceutical composition comprising a therapeutically effective amount of an FTO inhibitor, for use in the prevention or treatment of a cell proliferation related disease or disorder, in a subject in need thereof.

[0150] In some embodiments, an FTO inhibitor is selected from the group comprising: nucleic acid molecule, small molecule, polypeptide (and / or protein), or any combination thereof. In some embodiments, the polypeptide is an agonist or an antagonist of FTO. In some embodiments, the polypeptide is an antibody targeting, binding, blocking FTO, or any combination thereof.

[0151] In some embodiments, an FTO inhibitor is a small molecule. In some embodiments, an FTO inhibitor being a small molecule comprises the compound of the invention.

[0152] In some embodiments, an FTO inhibitor is a nucleic acid molecule. In some embodiments, the nucleic acid molecule is configured to hybridize RNA or DNA encoding FTO. In some embodiments, the nucleic acid molecule has a sequence complementary to FTO encoding RNA or DNA. In some embodiments, the nucleic acid molecule is a polynucleotide. In some embodiments, the nucleic acid molecule is an inhibitory nucleic acid molecule. In some embodiments, the inhibitory nucleic acid molecule is an RNA interfering nucleic acid molecule

[0153] In some embodiments, a polynucleotide is selected from: a single strand RNA, antisense RNA, siRNA, dsRNA, shRNA, guide RNA, micro RNA (miRNA), and DNA. As used herein, DNA refers to any deoxyribonucleic acid polymer, for example, complementary DNA (cDNA), a digested cDNA or genomic DNA (gDNA), a plasmid DNA, and the like. In some embodiments, an agent is any RNA interference (RNAi) inducing polynucleotide.

[0154] An antisense sequence as described herein comprises any one of: antisense oligonucleotide, ribozyme, external guide sequence (EGS) oligonucleotide, siRNA compound, single- or double-stranded RNA interference (RNAi) compound such as siRNA compound, modified bases / locked nucleic acid (LNA), antagomir, peptide nucleic acid (PNAs), or any other oligomeric compound or oligonucleotide mimetic capable of hybridizing to at least a portion of the target nucleic acid, such as a gene or a transcript thereof, and modulate its function. In some embodiments, the antisense sequence comprises an antisense RNA, antisense DNA, chimeric antisense oligonucleotide, antisense oligonucleotide comprising modified linkages, micro interfering RNA (miRNA), and a short hairpin RNA (shRNA).

[0155] As used herein, the term “interfering RNA” refers to any double stranded or single stranded RNA sequence, capable — either directly or indirectly (i.e., upon conversion) — of inhibiting or down regulating gene expression by mediating RNA interference. Interfering RNA includes but is not limited to siRNA and shRNA. RNAi refers to the selective degradation of a sequence-compatible messenger RNA transcript.

[0156] As used herein, the term “shRNA” refers to an RNA molecule comprising an antisense region, a loop portion, and a sense region, wherein the sense region has complementary nucleotides that base pair with the antisense region to form a duplex stem. Following post-transcriptional processing, the small hairpin RNA is converted into a small interfering RNA by a cleavage event mediated by the enzyme Dicer, which is a member of the RNase III family.

[0157] As used herein, the term siRNA refers to any small RNA molecule capable of inhibiting or down regulating gene expression by mediating RNA interference in a sequence specific manner. The small RNA can be, for example, about 18 to 21 nucleotides long.

[0158] As used herein, the term dsRNA refers to any double stranded RNA molecule capable of inhibiting or down regulating FTO gene expression by mediating RNA interference in a sequence specific manner. The dsRNA can be, for example, about 50 to 1,000 nucleotides long, about 50 to 500 nucleotides long, about 150 to 750 nucleotides long, or about 100 to 500 nucleotides long, or any value and range therebetween. Each possibility represents a separate embodiment of the invention.

[0159] In some embodiments, the disease / disorder is a proliferative disease. In some embodiments, the pharmaceutical composition is for use in the prevention or treatment of a proliferative disease. In some embodiments, the proliferative disease is associated with FTO expression within a cell of the subject. In some embodiments, the proliferative disease is associated with abnormal (e.g. enhanced) FTO activity, as compared to FTO activity / FTO expression within a cell of a healthy subject. In some embodiments, the pharmaceutical composition / compound of the invention is for inducing a cell cycle arrest at the G2 / M checkpoint. In some embodiments, the pharmaceutical composition / compound of the invention is for inducing cell apoptosis.

[0160] In some embodiments, the pharmaceutical composition is for use in the prevention or treatment of abnormal cell growth and / or metastasis of a cell expressing FTO in a subject in need thereof. In some embodiments, the pharmaceutical composition is for use in the prevention or treatment of abnormal proliferation of cells expressing FTO. In some embodiments, the pharmaceutical composition is for use in inducing apoptosis of a cell expressing FTO.

[0161] In some embodiments, the FTO-related disease is cancer. In some embodiments, the cell proliferation related disease is cancer. In some embodiments, the proliferative disease is cancer. In some embodiments, cancer comprises abnormal cell growth and / or metastasis. In some embodiments, the cell is a cancerous cell. In some embodiments, the cell expresses FTO. In some embodiments, the cell is characterized by an elevated expression of FTO. In some embodiments, the cell is characterized by normal FTO expression. In some embodiments, the cell is characterized by an elevated activation of FTO. In some embodiments, the cancer expresses FTO. In some embodiments, the cancer is characterized by an elevated expression of FTO. In some embodiments, the cancer is characterized by normal FTO expression. In some embodiments, the cancer is characterized by an elevated activation of FTO. In some embodiments, the cancer is FTO positive cancer. In some embodiments, the cancer is FTO over-expressing cancer.

[0162] In some embodiments, the cell is a cancer cell. In some embodiments, cancer is a FTO related cancer. In some embodiments, cancer is related to an abnormal expression of FTO. In some embodiments, the cancer cell is selected from the group comprising a pancreatic cell, kidney cell, a ling cell, a hematopoietic cell, or any combination thereof.

[0163] In some embodiments, the pharmaceutical composition is for use in the treatment of a cancer in a subject. In some embodiments, the cancer is an FTO related cancer. In some embodiments, an FTO related cancer is an FTO overexpressing cancer. In some embodiments, the FTO related cancer is selected from osteosarcoma, melanoma, bladder, pancreatic, kidney, cervical, lung, breast, ovarian, head and neck and hematopoietic cancer. In some embodiments, the FTO related cancer is selected from an osteosarcoma, a skin cancer, a bladder cancer, a pancreatic cancer, a kidney cancer, a cervical cancer, a lung cancer, a breast cancer, a prostate cancer, a liver cancer, an ovarian cancer, a head and neck cancer and a hematopoietic cancer. In some embodiments, the FTO related cancer isselected from a skin cancer, a bladder cancer, a pancreatic cancer, a kidney cancer, a cervical cancer, a lung cancer, a breast cancer, a prostate cancer, a liver cancer, an ovarian cancer, a head and neck cancer and a hematopoietic cancer. In some embodiments, the cancer is selected from the group comprising an osteosarcoma, a skin cancer, a bladder cancer, a pancreatic cancer, a kidney cancer, a cervical cancer, a lung cancer, a breast cancer, a prostate cancer, a liver cancer, an ovarian cancer, a head and neck cancer and a hematopoietic cancer comprising centrosome amplification.

[0164] In some embodiments, the cancer is kidney cancer. In some embodiments, kidney cancer is renal cell carcinoma (RCC). In some embodiments, the cancer is pancreatic cancer. In some embodiments, the pancreatic cancer is pancreatic carcinoma. In some embodiments, the pancreatic cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is lung cancer. In some embodiments, lung cancer is lung adenocarcinoma. In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the NSCLC is an NSCLC with centromere amplification. In some embodiments, the cancer is a carcinoma. In some embodiments, the cancer is an adenocarcinoma. In some embodiments, the cancer is ovarian cancer. In some embodiments, the ovarian cancer is ovarian carcinoma. In some embodiments, the ovarian cancer is ovarian adenocarcinoma. In some embodiments, the cancer is head and neck cancer. In some embodiments, the head and neck cancer is oral cancer. In some embodiments, the cancer is oral cancer. In some embodiments, the oral cancer is oral squamous cell carcinoma. In some embodiments, the cancer is squamous cell carcinoma. In some embodiments, the head and neck cancer is esophageal cancer. In some embodiments, the cancer is esophageal cancer. In some embodiments, the cancer is skin cancer. In some embodiments, the skin cancer is melanoma. In some embodiments, the cancer is a hematopoietic cancer. In some embodiments, a hematopoietic cancer is a blood cancer. In some embodiments, the blood cancer is leukemia. In some embodiments, the leukemia is Acute Myeloid Leukemia (AML). In some embodiments, the blood cancer is multiple myeloma (MM). In some embodiments, the cancer is selected from AML and MM. In some embodiments, the cancer is breast cancer. In some embodiments, the breast cancer is breast carcinoma. In some embodiments, the cancer is cervical cancer. In some embodiments, the cervical cancer is cervical carcinoma. In some embodiments, the canceris liver cancer. In some embodiments, the liver cancer is liver carcinoma. In some embodiments, the liver cancer is hepatocellular carcinoma. In some embodiments, the cancer is selected from lung cancer with centromere amplification, ovarian cancer with centromere amplification, head and neck cancer with centromere amplification, hematopoietic cancer with centromere amplification, skin cancer with centromere amplification, prostate cancer with centromere amplification, bladder cancer with centromere amplification, breast cancer with centromere amplification, cervical cancer with centromere amplification, liver cancer with centromere amplification, and pancreatic cancer with centromere amplification.

