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

Abstract

The present invention relates to novel c-MYC mRNA translation modulators, composition and methods of preparation thereof, and uses thereof in the treatment of cancer.

Description

c-MYC mRNA TRANSLATION MODULATORS AND USES THEREOFIN THE TREATMENT OF CANCERFIELD OF THE INVENTION

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

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

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

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

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

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

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

[0008] This invention provides a compound or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxidc. reverse amide analog, prodrug, isotopic variants (e.g., deuterated analog), PROTAC, pharmaceutical product or any combination thereof, represented by the structure of formula I and / or I(a)-I(n) and by the structures listed in Table 1, as defined herein below. In various embodiments, the compound is a c-MY C mRNA translation modulator. In various embodiments, the compound is a c-MY C mRNA transcription regulator. In various embodiments, the compound is a c-MYC inhibitor. In various embodiments, the compound is any combination of a c-MYC mRNA translation modulator, c-MY C mRNA transcription regulator and c-MYC inhibitor.

[0009] This invention further provides a pharmaceutical composition comprising a compound or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxidc. prodrug, isotopic variants (e.g., deuterated analog), PROTAC, pharmaceutical product or any combination thereof, represented by the structure of formula I and / or I(a)-I(n) and by the structures listed in Table 1, as defined herein below, and a pharmaceutically acceptable carrier.

[0010] This invention further provides a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting cancer in a subject, comprising administering a compound represented by the structure of formula I and / or I(a)-I(n) and by the structures listed in Table 1, as defined herein below, to a subject suffering from cancer under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit cancer in said subject.

[0011] This invention further provides a method for suppressing, reducing or inhibiting tumor growth in a subject, comprising administering a compound represented by the structure of formula I and / or 1(a)- I(n) and by the structures listed in Table 1, as defined herein below, to a subject, under conditions effective to suppress, reduce or inhibit tumor growth in said subject. In some embodiment, the tumor is cancerous. In some embodiment, the subject suffers from cancer.

[0012] This invention further provides a method of modulating c-MYC mRNA translation in a cell, comprising contacting a compound represented by the structure of formula I and / or I(a)-I(n) and by the structures listed in Table 1, as defined herein below, with a cell, thereby modulating c-MYC mRNA translation in said cell.

[0013] This invention further provides a method of regulating c-MYC mRNA transcription in a cell, comprising contacting a compound represented by the structure of formula I and / or I(a)-I(n) and by the structures listed in Table 1, as defined herein below, with a cell, thereby regulating c-MYC mRNA transcription in said cell.DETAILED DESCRIPTION OF THE INVENTION

[0014] In various embodiments, this invention is directed to a compound represented by the structure of formula (I):whereinX2, X3, and X4, are each independently CH, C(R) or N (e.g., C(CH3), C(O-CH2-cyclopropyl), C(O-CH2-methylcyclobutyl), C(NH-CH2-cyclopropyl), C(isopropoxy), C(O-CH(CH3)-CH2-O-CH3), C(CH2CH3), C-iPr, C-CH2-cyclopropyl, C(OCH3), C(OCH2CH3), C(O-(CH2)2-O-CH3, C(OCHF2), C(Cl), C(C(O)CH3), C(O-CH2CH2-O-CH3), C(OH)); X5 , X6 , X7, X8 and X9 are each independently nitrogen or carbon atoms; X10 is N, CH, C(R), or C=O; wherein if X10 is C=O then X11 is N (e.g., C(CH2-OH), C(CH2- CH2-OH), C(NH-CH2-cyclopropyl), C(COOH), C(CH3), C(cyclopropyl), C(isopropoxy)); X11 is N or C; wherein if X11 is N then X10 is C=O; X12is S, SO2, O, NH, N(R), N-OH, CH=CH, CH=CH(R), C(R)=CH, N=CH, N=C(R), CH=N or C(R)=N (e.g., N-CH2-COOH, N-CH2-CH2-OH, N-CH3, N-CH2CH3, N-iPr, N-cyclopropyl, N-CH2- cyclopropyl); R5is H or C1-C5linear or branched alkyl (e.g. methyl); R6is H, F, Cl, Br, I, OH, SH, R8-OH, R8-SH, -R8-O-R10(e.g., CH2-O-CH3, (CH2)2-O-CH3(CH2)3-O-CH3, (CH2)2-O-CH(CH3)2), R8-S-R10(e.g., (CH2)3-S-(CH2)2CH3), R8-NHC(O)-R10, -O-R8- R10, R8-(substituted or unsubstituted C3-C8cycloalkyl) (e.g., CH2-cyclopropyl, CH2-cyclobutanol, CH2- difluorocyclopropyl, CH2-methylcyclopropyl, CH2-dimethylamino-cyclohexyl, (CH2)2-cyclopentanole, CH2-cyclohexanol), R8-(substituted or unsubstituted, saturated, unsaturated or aromatic, single, fused or spiro 3-10 membered heterocyclic ring) (e.g., (CH2)3-piperidine, (CH2)3-4-fluoro-piperidine, (CH2)3- pyran, (CH2)2-pyrrazole, (CH2)2-imidazole, CH2-tetrahydrofurane, CH2-dioxane, CH2-oxetane, CH2- piperidine, CH2-triazole, CH2-1-oxa-8-azaspiro[4.5]decane, (CH2)3-diazabicyclo[2.2.1]heptane, CH2- methyl-THF, CH2-ethyl-piperidine, CH2-oxa-azaspirodecane, (CH2)3-dimethylpyrazole, CH2-2-oxo- methylpyrrolidine, CH2-methyl-azetidine, CH2-azaspiroheptane), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, NH(R10), N(R10)(R11), R8-N(R10)(R11) (e.g., (CH2)2-NH2, (CH2)3- N(CH2CH3)2, (CH2)3-N(CH(CH3)2)2, (CH2)3-piperidine, (CH2)3-4-fluoro-piperidine, (CH2)3-4-cyano- piperidine, (CH2)4-NH(CH3), (CH2)3-NH-CH3, (CH2)3-NH-CH2CH3, (CH2)3-N(CH2CH3)2, (CH2)3-NH2, (CH2)3-N(CH2CH3)(CH2CF3)), R9-R8-N(R10)(R11) (e.g., (CH2)2-C(O)-piperidine), B(OH)2, -OC(O)CF3,-OCH2Ph, NHC(O)-R10, NHCO-N(R10)(R11), COOH, -C(O)Ph, C(O)O-R10, R8-C(O)-R10, C(O)H, C(O)- R10 (e.g., C(O)CH3), C1-C5 linear or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR, C(O)N(R10)(R11), SO2R, SO2N(R10)(R11), CH(CF3)(NH-R10), C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., CH(CH3)CH2OCH3, CH(CH3)CH2NH2, CH(CH3)C(O)N(CH3)2, CH2-CH(OH)Ph, (CH2)3N(H)CH2CH3, CH(CH3)(CH2)2OH, CH(CH2OH)(CH2CH3), (CH2)3-OCH3, (CH2)2-OCH3, (CH2)2-OCH(CH3)2, CH(CH2OH)(CH2CH(CH3)2), CH2CH(CH3)(OCH3), CH2CH(N(CH3)2)(CH2CH3), benzyl, methyl, ethyl, CH2-OCH2-CH2-O-CH3, CH(CH3)C(O)N(CH3)2), C1-C5 linear or branched, substituted or unsubstituted alkenyl, C1-C5 linear or branched, or C3-C8 cyclic haloalkyl, substituted or unsubstituted C1-C5 linear or branched, or C3-C8 cyclic alkoxy (e.g. methoxy, O-(CH2)2-O-CH3), optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom, C1-C5 linear or branched thioalkoxy, C1-C5 linear or branched haloalkoxy, C1-C5 linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclohexyl, methoxycyclopropyl, methylcyclobutyl, aminomethyl-cyclobutyl, methoxycyclobutyl, 2,3-dihydro-1H- indenol), R8-(substituted or unsubstituted C3-C8 cycloalkyl), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., piperidine, 1-methyl-piperidine, azetidine, pyrrolidine, pyrrolidinone, quinuclidine, tetrahydropyran, azaspiro[3.3]heptane, imidazole, trifluoromethyl-oxetane, hydroxy- tetrahydrofurane, azepan-2-one, azabicyclohexane), substituted or unsubstituted aryl, substituted or unsubstituted R8-aryl (e.g., benzyl), substituted or unsubstituted benzyl; or R6and R5are joined to form a substituted or unsubstituted 5-8 membered heterocyclic ring (e.g., azepane, piperazine, 2-(piperazin-1-yl)acetamide; or R6is represented by the structure of formula B or Bi:wherein m is 0 or 1; and R12 is R20 or C1-C5 C(O)-alkyl, and R13 is R30; or R12 and R13 are both H;R12 and R13 are each independently H or substituted or unsubstituted C1-C5 alkyl (e.g., ethyl, trifluoroethyl); R12 and C3 are joined to form ring A and R13 is R30; or R12 and R13 are joined to form ring B; or R12 and C1 are joined to form ring C and R13 is R30; or C1 and C3 are joined to form ring D and R12 and R13 are each independently R30; or R13 and C2 are joined to form ring E, m is 1, and R12 is R30; or R12 and R13 are joined to form ring B and C1 and C3 are joined to form ring D; wherein Ring A, C and E are each independently a substituted or unsubstituted single spiro or fused 3-8 membered heterocyclic ring (e.g., A: pyrrolidine, methylpyrrolidine, ethylpyrrolidine); C: piperidine, pyrrolidine, methyl-2-oxopyrrolidine, pyran- pyrrolidine, methyl-azetidine, azabicyclooctane, 2-azabicyclo[2.1.1]hexane, 2- azaspiro[3.3]heptane; E: pyrrolidine, azetidine, ethylpyrrolidine, oxopyrrolidine, methylpiperidine; Ring B is a substituted or unsubstituted single, spiro or fused 3-8 membered heterocyclic ring (B: piperidine, piperidin-2-one, 4-fluoropiperidin-2-one, piperidine- 4-carbonitrile, 4-fluoropiperidine, 4-fluoro-2-methylpiperidine, methyl-piperidin, fluoropiperidine, difluoropiperidine, pyrrolidine, piperazine, methylpyrrolidine, thiomorpholine 1,1-dioxide, 2-oxa-6-azaspiro[3.3]heptane, methyl-piperazine, dimethyl-pyrazole, imidazole, 2-methyl-2,5-diazabicyclo[2.2.1]heptane, hydroxymethyl-pyrrolidine, diazabicyclo[2.2.1]heptane, 6-fluoro-3- azabicyclo[3.1.1]heptane; and Ring D is a substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclobutane, cyclohexane); R7is H, F, Cl, Br, I, OH, O-R20, SH, R8-OH, R8-SH, SR10, -R8-O-R10, -R8-S-R10, R8-(C3-C8cycloalkyl), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, NH(R10), N(R10)(R11), R8- N(R10)(R11), R9-R8-N(R10)(R11), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R10, NHCO-N(R10)(R11), COOH, -C(O)Ph, C(O)O-R10, R8-C(O)-R10, C(O)H, C(O)-R10, C1-C5linear or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR (e.g., C(O)NH(CH3)), C(O)N(R10)(R11) (e.g., C(O)NH(CH3), C(O)NH(CH2CH2OCH3), C(O)NH(CH2CH2OH)), SO2R, SO2N(R10)(R11), CH(CF3)(NH-R10), C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., methylimidazole, methyl, ethyl), C1-C5linear or branched, substituted or unsubstituted alkenyl, C1-C5linear or branched, or C3-C8cyclic haloalkyl (e.g., CHF2), C1-C5linear or branched, or C3-C8cyclic alkoxy (e.g. methoxy, ethoxy), optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom, C1-C5linear or branched thioalkyl, C1-C5linear or branched thioalkoxy, C1-C5linear or branched haloalkoxy, C1-C5linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8cycloalkyl (e.g., cyclopropyl, cyclopropanol, cyclohexyl), substituted or unsubstituted 4-7 membered heterocyclic ring (e.g.,morpholine (e.g., 2 or 3-morpholine), tetrahydrofuran, tetrahydropyran, oxetane, oxetan-3-ol, pyrrolidine, pyrrolidine-3-ol, 1-methylpyrrolidine, pyrrolidin-2-one, pyrrolidinone, imidazole, pyrazole, piperazine, piperidine, piperidine-4-ol, piperidine-4-carbonitrile, 4-fluoropiperidine, oxadiazole, triazole, 2-oxopyrrolidine, pyridine, 1-methylpyridine), R8-(substituted or unsubstituted single, fused or spiro 3-8 membered heterocyclic ring), substituted or unsubstituted aryl, substituted or unsubstituted benzyl; or R7 is represented by the structure of formula A: whereinX1is N or O; R1and R2are each independently H, F, Cl, Br, I, OH, SH, or CF3, substituted or unsubstituted C1-C5alkyl, C1-C5linear or branched, or C3-C8cyclic haloalkyl, substituted or unsubstituted C1-C5linear or branched, or C3-C8cyclic alkoxy; R1and R2are joined to form =O or a C3-C8carbocyclic or heterocyclic ring (e.g., cyclopropyl); R3and R4are each independently H, Me, substituted or unsubstituted C1-C5alkyl (e.g., methoxyethylene, methylaminoethyl, aminoethyl), -R8-O-R10(e.g., (CH2)2-O-CH3), R8- N(R10)(R11) (e.g., (CH2)2-NH(CH3)), substituted or unsubstituted C3-C8cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted 5-7 membered heterocyclic ring (e.g., pyrrolidine, methylpyrrolidine, piperidine), or R20; R3and R4are joined to form a 3-8 membered heterocyclic ring (e.g., pyrrolidine, 2- oxopyrrolidine, piperidine, morpholine, piperazine, imidazole); or R2and R4are joined to form a substituted or unsubstituted, saturated or unsaturated, 3-8 membered heterocyclic or carbocyclic ring (e.g., pyrrolidine, 1-methylpyrrolidine, pyrrolidin-2-one, pyridine, piperidine, tetrahydrofurane, tetrahydrothiophene, cyclopropyl, oxetane, imidazole, pyrimidine, triazole, oxadiazole, pyrazole), wherein if the ring is aromatic, then R1 and / or R3 are absent; wherein if X1 is O then R4 is absent; R7’ is H, F, Cl, Br, I, OH, O-R20, SH, R8-OH, R8-SH, -R8-O-R10, R8-(C3-C8 cycloalkyl), R8-(3- 8 membered heterocyclic ring), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, NH(R10), N(R10)(R11), R8-N(R10)(R11), R9-R8-N(R10)(R11), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)- R10, NHCO-N(R10)(R11), COOH, -C(O)Ph, C(O)O-R10, R8-C(O)-R10, C(O)H, C(O)-R10, C1-C5 linear or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR, C(O)N(R10)(R11), SO2R, SO2N(R10)(R11),CH(CF3)(NH-R10), C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., isopropyl, methyl, ethyl), C1-C5 linear or branched, substituted or unsubstituted alkenyl, C1-C5 linear or branched, or C3-C8 cyclic haloalkyl (e.g., CHF2), C1-C5 linear or branched, or C3-C8 cyclic alkoxy (e.g. methoxy), optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom, C1-C5 linear or branched thioalkoxy, C1-C5 linear or branched haloalkoxy, C1-C5 linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclohexyl), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., morpholine, pyran, oxetane, pyrrolidine, imidazole, piperazine, piperidine, dioxazole, 2-oxopyrrolidine), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted benzyl; or R7 and R7’ are joined to form a 5 or 6 membered substituted or unsubstituted, saturated, unsaturated or aromatic, carbocyclic or heterocyclic ring (e.g., piperidine, pyrrolidine, tetrahydrofuran, tetrahydropyran); R20 is represented by the following structure:R30is H, R20, F, Cl, Br, I, OH, SH, alkoxy, N(R)2, NH(R10), N(R10)(R11), CF3, CN, NO2, C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH2-CH2-O-CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), C1-C5linear or branched alkoxy, C1-C5linear or branched haloalkyl (e.g., CHF2, CF3, CF2CH3, CH2CF3,CF2CH2CH3,CH2CH2CF3,CF2CH(CH3)2,CF(CH3)-CH(CH3)2), R8-aryl (e.g., CH2-Ph), -R8-O-R8-O-R10(e.g. (CH2)2-O-(CH2)2-O-CH3), -R8-O-R10, -R8-R10(e.g., (CH2)2-O- CH3), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine); R is H, F, Cl, Br, I, OH, SH, COOH, CO(R10) (e.g., C(O)CH3), NH(R10), NH-CH2-cyclopropyl, N(R10)(R11), CF3, CN, NO2, C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, iPr, CH2-cyclopropyl, CH2-OH, CH2-CH2-OH, CH2-CH2-O-CH2-CH2-O-CH3, CH2-O-CH2-CH2- O-CH3), C3-C8substituted or unsubstituted cycloalkyl, cyclopropyl, substituted or unsubstituted C1-C5linear or branched alkoxy, (e.g., methoxy, ethoxy, O-(CH2CH3), OCHF2, O-(CH2)2-O-CH3, isopropoxy, O-(CH2)-cyclopropyl, O-CH2-methylcyclobutyl, O-CH2-3-methyloxetane, O-CH(CH3)-CH2-O-CH3) C1-C5linear or branched haloalkyl (e.g., CHF2, CF3, CF2CH3, CH2CF3,CF2CH2CH3,CH2CH2CF3,CF2CH(CH3)2,CF(CH3)-CH(CH3)2), R8-aryl (e.g., CH2-Ph), -R8-O-R8-O-R10(e.g. (CH2)2-O-(CH2)2-O- CH3), -R8-O-R10, O-R8-R10(e.g. O-(CH2)2-O-CH3, O-(CH2CH3), O-(CH2)-cyclopropyl), -R8-R10(e.g., (CH2)-cyclopropyl, (CH2)2-O-CH3, (CH2)-OH, (CH2)2-OH, (CH2)-COOH), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine); each R8is independently [CH2]pwherein p is between 1 and 10 (e.g., 1, 2); R9 is [CH]q, [C]q wherein q is between 2 and 10;R10 and R11 are each independently H, OH, COOH, C1-C5 substituted or unsubstituted linear or branched alkyl (e.g., methyl, ethyl, CH2-cyclopropyl, CH2-CH2-O-CH3), C3-C8 substituted or unsubstituted cycloalkyl (e.g., cyclopropyl), C1-C5 substituted or unsubstituted linear or branched haloalky (e.g., CH2CF3), C1-C5 linear or branched alkoxy (e.g., O-CH3), R20, C(O)R, or S(O)2R; or R10 and R11 are joined to form a substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., piperazine, piperidine), n is an integer between 0 and 4 (e.g., 1, 2); or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, pharmaceutical product or any combination thereof.

[0015] In some embodiments, at least one of X2, X3, and X4 is C(R). In some embodiments, X11 is N. In some embodiments, X12 is not S. In some embodiments, at least one of X2, X3, and X4 is C(R); X11 is N; or X12 is not S. In some embodiments, R is not H.

[0016] In various embodiments, this invention is directed to a compound represented by the structure of formula I(a):wherein X2, X3, and X4, are each independently CH, C(R) or N (e.g., C(CH3), C(O-CH2-cyclopropyl), C(O-CH2-methylcyclobutyl), C(NH-CH2-cyclopropyl), C(isopropoxy), C(O-CH(CH3)-CH2-O-CH3), C(CH2CH3), C-iPr, C-CH2-cyclopropyl, C(OCH3), C(OCH2CH3), C(O-(CH2)2-O-CH3, C(OCHF2), C(Cl), C(C(O)CH3), C(O-CH2CH2-O-CH3), C(OH)); X5, X6, X7, X8and X9are each independently nitrogen or carbon atoms; wherein if either one of X5, X6, X7, X8 and X9 is nitrogen, then the respective R7’, R7’’, R7, R7’’’, and R7’’’’ substitution is absent;X10 is N, CH, C(R), or C=O; wherein if X10 is C=O then X11 is N (e.g., C(CH2-OH), C(CH2- CH2-OH), C(NH-CH2-cyclopropyl), C(COOH), C(CH3), C(cyclopropyl), C(isopropoxy)); X11 is N or C; wherein if X11 is N then X10 is C=O; X12 is S, SO2, O, NH, N(R), N-OH, CH=CH, CH=CH(R), C(R)=CH, N=CH, N=C(R), CH=N or C(R)=N (e.g., N-CH2-COOH, N-CH2-CH2-OH, N-CH3, N-CH2CH3, N-iPr, N-cyclopropyl, N-CH2- cyclopropyl); R5 is H or C1-C5 linear or branched alkyl (e.g. methyl); R6 is H, F, Cl, Br, I, OH, SH, R8-OH, R8-SH, -R8-O-R10 (e.g., CH2-O-CH3, (CH2)2-O-CH3 (CH2)3-O-CH3, (CH2)2-O-CH(CH3)2), R8-S-R10 (e.g., (CH2)3-S-(CH2)2CH3), R8-NHC(O)-R10, -O-R8- R10, R8-(substituted or unsubstituted C3-C8 cycloalkyl) (e.g., CH2-cyclopropyl, CH2-cyclobutanol, CH2- difluorocyclopropyl, CH2-methylcyclopropyl, CH2-dimethylamino-cyclohexyl, (CH2)2-cyclopentanole, CH2-cyclohexanol), R8-(substituted or unsubstituted, saturated, unsaturated or aromatic, single, fused or spiro 3-10 membered heterocyclic ring) (e.g., (CH2)3-piperidine, (CH2)3-4-fluoro-piperidine, (CH2)3- pyran, (CH2)2-pyrrazole, (CH2)2-imidazole, CH2-tetrahydrofurane, CH2-dioxane, CH2-oxetane, CH2- piperidine, CH2-triazole, CH2-1-oxa-8-azaspiro[4.5]decane, (CH2)3-diazabicyclo[2.2.1]heptane, CH2- methyl-THF, CH2-ethyl-piperidine, CH2-oxa-azaspirodecane, (CH2)3-dimethylpyrazole, CH2-2-oxo- methylpyrrolidine, CH2-methyl-azetidine, CH2-azaspiroheptane), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, NH(R10), N(R10)(R11), R8-N(R10)(R11) (e.g., (CH2)2-NH2, (CH2)3- N(CH2CH3)2, (CH2)3-N(CH(CH3)2)2, (CH2)3-piperidine, (CH2)3-4-fluoro-piperidine, (CH2)3-4-cyano- piperidine, (CH2)4-NH(CH3), (CH2)3-NH-CH3, (CH2)3-NH-CH2CH3, (CH2)3-N(CH2CH3)2, (CH2)3-NH2, (CH2)3-N(CH2CH3)(CH2CF3)), R9-R8-N(R10)(R11) (e.g., (CH2)2-C(O)-piperidine), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R10, NHCO-N(R10)(R11), COOH, -C(O)Ph, C(O)O-R10, R8-C(O)-R10, C(O)H, C(O)- R10(e.g., C(O)CH3), C1-C5linear or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR, C(O)N(R10)(R11), SO2R, SO2N(R10)(R11), CH(CF3)(NH-R10), C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., CH(CH3)CH2OCH3, CH(CH3)CH2NH2, CH(CH3)C(O)N(CH3)2, CH2-CH(OH)Ph, (CH2)3N(H)CH2CH3, CH(CH3)(CH2)2OH, CH(CH2OH)(CH2CH3), (CH2)3-OCH3, (CH2)2-OCH3, (CH2)2-OCH(CH3)2, CH(CH2OH)(CH2CH(CH3)2), CH2CH(CH3)(OCH3), CH2CH(N(CH3)2)(CH2CH3), benzyl, methyl, ethyl, CH2-OCH2-CH2-O-CH3, CH(CH3)C(O)N(CH3)2), C1-C5linear or branched, substituted or unsubstituted alkenyl, C1-C5linear or branched, or C3-C8cyclic haloalkyl, substituted or unsubstituted C1-C5linear or branched, or C3-C8cyclic alkoxy (e.g. methoxy, O-(CH2)2-O-CH3), optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom, C1-C5linear or branched thioalkoxy, C1-C5linear or branched haloalkoxy, C1-C5linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclohexyl, methoxycyclopropyl, methylcyclobutyl, aminomethyl-cyclobutyl, methoxycyclobutyl, 2,3-dihydro-1H- indenol), R8-(substituted or unsubstituted C3-C8cycloalkyl), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., piperidine, 1-methyl-piperidine, azetidine, pyrrolidine, pyrrolidinone, quinuclidine, tetrahydropyran, azaspiro[3.3]heptane, imidazole, trifluoromethyl-oxetane, hydroxy-tetrahydrofurane, azepan-2-one, azabicyclohexane), substituted or unsubstituted aryl, substituted or unsubstituted R8-aryl (e.g., benzyl), substituted or unsubstituted benzyl; or R6 and R5 are joined to for a substituted or unsubstituted 5-8 membered heterocyclic ring (e.g., azepane, piperazine, 2-(piperazin-1-yl)acetamide; or R6 is represented by the structure of formula B or Bi:wherein m is 0 or 1; and R12is R20or C1-C5C(O)-alkyl, and R13is R30; or R12and R13are both H; R12and R13are each independently H or substituted or unsubstituted C1-C5alkyl (e.g., ethyl, trifluoroethyl); R12 and C3 are joined to form ring A and R13 is R30; or R12 and R13 are joined to form ring B; or R12 and C1 are joined to form ring C and R13 is R30; or C1 and C3 are joined to form ring D and R12 and R13 are each independently R30; or R13 and C2 are joined to form ring E, m is 1, and R12 is R30; or R12 and R13 are joined to form ring B and C1 and C3 are joined to form ring D; wherein Ring A, C and E are each independently a substituted or unsubstituted single spiro or fused 3-8 membered heterocyclic ring (e.g., A: pyrrolidine, methylpyrrolidine, ethylpyrrolidine); C: piperidine, pyrrolidine, methyl-2-oxopyrrolidine, pyran- pyrrolidine, methyl-azetidine, azabicyclooctane, 2-azabicyclo[2.1.1]hexane, 2- azaspiro[3.3]heptane; E: pyrrolidine, azetidine, ethylpyrrolidine, oxopyrrolidine, methylpiperidine);Ring B is a substituted or unsubstituted single, spiro or fused 3-8 membered heterocyclic ring (B: piperidine, piperidin-2-one, 4-fluoropiperidin-2-one, piperidine- 4-carbonitrile, 4-fluoropiperidine, 4-fluoro-2-methylpiperidine, methyl-piperidin, fluoropiperidine, difluoropiperidine, pyrrolidine, piperazine, methylpyrrolidine, thiomorpholine 1,1-dioxide, 2-oxa-6-azaspiro[3.3]heptane, methyl-piperazine, dimethyl-pyrazole, imidazole, 2-methyl-2,5-diazabicyclo[2.2.1]heptane, hydroxymethyl-pyrrolidine, diazabicyclo[2.2.1]heptane, 6-fluoro-3- azabicyclo[3.1.1]heptane; and Ring D is a substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclobutane, cyclohexane); R7 is H, F, Cl, Br, I, OH, O-R20, SH, R8-OH, R8-SH, SR10, -R8-O-R10, -R8-S-R10, R8-(C3-C8 cycloalkyl), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, NH(R10), N(R10)(R11), R8- N(R10)(R11), R9-R8-N(R10)(R11), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R10, NHCO-N(R10)(R11), COOH, -C(O)Ph, C(O)O-R10, R8-C(O)-R10, C(O)H, C(O)-R10, C1-C5 linear or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR (e.g., C(O)NH(CH3)), C(O)N(R10)(R11) (e.g., C(O)NH(CH3), C(O)NH(CH2CH2OCH3), C(O)NH(CH2CH2OH)), SO2R, SO2N(R10)(R11), CH(CF3)(NH-R10), C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., methylimidazole, methyl, ethyl), C1-C5 linear or branched, substituted or unsubstituted alkenyl, C1-C5 linear or branched, or C3-C8 cyclic haloalkyl (e.g., CHF2), C1-C5linear or branched, or C3-C8cyclic alkoxy (e.g. methoxy, ethoxy), optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom, C1-C5linear or branched thioalkyl, C1-C5linear or branched thioalkoxy, C1-C5linear or branched haloalkoxy, C1-C5linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8cycloalkyl (e.g., cyclopropyl, cyclopropanol, cyclohexyl), substituted or unsubstituted 4-7 membered heterocyclic ring (e.g., morpholine (e.g., 2 or 3-morpholine), tetrahydrofuran, tetrahydropyran, oxetane, oxetan-3-ol, pyrrolidine, pyrrolidine-3-ol, 1-methylpyrrolidine, pyrrolidin-2-one, pyrrolidinone, imidazole, pyrazole, piperazine, piperidine, piperidine-4-ol, piperidine-4-carbonitrile, 4-fluoropiperidine, oxadiazole, triazole, 2-oxopyrrolidine, pyridine, 1-methylpyridine), R8-(substituted or unsubstituted single, fused or spiro 3-8 membered heterocyclic ring), substituted or unsubstituted aryl, substituted or unsubstituted benzyl; or R7is represented by the structure of formula A: whereinX1 is N or O;R1 and R2 are each independently H, F, Cl, Br, I, OH, SH, or CF3, substituted or unsubstituted C1-C5 alkyl, C1-C5 linear or branched, or C3-C8 cyclic haloalkyl, substituted or unsubstituted C1-C5 linear or branched, or C3-C8 cyclic alkoxy; R1 and R2 are joined to form =O or a C3-C8 carbocyclic or heterocyclic ring (e.g., cyclopropyl); R3 and R4 are each independently H, Me, substituted or unsubstituted C1-C5 alkyl (e.g., methoxyethylene, methylaminoethyl, aminoethyl), -R8-O-R10 (e.g., (CH2)2-O-CH3), R8- N(R10)(R11) (e.g., (CH2)2-NH(CH3)), substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted 5-7 membered heterocyclic ring (e.g., pyrrolidine, methylpyrrolidine, piperidine), or R20; R3 and R4 are joined to form a 3-8 membered heterocyclic ring (e.g., pyrrolidine, 2- oxopyrrolidine, piperidine, morpholine, piperazine, imidazole); or R2 and R4 are joined to form a substituted or unsubstituted, saturated or unsaturated, 3-8 membered heterocyclic or carbocyclic ring (e.g., pyrrolidine, 1-methylpyrrolidine, pyrrolidin-2-one, pyridine, piperidine, tetrahydrofurane, tetrahydrothiophene, cyclopropyl, oxetane, imidazole, pyrimidine, triazole, oxadiazole, pyrazole), wherein if the ring is aromatic, then R1 and / or R3 are absent; wherein if X1 is O then R4 is absent; R7’, R7’’, R7’’’ and R7’’’’ are each independently H, F, Cl, Br, I, OH, O-R20, SH, R8-OH, R8- SH, -R8-O-R10, R8-(C3-C8cycloalkyl), R8-(3-8 membered heterocyclic ring), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, NH(R10), N(R10)(R11), R8-N(R10)(R11), R9-R8-N(R10)(R11), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R10, NHCO-N(R10)(R11), COOH, -C(O)Ph, C(O)O-R10, R8-C(O)-R10, C(O)H, C(O)-R10, C1-C5linear or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR, C(O)N(R10)(R11), SO2R, SO2N(R10)(R11), CH(CF3)(NH-R10), C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., isopropyl, methyl, ethyl), C1-C5 linear or branched, substituted or unsubstituted alkenyl, C1-C5 linear or branched, or C3-C8cyclic haloalkyl (e.g., CHF2), C1-C5linear or branched, or C3-C8cyclic alkoxy (e.g. methoxy), optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom, C1-C5linear or branched thioalkoxy, C1-C5linear or branched haloalkoxy, C1-C5linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8cycloalkyl (e.g., cyclopropyl, cyclohexyl), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., morpholine, pyran, oxetane, pyrrolidine, tetrahydrofuran, imidazole, piperazine, piperidine, dioxazole, 2-oxopyrrolidine), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted benzyl; or R7’ and R7’’ are joined to form a 3-8 membered substituted or unsubstituted, saturated, unsaturated or aromatic, carbocyclic or heterocyclic ring (e.g., cyclopentyl, cyclohexyl, piperidine, tetrahydrofuran, tetrahydropyran, pyrrolidine); or R7’’ and R7are joined to form a 3-8 membered substituted or unsubstituted carbocyclic or heterocyclic ring (e.g., cyclopentyl, cyclohexyl, piperidine, tetrahydrofuran, tetrahydropyran, pyrrolidine);or R7 and R7’’’ are joined to form a 3-8 membered substituted or unsubstituted carbocyclic or heterocyclic ring (e.g., cyclopentyl, cyclohexyl, piperidine, tetrahydrofuran, tetrahydropyran, pyrrolidine); or R7’’’ and R7’’’’ are joined to form a 3-8 membered substituted or unsubstituted carbocyclic or heterocyclic ring (e.g., cyclopentyl, cyclohexyl, piperidine, tetrahydrofuran, tetrahydropyran, pyrrolidine); R20 is represented by the following structure:R30 is H, R20, F, Cl, Br, I, OH, SH, alkoxy, N(R)2, NH(R10), N(R10)(R11), CF3, CN, NO2, C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH2-CH2-O-CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), C1-C5 linear or branched alkoxy, C1-C5 linear or branched haloalkyl (e.g., CHF2, CF3, CF2CH3, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2,CF(CH3)-CH(CH3)2), R8-aryl (e.g., CH2-Ph), -R8-O-R8-O-R10 (e.g. (CH2)2-O-(CH2)2-O-CH3), -R8-O-R10, -R8-R10 (e.g., (CH2)2-O- CH3), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine); R is H, F, Cl, Br, I, OH, SH, COOH, CO(R10) (e.g., C(O)CH3), NH(R10), NH-CH2-cyclopropyl, N(R10)(R11), CF3, CN, NO2, C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, iPr, CH2-cyclopropyl, CH2-OH, CH2-CH2-OH, CH2-CH2-O-CH2-CH2-O-CH3, CH2-O-CH2-CH2- O-CH3), C3-C8substituted or unsubstituted cycloalkyl, cyclopropyl, substituted or unsubstituted C1-C5linear or branched alkoxy, (e.g., methoxy, ethoxy, O-(CH2CH3), OCHF2, O-(CH2)2-O-CH3, isopropoxy, O-(CH2)-cyclopropyl, O-CH2-methylcyclobutyl, O-CH2-3-methyloxetane, O-CH(CH3)-CH2-O-CH3) C1-C5linear or branched haloalkyl (e.g., CHF2, CF3, CF2CH3, CH2CF3,CF2CH2CH3,CH2CH2CF3,CF2CH(CH3)2,CF(CH3)-CH(CH3)2), R8-aryl (e.g., CH2-Ph), -R8-O-R8-O-R10(e.g. (CH2)2-O-(CH2)2-O- CH3), -R8-O-R10, O-R8-R10(e.g. O-(CH2)2-O-CH3, O-(CH2CH3), O-(CH2)-cyclopropyl), -R8-R10(e.g., (CH2)-cyclopropyl, (CH2)2-O-CH3, (CH2)-OH, (CH2)2-OH, (CH2)-COOH), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine); each R8is independently [CH2]pwherein p is between 1 and 10 (e.g., 1, 2); R9is [CH]q, [C]qwherein q is between 2 and 10; R10and R11are each independently H, OH, COOH, C1-C5substituted or unsubstituted linear or branched alkyl (e.g., methyl, ethyl, CH2-cyclopropyl, CH2-CH2-O-CH3), C3-C8substituted or unsubstituted cycloalkyl (e.g., cyclopropyl), C1-C5substituted or unsubstituted linear or branched haloalky (e.g., CH2CF3), C1-C5linear or branched alkoxy (e.g., O-CH3), R20, C(O)R, or S(O)2R; or R10 and R11 are joined to form a substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., piperazine, piperidine),n is an integer between 0 and 4 (e.g., 1, 2); or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, pharmaceutical product or any combination thereof.

[0017] In some embodiments, at least one of R7, R7’, R7’’, R7’’’ and R7’’’’ is not H. In some embodiments, at least two of R7, R7’, R7’’, R7’’’ and R7’’’’ are not H. In some embodiments, at least one of R7’, R7’’, R7’’’ and R7’’’’ is not H. In some embodiments, at least two of R7’, R7’’, R7’’’ and R7’’’’ are not H. In some embodiments, at least two of R7’, R7’’, R7’’’ and R7’’’’ are different than eachother. In some embodiments, at least two of R7’, R7’’, R7’’’ and R7’’’’ are not H and are different than eachother.