[0165] In some embodiments, the cancer comprises centrosome amplification. In some embodiments, the cancer is characterized by centrosome amplification. As used herein, the term “centrosome amplification” refers to a cell comprises two or more centrosomes when the cell it is not in mitosis and more than two centrosomes in the cell during mitosis. In some embodiments, the cells of the cancer comprise at least two centrosomes when not in mitosis. In some embodiments, the cells of the cancer comprise more than two centrosomes when in mitosis. Methods of measuring centrosome number, such as staining with pericentrin, are well known in the art and any such method may be used to determine that a cancer comprises centrosome amplification. In some embodiments, the cancer comprises chromosomal instability. In some embodiments, the cancer is characterized by chromosomal instability. In some embodiments, chromosomal instability comprises multipolar mitosis. In some embodiments, the cancer is characterized or comprises cells undergoing multipolar mitosis. In some embodiments, chromosomal instability comprises the cell not being diploid. In some embodiments, a non-diploid cell is a cell with a chromosome number greater than 2. Methods of measuring chromosomal instability, such as staining chromosomes or counting spindles / chromosomes during mitosis are well known in the art and any such method may be used to determine that a cancer comprises chromosomal instability.Method

[0166] In another aspect, there provided herein is a method for preventing or treating a disease or a disorder, or ameliorating a condition in a subject, comprising administering to the subject the pharmaceutical composition of the invention, thereby (i) preventing ortreating a disease or a disorder; or (ii) ameliorating the condition associated with an abnormal or normal expression of FTO and / or activation in a subject. In some embodiments, the disease, the disorder or the condition is associated with FTO expression in the subject. In some embodiments, the disease, the disorder or the condition is associated with an abnormal or normal expression of FTO and / or activation in a subject. In another aspect, there provided herein is a method for preventing or treating a disease or a disorder, or ameliorating a condition associated with FTO expression in a subject, comprising administering to the subject the pharmaceutical composition of the invention, thereby preventing or treating a disease or a disorder. In some embodiments, there is a method for preventing or treating a disease or a disorder, wherein the disease is a proliferative disease, or any combination thereof.

[0167] In another aspect, there is provided a method of treating cancer in a subject in need thereof, the method comprising: a) selecting a subject suffering from a cancer confirmed to comprise centrosome amplification; and b) inhibiting FTO in said cancer; thereby treating cancer in a subject.

[0168] In another aspect, there is provided a method of treating cancer in a subject in need thereof, the method comprising: a) selecting a subj ect suffering from a cancer confirmed to express FTO and confirmed to comprise centrosome amplification; and b) inhibiting FTO in said cancer; thereby treating cancer in a subject.

[0169] In some embodiments, there is a method for preventing or treating cancer (e.g. cancer associated with FTO expression and / or with abnormal FTO activity) comprising administering to the subject the pharmaceutical composition or the compound of the invention. In some embodiments, the method is for preventing or treating cancer characterized by a cell expressing FTO (i.e. with overexpressed FTO and / or abnormal FTO activity). In some embodiments, the method is for preventing or treating cancer characterized by centrosome amplification. In some embodiments, the method is for preventing or treating cancer characterized by chromosomal instability.

[0170] In some embodiments, the method comprises administering a compound as described herein to a subject afflicted with cancer. In some embodiments, the method comprises administering a compound as described herein to a subject afflicted with cancer characterized by cancerous cells that express FTO and / or highly express FTO. In some embodiments, the method comprises administering a compound as described herein to a subject afflicted with cancer characterized by cancerous cells that express activated FTO. In some embodiments, the method further comprises selecting a subject afflicted with cancer, wherein the subject comprises a cancerous cell expressing FTO and / or highly expressing FTO. In some embodiments, the method comprises administering a compound as described herein to a subject afflicted with cancer characterized by centrosome amplification. In some embodiments, the cancer is characterized by both FTO and centrosome amplification.

[0171] In some embodiments, the disease or disorder is obesity. In some embodiments, the method is a method of treating or reducing obesity. It is well known in the art that FTO plays a role in FTO product! on / storage and that FTO knockout mice are skinnier than WT mice. Thus, FTO inhibition is known to be useful in weight loss and treating obesity. Thus, the inhibitors of the invention can be used to treat obesity. In some embodiments, obesity is a body mass index (BMI) of 25 or greater. In some embodiments, obesity is a BMI of 30 or greater. In some embodiments, the inhibitors of the invention are for use in producing weight loss.

[0172] According to another aspect, there is provided a method for treating a cell proliferation related disease or disorder in a subject in need thereof.

[0173] In some embodiments, the method comprises administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of an FTO inhibitor.

[0174] In some embodiments, an FTO inhibitor is selected from the group comprising: nucleic acid molecule, small molecule, polypeptide (and / or protein), or any combination thereof.

[0175] In some embodiments, preventing or treating comprises prolonging the duration of the G2 / M cell cycle stage of at least one cell of the subject. In some embodiments, preventing or treating comprises arresting cell cycle of at least one cell of the subject.

[0176] In some embodiments, preventing or treating comprises increasing the amount or abundance of cells arrested in the G2 / M cell cycle stage, in the subject. In some embodiments, preventing or treating comprises reducing the amount or abundance of cells undergoing cell division, in the subject. In some embodiments, cell division is mitosis.

[0177] In some embodiments, there is provided a method for arresting cell cycle of a cell. In some embodiments, the method comprises contacting a cell with an effective amount of an FTO inhibitor.

[0178] In some embodiments, arresting is in the G2 / M cell cycle stage of the cell.

[0179] In some embodiments, the cell is a cancer cell, a cancerous cell, a malignant cell, or any combination thereof. In some embodiments, the cell is a cell of a subject.

[0180] In some embodiments, the cell proliferation related disease is FTO positive, centrosome amplification positive cancer. In some embodiments, the cell proliferation related disease is cancer characterized by FTO expression and centrosome amplification. In some embodiments, the cell proliferation related disease is cancer comprising FTO expression and centrosome amplification. In some embodiments, FTO expression is FTO overexpression. In some embodiments, FTO expression is FTO activation.

[0181] In some embodiments, the method is an ex vivo or an in vitro method. In some embodiments, the method is an in vivo method.

[0182] In some embodiments, the method comprises administering a therapeutically effective amount of the pharmaceutical composition to the subject.

[0183] In some embodiments, administering is by an oral administration, a topical administration, a nasal administration, sublingual administration, buccal administration, a systemic administration, or a combination thereof.

[0184] In some embodiments, the method comprises administering the pharmaceutical composition of the invention at least 1 time, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 7 times, or at least 10 times per day or per week or per month, or any value and range therebetween. Each possibility represents a separate embodiment of the invention. In some embodiments, the method comprises administering the composition or the combination of the invention 1-2 times per day or per week or per month, 1-3 times per day or per week or per month, 1-4 times per day or per week or per month, 1-5 times per day, 1-7 times per day or per week or per month, 2-3 times per dayor per week or per month, 2-4 times per day or per week or per month, 2-5 times per day or per week or per month, 3-4 times per day or per week or per month, 3-5 times per day or per week or per month, or 5-7 times per day or per week or per month. Each possibility represents a separate embodiment of the invention.

[0185] In some embodiments, the method comprises administering the pharmaceutical composition of the invention to the subject at a daily or weekly or monthly dosage of 0.05 to 200 mg / kg, 0.05 to 150 mg / kg, 0.05 to 20 mg / kg, 0.05 to 0.1 mg / kg, 0.1 to 0.3 mg / kg, 0.3 to 0.5 mg / kg, 0.5 to 0.8 mg / kg, 0.8 to 1 mg / kg, 1 to 2 mg / kg, 2 to 5 mg / kg, 5 to 10 mg / kg, 10 to 15 mg / kg, 15 to 20 mg / kg including any range or value therebetween.

[0186] It should be apparent to one skilled in the art, that for example in- vitro and in- vivo assays may optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the formulation will also depend on the route of administration, and the nature of the disease or disorder, and should be decided according to the judgment of the practitioner and each patient's circumstances. Effective doses can be extrapolated from dose-response curves derived from in-vitro or in-vivo animal model test bioassays or systems.

[0187] In some embodiments, the subject is a mammal. In some embodiments, the subject is a lab animal. In some embodiments, the subject is a pet. In some embodiments, the subject is a rodent. In some embodiments, the subject is a farm animal. In some embodiments, the subject is a human subject.

[0188] In some embodiments, the composition of the present invention is administered in a therapeutically safe and effective amount. As used herein, the term “safe and effective amount” refers to the quantity of a component which is sufficient to yield a desired therapeutic response without undue adverse side effects, including but not limited to toxicity, such as calcemic toxicity, irritation, or allergic response, commensurate with a reasonable benefit / risk ratio when used in the presently described manner. The actual amount administered, and the rate and time-course of administration, will depend on the nature and severity of the condition being treated. Prescription of treatment, e.g. decisions on dosage, timing, etc., is within the responsibility of general practitioners or specialists, and typically takes account of the disorder to be treated, the condition of the individual patient, the site of delivery, the method of administration and other factors known topractitioners. Examples of techniques and protocols can be found in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins, Philadelphia, Pa., (2005).

[0189] In some embodiments, the effective amount or dose of the active ingredient can be estimated initially from in vitro assays. In one embodiment, a dose can be formulated in animal models and such information can be used to determine useful doses more accurately in humans.

[0190] In one embodiment, toxicity and therapeutic efficacy of the active ingredients described herein can be determined by standard pharmaceutical procedures in vitro, in cell cultures or experimental animals. In one embodiment, the data obtained from these in vitro and cell culture assays and animal studies can be used in formulating a range of dosage for use in human. In one embodiment, the dosages may vary depending on the dosage form employed and the route of administration utilized. In one embodiment, the exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. [See e.g., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 13th Ed., McGraw-Hill / Education, New York, NY (2017)].

[0191] In some embodiments, the subject is afflicted with a disease or disorder associated with overexpression or normal FTO expression and / or activation. In some embodiments, the subject is afflicted with a disease or disorder selected from the group comprising: pancreatic cancer, kidney, leukemia.

[0192] In some embodiments, the method is for reducing or inhibiting: abnormal cell proliferation, tumor growth, malignancy, or any combination thereof in a subject in need thereof. In some embodiments, the method is for reducing or inhibiting proliferation of cells expressing FTO. In some embodiments, the method is for selectively reducing or inhibiting proliferation of cells expressing FTO.

[0193] In some embodiments, reducing comprises at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 97%, at least 99% reduction of the cell proliferation, including any value therebetween.

[0194] In some embodiments, reducing comprises at least 10%, 20%, 30%, 40%, 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 92%, at least95%, at least 97%, at least 99% reduction of FTO activity, including any value therebetween.

[0195] In some embodiments, the compound of the invention has IC50 in inhibiting FTO activity between 0.1 and 1 nM, between 1 and 5 nM, between 5 and 10 nM, between 10 and 50 nM, between 50 and 100 nM, between 100 and 500 nM, between 500 and 1 pM, between 1 and 5 pM, between 5 and 10 pM, including any value therebetween.

[0196] In some embodiments, the method further comprises selecting a subject. In some embodiments, the selecting comprises selecting a subject suffering from cancer. In some embodiments, the selecting comprises selecting a subject suffering from FTO expressing cancer. In some embodiments, expressing is overexpressing. In some embodiments, the selecting comprises selecting a subject suffering from cancer comprising centrosome amplification. In some embodiments, the selecting comprises selecting a subject suffering from cancer comprising chromosomal instability. In some embodiments, the selecting comprises selecting a subject confirmed to suffer from a cancer comprising FTO expression. In some embodiments, the selecting comprises selecting a subject confirmed to suffer from a cancer comprising centrosome amplification. In some embodiments, the selecting comprises selecting a subject confirmed to suffer from a cancer comprising chromosomal instability. In some embodiments, the selecting comprises selecting a subject confirmed to suffer from a cancer comprising FTO expression and centrosome amplification.

[0197] In some embodiments, the method comprises receiving a cancer sample from the subject. In some embodiments, the cancer sample comprises cancer cells. In some embodiments, the method comprises measuring FTO expression in the sample. In some embodiments, method comprises selecting a subject with a sample that comprises cancer cells that express FTO. In some embodiments, express FTO is express FTO above a predetermined threshold. In some embodiments, overexpression is expressing FTO above a predetermined threshold. In some embodiments, the threshold is FTO expression in control cells. In some embodiments, control cells are healthy cells. In some embodiments, control cells are non-cancerous cells. In some embodiments, control cells are non- cancerous cells from the same tissue or cell type as the cancerous cells. In some embodiments, the method comprises measuring centrosome amplification in the cancercells. In some embodiments, the measuring centrosome amplification comprises counting centrosome in the cells. In some embodiments, the method comprises selecting a subject with a sample that comprises cancer cells with centrosome amplification. In some embodiments, a cancer with centrosome amplification comprises a number of cells with centrosome amplification above a predetermined threshold. In some embodiments, the threshold is the number of cells with centrosome amplification in a control sample. In some embodiments, the method comprises measuring chromosomal instability in the cancer cells. In some embodiments, the measuring chromosomal instability comprises counting chromosomes in the cells. In some embodiments, the method comprises selecting a subject with a sample that comprises cancer cells with chromosomal instability. In some embodiments, a cancer with chromosomal instability comprises a number of cells with chromosomal instability above a predetermined threshold. In some embodiments, the threshold is the number of cells with chromosomal instability in a control sample. In some embodiments, a control sample is a sample of control cells. In some embodiments, the confirming comprises receiving the sample and confirming in the sample. In some embodiments, the method comprises receiving a report containing the subject’s cancer’s FTO expression and centrosome amplification status and selecting a subject with a cancer comprising FTO expression and centrosome amplification. In some embodiments, confirming comprises receiving the report. Though FTO inhibition to treat cancer is known, the selection of a patient population in which the cancer is characterized by centrosome amplification was heretofore not known and FTO inhibition is particularly suited for treating this population of subjects.Definitions

[0198] The term “one or more” refers to any numerical value selected form of 1, 2, 3, 4, 5, or 6.

[0199] As used herein, the term "alkyl" describes an aliphatic hydrocarbon including straight chain and branched chain groups as well as a cyclic ring. The alkyl group has between 1 and 20, between 1 and 10, between 1 and 15, between 1 and 5, between 1 and 3, between 2 and 20, between 2 and 10, between 2 and 5, or 1, 2, 3, 4, 5, or 6 carbon atoms, including any range or value between. Whenever a numerical range e.g., “1-20”, is statedherein, it implies that the group, in this case the alkyl group, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms. The alkyl can be substituted or unsubstituted, as defined herein. The “alkyl” further encompasses a “heteroalkyl”, i.e. an alkyl including one or more heteroatoms (e.g. O, S, N, or NH) within the backbone of the alkyl chain and heterocyclyl.

[0200] The term "alkyl", as used herein, also encompasses saturated or unsaturated hydrocarbon, hence this term further encompasses alkenyl and alkynyl.

[0201] The term "alkenyl" describes an unsaturated alkyl, as defined herein, having at least two carbon atoms and at least one carbon-carbon double bond. The alkenyl may be substituted or unsubstituted by one or more substituents, as described hereinabove.

[0202] The term "alkynyl", as defined herein, is an unsaturated alkyl having at least two carbon atoms and at least one carbon-carbon triple bond. The alkynyl may be substituted or unsubstituted by one or more substituents, as described hereinabove.

[0203] The term "cycloalkyl" describes an all-carbon monocyclic or fused ring (i.e. rings which share an adjacent pair of carbon atoms) group where one or more of the rings does not have a completely conjugated pi-electron system. The cycloalkyl group may be substituted or unsubstituted, saturated or containing at least one unsaturated bond, as indicated herein.

[0204] The term “cyclyl” describes an aryl, a polycyclyl, a heteroaryl, a cycloalkyl, or heterocyclyl or any combinations thereof.

[0205] The term “polycyclic ring” or “polycyclyl” encompasses a plurality (e.g., 2, 3, 4, 5 or 6) of fused or adjacent rings (e.g., biaryl or bicyclohexyl), wherein each ring is independently selected from aryl, heteroaryl, an optionally unsaturated cycloalkyl, an optionally unsaturated heterocyclyl, or any combination thereof. In some embodiments, the term “polycyclyl” encompasses a polycyclic aromatic ring, a polycyclic aliphatic ring, or a mixed polycyclic ring. The term “polycyclic ring” or “polycyclyl” encompasses fused rings (e.g. fused aliphatic, fused aromatic and / or heteroaromatic ring), spirocyclic rings, bridged rings, a dicyclyl (two aromatic and / or aliphatic rings joined by a single carboncarbon bond), such as presented below:, wherein each B independently comprises any of: (i) an optionally substituted aliphatic ring, optionally comprising one or more heteroatoms, (ii) an optionally substituted aromatic or heteroaromatic ring, (iii) an optionally substituted bicyclic aliphatic, bicyclic aromatic / heteroaromatic, or a bicyclic mixed aromatic / heteroaromatic-aliphatic ring, wherein each of the rings optionally comprises one or more heteroatom(s); (iv) a polycyclic aromatic, polycyclic heteroaromatic, or polycyclic aliphatic ring, or a mixed polycyclic ring.

[0206] The term “mixed polycyclic ring” refers to any plurality of rings covalently bound to each other (e.g., fused rings, dicylyls, spirocyclic rings etc.) comprising at least one aromatic ring (aryl, or heteroaryl) and at least one aliphatic or non-aromatic ring (optionally a heterocyclyl and / or unsaturated cyclyl).

[0207] the term “bicyclic ring” encompasses a fused ring (fused aromatic and / or heteroaromatic ring), spirocyclic ring, a bridged ring, a dicyclyl (two aromatic and / or aliphatic rings joined by a single carbon-carbon bond). The terms “bicyclyl” and “bicyclic ring” are used herein interchangeably.

[0208] The term "aryl" describes an all-carbon monocyclic or fused-ring polycyclic (i.e. rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system. The aryl group may be substituted or unsubstituted, as indicated herein.

[0209] The term "alkoxy" describes both an O-alkyl and an -O-cycloalkyl group, as defined herein.

[0210] The term "aryloxy" describes an -O-aryl, as defined herein.

[0211] Each of the alkyl, cycloalkyl and aryl groups in the general formulas herein may be substituted by one or more substituents, whereby each substituent group can independently be, for example, halide, alkyl, alkoxy, cycloalkyl, nitro, amino, hydroxyl, thiol, thioalkoxy, carboxy, amide, aryl and aryloxy, depending on the substituted group and its position in the molecule. Additional substituents are also contemplated.

[0212] The term “halide”, “halogen” or “halo” describes fluorine, chlorine, bromine or iodine. The term “haloalkyl” describes an alkyl group as defined herein, further substituted by one or more halide(s). The term “haloalkoxy” describes an alkoxy group as defined herein, further substituted by one or more halide(s). The term “hydroxyl” or “hydroxy” describes a -OH group. The term “mercapto” or “thiol” describes a -SH group. The term “thioalkoxy” describes both an -S-alkyl group, and a -S-cycloalkyl group, as defined herein. The term “thioaryloxy” describes both an -S-aryl and a -S-heteroaryl group, as defined herein. The term “amino” describes a -NR’R’ ’ group, or a salt thereof, with R’ and R’ ’ as described herein .

[0213] The term "heterocyclyl" describes a monocyclic or fused ring group having in the ring(s) one or more atoms such as nitrogen, -NH-, oxygen, and sulfur. The rings may also have one or more double bonds. The terms "heterocyclyl" and "heterocyclic ring" are used herein interchangeably and further encompass a heteroaromatic ring, having a completely conjugated pi-electron system. Representative examples are pyrazole, imidazole, pyridine, thiazole, pyrrole, furan, piperidine, piperazine, tetrahydrofuran, tetrahydropyran, morpholino and the like.

[0214] The term “heteroatom” describes O, S, N, NH, NH2, or N(R’)I-2 as allowed by valency.

[0215] The term "carboxy" or "carboxylate" describes a -C(O)OR' group, where R' is hydrogen, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl (bonded through a Carbon) or heterocyclyl (bonded through a Carbon) as defined herein. The term “carboxy” describes a -C(O)OR’ group, or a carboxylate salt thereof, where R’ is hydrogen, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl (bonded through a Carbon) or heterocyclyl (bonded through a Carbon) as defined herein.

[0216] The term “carbonyl” describes a -C(O)R' group, where R' is as defined hereinabove.

[0217] The above-terms also encompass thio-derivatives thereof (thiocarboxy and thiocarbonyl).

[0218] The term “thiocarbonyl” describes a -C(S)R' group, where R' is as defined hereinabove.

[0219] A "thiocarboxy" group describes a -C(S)OR' group, where R' is as defined herein.

[0220] A "sulfinyl" group describes an -S(O)R' group, where R' is as defined herein.

[0221] A "sulfonyl" or “sulfonate” group describes an -S(O)2R' group, where R' is as defined herein.