[0018] In some embodiments, at least one of X2, X3, and X4 is C(R). In some embodiments, X11 is N. In some embodiments, X12 is not S. In some embodiments, at least one of X2, X3, and X4 is C(R); X11 is N; or X12 is not S. In some embodiments, R is not H.

[0019] In various embodiments, this invention is directed to a compound represented by the structure of formula I(b):wherein X2, X3, and X4, are each independently CH, C(R) or N (e.g., C(CH3), C(O-CH2-cyclopropyl), C(O-CH2-methylcyclobutyl), C(NH-CH2-cyclopropyl), C(isopropoxy), C(O-CH(CH3)-CH2-O-CH3), C(CH2CH3), C-iPr, C-CH2-cyclopropyl, C(OCH3), C(OCH2CH3), C(O-(CH2)2-O-CH3, C(OCHF2), C(Cl), C(C(O)CH3), C(O-CH2CH2-O-CH3), C(OH)); X5, X6, X7, X8 and X9 are each independently nitrogen or carbon atoms; X10 is N, CH, C(R), or C=O; wherein if X10 is C=O then X11 is N (e.g., C(CH2-OH), C(CH2- CH2-OH), C(NH-CH2-cyclopropyl), C(COOH), C(CH3), C(cyclopropyl), C(isopropoxy)); X11 is N or C; wherein if X11 is N then X10 is C=O;X12 is S, SO2, O, NH, N(R), N-OH, CH=CH, CH=CH(R), C(R)=CH, N=CH, N=C(R), CH=N or C(R)=N (e.g., N-CH2-COOH, N-CH2-CH2-OH, N-CH3, N-CH2CH3, N-iPr, N-cyclopropyl, N-CH2- cyclopropyl); X13 is CH2, CH(R) (e.g., CH-CH3), C(R)2, or C=O; Ring G is absent or is a substituted or unsubstituted 3-8 membered carbocyclic or heterocyclic ring (e.g., cyclobutane, cyclopentane, cyclohexane); R7 is H, F, Cl, Br, I, OH, O-R20, SH, R8-OH, R8-SH, SR10, -R8-O-R10, -R8-S-R10, R8-(C3-C8 cycloalkyl), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, NH(R10), N(R10)(R11), R8- N(R10)(R11), R9-R8-N(R10)(R11), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R10, NHCO-N(R10)(R11), COOH, -C(O)Ph, C(O)O-R10, R8-C(O)-R10, C(O)H, C(O)-R10, C1-C5 linear or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR (e.g., C(O)NH(CH3)), C(O)N(R10)(R11) (e.g., C(O)NH(CH3), C(O)NH(CH2CH2OCH3), C(O)NH(CH2CH2OH)), SO2R, SO2N(R10)(R11), CH(CF3)(NH-R10), C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., methylimidazole, methyl, ethyl), C1-C5 linear or branched, substituted or unsubstituted alkenyl, C1-C5 linear or branched, or C3-C8 cyclic haloalkyl (e.g., CHF2), C1-C5 linear or branched, or C3-C8 cyclic alkoxy (e.g. methoxy, ethoxy), optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom, C1-C5 linear or branched thioalkyl, C1-C5 linear or branched thioalkoxy, C1-C5 linear or branched haloalkoxy, C1-C5 linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclopropanol, cyclohexyl), substituted or unsubstituted 4-7 membered heterocyclic ring (e.g., morpholine (e.g., 2 or 3-morpholine), tetrahydrofuran, tetrahydropyran, oxetane, oxetan-3-ol, pyrrolidine, pyrrolidine-3-ol, 1-methylpyrrolidine, pyrrolidin-2-one, pyrrolidinone, imidazole, pyrazole, piperazine, piperidine, piperidine-4-ol, piperidine-4-carbonitrile, 4-fluoropiperidine, oxadiazole, triazole, 2-oxopyrrolidine, pyridine, 1-methylpyridine), R8-(substituted or unsubstituted single, fused or spiro 3-8 membered heterocyclic ring), substituted or unsubstituted aryl, substituted or unsubstituted benzyl; or R7is represented by the structure of formula A:wherein X1 is N or O; R1 and R2 are each independently H, F, Cl, Br, I, OH, SH, or CF3, substituted or unsubstituted C1-C5alkyl, C1-C5linear or branched, or C3-C8cyclic haloalkyl, substituted or unsubstituted C1-C5 linear or branched, or C3-C8 cyclic alkoxy;R1 and R2 are joined to form =O or a C3-C8 carbocyclic or heterocyclic ring (e.g., cyclopropyl); R3 and R4 are each independently H, Me, substituted or unsubstituted C1-C5 alkyl (e.g., methoxyethylene, methylaminoethyl, aminoethyl), -R8-O-R10 (e.g., (CH2)2-O-CH3), R8- N(R10)(R11) (e.g., (CH2)2-NH(CH3)), substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted 5-7 membered heterocyclic ring (e.g., pyrrolidine, methylpyrrolidine, piperidine), or R20; R3 and R4 are joined to form a 3-8 membered heterocyclic ring (e.g., pyrrolidine, 2- oxopyrrolidine, piperidine, morpholine, piperazine, imidazole); or R2 and R4 are joined to form a substituted or unsubstituted, saturated or unsaturated, 3-8 membered heterocyclic or carbocyclic ring (e.g., pyrrolidine, 1-methylpyrrolidine, pyrrolidin-2-one, pyridine, piperidine, tetrahydrofurane, tetrahydrothiophene, cyclopropyl, oxetane, imidazole, pyrimidine, triazole, oxadiazole, pyrazole), wherein if the ring is aromatic, then R1 and / or R3 are absent; wherein if X1 is O then R4 is absent; R7’ is H, F, Cl, Br, I, OH, O-R20, SH, R8-OH, R8-SH, -R8-O-R10, R8-(C3-C8 cycloalkyl), R8-(3- 8 membered heterocyclic ring), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, NH(R10), N(R10)(R11), R8-N(R10)(R11), R9-R8-N(R10)(R11), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)- R10, NHCO-N(R10)(R11), COOH, -C(O)Ph, C(O)O-R10, R8-C(O)-R10, C(O)H, C(O)-R10, C1-C5linear or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR, C(O)N(R10)(R11), SO2R, SO2N(R10)(R11), CH(CF3)(NH-R10), C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., isopropyl, methyl, ethyl), C1-C5linear or branched, substituted or unsubstituted alkenyl, C1-C5linear or branched, or C3-C8cyclic haloalkyl (e.g., CHF2), C1-C5linear or branched, or C3-C8cyclic alkoxy (e.g. methoxy), optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom, C1-C5 linear or branched thioalkoxy, C1-C5 linear or branched haloalkoxy, C1-C5 linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8cycloalkyl (e.g., cyclopropyl, cyclohexyl), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., morpholine, pyran, oxetane, pyrrolidine, imidazole, piperazine, piperidine, dioxazole, 2-oxopyrrolidine), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted benzyl; or R7and R7’ are joined to form a 5 or 6 membered substituted or unsubstituted, saturated, unsaturated or aromatic, carbocyclic or heterocyclic ring (e.g., piperidine, pyrrolidine, tetrahydrofuran, tetrahydropyran); R20is represented by the following structure:R30 is H, R20, F, Cl, Br, I, OH, SH, alkoxy, N(R)2, NH(R10), N(R10)(R11), CF3, CN, NO2, C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH2-CH2-O-CH2-CH2-O-CH3,CH2-O-CH2-CH2-O-CH3), C1-C5 linear or branched alkoxy, C1-C5 linear or branched haloalkyl (e.g., CHF2, CF3, CF2CH3, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2,CF(CH3)-CH(CH3)2), R8-aryl (e.g., CH2-Ph), -R8-O-R8-O-R10 (e.g. (CH2)2-O-(CH2)2-O-CH3), -R8-O-R10, -R8-R10 (e.g., (CH2)2-O- CH3), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine); R50 is H, R20, F, Cl, Br, I, OH, SH, N(R)2, NH(R10), N(R10)(R11), CF3, CN, NO2, C1-C5 linear or branched, substituted or unsubstituted alkyl C1-C5 linear or branched alkoxy, C1-C5 linear or branched haloalkyl, -R8-R10 (e.g., (CH2)2-O-CH3), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine); R is H, F, Cl, Br, I, OH, SH, COOH, CO(R10) (e.g., C(O)CH3), NH(R10), NH-CH2-cyclopropyl, N(R10)(R11), CF3, CN, NO2, C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, iPr, CH2-cyclopropyl, CH2-OH, CH2-CH2-OH, CH2-CH2-O-CH2-CH2-O-CH3, CH2-O-CH2-CH2- O-CH3), C3-C8 substituted or unsubstituted cycloalkyl, cyclopropyl, substituted or unsubstituted C1-C5 linear or branched alkoxy, (e.g., methoxy, ethoxy, O-(CH2CH3), OCHF2, O-(CH2)2-O-CH3, isopropoxy, O-(CH2)-cyclopropyl, O-CH2-methylcyclobutyl, O-CH2-3-methyloxetane, O-CH(CH3)-CH2-O-CH3) C1-C5 linear or branched haloalkyl (e.g., CHF2, CF3, CF2CH3, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2,CF(CH3)-CH(CH3)2), R8-aryl (e.g., CH2-Ph), -R8-O-R8-O-R10 (e.g. (CH2)2-O-(CH2)2-O- CH3), -R8-O-R10, O-R8-R10 (e.g. O-(CH2)2-O-CH3, O-(CH2CH3), O-(CH2)-cyclopropyl), -R8-R10 (e.g., (CH2)-cyclopropyl, (CH2)2-O-CH3, (CH2)-OH, (CH2)2-OH, (CH2)-COOH), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine); each R8is independently [CH2]pwherein p is between 1 and 10 (e.g., 1, 2); R9is [CH]q, [C]qwherein q is between 2 and 10; R10 and R11 are each independently H, OH, COOH, C1-C5 substituted or unsubstituted linear or branched alkyl (e.g., methyl, ethyl, CH2-cyclopropyl, CH2-CH2-O-CH3), C3-C8substituted or unsubstituted cycloalkyl (e.g., cyclopropyl), C1-C5substituted or unsubstituted linear or branched haloalky (e.g., CH2CF3), C1-C5linear or branched alkoxy (e.g., O-CH3), R20, C(O)R, or S(O)2R; or R10and R11are joined to form a substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., piperazine, piperidine), n is an integer between 0 and 4 (e.g., 1, 2); or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, pharmaceutical product or any combination thereof.

[0020] In some embodiments, at least one of X2, X3, and X4is C(R). In some embodiments, X11is N. In some embodiments, X12is not S. In some embodiments, at least one of X2, X3, and X4is C(R); X11is N; or X12is not S. In some embodiments, R is not H.

[0021] In various embodiments, this invention is directed to a compound represented by the structure of formula I(c):wherein X2, X3, and X4, are each independently CH, C(R) or N (e.g., C(CH3), C(O-CH2-cyclopropyl), C(O-CH2-methylcyclobutyl), C(NH-CH2-cyclopropyl), C(isopropoxy), C(O-CH(CH3)-CH2-O-CH3), C(CH2CH3), C-iPr, C-CH2-cyclopropyl, C(OCH3), C(OCH2CH3), C(O-(CH2)2-O-CH3, C(OCHF2), C(Cl), C(C(O)CH3), C(O-CH2CH2-O-CH3), C(OH)); X5, X6, X7, X8 and X9 are each independently nitrogen or carbon atoms; wherein if either one of X5, X6, X7, X8 and X9 is nitrogen, then the respective R7’, R7’’, R7, R7’’’, and R7’’’’ substitution is absent; X10 is N, CH, C(R), or C=O; wherein if X10 is C=O then X11 is N (e.g., C(CH2-OH), C(CH2- CH2-OH), C(NH-CH2-cyclopropyl), C(COOH), C(CH3), C(cyclopropyl), C(isopropoxy)); X11 is N or C; wherein if X11 is N then X10 is C=O; X12 is S, SO2, O, NH, N(R), N-OH, CH=CH, CH=CH(R), C(R)=CH, N=CH, N=C(R), CH=N or C(R)=N (e.g., N-CH2-COOH, N-CH2-CH2-OH, N-CH3, N-CH2CH3, N-iPr, N-cyclopropyl, N-CH2- cyclopropyl); X13 is CH2, CH(R) (e.g., CH-CH3), C(R)2, or C=O; Ring G is absent or is a substituted or unsubstituted 3-8 membered carbocyclic or heterocyclic ring (e.g., cyclobutane, cyclopentane, cyclohexane); R7 is H, F, Cl, Br, I, OH, O-R20, SH, R8-OH, R8-SH, SR10, -R8-O-R10, -R8-S-R10, R8-(C3-C8 cycloalkyl), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, NH(R10), N(R10)(R11), R8- N(R10)(R11), R9-R8-N(R10)(R11), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R10, NHCO-N(R10)(R11), COOH, -C(O)Ph, C(O)O-R10, R8-C(O)-R10, C(O)H, C(O)-R10, C1-C5 linear or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR (e.g., C(O)NH(CH3)), C(O)N(R10)(R11) (e.g., C(O)NH(CH3), C(O)NH(CH2CH2OCH3), C(O)NH(CH2CH2OH)), SO2R, SO2N(R10)(R11), CH(CF3)(NH-R10), C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., methylimidazole, methyl, ethyl), C1-C5 linearor branched, substituted or unsubstituted alkenyl, C1-C5 linear or branched, or C3-C8 cyclic haloalkyl (e.g., CHF2), C1-C5 linear or branched, or C3-C8 cyclic alkoxy (e.g. methoxy, ethoxy), optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom, C1-C5 linear or branched thioalkyl, C1-C5 linear or branched thioalkoxy, C1-C5 linear or branched haloalkoxy, C1-C5 linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclopropanol, cyclohexyl), substituted or unsubstituted 4-7 membered heterocyclic ring (e.g., morpholine (e.g., 2 or 3-morpholine), tetrahydrofuran, tetrahydropyran, oxetane, oxetan-3-ol, pyrrolidine, pyrrolidine-3-ol, 1-methylpyrrolidine, pyrrolidin-2-one, pyrrolidinone, imidazole, pyrazole, piperazine, piperidine, piperidine-4-ol, piperidine-4-carbonitrile, 4-fluoropiperidine, oxadiazole, triazole, 2-oxopyrrolidine, pyridine, 1-methylpyridine), R8-(substituted or unsubstituted single, fused or spiro 3-8 membered heterocyclic ring), substituted or unsubstituted aryl, substituted or unsubstituted benzyl; or R7 is represented by the structure of formula A:wherein X1is N or O; R1and R2are each independently H, F, Cl, Br, I, OH, SH, or CF3, substituted or unsubstituted C1-C5alkyl, C1-C5linear or branched, or C3-C8cyclic haloalkyl, substituted or unsubstituted C1-C5linear or branched, or C3-C8cyclic alkoxy; R1and R2are joined to form =O or a C3-C8carbocyclic or heterocyclic ring (e.g., cyclopropyl); R3and R4are each independently H, Me, substituted or unsubstituted C1-C5alkyl (e.g., methoxyethylene, methylaminoethyl, aminoethyl), -R8-O-R10(e.g., (CH2)2-O-CH3), R8- N(R10)(R11) (e.g., (CH2)2-NH(CH3)), substituted or unsubstituted C3-C8cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted 5-7 membered heterocyclic ring (e.g., pyrrolidine, methylpyrrolidine, piperidine), or R20; R3 and R4 are joined to form a 3-8 membered heterocyclic ring (e.g., pyrrolidine, 2- oxopyrrolidine, piperidine, morpholine, piperazine, imidazole); or R2 and R4 are joined to form a substituted or unsubstituted, saturated or unsaturated, 3-8 membered heterocyclic or carbocyclic ring (e.g., pyrrolidine, 1-methylpyrrolidine, pyrrolidin-2-one, pyridine, piperidine, tetrahydrofurane, tetrahydrothiophene, cyclopropyl, oxetane, imidazole, pyrimidine, triazole, oxadiazole, pyrazole), wherein if the ring is aromatic, then R1 and / or R3 are absent;wherein if X1 is O then R4 is absent; R7’, R7’’, R7’’’ and R7’’’’ are each independently H, F, Cl, Br, I, OH, O-R20, SH, R8-OH, R8- SH, -R8-O-R10, R8-(C3-C8 cycloalkyl), R8-(3-8 membered heterocyclic ring), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, NH(R10), N(R10)(R11), R8-N(R10)(R11), R9-R8-N(R10)(R11), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R10, NHCO-N(R10)(R11), COOH, -C(O)Ph, C(O)O-R10, R8-C(O)-R10, C(O)H, C(O)-R10, C1-C5 linear or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR, C(O)N(R10)(R11), SO2R, SO2N(R10)(R11), CH(CF3)(NH-R10), C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., isopropyl, methyl, ethyl), C1-C5 linear or branched, substituted or unsubstituted alkenyl, C1-C5 linear or branched, or C3-C8 cyclic haloalkyl (e.g., CHF2), C1-C5 linear or branched, or C3-C8 cyclic alkoxy (e.g. methoxy), optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom, C1-C5 linear or branched thioalkoxy, C1-C5 linear or branched haloalkoxy, C1-C5 linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclohexyl), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., morpholine, pyran, oxetane, pyrrolidine, tetrahydrofuran, imidazole, piperazine, piperidine, dioxazole, 2-oxopyrrolidine), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted benzyl; or R7’ and R7’’ are joined to form a 3-8 membered substituted or unsubstituted, saturated, unsaturated or aromatic, carbocyclic or heterocyclic ring (e.g., cyclopentyl, cyclohexyl, piperidine, tetrahydrofuran, tetrahydropyran, pyrrolidine); or R7’’ and R7are joined to form a 3-8 membered substituted or unsubstituted carbocyclic or heterocyclic ring (e.g., cyclopentyl, cyclohexyl, piperidine, tetrahydrofuran, tetrahydropyran, pyrrolidine); or R7and R7’’’ are joined to form a 3-8 membered substituted or unsubstituted carbocyclic or heterocyclic ring (e.g., cyclopentyl, cyclohexyl, piperidine, tetrahydrofuran, tetrahydropyran, pyrrolidine); or R7’’’ and R7’’’’ are joined to form a 3-8 membered substituted or unsubstituted carbocyclic or heterocyclic ring (e.g., cyclopentyl, cyclohexyl, piperidine, tetrahydrofuran, tetrahydropyran, pyrrolidine); R20is represented by the following structure:R30is H, R20, F, Cl, Br, I, OH, SH, alkoxy, N(R)2, NH(R10), N(R10)(R11), CF3, CN, NO2, C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH2-CH2-O-CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), C1-C5linear or branched alkoxy, C1-C5linear or branched haloalkyl (e.g., CHF2, CF3, CF2CH3, CH2CF3,CF2CH2CH3,CH2CH2CF3,CF2CH(CH3)2,CF(CH3)-CH(CH3)2), R8-aryl (e.g., CH2-Ph), -R8-O-R8-O-R10(e.g. (CH2)2-O-(CH2)2-O-CH3), -R8-O-R10, -R8-R10(e.g., (CH2)2-O- CH3), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine);R50 is H, R20, F, Cl, Br, I, OH, SH, N(R)2, NH(R10), N(R10)(R11), CF3, CN, NO2, C1-C5 linear or branched, substituted or unsubstituted alkyl C1-C5 linear or branched alkoxy, C1-C5 linear or branched haloalkyl, -R8-R10 (e.g., (CH2)2-O-CH3), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine); R is H, F, Cl, Br, I, OH, SH, COOH, CO(R10) (e.g., C(O)CH3), NH(R10), NH-CH2-cyclopropyl, N(R10)(R11), CF3, CN, NO2, C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, iPr, CH2-cyclopropyl, CH2-OH, CH2-CH2-OH, CH2-CH2-O-CH2-CH2-O-CH3, CH2-O-CH2-CH2- O-CH3), C3-C8 substituted or unsubstituted cycloalkyl, cyclopropyl, substituted or unsubstituted C1-C5 linear or branched alkoxy, (e.g., methoxy, ethoxy, O-(CH2CH3), OCHF2, O-(CH2)2-O-CH3, isopropoxy, O-(CH2)-cyclopropyl, O-CH2-methylcyclobutyl, O-CH2-3-methyloxetane, O-CH(CH3)-CH2-O-CH3) C1-C5 linear or branched haloalkyl (e.g., CHF2, CF3, CF2CH3, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2,CF(CH3)-CH(CH3)2), R8-aryl (e.g., CH2-Ph), -R8-O-R8-O-R10 (e.g. (CH2)2-O-(CH2)2-O- CH3), -R8-O-R10, O-R8-R10 (e.g. O-(CH2)2-O-CH3, O-(CH2CH3), O-(CH2)-cyclopropyl), -R8-R10 (e.g., (CH2)-cyclopropyl, (CH2)2-O-CH3, (CH2)-OH, (CH2)2-OH, (CH2)-COOH), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine); each R8 is independently [CH2]p wherein p is between 1 and 10 (e.g., 1, 2); R9 is [CH]q, [C]q wherein q is between 2 and 10; R10and R11are each independently H, OH, COOH, C1-C5substituted or unsubstituted linear or branched alkyl (e.g., methyl, ethyl, CH2-cyclopropyl, CH2-CH2-O-CH3), C3-C8substituted or unsubstituted cycloalkyl (e.g., cyclopropyl), C1-C5substituted or unsubstituted linear or branched haloalky (e.g., CH2CF3), C1-C5linear or branched alkoxy (e.g., O-CH3), R20, C(O)R, or S(O)2R; or R10 and R11 are joined to form a substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., piperazine, piperidine), n is an integer between 0 and 4 (e.g., 1, 2); or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, pharmaceutical product or any combination thereof.

[0022] In some embodiments, at least one of R7, R7’, R7’’, R7’’’ and R7’’’’ is not H. In some embodiments, at least two of R7, R7’, R7’’, R7’’’ and R7’’’’ are not H. In some embodiments, at least one of R7’, R7’’, R7’’’ and R7’’’’ is not H. In some embodiments, at least two of R7’, R7’’, R7’’’ and R7’’’’ are not H. In some embodiments, at least two of R7’, R7’’, R7’’’ and R7’’’’ are different than eachother. In some embodiments, at least two of R7’, R7’’, R7’’’ and R7’’’’ are not H and are different than eachother.

[0023] In some embodiments, at least one of X2, X3, and X4 is C(R). In some embodiments, X11 is N. In some embodiments, X12 is not S. In some embodiments, at least one of X2, X3, and X4 is C(R); X11 is N; or X12 is not S. In some embodiments, R is not H.

[0024] In various embodiments, this invention is directed to a compound represented by the structure of formula I(d):wherein X2, X3, and X4, are each independently CH, C(R) or N (e.g., C(CH3), C(O-CH2-cyclopropyl), C(O-CH2-methylcyclobutyl), C(NH-CH2-cyclopropyl), C(isopropoxy), C(O-CH(CH3)-CH2-O-CH3), C(CH2CH3), C-iPr, C-CH2-cyclopropyl, C(OCH3), C(OCH2CH3), C(O-(CH2)2-O-CH3, C(OCHF2), C(Cl), C(C(O)CH3), C(O-CH2CH2-O-CH3), C(OH)); X5, X6, X7, X8 and X9 are each independently nitrogen or carbon atoms; X10 is N, CH, C(R), or C=O; wherein if X10 is C=O then X11 is N (e.g., C(CH2-OH), C(CH2- CH2-OH), C(NH-CH2-cyclopropyl), C(COOH), C(CH3), C(cyclopropyl), C(isopropoxy)); X11is N or C; wherein if X11is N then X10is C=O; X12is S, SO2, O, NH, N(R), N-OH, CH=CH, CH=CH(R), C(R)=CH, N=CH, N=C(R), CH=N or C(R)=N (e.g., N-CH2-COOH, N-CH2-CH2-OH, N-CH3, N-CH2CH3, N-iPr, N-cyclopropyl, N-CH2- cyclopropyl); Ring F is absent or is a substituted or unsubstituted, saturated or unsaturated, 3-8 membered heterocyclic or carbocyclic ring (e.g., pyrrolidine, 1-methylpyrrolidine, pyrrolidin-2-one, pyrrolidin-3- ol, morpholine, pyridine, piperidine, tetrahydrofurane, tetrahydrothiophene, cyclopropyl, oxetane, imidazole, pyrimidine, triazole, oxadiazole, pyrazole); R1and R2are each independently H, F, Cl, Br, I, OH, SH, or CF3, substituted or unsubstituted C1-C5alkyl, C1-C5linear or branched, or C3-C8cyclic haloalkyl, substituted or unsubstituted C1-C5linear or branched, or C3-C8cyclic alkoxy;or R1 and R2 are joined to form a C=O, or a 3-8 membered carbocyclic or heterocyclic ring (e.g., cyclopropyl); or R2 and R4 are joined to form Ring F as defined above (e.g., pyrrolidine, pyrrolidin-2-one, pyrrolidin-3-ol, morpholine, pyridine, pyrimidine, triazole, oxadiazole, pyrazole), wherein if Ring F is aromatic, then R1 and / or R3 are absent; R3 and R4 are each independently H, Me, substituted or unsubstituted C1-C5 alkyl (e.g., methoxyethylene, methylaminoethyl, aminoethyl), -R8-O-R10 (e.g., (CH2)2-O-CH3), R8-N(R10)(R11) (e.g., (CH2)2-NH(CH3)), substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted 5-7 membered heterocyclic ring (e.g., pyrrolidine, methylpyrrolidine, piperidine), or R20; or R3 and R4 are joined to form a 3-8 membered heterocyclic ring (e.g., pyrrolidine, pyrrolidone, 2-oxopyrrolidine, piperidine, morpholine, piperazine, imidazole); R5 is H or C1-C5 linear or branched alkyl (e.g. methyl); R6 is H, F, Cl, Br, I, OH, SH, R8-OH, R8-SH, -R8-O-R10 (e.g., CH2-O-CH3, (CH2)2-O-CH3 (CH2)3-O-CH3, (CH2)2-O-CH(CH3)2), R8-S-R10 (e.g., (CH2)3-S-(CH2)2CH3), R8-NHC(O)-R10, -O-R8- R10, R8-(substituted or unsubstituted C3-C8 cycloalkyl) (e.g., CH2-cyclopropyl, CH2-cyclobutanol, CH2- difluorocyclopropyl, CH2-methylcyclopropyl, CH2-dimethylamino-cyclohexyl, (CH2)2-cyclopentanole, CH2-cyclohexanol), R8-(substituted or unsubstituted, saturated, unsaturated or aromatic, single, fused or spiro 3-10 membered heterocyclic ring) (e.g., (CH2)3-piperidine, (CH2)3-4-fluoro-piperidine, (CH2)3- pyran, (CH2)2-pyrrazole, (CH2)2-imidazole, CH2-tetrahydrofurane, CH2-dioxane, CH2-oxetane, CH2- piperidine, CH2-triazole, CH2-1-oxa-8-azaspiro[4.5]decane, (CH2)3-diazabicyclo[2.2.1]heptane, CH2- methyl-THF, CH2-ethyl-piperidine, CH2-oxa-azaspirodecane, (CH2)3-dimethylpyrazole, CH2-2-oxo- methylpyrrolidine, CH2-methyl-azetidine, CH2-azaspiroheptane), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, NH(R10), N(R10)(R11), R8-N(R10)(R11) (e.g., (CH2)2-NH2, (CH2)3- N(CH2CH3)2, (CH2)3-N(CH(CH3)2)2, (CH2)3-piperidine, (CH2)3-4-fluoro-piperidine, (CH2)3-4-cyano- piperidine, (CH2)4-NH(CH3), (CH2)3-NH-CH3, (CH2)3-NH-CH2CH3, (CH2)3-N(CH2CH3)2, (CH2)3-NH2, (CH2)3-N(CH2CH3)(CH2CF3)), R9-R8-N(R10)(R11) (e.g., (CH2)2-C(O)-piperidine), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R10, NHCO-N(R10)(R11), COOH, -C(O)Ph, C(O)O-R10, R8-C(O)-R10, C(O)H, C(O)- R10(e.g., C(O)CH3), C1-C5linear or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR, C(O)N(R10)(R11), SO2R, SO2N(R10)(R11), CH(CF3)(NH-R10), C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., CH(CH3)CH2OCH3, CH(CH3)CH2NH2, CH(CH3)C(O)N(CH3)2, CH2-CH(OH)Ph, (CH2)3N(H)CH2CH3, CH(CH3)(CH2)2OH, CH(CH2OH)(CH2CH3), (CH2)3-OCH3, (CH2)2-OCH3, (CH2)2-OCH(CH3)2, CH(CH2OH)(CH2CH(CH3)2), CH2CH(CH3)(OCH3), CH2CH(N(CH3)2)(CH2CH3), benzyl, methyl, ethyl, CH2-OCH2-CH2-O-CH3, CH(CH3)C(O)N(CH3)2), C1-C5linear or branched, substituted or unsubstituted alkenyl, C1-C5linear or branched, or C3-C8cyclic haloalkyl, substituted or unsubstituted C1-C5linear or branched, or C3-C8cyclic alkoxy (e.g. methoxy, O-(CH2)2-O-CH3), optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom, C1-C5linear or branched thioalkoxy, C1-C5linear or branched haloalkoxy, C1-C5linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8cycloalkyl (eg cyclopropyl, cyclobutyl, cyclohexyl,methoxycyclopropyl, methylcyclobutyl, aminomethyl-cyclobutyl, methoxycyclobutyl, 2,3-dihydro-1H- indenol), R8-(substituted or unsubstituted C3-C8 cycloalkyl), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., piperidine, 1-methyl-piperidine, azetidine, pyrrolidine, pyrrolidinone, quinuclidine, tetrahydropyran, azaspiro[3.3]heptane, imidazole, trifluoromethyl-oxetane, hydroxy- tetrahydrofurane, azepan-2-one, azabicyclohexane), substituted or unsubstituted aryl, substituted or unsubstituted R8-aryl (e.g., benzyl), substituted or unsubstituted benzyl; or R6 and R5 are joined to for a substituted or unsubstituted 5-8 membered heterocyclic ring (e.g., azepane, piperazine, 2-(piperazin-1-yl)acetamide; or R6 is represented by the structure of formula B or Bi:wherein m is 0 or 1; and R12 is R20 or C1-C5 C(O)-alkyl, and R13 is R30; or R12 and R13 are both H; R12 and R13 are each independently H or substituted or unsubstituted C1-C5 alkyl (e.g., ethyl, trifluoroethyl); R12 and C3 are joined to form ring A and R13 is R30; or R12 and R13 are joined to form ring B; or R12 and C1 are joined to form ring C and R13 is R30; or C1 and C3 are joined to form ring D and R12 and R13 are each independently R30; or R13 and C2 are joined to form ring E, m is 1, and R12 is R30; or R12 and R13 are joined to form ring B and C1 and C3 are joined to form ring D; wherein Ring A, C and E are each independently a substituted or unsubstituted single spiro or fused 3-8 membered heterocyclic ring (e.g., A: pyrrolidine, methylpyrrolidine,ethylpyrrolidine); C: piperidine, pyrrolidine, methyl-2-oxopyrrolidine, pyran- pyrrolidine, methyl-azetidine, azabicyclooctane, 2-azabicyclo[2.1.1]hexane, 2- azaspiro[3.3]heptane; E: pyrrolidine, azetidine, ethylpyrrolidine, oxopyrrolidine, methylpiperidine); Ring B is a substituted or unsubstituted single, spiro or fused 3-8 membered heterocyclic ring (B: piperidine, piperidin-2-one, 4-fluoropiperidin-2-one, piperidine- 4-carbonitrile, 4-fluoropiperidine, 4-fluoro-2-methylpiperidine, methyl-piperidin, fluoropiperidine, difluoropiperidine, pyrrolidine, piperazine, methylpyrrolidine, thiomorpholine 1,1-dioxide, 2-oxa-6-azaspiro[3.3]heptane, methyl-piperazine, dimethyl-pyrazole, imidazole, 2-methyl-2,5-diazabicyclo[2.2.1]heptane, hydroxymethyl-pyrrolidine, diazabicyclo[2.2.1]heptane, 6-fluoro-3- azabicyclo[3.1.1]heptane; and Ring D is a substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclobutane, cyclohexane); R7’ is H, F, Cl, Br, I, OH, O-R20, SH, R8-OH, R8-SH, -R8-O-R10, R8-(C3-C8 cycloalkyl), R8-(3- 8 membered heterocyclic ring), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, NH(R10), N(R10)(R11), R8-N(R10)(R11), R9-R8-N(R10)(R11), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)- R10, NHCO-N(R10)(R11), COOH, -C(O)Ph, C(O)O-R10, R8-C(O)-R10, C(O)H, C(O)-R10, C1-C5 linear or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR, C(O)N(R10)(R11), SO2R, SO2N(R10)(R11), CH(CF3)(NH-R10), C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., isopropyl, methyl, ethyl), C1-C5linear or branched, substituted or unsubstituted alkenyl, C1-C5linear or branched, or C3-C8cyclic haloalkyl (e.g., CHF2), C1-C5linear or branched, or C3-C8cyclic alkoxy (e.g. methoxy), optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom, C1-C5linear or branched thioalkoxy, C1-C5 linear or branched haloalkoxy, C1-C5 linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclohexyl), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., morpholine, pyran, oxetane, pyrrolidine, imidazole, piperazine, piperidine, dioxazole, 2-oxopyrrolidine), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted benzyl; R20is represented by the following structure:R is H, F, Cl, Br, I, OH, SH, COOH, CO(R10) (e.g., C(O)CH3), NH(R10), NH-CH2-cyclopropyl, N(R10)(R11), CF3, CN, NO2, C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, iPr, CH2-cyclopropyl, CH2-OH, CH2-CH2-OH, CH2-CH2-O-CH2-CH2-O-CH3, CH2-O-CH2-CH2- O-CH3), C3-C8substituted or unsubstituted cycloalkyl, cyclopropyl, substituted or unsubstituted C1-C5linear or branched alkoxy, (e.g., methoxy, ethoxy, O-(CH2CH3), OCHF2, O-(CH2)2-O-CH3, isopropoxy, O-(CH2)-cyclopropyl, O-CH2-methylcyclobutyl, O-CH2-3-methyloxetane, O-CH(CH3)-CH2-O-CH3)C1-C5 linear or branched haloalkyl (e.g., CHF2, CF3, CF2CH3, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2,CF(CH3)-CH(CH3)2), R8-aryl (e.g., CH2-Ph), -R8-O-R8-O-R10 (e.g. (CH2)2-O-(CH2)2-O- CH3), -R8-O-R10, O-R8-R10 (e.g. O-(CH2)2-O-CH3, O-(CH2CH3), O-(CH2)-cyclopropyl), -R8-R10 (e.g., (CH2)-cyclopropyl, (CH2)2-O-CH3, (CH2)-OH, (CH2)2-OH, (CH2)-COOH), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine); R30 is H, R20, F, Cl, Br, I, OH, SH, alkoxy, N(R)2, NH(R10), N(R10)(R11), CF3, CN, NO2, C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH2-CH2-O-CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), C1-C5 linear or branched alkoxy, C1-C5 linear or branched haloalkyl (e.g., CHF2, CF3, CF2CH3, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2,CF(CH3)-CH(CH3)2), R8-aryl (e.g., CH2-Ph), -R8-O-R8-O-R10 (e.g. (CH2)2-O-(CH2)2-O-CH3), -R8-O-R10, -R8-R10 (e.g., (CH2)2-O- CH3), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine); each R8 is independently [CH2]p wherein p is between 1 and 10 (e.g., 1, 2); R9 is [CH]q, [C]q wherein q is between 2 and 10; R10 and R11 are each independently H, OH, COOH, C1-C5 substituted or unsubstituted linear or branched alkyl (e.g., methyl, ethyl, CH2-cyclopropyl, CH2-CH2-O-CH3), C3-C8 substituted or unsubstituted cycloalkyl (e.g., cyclopropyl), C1-C5substituted or unsubstituted linear or branched haloalky (e.g., CH2CF3), C1-C5linear or branched alkoxy (e.g., O-CH3), R20, C(O)R, or S(O)2R; or R10and R11are joined to form a substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., piperazine, piperidine), n is an integer between 0 and 4 (e.g., 1, 2); or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, pharmaceutical product or any combination thereof.