[0222] A "carbamyl" or “carbamate” group describes an -OC(O)NR'R" group, where R' is as defined herein and R" is as defined for R'.

[0223] A "nitro" group refers to a -NO2 group.

[0224] The term "amide" as used herein encompasses C-amide and N-amide.

[0225] The term "C-amide" describes a -C(O)NR'R" end group or a -C(O)NR'-linking group, as these phrases are defined hereinabove, where R' and R" are as defined herein.

[0226] The term "N-amide" describes a -NR"C(O)R' end group or a -NR'C(O)- linking group, as these phrases are defined hereinabove, where R' and R" are as defined herein.

[0227] The term "carboxylic acid derivative" as used herein encompasses carboxy, amide, carbonyl, anhydride, carbonate ester, and carbamate.

[0228] A "cyano" or "nitrile" group refers to a -CN group.

[0229] The term "azo" or "diazo" describes an -N=NR end group or an -N=N- linking group, as these phrases are defined hereinabove, with R' as defined hereinabove.

[0230] The term "guanidine" describes a -R'NC(N)NR"R"' end group or a -R'NC(N) NR"- linking group, as these phrases are defined hereinabove, where R', R" and R'" are as defined herein.

[0231] As used herein, the term “azide” refers to a -N3 group.

[0232] The term “sulfonamide” refers to a -S(O)2NR'R" group, with R' and R" as defined herein.

[0233] The term “phosphonyl” or “phosphonate” describes an -OP(O)-(OR')2 group, with as defined hereinabove.

[0234] The term “phosphinyl” describes a -PR'R" group, with R' and R" as defined hereinabove.

[0235] The term “alkylaryl” describes an alkyl, as defined herein, which is substituted by an aryl, as described herein. An exemplary alkylaryl is benzyl.

[0236] The term "heteroaryl" describes a monocyclic (e.g. C5-C6 heteroaryl ring) or fused ring (i.e. rings which share an adjacent pair of atoms) group having in the ring(s) one or more atoms, such as, for example, nitrogen, oxygen, and sulfur and, in addition, havinga completely conjugated pi-electron system. In some embodiments, the terms “heteroaryl” and “C5-C6 heteroaryl” are used herein interchangeably. Examples, without limitation, of heteroaryl groups include pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline and purine. The heteroaryl group may be substituted or unsubstituted by one or more substituents, as described hereinabove. Representative examples are thiadiazol, pyridine, pyrrole, oxazole, indole, purine, and the like. In some embodiments, a heteroaryl group is selected from among pyrrolyl, furanyl (furyl), thiophenyl (thienyl), imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1 ,2,4-triazolyl, 1,3- oxazolyl (oxazolyl), 1,2-oxazolyl (isoxazolyl), oxadiazolyl, 1,3-thiazolyl (thiazolyl), 1,2- thiazolyl (isothiazolyl), tetrazolyl, pyridinyl (pyridyl)pyridazinyl, pyrimidinyl, pyrazinyl,1.2.3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, indazolyl, indolyl, benzothiophenyl, benzofuranyl, benzothiazolyl, benzimidazolyl, benzodioxolyl, acridinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, thi enothiophenyl, 1,8- naphthyridinyl, other naphthyridinyls, pteridinyl or phenothiazinyl. Where the heteroaryl group includes more than one ring, each additional ring is the saturated form (perhydro form) or the partially unsaturated form (e.g., the dihydro form or tetrahydro form) or the maximally unsaturated (nonaromatic) form. The term heteroaryl thus includes bicyclic radicals in which the two rings are aromatic and bicyclic radicals in which only one ring is aromatic. Such examples of heteroaryl are include 3H-indolinyl, 2(lH)-quinolinonyl, 4- oxo-l,4-dihydroquinolinyl, 2H-1 -oxoisoquinolyl, 1,2-dihydroquinolinyl, (2H)quinolinyl N-oxide, 3,4-dihydroquinolinyl, 1,2-dihydroisoquinolinyl, 3,4-dihydro-isoquinolinyl, chromonyl, 3,4-dihydroiso-quinoxalinyl, 4-(3H)quinazolinonyl, 4H-chromenyl, 4- chromanonyl, oxindolyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro-quinolinyl, lH-2,3-dihydroisoindolyl, 2,3-dihydrobenzo[f]isoindolyl, 1,2,3,4-tetrahydrobenzo- [g] isoquinolinyl, l,2,3,4-tetrahydro-benzo[g]isoquinolinyl, chromanyl, isochromanonyl,2.3-dihydrochromonyl, 1 ,4-benzo-dioxanyl, 1,2,3,4-tetrahydro-quinoxalinyl, 5,6-dihydro- quinolyl, 5,6-dihydroiso-quinolyl, 5,6-dihydroquinoxalinyl, 5,6-dihydroquinazolinyl, 4,5- dihydro-lH-benzimidazolyl, 4,5-dihydro-benzoxazolyl, 1 ,4-naphthoquinolyl, 5, 6,7,8- tetrahydro-quinolinyl, 5,6,7,8-tetrahydro-isoquinolyl, 5,6,7,8-tetrahydroquinoxalinyl, 5,6,7, 8-tetrahydroquinazolyl, 4,5,6,7-tetrahydro-lH-benzimidazolyl, 4,5,6,7-tetrahydro- benzoxazolyl, lH-4-oxa-l ,5-diaza-naphthalen-2-onyl, 1 ,3-dihydroimidizolo-[4,5]-pyridin-2-onyl, 2,3-dihydro-l ,4-dinaphtho-quinonyl, 2,3-dihydro-lH-pyrrol[3,4- b]quinolinyl, l,2,3,4-tetrahydrobenzo[b]-[l,7]naphthyridinyl, 1,2,3,4-tetra- hydrobenz[b][l,6]-naphthyridinyl, l,2,3,4-tetrahydro-9H-pyrido[3,4-b]indolyl, 1,2, 3, 4- tetrahydro-9H-pyrido[4,3-b]indolyl, 2,3-dihydro-lH-pyrrolo-[3,4-b]indolyl, 1H-2, 3,4,5- tetrahydro-azepino [3 ,4-b] indolyl, 1 H-2,3 ,4, 5 -tetrahydroazepino- [4, 3 -b] indolyl, 1 H- 2,3,4,5-tetrahydro-azepino[4,5-b]indolyl, 5,6,7,8-tetrahydro[l,7]napthyridinyl, 1, 2,3,4- tetrahydro-[2,7]-naphthyridyl, 2,3-dihydro[l,4]dioxino[2,3-b]pyridyl, 2,3-dihydro[l,4]- dioxino[2,3-b]51escry51, 3,4-dihydro-2H-l-oxa[4,6]diazanaphthalenyl, 4, 5,6,7- tetrahydro-3H-imidazo-[4,5-c]pyridyl, 6,7-dihydro[5,8]diazanaphthalenyl, 1, 2,3,4- tetrahydro[ 1 ,5]-napthyridinyl, 1 ,2,3,4-tetrahydro[l ,6]napthyridinyl, 1 ,2,3,4- tetrahydro[l,7]napthyridinyl, l,2,3,4-tetrahydro-[l,8]napthyridinyl or 1, 2,3,4- tetrahydro[2,6]napthyridinyl. In some embodiments, heteroaryl groups are optionally substituted. In one embodiment, the one or more substituents are each independently selected from among halo, hydroxy, amino, cyano, nitro, alkylamido, acyl, Cl-6-alkyl, Cl- 6-haloalkyl, Cl-6-hydroxyalkyl, Cl-6-aminoalkyl, Cl-6-alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl, or trifluoromethyl.

[0237] Examples of heteroaryl groups include, but are not limited to, unsubstituted and mono- or di-substituted derivatives of furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole, indazole, tetrazole, quinoline, isoquinoline, pyridazine, pyrimidine, purine and pyrazine, furazan, 1,2,3- oxadiazole, 1,2, 3 -thiadiazole, 1,2,4-thiadiazole, triazole, benzotriazole, pteridine, phenoxazole, oxadiazole, benzopyrazole, quinolizine, cinnoline, phthalazine, quinazoline and quinoxaline. In some embodiments, the substituents are halo, hydroxy, cyano, O — Cl- 6-alkyl, Cl-6-alkyl, hydroxy-Cl-6-alkyl and amino-Cl-6-alkyl.

[0238] As used herein, the terms "halo" and "halide", which are referred to herein interchangeably, describe an atom of a halogen, that is fluorine, chlorine, bromine, or iodine, also referred to herein as fluoride, chloride, bromide, and iodide.

[0239] The term “haloalkyl” describes an alkyl group as defined above, further substituted by one or more halide(s).

[0240] Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2H, 3H, 11C, 13C, 15N, 170, 180, 18F, 3 IP, 32P, 35S, 36C1, and 1251, respectively. In one embodiment, isotopically labeled compounds can be used in metabolic studies (with 14C), reaction kinetic studies (with, for example 2H or 3H), detection or imaging techniques, such as positron emission tomography (PET) or singlephoton emission computed tomography (SPECT) including drug and substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an 18F labeled compound may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed herein by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0241] By way of general example and without limitation, isotopes of hydrogen, for example deuterium (D) and tritium (3H) may optionally be used anywhere in described structures that achieves the desired result. Alternatively or in addition, isotopes of carbon, e.g., 13C and 14C, may be used. In one embodiment, the isotopic substitution is replacing hydrogen with a deuterium at one or more locations on the molecule to improve the performance of the molecule as a drug, for example, the pharmacodynamics, pharmacokinetics, biodistribution, half-life, stability, AUC, Tmax, Cmax, etc. For example, the deuterium can be bound to carbon in allocation of bond breakage during metabolism (an alpha-deuterium kinetic isotope effect) or next to or near the site of bond breakage (a beta-deuterium kinetic isotope effect).

[0242] Isotopic substitutions, for example deuterium substitutions, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted with deuterium. In certain embodiments, the isotope is 80, 85, 90, 95, or 99% or more enriched in an isotope at any location of interest. In some embodiments, deuterium is 80, 85, 90, 95, or 99% enriched at a desired location. Unless otherwise stated, the enrichment at any point is above natural abundance, and in an embodiment is enough to alter a detectable property of the compounds as a drug in a human.

[0243] The compounds of the present disclosure may form a solvate with solvents (including water). Therefore, in one embodiment, the invention includes a solvated formof the active compound. The term “solvate” refers to a molecular complex of a compound of the present invention (including a salt thereof) with one or more solvent molecules. Nonlimiting examples of solvents are water, ethanol, dimethyl sulfoxide, acetone and other common organic solvents. The term “hydrate” refers to a molecular complex comprising a disclosed compound and water. Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g., D2O, d6-acetone, or d6-DMSO. A solvate can be in a liquid or solid form. General

[0244] As used herein, the terms “treatment” or “treating” of a disease, disorder, or condition encompasses alleviation of at least one symptom thereof, a reduction in the severity thereof, or inhibition of the progression thereof. Treatment need not mean that the disease, disorder, or condition is totally cured. To be an effective treatment, a useful composition herein needs only to reduce the severity of a disease, disorder, or condition, reduce the severity of symptoms associated therewith, or provide improvement to a patient or subject’s quality of life.

[0245] As used herein, the term “prevention” of a disease, disorder, or condition encompasses the delay, prevention, suppression, or inhibition of the onset of a disease, disorder, or condition. As used in accordance with the presently described subject matter, the term "prevention" relates to a process of prophylaxis in which a subject is exposed to the presently described active ingredients prior to the induction or onset of the disease / disorder process. This could be done where an individual has a genetic pedigree indicating a predisposition toward occurrence of the disease / disorder to be prevented. For example, this might be true of an individual whose ancestors show a predisposition toward certain types of inflammatory disorders.

[0246] The term "suppression" is used to describe a condition wherein the disease / disorder process has already begun but obvious symptoms of the condition have yet to be realized. Thus, the cells of an individual may have the disease / disorder, but no outside signs of the disease / disorder have yet been clinically recognized. In either case, the term prophylaxis can be applied to encompass both prevention and suppression.

[0247] In some embodiments, the term “reducing”, or “enhancing” including any grammatical from thereof relates to at least 50%, at least 60%, at least 70%, at least 80%,at least 85%, at least 90%, at least 92%, at least 95%, at least 97%, at least 99% reduction / enhancement (e.g. of enzymatic activity), compared to a control or a baseline, including any range between.

[0248] Conversely, the term "treatment" refers to the clinical application of active agents to combat an already existing condition whose clinical presentation has already been realized in a patient.

[0249] In the discussion unless otherwise stated, adjectives such as “substantially” and “about” modifying a condition or relationship characteristic of a feature or features of an embodiment of the invention, are understood to mean that the condition or characteristic is defined to within tolerances that are acceptable for operation of the embodiment for an application for which it is intended. Unless otherwise indicated, the word “or” in the specification and claims is considered to be the inclusive “or” rather than the exclusive or, and indicates at least one of, or any combination of items it conjoins.

[0250] It should be understood that the terms “a” and “an” as used above and elsewhere herein refer to “one or more” of the enumerated components. It will be clear to one of ordinary skill in the art that the use of the singular includes the plural unless specifically stated otherwise. Therefore, the terms “a”, “an” and “at least one” are used interchangeably in this application.

[0251] As used herein the term “about” refers to ± 10 %.

[0252] The terms “comprises”, “comprising”, “includes”, “including”, “having” and their conjugates mean “including but not limited to”.

[0253] For purposes of better understanding the present teachings and in no way limiting the scope of the teachings, unless otherwise indicated, all numbers expressing quantities, percentages or proportions, and other numerical values used in the specification and claims, are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0254] In the description and claims of the present application, each of the verbs, “comprise”, “include”, and “have” and conjugates thereof, are used to indicate that the object or objects of the verb are not necessarily a complete listing of components, elements or parts of the subject or subjects of the verb.

[0255] Other terms as used herein are meant to be defined by their well-known meanings in the art.

[0256] Unless specifically stated or obvious from context, as used herein, the term "or" is understood to be inclusive.

[0257] Throughout this specification and claims, the word “comprise” or variations such as “comprises” or “comprising” indicate the inclusion of any recited integer or group of integers but not the exclusion of any other integer or group of integers.

[0258] As used herein, the term “consists essentially of’ or variations such as “consist essentially of’ or “consisting essentially of’ as used throughout the specification and claims, indicate the inclusion of any recited integer or group of integers, and the optional inclusion of any recited integer or group of integers that do not materially change the basic or novel properties of the specified method, structure, or composition.

[0259] As used herein, the terms "comprises", "comprising", "containing", "having" and the like can mean "includes", "including", and the like; "consisting essentially of or "consists essentially" likewise has the meaning ascribed in U.S. patent law and the term is open-ended, allowing for the presence of more than that which is recited so long as basic or novel characteristics of that which is recited is not changed by the presence of more than that which is recited, but excludes prior art embodiments. In one embodiment, the terms "comprises" "comprising", and "having" are / is interchangeable with "consisting".

[0260] Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications, and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.

[0261] All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent, or patent application was specifically andindividually indicated to be incorporated herein by reference. In addition, citation, or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention. To the extent that section headings are used, they should not be construed as necessarily limiting.EXAMPLES

[0262] Generally, the nomenclature used herein, and the laboratory procedures utilized in the present invention include molecular, biochemical, and microbiological techniques. Such techniques are thoroughly explained in the literature.EXAMPLE 1GENERAL SCHEMES FOR PREPARATION OF THE EXEMPLARY COMPOUNDS OF THE INVENTIONGeneral scheme 1

[0263] Representative example of the synthesis according to General Scheme 1

[0264] Synthesis of RNB-557-Int-2. To a solution of RNB-557-Int-l (0.400g, 1.60mmol, l.Oeq) in pyridine (5mL) was added 1 -ethyl- lH-pyrazole-4-sulfonyl chloride (0.312g, 1.60mmol, l.Oeq) at 0 °C. The reaction mixture was stirred at 0 °C to RT for 3 h. After completion of reaction, the reaction mixture was quenched into water (20mL) and product was extracted with ethyl acetate (2 x 30mL). Combined organic layer were washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain crude which was further purified by n-Hexane trituration to get crude RNB-557-int- 2 which was used without further purification (0.400g, crude). MS(ES) : m / z 408.43 [M+H]+.

[0265] Synthesis of RNB-557 & RNB-558. To a solution of RNB-557 (0.400g, 0.98mmol, l.Oeq) in Pyridine (5mL) were added 3H-imidazo[4,5-c] pyridine (0.234g, 1.96mmol, 2.0eq) and DMAP (0.479g ,3.93mmol, 4.0eq) at room temperature. The reaction mixture was degassed for 10 min under oxygen atmosphere. Copper acetate (0.355g, 1.96mmol, 2eq) was added to reaction mixture, and purged by oxygen for 10 min. The reaction mixture was stirred at 110 °C for 16 h. After completion of the reaction, the crude mixture was quenched into water (10 mL) and product was extracted with ethyl acetate (2 x 15mL). Combined organic layers were washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain crude, which was purified by Prep-HPLC (0.1% FA in water and 100% ACN) to get pure RNB-557 (0.015g, yield- 3.83%) MS(ES): m / z 399.45 [M-H]+. LCMS purity: 99.45%, HPLC purity: 99.99% and RNB-558 (0.015g, yield- 3.83%) MS(ES): m / z 399.45 [M-H]+. LCMS purity: 97.91%, HPLC purity: 98.52%General procedure for l-ethyl-N-(2-methoxy-5-nitrophenyl)-lH-pyrazole-4- sulfonamideGeneral procedure for preparation of N-(5-anuno-2-methoxyphenyl)-l-ethyl-lH- pyrazole-4- sulfonamide

[0269] 2 3To a solution of 1- ethyl-N-(2-methoxy-5-nitro-phenyl)pyrazole-4-sulfonamide (950 mg, 2.91 mmol) in EtOH (10 mL) and H2O (1 mL) was added Fe (1.63 g, 29.1 mmol) and NH4C1 (1.56 g, 29.1 mmol). The mixture was stirred at 70 °C for 18 hours. The reaction mixture was filtered and the filtrate was concentrated to give N-(5-amino-2-methoxyphenyl)-l-ethyl- lH-pyrazole-4-sulfonamide (830 mg, crude) as a black brown solid. LCMS: MS (ESI) m / z = 297.1 [M+H]+.

[0270] ’H NMR (400 MHz, DMSO-^) 5 8.91 - 8.65 (m, 1H), 8.15 (s, 1H), 7.67 - 7.56 (m, 1H), 6.65 (s, 2H), 6.31 (d, J = 7.2 Hz, 1H), 5.09 - 4.78 (m, 2H), 4.12 (d, J = 6.4 Hz, 2H), 3.48 (s, 3H), 1.32 (s, 3H).General procedure for preparation of N-(5-amino-2-meth oxyphenyl)- 1-ethyl-lH- pyrazole-4- sulfonamide

[0271] 3 4To a solution of N-(5-amino-2-methoxyphenyl)-l-ethyl-lH-pyrazole-4-sulfonamide (830 mg, 2.80 mmol,) in EtOH (8 mL) was added 3-fluoro-4-nitropyridine 1-oxide (531 mg, 3.36 mmol). The mixture was stirred at 70 °C for 12 hours. The reaction mixture was used into the next step without further purification. LCMS: MS (ESI) m / z = 435.1 [M+H]+.General procedure for preparation of 3-((3-((l-ethyl-lH-pyrazole)-4-sulfonamido)-4- methoxyphenyl) amino)-4-nitropyridine 1-oxide4 5

[0272] To a solution of N-(5-amino-2-methoxyphenyl)-l-ethyl-lH-pyrazole-4- sulfonamide (1.2 g, crude) in EtOH (12 mL) and H2O (1.2 mL) was added Fe (1.54 g, 27.6 mmol) and NH4C1 (1.48 g, 27.6 mmol). The mixture was stirred at 80 °C for 8 hours. The reaction mixture was filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography on silica gel (Dichloromethane: Methanol =10:0 to 0:1) to give 3-((3-((l-ethyl-lH-pyrazole)-4-sulfonamido)-4-methoxyphenyl)amino)-4- nitropyridine 1-oxide (800 mg, 2.06 mmol, 74.5% yield) as a black brown solid.