[0025] In some embodiments, at least one of X2, X3, and X4is C(R). In some embodiments, X11is N. In some embodiments, X12is not S. In some embodiments, at least one of X2, X3, and X4is C(R); X11is N; or X12is not S. In some embodiments, R is not H. In some embodiments, if R1and R2are joined to form a C=O, then at least one of X2, X3, X4, and X10is not CH;

[0026] In various embodiments, this invention is directed to a compound represented by the structure of formula I(e):wherein X2, X3, and X4, are each independently CH, C(R) or N (e.g., C(CH3), C(O-CH2-cyclopropyl), C(O-CH2-methylcyclobutyl), C(NH-CH2-cyclopropyl), C(isopropoxy), C(O-CH(CH3)-CH2-O-CH3), C(CH2CH3), C-iPr, C-CH2-cyclopropyl, C(OCH3), C(OCH2CH3), C(O-(CH2)2-O-CH3, C(OCHF2), C(Cl), C(C(O)CH3), C(O-CH2CH2-O-CH3), C(OH)); X5, X6, X7, X8 and X9 are each independently nitrogen or carbon atoms; wherein if either one of X5, X6 , X8 and X9 is nitrogen, then the respective R7’, R7’’, R7’’’, and R7’’’’ substitution is absent; X10 is N, CH, C(R), or C=O; wherein if X10 is C=O then X11 is N (e.g., C(CH2-OH), C(CH2- CH2-OH), C(NH-CH2-cyclopropyl), C(COOH), C(CH3), C(cyclopropyl), C(isopropoxy)); X11 is N or C; wherein if X11 is N then X10 is C=O; X12is S, SO2, O, NH, N(R), N-OH, CH=CH, CH=CH(R), C(R)=CH, N=CH, N=C(R), CH=N or C(R)=N (e.g., N-CH2-COOH, N-CH2-CH2-OH, N-CH3, N-CH2CH3, N-iPr, N-cyclopropyl, N-CH2- cyclopropyl); Ring F is absent or is a substituted or unsubstituted, saturated or unsaturated, 3-8 membered heterocyclic or carbocyclic ring (e.g., pyrrolidine, 1-methylpyrrolidine, pyrrolidin-2-one, pyrrolidin-3- ol, morpholine, pyridine, piperidine, tetrahydrofurane, tetrahydrothiophene, cyclopropyl, oxetane, imidazole, pyrimidine, triazole, oxadiazole, pyrazole); R1and R2are each independently H, F, Cl, Br, I, OH, SH, or CF3, substituted or unsubstituted C1-C5alkyl, C1-C5linear or branched, or C3-C8cyclic haloalkyl, substituted or unsubstituted C1-C5linear or branched, or C3-C8cyclic alkoxy; or R1and R2are joined to form a C=O, or a 3-8 membered carbocyclic or heterocyclic ring (e.g., cyclopropyl);or R2 and R4 are joined to form Ring F as defined above (e.g., pyrrolidine, pyrrolidin-2-one, pyrrolidin-3-ol, morpholine, pyridine, pyrimidine, triazole, oxadiazole, pyrazole), wherein if Ring F is aromatic, then R1 and / or R3 are absent; R3 and R4 are each independently H, Me, substituted or unsubstituted C1-C5 alkyl (e.g., methoxyethylene, methylaminoethyl, aminoethyl), -R8-O-R10 (e.g., (CH2)2-O-CH3), R8-N(R10)(R11) (e.g., (CH2)2-NH(CH3)), substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted 5-7 membered heterocyclic ring (e.g., pyrrolidine, methylpyrrolidine, piperidine), or R20; or R3 and R4 are joined to form a 3-8 membered heterocyclic ring (e.g., pyrrolidine, , pyrrolidone, 2-oxopyrrolidine, piperidine, morpholine, piperazine, imidazole); R5 is H or C1-C5 linear or branched alkyl (e.g. methyl); R6 is H, F, Cl, Br, I, OH, SH, R8-OH, R8-SH, -R8-O-R10 (e.g., CH2-O-CH3, (CH2)2-O-CH3 (CH2)3-O-CH3, (CH2)2-O-CH(CH3)2), R8-S-R10 (e.g., (CH2)3-S-(CH2)2CH3), R8-NHC(O)-R10, -O-R8- R10, R8-(substituted or unsubstituted C3-C8 cycloalkyl) (e.g., CH2-cyclopropyl, CH2-cyclobutanol, CH2- difluorocyclopropyl, CH2-methylcyclopropyl, CH2-dimethylamino-cyclohexyl, (CH2)2-cyclopentanole, CH2-cyclohexanol), R8-(substituted or unsubstituted, saturated, unsaturated or aromatic, single, fused or spiro 3-10 membered heterocyclic ring) (e.g., (CH2)3-piperidine, (CH2)3-4-fluoro-piperidine, (CH2)3- pyran, (CH2)2-pyrrazole, (CH2)2-imidazole, CH2-tetrahydrofurane, CH2-dioxane, CH2-oxetane, CH2- piperidine, CH2-triazole, CH2-1-oxa-8-azaspiro[4.5]decane, (CH2)3-diazabicyclo[2.2.1]heptane, CH2- methyl-THF, CH2-ethyl-piperidine, CH2-oxa-azaspirodecane, (CH2)3-dimethylpyrazole, CH2-2-oxo- methylpyrrolidine, CH2-methyl-azetidine, CH2-azaspiroheptane), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, NH(R10), N(R10)(R11), R8-N(R10)(R11) (e.g., (CH2)2-NH2, (CH2)3- N(CH2CH3)2, (CH2)3-N(CH(CH3)2)2, (CH2)3-piperidine, (CH2)3-4-fluoro-piperidine, (CH2)3-4-cyano- piperidine, (CH2)4-NH(CH3), (CH2)3-NH-CH3, (CH2)3-NH-CH2CH3, (CH2)3-N(CH2CH3)2, (CH2)3-NH2, (CH2)3-N(CH2CH3)(CH2CF3)), R9-R8-N(R10)(R11) (e.g., (CH2)2-C(O)-piperidine), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R10, NHCO-N(R10)(R11), COOH, -C(O)Ph, C(O)O-R10, R8-C(O)-R10, C(O)H, C(O)- R10(e.g., C(O)CH3), C1-C5linear or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR, C(O)N(R10)(R11), SO2R, SO2N(R10)(R11), CH(CF3)(NH-R10), C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., CH(CH3)CH2OCH3, CH(CH3)CH2NH2, CH(CH3)C(O)N(CH3)2, CH2-CH(OH)Ph, (CH2)3N(H)CH2CH3, CH(CH3)(CH2)2OH, CH(CH2OH)(CH2CH3), (CH2)3-OCH3, (CH2)2-OCH3, (CH2)2-OCH(CH3)2, CH(CH2OH)(CH2CH(CH3)2), CH2CH(CH3)(OCH3), CH2CH(N(CH3)2)(CH2CH3), benzyl, methyl, ethyl, CH2-OCH2-CH2-O-CH3, CH(CH3)C(O)N(CH3)2), C1-C5linear or branched, substituted or unsubstituted alkenyl, C1-C5linear or branched, or C3-C8cyclic haloalkyl, substituted or unsubstituted C1-C5linear or branched, or C3-C8cyclic alkoxy (e.g. methoxy, O-(CH2)2-O-CH3), optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom, C1-C5linear or branched thioalkoxy, C1-C5linear or branched haloalkoxy, C1-C5linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclohexyl, methoxycyclopropyl, methylcyclobutyl, aminomethyl-cyclobutyl, methoxycyclobutyl, 2,3-dihydro-1H- indenol), R8-(substituted or unsubstituted C3-C8cycloalkyl) substituted or unsubstituted 3-8 memberedheterocyclic ring (e.g., piperidine, 1-methyl-piperidine, azetidine, pyrrolidine, pyrrolidinone, quinuclidine, tetrahydropyran, azaspiro[3.3]heptane, imidazole, trifluoromethyl-oxetane, hydroxy- tetrahydrofurane, azepan-2-one, azabicyclohexane), substituted or unsubstituted aryl, substituted or unsubstituted R8-aryl (e.g., benzyl), substituted or unsubstituted benzyl; or R6 and R5 are joined to for a substituted or unsubstituted 5-8 membered heterocyclic ring (e.g., azepane, piperazine, 2-(piperazin-1-yl)acetamide; or R6 is represented by the structure of formula B or Bi:wherein m is 0 or 1; and R12 is R20 or C1-C5 C(O)-alkyl, and R13 is R30; or R12 and R13 are both H; R12 and R13 are each independently H or substituted or unsubstituted C1-C5 alkyl (e.g., ethyl, trifluoroethyl); R12 and C3 are joined to form ring A and R13 is R30; or R12 and R13 are joined to form ring B; or R12 and C1 are joined to form ring C and R13 is R30; or C1 and C3 are joined to form ring D and R12 and R13 are each independently R30; or R13 and C2 are joined to form ring E, m is 1, and R12 is R30; or R12 and R13 are joined to form ring B and C1 and C3 are joined to form ring D; wherein Ring A, C and E are each independently a substituted or unsubstituted single spiro or fused 3-8 membered heterocyclic ring (e.g., A: pyrrolidine, methylpyrrolidine, ethylpyrrolidine); C: piperidine, pyrrolidine, methyl-2-oxopyrrolidine, pyran- pyrrolidine, methyl-azetidine, azabicyclooctane, 2-azabicyclo[2.1.1]hexane, 2-azaspiro[3.3]heptane; E: pyrrolidine, azetidine, ethylpyrrolidine, oxopyrrolidine, methylpiperidine); Ring B is a substituted or unsubstituted single, spiro or fused 3-8 membered heterocyclic ring (B: piperidine, piperidin-2-one, 4-fluoropiperidin-2-one, piperidine- 4-carbonitrile, 4-fluoropiperidine, 4-fluoro-2-methylpiperidine, methyl-piperidin, fluoropiperidine, difluoropiperidine, pyrrolidine, piperazine, methylpyrrolidine, thiomorpholine 1,1-dioxide, 2-oxa-6-azaspiro[3.3]heptane, methyl-piperazine, dimethyl-pyrazole, imidazole, 2-methyl-2,5-diazabicyclo[2.2.1]heptane, hydroxymethyl-pyrrolidine, diazabicyclo[2.2.1]heptane, 6-fluoro-3- azabicyclo[3.1.1]heptane; and Ring D is a substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclobutane, cyclohexane); R7’, R7’’, R7’’’ and R7’’’’ are each independently H, F, Cl, Br, I, OH, O-R20, SH, R8-OH, R8- SH, -R8-O-R10, R8-(C3-C8 cycloalkyl), R8-(3-8 membered heterocyclic ring), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, NH(R10), N(R10)(R11), R8-N(R10)(R11), R9-R8-N(R10)(R11), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R10, NHCO-N(R10)(R11), COOH, -C(O)Ph, C(O)O-R10, R8-C(O)-R10, C(O)H, C(O)-R10, C1-C5 linear or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR, C(O)N(R10)(R11), SO2R, SO2N(R10)(R11), CH(CF3)(NH-R10), C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., isopropyl, methyl, ethyl), C1-C5linear or branched, substituted or unsubstituted alkenyl, C1-C5linear or branched, or C3-C8cyclic haloalkyl (e.g., CHF2), C1-C5linear or branched, or C3-C8cyclic alkoxy (e.g. methoxy), optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom, C1-C5linear or branched thioalkoxy, C1-C5linear or branched haloalkoxy, C1-C5linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8cycloalkyl (e.g., cyclopropyl, cyclohexyl), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., morpholine, pyran, oxetane, pyrrolidine, tetrahydrofuran, imidazole, piperazine, piperidine, dioxazole, 2-oxopyrrolidine), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted benzyl; or R7’ and R7’’ are joined to form a 3-8 membered substituted or unsubstituted, saturated, unsaturated or aromatic, carbocyclic or heterocyclic ring (e.g., cyclopentyl, cyclohexyl, piperidine, tetrahydrofuran, tetrahydropyran, pyrrolidine); or R7’’’ and R7’’’’ are joined to form a 3-8 membered substituted or unsubstituted carbocyclic or heterocyclic ring (e.g., cyclopentyl, cyclohexyl, piperidine, tetrahydrofuran, tetrahydropyran, pyrrolidine); R20is represented by the following structure:R is H, F, Cl, Br, I, OH, SH, COOH, CO(R10) (e.g., C(O)CH3), NH(R10), NH-CH2-cyclopropyl, N(R10)(R11), CF3, CN, NO2, C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl,ethyl, iPr, CH2-cyclopropyl, CH2-OH, CH2-CH2-OH, CH2-CH2-O-CH2-CH2-O-CH3, CH2-O-CH2-CH2- O-CH3), C3-C8 substituted or unsubstituted cycloalkyl, cyclopropyl, substituted or unsubstituted C1-C5 linear or branched alkoxy, (e.g., methoxy, ethoxy, O-(CH2CH3), OCHF2, O-(CH2)2-O-CH3, isopropoxy, O-(CH2)-cyclopropyl, O-CH2-methylcyclobutyl, O-CH2-3-methyloxetane, O-CH(CH3)-CH2-O-CH3) C1-C5 linear or branched haloalkyl (e.g., CHF2, CF3, CF2CH3, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2,CF(CH3)-CH(CH3)2), R8-aryl (e.g., CH2-Ph), -R8-O-R8-O-R10 (e.g. (CH2)2-O-(CH2)2-O- CH3), -R8-O-R10, O-R8-R10 (e.g. O-(CH2)2-O-CH3, O-(CH2CH3), O-(CH2)-cyclopropyl), -R8-R10 (e.g., (CH2)-cyclopropyl, (CH2)2-O-CH3, (CH2)-OH, (CH2)2-OH, (CH2)-COOH), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine); R30 is H, R20, F, Cl, Br, I, OH, SH, alkoxy, N(R)2, NH(R10), N(R10)(R11), CF3, CN, NO2, C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH2-CH2-O-CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), C1-C5 linear or branched alkoxy, C1-C5 linear or branched haloalkyl (e.g., CHF2, CF3, CF2CH3, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2,CF(CH3)-CH(CH3)2), R8-aryl (e.g., CH2-Ph), -R8-O-R8-O-R10 (e.g. (CH2)2-O-(CH2)2-O-CH3), -R8-O-R10, -R8-R10 (e.g., (CH2)2-O- CH3), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine); each R8 is independently [CH2]p wherein p is between 1 and 10 (e.g., 1, 2); R9is [CH]q, [C]qwherein q is between 2 and 10; R10and R11are each independently H, OH, COOH, C1-C5substituted or unsubstituted linear or branched alkyl (e.g., methyl, ethyl, CH2-cyclopropyl, CH2-CH2-O-CH3), C3-C8substituted or unsubstituted cycloalkyl (e.g., cyclopropyl), C1-C5substituted or unsubstituted linear or branched haloalky (e.g., CH2CF3), C1-C5 linear or branched alkoxy (e.g., O-CH3), R20, C(O)R, or S(O)2R; or R10 and R11 are joined to form a substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., piperazine, piperidine), n is an integer between 0 and 4 (e.g., 1, 2); or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, pharmaceutical product or any combination thereof.

[0027] In some embodiments, at least one of R7’, R7’’, R7’’’ and R7’’’’ is not H. In some embodiments, at least two of R7’, R7’’, R7’’’ and R7’’’’ are not H. In some embodiments, at least two of R7’, R7’’, R7’’’ and R7’’’’ are different than eachother. In some embodiments, at least two of R7’, R7’’, R7’’’ and R7’’’’ are not H and are different than eachother.

[0028] In some embodiments, at least one of X2, X3, and X4is C(R). In some embodiments, X11is N. In some embodiments, X12is not S. In some embodiments, at least one of X2, X3, and X4is C(R); X11isN; or X12 is not S. In some embodiments, R is not H. In some embodiments, if R1 and R2 are joined to form a C=O, then at least one of X2, X3, X4, and X10 is not CH;

[0029] In various embodiments, this invention is directed to a compound represented by the structure of formula I(f):wherein X2, X3, and X4, are each independently CH, C(R) or N (e.g., C(CH3), C(O-CH2-cyclopropyl), C(O-CH2-methylcyclobutyl), C(NH-CH2-cyclopropyl), C(isopropoxy), C(O-CH(CH3)-CH2-O-CH3), C(CH2CH3), C-iPr, C-CH2-cyclopropyl, C(OCH3), C(OCH2CH3), C(O-(CH2)2-O-CH3, C(OCHF2), C(Cl), C(C(O)CH3), C(O-CH2CH2-O-CH3), C(OH)); X5, X6, X7, X8and X9are each independently nitrogen or carbon atoms; wherein if either one of X5, X6, X8and X9is nitrogen, then the respective R7’, R7’’, R7’’’, and R7’’’’ substitution is absent; X10is N, CH, C(R), or C=O; wherein if X10is C=O then X11is N (e.g., C(CH2-OH), C(CH2- CH2-OH), C(NH-CH2-cyclopropyl), C(COOH), C(CH3), C(cyclopropyl), C(isopropoxy)); X11is N or C; wherein if X11is N then X10is C=O; X12is S, SO2, O, NH, N(R), N-OH, CH=CH, CH=CH(R), C(R)=CH, N=CH, N=C(R), CH=N or C(R)=N (e.g., N-CH2-COOH, N-CH2-CH2-OH, N-CH3, N-CH2CH3, N-iPr, N-cyclopropyl, N-CH2- cyclopropyl); X13is CH2, CH(R) (e.g., CH-CH3), C(R)2, or C=O; Ring G is absent or is a substituted or unsubstituted 3-8 membered carbocyclic or heterocyclic ring (e.g., cyclobutane, cyclopentane, cyclohexane); Ring F is absent or is a substituted or unsubstituted, saturated or unsaturated, 3-8 membered heterocyclic or carbocyclic ring (e.g., pyrrolidine, 1-methylpyrrolidine, pyrrolidin-2-one, pyrrolidin-3- ol, morpholine, pyridine, piperidine, tetrahydrofurane, tetrahydrothiophene, cyclopropyl, oxetane, imidazole, pyrimidine, triazole, oxadiazole, pyrazole);R1 and R2 are each independently H, F, Cl, Br, I, OH, SH, or CF3, substituted or unsubstituted C1-C5 alkyl, C1-C5 linear or branched, or C3-C8 cyclic haloalkyl, substituted or unsubstituted C1-C5 linear or branched, or C3-C8 cyclic alkoxy; or R1 and R2 are joined to form a C=O, or a 3-8 membered carbocyclic or heterocyclic ring (e.g., cyclopropyl); or R2 and R4 are joined to form Ring F as defined above (e.g., pyrrolidine, pyrrolidin-2-one, pyrrolidin-3-ol, morpholine, pyridine, pyrimidine, triazole, oxadiazole, pyrazole), wherein if Ring F is aromatic, then R1 and / or R3 are absent; R3 and R4 are each independently H, Me, substituted or unsubstituted C1-C5 alkyl (e.g., methoxyethylene, methylaminoethyl, aminoethyl), -R8-O-R10 (e.g., (CH2)2-O-CH3), R8-N(R10)(R11) (e.g., (CH2)2-NH(CH3)), substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted 5-7 membered heterocyclic ring (e.g., pyrrolidine, methylpyrrolidine, piperidine), or R20; or R3 and R4 are joined to form a 3-8 membered heterocyclic ring (e.g., pyrrolidine, , pyrrolidone, 2-oxopyrrolidine, piperidine, morpholine, piperazine, imidazole); R7’, R7’’, R7’’’ and R7’’’’ are each independently H, F, Cl, Br, I, OH, O-R20, SH, R8-OH, R8- SH, -R8-O-R10, R8-(C3-C8 cycloalkyl), R8-(3-8 membered heterocyclic ring), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, NH(R10), N(R10)(R11), R8-N(R10)(R11), R9-R8-N(R10)(R11), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R10, NHCO-N(R10)(R11), COOH, -C(O)Ph, C(O)O-R10, R8-C(O)-R10, C(O)H, C(O)-R10, C1-C5linear or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR, C(O)N(R10)(R11), SO2R, SO2N(R10)(R11), CH(CF3)(NH-R10), C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., isopropyl, methyl, ethyl), C1-C5linear or branched, substituted or unsubstituted alkenyl, C1-C5linear or branched, or C3-C8cyclic haloalkyl (e.g., CHF2), C1-C5linear or branched, or C3-C8cyclic alkoxy (e.g. methoxy), optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom, C1-C5 linear or branched thioalkoxy, C1-C5 linear or branched haloalkoxy, C1-C5 linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclohexyl), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., morpholine, pyran, oxetane, pyrrolidine, tetrahydrofuran, imidazole, piperazine, piperidine, dioxazole, 2-oxopyrrolidine), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted benzyl; or R7’ and R7’’ are joined to form a 3-8 membered substituted or unsubstituted, saturated, unsaturated or aromatic, carbocyclic or heterocyclic ring (e.g., cyclopentyl, cyclohexyl, piperidine, tetrahydrofuran, tetrahydropyran, pyrrolidine); or R7’’’ and R7’’’’ are joined to form a 3-8 membered substituted or unsubstituted carbocyclic or heterocyclic ring (e.g., cyclopentyl, cyclohexyl, piperidine, tetrahydrofuran, tetrahydropyran, pyrrolidine); R20is represented by the following structure:R30 is H, R20, F, Cl, Br, I, OH, SH, alkoxy, N(R)2, NH(R10), N(R10)(R11), CF3, CN, NO2, C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH2-CH2-O-CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), C1-C5 linear or branched alkoxy, C1-C5 linear or branched haloalkyl (e.g., CHF2, CF3, CF2CH3, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2,CF(CH3)-CH(CH3)2), R8-aryl (e.g., CH2-Ph), -R8-O-R8-O-R10 (e.g. (CH2)2-O-(CH2)2-O-CH3), -R8-O-R10, -R8-R10 (e.g., (CH2)2-O- CH3), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine); R50 is H, R20, F, Cl, Br, I, OH, SH, N(R)2, NH(R10), N(R10)(R11), CF3, CN, NO2, C1-C5 linear or branched, substituted or unsubstituted alkyl C1-C5 linear or branched alkoxy, C1-C5 linear or branched haloalkyl, -R8-R10 (e.g., (CH2)2-O-CH3), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine); R is H, F, Cl, Br, I, OH, SH, COOH, CO(R10) (e.g., C(O)CH3), NH(R10), NH-CH2-cyclopropyl, N(R10)(R11), CF3, CN, NO2, C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, iPr, CH2-cyclopropyl, CH2-OH, CH2-CH2-OH, CH2-CH2-O-CH2-CH2-O-CH3, CH2-O-CH2-CH2- O-CH3), C3-C8 substituted or unsubstituted cycloalkyl, cyclopropyl, substituted or unsubstituted C1-C5 linear or branched alkoxy, (e.g., methoxy, ethoxy, O-(CH2CH3), OCHF2, O-(CH2)2-O-CH3, isopropoxy, O-(CH2)-cyclopropyl, O-CH2-methylcyclobutyl, O-CH2-3-methyloxetane, O-CH(CH3)-CH2-O-CH3) C1-C5 linear or branched haloalkyl (e.g., CHF2, CF3, CF2CH3, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2,CF(CH3)-CH(CH3)2), R8-aryl (e.g., CH2-Ph), -R8-O-R8-O-R10(e.g. (CH2)2-O-(CH2)2-O- CH3), -R8-O-R10, O-R8-R10(e.g. O-(CH2)2-O-CH3, O-(CH2CH3), O-(CH2)-cyclopropyl), -R8-R10(e.g., (CH2)-cyclopropyl, (CH2)2-O-CH3, (CH2)-OH, (CH2)2-OH, (CH2)-COOH), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine); each R8is independently [CH2]pwherein p is between 1 and 10 (e.g., 1, 2); R9 is [CH]q, [C]q wherein q is between 2 and 10; R10and R11are each independently H, OH, COOH, C1-C5substituted or unsubstituted linear or branched alkyl (e.g., methyl, ethyl, CH2-cyclopropyl, CH2-CH2-O-CH3), C3-C8substituted or unsubstituted cycloalkyl (e.g., cyclopropyl), C1-C5substituted or unsubstituted linear or branched haloalky (e.g., CH2CF3), C1-C5linear or branched alkoxy (e.g., O-CH3), R20, C(O)R, or S(O)2R; or R10and R11are joined to form a substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., piperazine, piperidine), n is an integer between 0 and 4 (e.g., 1, 2); or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, pharmaceutical product or any combination thereof.

[0030] In some embodiments, at least one of R7’, R7’’, R7’’’ and R7’’’’ is not H. In some embodiments, at least two of R7’, R7’’, R7’’’ and R7’’’’ are not H. In some embodiments, at least two of R7’, R7’’, R7’’’ and R7’’’’ are different than eachother. In some embodiments, at least two of R7’, R7’’, R7’’’ and R7’’’’ are not H and are different than eachother. In some embodiments, if R1 and R2 are joined to form a C=O, then at least one of X2, X3, X4, and X10 is not CH;

[0031] In some embodiments, at least one of X2, X3, and X4 is C(R). In some embodiments, X11 is N. In some embodiments, X12 is not S. In some embodiments, at least one of X2, X3, and X4 is C(R); X11 is N; or X12 is not S. In some embodiments, R is not H.

[0032] In various embodiments, this invention is directed to a compound represented by the structure of formula I(g):wherein X2, X3, and X4, are each independently CH, C(R) or N (e.g., C(CH3), C(O-CH2-cyclopropyl), C(O-CH2-methylcyclobutyl), C(NH-CH2-cyclopropyl), C(isopropoxy), C(O-CH(CH3)-CH2-O-CH3), C(CH2CH3), C-iPr, C-CH2-cyclopropyl, C(OCH3), C(OCH2CH3), C(O-(CH2)2-O-CH3, C(OCHF2), C(Cl), C(C(O)CH3), C(O-CH2CH2-O-CH3), C(OH)); X5, X6, X7, X8and X9are each independently nitrogen or carbon atoms; wherein if either one of X5, X6, X8and X9is nitrogen, then the respective R7’, R7’’, R7’’’, and R7’’’’ substitution is absent; X10is N, CH, C(R), or C=O; wherein if X10is C=O then X11is N (e.g., C(CH2-OH), C(CH2- CH2-OH), C(NH-CH2-cyclopropyl), C(COOH), C(CH3), C(cyclopropyl), C(isopropoxy)); X11is N or C; wherein if X11is N then X10is C=O;X12 is S, SO2, O, NH, N(R), N-OH, CH=CH, CH=CH(R), C(R)=CH, N=CH, N=C(R), CH=N or C(R)=N (e.g., N-CH2-COOH, N-CH2-CH2-OH, N-CH3, N-CH2CH3, N-iPr, N-cyclopropyl, N-CH2- cyclopropyl); X14 is S, O, N or CH, wherein if X14 is CH then Ring F is not absent and if X14 is S or O then R3 is absent; Ring F is absent or is a substituted or unsubstituted, saturated or unsaturated, 3-8 membered heterocyclic or carbocyclic ring (e.g., pyrrolidine, 1-methylpyrrolidine, pyrrolidin-2-one, pyrrolidin-3- ol, morpholine, pyridine, piperidine, tetrahydrofurane, tetrahydrothiophene, cyclopropyl, oxetane, imidazole, pyrimidine, triazole, oxadiazole, pyrazole); R1 and R2 are each independently H, F, Cl, Br, I, OH, SH, or CF3, substituted or unsubstituted C1-C5 alkyl, C1-C5 linear or branched, or C3-C8 cyclic haloalkyl, substituted or unsubstituted C1-C5 linear or branched, or C3-C8 cyclic alkoxy; or R1 and R2 are joined to form a C=O, or a 3-8 membered carbocyclic or heterocyclic ring (e.g., cyclopropyl); or R2 and R4 are joined to form Ring F as defined above (e.g., pyrrolidine, pyrrolidin-2-one, pyrrolidin-3-ol, morpholine, pyridine, pyrimidine, triazole, oxadiazole, pyrazole), wherein if Ring F is aromatic, then R1 and / or R3 are absent; R3 and R4 are each independently H, Me, substituted or unsubstituted C1-C5 alkyl (e.g., methoxyethylene, methylaminoethyl, aminoethyl), -R8-O-R10(e.g., (CH2)2-O-CH3), R8-N(R10)(R11) (e.g., (CH2)2-NH(CH3)), substituted or unsubstituted C3-C8cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted 5-7 membered heterocyclic ring (e.g., pyrrolidine, methylpyrrolidine, piperidine), or R20;or R3and R4are joined to form a 3-8 membered heterocyclic ring (e.g., pyrrolidine, , pyrrolidone, 2-oxopyrrolidine, piperidine, morpholine, piperazine, imidazole); wherein if X14 is S or O then R3 is absent; R5 is H or C1-C5 linear or branched alkyl (e.g. methyl); R6is H, F, Cl, Br, I, OH, SH, R8-OH, R8-SH, -R8-O-R10(e.g., CH2-O-CH3, (CH2)2-O-CH3(CH2)3-O-CH3, (CH2)2-O-CH(CH3)2), R8-S-R10(e.g., (CH2)3-S-(CH2)2CH3), R8-NHC(O)-R10, -O-R8- R10, R8-(substituted or unsubstituted C3-C8cycloalkyl) (e.g., CH2-cyclopropyl, CH2-cyclobutanol, CH2- difluorocyclopropyl, CH2-methylcyclopropyl, CH2-dimethylamino-cyclohexyl, (CH2)2-cyclopentanole, CH2-cyclohexanol), R8-(substituted or unsubstituted, saturated, unsaturated or aromatic, single, fused or spiro 3-10 membered heterocyclic ring) (e.g., (CH2)3-piperidine, (CH2)3-4-fluoro-piperidine, (CH2)3- pyran, (CH2)2-pyrrazole, (CH2)2-imidazole, CH2-tetrahydrofurane, CH2-dioxane, CH2-oxetane, CH2- piperidine, CH2-triazole, CH2-1-oxa-8-azaspiro[4.5]decane, (CH2)3-diazabicyclo[2.2.1]heptane, CH2- methyl-THF, CH2-ethyl-piperidine, CH2-oxa-azaspirodecane, (CH2)3-dimethylpyrazole, CH2-2-oxo- methylpyrrolidine, CH2-methyl-azetidine, CH2-azaspiroheptane), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, NH(R10), N(R10)(R11), R8-N(R10)(R11) (e.g., (CH2)2-NH2, (CH2)3- N(CH2CH3)2, (CH2)3-N(CH(CH3)2)2, (CH2)3-piperidine, (CH2)3-4-fluoro-piperidine, (CH2)3-4-cyano- piperidine, (CH2)4-NH(CH3), (CH2)3-NH-CH3(CH2)3-NH-CH2CH3(CH2)3-N(CH2CH3)2, (CH2)3-NH2,(CH2)3-N(CH2CH3)(CH2CF3)), R9-R8-N(R10)(R11) (e.g., (CH2)2-C(O)-piperidine), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R10, NHCO-N(R10)(R11), COOH, -C(O)Ph, C(O)O-R10, R8-C(O)-R10, C(O)H, C(O)- R10 (e.g., C(O)CH3), C1-C5 linear or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR, C(O)N(R10)(R11), SO2R, SO2N(R10)(R11), CH(CF3)(NH-R10), C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., CH(CH3)CH2OCH3, CH(CH3)CH2NH2, CH(CH3)C(O)N(CH3)2, CH2-CH(OH)Ph, (CH2)3N(H)CH2CH3, CH(CH3)(CH2)2OH, CH(CH2OH)(CH2CH3), (CH2)3-OCH3, (CH2)2-OCH3, (CH2)2-OCH(CH3)2, CH(CH2OH)(CH2CH(CH3)2), CH2CH(CH3)(OCH3), CH2CH(N(CH3)2)(CH2CH3), benzyl, methyl, ethyl, CH2-OCH2-CH2-O-CH3, CH(CH3)C(O)N(CH3)2), C1-C5 linear or branched, substituted or unsubstituted alkenyl, C1-C5 linear or branched, or C3-C8 cyclic haloalkyl, substituted or unsubstituted C1-C5 linear or branched, or C3-C8 cyclic alkoxy (e.g. methoxy, O-(CH2)2-O-CH3), optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom, C1-C5 linear or branched thioalkoxy, C1-C5 linear or branched haloalkoxy, C1-C5 linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclohexyl, methoxycyclopropyl, methylcyclobutyl, aminomethyl-cyclobutyl, methoxycyclobutyl, 2,3-dihydro-1H- indenol), R8-(substituted or unsubstituted C3-C8 cycloalkyl), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., piperidine, 1-methyl-piperidine, azetidine, pyrrolidine, pyrrolidinone, quinuclidine, tetrahydropyran, azaspiro[3.3]heptane, imidazole, trifluoromethyl-oxetane, hydroxy- tetrahydrofurane, azepan-2-one, azabicyclohexane), substituted or unsubstituted aryl, substituted or unsubstituted R8-aryl (e.g., benzyl), substituted or unsubstituted benzyl; or R6and R5are joined to for a substituted or unsubstituted 5-8 membered heterocyclic ring (e.g., azepane, piperazine, 2-(piperazin-1-yl)acetamide; or R6is represented by the structure of formula B or Bi:wherein m is 0 or 1; andR12 is R20 or C1-C5 C(O)-alkyl, and R13 is R30; or R12 and R13 are both H; R12 and R13 are each independently H or substituted or unsubstituted C1-C5 alkyl (e.g., ethyl, trifluoroethyl); R12 and C3 are joined to form ring A and R13 is R30; or R12 and R13 are joined to form ring B; or R12 and C1 are joined to form ring C and R13 is R30; or C1 and C3 are joined to form ring D and R12 and R13 are each independently R30; or R13 and C2 are joined to form ring E, m is 1, and R12 is R30; or R12 and R13 are joined to form ring B and C1 and C3 are joined to form ring D; wherein Ring A, C and E are each independently a substituted or unsubstituted single spiro or fused 3-8 membered heterocyclic ring (e.g., A: pyrrolidine, methylpyrrolidine, ethylpyrrolidine); C: piperidine, pyrrolidine, methyl-2-oxopyrrolidine, pyran- pyrrolidine, methyl-azetidine, azabicyclooctane, 2-azabicyclo[2.1.1]hexane, 2- azaspiro[3.3]heptane; E: pyrrolidine, azetidine, ethylpyrrolidine, oxopyrrolidine, methylpiperidine); Ring B is a substituted or unsubstituted single, spiro or fused 3-8 membered heterocyclic ring (B: piperidine, piperidin-2-one, 4-fluoropiperidin-2-one, piperidine- 4-carbonitrile, 4-fluoropiperidine, 4-fluoro-2-methylpiperidine, methyl-piperidin, fluoropiperidine, difluoropiperidine, pyrrolidine, piperazine, methylpyrrolidine, thiomorpholine 1,1-dioxide, 2-oxa-6-azaspiro[3.3]heptane, methyl-piperazine, dimethyl-pyrazole, imidazole, 2-methyl-2,5-diazabicyclo[2.2.1]heptane, hydroxymethyl-pyrrolidine, diazabicyclo[2.2.1]heptane, 6-fluoro-3- azabicyclo[3.1.1]heptane; and Ring D is a substituted or unsubstituted C3-C8cycloalkyl (e.g., cyclobutane, cyclohexane); R7’, R7’’, R7’’’ and R7’’’’ are each independently H, F, Cl, Br, I, OH, O-R20, SH, R8-OH, R8- SH, -R8-O-R10, R8-(C3-C8cycloalkyl), R8-(3-8 membered heterocyclic ring), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, NH(R10), N(R10)(R11), R8-N(R10)(R11), R9-R8-N(R10)(R11), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R10, NHCO-N(R10)(R11), COOH, -C(O)Ph, C(O)O-R10, R8-C(O)-R10, C(O)H, C(O)-R10, C1-C5linear or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR, C(O)N(R10)(R11), SO2R, SO2N(R10)(R11), CH(CF3)(NH-R10), C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., isopropyl, methyl, ethyl), C1-C5linear or branched, substituted or unsubstituted alkenyl, C1-C5linear or branched, or C3-C8cyclic haloalkyl (e.g., CHF2), C1-C5linear or branched, or C3-C8cyclic alkoxy (e.g. methoxy), optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom, C1-C5linear or branched thioalkoxy, C1-C5linear or branched haloalkoxy, C1-C5linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8cycloalkyl (e.g., cyclopropyl,cyclohexyl), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., morpholine, pyran, oxetane, pyrrolidine, tetrahydrofuran, imidazole, piperazine, piperidine, dioxazole, 2-oxopyrrolidine), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted benzyl; or R7’ and R7’’ are joined to form a 3-8 membered substituted or unsubstituted, saturated, unsaturated or aromatic, carbocyclic or heterocyclic ring (e.g., cyclopentyl, cyclohexyl, piperidine, tetrahydrofuran, tetrahydropyran, pyrrolidine); or R7’’’ and R7’’’’ are joined to form a 3-8 membered substituted or unsubstituted carbocyclic or heterocyclic ring (e.g., cyclopentyl, cyclohexyl, piperidine, tetrahydrofuran, tetrahydropyran, pyrrolidine); R20 is represented by the following structure:R is H, F, Cl, Br, I, OH, SH, COOH, CO(R10) (e.g., C(O)CH3), NH(R10), NH-CH2-cyclopropyl, N(R10)(R11), CF3, CN, NO2, C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, iPr, CH2-cyclopropyl, CH2-OH, CH2-CH2-OH, CH2-CH2-O-CH2-CH2-O-CH3, CH2-O-CH2-CH2- O-CH3), C3-C8substituted or unsubstituted cycloalkyl, cyclopropyl, substituted or unsubstituted C1-C5linear or branched alkoxy, (e.g., methoxy, ethoxy, O-(CH2CH3), OCHF2, O-(CH2)2-O-CH3, isopropoxy, O-(CH2)-cyclopropyl, O-CH2-methylcyclobutyl, O-CH2-3-methyloxetane, O-CH(CH3)-CH2-O-CH3) C1-C5linear or branched haloalkyl (e.g., CHF2, CF3, CF2CH3, CH2CF3,CF2CH2CH3,CH2CH2CF3,CF2CH(CH3)2,CF(CH3)-CH(CH3)2), R8-aryl (e.g., CH2-Ph), -R8-O-R8-O-R10(e.g. (CH2)2-O-(CH2)2-O- CH3), -R8-O-R10, O-R8-R10(e.g. O-(CH2)2-O-CH3, O-(CH2CH3), O-(CH2)-cyclopropyl), -R8-R10(e.g., (CH2)-cyclopropyl, (CH2)2-O-CH3, (CH2)-OH, (CH2)2-OH, (CH2)-COOH), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine); R30is H, R20, F, Cl, Br, I, OH, SH, alkoxy, N(R)2, NH(R10), N(R10)(R11), CF3, CN, NO2, C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH2-CH2-O-CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), C1-C5linear or branched alkoxy, C1-C5linear or branched haloalkyl (e.g., CHF2, CF3, CF2CH3, CH2CF3,CF2CH2CH3,CH2CH2CF3,CF2CH(CH3)2,CF(CH3)-CH(CH3)2), R8-aryl (e.g., CH2-Ph), -R8-O-R8-O-R10(e.g. (CH2)2-O-(CH2)2-O-CH3), -R8-O-R10, -R8-R10(e.g., (CH2)2-O- CH3), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine); each R8is independently [CH2]pwherein p is between 1 and 10 (e.g., 1, 2); R9is [CH]q, [C]qwherein q is between 2 and 10; R10and R11are each independently H, OH, COOH, C1-C5substituted or unsubstituted linear or branched alkyl (e.g., methyl, ethyl, CH2-cyclopropyl, CH2-CH2-O-CH3), C3-C8 substituted orunsubstituted cycloalkyl (e.g., cyclopropyl), C1-C5 substituted or unsubstituted linear or branched haloalky (e.g., CH2CF3), C1-C5 linear or branched alkoxy (e.g., O-CH3), R20, C(O)R, or S(O)2R; or R10 and R11 are joined to form a substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., piperazine, piperidine), n is an integer between 0 and 4 (e.g., 1, 2); or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, pharmaceutical product or any combination thereof.