[0273] LCMS: MS (ESI) m / z = 389.1 [M+H]+. ’H NMR (400 MHz, DMSO-^) 5 9.20 (s, 1H), 8.22 (s, 1H), 7.93 (d, J = 6.4 Hz, 1H), 7.83 (s, 1H), 7.63 (d, J = 4.0 Hz, 4H), 7.00(d, J = 2.8 Hz, 1H), 6.94 - 6.88 (m, 2H), 6.76 (J = 2.8, 8.8 Hz, 1H), 4.15 (q, J = 7.2 Hz, 2H), 3.59 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H).General procedure for N-(5-(3H-imidazo[4,5-c]pyridin-3-yl)-2-methoxyphenyl)-l- ethyl-lH -pyrazole-4-sulfonamide (RNB-557)To a solution of 3-((3-((l-ethyl-lH-pyrazole)-4-sulfonamido)-4-methoxyphenyl) amino)- 4-nitropyridine 1 -oxide (500 mg, 1.29 mmol) in trimethyl orthoformate (10 mL) was added TEA (130.25 mg, 1.29 mmol, 179 pL). The mixture was stirred at 110 °C for 0.5 hour. The reaction mixture was filtered and the filtrate was concentrated to give a residue. The residue was triturated with MeCN (8 ml) at 25 °C for 30 min to give N-(5-(3H-imidazo[4,5- c]pyridin-3-yl)-2-methoxyphenyl)-l-ethyl-lH -pyrazole-4-sulfonamide (0.123 g, 306 pmol, 23.8% yield, 99.5% purity) as an off-white solid.LCMS: MS (ESI) m / z = 399.1 [M+H], ’H NMR (400 MHz, DMSO-^) 5 9.63 (s, 1H), 8.80 (d, J = 0.9 Hz, 1H), 8.72 - 8.70 (m, 1H), 8.44 (d, J = 5.6 Hz, 1H), 8.25 (s, 1H), 7.79 (dd, J = 1.2, 5.6 Hz, 1H), 7.70 (s, 1H), 7.56 (d, J = 2.8 Hz, 1H), 7.54 - 7.49 (m, 1H), 7.22 (d, J = 8.8 Hz, 1H), 4.15 (q, J = 7.2 Hz, 2H), 3.74 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H).General procedure for preparation of RNB-691RNB-691General procedure for preparation of N-(2-cyclobutoxy-5-(imidazo[l,2-c]pyrimidin- 3-yl)phenyl)-l-ethyl-lH-pyrazole-4-sulfonamide (RNB-698)EXAMPLE 2 RECOMBINANT FTO ASSAY

[0275] In order to set a drug discovery program we established several assays allowing measurement of FTO activity in both cell-free and cell-based systems.

[0276] For the cell-free recombinant FTO assay, we first set m6A-RNA detection assay in an ELISA format (Figure 6A). Biotinylated ssRNA sequences containing the FTO recognition motif (GG-m6A-CU) were adhered to Strepavidin (SA) coated plate (Pierce™ Streptavidin Coated Plate). ssRNA-m6A (Biotin-GG-m6A-CUGG-m6A-CUGG-m6A- CUGG-m6A-CU) sequence was calibrated vs an unmethylated ssRNA (Biotin-GG-A- CUGG-A-CUGG-A-CUGG-A-CU) to give the best detection window with an anti m6A- RNA antibody (Several anti-m6A-RNA antibodies were screened for best signal-to-noise ratio and Abeam ab284130 was selected) (data not shown). Then, we calibrated m6A- ssRNA (lOnM ssRNA-m6A) detection using different concentrations of the primary anti- m6A antibody (Abeam ab284130) and secondary anti-Rb HRP antibody (Abeam ab97051) (Figure 6B). 1 / 4000 anti m6A-RNA primary antibody (0.144pg / mL) and 1 / 1250 2ndanti IgG antibody were selected for m6A-ssRNA ELISA detection. We then calibrated the cell- free recombinant FTO activity. Different ratios of recombinant FTO enzyme (Detected by an anti-human FTO antibody by Western Blot;Figure 6C) and ssRNA-m6A concentrations were incubated for 30min at 37c, in order to set the concentrations for FTO demethylation activity (Figure 6D). In this setup, m6A-RNA detection linear range was between 5nM- 50nM (Figure 6D-no FTO). Clear FTO dose-dependent ssRNA demethylation was detected at 12.5nM-25nM m6A-ssRNA concentrations (Figure 6D and 6E). FTO activity was also validated by analysis of the m6A-ssRNA utilizing m6A-RNA dot blot (Figure 6F,see also Figure 7 below). The final setup of the m6A cell-free screen includes 0.4pM FTO enzyme and 25nM ssRNA. In each screening experiment, 7 tested compounds at 30pM, lOpM and 3pM, and selected controls: lOpM FB23 and lOpM MA (known FTO inhibitors), ssRNA without FTO enzyme and no-m6A oligo for background / non-specific detection (Figure 6G).

[0277] The assay is an m6A-RNA detection assay in an ELISA format to analyze remaining m6A-RNA post enzymatic reaction with recombinant FTO. m6A-RNA signal is proportional to FTO activity allowing screening of FTO inhibitors and determination of their IC50 values. IC50 values of the exemplary compounds of the invention are presented in Table 1 below.Table 1. Recombinant FTO assay IC50 values of exemplary compounds.EXAMPLE 3CETSA TARGET ENGAGEMENT ASSAY

[0278] The C6llular Thermal Shift Assay (CETSA) is used to study protein-drug interactions within cells. Intact cells were treated with the compound of interest. Each compound was dissolved in DMSO and subsequently diluted with an aqueous solvent to arrive at the final DMSO concentration of 0.1%.

[0279] Samples were subjected to a gradient of increasing temperatures. At each temperature, samples were lysed to release proteins, which are then separated into soluble and aggregated fractions. The presence of the target protein in the soluble fraction was analyzed. A shift in the protein's melting temperature indicates binding by the compound.

[0280] A single temperature of 62°C was used, where cellular FTO degrades after 0.1% DMSO (vehicle) treatment. The ratio of FTO levels after 62°C degradation in compound- treated cells versus 0.1% DMSO (vehicle) treated cells is used as a score for FTO and compound interactions. Significant >1 elevation of this score is indicative of binding.TABLE 2. CETSA FTO score as an indication of target binding in cells.* Relative activity compared to a vehicle (aqueous solution of DMSO at 0.1%) used as a negative control.EXAMPLE 4CELL-BASED ANTI-PROLIFERATION ASSAY

[0281] Protocol: To monitor the proliferation, cell counts were measured 96 hours post compound treatments at different concentrations. C6lls were either counted by automated microscopy counts of stained nuclei (adheC6lls) or by C6ll Titer Glow assay (Promega G7571) (AML cells, ccRenal cells & PBMCs cells).

[0282] The data show that the lowest IC50 values in the range of 0.3- 1 pM received for MV411 cells (AML), and in the range of 1-3 pM for 786-o (cc-Renal) cell line versus the normal cells, PBMC, presented in Table 3.Table 3. IC50 values of the exemplary compounds of the invention.00283] As evident from Table 3, the tested compounds inhibited proliferation of cancer cells with high specificity, compared to normal PBMC cells. Accordingly, it is expected that the compounds of the invention can be used for cancer treatment (e.g. FTO-related cancer).EXAMPLE 5 (CETSA target engagement assay)

[0284] A comparison of RNB-557 versus the current AML approved drugs was performed (Figure 3A-C). The utility of RNB-557 in pancreatic and ccRenal cancers is shown in Table 4.Table 4. A comparison of RNB-557 to current AML approved drugs.00285] Fig 3C shows a comparison of the exemplary compounds of the invention (RNB- 557, 675 and 637) and currently approved drugs (5 -Azacytidine, Cytarabine, Midostaurin) for AML treatment in cells. As evident from Figs. 3C-3D, the exemplary compounds of the invention have an AML activity comparable to or superior over the drugs currently approved for AML treatment (5 -Azacytidine, Cytarabine, Midostaurin).EXAMPLE 6 (efficacy of rnb-557 in different cancer cell lines)

[0286] The effect of RNB-557 on cell proliferation of various cancer cell lines (blood cancer, bladder cancer, pancreatic cancer, renal cancer, melanoma cancer, osteosarcoma) after 120h of incubation with RNB-557 (3pM) was measured. Relative cell count after 120h was performed and the results are summarized in Fig. 4. As evident from Fig. 4,exemplary FTO inhibitor, RNB-557, demonstrates a solid viability reduction of cancer cell lines from different origins.

[0287] Also, normal cells were compared to cancer cells. AML cell lines (Kasumi-1, THP-1, NKM-1 MV411) and normal PBMCs (Peripheral blood mononuclear cells) were treated for 96 hours with RNB-557 at the indicated concentrations before measuring the cell viability using C6ll Titer Glow assay. The analysis showed that the healthy PBMCs cells were not affected by RNB-557 FTO inhibitor as presented in Fig. 5, thus pointing out specificity / selectivity of the tested compound of the invention to FTO -expressing cancer cells. Surprisingly, RNB-558 which is a close structural analog of RNB-557 was almost inactive in the tested cells even at a concentration of 1 uM (see Fig. 14C).EXAMPLE 7

[0288] The inventors tested the efficacy of the exemplary compound of the invention (RNB-557) in an in-vivo AML cancer model. In an in vivo efficacy experiment, 6-8-week- old female CB17 SCID mice (n=10 per group, 2 groups) were inoculated with 10xl0A6 Thp-1 AML cancer cells via subcutaneous injection and treated with either a vehicle or 100 mg / kg of RNB-557. Mice were administered orally twice daily (BID) for 17 days following the development of 100 mmA3 tumors. The RNB-557 treatment showed significant tumor growth inhibition (TGI) of 73.89% compared to the vehicle group (Figure 7A) with tumor sizes reduced to 470 ± 63 mmA3 versus 1486 ± 205 mmA3 in the control (p=0.0007). While efficacy was demonstrated, no toxicity adverse affects were observed (Figure 7B).EXAMPLE 8

[0289] For studying the connection between FTO and mRNA stabilization in different cell lines, we have calibrated FTO siRNA knockdown. FTO siRNA transfection was efficient and lead to more than 80% reduction in both FTO mRNA and protein levels as measured compared to non-target siRNA control (Figures 8A-D).

[0290] In order to validate FTO sensitivity to different cancer types we have set an FTO siRNA screen in which cell titer is measured 96 hours post FTO siRNA transfection by imaging and summarized values are presented in Table 5.