[0033] In some embodiments, at least one of R7’, R7’’, R7’’’ and R7’’’’ is not H. In some embodiments, at least two of R7’, R7’’, R7’’’ and R7’’’’ are not H. In some embodiments, at least two of R7’, R7’’, R7’’’ and R7’’’’ are different then eachother. In some embodiments, at least two of R7’, R7’’, R7’’’ and R7’’’’ are not H and are different then eachother.

[0034] In some embodiments, at least one of X2, X3, and X4 is C(R). In some embodiments, X11 is N. In some embodiments, X12 is not S. In some embodiments, at least one of X2, X3, and X4 is C(R); X11 is N; or X12 is not S. In some embodiments, R is not H. In some embodiments, if R1 and R2 are joined to form a C=O, then at least one of X2, X3, X4, and X10 is not CH;

[0035] In various embodiments, this invention is directed to a compound represented by the structure of formula I(h):( ) X2, X3, and X4, are each independently CH, C(R) or N (e.g., C(CH3), C(O-CH2-cyclopropyl), C(O-CH2-methylcyclobutyl), C(NH-CH2-cyclopropyl), C(isopropoxy), C(O-CH(CH3)-CH2-O-CH3), C(CH2CH3), C-iPr, C-CH2-cyclopropyl, C(OCH3), C(OCH2CH3), C(O-(CH2)2-O-CH3, C(OCHF2), C(Cl), C(C(O)CH3), C(O-CH2CH2-O-CH3), C(OH)); X5, X6, X7, X8 and X9 are each independently nitrogen or carbon atoms;wherein if either one of X5, X6 , X8 and X9 is nitrogen, then the respective R7’, R7’’, R7’’’, and R7’’’’ substitution is absent; X10 is N, CH, C(R), or C=O; wherein if X10 is C=O then X11 is N (e.g., C(CH2-OH), C(CH2- CH2-OH), C(NH-CH2-cyclopropyl), C(COOH), C(CH3), C(cyclopropyl), C(isopropoxy)); X11 is N or C; wherein if X11 is N then X10 is C=O; X12 is S, SO2, O, NH, N(R), N-OH, CH=CH, CH=CH(R), C(R)=CH, N=CH, N=C(R), CH=N or C(R)=N (e.g., N-CH2-COOH, N-CH2-CH2-OH, N-CH3, N-CH2CH3, N-iPr, N-cyclopropyl, N-CH2- cyclopropyl); X13 is CH2, CH(R) (e.g., CH-CH3), C(R)2, or C=O; X14 is S, O, N or CH, wherein if X14 is CH then Ring F is not absent and if X14 is S or O then R3 is absent; Ring G is absent or is a substituted or unsubstituted 3-8 membered carbocyclic or heterocyclic ring (e.g., cyclobutane, cyclopentane, cyclohexane); Ring F is absent or is a substituted or unsubstituted, saturated or unsaturated, 3-8 membered heterocyclic or carbocyclic ring (e.g., pyrrolidine, 1-methylpyrrolidine, pyrrolidin-2-one, pyrrolidin-3- ol, morpholine, pyridine, piperidine, tetrahydrofurane, tetrahydrothiophene, cyclopropyl, oxetane, imidazole, pyrimidine, triazole, oxadiazole, pyrazole); R1 and R2 are each independently H, F, Cl, Br, I, OH, SH, or CF3, substituted or unsubstituted C1-C5alkyl, C1-C5linear or branched, or C3-C8cyclic haloalkyl, substituted or unsubstituted C1-C5linear or branched, or C3-C8cyclic alkoxy; or R1and R2are joined to form a C=O, or a 3-8 membered carbocyclic or heterocyclic ring (e.g., cyclopropyl); or R2and R4are joined to form Ring F as defined above (e.g., pyrrolidine, pyrrolidin-2-one, pyrrolidin-3-ol, morpholine, pyridine, pyrimidine, triazole, oxadiazole, pyrazole), wherein if Ring F is aromatic, then R1 and / or R3 are absent; R3and R4are each independently H, Me, substituted or unsubstituted C1-C5alkyl (e.g., methoxyethylene, methylaminoethyl, aminoethyl), -R8-O-R10(e.g., (CH2)2-O-CH3), R8-N(R10)(R11) (e.g., (CH2)2-NH(CH3)), substituted or unsubstituted C3-C8cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted 5-7 membered heterocyclic ring (e.g., pyrrolidine, methylpyrrolidine, piperidine), or R20;or R3and R4are joined to form a 3-8 membered heterocyclic ring (e.g., pyrrolidine, , pyrrolidone, 2-oxopyrrolidine, piperidine, morpholine, piperazine, imidazole); R7’, R7’’, R7’’’ and R7’’’’ are each independently H, F, Cl, Br, I, OH, O-R20, SH, R8-OH, R8- SH, -R8-O-R10, R8-(C3-C8cycloalkyl), R8-(3-8 membered heterocyclic ring), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, NH(R10), N(R10)(R11), R8-N(R10)(R11), R9-R8-N(R10)(R11), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R10, NHCO-N(R10)(R11), COOH, -C(O)Ph, C(O)O-R10, R8-C(O)-R10, C(O)H, C(O)-R10, C1-C5linear or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR, C(O)N(R10)(R11), SO2R, SO2N(R10)(R11), CH(CF3)(NH-R10), C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., isopropyl, methyl, ethyl), C1-C5linear or branched substituted or unsubstituted alkenyl, C1-C5linear or branched, or C3-C8 cyclic haloalkyl (e.g., CHF2), C1-C5 linear or branched, or C3-C8 cyclic alkoxy (e.g. methoxy), optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom, C1-C5 linear or branched thioalkoxy, C1-C5 linear or branched haloalkoxy, C1-C5 linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclohexyl), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., morpholine, pyran, oxetane, pyrrolidine, tetrahydrofuran, imidazole, piperazine, piperidine, dioxazole, 2-oxopyrrolidine), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted benzyl; or R7’ and R7’’ are joined to form a 3-8 membered substituted or unsubstituted, saturated, unsaturated or aromatic, carbocyclic or heterocyclic ring (e.g., cyclopentyl, cyclohexyl, piperidine, tetrahydrofuran, tetrahydropyran, pyrrolidine); or R7’’’ and R7’’’’ are joined to form a 3-8 membered substituted or unsubstituted carbocyclic or heterocyclic ring (e.g., cyclopentyl, cyclohexyl, piperidine, tetrahydrofuran, tetrahydropyran, pyrrolidine); R20 is represented by the following structure:R30is H, R20, F, Cl, Br, I, OH, SH, alkoxy, N(R)2, NH(R10), N(R10)(R11), CF3, CN, NO2, C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH2-CH2-O-CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), C1-C5linear or branched alkoxy, C1-C5linear or branched haloalkyl (e.g., CHF2, CF3, CF2CH3, CH2CF3,CF2CH2CH3,CH2CH2CF3,CF2CH(CH3)2,CF(CH3)-CH(CH3)2), R8-aryl (e.g., CH2-Ph), -R8-O-R8-O-R10(e.g. (CH2)2-O-(CH2)2-O-CH3), -R8-O-R10, -R8-R10(e.g., (CH2)2-O- CH3), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine); R50is H, R20, F, Cl, Br, I, OH, SH, N(R)2, NH(R10), N(R10)(R11), CF3, CN, NO2, C1-C5linear or branched, substituted or unsubstituted alkyl C1-C5linear or branched alkoxy, C1-C5linear or branched haloalkyl, -R8-R10(e.g., (CH2)2-O-CH3), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine); R is H, F, Cl, Br, I, OH, SH, COOH, CO(R10) (e.g., C(O)CH3), NH(R10), NH-CH2-cyclopropyl, N(R10)(R11), CF3, CN, NO2, C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, iPr, CH2-cyclopropyl, CH2-OH, CH2-CH2-OH, CH2-CH2-O-CH2-CH2-O-CH3, CH2-O-CH2-CH2- O-CH3), C3-C8substituted or unsubstituted cycloalkyl, cyclopropyl, substituted or unsubstituted C1-C5linear or branched alkoxy, (e.g., methoxy, ethoxy, O-(CH2CH3), OCHF2, O-(CH2)2-O-CH3, isopropoxy, O-(CH2)-cyclopropyl, O-CH2-methylcyclobutyl, O-CH2-3-methyloxetane, O-CH(CH3)-CH2-O-CH3) C1-C5linear or branched haloalkyl (e.g., CHF2, CF3, CF2CH3, CH2CF3,CF2CH2CH3,CH2CH2CF3,CF2CH(CH3)2,CF(CH3)-CH(CH3)2), R8-aryl (e.g., CH2-Ph), -R8-O-R8-O-R10(e.g. (CH2)2-O-(CH2)2-O- CH3), -R8-O-R10, O-R8-R10 (e.g. O-(CH2)2-O-CH3, O-(CH2CH3), O-(CH2)-cyclopropyl), -R8-R10 (e.g.,(CH2)-cyclopropyl, (CH2)2-O-CH3, (CH2)-OH, (CH2)2-OH, (CH2)-COOH), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine); each R8 is independently [CH2]p wherein p is between 1 and 10 (e.g., 1, 2); R9 is [CH]q, [C]q wherein q is between 2 and 10; R10 and R11 are each independently H, OH, COOH, C1-C5 substituted or unsubstituted linear or branched alkyl (e.g., methyl, ethyl, CH2-cyclopropyl, CH2-CH2-O-CH3), C3-C8 substituted or unsubstituted cycloalkyl (e.g., cyclopropyl), C1-C5 substituted or unsubstituted linear or branched haloalky (e.g., CH2CF3), C1-C5 linear or branched alkoxy (e.g., O-CH3), R20, C(O)R, or S(O)2R; or R10 and R11 are joined to form a substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., piperazine, piperidine), n is an integer between 0 and 4 (e.g., 1, 2); or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, pharmaceutical product or any combination thereof.

[0036] In some embodiments, at least one of R7’, R7’’, R7’’’ and R7’’’’ is not H. In some embodiments, at least two of R7’, R7’’, R7’’’ and R7’’’’ are not H. In some embodiments, at least two of R7’, R7’’, R7’’’ and R7’’’’ are different then eachother. In some embodiments, at least two of R7’, R7’’, R7’’’ and R7’’’’ are not H and are different then eachother.

[0037] In some embodiments, at least one of X2, X3, and X4is C(R). In some embodiments, X11is N. In some embodiments, X12is not S. In some embodiments, at least one of X2, X3, and X4is C(R); X11is N; or X12 is not S. In some embodiments, R is not H.

[0038] In various embodiments, this invention is directed to a compound represented by the structure of formula I(i):wherein X2, X3, and X4, are each independently CH, C(R) or N (e.g., C(CH3), C(O-CH2-cyclopropyl), C(O-CH2-methylcyclobutyl), C(NH-CH2-cyclopropyl), C(isopropoxy), C(O-CH(CH3)-CH2-O-CH3), C(CH2CH3), C-iPr, C-CH2-cyclopropyl, C(OCH3), C(OCH2CH3), C(O-(CH2)2-O-CH3, C(OCHF2), C(Cl), C(C(O)CH3), C(O-CH2CH2-O-CH3), C(OH)); X5, X6, X8and X9are each independently nitrogen or carbon atoms; wherein if either one of X5, X6, X8and X9is nitrogen, then the respective R7’, R7’’, R7’’’, and R7’’’’ substitution is absent; X10is N, CH, C(R), or C=O; wherein if X10is C=O then X11is N (e.g., C(CH2-OH), C(CH2- CH2-OH), C(NH-CH2-cyclopropyl), C(COOH), C(CH3), C(cyclopropyl), C(isopropoxy)); X11is N or C; wherein if X11is N then X10is C=O; X12is S, SO2, O, NH, N(R), N-OH, CH=CH, CH=CH(R), C(R)=CH, N=CH, N=C(R), CH=N or C(R)=N (e.g., N-CH2-COOH, N-CH2-CH2-OH, N-CH3, N-CH2CH3, N-iPr, N-cyclopropyl, N-CH2- cyclopropyl); R5is H or C1-C5linear or branched alkyl (e.g. methyl); R6is H, F, Cl, Br, I, OH, SH, R8-OH, R8-SH, -R8-O-R10(e.g., CH2-O-CH3, (CH2)2-O-CH3(CH2)3-O-CH3, (CH2)2-O-CH(CH3)2), R8-S-R10 (e.g., (CH2)3-S-(CH2)2CH3), R8-NHC(O)-R10, -O-R8- R10, R8-(substituted or unsubstituted C3-C8 cycloalkyl) (e.g., CH2-cyclopropyl, CH2-cyclobutanol, CH2- difluorocyclopropyl, CH2-methylcyclopropyl, CH2-dimethylamino-cyclohexyl, (CH2)2-cyclopentanole, CH2-cyclohexanol), R8-(substituted or unsubstituted, saturated, unsaturated or aromatic, single, fused or spiro 3-10 membered heterocyclic ring) (e.g., (CH2)3-piperidine, (CH2)3-4-fluoro-piperidine, (CH2)3- pyran, (CH2)2-pyrrazole, (CH2)2-imidazole, CH2-tetrahydrofurane, CH2-dioxane, CH2-oxetane, CH2- piperidine, CH2-triazole, CH2-1-oxa-8-azaspiro[4.5]decane, (CH2)3-diazabicyclo[2.2.1]heptane, CH2- methyl-THF, CH2-ethyl-piperidine, CH2-oxa-azaspirodecane, (CH2)3-dimethylpyrazole, CH2-2-oxo- methylpyrrolidine, CH2-methyl-azetidine, CH2-azaspiroheptane), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, NH(R10), N(R10)(R11), R8-N(R10)(R11) (e.g., (CH2)2-NH2, (CH2)3- N(CH2CH3)2, (CH2)3-N(CH(CH3)2) (CH ) i idi (CH ) 4 fluoro-piperidine, (CH2)3-4-cyano-piperidine, (CH2)4-NH(CH3), (CH2)3-NH-CH3, (CH2)3-NH-CH2CH3, (CH2)3-N(CH2CH3)2, (CH2)3-NH2, (CH2)3-N(CH2CH3)(CH2CF3)), R9-R8-N(R10)(R11) (e.g., (CH2)2-C(O)-piperidine), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R10, NHCO-N(R10)(R11), COOH, -C(O)Ph, C(O)O-R10, R8-C(O)-R10, C(O)H, C(O)- R10 (e.g., C(O)CH3), C1-C5 linear or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR, C(O)N(R10)(R11), SO2R, SO2N(R10)(R11), CH(CF3)(NH-R10), C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., CH(CH3)CH2OCH3, CH(CH3)CH2NH2, CH(CH3)C(O)N(CH3)2, CH2-CH(OH)Ph, (CH2)3N(H)CH2CH3, CH(CH3)(CH2)2OH, CH(CH2OH)(CH2CH3), (CH2)3-OCH3, (CH2)2-OCH3, (CH2)2-OCH(CH3)2, CH(CH2OH)(CH2CH(CH3)2), CH2CH(CH3)(OCH3), CH2CH(N(CH3)2)(CH2CH3), benzyl, methyl, ethyl, CH2-OCH2-CH2-O-CH3, CH(CH3)C(O)N(CH3)2), C1-C5 linear or branched, substituted or unsubstituted alkenyl, C1-C5 linear or branched, or C3-C8 cyclic haloalkyl, substituted or unsubstituted C1-C5 linear or branched, or C3-C8 cyclic alkoxy (e.g. methoxy, O-(CH2)2-O-CH3), optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom, C1-C5 linear or branched thioalkoxy, C1-C5 linear or branched haloalkoxy, C1-C5 linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclohexyl, methoxycyclopropyl, methylcyclobutyl, aminomethyl-cyclobutyl, methoxycyclobutyl, 2,3-dihydro-1H- indenol), R8-(substituted or unsubstituted C3-C8 cycloalkyl), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., piperidine, 1-methyl-piperidine, azetidine, pyrrolidine, pyrrolidinone, quinuclidine, tetrahydropyran, azaspiro[3.3]heptane, imidazole, trifluoromethyl-oxetane, hydroxy- tetrahydrofurane, azepan-2-one, azabicyclohexane), substituted or unsubstituted aryl, substituted or unsubstituted R8-aryl (e.g., benzyl), substituted or unsubstituted benzyl; or R6and R5are joined to for a substituted or unsubstituted 5-8 membered heterocyclic ring (e.g., azepane, piperazine, 2-(piperazin-1-yl)acetamide; or R6is represented by the structure of formula B or Bi:whereinm is 0 or 1; and R12 is R20 or C1-C5 C(O)-alkyl, and R13 is R30; or R12 and R13 are both H; R12 and R13 are each independently H or substituted or unsubstituted C1-C5 alkyl (e.g., ethyl, trifluoroethyl); R12 and C3 are joined to form ring A and R13 is R30; or R12 and R13 are joined to form ring B; or R12 and C1 are joined to form ring C and R13 is R30; or C1 and C3 are joined to form ring D and R12 and R13 are each independently R30; or R13 and C2 are joined to form ring E, m is 1, and R12 is R30; or R12 and R13 are joined to form ring B and C1 and C3 are joined to form ring D; wherein Ring A, C and E are each independently a substituted or unsubstituted single spiro or fused 3-8 membered heterocyclic ring (e.g., A: pyrrolidine, methylpyrrolidine, ethylpyrrolidine); C: piperidine, pyrrolidine, methyl-2-oxopyrrolidine, pyran- pyrrolidine, methyl-azetidine, azabicyclooctane, 2-azabicyclo[2.1.1]hexane, 2- azaspiro[3.3]heptane; E: pyrrolidine, azetidine, ethylpyrrolidine, oxopyrrolidine, methylpiperidine); Ring B is a substituted or unsubstituted single, spiro or fused 3-8 membered heterocyclic ring (B: piperidine, piperidin-2-one, 4-fluoropiperidin-2-one, piperidine- 4-carbonitrile, 4-fluoropiperidine, 4-fluoro-2-methylpiperidine, methyl-piperidin, fluoropiperidine, difluoropiperidine, pyrrolidine, piperazine, methylpyrrolidine, thiomorpholine 1,1-dioxide, 2-oxa-6-azaspiro[3.3]heptane, methyl-piperazine, dimethyl-pyrazole, imidazole, 2-methyl-2,5-diazabicyclo[2.2.1]heptane, hydroxymethyl-pyrrolidine, diazabicyclo[2.2.1]heptane, 6-fluoro-3- azabicyclo[3.1.1]heptane; and Ring D is a substituted or unsubstituted C3-C8cycloalkyl (e.g., cyclobutane, cyclohexane); R7, R7’, R7’’, R7’’’ and R7’’’’ are each independently H, F, Cl, Br, I, OH, O-R20, SH, R8-OH, R8-SH, -R8-O-R10, R8-(C3-C8cycloalkyl), R8-(3-8 membered heterocyclic ring), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, NH(R10), N(R10)(R11), R8-N(R10)(R11), R9-R8-N(R10)(R11), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R10, NHCO-N(R10)(R11), COOH, -C(O)Ph, C(O)O-R10, R8- C(O)-R10, C(O)H, C(O)-R10, C1-C5linear or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR, C(O)N(R10)(R11), SO2R, SO2N(R10)(R11), CH(CF3)(NH-R10), C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., isopropyl, methyl, ethyl), C1-C5linear or branched, substituted or unsubstituted alkenyl, C1-C5linear or branched, or C3-C8cyclic haloalkyl (e.g., CHF2), C1-C5linear or branched, or C3-C8cyclic alkoxy (e.g. methoxy), optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom C1-C5linear or branched thioalkoxy, C1-C5linear or branchedhaloalkoxy, C1-C5 linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclohexyl), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., morpholine, pyran, oxetane, pyrrolidine, tetrahydrofuran, imidazole, piperazine, piperidine, dioxazole, 2-oxopyrrolidine), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted benzyl; or R7’ and R7’’ are joined to form a 3-8 membered substituted or unsubstituted, saturated, unsaturated or aromatic, carbocyclic or heterocyclic ring (e.g., cyclopentyl, cyclohexyl, piperidine, tetrahydrofuran, tetrahydropyran, pyrrolidine); or R7’’ and R7 are joined to form a 3-8 membered substituted or unsubstituted carbocyclic or heterocyclic ring (e.g., cyclopentyl, cyclohexyl, piperidine, tetrahydrofuran, tetrahydropyran, pyrrolidine); or R7 and R7’’’ are joined to form a 3-8 membered substituted or unsubstituted carbocyclic or heterocyclic ring (e.g., cyclopentyl, cyclohexyl, piperidine, tetrahydrofuran, tetrahydropyran, pyrrolidine); or R7’’’ and R7’’’’ are joined to form a 3-8 membered substituted or unsubstituted carbocyclic or heterocyclic ring (e.g., cyclopentyl, cyclohexyl, piperidine, tetrahydrofuran, tetrahydropyran, pyrrolidine); R20 is represented by the following structure:R is H, F, Cl, Br, I, OH, SH, COOH, CO(R10) (e.g., C(O)CH3), NH(R10), NH-CH2-cyclopropyl, N(R10)(R11), CF3, CN, NO2, C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, iPr, CH2-cyclopropyl, CH2-OH, CH2-CH2-OH, CH2-CH2-O-CH2-CH2-O-CH3, CH2-O-CH2-CH2- O-CH3), C3-C8substituted or unsubstituted cycloalkyl, cyclopropyl, substituted or unsubstituted C1-C5linear or branched alkoxy, (e.g., methoxy, ethoxy, O-(CH2CH3), OCHF2, O-(CH2)2-O-CH3, isopropoxy, O-(CH2)-cyclopropyl, O-CH2-methylcyclobutyl, O-CH2-3-methyloxetane, O-CH(CH3)-CH2-O-CH3) C1-C5linear or branched haloalkyl (e.g., CHF2, CF3, CF2CH3, CH2CF3,CF2CH2CH3,CH2CH2CF3,CF2CH(CH3)2,CF(CH3)-CH(CH3)2), R8-aryl (e.g., CH2-Ph), -R8-O-R8-O-R10(e.g. (CH2)2-O-(CH2)2-O- CH3), -R8-O-R10, O-R8-R10(e.g. O-(CH2)2-O-CH3, O-(CH2CH3), O-(CH2)-cyclopropyl), -R8-R10(e.g., (CH2)-cyclopropyl, (CH2)2-O-CH3, (CH2)-OH, (CH2)2-OH, (CH2)-COOH), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine); R30is H, R20, F, Cl, Br, I, OH, SH, alkoxy, N(R)2, NH(R10), N(R10)(R11), CF3, CN, NO2, C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH2-CH2-O-CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), C1-C5linear or branched alkoxy, C1-C5linear or branched haloalkyl (e.g., CHF2, CF3, CF2CH3, CH2CF3,CF2CH2CH3,CH2CH2CF3,CF2CH(CH3)2,CF(CH3)-CH(CH3)2), R8-aryl (e.g., CH2-Ph), -R8-O-R8-O-R10(e.g. (CH2)2-O-(CH2)2-O-CH3), -R8-O-R10, -R8-R10(e.g., (CH2)2-O- CH3), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine);R50 is H, R20, F, Cl, Br, I, OH, SH, N(R)2, NH(R10), N(R10)(R11), CF3, CN, NO2, C1-C5 linear or branched, substituted or unsubstituted alkyl C1-C5 linear or branched alkoxy, C1-C5 linear or branched haloalkyl, -R8-R10 (e.g., (CH2)2-O-CH3), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine); R is H, F, Cl, Br, I, OH, SH, COOH, CO(R10) (e.g., C(O)CH3), NH(R10), NH-CH2-cyclopropyl, N(R10)(R11), CF3, CN, NO2, C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, iPr, CH2-cyclopropyl, CH2-OH, CH2-CH2-OH, CH2-CH2-O-CH2-CH2-O-CH3, CH2-O-CH2-CH2- O-CH3), C3-C8 substituted or unsubstituted cycloalkyl, cyclopropyl, substituted or unsubstituted C1-C5 linear or branched alkoxy, (e.g., methoxy, ethoxy, O-(CH2CH3), OCHF2, O-(CH2)2-O-CH3, isopropoxy, O-(CH2)-cyclopropyl, O-CH2-methylcyclobutyl, O-CH2-3-methyloxetane, O-CH(CH3)-CH2-O-CH3) C1-C5 linear or branched haloalkyl (e.g., CHF2, CF3, CF2CH3, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2,CF(CH3)-CH(CH3)2), R8-aryl (e.g., CH2-Ph), -R8-O-R8-O-R10 (e.g. (CH2)2-O-(CH2)2-O- CH3), -R8-O-R10, O-R8-R10 (e.g. O-(CH2)2-O-CH3, O-(CH2CH3), O-(CH2)-cyclopropyl), -R8-R10 (e.g., (CH2)-cyclopropyl, (CH2)2-O-CH3, (CH2)-OH, (CH2)2-OH, (CH2)-COOH), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine); each R8 is independently [CH2]p wherein p is between 1 and 10 (e.g., 1, 2); R9 is [CH]q, [C]q wherein q is between 2 and 10; R10and R11are each independently H, OH, COOH, C1-C5substituted or unsubstituted linear or branched alkyl (e.g., methyl, ethyl, CH2-cyclopropyl, CH2-CH2-O-CH3), C3-C8substituted or unsubstituted cycloalkyl (e.g., cyclopropyl), C1-C5substituted or unsubstituted linear or branched haloalky (e.g., CH2CF3), C1-C5linear or branched alkoxy (e.g., O-CH3), R20, C(O)R, or S(O)2R; or R10 and R11 are joined to form a substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., piperazine, piperidine), n is an integer between 0 and 4 (e.g., 1, 2); or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, pharmaceutical product or any combination thereof.

[0039] In some embodiments, at least one of R7, R7’, R7’’, R7’’’ and R7’’’’ is not H. In some embodiments, at least two of R7, R7’, R7’’, R7’’’ and R7’’’’ are not H. In some embodiments, at least one of R7’, R7’’, R7’’’ and R7’’’’ is not H. In some embodiments, at least two of R7’, R7’’, R7’’’ and R7’’’’ are not H. In some embodiments, at least two of R7’, R7’’, R7’’’ and R7’’’’ are different then eachother. In some embodiments, at least two of R7’, R7’’, R7’’’ and R7’’’’ are not H and are different then eachother.

[0040] In some embodiments, at least one of X2, X3, and X4is C(R). In some embodiments, R is not H.

[0041] In various embodiments, this invention is directed to a compound represented by the structure of formula I(j):wherein X2, X3, and X4, are each independently CH, C(R) or N (e.g., C(CH3), C(O-CH2-cyclopropyl), C(O-CH2-methylcyclobutyl), C(NH-CH2-cyclopropyl), C(isopropoxy), C(O-CH(CH3)-CH2-O-CH3), C(CH2CH3), C-iPr, C-CH2-cyclopropyl, C(OCH3), C(OCH2CH3), C(O-(CH2)2-O-CH3, C(OCHF2), C(Cl), C(C(O)CH3), C(O-CH2CH2-O-CH3), C(OH)); X5, X6, X7, X8and X9are each independently nitrogen or carbon atoms; wherein if either one of X5, X6 , X7, X8 and X9 is nitrogen, then the respective R7’, R7’’, R7, R7’’’, and R7’’’’ substitution is absent; X10 is nitrogen, carbon, CH or C(R) (e.g., C(CH2-OH), C(CH2-CH2-OH), C(NH-CH2- cyclopropyl), C(COOH), C(CH3), C(cyclopropyl), C(isopropoxy)); X11is N or C; wherein if X11is N then X10is C=O; X12is S, SO2, O, NH, N(R), N-OH, CH=CH, CH=CH(R), C(R)=CH, N=CH, N=C(R), CH=N or C(R)=N (e.g., N-CH2-COOH, N-CH2-CH2-OH, N-CH3, N-CH2CH3, N-iPr, N-cyclopropyl, N-CH2- cyclopropyl); R5 is H or C1-C5 linear or branched alkyl (e.g. methyl); R6 is H, F, Cl, Br, I, OH, SH, R8-OH, R8-SH, -R8-O-R10 (e.g., CH2-O-CH3, (CH2)2-O-CH3 (CH2)3-O-CH3, (CH2)2-O-CH(CH3)2), R8-S-R10 (e.g., (CH2)3-S-(CH2)2CH3), R8-NHC(O)-R10, -O-R8- R10, R8-(substituted or unsubstituted C3-C8 cycloalkyl) (e.g., CH2-cyclopropyl, CH2-cyclobutanol, CH2- difluorocyclopropyl, CH2-methylcyclopropyl, CH2-dimethylamino-cyclohexyl, (CH2)2-cyclopentanole, CH2-cyclohexanol), R8-(substituted or unsubstituted, saturated, unsaturated or aromatic, single, fused or spiro 3-10 membered heterocyclic ring) (e.g., (CH2)3-piperidine, (CH2)3-4-fluoro-piperidine, (CH2)3- pyran, (CH2)2-pyrrazole, (CH2)2-imidazole, CH2-tetrahydrofurane, CH2-dioxane, CH2-oxetane, CH2- piperidine, CH2-triazole, CH2-1-oxa-8-azaspiro[4.5]decane, (CH2)3-diazabicyclo[2.2.1]heptane, CH2- methyl-THF, CH2-ethyl-piperidine, CH2-oxa-azaspirodecane, (CH2)3-dimethylpyrazole, CH2-2-oxo- methylpyrrolidine, CH2-methyl-azetidine, CH2-azaspiroheptane), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, NH(R10), N(R10)(R11), R8-N(R10)(R11) (e.g., (CH2)2-NH2, (CH2)3- N(CH2CH3)2, (CH2)3-N(CH(CH3)2)2, (CH2)3-piperidine, (CH2)3-4-fluoro-piperidine, (CH2)3-4-cyano- piperidine, (CH2)4-NH(CH3), (CH2) CH2)3-N(CH2CH3)2, (CH2)3-NH2,(CH2)3-N(CH2CH3)(CH2CF3)), R9-R8-N(R10)(R11) (e.g., (CH2)2-C(O)-piperidine), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R10, NHCO-N(R10)(R11), COOH, -C(O)Ph, C(O)O-R10, R8-C(O)-R10, C(O)H, C(O)- R10 (e.g., C(O)CH3), C1-C5 linear or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR, C(O)N(R10)(R11), SO2R, SO2N(R10)(R11), CH(CF3)(NH-R10), C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., CH(CH3)CH2OCH3, CH(CH3)CH2NH2, CH(CH3)C(O)N(CH3)2, CH2-CH(OH)Ph, (CH2)3N(H)CH2CH3, CH(CH3)(CH2)2OH, CH(CH2OH)(CH2CH3), (CH2)3-OCH3, (CH2)2-OCH3, (CH2)2-OCH(CH3)2, CH(CH2OH)(CH2CH(CH3)2), CH2CH(CH3)(OCH3), CH2CH(N(CH3)2)(CH2CH3), benzyl, methyl, ethyl, CH2-OCH2-CH2-O-CH3, CH(CH3)C(O)N(CH3)2), C1-C5 linear or branched, substituted or unsubstituted alkenyl, C1-C5 linear or branched, or C3-C8 cyclic haloalkyl, substituted or unsubstituted C1-C5 linear or branched, or C3-C8 cyclic alkoxy (e.g. methoxy, O-(CH2)2-O-CH3), optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom, C1-C5 linear or branched thioalkoxy, C1-C5 linear or branched haloalkoxy, C1-C5 linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclohexyl, methoxycyclopropyl, methylcyclobutyl, aminomethyl-cyclobutyl, methoxycyclobutyl, 2,3-dihydro-1H- indenol), R8-(substituted or unsubstituted C3-C8 cycloalkyl), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., piperidine, 1-methyl-piperidine, azetidine, pyrrolidine, pyrrolidinone, quinuclidine, tetrahydropyran, azaspiro[3.3]heptane, imidazole, trifluoromethyl-oxetane, hydroxy- tetrahydrofurane, azepan-2-one, azabicyclohexane), substituted or unsubstituted aryl, substituted or unsubstituted R8-aryl (e.g., benzyl), substituted or unsubstituted benzyl; or R6and R5are joined to form a substituted or unsubstituted saturated, unsaturated or aromatic, single, fused or spiro 5-8 membered heterocyclic ring (e.g., azepane, piperazine, 2-(piperazin-1- yl)acetamide; or R6is represented by the structure of formula B or Bi:whereinm is 0 or 1; and R12 is R20 or C1-C5 C(O)-alkyl, and R13 is R30; or R12 and R13 are both H; R12 and R13 are each independently H or substituted or unsubstituted C1-C5 alkyl (e.g., ethyl, trifluoroethyl); R12 and C3 are joined to form ring A and R13 is R30; or R12 and R13 are joined to form ring B; or R12 and C1 are joined to form ring C and R13 is R30; or C1 and C3 are joined to form ring D and R12 and R13 are each independently R30; or R13 and C2 are joined to form ring E, m is 1, and R12 is R30; or R12 and R13 are joined to form ring B and C1 and C3 are joined to form ring D; wherein Ring A, C and E are each independently a substituted or unsubstituted single spiro or fused 3-8 membered heterocyclic ring (e.g., A: pyrrolidine, methylpyrrolidine, ethylpyrrolidine); C: piperidine, pyrrolidine, methyl-2-oxopyrrolidine, pyran- pyrrolidine, methyl-azetidine, azabicyclooctane, 2-azabicyclo[2.1.1]hexane, 2- azaspiro[3.3]heptane; E: pyrrolidine, azetidine, ethylpyrrolidine, oxopyrrolidine, methylpiperidine); Ring B is a substituted or unsubstituted single, spiro or fused 3-8 membered heterocyclic ring (B: piperidine, piperidin-2-one, 4-fluoropiperidin-2-one, piperidine- 4-carbonitrile, 4-fluoropiperidine, 4-fluoro-2-methylpiperidine, methyl-piperidin, fluoropiperidine, difluoropiperidine, pyrrolidine, piperazine, methylpyrrolidine, thiomorpholine 1,1-dioxide, 2-oxa-6-azaspiro[3.3]heptane, methyl-piperazine, dimethyl-pyrazole, imidazole, 2-methyl-2,5-diazabicyclo[2.2.1]heptane, hydroxymethyl-pyrrolidine, diazabicyclo[2.2.1]heptane, 6-fluoro-3- azabicyclo[3.1.1]heptane; and Ring D is a substituted or unsubstituted C3-C8cycloalkyl (e.g., cyclobutane, cyclohexane); R7, R7’, R7’’, R7’’’ and R7’’’’ are each independently H, F, Cl, Br, I, OH, O-R20, SH, R8-OH, R8-SH, -R8-O-R10, R8-(C3-C8cycloalkyl), R8-(3-8 membered heterocyclic ring), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, NH(R10), N(R10)(R11), R8-N(R10)(R11), R9-R8-N(R10)(R11), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R10, NHCO-N(R10)(R11), COOH, -C(O)Ph, C(O)O-R10, R8- C(O)-R10, C(O)H, C(O)-R10, C1-C5linear or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR, C(O)N(R10)(R11), SO2R, SO2N(R10)(R11), CH(CF3)(NH-R10), C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., isopropyl, methyl, ethyl), C1-C5linear or branched, substituted or unsubstituted alkenyl, C1-C5linear or branched, or C3-C8cyclic haloalkyl (e.g., CHF2), C1-C5linear or branched, or C3-C8cyclic alkoxy (e.g. methoxy), optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom C1-C5linear or branched thioalkoxy, C1-C5linear or branchedhaloalkoxy, C1-C5 linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclohexyl), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., morpholine, pyran, oxetane, pyrrolidine, tetrahydrofuran, imidazole, piperazine, piperidine, dioxazole, 2-oxopyrrolidine), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted benzyl; or R7’ and R7’’ are joined to form a 3-8 membered substituted or unsubstituted, saturated, unsaturated or aromatic, carbocyclic or heterocyclic ring (e.g., cyclopentyl, cyclohexyl, piperidine, tetrahydrofuran, tetrahydropyran, pyrrolidine); or R7’’ and R7 are joined to form a 3-8 membered substituted or unsubstituted carbocyclic or heterocyclic ring (e.g., cyclopentyl, cyclohexyl, piperidine, tetrahydrofuran, tetrahydropyran, pyrrolidine); or R7 and R7’’’ are joined to form a 3-8 membered substituted or unsubstituted carbocyclic or heterocyclic ring (e.g., cyclopentyl, cyclohexyl, piperidine, tetrahydrofuran, tetrahydropyran, pyrrolidine); or R7’’’ and R7’’’’ are joined to form a 3-8 membered substituted or unsubstituted carbocyclic or heterocyclic ring (e.g., cyclopentyl, cyclohexyl, piperidine, tetrahydrofuran, tetrahydropyran, pyrrolidine); R20 is represented by the following structure:R is H, F, Cl, Br, I, OH, SH, COOH, CO(R10) (e.g., C(O)CH3), NH(R10), NH-CH2-cyclopropyl, N(R10)(R11), CF3, CN, NO2, C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, iPr, CH2-cyclopropyl, CH2-OH, CH2-CH2-OH, CH2-CH2-O-CH2-CH2-O-CH3, CH2-O-CH2-CH2- O-CH3), C3-C8substituted or unsubstituted cycloalkyl, cyclopropyl, substituted or unsubstituted C1-C5linear or branched alkoxy, (e.g., methoxy, ethoxy, O-(CH2CH3), OCHF2, O-(CH2)2-O-CH3, isopropoxy, O-(CH2)-cyclopropyl, O-CH2-methylcyclobutyl, O-CH2-3-methyloxetane, O-CH(CH3)-CH2-O-CH3) C1-C5linear or branched haloalkyl (e.g., CHF2, CF3, CF2CH3, CH2CF3,CF2CH2CH3,CH2CH2CF3,CF2CH(CH3)2,CF(CH3)-CH(CH3)2), R8-aryl (e.g., CH2-Ph), -R8-O-R8-O-R10(e.g. (CH2)2-O-(CH2)2-O- CH3), -R8-O-R10, O-R8-R10(e.g. O-(CH2)2-O-CH3, O-(CH2CH3), O-(CH2)-cyclopropyl), -R8-R10(e.g., (CH2)-cyclopropyl, (CH2)2-O-CH3, (CH2)-OH, (CH2)2-OH, (CH2)-COOH), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine); R30is H, R20, F, Cl, Br, I, OH, SH, alkoxy, N(R)2, NH(R10), N(R10)(R11), CF3, CN, NO2, C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH2-CH2-O-CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), C1-C5linear or branched alkoxy, C1-C5linear or branched haloalkyl (e.g., CHF2, CF3, CF2CH3, CH2CF3,CF2CH2CH3,CH2CH2CF3,CF2CH(CH3)2,CF(CH3)-CH(CH3)2), R8-aryl (e.g., CH2-Ph), -R8-O-R8-O-R10(e.g. (CH2)2-O-(CH2)2-O-CH3), -R8-O-R10, -R8-R10(e.g., (CH2)2-O- CH3), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine);each R8 is independently [CH2]p wherein p is between 1 and 10 (e.g., 1, 2); R9 is [CH]q, [C]q wherein q is between 2 and 10; R10 and R11 are each independently H, OH, COOH, C1-C5 substituted or unsubstituted linear or branched alkyl (e.g., methyl, ethyl, CH2-cyclopropyl, CH2-CH2-O-CH3), C3-C8 substituted or unsubstituted cycloalkyl (e.g., cyclopropyl), C1-C5 substituted or unsubstituted linear or branched haloalky (e.g., CH2CF3), C1-C5 linear or branched alkoxy (e.g., O-CH3), R20, C(O)R, or S(O)2R; or R10 and R11 are joined to form a substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., piperazine, piperidine), n is an integer between 0 and 4 (e.g., 1, 2); or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, pharmaceutical product or any combination thereof.

[0042] In some embodiments, at least one of R7, R7’, R7’’, R7’’’ and R7’’’’ is not H. In some embodiments, at least two of R7, R7’, R7’’, R7’’’ and R7’’’’ are not H. In some embodiments, at least one of R7’, R7’’, R7’’’ and R7’’’’ is not H. In some embodiments, at least two of R7’, R7’’, R7’’’ and R7’’’’ are not H. In some embodiments, at least two of R7’, R7’’, R7’’’ and R7’’’’ are different than eachother. In some embodiments, at least two of R7’, R7’’, R7’’’ and R7’’’’ are not H and are different than eachother.

[0043] In some embodiments, at least one of X2, X3, and X4is C(R). In some embodiments, X11is N. In some embodiments, X12is not S. In some embodiments, at least one of X2, X3, and X4is C(R); X11is N; or X12is not S. In some embodiments, R is not H.

[0044] In various embodiments, this invention is directed to a compound represented by the structure of formula I(k):I(k) wherein Ring W may be either aromatic or non-aromatic ring, wherein if ring W is aromatic then X2, X3, and X4, are each independently CH, C(R) or N (e.g., C(CH3), C(O- CH2-cyclopropyl), C(O-CH2-methylcyclobutyl), C(NH-CH2-cyclopropyl), C(isopropoxy), C(O-CH(CH3)-CH2-O-CH3), C(CH2CH3), C-iPr, C-CH2-cyclopropyl, C(OCH3), C(OCH2CH3), C(O-(CH2)2-O-CH3, C(OCHF2), C(Cl), C(C(O)CH3), C(O- CH2CH2-O-CH3), C(OH)); X15 is C; wherein if ring W is non-aromatic then X2, X3, and X4, are each independently CH2, CH(R), C(R)2, NH, N(R), O, S, S=O or SO2 (e.g., CH2); X15 is CH, C(R) or N (e.g., CH, N); X5, X6 , X7, X8 and X9 are each independently nitrogen or carbon atoms; wherein if either one of X5, X6, X7, X8 and X9 is nitrogen, then the respective R7’, R7’’, R7, R7’’’, and R7’’’’ substitution is absent; X10 is N, CH, C(R), or C=O; wherein if X10 is C=O then X11 is N (e.g., C(CH2-OH), C(CH2- CH2-OH), C(NH-CH2-cyclopropyl), C(COOH), C(CH3), C(cyclopropyl), C(isopropoxy)); X11is N or C; wherein if X11is N then X10is C=O; Ring W’ may be either aromatic or non-aromatic ring, wherein if ring W’ is aromatic then X12is S, SO2, O, NH, N(R), N-OH, CH=CH, CH=CH(R), C(R)=CH, N=CH, N=C(R), CH=N or C(R)=N (e.g., N-CH2-COOH, N-CH2-CH2-OH, N-CH3, N-CH2CH3, N-iPr, N-cyclopropyl, N-CH2-cyclopropyl); wherein if ring W’ is non-aromatic then X12is CH=CH, CH=CH(R), C(R)=CH, OCH2, CH2O, SCH2, CH2S, CH=N, C(R)=N, N=CH, N=C(R); R5is H or C1-C5linear or branched alkyl (e.g. methyl); R6is H, F, Cl, Br, I, OH, SH, R8-OH, R8-SH, -R8-O-R10(e.g., CH2-O-CH3, (CH2)2-O-CH3(CH2)3-O-CH3, (CH2)2-O-CH(CH3)2), R8-S-R10(e.g., (CH2)3-S-(CH2)2CH3), R8-NHC(O)-R10, -O-R8- R10, R8-(substituted or unsubstituted C3-C8cycloalkyl) (e.g., CH2-cyclopropyl, CH2-cyclobutanol, CH2- difluorocyclopropyl, CH2-methylcyclopropyl, CH2-dimethylamino-cyclohexyl, (CH2)2-cyclopentanole, CH2-cyclohexanol), R8-(substituted or unsubstituted, saturated, unsaturated or aromatic, single, fused or spiro 3-10 membered heterocyclic ring) (e.g., (CH2)3-piperidine, (CH2)3-4-fluoro-piperidine, (CH2)3- pyran, (CH2)2-pyrrazole, (CH2)2-imidazole, CH2-tetrahydrofurane, CH2-dioxane, CH2-oxetane, CH2- piperidine, CH2-triazole, CH2-1-oxa-8-azaspiro[4.5]decane, (CH2)3-diazabicyclo[2.2.1]heptane, CH2- methyl-THF, CH2-ethyl-piperidine CH2-oxa-azaspirodecane (CH2)3-dimethylpyrazole, CH2-2-oxo-methylpyrrolidine, CH2-methyl-azetidine, CH2-azaspiroheptane), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, NH(R10), N(R10)(R11), R8-N(R10)(R11) (e.g., (CH2)2-NH2, (CH2)3- N(CH2CH3)2, (CH2)3-N(CH(CH3)2)2, (CH2)3-piperidine, (CH2)3-4-fluoro-piperidine, (CH2)3-4-cyano- piperidine, (CH2)4-NH(CH3), (CH2)3-NH-CH3, (CH2)3-NH-CH2CH3, (CH2)3-N(CH2CH3)2, (CH2)3-NH2, (CH2)3-N(CH2CH3)(CH2CF3)), R9-R8-N(R10)(R11) (e.g., (CH2)2-C(O)-piperidine), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R10, NHCO-N(R10)(R11), COOH, -C(O)Ph, C(O)O-R10, R8-C(O)-R10, C(O)H, C(O)- R10 (e.g., C(O)CH3), C1-C5 linear or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR, C(O)N(R10)(R11), SO2R, SO2N(R10)(R11), CH(CF3)(NH-R10), C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., CH(CH3)CH2OCH3, CH(CH3)CH2NH2, CH(CH3)C(O)N(CH3)2, CH2-CH(OH)Ph, (CH2)3N(H)CH2CH3, CH(CH3)(CH2)2OH, CH(CH2OH)(CH2CH3), (CH2)3-OCH3, (CH2)2-OCH3, (CH2)2-OCH(CH3)2, CH(CH2OH)(CH2CH(CH3)2), CH2CH(CH3)(OCH3), CH2CH(N(CH3)2)(CH2CH3), benzyl, methyl, ethyl, CH2-OCH2-CH2-O-CH3, CH(CH3)C(O)N(CH3)2), C1-C5 linear or branched, substituted or unsubstituted alkenyl, C1-C5 linear or branched, or C3-C8 cyclic haloalkyl, substituted or unsubstituted C1-C5 linear or branched, or C3-C8 cyclic alkoxy (e.g. methoxy, O-(CH2)2-O-CH3), optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom, C1-C5 linear or branched thioalkoxy, C1-C5 linear or branched haloalkoxy, C1-C5 linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclohexyl, methoxycyclopropyl, methylcyclobutyl, aminomethyl-cyclobutyl, methoxycyclobutyl, 2,3-dihydro-1H- indenol), R8-(substituted or unsubstituted C3-C8cycloalkyl), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., piperidine, 1-methyl-piperidine, azetidine, pyrrolidine, pyrrolidinone, quinuclidine, tetrahydropyran, azaspiro[3.3]heptane, imidazole, trifluoromethyl-oxetane, hydroxy- tetrahydrofurane, azepan-2-one, azabicyclohexane), substituted or unsubstituted aryl, substituted or unsubstituted R8-aryl (e.g., benzyl), substituted or unsubstituted benzyl; or R6 and R5 are joined to for a substituted or unsubstituted 5-8 membered heterocyclic ring (e.g., azepane, piperazine, 2-(piperazin-1-yl)acetamide; or R6is represented by the structure of formula B or Bi:Bi wherein m is 0 or 1; and R12 is R20 or C1-C5 C(O)-alkyl, and R13 is R30; or R12 and R13 are both H; R12 and R13 are each independently H or substituted or unsubstituted C1-C5 alkyl (e.g., ethyl, trifluoroethyl); R12 and C3 are joined to form ring A and R13 is R30; or R12 and R13 are joined to form ring B; or R12 and C1 are joined to form ring C and R13 is R30; or C1 and C3 are joined to form ring D and R12 and R13 are each independently R30; or R13 and C2 are joined to form ring E, m is 1, and R12 is R30; or R12 and R13 are joined to form ring B and C1 and C3 are joined to form ring D; wherein Ring A, C and E are each independently a substituted or unsubstituted single spiro or fused 3-8 membered heterocyclic ring (e.g., A: pyrrolidine, methylpyrrolidine, ethylpyrrolidine); C: piperidine, pyrrolidine, methyl-2-oxopyrrolidine, pyran- pyrrolidine, methyl-azetidine, azabicyclooctane, 2-azabicyclo[2.1.1]hexane, 2- azaspiro[3.3]heptane; E: pyrrolidine, azetidine, ethylpyrrolidine, oxopyrrolidine, methylpiperidine); Ring B is a substituted or unsubstituted single, spiro or fused 3-8 membered heterocyclic ring (B: piperidine, piperidin-2-one, 4-fluoropiperidin-2-one, piperidine- 4-carbonitrile, 4-fluoropiperidine, 4-fluoro-2-methylpiperidine, methyl-piperidin, fluoropiperidine, difluoropiperidine, pyrrolidine, piperazine, methylpyrrolidine, thiomorpholine 1,1-dioxide, 2-oxa-6-azaspiro[3.3]heptane, methyl-piperazine, dimethyl-pyrazole, imidazole, 2-methyl-2,5-diazabicyclo[2.2.1]heptane, hydroxymethyl-pyrrolidine, diazabicyclo[2.2.1]heptane, 6-fluoro-3- azabicyclo[3.1.1]heptane; and Ring D is a substituted or unsubstituted C3-C8cycloalkyl (e.g., cyclobutane, cyclohexane); R7is H, F, Cl, Br, I, OH, O-R20, SH, R8-OH, R8-SH, SR10, -R8-O-R10, -R8-S-R10, R8-(C3-C8cycloalkyl), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, NH(R10), N(R10)(R11), R8- N(R10)(R11), R9-R8-N(R10)(R11), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R10, NHCO-N(R10)(R11), COOH, -C(O)Ph, C(O)O-R10, R8-C(O)-R10, C(O)H, C(O)-R10, C1-C5linear or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR (e.g., C(O)NH(CH3)), C(O)N(R10)(R11) (e.g., C(O)NH(CH3), C(O)NH(CH2CH2OCH3), C(O)NH(CH2CH2OH)), SO2R, SO2N(R10)(R11), CH(CF3)(NH-R10), C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., methylimidazole, methyl, ethyl), C1-C5linear or branched, substituted or unsubstituted alkenyl C1-C5linear or branched, or C3-C8cyclic haloalkyl(e.g., CHF2), C1-C5 linear or branched, or C3-C8 cyclic alkoxy (e.g. methoxy, ethoxy), optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom, C1-C5 linear or branched thioalkyl, C1-C5 linear or branched thioalkoxy, C1-C5 linear or branched haloalkoxy, C1-C5 linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclopropanol, cyclohexyl), substituted or unsubstituted 4-7 membered heterocyclic ring (e.g., morpholine (e.g., 2 or 3-morpholine), tetrahydrofuran, tetrahydropyran, oxetane, oxetan-3-ol, pyrrolidine, pyrrolidine-3-ol, 1-methylpyrrolidine, pyrrolidin-2-one, pyrrolidinone, imidazole, pyrazole, piperazine, piperidine, piperidine-4-ol, piperidine-4-carbonitrile, 4-fluoropiperidine, oxadiazole, triazole, 2-oxopyrrolidine, pyridine, 1-methylpyridine), R8-(substituted or unsubstituted single, fused or spiro 3-8 membered heterocyclic ring), substituted or unsubstituted aryl, substituted or unsubstituted benzyl; or R7 is represented by the structure of formula A:wherein X1is N or O; R1and R2are each independently H, F, Cl, Br, I, OH, SH, or CF3, substituted or unsubstituted C1-C5alkyl, C1-C5linear or branched, or C3-C8cyclic haloalkyl, substituted or unsubstituted C1-C5linear or branched, or C3-C8cyclic alkoxy; R1and R2are joined to form =O or a C3-C8carbocyclic or heterocyclic ring (e.g., cyclopropyl); R3and R4are each independently H, Me, substituted or unsubstituted C1-C5alkyl (e.g., methoxyethylene, methylaminoethyl, aminoethyl), -R8-O-R10(e.g., (CH2)2-O-CH3), R8- N(R10)(R11) (e.g., (CH2)2-NH(CH3)), substituted or unsubstituted C3-C8cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted 5-7 membered heterocyclic ring (e.g., pyrrolidine, methylpyrrolidine, piperidine), or R20; R3 and R4 are joined to form a 3-8 membered heterocyclic ring (e.g., pyrrolidine, 2- oxopyrrolidine, piperidine, morpholine, piperazine, imidazole); or R2 and R4 are joined to form a substituted or unsubstituted, saturated or unsaturated, 3-8 membered heterocyclic or carbocyclic ring (e.g., pyrrolidine, 1-methylpyrrolidine, pyrrolidin-2-one, pyridine, piperidine, tetrahydrofurane, tetrahydrothiophene, cyclopropyl, oxetane, imidazole, pyrimidine, triazole, oxadiazole, pyrazole), wherein if the ring is aromatic, then R1 and / or R3 are absent; wherein if X1 is O then R4 is absent;R7’, R7’’, R7’’’ and R7’’’’ are each independently H, F, Cl, Br, I, OH, O-R20, SH, R8-OH, R8- SH, -R8-O-R10, R8-(C3-C8 cycloalkyl), R8-(3-8 membered heterocyclic ring), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, NH(R10), N(R10)(R11), R8-N(R10)(R11), R9-R8-N(R10)(R11), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R10, NHCO-N(R10)(R11), COOH, -C(O)Ph, C(O)O-R10, R8-C(O)-R10, C(O)H, C(O)-R10, C1-C5 linear or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR, C(O)N(R10)(R11), SO2R, SO2N(R10)(R11), CH(CF3)(NH-R10), C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., isopropyl, methyl, ethyl), C1-C5 linear or branched, substituted or unsubstituted alkenyl, C1-C5 linear or branched, or C3-C8 cyclic haloalkyl (e.g., CHF2), C1-C5 linear or branched, or C3-C8 cyclic alkoxy (e.g. methoxy), optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom, C1-C5 linear or branched thioalkoxy, C1-C5 linear or branched haloalkoxy, C1-C5 linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclohexyl), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., morpholine, pyran, oxetane, pyrrolidine, tetrahydrofuran, imidazole, piperazine, piperidine, dioxazole, 2-oxopyrrolidine), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted benzyl; or R7’ and R7’’ are joined to form a 3-8 membered substituted or unsubstituted, saturated, unsaturated or aromatic, carbocyclic or heterocyclic ring (e.g., cyclopentyl, cyclohexyl, piperidine, tetrahydrofuran, tetrahydropyran, pyrrolidine); or R7’’ and R7 are joined to form a 3-8 membered substituted or unsubstituted carbocyclic or heterocyclic ring (e.g., cyclopentyl, cyclohexyl, piperidine, tetrahydrofuran, tetrahydropyran, pyrrolidine); or R7and R7’’’ are joined to form a 3-8 membered substituted or unsubstituted carbocyclic or heterocyclic ring (e.g., cyclopentyl, cyclohexyl, piperidine, tetrahydrofuran, tetrahydropyran, pyrrolidine); or R7’’’ and R7’’’’ are joined to form a 3-8 membered substituted or unsubstituted carbocyclic or heterocyclic ring (e.g., cyclopentyl, cyclohexyl, piperidine, tetrahydrofuran, tetrahydropyran, pyrrolidine); R20is represented by the following structure:R30is H, R20, F, Cl, Br, I, OH, SH, alkoxy, N(R)2, NH(R10), N(R10)(R11), CF3, CN, NO2, C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH2-CH2-O-CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), C1-C5linear or branched alkoxy, C1-C5linear or branched haloalkyl (e.g., CHF2, CF3, CF2CH3, CH2CF3,CF2CH2CH3,CH2CH2CF3,CF2CH(CH3)2,CF(CH3)-CH(CH3)2), R8-aryl (e.g., CH2-Ph), -R8-O-R8-O-R10(e.g. (CH2)2-O-(CH2)2-O-CH3), -R8-O-R10, -R8-R10(e.g., (CH2)2-O- CH3), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine);R is H, F, Cl, Br, I, OH, SH, COOH, CO(R10) (e.g., C(O)CH3), NH(R10), NH-CH2-cyclopropyl, N(R10)(R11), CF3, CN, NO2, C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, iPr, CH2-cyclopropyl, CH2-OH, CH2-CH2-OH, CH2-CH2-O-CH2-CH2-O-CH3, CH2-O-CH2-CH2- O-CH3), C3-C8 substituted or unsubstituted cycloalkyl, cyclopropyl, substituted or unsubstituted C1-C5 linear or branched alkoxy, (e.g., methoxy, ethoxy, O-(CH2CH3), OCHF2, O-(CH2)2-O-CH3, isopropoxy, O-(CH2)-cyclopropyl, O-CH2-methylcyclobutyl, O-CH2-3-methyloxetane, O-CH(CH3)-CH2-O-CH3) C1-C5 linear or branched haloalkyl (e.g., CHF2, CF3, CF2CH3, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2,CF(CH3)-CH(CH3)2), R8-aryl (e.g., CH2-Ph), -R8-O-R8-O-R10 (e.g. (CH2)2-O-(CH2)2-O- CH3), -R8-O-R10, O-R8-R10 (e.g. O-(CH2)2-O-CH3, O-(CH2CH3), O-(CH2)-cyclopropyl), -R8-R10 (e.g., (CH2)-cyclopropyl, (CH2)2-O-CH3, (CH2)-OH, (CH2)2-OH, (CH2)-COOH), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine); each R8 is independently [CH2]p wherein p is between 1 and 10 (e.g., 1, 2); R9 is [CH]q, [C]q wherein q is between 2 and 10; R10 and R11 are each independently H, OH, COOH, C1-C5 substituted or unsubstituted linear or branched alkyl (e.g., methyl, ethyl, CH2-cyclopropyl, CH2-CH2-O-CH3), C3-C8 substituted or unsubstituted cycloalkyl (e.g., cyclopropyl), C1-C5 substituted or unsubstituted linear or branched haloalky (e.g., CH2CF3), C1-C5linear or branched alkoxy (e.g., O-CH3), R20, C(O)R, or S(O)2R; or R10and R11are joined to form a substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., piperazine, piperidine), n is an integer between 0 and 4 (e.g., 1, 2); or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, pharmaceutical product or any combination thereof.

[0045] In some embodiments, at least one of R7, R7’, R7’’, R7’’’ and R7’’’’ is not H. In some embodiments, at least two of R7, R7’, R7’’, R7’’’ and R7’’’’ are not H. In some embodiments, at least one of R7’, R7’’, R7’’’ and R7’’’’ is not H. In some embodiments, at least two of R7’, R7’’, R7’’’ and R7’’’’ are not H. In some embodiments, at least two of R7’, R7’’, R7’’’ and R7’’’’ are different than eachother. In some embodiments, at least two of R7’, R7’’, R7’’’ and R7’’’’ are not H and are different than eachother.

[0046] In some embodiments, Ring W is aromatic and at least one of X2, X3, and X4is C(R). In some embodiments, Ring W is aromatic and X11is N. In some embodiments, Ring W is aromatic and X12is not S. In some embodiments, if Ring W is aromatic then at least one of X2, X3, and X4is C(R); X11is N; or X12is not S. In some embodiments, R is not H. In some embodiments, if both Ring W and Ring W' are aromatic, then at least one of X2, X3, and X4is C(R); X11is N; or X12is not S.

[0047] In various embodiments, this invention is directed to a compound represented by the structure of formula I(l):wherein Ring W may be either aromatic or non-aromatic ring, wherein if ring W is aromatic then X2, X3, and X4, are each independently CH, C(R) or N (e.g., C(CH3), C(O- CH2-cyclopropyl), C(O-CH2-methylcyclobutyl), C(NH-CH2-cyclopropyl), C(isopropoxy), C(O-CH(CH3)-CH2-O-CH3), C(CH2CH3), C-iPr, C-CH2-cyclopropyl, C(OCH3), C(OCH2CH3), C(O-(CH2)2-O-CH3, C(OCHF2), C(Cl), C(C(O)CH3), C(O- CH2CH2-O-CH3), C(OH)); X15is C; wherein if ring W is non-aromatic then X2, X3, and X4, are each independently CH2, CH(R), C(R)2, NH, N(R), O, S, S=O or SO2(e.g., CH2); X15is CH, C(R) or N (e.g., CH, N); X5, X6, X7, X8and X9are each independently nitrogen or carbon atoms; wherein if either one of X5, X6, X7, X8and X9is nitrogen, then the respective R7’, R7’’, R7, R7’’’, and R7’’’’ substitution is absent; X10is N, CH, C(R), or C=O; wherein if X10is C=O then X11is N (e.g., C(CH2-OH), C(CH2- CH2-OH), C(NH-CH2-cyclopropyl), C(COOH), C(CH3), C(cyclopropyl), C(isopropoxy)); X11is N or C; wherein if X11is N then X10is C=O; Ring W’ may be either aromatic or non-aromatic ring, wherein if ring W’ is aromatic then X12 is S, SO2, O, NH, N(R), N-OH, CH=CH, CH=CH(R), C(R)=CH, N=CH, N=C(R), CH=N or C(R)=N (e.g., N-CH2-COOH, N-CH2-CH2-OH, N-CH3, N-CH2CH3, N-iPr, N-cyclopropyl, N-CH2-cyclopropyl);wherein if ring W’ is non-aromatic then X12 is CH=CH, CH=CH(R), C(R)=CH, OCH2, SCH2, CH=N, C(R)=N, N=CH, N=C(R); X14 is S, O, N or CH, wherein if X14 is CH then Ring F is not absent and if X14 is S or O then R3 is absent; Ring F is absent or is a substituted or unsubstituted, saturated or unsaturated, 3-8 membered heterocyclic or carbocyclic ring (e.g., pyrrolidine, 1-methylpyrrolidine, pyrrolidin-2-one, pyrrolidin-3- ol, morpholine, pyridine, piperidine, tetrahydrofurane, tetrahydrothiophene, cyclopropyl, oxetane, imidazole, pyrimidine, triazole, oxadiazole, pyrazole); R1 and R2 are each independently H, F, Cl, Br, I, OH, SH, or CF3, substituted or unsubstituted C1-C5 alkyl, C1-C5 linear or branched, or C3-C8 cyclic haloalkyl, substituted or unsubstituted C1-C5 linear or branched, or C3-C8 cyclic alkoxy; or R1 and R2 are joined to form a C=O, or a 3-8 membered carbocyclic or heterocyclic ring (e.g., cyclopropyl); or R2 and R4 are joined to form Ring F as defined above (e.g., pyrrolidine, pyrrolidin-2-one, pyrrolidin-3-ol, morpholine, pyridine, pyrimidine, triazole, oxadiazole, pyrazole), wherein if Ring F is aromatic, then R1 and / or R3 are absent; R3 and R4 are each independently H, Me, substituted or unsubstituted C1-C5 alkyl (e.g., methoxyethylene, methylaminoethyl, aminoethyl), -R8-O-R10(e.g., (CH2)2-O-CH3), R8-N(R10)(R11) (e.g., (CH2)2-NH(CH3)), substituted or unsubstituted C3-C8cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted 5-7 membered heterocyclic ring (e.g., pyrrolidine, methylpyrrolidine, piperidine), or R20;or R3and R4are joined to form a 3-8 membered heterocyclic ring (e.g., pyrrolidine, , pyrrolidone, 2-oxopyrrolidine, piperidine, morpholine, piperazine, imidazole); wherein if X14 is S or O then R3 is absent; R5 is H or C1-C5 linear or branched alkyl (e.g. methyl); R6is H, F, Cl, Br, I, OH, SH, R8-OH, R8-SH, -R8-O-R10(e.g., CH2-O-CH3, (CH2)2-O-CH3(CH2)3-O-CH3, (CH2)2-O-CH(CH3)2), R8-S-R10(e.g., (CH2)3-S-(CH2)2CH3), R8-NHC(O)-R10, -O-R8- R10, R8-(substituted or unsubstituted C3-C8cycloalkyl) (e.g., CH2-cyclopropyl, CH2-cyclobutanol, CH2- difluorocyclopropyl, CH2-methylcyclopropyl, CH2-dimethylamino-cyclohexyl, (CH2)2-cyclopentanole, CH2-cyclohexanol), R8-(substituted or unsubstituted, saturated, unsaturated or aromatic, single, fused or spiro 3-10 membered heterocyclic ring) (e.g., (CH2)3-piperidine, (CH2)3-4-fluoro-piperidine, (CH2)3- pyran, (CH2)2-pyrrazole, (CH2)2-imidazole, CH2-tetrahydrofurane, CH2-dioxane, CH2-oxetane, CH2- piperidine, CH2-triazole, CH2-1-oxa-8-azaspiro[4.5]decane, (CH2)3-diazabicyclo[2.2.1]heptane, CH2- methyl-THF, CH2-ethyl-piperidine, CH2-oxa-azaspirodecane, (CH2)3-dimethylpyrazole, CH2-2-oxo- methylpyrrolidine, CH2-methyl-azetidine, CH2-azaspiroheptane), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, NH(R10), N(R10)(R11), R8-N(R10)(R11) (e.g., (CH2)2-NH2, (CH2)3- N(CH2CH3)2, (CH2)3-N(CH(CH3)2)2, (CH2)3-piperidine, (CH2)3-4-fluoro-piperidine, (CH2)3-4-cyano- piperidine, (CH2)4-NH(CH3), (CH2)3-NH-CH3(CH2)3-NH-CH2CH3(CH2)3-N(CH2CH3)2, (CH2)3-NH2,(CH2)3-N(CH2CH3)(CH2CF3)), R9-R8-N(R10)(R11) (e.g., (CH2)2-C(O)-piperidine), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R10, NHCO-N(R10)(R11), COOH, -C(O)Ph, C(O)O-R10, R8-C(O)-R10, C(O)H, C(O)- R10 (e.g., C(O)CH3), C1-C5 linear or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR, C(O)N(R10)(R11), SO2R, SO2N(R10)(R11), CH(CF3)(NH-R10), C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., CH(CH3)CH2OCH3, CH(CH3)CH2NH2, CH(CH3)C(O)N(CH3)2, CH2-CH(OH)Ph, (CH2)3N(H)CH2CH3, CH(CH3)(CH2)2OH, CH(CH2OH)(CH2CH3), (CH2)3-OCH3, (CH2)2-OCH3, (CH2)2-OCH(CH3)2, CH(CH2OH)(CH2CH(CH3)2), CH2CH(CH3)(OCH3), CH2CH(N(CH3)2)(CH2CH3), benzyl, methyl, ethyl, CH2-OCH2-CH2-O-CH3, CH(CH3)C(O)N(CH3)2), C1-C5 linear or branched, substituted or unsubstituted alkenyl, C1-C5 linear or branched, or C3-C8 cyclic haloalkyl, substituted or unsubstituted C1-C5 linear or branched, or C3-C8 cyclic alkoxy (e.g. methoxy, O-(CH2)2-O-CH3), optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom, C1-C5 linear or branched thioalkoxy, C1-C5 linear or branched haloalkoxy, C1-C5 linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclohexyl, methoxycyclopropyl, methylcyclobutyl, aminomethyl-cyclobutyl, methoxycyclobutyl, 2,3-dihydro-1H- indenol), R8-(substituted or unsubstituted C3-C8 cycloalkyl), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., piperidine, 1-methyl-piperidine, azetidine, pyrrolidine, pyrrolidinone, quinuclidine, tetrahydropyran, azaspiro[3.3]heptane, imidazole, trifluoromethyl-oxetane, hydroxy- tetrahydrofurane, azepan-2-one, azabicyclohexane), substituted or unsubstituted aryl, substituted or unsubstituted R8-aryl (e.g., benzyl), substituted or unsubstituted benzyl; or R6and R5are joined to for a substituted or unsubstituted 5-8 membered heterocyclic ring (e.g., azepane, piperazine, 2-(piperazin-1-yl)acetamide; or R6is represented by the structure of formula B or Bi:wherein m is 0 or 1; andR12 is R20 or C1-C5 C(O)-alkyl, and R13 is R30; or R12 and R13 are both H; R12 and R13 are each independently H or substituted or unsubstituted C1-C5 alkyl (e.g., ethyl, trifluoroethyl); R12 and C3 are joined to form ring A and R13 is R30; or R12 and R13 are joined to form ring B; or R12 and C1 are joined to form ring C and R13 is R30; or C1 and C3 are joined to form ring D and R12 and R13 are each independently R30; or R13 and C2 are joined to form ring E, m is 1, and R12 is R30; or R12 and R13 are joined to form ring B and C1 and C3 are joined to form ring D; wherein Ring A, C and E are each independently a substituted or unsubstituted single spiro or fused 3-8 membered heterocyclic ring (e.g., A: pyrrolidine, methylpyrrolidine, ethylpyrrolidine); C: piperidine, pyrrolidine, methyl-2-oxopyrrolidine, pyran- pyrrolidine, methyl-azetidine, azabicyclooctane, 2-azabicyclo[2.1.1]hexane, 2- azaspiro[3.3]heptane; E: pyrrolidine, azetidine, ethylpyrrolidine, oxopyrrolidine, methylpiperidine); Ring B is a substituted or unsubstituted single, spiro or fused 3-8 membered heterocyclic ring (B: piperidine, piperidin-2-one, 4-fluoropiperidin-2-one, piperidine- 4-carbonitrile, 4-fluoropiperidine, 4-fluoro-2-methylpiperidine, methyl-piperidin, fluoropiperidine, difluoropiperidine, pyrrolidine, piperazine, methylpyrrolidine, thiomorpholine 1,1-dioxide, 2-oxa-6-azaspiro[3.3]heptane, methyl-piperazine, dimethyl-pyrazole, imidazole, 2-methyl-2,5-diazabicyclo[2.2.1]heptane, hydroxymethyl-pyrrolidine, diazabicyclo[2.2.1]heptane, 6-fluoro-3- azabicyclo[3.1.1]heptane; and Ring D is a substituted or unsubstituted C3-C8cycloalkyl (e.g., cyclobutane, cyclohexane); R7’, R7’’, R7’’’ and R7’’’’ are each independently H, F, Cl, Br, I, OH, O-R20, SH, R8-OH, R8- SH, -R8-O-R10, R8-(C3-C8cycloalkyl), R8-(3-8 membered heterocyclic ring), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, NH(R10), N(R10)(R11), R8-N(R10)(R11), R9-R8-N(R10)(R11), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R10, NHCO-N(R10)(R11), COOH, -C(O)Ph, C(O)O-R10, R8-C(O)-R10, C(O)H, C(O)-R10, C1-C5linear or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR, C(O)N(R10)(R11), SO2R, SO2N(R10)(R11), CH(CF3)(NH-R10), C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., isopropyl, methyl, ethyl), C1-C5linear or branched, substituted or unsubstituted alkenyl, C1-C5linear or branched, or C3-C8cyclic haloalkyl (e.g., CHF2), C1-C5linear or branched, or C3-C8cyclic alkoxy (e.g. methoxy), optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom, C1-C5linear or branched thioalkoxy, C1-C5linear or branched haloalkoxy, C1-C5linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8cycloalkyl (e.g., cyclopropyl,cyclohexyl), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., morpholine, pyran, oxetane, pyrrolidine, tetrahydrofuran, imidazole, piperazine, piperidine, dioxazole, 2-oxopyrrolidine), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted benzyl; or R7’ and R7’’ are joined to form a 3-8 membered substituted or unsubstituted, saturated, unsaturated or aromatic, carbocyclic or heterocyclic ring (e.g., cyclopentyl, cyclohexyl, piperidine, tetrahydrofuran, tetrahydropyran, pyrrolidine); or R7’’’ and R7’’’’ are joined to form a 3-8 membered substituted or unsubstituted carbocyclic or heterocyclic ring (e.g., cyclopentyl, cyclohexyl, piperidine, tetrahydrofuran, tetrahydropyran, pyrrolidine); R20 is represented by the following structure:R is H, F, Cl, Br, I, OH, SH, COOH, CO(R10) (e.g., C(O)CH3), NH(R10), NH-CH2-cyclopropyl, N(R10)(R11), CF3, CN, NO2, C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, iPr, CH2-cyclopropyl, CH2-OH, CH2-CH2-OH, CH2-CH2-O-CH2-CH2-O-CH3, CH2-O-CH2-CH2- O-CH3), C3-C8substituted or unsubstituted cycloalkyl, cyclopropyl, substituted or unsubstituted C1-C5linear or branched alkoxy, (e.g., methoxy, ethoxy, O-(CH2CH3), OCHF2, O-(CH2)2-O-CH3, isopropoxy, O-(CH2)-cyclopropyl, O-CH2-methylcyclobutyl, O-CH2-3-methyloxetane, O-CH(CH3)-CH2-O-CH3) C1-C5linear or branched haloalkyl (e.g., CHF2, CF3, CF2CH3, CH2CF3,CF2CH2CH3,CH2CH2CF3,CF2CH(CH3)2,CF(CH3)-CH(CH3)2), R8-aryl (e.g., CH2-Ph), -R8-O-R8-O-R10(e.g. (CH2)2-O-(CH2)2-O- CH3), -R8-O-R10, O-R8-R10(e.g. O-(CH2)2-O-CH3, O-(CH2CH3), O-(CH2)-cyclopropyl), -R8-R10(e.g., (CH2)-cyclopropyl, (CH2)2-O-CH3, (CH2)-OH, (CH2)2-OH, (CH2)-COOH), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine); R30is H, R20, F, Cl, Br, I, OH, SH, alkoxy, N(R)2, NH(R10), N(R10)(R11), CF3, CN, NO2, C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH2-CH2-O-CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), C1-C5linear or branched alkoxy, C1-C5linear or branched haloalkyl (e.g., CHF2, CF3, CF2CH3, CH2CF3,CF2CH2CH3,CH2CH2CF3,CF2CH(CH3)2,CF(CH3)-CH(CH3)2), R8-aryl (e.g., CH2-Ph), -R8-O-R8-O-R10(e.g. (CH2)2-O-(CH2)2-O-CH3), -R8-O-R10, -R8-R10(e.g., (CH2)2-O- CH3), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine); each R8is independently [CH2]pwherein p is between 1 and 10 (e.g., 1, 2); R9is [CH]q, [C]qwherein q is between 2 and 10; R10and R11are each independently H, OH, COOH, C1-C5substituted or unsubstituted linear or branched alkyl (e.g., methyl, ethyl, CH2-cyclopropyl, CH2-CH2-O-CH3), C3-C8 substituted orunsubstituted cycloalkyl (e.g., cyclopropyl), C1-C5 substituted or unsubstituted linear or branched haloalky (e.g., CH2CF3), C1-C5 linear or branched alkoxy (e.g., O-CH3), R20, C(O)R, or S(O)2R; or R10 and R11 are joined to form a substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., piperazine, piperidine), n is an integer between 0 and 4 (e.g., 1, 2); or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, pharmaceutical product or any combination thereof.