[0291] Table 5: siRNA FTO effect on cell proliferation of cancer cell lines

[0292] Without being bound to any particular theory, the inventors postulate that the mechanism of action of RNB-557 and RNB-637 on the AML cells is via a cell cycle arrest at the G2 / M checkpoint, as demonstrated in Figures 9A-9B.

[0293] Furthermore, as evident from Figures 10A-10B, Pancreatic cancer cells (BxPC- 3) also undergo cell cycle arrest at the G2 / M checkpoint, which emphasizes the mechanism of action for FTO targeting in another different type of cancer. Adherent Pancreatic cancer cells (BxPC-3) G2 / M arrest phenotype can also be visualized by microscope using DNA staining (Figure 10B). These cells showed a unique Mitotic defect also known as Mitotic catastrophe.

[0294] For further examination for cell cycle G2 / M phenotype in pancreatic cancer (BxPC-3) cells were treated with FTO targeting compound RNB-637. The cells were stained for DNA and tubulin fibers which indicate that these cells have an intact tubulin spindle but aberrant mitosis. Compared to regular mitosis in control DMSO treated cells, RNB-637 treated cells are apparently inhibited in the Prometaphase (Figures 11A-B). The aberrant mitosis is developing into a Mitotic catastrophe which eventually pushes the cells into apoptosis.EXAMPLE 9

[0295] The centrosome is a key organelle that serves as the primary microtubuleorganizing center (MTOC) in eukaryotic cells. During mitosis, it plays a critical role in forming the bipolar mitotic spindle, which ensures accurate segregation of chromosomes into two daughter cells. In healthy cells, the centrosome duplicates once per cell cycle, and the resulting pair migrates to opposite poles of the cell, maintaining spindle symmetry andgenomic stability. In contrast, many cancer cells exhibit centrosome amplification (CA), characterized by the presence of more than one centrosome during the G1 cell cycle phase and more than 2 centrosomes during mitosis. To avoid lethal multipolar divisions, these cells cluster their excess centrosomes to form a pseudo-bipolar spindle. Disruption of this clustering leads to catastrophic mitosis, marked by multipolar spindles, chromosome misalignment, and apoptosis. In light of the observation of mitotic catastrophe (Fig. 10B), it was hypothesized that FTO may play a role in centromere clustering. This was reinforced by the enrichment of FTO protein at the centromere (Fig. 12A) and by the mislocalizaiton of KIFC1, a motor protein essential for cancer cells harboring CA (Fig. 12B). Specifically, RNB-637 treatment decreased KIFC1 localization between centrosomes (Fig. 12C) and decreased the distance between centrosomes during mitosis (Fig. 12D).

[0296] To further test FTO’s role in centromere clustering, BxPC3 pancreatic cells were treated with an siRNA to knockdown FTO and centromeres were visualized by staining for pericentrin (Fig. 13A). C6lls with significant FTO knockdown were often observed to have more than 1 centromere, while cells without significant knockdown (even in the culture that received the siRNA) were consistently observed to have a single centromere. After quantification, more that 20% of FTO knocked down cells showed 2 centromeres (Fig. 13B) and more than 40% of knocked-down mitotic cells showed chromosome misalignment (Fig. 13C).

[0297] The FTO inhibitor RNB-637 (1.1 uM) was tested in the lung cancer cell line Calu- 6. This cell line is known to have centrosome amplification. The inhibitor of the invention caused centrosome declustering in most of the cells (Fig. 14A). A dose escalation with RNB-637 was carried out in BxPC3 cells and instances of chromosome misalignment increased in a dose dependent manner (Fig. 14B). Further, cancer cell apoptosis also increased in a dose dependent manner (Fig. 14C). The same was observed with a second FTO inhibitor of the invention, RNB 557 (Fig. 14C), but not with an inactive control molecule.

[0298] C6ntrosome amplification in certain cancers offers a way to selectively target only cancer cells while sparing healthy cells for the most part. To test this, normal human peripheral blood mononuclear cells (PBMCs), normal lung fibroblasts, normal skin fibroblasts and the osteosarcoma cell line U2OS which is known not to have CA (Fig. 15A-15C) were exposed to increasing doses of inhibitor RNB-637 and relative cell number was calculated (Fig. 15D). Three cancer cell lines that do have CA, BxPC3, ovarian cancer cell line OVCAR-3 and squamous cell carcinoma line Cal 27 (Fig. 15A-15C) were also exposed to increasing doses of the inhibitor and cell number was calculated (Fig. 15D). At the -6 log(M) concentration all three types of cancer cells were effectively killed while the healthy cells, and even the cancer cells without CA (U2OS), were essentially spared. The same results were observed with a fourth CA+ cancer cell line, Calu-6 (Fig. 15E). The IC50 for the healthy cells were more than 4 times higher than for the cancer cells, indicating a dosing window that would be effective against cancer cells while sparing healthy cells. The IC50 for various cancer cells with CA (Thp-1, BxPC3, Calu-6, Ovcar3) and cells without CA (A549, WI38 lung fibroblasts, Skin fibroblasts) are provided in Figure 15F. This indicates that a proper dose can be selected by a skilled artisan for each cancer.EXAMPLE 10EFFICACY OF RNB-637 IN DIFFERENT CANCER CELL LINES.

[0299] The effect of RNB-637 on cell proliferation of various cancer cell lines (pancreatic cancer, leukemia, skin cancer, prostate cancer, bladder cancer, breast cancer, multiple myeloma (MM), cervical cancer, liver cancer, ovarian cancer, lung cancer and head and neck cancer) was measured after incubation with 1 pM RNB-637. The results are summarized in Figure 16. As evident from Figure 16, exemplary FTO inhibitor, RNB-637, demonstrates a solid viability reduction of cancer cell lines from different origins. At least a -50% reduction was possible in cell lines from all the cancer types, indicating FTO inhibition is useful for treatment all of these types of cancers. The variability observed is potentially due to the varying levels of CA and chromosomal instability present in the various cell lines. In summary, it is demonstrated that FTO, a known m6A RNA demethylase, localizes to centrosomes and is essential for centrosome clustering in cancer cells with CA. Inhibition of FTO — through siRNA knockdown or small-molecule inhibitors — results in centrosome delustering, mitotic defects, and apoptosis. Importantly, this apoptosis occurs selectively in cancer cells with amplified centrosomes but not in normal / healthy cells.

Claims

CLAIMS1. A compound represented by Formula I’ :, including any salt thereof, wherein: each X and Xi independently represents -N- or -(CH)-; R2represents any one of: an optionally substituted heterocyclic ring, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl; each R1and R independently represents hydrogen or one or more substituent(s) selected from halo, thioxo, carbonyl, imino, amino, -NO2, -CN, -OH, -OR”, -CONH2, -C0NR”2, -CNNR”2, -CSNR’2, -CONH-OH, -C0NH-NH2, oxo, -NHCOR”, -NHCSR”, -NHCNR”, - NC(=0)0R”, -NC(=0)NR”, -NC(=S)OR”, -NC(=S)NR”, -SO2R”, -SOR”, -SR”, - SO2OR”, -SO2N(R”)2, -NHNR”2, -NNR”, C1-C6haloalkyl, optionally substituted C1-C6alkyl, -NR”2, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, Ci-C6alkoxy, Ci-C6haloalkoxy, hydroxy(C1-C6alkyl), hydroxy(C1-C6alkoxy), alkoxy(C1-C6alkyl), alkoxy(C1-C6alkoxy), C1-C6alkyl-NR”2, C1-C6alkyl-SR”, -CONH(C1-C6 alkyl), - CON(C1-C6 alkyl)2, -C02H, -C02R”, -0C0R”, -OC(=O)OR”, -0C(=0)NR”, - OC(=S)OR”, -OC(=S)NR”, C1-C6alkyl-OR” and R” or a combination thereof; each R” independently represents hydrogen, or is selected from the group comprising optionally substituted C1-C10 alkyl, optionally substituted C1-C10 alkenyl, optionally substituted Ci- C10 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C1-C10 alkyl- C3-C10 cycloalkyl, optionally substituted C3-C10 heterocyclyl, optionally substituted C1-C10 alkyl-C3-C10heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted C1-C10 alkyl-aryl / heteroaryl, hydroxy, -OR”, amino, -NH2, -NR”2, - NR”(C1-C6alkyl), -N(C1-C6alkyl)2, C1-C6alkoxy, C1-C6haloalkoxy, hydroxy(C1-C6alkyl), hydroxy(C1-C6alkoxy), alkoxy(C1-C6alkyl), alkoxy(C1-C6alkoxy), C1-C6alkyl- NR”2, C1-C6alkyl-SR”, C1-C6alkyl-OR” or a combination thereof.

2. The compound of claim 1, wherein R1is atached to ring A at a position 1, 2, 3, 4 or any combination thereof.

3. The compound of claim 1 or 2, wherein the compound is represented byFormula II:

4. The compound of claim 1 or 2, wherein the compound is represented byFormula IIB:

5. The compound of any one of claims 1 to 4, wherein R is selected from hydrogen, C1-C6alkyl and halo.

6. The compound of any one of claims 1 to 5, wherein R1is selected from -H, -OH, Cl, F, Br, I, NH2, NHR”, NR”2, C1-C6alkyl, -O-R”, R” and Ci-C6alkyl-OR”.

7. The compound of any one of claims 1 to 6, wherein R2is an optionally substituted heterocyclic ring.

8. The compound of claim 7, wherein R2is Pyrazole-Rx and wherein Rx represents any one of H, R”, Y-R”, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted (C1-C6hetereoalkyl)- aryl, an optionally substituted (C1-C6hetereoalkyl)-cycloalkyl, an optionally substituted (C1-C6hetereoalkyl)-heterocyclyl, an optionally substituted (C1-C6alkyl)-aryl, an optionally substituted (C1-C6alkyl)-cycloalkyl, an optionally substituted (C1-C6alkyl)- heterocyclyl, an optionally substituted (C1-C6alkyl)-Y-aryl, an optionally substituted (Ci- C6alkyl)-Y-cycloalkyl, an optionally substituted (C1-C6alkyl)-Y-heterocyclyl and anoptionally substituted heteroaryl, wherein Y represents a heteroatom selected from S, O, N, and NH or is any one of: -CONR”, -CNNR”, -CSNR”, -CONH-O, -CONH-NH, carbonyl, -NHCOR”, -NHCSR”, -NHCNR”, -NHC(=O)O, -NHC(=O)NH, -NHC(=S)O, - NHC(=S)NH, -SO2, -SO, -SO2O, -SO2NR”, -NHNR”, -NN, -NR”, -CO2, -OCO, - OC(=O)O, -OC(=O)NR”, -OC(=S)O and -OC(=S)NR”9. The compound of claim 8, wherein the compound is represented by FormulaIII:, wherein R1 is selected from O-R”, C1-C6alkyl-OR” and R”, or is absent.