[0048] In some embodiments, at least one of R7’, R7’’, R7’’’ and R7’’’’ is not H. In some embodiments, at least two of R7’, R7’’, R7’’’ and R7’’’’ are not H. In some embodiments, at least two of R7’, R7’’, R7’’’ and R7’’’’ are different then eachother. In some embodiments, at least two of R7’, R7’’, R7’’’ and R7’’’’ are not H and are different then eachother.

[0049] In some embodiments, Ring W is aromatic and at least one of X2, X3, and X4 is C(R). In some embodiments, Ring W is aromatic and X11 is N. In some embodiments, Ring W is aromatic and X12 is not S. In some embodiments, if Ring W is aromatic then at least one of X2, X3, and X4 is C(R); X11 is N; or X12 is not S. In some embodiments, if both Ring W and Ring W' are aromatic, then at least one of X2, X3, and X4 is C(R); X11 is N; or X12 is not S. In some embodiments, R is not H.

[0050] In some embodiments, if R1and R2are joined to form a C=O, then at least one of X2, X3, X4, and X10is not CH;

[0051] In various embodiments, this invention is directed to a compound represented by the structure of formula I(m):wherein Ring W may be either aromatic or non-aromatic ring, wherein if ring W is aromatic thenX2, X3, and X4, are each independently CH, C(R) or N (e.g., C(CH3), C(O- CH2-cyclopropyl), C(O-CH2-methylcyclobutyl), C(NH-CH2-cyclopropyl), C(isopropoxy), C(O-CH(CH3)-CH2-O-CH3), C(CH2CH3), C-iPr, C-CH2-cyclopropyl, C(OCH3), C(OCH2CH3), C(O-(CH2)2-O-CH3, C(OCHF2), C(Cl), C(C(O)CH3), C(O- CH2CH2-O-CH3), C(OH)); X15 is C; wherein if ring W is non-aromatic then X2, X3, and X4, are each independently CH2, CH(R), C(R)2, NH, N(R), O, S, S=O or SO2 (e.g., CH2); X15 is CH, C(R) or N (e.g., CH, N); X5, X6, X7, X8 and X9 are each independently nitrogen or carbon atoms; wherein if either one of X5, X6 , X8 and X9 is nitrogen, then the respective R7’, R7’’, R7’’’, and R7’’’’ substitution is absent; X10 is N, CH, C(R), or C=O; wherein if X10 is C=O then X11 is N (e.g., C(CH2-OH), C(CH2- CH2-OH), C(NH-CH2-cyclopropyl), C(COOH), C(CH3), C(cyclopropyl), C(isopropoxy)); X11 is N or C; wherein if X11 is N then X10 is C=O; Ring W’ may be either aromatic or non-aromatic ring, wherein if ring W’ is aromatic then X12is S, SO2, O, NH, N(R), N-OH, CH=CH, CH=CH(R), C(R)=CH, N=CH, N=C(R), CH=N or C(R)=N (e.g., N-CH2-COOH, N-CH2-CH2-OH, N-CH3, N-CH2CH3, N-iPr, N-cyclopropyl, N-CH2-cyclopropyl); wherein if ring W’ is non-aromatic then X12is CH=CH, CH=CH(R), C(R)=CH, OCH2, SCH2, CH=N, C(R)=N, N=CH, N=C(R); X13 is CH2, CH(R) (e.g., CH-CH3), C(R)2, or C=O; X14is S, O, N or CH, wherein if X14is CH then Ring F is not absent and if X14is S or O then R3is absent; Ring G is absent or is a substituted or unsubstituted 3-8 membered carbocyclic or heterocyclic ring (e.g., cyclobutane, cyclopentane, cyclohexane); Ring F is absent or is a substituted or unsubstituted, saturated or unsaturated, 3-8 membered heterocyclic or carbocyclic ring (e.g., pyrrolidine, 1-methylpyrrolidine, pyrrolidin-2-one, pyrrolidin-3- ol, morpholine, pyridine, piperidine, tetrahydrofurane, tetrahydrothiophene, cyclopropyl, oxetane, imidazole, pyrimidine, triazole, oxadiazole, pyrazole); R1and R2are each independently H, F, Cl, Br, I, OH, SH, or CF3, substituted or unsubstituted C1-C5alkyl, C1-C5linear or branched, or C3-C8cyclic haloalkyl, substituted or unsubstituted C1-C5linear or branched, or C3-C8cyclic alkoxy; or R1and R2are joined to form a C=O, or a 3-8 membered carbocyclic or heterocyclic ring (e.g., cyclopropyl);or R2 and R4 are joined to form Ring F as defined above (e.g., pyrrolidine, pyrrolidin-2-one, pyrrolidin-3-ol, morpholine, pyridine, pyrimidine, triazole, oxadiazole, pyrazole), wherein if Ring F is aromatic, then R1 and / or R3 are absent; R3 and R4 are each independently H, Me, substituted or unsubstituted C1-C5 alkyl (e.g., methoxyethylene, methylaminoethyl, aminoethyl), -R8-O-R10 (e.g., (CH2)2-O-CH3), R8-N(R10)(R11) (e.g., (CH2)2-NH(CH3)), substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted 5-7 membered heterocyclic ring (e.g., pyrrolidine, methylpyrrolidine, piperidine), or R20; or R3 and R4 are joined to form a 3-8 membered heterocyclic ring (e.g., pyrrolidine, , pyrrolidone, 2-oxopyrrolidine, piperidine, morpholine, piperazine, imidazole); R7’, R7’’, R7’’’ and R7’’’’ are each independently H, F, Cl, Br, I, OH, O-R20, SH, R8-OH, R8- SH, -R8-O-R10, R8-(C3-C8 cycloalkyl), R8-(3-8 membered heterocyclic ring), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, NH(R10), N(R10)(R11), R8-N(R10)(R11), R9-R8-N(R10)(R11), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R10, NHCO-N(R10)(R11), COOH, -C(O)Ph, C(O)O-R10, R8-C(O)-R10, C(O)H, C(O)-R10, C1-C5 linear or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR, C(O)N(R10)(R11), SO2R, SO2N(R10)(R11), CH(CF3)(NH-R10), C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., isopropyl, methyl, ethyl), C1-C5 linear or branched, substituted or unsubstituted alkenyl, C1-C5 linear or branched, or C3-C8 cyclic haloalkyl (e.g., CHF2), C1-C5 linear or branched, or C3-C8 cyclic alkoxy (e.g. methoxy), optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom, C1-C5linear or branched thioalkoxy, C1-C5linear or branched haloalkoxy, C1-C5linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8cycloalkyl (e.g., cyclopropyl, cyclohexyl), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., morpholine, pyran, oxetane, pyrrolidine, tetrahydrofuran, imidazole, piperazine, piperidine, dioxazole, 2-oxopyrrolidine), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted benzyl; or R7’ and R7’’ are joined to form a 3-8 membered substituted or unsubstituted, saturated, unsaturated or aromatic, carbocyclic or heterocyclic ring (e.g., cyclopentyl, cyclohexyl, piperidine, tetrahydrofuran, tetrahydropyran, pyrrolidine); or R7’’’ and R7’’’’ are joined to form a 3-8 membered substituted or unsubstituted carbocyclic or heterocyclic ring (e.g., cyclopentyl, cyclohexyl, piperidine, tetrahydrofuran, tetrahydropyran, pyrrolidine); R20is represented by the following structure:R30is H, R20, F, Cl, Br, I, OH, SH, alkoxy, N(R)2, NH(R10), N(R10)(R11), CF3, CN, NO2, C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH2-CH2-O-CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), C1-C5linear or branched alkoxy, C1-C5linear or branched haloalkyl (e.g., CHF2, CF3, CF2CH3, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2,CF(CH3)-CH(CH3)2), R8-aryl (e.g., CH2-Ph), -R8-O-R8-O-R10 (e.g. (CH2)2-O-(CH2)2-O-CH3), -R8-O-R10, -R8-R10 (e.g., (CH2)2-O-CH3), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine); R50 is H, R20, F, Cl, Br, I, OH, SH, N(R)2, NH(R10), N(R10)(R11), CF3, CN, NO2, C1-C5 linear or branched, substituted or unsubstituted alkyl C1-C5 linear or branched alkoxy, C1-C5 linear or branched haloalkyl, -R8-R10 (e.g., (CH2)2-O-CH3), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine); R is H, F, Cl, Br, I, OH, SH, COOH, CO(R10) (e.g., C(O)CH3), NH(R10), NH-CH2-cyclopropyl, N(R10)(R11), CF3, CN, NO2, C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, iPr, CH2-cyclopropyl, CH2-OH, CH2-CH2-OH, CH2-CH2-O-CH2-CH2-O-CH3, CH2-O-CH2-CH2- O-CH3), C3-C8 substituted or unsubstituted cycloalkyl, cyclopropyl, substituted or unsubstituted C1-C5 linear or branched alkoxy, (e.g., methoxy, ethoxy, O-(CH2CH3), OCHF2, O-(CH2)2-O-CH3, isopropoxy, O-(CH2)-cyclopropyl, O-CH2-methylcyclobutyl, O-CH2-3-methyloxetane, O-CH(CH3)-CH2-O-CH3) C1-C5 linear or branched haloalkyl (e.g., CHF2, CF3, CF2CH3, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2,CF(CH3)-CH(CH3)2), R8-aryl (e.g., CH2-Ph), -R8-O-R8-O-R10 (e.g. (CH2)2-O-(CH2)2-O- CH3), -R8-O-R10, O-R8-R10 (e.g. O-(CH2)2-O-CH3, O-(CH2CH3), O-(CH2)-cyclopropyl), -R8-R10 (e.g., (CH2)-cyclopropyl, (CH2)2-O-CH3, (CH2)-OH, (CH2)2-OH, (CH2)-COOH), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine); each R8 is independently [CH2]p wherein p is between 1 and 10 (e.g., 1, 2); R9is [CH]q, [C]qwherein q is between 2 and 10; R10and R11are each independently H, OH, COOH, C1-C5substituted or unsubstituted linear or branched alkyl (e.g., methyl, ethyl, CH2-cyclopropyl, CH2-CH2-O-CH3), C3-C8substituted or unsubstituted cycloalkyl (e.g., cyclopropyl), C1-C5 substituted or unsubstituted linear or branched haloalky (e.g., CH2CF3), C1-C5 linear or branched alkoxy (e.g., O-CH3), R20, C(O)R, or S(O)2R; or R10and R11are joined to form a substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., piperazine, piperidine), n is an integer between 0 and 4 (e.g., 1, 2); or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, pharmaceutical product or any combination thereof.

[0052] In some embodiments, at least one of R7’, R7’’, R7’’’ and R7’’’’ is not H. In some embodiments, at least two of R7’, R7’’, R7’’’ and R7’’’’ are not H. In some embodiments, at least two of R7’, R7’’, R7’’’ and R7’’’’ are different then eachother. In some embodiments, at least two of R7’, R7’’, R7’’’ and R7’’’’ are not H and are different then eachother.

[0053] In some embodiments, Ring W is aromatic and at least one of X2, X3, and X4is C(R). In some embodiments, Ring W is aromatic and X11is N In some embodiments, Ring W is aromatic and X12isnot S. In some embodiments, if Ring W is aromatic then at least one of X2, X3, and X4 is C(R); X11 is N; or X12 is not S. In some embodiments, if both Ring W and Ring W' are aromatic, then at least one of X2, X3, and X4 is C(R); X11 is N; or X12 is not S. In some embodiments, R is not H.

[0054] In various embodiments, this invention is directed to a compound represented by the structure of formula I(n): whereinX5, X6, X7, X8and X9are each independently nitrogen or carbon atoms; wherein if either one of X5, X6, X8and X9is nitrogen, then the respective R7’, R7’’, R7’’’, and R7’’’’ substitution is absent; X10is N, CH, C(R), or C=O; wherein if X10is C=O then X11is N (e.g., C(CH2-OH), C(CH2- CH2-OH), C(NH-CH2-cyclopropyl), C(COOH), C(CH3), C(cyclopropyl), C(isopropoxy)); X11is N or C; wherein if X11is N then X10is C=O; X12 is S, SO2, O, NH, N(R), N-OH, CH=CH, CH=CH(R), C(R)=CH, N=CH, N=C(R), CH=N or C(R)=N (e.g., N-CH2-COOH, N-CH2-CH2-OH, N-CH3, N-CH2CH3, N-iPr, N-cyclopropyl, N-CH2- cyclopropyl); R5 is H or C1-C5 linear or branched alkyl (e.g. methyl); R6 is H, F, Cl, Br, I, OH, SH, R8-OH, R8-SH, -R8-O-R10 (e.g., CH2-O-CH3, (CH2)2-O-CH3 (CH2)3-O-CH3, (CH2)2-O-CH(CH3)2), R8-S-R10 (e.g., (CH2)3-S-(CH2)2CH3), R8-NHC(O)-R10, -O-R8- R10, R8-(substituted or unsubstituted C3-C8 cycloalkyl) (e.g., CH2-cyclopropyl, CH2-cyclobutanol, CH2- difluorocyclopropyl, CH2-methylcyclopropyl, CH2-dimethylamino-cyclohexyl, (CH2)2-cyclopentanole, CH2-cyclohexanol), R8-(substituted or unsubstituted, saturated, unsaturated or aromatic, single, fused or spiro 3-10 membered heterocyclic ring) (e.g., (CH2)3-piperidine, (CH2)3-4-fluoro-piperidine, (CH2)3- pyran, (CH2)2-pyrrazole, (CH2)2-imidazole, CH2-tetrahydrofurane, CH2-dioxane, CH2-oxetane, CH2- piperidine, CH2-triazole, CH2-1-oxa-8-azaspiro[4.5]decane, (CH2)3-diazabicyclo[2.2.1]heptane, CH2- methyl-THF, CH2-ethyl-piperidine, CH2-oxa-azaspirodecane, (CH2)3-dimethylpyrazole, CH2-2-oxo- methylpyrrolidine, CH2-methyl-azetidine, CH2-azaspiroheptane), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, NH(R10) N(R10)(R11) R8 N(R10)(R11) (e.g., (CH2)2-NH2, (CH2)3-N(CH2CH3)2, (CH2)3-N(CH(CH3)2)2, (CH2)3-piperidine, (CH2)3-4-fluoro-piperidine, (CH2)3-4-cyano- piperidine, (CH2)4-NH(CH3), (CH2)3-NH-CH3, (CH2)3-NH-CH2CH3, (CH2)3-N(CH2CH3)2, (CH2)3-NH2, (CH2)3-N(CH2CH3)(CH2CF3)), R9-R8-N(R10)(R11) (e.g., (CH2)2-C(O)-piperidine), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R10, NHCO-N(R10)(R11), COOH, -C(O)Ph, C(O)O-R10, R8-C(O)-R10, C(O)H, C(O)- R10 (e.g., C(O)CH3), C1-C5 linear or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR, C(O)N(R10)(R11), SO2R, SO2N(R10)(R11), CH(CF3)(NH-R10), C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., CH(CH3)CH2OCH3, CH(CH3)CH2NH2, CH(CH3)C(O)N(CH3)2, CH2-CH(OH)Ph, (CH2)3N(H)CH2CH3, CH(CH3)(CH2)2OH, CH(CH2OH)(CH2CH3), (CH2)3-OCH3, (CH2)2-OCH3, (CH2)2-OCH(CH3)2, CH(CH2OH)(CH2CH(CH3)2), CH2CH(CH3)(OCH3), CH2CH(N(CH3)2)(CH2CH3), benzyl, methyl, ethyl, CH2-OCH2-CH2-O-CH3, CH(CH3)C(O)N(CH3)2), C1-C5 linear or branched, substituted or unsubstituted alkenyl, C1-C5 linear or branched, or C3-C8 cyclic haloalkyl, substituted or unsubstituted C1-C5 linear or branched, or C3-C8 cyclic alkoxy (e.g. methoxy, O-(CH2)2-O-CH3), optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom, C1-C5 linear or branched thioalkoxy, C1-C5 linear or branched haloalkoxy, C1-C5 linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclohexyl, methoxycyclopropyl, methylcyclobutyl, aminomethyl-cyclobutyl, methoxycyclobutyl, 2,3-dihydro-1H- indenol), R8-(substituted or unsubstituted C3-C8 cycloalkyl), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., piperidine, 1-methyl-piperidine, azetidine, pyrrolidine, pyrrolidinone, quinuclidine, tetrahydropyran, azaspiro[3.3]heptane, imidazole, trifluoromethyl-oxetane, hydroxy- tetrahydrofurane, azepan-2-one, azabicyclohexane), substituted or unsubstituted aryl, substituted or unsubstituted R8-aryl (e.g., benzyl), substituted or unsubstituted benzyl; or R6and R5are joined to for a substituted or unsubstituted 5-8 membered heterocyclic ring (e.g., azepane, piperazine, 2-(piperazin-1-yl)acetamide; or R6 is represented by the structure of formula B or Bi:wherein m is 0 or 1; and R12 is R20 or C1-C5 C(O)-alkyl, and R13 is R30; or R12 and R13 are both H; R12 and R13 are each independently H or substituted or unsubstituted C1-C5 alkyl (e.g., ethyl, trifluoroethyl); R12 and C3 are joined to form ring A and R13 is R30; or R12 and R13 are joined to form ring B; or R12 and C1 are joined to form ring C and R13 is R30; or C1 and C3 are joined to form ring D and R12 and R13 are each independently R30; or R13 and C2 are joined to form ring E, m is 1, and R12 is R30; or R12 and R13 are joined to form ring B and C1 and C3 are joined to form ring D; wherein Ring A, C and E are each independently a substituted or unsubstituted single spiro or fused 3-8 membered heterocyclic ring (e.g., A: pyrrolidine, methylpyrrolidine, ethylpyrrolidine); C: piperidine, pyrrolidine, methyl-2-oxopyrrolidine, pyran- pyrrolidine, methyl-azetidine, azabicyclooctane, 2-azabicyclo[2.1.1]hexane, 2- azaspiro[3.3]heptane; E: pyrrolidine, azetidine, ethylpyrrolidine, oxopyrrolidine, methylpiperidine); Ring B is a substituted or unsubstituted single, spiro or fused 3-8 membered heterocyclic ring (B: piperidine, piperidin-2-one, 4-fluoropiperidin-2-one, piperidine- 4-carbonitrile, 4-fluoropiperidine, 4-fluoro-2-methylpiperidine, methyl-piperidin, fluoropiperidine, difluoropiperidine, pyrrolidine, piperazine, methylpyrrolidine, thiomorpholine 1,1-dioxide, 2-oxa-6-azaspiro[3.3]heptane, methyl-piperazine, dimethyl-pyrazole, imidazole, 2-methyl-2,5-diazabicyclo[2.2.1]heptane, hydroxymethyl-pyrrolidine, diazabicyclo[2.2.1]heptane, 6-fluoro-3- azabicyclo[3.1.1]heptane; and Ring D is a substituted or unsubstituted C3-C8cycloalkyl (e.g., cyclobutane, cyclohexane); R7, R7’, R7’’, R7’’’ and R7’’’’ are each independently H, F, Cl, Br, I, OH, O-R20, SH, R8-OH, R8-SH, -R8-O-R10, R8-(C3-C8cycloalkyl), R8-(3-8 membered heterocyclic ring), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, NH(R10), N(R10)(R11), R8-N(R10)(R11), R9-R8-N(R10)(R11), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R10, NHCO-N(R10)(R11), COOH, -C(O)Ph, C(O)O-R10, R8- C(O)-R10, C(O)H, C(O)-R10, C1-C5linear or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR, C(O)N(R10)(R11), SO2R, SO2N(R10)(R11), CH(CF3)(NH-R10), C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., isopropyl, methyl, ethyl), C1-C5linear or branched, substituted or unsubstituted alkenyl, C1-C5linear or branched, or C3-C8cyclic haloalkyl (e.g., CHF2), C1-C5linear or branched, or C3-C8cyclic alkoxy (e.g. methoxy), optionally wherein at least one methylene group (CH2) in the alkoxyis replaced with an oxygen atom, C1-C5 linear or branched thioalkoxy, C1-C5 linear or branched haloalkoxy, C1-C5 linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclohexyl), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., morpholine, pyran, oxetane, pyrrolidine, tetrahydrofuran, imidazole, piperazine, piperidine, dioxazole, 2-oxopyrrolidine), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted benzyl; or R7’ and R7’’ are joined to form a 3-8 membered substituted or unsubstituted, saturated, unsaturated or aromatic, carbocyclic or heterocyclic ring (e.g., cyclopentyl, cyclohexyl, piperidine, tetrahydrofuran, tetrahydropyran, pyrrolidine); or R7’’ and R7 are joined to form a 3-8 membered substituted or unsubstituted carbocyclic or heterocyclic ring (e.g., cyclopentyl, cyclohexyl, piperidine, tetrahydrofuran, tetrahydropyran, pyrrolidine); or R7 and R7’’’ are joined to form a 3-8 membered substituted or unsubstituted carbocyclic or heterocyclic ring (e.g., cyclopentyl, cyclohexyl, piperidine, tetrahydrofuran, tetrahydropyran, pyrrolidine); or R7’’’ and R7’’’’ are joined to form a 3-8 membered substituted or unsubstituted carbocyclic or heterocyclic ring (e.g., cyclopentyl, cyclohexyl, piperidine, tetrahydrofuran, tetrahydropyran, pyrrolidine); R20 is represented by the following structure:R30is H, R20, F, Cl, Br, I, OH, SH, alkoxy, N(R)2, NH(R10), N(R10)(R11), CF3, CN, NO2, C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH2-CH2-O-CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), C1-C5linear or branched alkoxy, C1-C5linear or branched haloalkyl (e.g., CHF2, CF3, CF2CH3, CH2CF3,CF2CH2CH3,CH2CH2CF3,CF2CH(CH3)2,CF(CH3)-CH(CH3)2), R8-aryl (e.g., CH2-Ph), -R8-O-R8-O-R10(e.g. (CH2)2-O-(CH2)2-O-CH3), -R8-O-R10, -R8-R10(e.g., (CH2)2-O- CH3), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine); R is H, F, Cl, Br, I, OH, SH, COOH, CO(R10) (e.g., C(O)CH3), NH(R10), NH-CH2-cyclopropyl, N(R10)(R11), CF3, CN, NO2, C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, iPr, CH2-cyclopropyl, CH2-OH, CH2-CH2-OH, CH2-CH2-O-CH2-CH2-O-CH3, CH2-O-CH2-CH2- O-CH3), C3-C8substituted or unsubstituted cycloalkyl, cyclopropyl, substituted or unsubstituted C1-C5linear or branched alkoxy, (e.g., methoxy, ethoxy, O-(CH2CH3), OCHF2, O-(CH2)2-O-CH3, isopropoxy, O-(CH2)-cyclopropyl, O-CH2-methylcyclobutyl, O-CH2-3-methyloxetane, O-CH(CH3)-CH2-O-CH3) C1-C5linear or branched haloalkyl (e.g., CHF2, CF3, CF2CH3, CH2CF3,CF2CH2CH3,CH2CH2CF3,CF2CH(CH3)2,CF(CH3)-CH(CH3)2), R8-aryl (e.g., CH2-Ph), -R8-O-R8-O-R10(e.g. (CH2)2-O-(CH2)2-O- CH3), -R8-O-R10, O-R8-R10 (e.g. O-(CH2)2-O-CH3, O-(CH2CH3), O-(CH2)-cyclopropyl), -R8-R10 (e.g.,(CH2)-cyclopropyl, (CH2)2-O-CH3, (CH2)-OH, (CH2)2-OH, (CH2)-COOH), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine); each R8 is independently [CH2]p wherein p is between 1 and 10 (e.g., 1, 2); R9 is [CH]q, [C]q wherein q is between 2 and 10; R10 and R11 are each independently H, OH, COOH, C1-C5 substituted or unsubstituted linear or branched alkyl (e.g., methyl, ethyl, CH2-cyclopropyl, CH2-CH2-O-CH3), C3-C8 substituted or unsubstituted cycloalkyl (e.g., cyclopropyl), C1-C5 substituted or unsubstituted linear or branched haloalky (e.g., CH2CF3), C1-C5 linear or branched alkoxy (e.g., O-CH3), R20, C(O)R, or S(O)2R; or R10 and R11 are joined to form a substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., piperazine, piperidine), n is an integer between 0 and 4 (e.g., 1, 2); or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, pharmaceutical product or any combination thereof.

[0055] In some embodiments, at least one of R7’, R7’’, R7’’’ and R7’’’’ is not H. In some embodiments, at least two of R7’, R7’’, R7’’’ and R7’’’’ are not H. In some embodiments, at least two of R7’, R7’’, R7’’’ and R7’’’’ are different than eachother. In some embodiments, at least two of R7’, R7’’, R7’’’ and R7’’’’ are not H and are different than eachother.

[0056] In some embodiments, at least one of X2, X3, and X4is C(R). In some embodiments, X11is N. In some embodiments, X12is not S. In some embodiments, at least one of X2, X3, and X4is C(R); X11is N; or X12 is not S. In some embodiments, R is not H.

[0057] In some embodiments, X2of formula I and / or I(a)-I(j) is N. In other embodiments, X2is a CH. In other embodiments, X2is a C(R). In other embodiments, X2is C(CH3). In other embodiments, X2is C(CH2CH3). In other embodiments, X2is C-iPr. In other embodiments, X2is C-CH2-cyclopropyl. In other embodiments, X2is C(O-CH2-cyclopropyl). In other embodiments, X2is C(O-CH2- methylcyclobutyl). In other embodiments, X2is C(O-CH2-3-methyloxetane). In other embodiments, X2is C(OCH3) In other embodiments, X2is C(OCH2CH3) In other embodiments, X2is C(O-(CH2)2-O-CH3. In other embodiments, X2is C(NH-CH2-cyclopropyl). In other embodiments, X2is C(isopropoxy). In other embodiments, X2is C(O-CH(CH3)-CH2-O-CH3). In other embodiments, X2is C(OCHF2). In other embodiments, X2is C(Cl). In other embodiments, X2is C(C(O)CH3). In other embodiments, X2is C(OH).

[0058] In some embodiments, Ring W of formula I(k)-I(m) is aromatic or non-aromatic. In some embodiments, if Ring W is aromatic, then X2is a CH. In other embodiments, if Ring W is aromatic, then X2is a C(R). In other embodiments if Ring W is aromatic, then X2is C(CH3). In otherembodiments, if Ring W is aromatic, then X2 is C(CH2CH3). In other embodiments, if Ring W is aromatic, then X2 is C-iPr. In other embodiments, if Ring W is aromatic, then X2 is C-CH2-cyclopropyl. In other embodiments, if Ring W is aromatic, then X2 is C(O-CH2-cyclopropyl). In other embodiments, if Ring W is aromatic, then X2 is C(O-CH2-methylcyclobutyl). In other embodiments, if Ring W is aromatic, then X2 is C(O-CH2-3-methyloxetane). In other embodiments, if Ring W is aromatic, then X2 is C(OCH3) In other embodiments, if Ring W is aromatic, then X2 is C(OCH2CH3). In other embodiments, if Ring W is aromatic, then X2 is C(O-(CH2)2-O-CH3. In other embodiments, if Ring W is aromatic X2 is C(NH-CH2-cyclopropyl). In other embodiments, if Ring W is aromatic X2 is C(isopropoxy). In other embodiments, if Ring W is aromatic X2 is C(O-CH(CH3)-CH2-O-CH3). In other embodiments, if Ring W is aromatic X2 is C(OCHF2). In other embodiments, if Ring W is aromatic X2 is C(Cl). In other embodiments, if Ring W is aromatic X2 is C(C(O)CH3). In other embodiments, if Ring W is aromatic X2 is C(OH). In some embodiments, if Ring W is non-aromatic then X2 is CH2. In some embodiments, if Ring W is non-aromatic then X2 is CH(R). In some embodiments, if Ring W is non- aromatic then X2 is C(R)2. In some embodiments, if Ring W is non-aromatic then X2 is NH. In some embodiments, if Ring W is non-aromatic then X2 is N(R). In some embodiments, if Ring W is non- aromatic then X2 is O. In some embodiments, if Ring W is non-aromatic then X2 is S. In some embodiments, if Ring W is non-aromatic then X2 is S=O. In some embodiments, if Ring W is non- aromatic then X2 is SO2.

[0059] In some embodiments, X3of formula I and / or I(a)-I(j) is N. In other embodiments, X3is a CH. In other embodiments, X3is a CH. In other embodiments, X3is a C(R). In other embodiments, X3is C(CH3). In other embodiments, X3is C(CH2CH3). In other embodiments, X3is C-iPr. In other embodiments, X3is C-CH2-cyclopropyl. In other embodiments, X3is C(O-CH2-cyclopropyl). In other embodiments, X3is C(O-CH2-methylcyclobutyl). In other embodiments, X3is C(O-CH2-3- methyloxetane). In other embodiments, X3 is C(OCH3) In other embodiments, X3 is C(OCH2CH3) In other embodiments, X3 is C(O-(CH2)2-O-CH3. In other embodiments, X3 is C(NH-CH2-cyclopropyl). In other embodiments, X3is C(isopropoxy). In other embodiments, X3is C(O-CH(CH3)-CH2-O-CH3). In other embodiments, X3is C(OCHF2). In other embodiments, X3is C(Cl). In other embodiments, X2is C(C(O)CH3). In other embodiments, X3is C(OH).

[0060] In some embodiments, Ring W of formula I(k)-I(m) is aromatic or non-aromatic. In some embodiments, if Ring W is aromatic, then X3is a CH. In other embodiments, if Ring W is aromatic, then X3is a C(R). In other embodiments, if Ring W is aromatic, then X3is C(CH3). In other embodiments, if Ring W is aromatic, then X3is C(CH2CH3). In other embodiments, if Ring W is aromatic, then X3is C-iPr. In other embodiments, if Ring W is aromatic, then X3is C-CH2-cyclopropyl. In other embodiments, if Ring W is aromatic, then X3is C(O-CH2-cyclopropyl). In other embodiments, if Ring W is aromatic, then X3is C(O-CH2-methylcyclobutyl). In other embodiments, if Ring W is aromatic, then X3is C(O-CH2-3-methyloxetane). In other embodiments, if Ring W is aromatic, then X3is C(OCH3) In other embodiments, if Ring W is aromatic, then X3is C(OCH2CH3). In other embodiments, if Ring W is aromatic then X3is C(O-(CH2)2-O-CH3In other embodiments, if Ring Wis aromatic X3 is C(NH-CH2-cyclopropyl). In other embodiments, if Ring W is aromatic X3 is C(isopropoxy). In other embodiments, if Ring W is aromatic X3 is C(O-CH(CH3)-CH2-O-CH3). In other embodiments, if Ring W is aromatic X3 is C(OCHF2). In other embodiments, if Ring W is aromatic X3 is C(Cl). In other embodiments, if Ring W is aromatic X3 is C(C(O)CH3). In other embodiments, if Ring W is aromatic X3 is C(OH). In some embodiments, if Ring W is non-aromatic then X3 is CH2. In some embodiments, if Ring W is non-aromatic then X3 is CH(R). In some embodiments, if Ring W is non- aromatic then X3 is C(R)2. In some embodiments, if Ring W is non-aromatic then X3 is NH. In some embodiments, if Ring W is non-aromatic then X3 is N(R). In some embodiments, if Ring W is non- aromatic then X3 is O. In some embodiments, if Ring W is non-aromatic then X3 is S. In some embodiments, if Ring W is non-aromatic then X3 is S=O. In some embodiments, if Ring W is non- aromatic then X3 is SO2.