10. The compound of claim 8, wherein the compound is represented by Formulawherein R1 is selected from O-R”, C1-C6alkyl-OR” and R”, or is absent.

11. The compound of any one of claims 1 to 10, wherein each R” independently represents hydrogen, or is selected from the group comprising optionally substituted Ci- C10 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C1-C10 alkyl-Cs- C10 cycloalkyl, optionally substituted C3-C10 heterocyclyl, optionally substituted C1-C10 alkyl-C3-C10heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted C1-C10 alkyl-aryl / heteroaryl or a combination thereof.

12. The compound of any one of claims 9 to 11, wherein R” is or comprises any one of: optionally substituted C1-C10 alkyl-C3-C10cycloalkyl, optionally substituted C1-C10alkyl-C3-C10heterocyclyl, optionally substituted C1-C10 alkyl-C3-C10aryl / heteroaryl, an optionally substituted alkyl and an optionally substituted cycloalkyl.

13. The compound of any one of claims 1 to 12, wherein R1represents a single substituent and is attached to ring A at the position 2.

14. The compound of any one of claims 8 to 13, wherein Rx represents any one of H, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted aryl, (C1-C6alkyl)-aryl and an optionally substituted heteroaryl.

15. The compound of any one of claims 1 to 14, wherein the compound is or comprises any one of RNB-557 / 637 / 631 / 675 / 1705 / 476 / 1701 / 1702 / 1703 / 1710 / 1720 / 1729 / 1734 / 1735 / 683 / 691 / 698, including any salt thereof.

16. A compound represented by Formula (IV):wherein: each R1and R independently represents hydrogen or one or more substituent(s) selected from halo, thioxo, carbonyl, imino, ammo, -NO2, -CN, -OH, -OR”, -CONH2, -CONR”2, -CNNR”2, -CSNR’2, -CONH-OH, -CONH-NH2, OXO, -NHCOR”, -NHCSR”, -NHCNR”, -NC(=O)OR”, -NC(=O)NR”, - NC(=S)OR”, -NC(=S)NR”, -SO2R”, -SOR”, -SR”, -SO2OR”, -SO2N(R”)2, -NHNR”2, - NNR”, C1-C6haloalkyl, optionally substituted C1-C6alkyl, -NR”2, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6alkoxy, C1-C6haloalkoxy, hydroxy(C1-C6alkyl), hydroxy(C1-C6alkoxy), alkoxy(C1-C6alkyl), alkoxy(C1-C6alkoxy), C1-C6alkyl-NR”2, Ci-C6alkyl-SR”, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, -CO2H, -CO2R”, - OCOR”, -OC(=O)OR”, -OC(=O)NR”, -OC(=S)OR”, -OC(=S)NR”, Ci-C6alkyl-OR” and R” or a combination thereof; each R” independently represents hydrogen, or is selected from the group comprising optionally substituted Ci-Cio alkyl, optionally substituted Ci-Cio alkenyl, optionally substituted Ci-Cio alkynyl, optionally substitutedC3-C10 cycloalkyl, optionally substituted C1-C10 alkyl-C3-C10cycloalkyl, optionally substituted C3-C10 heterocyclyl, optionally substituted C1-C10 alkyl-C3-C10heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted Ci- C10 alkyl-aryl / heteroaryl, hydroxy, -OR”, amino, -NH2, -NR”2, -NR”(C1-C6alkyl), - N(C1-C6alkyl)2, C1-C6alkoxy, C1-C6haloalkoxy, hydroxy(C1-C6alkyl), hydroxy(Ci- C6alkoxy), alkoxy(C1-C6alkyl), alkoxy(C1-C6alkoxy), C1-C6alkyl-NR”2, C1-C6alkyl -SR”, C1-C6alkyl-OR” or a combination thereof; and R2represents any one of: an optionally substituted heterocyclic ring, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl; wherein if R1is hydrogen than R2is the optionally substituted heterocyclic ring.

17. The compound of claim 16, wherein if R1is hydrogen than R2is an optionally substituted pyrazole.

18. The compound of claim 16 or 17, wherein each R1independently represents -H, -OH, Cl, F, Br, I2, NH2, NHR”, NR”2, C1-C6alkyl, or -O-R”, and wherein R” comprises an optionally substituted C1-C6alkyl, or an optionally substituted cycloalkyl.

19. The compound of any one of claims 16 to 18, wherein the compound is any one of:including any salt thereof.

20. A pharmaceutical composition comprising the compound of any one of claims 1 to 19 and a pharmaceutically acceptable carrier.

21. The pharmaceutical composition of claim 20, comprising a therapeutically effective amount of said compound.

22. The pharmaceutical composition of claims 20 or 21, for use in the inhibition of FTO activity within a cell.

23. The pharmaceutical composition of any one of claims 20 to 22, for use in the treatment of a cancer in a subject.

24. The pharmaceutical composition for use of claim 23, wherein said cancer is an FTO related cancer.

25. The pharmaceutical composition for use of claim 24, wherein the FTO related cancer is selected from osteosarcoma, skin cancer, bladder cancer, pancreatic cancer, kidney cancer, cervical cancer, lung cancer, breast cancer, prostate cancer, liver cancer, ovarian cancer, head and neck cancer and hematopoietic cancer.

26. The pharmaceutical composition for use of any one of claims 23 to 25, wherein said cancer comprises centrosome amplification.

27. A method for preventing or treating a disease in a subject, comprising administering to the subject the pharmaceutical composition of claim 20 or 21, thereby preventing or treating the disease or the disorder in the subject.

28. The method of claim 27, wherein said disease a proliferative disease.

29. The method of claim 28, wherein said proliferative disease is associated with FTO overexpression in the subject.

30. The method of claim 28 or 29, wherein said proliferative disease comprises centrosome amplification.

31. The method of any one of claims 27 to 30, comprising administering a therapeutically effective amount of the pharmaceutical composition to said subject.

32. The method of claim 31, wherein said administering comprises any one of: oral administration, rectal administration, vaginal administration, transdermal administration, ophthalmic administration, subcutaneous administration, intramuscular administration, intravenous administration, topical administration, nasal administration, sublingual administration, buccal administration, systemic administration, or any combination thereof.

33. A method for preventing or treating a cancer with centrosome amplification in a subject, comprising administering to the subject a therapeutically effective amount of an FTO inhibitor, thereby preventing or treating the cancer with centrosome amplification in the subject.

34. The method of claim 33, wherein said FTO inhibitor comprises one or more of: nucleic acid molecule, small molecule, polypeptide or protein, including any combination thereof.

35. The method of claim 33, wherein said FTO inhibitor is a compound of any one of claims 1 to 20, or a compound of Formula I:, including any salt thereof, wherein: each of B and C independently represents a heterocyclic ring (i.e. an aromatic or aliphatic heterocyclyl); X represents -N- or -(CH)-; R2represents any one of: an optionally substituted cyclyl, an optionally substituted alkyl, an optionally substituted heterocyclic ring, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl; each R1and R independently represents hydrogen or a substituent selected from halo, thioxo, carbonyl, imino, amino, -NO2, -CN, -OH, -OR”, -CONH2, - CONR”2, -CNNR”2, -CSNR’2, -CONH-OH, -CONH-NH2, oxo, -NHCOR”, -NHCSR”, - NHCNR”, -NC(=0)0R”, -NC(=0)NR”, -NC(=S)OR”, -NC(=S)NR”, -SO2R”, -SOR”, - SR”, -SO2OR”, -SO2N(R”)2, -NHNR”2, -NNR”, C1-C6haloalkyl, optionally substituted Ci-C6alkyl, -NR”2, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, Ci-C6alkoxy, Ci-C6haloalkoxy, hydroxy(C1-C6alkyl), hydroxy(C1-C6alkoxy), alkoxy(C1-C6alkyl), alkoxy(C1-C6alkoxy), C1-C6alkyl-NR”2, C1-C6alkyl-SR”, -CONH(C1-C6 alkyl), - CON(C1-C6 alkyl)2, -C02H, -C02R”, -0C0R”, -0C(=0)0R”, -0C(=0)NR”, - OC(=S)OR”, -OC(=S)NR”, C1-C6alkyl-OR” and R” or a combination thereof; each R” independently represents hydrogen, or is selected from the group comprising optionally substituted C1-C10 alkyl, optionally substituted C1-C10 alkenyl, optionally substituted Ci- C10 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C1-C10 alkyl- C3-C10 cycloalkyl, optionally substituted C3-C10 heterocyclyl, optionally substituted C1-C10 alkyl-C3-C10heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted C1-C10 alkyl-aryl / heteroaryl, hydroxy, -OR”, amino, -NH2, -NR”2, - NR”(C1-C6alkyl), -N(C1-C6alkyl)2, C1-C6alkoxy, C1-C6haloalkoxy, hydroxy(C1-C6alkyl), hydroxy(C1-C6alkoxy), alkoxy(C1-C6alkyl), alkoxy(C1-C6alkoxy), C1-C6alkyl- NR”2, C1-C6alkyl-SR”, C1-C6alkyl-OR” or a combination thereof.

36. The method of any one of claims 33 to 35, wherein said cancer comprising centrosome amplification is selected from the group consisting of an osteosarcoma, a skin cancer, a bladder cancer, a pancreatic cancer, a kidney cancer, a cervical cancer, a lung cancer, a breast cancer, a prostate cancer, a liver cancer, an ovarian cancer, a head and neck cancer and a hematopoietic cancer comprising centrosome amplification.

37. The method of any one of claims 33 to 36, further comprising selecting a subject confirmed to suffer from a cancer comprising centrosome amplification.

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