[0061] In some embodiments, X4 of formula I and / or I(a)-I(j) is N. In other embodiments, X4 is a CH. In other embodiments, X4 is a C(R). In other embodiments, X4 is C(CH3). In other embodiments, X4 is C(CH2CH3). In other embodiments, X4 is C-iPr. In other embodiments, X4 is C-CH2-cyclopropyl. In other embodiments, X4 is C(O-CH2-cyclopropyl). In other embodiments, X4 is C(O-CH2- methylcyclobutyl). In other embodiments, X4 is C(O-CH2-3-methyloxetane). In other embodiments, X4 is C(OCH3) In other embodiments, X4 is C(OCH2CH3) In other embodiments, X4 is C(O-(CH2)2-O-CH3. In other embodiments, X4 is C(NH-CH2-cyclopropyl). In other embodiments, X4 is C(isopropoxy). In other embodiments, X4is C(O-CH(CH3)-CH2-O-CH3). In other embodiments, X4is C(OCHF2). In other embodiments, X4is C(Cl). In other embodiments, X4is C(C(O)CH3). In other embodiments, X4is C(OH).

[0062] In some embodiments, Ring W of formula I(k)-I(m) is aromatic or non-aromatic. In some embodiments, if Ring W is aromatic, then X4is a CH. In other embodiments, if Ring W is aromatic, then X4 is a C(R). In other embodiments, if Ring W is aromatic, then X4 is C(CH3). In other embodiments, if Ring W is aromatic, then X4 is C(CH2CH3). In other embodiments, if Ring W is aromatic, then X4is C-iPr. In other embodiments, if Ring W is aromatic, then X4is C-CH2-cyclopropyl. In other embodiments, if Ring W is aromatic, then X4is C(O-CH2-cyclopropyl). In other embodiments, if Ring W is aromatic, then X4is C(O-CH2-methylcyclobutyl). In other embodiments, if Ring W is aromatic, then X4is C(O-CH2-3-methyloxetane). In other embodiments, if Ring W is aromatic, then X4is C(OCH3) In other embodiments, if Ring W is aromatic, then X4is C(OCH2CH3). In other embodiments, if Ring W is aromatic, then X4is C(O-(CH2)2-O-CH3. In other embodiments, if Ring W is aromatic X4is C(NH-CH2-cyclopropyl). In other embodiments, if Ring W is aromatic X4is C(isopropoxy). In other embodiments, if Ring W is aromatic X4is C(O-CH(CH3)-CH2-O-CH3). In other embodiments, if Ring W is aromatic X4is C(OCHF2). In other embodiments, if Ring W is aromatic X4is C(Cl). In other embodiments, if Ring W is aromatic X4is C(C(O)CH3). In other embodiments, if Ring W is aromatic X4is C(OH). In some embodiments, if Ring W is non-aromatic then X4is CH2. In some embodiments, if Ring W is non-aromatic then X4is CH(R). In some embodiments, if Ring W is non- aromatic then X4is C(R)2. In some embodiments if Ring W is non-aromatic then X4is NH. In someembodiments, if Ring W is non-aromatic then X4 is N(R). In some embodiments, if Ring W is non- aromatic then X4 is O. In some embodiments, if Ring W is non-aromatic then X4 is S. In some embodiments, if Ring W is non-aromatic then X4 is S=O. In some embodiments, if Ring W is non- aromatic then X4 is SO2.

[0063] In some embodiments, X5 of formula I and / or I(a)-I(n) is a nitrogen atom. In other embodiments, X5 is a carbon atom. In some embodiments, if X5 is nitrogen, then the respective R7’ is absent.

[0064] In some embodiments, X6 of formula I and / or I(a)-I(n) is a nitrogen atom. In other embodiments, X6 is a carbon atom. In some embodiments, if X6 is nitrogen, then the respective R7’’ is absent.

[0065] In some embodiments, X7 of formula I and / or I(a)-I(k) and / or I(n) is a nitrogen atom. In other embodiments, X7 is a carbon atom. In some embodiments, if X7 is nitrogen, then the respective R7 is absent.

[0066] In some embodiments, X8 of formula I and / or I(a)-I(n) is a nitrogen atom. In other embodiments, X8 is a carbon atom. In some embodiments, if X8 is nitrogen, then the respective R7’’’ is absent.

[0067] In some embodiments, X9 of formula I and / or I(a)-I(n) is a nitrogen atom. In other embodiments, X9 is a carbon atom. In some embodiments, if X9 is nitrogen, then the respective R7’’’’ is absent.

[0068] In some embodiments, X10of formula I and / or I(a)-I(n) is a nitrogen atom. In other embodiments, X10is carbon. In other embodiments, X10is N. In other embodiments, X10is CH. In other embodiments, X10is C(R), wherein R is as defined below. In other embodiments, X10is C(R), wherein R is an alkyl. In other embodiments, X10is C(R), wherein R is a methyl, a substituted methyl, CH2-OH, an ethyl, a substituted ethyl, CH2-CH2-OH, NH(R10), NH-CH2-cyclopropyl, COOH, cycloalkyl such as cyclopropyl, alkoxy such as isopropoxy; each represents a separate embodiment according to this invention. In other embodiments, X10is C(R), wherein R is a substituted alkyl. In other embodiments, X10is C(R), wherein R is CH2-OH. In other embodiments, X10is C(R), wherein R is CH2-CH2-OH. In other embodiments, X10is C(R), wherein R is a cycloalkyl. In other embodiments, X10is C(R), wherein R is a cyclopropyl. In other embodiments, X10is C(R), wherein R is not methyl. In other embodiments, X10is C(R), wherein R is an alkoxy. In other embodiments, X10is C(R), wherein R is an isopropoxy. In other embodiments, X10is C(CH2-OH). In other embodiments, X10is C(CH2-CH2-OH). In other embodiments, X10is C(R), wherein R is N(H)R10; and R10is a substituted alkyl. In other embodiments, X10is C(NH-CH2-cyclopropyl). In other embodiments, X10is C(COOH). In other embodiments, X10is C(CH3). In other embodiments, X10is C(cyclopropyl). In other embodiments, X10is C(isopropoxy). In other embodiments, X10is C=O. In other embodiments, if X10is C=O then X11is N.

[0069] In some embodiments, X11of formula I and / or I(a)-I(n) is a nitrogen atom. In other embodiments, X11is carbon atom. In other embodiments, X11is N. In other embodiments, X11is C. Inother embodiments, if X11 is N then X10 is C=O. In other embodiments, if X10 is C=O then X11 is N. In some embodiments, X11 of formula I(j) is CH. In some embodiments, X11 of formula I(j) is C(R).

[0070] In some embodiments, X12 of formula I and / or I(a)-I(j) is S. In other embodiments, X12 is not S. In other embodiments, X12 is SO2,. In other embodiments, X12 is O. In other embodiments, X12 is NH. In other embodiments, X12 is N(R). In other embodiments, X12 is N-CH2-COOH. In other embodiments, X12 is N-CH2-CH2-OH. In other embodiments, X12 is N-CH3. In other embodiments, X12 is N-OH. In other embodiments, X12 is CH=CH. In other embodiments, X12 is CH=CH(R). In other embodiments, X12 is C(R)=CH. In other embodiments, X12 is N=CH. In other embodiments, X12 is N=C(R). In other embodiments, X12 is CH=N. In other embodiments, X12 is C(R)=N. In other embodiments, X12 is N- CH2CH3. In other embodiments, X12 is N-iPr. In other embodiments, X12 is N-cyclopropyl. In other embodiments, X12 is N-CH2-cyclopropyl.

[0071] In some embodiments, Ring W' of formula I(k)-I(m) is aromatic or non-aromatic. In some embodiments, if Ring W' is aromatic, then X12 is S. In other embodiments, if Ring W' is aromatic, then X12 is not S. In other embodiments, if Ring W' is aromatic, then X12 is SO2,. In other embodiments, if Ring W' is aromatic, then X12 is O. In other embodiments, if Ring W' is aromatic, then X12 is NH. In other embodiments, if Ring W' is aromatic, then X12 is N(R). In other embodiments, if Ring W' is aromatic, then X12 is N-CH2-COOH. In other embodiments, if Ring W' is aromatic, then X12 is N-CH2- CH2-OH. In other embodiments, if Ring W' is aromatic, then X12 is N-CH3. In other embodiments, if Ring W' is aromatic, then X12is N-OH. In other embodiments, if Ring W' is aromatic, then X12is CH=CH. In other embodiments, if Ring W' is aromatic, then X12is CH=CH(R). In other embodiments, if Ring W' is aromatic, then X12is C(R)=CH. In other embodiments, if Ring W' is aromatic, then X12is N=CH. In other embodiments, if Ring W' is aromatic, then X12is N=C(R). In other embodiments, if Ring W' is aromatic, then X12is CH=N. In other embodiments, if Ring W' is aromatic, then X12is C(R)=N. In other embodiments, if Ring W' is aromatic, then X12 is N-CH2CH3. In other embodiments, if Ring W' is aromatic, then X12 is N-iPr. In other embodiments, if Ring W' is aromatic, then X12 is N- cyclopropyl. In other embodiments, if Ring W' is aromatic, then X12is N-CH2-cyclopropyl. In other embodiments, if Ring W' is non-aromatic, then X12is CH=CH. In other embodiments, if Ring W' is non-aromatic, then X12is CH=CH(R). In other embodiments, if Ring W' is non-aromatic, then X12is C(R)=CH. In other embodiments, if Ring W' is non-aromatic, then X12is OCH2. In other embodiments, if Ring W' is non-aromatic, then X12is CH2O. In other embodiments, if Ring W' is non-aromatic, then X12is SCH2. In other embodiments, if Ring W' is non-aromatic, then X12is CH2S. In other embodiments, if Ring W' is non-aromatic, then X12is CH=N. In other embodiments, if Ring W' is non-aromatic, then X12is C(R)=N. In other embodiments, if Ring W' is non-aromatic, then X12is N=CH. In other embodiments, if Ring W' is non-aromatic, then X12is N=C(R).

[0072] In some embodiments, X13of formula I(b), I(c), I(f), I(h) and / or I(m) is CH2. In other embodiments, X13is CH(R). In other embodiments, X13is CH-CH3. In other embodiments, X13is C(R)2. In other embodiments, X13is C=O.

[0073] In some embodiments, X14 of formula I(g), I(h), I(l) and / or I(m) is S. In other embodiments, X14 is O. In other embodiments, X14 is N. In other embodiments, X14 is CH. In other embodiments, if X14 is CH then Ring F is not absent. In other embodiments, if X14 is S then R3 is absent. In other embodiments, if X14 is O then R3 is absent.

[0074] In some embodiments, at least one of X2, X3, X4, X5, X6 , X7, X8 and X9 of formula I, I(a)-I(c), and / or I(i)-I(k) is a nitrogen atom. In some embodiments, at least one of X2, X3, X4, X5, X6 , X8 and X9 of formula I, and / or I(a)-I(m) is a nitrogen atom. In some embodiments, at least one of X2, X3, X4, X5, X6, X7, X8 and X9 of formula I(d) is a nitrogen atom. In some embodiments, at least one of X2, X3, X4, X5, X6, X7, X8, X9 and X10 of formula I(d) is a nitrogen atom. In some embodiments, if either one of X5, X6 , X7, X8 and X9 is nitrogen, then the respective R7’, R7’’, R7, R7’’’, and R7’’’’ substitution is absent.

[0075] In some embodiments, if Ring W is aromatic, then X15 of formula I(k)-I(m) is C. In some embodiments, if Ring W is non-aromatic, then X15 is CH, C(R) or N; each represents a separate embodiment according to this invention. In some embodiments, if Ring W is non-aromatic, then X15 is CH. In some embodiments, if Ring W is non-aromatic, then X15 is C(R). In some embodiments, if Ring W is non-aromatic, then X15 is N.

[0076] In some embodiments, R5 of formula I, I(a), I(d), I(e), I(g) and / or I(i)-I(n) is H. In other embodiments, R5 is C1-C5 linear or branched alkyl. In other embodiments, R5 is methyl. In other embodiments, R5 is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, iso-butyl, pentyl, neopentyl; each represents a separate embodiment according to this invention.

[0077] In some embodiments, R5and R6of formula I, I(a), I(d), I(e), I(g), and / or I(i)-I(n) are joined to form a substituted or unsubstituted 5-8 membered heterocyclic ring. In some embodiments, R5and R6are joined to form a substituted 5-8 membered heterocyclic ring. In some embodiments, R5and R6are joined to form an unsubstituted 5-8 membered heterocyclic ring. In some embodiments, the heterocyclic ring is azepane, piperazine or 2-(piperazin-1-yl)acetamide; each represents a separate embodiment according to this invention. In some embodiments, the heterocyclic ring is substituted with at least one substitution selected from: F, Cl, Br, I, CF3, R20, C1-C5linear or branched alkyl, C1-C5linear or branched haloalkyl, OH, alkoxy , R8-OH (e.g., CH2-OH), OMe, amide , C(O)N(R)2, C(O)N(R10)(R11), R8-C(O)N(R10)(R11), C(O)-pyrrolidine, C(O)-piperidine, N(R)2, NH(R10), N(R10)(R11), N(CH3)2, NH2, CF3, aryl, phenyl, heteroaryl, substituted or unsubstituted C3-C8cycloalkyl , cyclobutanol, substituted or unsubstituted 3-8 membered heterocyclic ring, which may be saturated, unsaturated, aromatice, single fused or spiral, pyran, oxetane, piperidine, pyrazole, methyl-pyrrazole, triazole, imidazole, halophenyl, (benzyloxy)phenyl, CN, and NO2; each is a separate embodiment according to this invention.

[0078] In some embodiments, R6of formula I, I(a), I(d), I(e), I(g), I(i), I(j)-I(l) and / or I(n) is H. In other embodiments, R6is H, F, Cl, Br, I, OH, SH, R8-OH, R8-SH, -R8-O-R10, CH2-O-CH3, (CH2)2-O- CH3(CH2)3-O-CH3, (CH2)2-O-CH(CH3)2, R8-S-R10, (CH2)3-S-(CH2)2CH3, R8-NHC(O)-R10, -O-R8-R10, R8-(substituted or unsubstituted C3-C8cycloalkyl), CH2-cyclopropyl, CH2-cyclobutanol, CH2- difluorocyclopropyl, CH2-methylcyclopropyl, CH2-dimethylamino-cyclohexyl, (CH2)2-cyclopentanole, CH2-cyclohexanol), R8-(substituted or unsubstituted saturated unsaturated or aromatic, single, fused orspiro 3-10 membered heterocyclic ring), (CH2)3-piperidine, (CH2)3-4-fluoro-piperidine, (CH2)3-pyran, (CH2)2-pyrrazole, (CH2)2-imidazole, CH2-tetrahydrofurane, CH2-dioxane, CH2-oxetane, CH2- piperidine, CH2-triazole, CH2-1-oxa-8-azaspiro[4.5]decane, (CH2)3-diazabicyclo[2.2.1]heptane, CH2- methyl-THF, CH2-ethyl-piperidine, CH2-oxa-azaspirodecane, (CH2)3-dimethylpyrazole, CH2-2-oxo- methylpyrrolidine, CH2-methyl-azetidine, CH2-azaspiroheptane, CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, NH(R10), N(R10)(R11), R8-N(R10)(R11), (CH2)2-NH2, (CH2)3-N(CH2CH3)2, (CH2)3-N(CH(CH3)2)2, (CH2)3-piperidine, (CH2)3-4-fluoro-piperidine, (CH2)3-piperidine-2-one, (CH2)3- 4-cyano-piperidine, (CH2)3-4-trifluoromethyl-piperidine, (CH2)4-NH(CH3), (CH2)3-NH-CH3, (CH2)3- NH-CH2CH3, (CH2)3-N(CH2CH3)2, (CH2)3-NH2, (CH2)3-N(CH2CH3)(CH2CF3), R8-C(O)N(R10)(R11), (CH2)2-C(O)-piperidine, R9-R8-N(R10)(R11), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R10, NHCO- N(R10)(R11), COOH, -C(O)Ph, C(O)O-R10, R8-C(O)-R10, C(O)H, C(O)-R10 (e.g., C(O)CH3), C1-C5 linear or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR, C(O)N(R10)(R11), SO2R, SO2N(R10)(R11), CH(CF3)(NH-R10), C1-C5 linear or branched, substituted or unsubstituted alkyl, CH(CH3)CH2OCH3, CH(CH3)CH2NH2, CH(CH3)C(O)N(CH3)2, CH2-CH(OH)Ph, (CH2)3N(H)CH2CH3, CH(CH3)(CH2)2OH, CH(CH2OH)(CH2CH3), (CH2)3-OCH3, (CH2)2-OCH3, (CH2)2-OCH(CH3)2, CH(CH2OH)(CH2CH(CH3)2), CH2CH(CH3)(OCH3), CH2CH(N(CH3)2)(CH2CH3), benzyl, methyl, ethyl, CH2-OCH2-CH2-O-CH3, CH(CH3)C(O)N(CH3)2, C1-C5 linear or branched, substituted or unsubstituted alkenyl, C1-C5 linear or branched, or C3-C8 cyclic haloalkyl, substituted or unsubstituted C1-C5linear or branched, or C3-C8cyclic alkoxy methoxy, optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom, O-(CH2)2-O-CH3, C1-C5linear or branched thioalkoxy, C1-C5linear or branched haloalkoxy, C1-C5linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8cycloalkyl, cyclopropyl, cyclobutyl, cyclohexyl, methoxycyclopropyl, methylcyclobutyl, cyclopropyl, aminomethyl-cyclobutyl, methoxycyclobutyl, 2,3-dihydro-1H-indenol, R8-(substituted or unsubstituted C3-C8 cycloalkyl), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., piperidine, 1-methyl-piperidine, azetidine, pyrrolidine, pyrrolidinone, quinuclidine, tetrahydropyran, azaspiro[3.3]heptane, imidazole, trifluoromethyl-oxetane, hydroxy- tetrahydrofurane, azepan-2-one, azabicyclohexane), substituted or unsubstituted aryl, substituted or unsubstituted R8-aryl (e.g., benzyl), or substituted or unsubstituted benzyl; each represents a separate embodiment according to this invention. In some embodiments, R6may be further substituted with at least one substitution selected from: F, Cl, Br, I, C1-C5linear or branched alkyl, OH, alkoxy , OMe, amide , C(O)N(R)2, C(O)-alkyl, C(O)-pyrrolidine, C(O)-piperidine, N(R)2, NH(R10), N(R10)(R11), N(CH3)2, NH2, CF3, aryl, phenyl, heteroaryl, substituted or unsubstituted C3-C8cycloalkyl , cyclobutanol, substituted or unsubstituted 3-8 membered heterocyclic ring pyran, oxetane, piperidine, pyrazole, methyl-pyrrazole, triazole, imidazole, halophenyl, (benzyloxy)phenyl, CN, and NO2; each represents a separate embodiment according to this invention. In some embodiments, R6is H. In some embodiments, R6is -R8-O-R10. In some embodiments, R6is CH2-O-CH3. In some embodiments, R6is R8-S-R10. In some embodiments, R6is (CH2)3-S-(CH2)2CH3. In some embodiments, R6is R8-NHC(O)- R10. In some embodiments, R6is (CH2)3-NHC(O)-R10In some embodiments, R6is (CH2)-NHC(O)-R10.In some embodiments, R6 is R8-(substituted or unsubstituted C3-C8 cycloalkyl). Examples of R8- (substituted or unsubstituted C3-C8 cycloalkyl) include but not limited to: CH2-cyclobutanol, CH2- difluorocyclopropyl, CH2-methylcyclopropyl, CH2-dimethylamino-cyclohexyl, (CH2)2-cyclopentanole, and CH2-cyclohexanol; each represents a separate embodiment according to this invention. In some embodiments, R6 is R8-(substituted or unsubstituted saturated, unsaturated or aromatic, single, fused or spiro 3-8 membered heterocyclic ring). In some embodiments, R6 is R8-(substituted or unsubstituted saturated, single 3-8 membered heterocyclic ring). In some embodiments, R6 is R8-(substituted or unsubstituted unsaturated, single 3-8 membered heterocyclic ring). In some embodiments, R6 is R8- (substituted or unsubstituted aromatic, single 3-8 membered heterocyclic ring). In some embodiments, R6 is R8-(substituted or unsubstituted saturated, fused 3-8 membered heterocyclic ring). In some embodiments, R6 is R8-(substituted or unsubstituted unsaturated, fused 3-8 membered heterocyclic ring). In some embodiments, R6 is R8-(substituted or unsubstituted aromatic, fused 3-8 membered heterocyclic ring). In some embodiments, R6 is R8-(substituted or unsubstituted spiro 3-8 membered heterocyclic ring). Examples of R8-(substituted or unsubstituted saturated, unsaturated or aromatic, single, fused or spiro 3-8 membered heterocyclic ring) include but not limited to: (CH2)3-piperidine, (CH2)3-4-fluoro- piperidine, (CH2)3-pyran, (CH2)2-pyrrazole, (CH2)2-imidazole, CH2-tetrahydrofurane, CH2-dioxane, CH2-oxetane, CH2-piperidine, CH2-triazole, CH2-1-oxa-8-azaspiro[4.5]decane, (CH2)3- diazabicyclo[2.2.1]heptane, CH2-methyl-THF, CH2-ethyl-piperidine, CH2-oxa-azaspirodecane, (CH2)3- dimethylpyrazole, CH2-2-oxo-methylpyrrolidine, CH2-methyl-azetidine, and CH2-azaspiroheptane. In some embodiments, R6is NH2. In some embodiments, R6is NHR. In some embodiments, R6is N(R)2. In some embodiments, R6is NH(R10). In some embodiments, R6is N(R10)(R11). In some embodiments, R6is R8-N(R10)(R11). In some embodiments, R8-N(R10)(R11) includes but not limited to: (CH2)3- N(CH2CH3)2, (CH2)3-N(CH(CH3)2)2, (CH2)3-piperidine, (CH2)4-NH(CH3), (CH2)3-NH-CH3, (CH2)3- NH-CH2CH3, (CH2)3-N(CH2CH3)2, (CH2)2-NH2, (CH2)3-NH2, and (CH2)3-N(CH2CH3)(CH2CF3). In some embodiments, R6 is R8-C(O)N(R10)(R11) such as (CH2)2-C(O)-piperidine. In some embodiments, R6is C1-C5linear or branched, substituted or unsubstituted alkyl. Examples of C1-C5linear or branched, substituted or unsubstituted alkyl include but not limited to: CH(CH3)CH2OCH3, CH(CH3)CH2NH2, CH(CH3)C(O)N(CH3)2, CH2-CH(OH)Ph, (CH2)3N(H)CH2CH3, CH(CH3)(CH2)2OH, CH(CH2OH)(CH2CH3), (CH2)3-OCH3, (CH2)2-OCH3, (CH2)2-OCH(CH3)2, CH(CH2OH)(CH2CH(CH3)2), CH2CH(CH3)(OCH3), CH2CH(N(CH3)2)(CH2CH3), CH(CH3)C(O)N(CH3)2, benzyl, methyl, ethyl, and CH2-OCH2-CH2-O-CH3. In some embodiments, R6is methyl. In some embodiments, R6is substituted or unsubstituted C3-C8cycloalkyl. In some embodiments, substituted or unsubstituted C3-C8cycloalkyl include: cyclopropyl, cyclobutyl, cyclohexyl, methoxycyclopropyl, methylcyclobutyl, cyclopropyl, aminomethyl-cyclobutyl, methoxycyclobutyl and 2,3-dihydro-1H-indeno. In some embodiments, R6is R8-(substituted or unsubstituted C3-C8cycloalkyl). In some embodiments, R6is substituted or unsubstituted saturated, unsaturated or aromatic, single, fused or spiro 3-10 membered heterocyclic ring. In some embodiments, the substituted or unsubstituted saturated unsaturated or aromatic single, fused or spiro 3-10 memberedheterocyclic ring is piperidine, 1-methyl-piperidine, azetidine, pyrrolidine, pyrrolidinone, quinuclidine, tetrahydropyran, azaspiro[3.3]heptane, imidazole, trifluoromethyl-oxetane, hydroxy-tetrahydrofurane, azepan-2-one, azabicyclohexane; each represents a separate embodiment according to this invention. In some embodiments, R6 is piperidine. In some embodiments, R6 is 1-methyl-piperidine. In some embodiments, R6 is tetrahydropyran. In some embodiments, R6 is substituted or unsubstituted R8-aryl, such as benzyl. In some embodiments, R6 may be further substituted by at least one substitution selected from: F, Cl, Br, I, CF3, R20, C1-C5 linear or branched alkyl, C1-C5 linear or branched haloalkyl, OH, alkoxy , R8-OH (e.g., CH2-OH), OMe, amide , C(O)N(R)2, C(O)N(R10)(R11), R8-C(O)N(R10)(R11), C(O)- pyrrolidine, C(O)-piperidine, N(R)2, NH(R10), N(R10)(R11), N(CH3)2, NH2, CF3, aryl, phenyl, heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl , cyclobutanol, substituted or unsubstituted 3-8 membered heterocyclic ring, which may be saturated, unsaturated, aromatice, single fused or spiral, pyran, oxetane, piperidine, pyrazole, methyl-pyrrazole, triazole, imidazole, halophenyl, (benzyloxy)phenyl, CN, and NO2; each is a separate embodiment according to this invention.

[0079] In some embodiments, R6 and R5 of formula I, I(a), I(d), I(e), I(g), I(i), I(j)-I(l) and / or I(n) are joined to form a substituted or unsubstituted saturated, unsaturated or aromatic, single, fused or spiro 5- 8 membered heterocyclic ring. In some embodiments, the substituted or unsubstituted saturated, unsaturated or aromatic, single, fused or spiro 5-8 membered heterocyclic ring is azepane, piperazine, or 2-(piperazin-1-yl)acetamide; each represents a separate embodiment according to this invention. In some embodiments, the ring may be further substituted by at least one substitution selected from: F, Cl, Br, I, C1-C5linear or branched alkyl, OH, alkoxy (e.g., OMe), amide (e.g., C(O)N(R)2, C(O)-pyrrolidine, C(O)-piperidine, N(R)2NH(R10), N(R10)(R11), (e.g., N(CH3)2, NH2), CF3, aryl, phenyl, heteroaryl, substituted or unsubstituted C3-C8cycloalkyl (e.g., cyclobutanol), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g. pyran, oxetane, piperidine, pyrazole, methyl-pyrrazole, triazole, imidazole), halophenyl, (benzyloxy)phenyl, CN and NO2; each represents a separate embodiment according to this invention.

[0080] In some embodiments, R6of formula I, I(a), I(d), I(e), I(g), I(i), I(j)-I(l) and / or I(n) is represented by the structure of formula B:wherein m is 0 or 1; and R12is R20or C1-C5C(O)-alkyl, and R13is R30; or R12and R13are both H; or R12and R13are each independently H or substituted or unsubstituted C1-C5alkyl (e.g., ethyl, trifluoroethyl); orR12 and C3 are joined to form ring A and R13 is R30; or R12 and R13 are joined to form ring B; or R12 and C1 are joined to form ring C and R13 is R30; or C1 and C3 are joined to form ring D and R12 and R13 are each independently R30; or R13 and C2 are joined to form ring E, m is 1, and R12 is R30; or R12 and R13 are joined to form ring B and C1 and C3 are joined to form ring D; wherein Ring A, C and E are each independently a substituted or unsubstituted single spiro or fused 3-8 membered heterocyclic rings; Ring B is a substituted or unsubstituted single, spiro or fused 3-8 membered heterocyclic ring; and Ring D is a substituted or unsubstituted C3-C8 cycloalkyl;

[0081] In some embodiments, formula B is represented by formula Bi.

[0082] In some embodiments, R6 of formula I, I(a), I(d), I(e), I(g), I(i), I(j)-I(l) and / or I(n) is represented by the structure of formula Bi: whereinm is 0 or 1; and R12is R20or C1-C5C(O)-alkyl, and R13is R30; or R12 and R13 are both H; or R12 and R13 are each independently H or substituted or unsubstituted C1-C5 alkyl (e.g., ethyl, trifluoroethyl); or R12 and C3 are joined to form ring A and R13 is R30; or R12 and R13 are joined to form ring B; or R12 and C1 are joined to form ring C and R13 is R30; or C1 and C3 are joined to form ring D and R12 and R13 are each independently R30; or R13 and C2 are joined to form ring E, m is 1, and R12 is R30; or R12 and R13 are joined to form ring B and C1 and C3 are joined to form ring D; wherein Ring A, C and E are each independently a substituted or unsubstituted single spiro or fused 3-8 membered heterocyclic rings;Ring B is a substituted or unsubstituted single, spiro or fused 3-8 membered heterocyclic ring; and Ring D is a substituted or unsubstituted C3-C8 cycloalkyl;

[0083] In some embodiments, R12 of formula B and / or Bi is H. In some embodiments, R12 is R20. In other embodiments, R12 is R30. In some embodiments, R12 is C1-C5 C(O)-alkyl. In some embodiments, R12 is substituted or unsubstituted C1-C5 alkyl. In some embodiments, R12 is unsubstituted C1-C5 alkyl. In some embodiments, the alkyl is ethyl. In some embodiments, R12 is substituted C1-C5 alkyl. In some embodiments,the alkyl is trifluoroethyl.

[0084] In some embodiments, R13 of formula B and / or Bi is H. In other embodiments, R13 is R30. In some embodiments, R13 is substituted or unsubstituted C1-C5 alkyl. In some embodiments, R13 is unsubstituted C1-C5 alkyl. In some embodiments, the alkyl is ethyl. In some embodiments, R13 is substituted C1-C5 alkyl. In some embodiments,the alkyl is trifluoroethyl.

[0085] In some embodiments, R6 of formula I, I(a), I(d), I(e), I(g), I(i), I(j)-I(l) and / or I(n) is represented by formula B. In some embodiments, R12 of formula B is R20 or C1-C5 C(O)-alkyl, and R13 is R30. In some embodiments, R12 and R13 of formula B are both H. In some embodiments, R12 and R13 of formula B are each independently H or substituted or unsubstituted C1-C5 alkyl (e.g., ethyl, trifluoroethyl). In some embodiments, R12 and R13 of formula B are each independently H or trifluoroethyl. In some embodiments, R12 and C3 of formula B are joined to form ring A and R13 is R30. In some embodiments, R12and R13of formula B are joined to form ring B. In some embodiments, R12and C1 of formula B are joined to form ring C and R13is R30. In some embodiments, C1 and C3 of formula B are joined to form ring D and R12and R13of formula B are each independently R30. In some embodiments, R13and C2 of formula B are joined to form ring E, m is 1, and R12of formula B is R30. In some embodiments, R12and R13of formula B are joined to form ring B and C1 and C3 of formula B are joined to form ring D.

[0086] In some embodiments, R6 of formula I, I(a), I(d), I(e), I(g), I(i), I(j)-I(l) and / or I(n) is represented by formula Bi. in some embodiments, R12of formula Bi is R20or C1-C5C(O)-alkyl, and R13is R30. In some embodiments, R12and R13of formula Bi are both H. In some embodiments, R12and R13of formula Bi are each independently H or substituted or unsubstituted C1-C5alkyl (e.g., ethyl, trifluoroethyl). In some embodiments, R12and R13of formula Bi are each independently H or trifluoroethyl. In some embodiments, R12and C3 of formula Bi are joined to form ring A and R13is R30. In some embodiments, R12and R13of formula Bi are joined to form ring B. In some embodiments, R12and C1 of formula Bi are joined to form ring C and R13is R30. In some embodiments, C1 and C3 of formula Bi are joined to form ring D and R12and R13of formula Bi are each independently R30. In some embodiments, R13and C2 of formula Bi are joined to form ring E, m is 1, and R12of formula Bi is R30. In some embodiments, R12and R13of formula Bi are joined to form ring B and C1 and C3 of formula Bi are joined to form ring D.

[0087] In some embodiments, R6of formula I, I(a), I(d), I(e), I(g), I(i), I(j)-I(l) and / or I(n) is represented by formula Bi and / or B andR12 of formula Bi and / or B is R20 or C1-C5 C(O)-alkyl, and R13 of formula Bi and / or B is R30; or R12 and R13 are both H, or R12 and R13 are each independently H or trifluoroethyl; or R12 and C3 are joined to form ring A and R13 is R30; or R12 and R13 are joined to form a substituted or unsubstituted pyrrolidine ring, piperazine, thiomorpholine 1,1-dioxide 2-oxa-6-azaspiro[3.3]heptane, pyrazole, imidazole, 2,5- diazabicyclo[2.2.1]heptane or a diazabicyclo[2.2.1]heptane; or R12 and C1 are joined to form ring C and R13 is R30; or C1 and C3 are joined to form ring D and R12 and R13 are each independently R30; or R13 and C2 are joined to form ring E, m is 1, and R12 is R30; or R12 and R13 are joined to form ring B and C1 and C3 are joined to form ring D.

[0088] In some embodiments, R6 of formula I, I(a), I(d), I(e), I(g), I(i), I(j)-I(l) and / or I(n) is represented by formula Bi and / or B and R12 of formula Bi and / or B is R20 or C1-C5 C(O)-alkyl, and R13 of formula Bi and / or B is R30; or R12 and C3 are joined to form ring A and R13 is R30; or R12 and R13 are joined to form a substituted or unsubstituted pyrrolidine ring, piperazine, thiomorpholine 1,1-dioxide 2-oxa-6-azaspiro[3.3]heptane, pyrazole, imidazole, 2,5- diazabicyclo[2.2.1]heptane or a diazabicyclo[2.2.1]heptane; or R12and C1 are joined to form ring C and R13is R30; or C1 and C3 are joined to form ring D and R12and R13are each independently R30; or R13and C2 are joined to form ring E, m is 1, and R12is R30; or R12 and R13 are joined to form ring B and C1 and C3 are joined to form ring D.

[0089] In some embodiments, ring A of formula Bi, is a substituted or unsubstituted single spiro or fused 3-8 membered heterocyclic ring. In some embodiments, ring A, is an unsubstituted single 3-8 membered heterocyclic ring. In some embodiments, ring A, is an unsubstituted spiro 3-8 membered heterocyclic ring. In some embodiments, ring A, is an unsubstituted fused 3-8 membered heterocyclic ring. In some embodiments, ring A, is a substituted single 3-8 membered heterocyclic ring. In some embodiments, ring A, is a substituted spiro 3-8 membered heterocyclic ring. In some embodiments, ring A, is a substituted fused 3-8 membered heterocyclic ring. In some embodiments, ring A is: pyrrolidine, methylpyrrolidine, ethylpyrrolidine, 2-oxopyrrolidine, piperidine, methylpiperidine, methyl-2- oxopyrrolidine, pyran- azetidine, methyl-azetidine, azabicyclooctane, 2-azabicyclo[2.1.1]hexane, or 2- azaspiro[3.3]heptane; each represents a separate embodiment according to this invention. In some embodiments, ring A is: pyrrolidine, methylpyrrolidine, or ethylpyrrolidine; each represents a separate embodiment according to this invention.

[0090] In some embodiments, ring B of formula Bi, is a substituted or unsubstituted single spiro or fused 3-8 membered heterocyclic ring In some embodiments ring B, is an unsubstituted single 3-8membered heterocyclic ring. In some embodiments, ring B, is an unsubstituted spiro 3-8 membered heterocyclic ring. In some embodiments, ring B, is an unsubstituted fused 3-8 membered heterocyclic ring. In some embodiments, ring B, is a substituted single 3-8 membered heterocyclic ring. In some embodiments, ring B, is a substituted spiro 3-8 membered heterocyclic ring. In some embodiments, ring B, is a substituted fused 3-8 membered heterocyclic ring. In some embodiments, ring B is: pyrrolidine, methylpyrrolidine, ethylpyrrolidine, 2-oxopyrrolidine, hydroxymethyl-pyrrolidine, piperidine, piperidin-2-one, 4-fluoropiperidin-2-one, piperidine-4-carbonitrile, methylpiperidine, fluoropiperidine, 4-fluoropiperidine, 4-fluoro-2-methylpiperidine, difluoropiperidine, piperazine, methyl-piperazine, dimethyl-pyrazole, methyl-2-oxopyrrolidine, pyran-, azetidine, methyl-azetidine, imidazole, azabicyclooctane, 2-azabicyclo[2.1.1]hexane, or 2-azaspiro[3.3]heptane, diazabicyclo[2.2.1]heptane, 2- methyl-2,5-diazabicyclo[2.2.1]heptane, thiomorpholine, or 1,1-dioxide-2-oxa-6-azaspiro[3.3]heptane; each represents a separate embodiment according to this invention. In some embodiments, ring B is: piperidine, methyl-piperidin, fluoropiperidine, difluoropiperidine, pyrrolidine, piperazine, methylpyrrolidine, thiomorpholine, methyl-piperazine, dimethyl-pyrazole, imidazole, 2-methyl-2,5- diazabicyclo[2.2.1]heptane, 1,1-dioxide-2-oxa-6-azaspiro[3.3]heptane, hydroxymethyl-pyrrolidine or diazabicyclo[2.2.1]heptane, 6-fluoro-3-azabicyclo[3.1.1]heptane; each represents a separate embodiment according to this invention. In some embodiments, ring B is 4-fluoropiperidine.

[0091] In some embodiments, ring C of formula Bi, is a substituted or unsubstituted single spiro or fused 3-8 membered heterocyclic ring. In some embodiments, ring C, is an unsubstituted single 3-8 membered heterocyclic ring. In some embodiments, ring C, is an unsubstituted spiro 3-8 membered heterocyclic ring. In some embodiments, ring C, is an unsubstituted fused 3-8 membered heterocyclic ring. In some embodiments, ring C, is a substituted single 3-8 membered heterocyclic ring. In some embodiments, ring C, is a substituted spiro 3-8 membered heterocyclic ring. In some embodiments, ring C, is a substituted fused 3-8 membered heterocyclic ring. In some embodiments, ring C is: pyrrolidine, methylpyrrolidine, ethylpyrrolidine, 2-oxopyrrolidine, piperidine, methylpiperidine, methyl-2- oxopyrrolidine, pyran- azetidine, methyl-azetidine, azabicyclooctane, 2-azabicyclo[2.1.1]hexane, or 2- azaspiro[3.3]heptane; each represents a separate embodiment according to this invention. In some embodiments, ring C is: piperidine, pyrrolidine, methyl-2-oxopyrrolidine, pyran-pyrrolidine, methyl- azetidine, azabicyclooctane, 2-azabicyclo[2.1.1]hexane, or 2-azaspiro[3.3]heptane; each represents a separate embodiment according to this invention.

[0092] In some embodiments, ring D of formula Bi, is a substituted or unsubstituted C3-C8cycloalkyl. In some embodiments, ring D, is a substituted C3-C8cycloalkyl. In some embodiments, ring D, is an unsubstituted C3-C8cycloalkyl. In some embodiments, ring D is cyclopropane, cyclobutane, cyclopentane, cyclohexane or cycloheptane; each represents a separate embodiment according to this invention.

[0093] In some embodiments, ring E of formula Bi, is a substituted or unsubstituted single spiro or fused 3-8 membered heterocyclic ring. In some embodiments, ring E, is an unsubstituted single 3-8 membered heterocyclic ring. In some embodiments ring E is an unsubstituted spiro 3-8 memberedheterocyclic ring. In some embodiments, ring E, is an unsubstituted fused 3-8 membered heterocyclic ring. In some embodiments, ring E, is a substituted single 3-8 membered heterocyclic ring. In some embodiments, ring E, is a substituted spiro 3-8 membered heterocyclic ring. In some embodiments, ring E, is a substituted fused 3-8 membered heterocyclic ring. In some embodiments, ring E is: pyrrolidine, methylpyrrolidine, ethylpyrrolidine, 2-oxopyrrolidine, piperidine, methylpiperidine, methyl-2- oxopyrrolidine, pyran- azetidine, methyl-azetidine, azabicyclooctane, 2-azabicyclo[2.1.1]hexane, or 2- azaspiro[3.3]heptane; each represents a separate embodiment according to this invention. In some embodiments, ring E is: pyrrolidine, azetidine, ethylpyrrolidine, oxopyrrolidine, or methylpiperidine; each represents a separate embodiment according to this invention.

[0094] In some embodiments, R6 of formula I, I(a), I(d), I(e), I(g), I(i), I(j)-I(l) and / or I(n) is F, Cl, Br, I, OH, SH, R8-OH, R8-SH, -R8-O-R10 (e.g., CH2-O-CH3), R8-S-R10 (e.g., (CH2)3-S-(CH2)2CH3), R8- NHC(O)-R10, -O-R8-R10, R8-(substituted or unsubstituted C3-C8 cycloalkyl) (e.g., CH2-cyclobutanol, CH2-difluorocyclopropyl, CH2-methylcyclopropyl, CH2-dimethylamino-cyclohexyl, (CH2)2- cyclopentanole, CH2-cyclohexanol), (CH2)3-pyran, CH2-tetrahydrofurane, CH2-dioxane, CH2-methyl- THF, CH2-oxa-azaspirodecane, (CH2)3-dimethylpyrazole, CH2-methyl-azetidine, CH2-azaspiroheptane, CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, NH(R10), N(R10)(R11), R9-R8- N(R10)(R11), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R10, NHCO-N(R10)(R11), COOH, -C(O)Ph, C(O)O-R10, R8-C(O)-R10, C(O)H, C(O)-R10 (e.g., C(O)CH3), C1-C5 linear or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR, C(O)N(R10)(R11), SO2R, SO2N(R10)(R11), CH(CF3)(NH-R10), C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., CH(CH3)CH2OCH3, CH(CH3)CH2NH2, CH(CH3)C(O)N(CH3)2, CH2-CH(OH)Ph, (CH2)3N(H)CH2CH3, CH(CH3)(CH2)2OH, CH(CH2OH)(CH2CH3), (CH2)3-OCH3, (CH2)2-OCH3, (CH2)2-OCH(CH3)2, CH(CH2OH)(CH2CH(CH3)2), CH2CH(CH3)(OCH3), CH2CH(N(CH3)2)(CH2CH3), benzyl, methyl, ethyl, CH2-OCH2-CH2-O-CH3), C1-C5 linear or branched, substituted or unsubstituted alkenyl, C1-C5 linear or branched, or C3-C8 cyclic haloalkyl, substituted or unsubstituted C1-C5 linear or branched, or C3-C8cyclic alkoxy (e.g. methoxy, O-(CH2)2-O-CH3), optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom, C1-C5linear or branched thioalkoxy, C1-C5linear or branched haloalkoxy, C1-C5linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8cycloalkyl (e.g., methoxycyclopropyl, methylcyclobutyl, cyclopropyl, aminomethyl-cyclobutyl, methoxycyclobutyl, 2,3-dihydro-1H-indenol), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., trifluoromethyl-oxetane, hydroxy-tetrahydrofurane, 1-methylazepan-2-one, 3- azabicyclo[3.1.0]hexane), substituted or unsubstituted aryl, or substituted or unsubstituted benzyl; each represents a separate embodiment according to this invention. In some embodiments, R6may be further substituted with at least one substitution selected from: F, Cl, Br, I, C1-C5linear or branched alkyl, OH, alkoxy (e.g., OMe), amide (e.g., C(O)N(R)2), C(O)-alkyl, C(O)-pyrrolidine, C(O)-piperidine, N(R)2(e.g., N(CH3)2, NH2), NH(R10), N(R10)(R11), CF3, aryl, phenyl, heteroaryl, substituted or unsubstituted C3-C8cycloalkyl (e.g., cyclobutanol), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g.pyran, oxetane, piperidine, pyrazole, methyl-pyrrazole, triazole, imidazole), halophenyl, (benzyloxy)phenyl, CN, and NO2; each represents a separate embodiment according to this invention.

[0095] In some embodiments, R6 of formula I, I(a), I(d), I(e), I(g), I(i), I(j)-I(l) and / or I(n) is -R8-O- R10. In some embodiments, -R8-O-R10 is CH2-O-CH3. In some embodiments, R6 is R8-S-R10. In some embodiments, R8-S-R10 is (CH2)3-S-(CH2)2CH3. In some embodiments, R6 is R8-NHC(O)-R10. In some embodiments, R6 is R8-(substituted or unsubstituted C3-C8 cycloalkyl). In some embodiments, the R8- (substituted or unsubstituted C3-C8 cycloalkyl) is CH2-cyclobutanol, CH2-difluorocyclopropyl, CH2- methylcyclopropyl, CH2-dimethylamino-cyclohexyl, (CH2)2-cyclopentanole, CH2-cyclohexanol). ; each represents a separate embodiment according to this invention. In some embodiments, R6 is R8- (substituted or unsubstituted, saturated, unsaturated or aromatic, single, fused or spiro 3-10 membered heterocyclic ring). In some embodiments, R6 is (CH2)3-piperidine. In some embodiments, R6 is (CH2)2- NH2. In some embodiments, R6 is (CH2)3-NH2. In some embodiments, R6 is (CH2)3-4-fluoro-piperidine. In some embodiments, R6 is (CH2)3-pyran, CH2-tetrahydrofurane, CH2-dioxane, CH2-methyl-THF, CH2- oxa-azaspirodecane, (CH2)3-dimethylpyrazole, CH2-methyl-azetidine, or CH2-azaspiroheptane; each represents a separate embodiment according to this invention. In some embodiments, R6 is C1-C5 linear or branched, substituted or unsubstituted alkyl. In some embodiments, R6 is C1-C5 linear or branched, substituted alkyl. In some embodiments, the substituted alkyl is CH(CH3)CH2OCH3, CH(CH3)CH2NH2, CH(CH3)C(O)N(CH3)2, CH2-CH(OH)Ph, (CH2)3N(H)CH2CH3, CH(CH3)(CH2)2OH, CH(CH2OH)(CH2CH3), (CH2)3-OCH3, (CH2)2-OCH3, (CH2)2-OCH(CH3)2, CH(CH2OH)(CH2CH(CH3)2), CH2CH(CH3)(OCH3), CH2CH(N(CH3)2)(CH2CH3), CH2-OCH2-CH2-O- CH3or benzyl; each represents a separate embodiment according to this invention. In some embodiments, R6is C1-C5linear or branched, unsubstituted alkyl. In some embodiments, the unsubstituted alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, or neopentyl; each represents a separate embodiment according to this invention. In some embodiments, R6 is substituted or unsubstituted C3-C8 cycloalkyl. In some embodiments, R6 is substituted C3-C8 cycloalkyl. In some embodiments, the substituted cycloalkyl is methoxycyclopropyl, methylcyclobutyl, aminomethyl-cyclobutyl, or methoxycyclobutyl, 2,3-dihydro-1H-indenol; each represents a separate embodiment according to this invention. In some embodiments, R6is unsubstituted C3-C8cycloalkyl. In some embodiments, the unsubstituted cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; each represents a separate embodiment according to this invention. In some embodiments, R6is substituted or unsubstituted 3-8 membered heterocyclic ring. In some embodiments, the substituted heterocyclic ring is piperidine, 1-methyl-piperidine, tetrahydropyran, trifluoromethyl- oxetane, hydroxy-tetrahydrofurane, 1-methylazepan-2-one, or 3-azabicyclo[3.1.0]hexane; each represents a separate embodiment according to this invention. In some embodiments, R6is piperidine.. In some embodiments, R6is 1-methyl-piperidine.. In some embodiments, R6is tetrahydropyran.

[0096] In some embodiments, R7of formula I, I(a)-I(c(, I(i), I(j), I(k) and / or I(n) is H, F, Cl, Br, I, OH, O-R20, SH, R8-OH, R8-SH, SR10, -R8-O-R10, -R8-S-R10, R8-(C3-C8cycloalkyl), R8-(3-8 membered heterocyclic ring), CF3, CD3, OCD3CN NO2-CH2CN -R8CN, NH2, NHR, N(R)2, NH(R10),N(R10)(R11), R8-N(R10)(R11), R9-R8-N(R10)(R11), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R10, NHCO- N(R10)(R11), COOH, -C(O)Ph, C(O)O-R10, R8-C(O)-R10, C(O)H, C(O)-R10, C1-C5 linear or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR, C(O)N(R10)(R11), C(O)NH(CH3), SO2R, SO2N(R10)(R11), CH(CF3)(NH-R10), C1-C5 linear or branched, substituted or unsubstituted alkyl, methyl, C1-C5 linear or branched, substituted or unsubstituted alkenyl, C1-C5 linear or branched, or C3-C8 cyclic haloalkyl, C1- C5 linear or branched, or C3-C8 cyclic alkoxy optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom, C1-C5 linear or branched thioalkyl, C1-C5 linear or branched thioalkoxy, C1-C5 linear or branched haloalkoxy, C1-C5 linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic ring, substituted or unsubstituted aryl, or substituted or unsubstituted benzyl; each represents a separate embodiment according to this invention. In some embodiments, R7 is further substituted with at least one substitution selected from: F, Cl, Br, I, C1-C5 linear or branched alkyl, OH, alkoxy (e.g., OMe), amide (e.g., C(O)N(R)2), C(O)-alkyl, C(O)-pyrrolidine, C(O)-piperidine, N(R)2 NH(R10), N(R10)(R11), (e.g., N(CH3)2, NH2), CF3, aryl, phenyl, heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclobutanol), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g. pyran, oxetane, piperidine, pyrazole, methyl-pyrrazole, triazole, imidazole), halophenyl, (benzyloxy)phenyl, CN and NO2; each represents a separate embodiment according to this invention.

[0097] In some embodiments, R7 of formula I, I(a)-I(c(, I(i), I(j), I(k) and / or I(n) is H. In some embodiments, R7is F. In some embodiments, R7is Cl. In some embodiments, R7is Br. In some embodiments, R7is I. In some embodiments, R7is OH. In some embodiments, R7is O-R20. In some embodiments, R7is CF3. In some embodiments, R7is CN. In some embodiments, R7is NH2. In some embodiments, R7is NHR. In some embodiments, R7is N(R)2. In some embodiments, R7is NH(R10). In some embodiments, R7is N(R10)(R11). In some embodiments, R7is NHC(O)-R10. In some embodiments, R7 is COOH. In some embodiments, R7 is -C(O)Ph. In some embodiments, R7 is C(O)O-R10. In some embodiments, R7 is C(O)H. In some embodiments, R7 is C(O)-R10. In some embodiments, R7 is C1-C5 linear or branched C(O)-haloalkyl. In some embodiments, R7is -C(O)NH2. In some embodiments, R7is C(O)NHR. In some embodiments, C(O)NHR is C(O)NH(CH3). In some embodiments, R7is C(O)N(R10)(R11). In some embodiments, C(O)N(R10)(R11) is C(O)NH(CH3), C(O)NH(CH2CH2OCH3), or C(O)NH(CH2CH2OH); each represents a separate embodiment according to this invention. In some embodiments, R7is SO2R. In some embodiments, R7is C1-C5linear or branched, substituted or unsubstituted alkyl. In some embodiments, the alkyl is methylimidazole, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl or hexyl; each represents a separate embodiment according to this invention. In some embodiments, R7is C1-C5linear or branched, or C3-C8cyclic haloalkyl. In some embodiments, R7is C1-C5linear haloalkyl. In some embodiments, the haloalkyl is CHF2. In some embodiments, R7is C1-C5branched haloalkyl. In some embodiments, R7is C3-C8cyclic haloalkyl. In some embodiments, R7is C1-C5linear or branched, or C3-C8cyclic alkoxy optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom. In some embodiments, R7is C1-C5linear alkoxy In some embodiments the alkoxy is methoxy. In someembodiments, the alkoxy is ethoxy. In some embodiments, R7 is C1-C5 branched alkoxy. In some embodiments, R7 is C3-C8 cyclic alkoxy. In some embodiments, R7 is C1-C5 linear or branched thioalkyl. In some embodiments, R7 is C1-C5 linear or branched haloalkoxy. In some embodiments, R7 is C1-C5 linear haloalkoxy. In some embodiments, R7 is C1-C5 branched haloalkoxy. In some embodiments, R7 is C1-C5 linear or branched alkoxyalkyl. In some embodiments, R7 is substituted or unsubstituted C3-C8 cycloalkyl. In some embodiments, the cycloalkyl is cyclopropyl, cyclopropanol, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; each represents a separate embodiment according to this invention. In some embodiments, R7 is substituted or unsubstituted 3-8 membered heterocyclic ring. In some embodiments, R7 is unsubstituted 3-8 membered heterocyclic ring. In some embodiments, R7 is substituted 3-8 membered heterocyclic ring. In some embodiments, R7 is substituted or unsubstituted 4-7 membered heterocyclic ring. In some embodiments, R7 is unsubstituted 4-7 membered heterocyclic ring. In some embodiments, R7 is substituted 4-7 membered heterocyclic ring. In some embodiments, the heterocyclic ring is morpholine (e.g., 2 or 3-morpholine), tetrahydrofuran, tetrahydropyran, oxetane, oxetan-3-ol, pyrrolidine, pyrrolidine-3-ol, 1-methylpyrrolidine, pyrrolidin-2-one, pyrrolidinone, imidazole, pyrazole, piperazine, piperidine, piperidine-4-ol, piperidine-4-carbonitrile, 4- fluoropiperidine, oxadiazole, triazole, 2-oxopyrrolidine, pyridine, or 1-methylpyridine; each represents a separate embodiment according to this invention. In some embodiments, R7 is R8-(substituted or unsubstituted single, fused or spiro 3-8 membered heterocyclic ring). In some embodiments, R7 is R8- (unsubstituted single 3-8 membered heterocyclic ring). In some embodiments, R7is R8-( unsubstituted fused 3-8 membered heterocyclic ring). In some embodiments, R7is R8-(unsubstituted spiro 3-8 membered heterocyclic ring). In some embodiments, R7is R8-(substituted single 3-8 membered heterocyclic ring). In some embodiments, R7is R8-(substituted fused 3-8 membered heterocyclic ring). In some embodiments, R7is R8-(substituted spiro 3-8 membered heterocyclic ring). In some embodiments, the heterocyclic ring may be saturated. In some embodiments, the heterocyclic ring may be unsaturated. In some embodiments, the hetrocyclic ring may be aromatic. In some embodiments, R7 is substituted or unsubstituted aryl. In some embodiments, R7is phenyl. In some embodiments, R7may be further substituted with at least one substitution selected from: F, Cl, Br, I, C1-C5linear or branched alkyl, OH, alkoxy (e.g., OMe), amide (e.g., C(O)N(R)2, C(O)-pyrrolidine, C(O)-piperidine, N(R)2NH(R10), N(R10)(R11), (e.g., N(CH3)2, NH2), CF3, aryl, phenyl, heteroaryl, substituted or unsubstituted C3-C8cycloalkyl (e.g., cyclobutanol), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g. pyran, oxetane, piperidine, pyrazole, methyl-pyrrazole, triazole, imidazole), halophenyl, (benzyloxy)phenyl, CN and NO2; each represents a separate embodiment according to this invention.

[0098] In some embodiments, R7of formula I, I(a)-I(c(, I(i), I(j), I(k) and / or I(n) is O-R20. In some embodiments, R7is substituted or unsubstituted 4-7 membered heterocyclic ring. In some embodiments, R7is unsubstituted 4-7 membered heterocyclic ring. In some embodiments, R7is substituted 4-7 membered heterocyclic ring. In some embodiments, the heterocyclic ring is morpholine, (e.g., 2 or 3- morpholine), pyran, oxetane, pyrrolidine, pyrrolidine-3-ol, tetrahydrofuran, imidazole, piperazine, piperidine, piperidine-4-ol, dioxazole triazole pyridine 1-methylpyridine, or 2-oxopyrrolidine; eachrepresents a separate embodiment according to this invention. In some embodiments, R7 is substituted or unsubstituted aryl. In some embodiments, R7 is phenyl. In some embodiments, R7 may be further substituted with at least one substitution selected from F, Cl, Br, I, C1-C5 linear or branched alkyl, OH, alkoxy (e.g., OMe), amide (e.g., C(O)N(R)2, C(O)-pyrrolidine, C(O)-piperidine, N(R)2 NH(R10), N(R10)(R11), (e.g., N(CH3)2, NH2), CF3, aryl, phenyl, heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclobutanol), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g. pyran, oxetane, piperidine, pyrazole, methyl-pyrrazole, triazole, imidazole), halophenyl, (benzyloxy)phenyl, CN and NO2; each represents a separate embodiment according to this invention.

[0099] In some embodiments, R7 of formula I, I(a)-I(c(, I(i), I(j), I(k) and / or I(n) is not H, F, Cl, C1- C5 linear or branched, or C3-C8 cyclic alkoxy , C1-C5 linear or branched haloalkoxy or C1-C5 linear or branched, substituted or unsubstituted alkyl.

[0100] In some embodiments, R7 of formula I, I(a)-I(c(, I(i), I(j), I(k) and / or I(n) is represented by the structure of formula A: whereinX1is N or O; R1and R2are each independently H, F, Cl, Br, I, OH, SH, or CF3, substituted or unsubstituted C1-C5alkyl, C1-C5linear or branched, or C3-C8cyclic haloalkyl, substituted or unsubstituted C1-C5linear or branched, or C3-C8cyclic alkoxy; or R1and R2are joined to form =O or a C3-C8carbocyclic or heterocyclic ring (e.g., cyclopropyl); each is a separate embodiment according to this invention; R3and R4are each independently H, Me, substituted or unsubstituted C1-C5alkyl (e.g., methoxyethyl, methylaminoethyl, aminoethyl), -R8-O-R10(e.g., (CH2)2-O-CH3), R8-N(R10)(R11) (e.g., (CH2)2-NH(CH3)), substituted or unsubstituted C3-C8cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted 5-7 membered heterocyclic ring (e.g., pyrrolidine, methylpyrrolidine, piperidine), or R20; each is a separate embodiment according to this invention; or R3 and R4 are joined to form a 3-8 membered heterocyclic ring (e.g., pyrrolidine, 2- oxopyrrolidine, piperidine, morpholine, piperazine, imidazole; each is a separate embodiment according to this invention); or R2and R4are joined to form a substituted or unsubstituted, saturated or unsaturated, 3-8 membered heterocyclic or carbocyclic ring (e.g., pyrrolidine, 1-methylpyrrolidine, pyrrolidin-2-one, pyridine, piperidine, tetrahydrofurane, tetrahydrothiophene, cyclopropyl,oxetane, imidazole, pyrimidine, triazole, oxadiazole, pyrazole; each is a separate embodiment according to this invention), wherein if the ring is aromatic, then R1 and / or R3 are absent; wherein if X1 is O then R4 is absent;

[0101] In some embodiments, X1 of formula A is N. In other embodiments X1 is O.

[0102] In some embodiments, R1 of formula A is H. In other embodiments R1 is F. In other embodiments R1 is CF3.

[0103] In some embodiments, R2 of formula A is H. In other embodiments R2 is F. In other embodiments R2 is CF3.

[0104] In some embodiments, R1 and R2 of formula A are joined to form =O. In other embodiments, R1 and R2 are joined to form a C3-C8 carbocyclic or heterocyclic ring. In other embodiments, R1 and R2 are joined to form a C3-C8 carbocyclic ring. In some embodiments, the carbocyclic ring is cyclopropyl. In other embodiments, R1 and R2 are joined to form a 3-8 membered heterocyclic ring.

[0105] In some embodiments, R1 and R2 of formula A of formula I, I(a)-I(c), I(i) and / or I(k)-I(n), are not joined to form =O.

[0106] In some embodiments, R3 of formula A is H. In some embodiments, R3 is methyl. In some embodiments, R3 is substituted or unsubstituted C1-C5 alkyl. In some embodiments, the alkyl is methoxyethylene, methylaminoethylene, aminoethylene; each represents a separate embodiment according to this invention. In some embodiments, R3 is substituted or unsubstituted C3-C8 cycloalkyl. In some embodiments, the cycloalkyl is cyclopropyl. In some embodiments, R3is substituted or unsubstituted 5-7 membered heterocyclic ring. In some embodiments, the heterocyclic ring is pyrrolidine, methylpyrrolidine, or piperidine; each represents a separate embodiment according to this invention. In some embodiments, R3is R20as defined hereinbelow.

[0107] In some embodiments, R4of formula A is H. In some embodiments, R4is methyl. In some embodiments, R4 is substituted or unsubstituted C1-C5 alkyl. In some embodiments, the alkyl is methoxyethylene, methylaminoethylene, aminoethylene; each represents a separate embodiment according to this invention. In some embodiments, R4is substituted or unsubstituted C3-C8cycloalkyl. In some embodiments, the cycloalkyl is cyclopropyl. In some embodiments, R4is substituted or unsubstituted 5-7 membered heterocyclic ring. In some embodiments, the heterocyclic ring is pyrrolidine, methylpyrrolidine, or piperidine; each represents a separate embodiment according to this invention. In some embodiments, R4is R20as defined hereinbelow.

[0108] In some embodiments, R3and R4of formula A are joined to form a 3-8 membered heterocyclic ring. In some embodiments, the heterocyclic ring is imidazole, pyrrolidine, 2-oxopyrrolidine, piperidine, morpholine, or piperazine; each represents a separate embodiment according to this invention.

[0109] In some embodiments, if X1of formula A is O then R4is absent.

[0110] In some embodiments, R7of formula I, I(a)-I(c(, I(i), I(j), I(k) and / or I(n) is O-R20, substituted or unsubstituted 4-7 membered heterocyclic ring (e.g., morpholine, pyran, oxetane, pyrrolidine, imidazole, piperazine, piperidine, dioxazole, triazole, 2-oxopyrrolidine), or substituted or unsubstituted aryl. In some embodiments, R7of formula I I(a)-I(c( I(i) I(j) I(k) and / or I(n) is represented byformula A, wherein X1, R1, R2, R3 and R4 are as defined above except that R1 and R2 cannot be joined to form =O.

[0111] In some embodiments, R7’ of formula I, and / or I(a)-I(n) is not H.

[0112] In some embodiments, R7’ of formula I and / or I(a)-I(n) is H. In some embodiments, R7’ of formula I and / or I(a)-I(n) is F, Cl, Br, I, OH, O-R20, SH, R8-OH, R8-SH, -R8-O-R10, R8-(C3-C8 cycloalkyl), R8-(3-8 membered heterocyclic ring), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, NH(R10), N(R10)(R11), R8-N(R10)(R11), R9-R8-N(R10)(R11), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R10, NHCO-N(R10)(R11), COOH, -C(O)Ph, C(O)O-R10, R8-C(O)-R10, C(O)H, C(O)-R10, C1-C5 linear or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR, C(O)N(R10)(R11), SO2R, SO2N(R10)(R11), CH(CF3)(NH-R10), C1-C5 linear or branched, substituted or unsubstituted alkyl, isopropyl, methyl, ethyl, C1-C5 linear or branched, substituted or unsubstituted alkenyl, C1-C5 linear or branched, or C3-C8 cyclic haloalkyl, C1-C5 linear or branched, or C3-C8 cyclic alkoxy optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom, C1-C5 linear or branched thioalkoxy, C1-C5 linear or branched haloalkoxy, C1-C5 linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, cyclopropyl, cyclohexyl, substituted or unsubstituted 3-8 membered heterocyclic ring, substituted or unsubstituted aryl, phenyl, or substituted or unsubstituted benzyl; each represents a separate embodiment according to this invention. In some embodiments, R7’ is further substituted with at least one substitution selected from: F, Cl, Br, I, C1-C5 linear or branched alkyl, OH, alkoxy (e.g., OMe), amide (e.g., C(O)N(R)2, C(O)-pyrrolidine, C(O)-piperidine, N(R)2NH(R10), N(R10)(R11), (e.g., N(CH3)2, NH2), CF3, aryl, phenyl, heteroaryl, substituted or unsubstituted C3-C8cycloalkyl (e.g., cyclobutanol), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g. pyran, oxetane, piperidine, pyrazole, methyl-pyrrazole, triazole, imidazole), halophenyl, (benzyloxy)phenyl, CN and NO2; each represents a separate embodiment according to this invention.

[0113] In some embodiments, R7’ of formula I and / or I(a)-I(n) is H. In some embodiments, R7’ is F. In some embodiments, R7’ is Cl. In some embodiments, R7’ is Br. In some embodiments, R7’ is I. In some embodiments, R7’ is CF3. In some embodiments, R7’ is C1-C5linear or branched, substituted or unsubstituted alkyl. In some embodiments, R7’ is C1-C5linear or branched unsubstituted alkyl. In some embodiemnts, the alkyl is isopropyl, methyl, ethyl; each represents a separate embodiment according to this invention. In some embodiments, R7’ is C1-C5linear or branched substituted alkyl. In some embodiments, R7’ is isopropyl. In some embodiments, R7’ is methyl. In some embodiments, R7’ is ethyl. In some embodiments, R7’ is C1-C5linear or branched, or C3-C8cyclic haloalkyl. In some embodiments, R7’ is C1-C5linear or branched haloalkyl. In some embodiments, the haloalkyl is CHF2. In some embodiments, R7’ is C3-C8cyclic haloalkyl. In some embodiments, R7’ is substituted or unsubstituted C3-C8cycloalkyl. In some embodiments, the cycloalkyl is cyclopropyl. In some embodiments, the cycloalkyl is cyclohexyl. In some embodiments, R7’ is substituted or unsubstituted aryl. In some embodiments, R7’ is phenyl. In some embodiments, R7’ is C1-C5linear or branched, or C3-C8cyclic alkoxy. In some embodiments, R7’ is methoxy.

[0114] In some embodiments, R7 and R7’ of formula I, I(a)-I(c) and / or I(i)-I(n) are joined to form a 5 or 6 membered substituted or unsubstituted, saturated, unsaturated or aromatic, carbocyclic or heterocyclic ring. In some embodiments, R7 and R7’ are joined to form a 5 membered unsubstituted saturated or unsaturated carbocyclic ring. In some embodiments, R7 and R7’ are joined to form 6 membered unsubstituted saturated or unsaturated carbocyclic ring. In some embodiments, R7 and R7’ are joined to form a 5 membered substituted saturated or unsaturated carbocyclic ring. In some embodiments, R7 and R7’ are joined to form 6 membered substituted saturated or unsaturated carbocyclic ring. In some embodiments, R7 and R7’ are joined to form a 6 membered substituted or unsubstituted, aromatic, carbocyclic ring. In some embodiments, R7 and R7’ are joined to form a 5 or 6 membered substituted or unsubstituted, aromatic, heterocyclic ring. In some embodiments, R7 and R7’ are joined to form a 5 or 6 membered substituted or unsubstituted, heterocyclic ring. In some embodiments, R7 and R7’ are joined to form a 6 membered substituted or unsubstituted, heterocyclic ring. In some embodiments, R7 and R7’ are joined to form a piperidine. In some embodiments, R7 and R7’ are joined to form a tetrahydropyran. In some embodiments, R7 and R7’ are joined to form a 5 membered substituted or unsubstituted, heterocyclic ring. In some embodiments, R7 and R7’ are joined to form a pyrrolidine. In some embodiments, R7 and R7’ are joined to form a tetrahydrofuran.

[0115] In some embodiments, R7 and R7’ of formula I, I(a)-I(c), I(i)-I(k) and / or I(n) are different. In some embodiments, R7 and R7’ of formula I, I(a)-I(c), I(i)-I(k) and / or I(n) are not H, F, Cl, C1-C5 linear or branched, or C3-C8cyclic alkoxy , C1-C5linear or branched haloalkoxy or C1-C5linear or branched, substituted or unsubstituted alkyl; each represents a separate embodiment according to this invention.

[0116] In some embodiments, R7’’ of formula I(a), I(c), I(e), and / or I(f)-I(n) is not H.

[0117] In some embodiments, R7’’ of formula I(a), I(c), I(e), and / or I(f)-I(n) is H. In some embodiments, R7’’ of formula I(a), I(c), I(e), and / or I(f)-I(n) is F, Cl, Br, I, OH, O-R20, SH, R8-OH, R8- SH, -R8-O-R10, R8-(C3-C8 cycloalkyl), R8-(3-8 membered heterocyclic ring), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, NH(R10), N(R10)(R11), R8-N(R10)(R11), R9-R8-N(R10)(R11), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R10, NHCO-N(R10)(R11), COOH, -C(O)Ph, C(O)O-R10, R8-C(O)-R10, C(O)H, C(O)-R10, C1-C5linear or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR, C(O)N(R10)(R11), SO2R, SO2N(R10)(R11), CH(CF3)(NH-R10), C1-C5linear or branched, substituted or unsubstituted alkyl, C1-C5linear or branched, substituted or unsubstituted alkenyl, C1-C5linear or branched, or C3-C8cyclic haloalkyl, C1-C5linear or branched, or C3-C8cyclic alkoxy optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom, C1-C5linear or branched thioalkoxy, C1-C5linear or branched haloalkoxy, C1-C5linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8cycloalkyl, cyclopropyl, cyclohexyl, substituted or unsubstituted 3-8 membered heterocyclic ring, substituted or unsubstituted aryl, phenyl, or substituted or unsubstituted benzyl; each represents a separate embodiment according to this invention. In some embodiments, R7’’ is further substituted with at least one substitution selected from: F, Cl, Br, I, C1-C5linear or branched alkyl, OH, alkoxy (e.g., OMe), amide (e.g., C(O)N(R)2, C(O)-pyrrolidine, C(O)-piperidine, N(R)2NH(R10), N(R10)(R11), (e.g., N(CH3)2, NH2), CF3, aryl, phenyl heteroaryl substituted or unsubstituted C3-C8cycloalkyl (e.g.,cyclobutanol), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g. pyran, oxetane, piperidine, pyrazole, methyl-pyrrazole, triazole, imidazole), halophenyl, (benzyloxy)phenyl, CN and NO2; each represents a separate embodiment according to this invention.

[0118] In some embodiments, R7’’ of formula I(a), I(c), I(e), and / or I(f)-I(n) is H. In some embodiments, R7’’ is F. In some embodiments, R7’’ is Cl. In some embodiments, R7’’ is Br. In some embodiments, R7’’ is I. In some embodiments, R7’’ is CF3. In some embodiments, R7’’ is C1-C5 linear or branched, substituted or unsubstituted alkyl. In some embodiments, R7’’ is C1-C5 linear or branched unsubstituted alkyl. In some embodiemnts, the alkyl is isopropyl, methyl, ethyl; each represents a separate embodiment according to this invention. In some embodiments, R7’’ is C1-C5 linear or branched substituted alkyl. In some embodiments, R7’’ is isopropyl. In some embodiments, R7’’ is methyl. In some embodiments, R7’’ is ethyl. In some embodiments, R7’’ is C1-C5 linear or branched, or C3-C8 cyclic haloalkyl. In some embodiments, R7’’ is C1-C5 linear or branched haloalkyl. In some embodiments, the haloalkyl is CHF2. In some embodiments, R7’’ is C3-C8 cyclic haloalkyl. In some embodiments, R7’’ is substituted or unsubstituted C3-C8 cycloalkyl. In some embodiments, the cycloalkyl is cyclopropyl. In some embodiments, the cycloalkyl is cyclohexyl. In some embodiments, R7’’ is substituted or unsubstituted aryl. In some embodiments, R7’’ is phenyl. In some embodiments, R7’’ is C1-C5 linear or branched, or C3-C8 cyclic alkoxy. In some embodiments, R7’’ is methoxy.

[0119] In some embodiments, R7’’’ of formula I(a), I(c), I(e), and / or I(f)-I(n) is not H.

[0120] In some embodiments, R7’’’ of formula I(a), I(c), I(e), and / or I(f)-I(n) is H. In some embodiments, R7’’’ of formula I(i) is F, Cl, Br, I, OH, O-R20, SH, R8-OH, R8-SH, -R8-O-R10, R8-(C3-C8cycloalkyl), R8-(3-8 membered heterocyclic ring), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, NH(R10), N(R10)(R11), R8-N(R10)(R11), R9-R8-N(R10)(R11), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R10, NHCO-N(R10)(R11), COOH, -C(O)Ph, C(O)O-R10, R8-C(O)-R10, C(O)H, C(O)-R10, C1-C5linear or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR, C(O)N(R10)(R11), SO2R, SO2N(R10)(R11), CH(CF3)(NH-R10), C1-C5 linear or branched, substituted or unsubstituted alkyl, C1-C5 linear or branched, substituted or unsubstituted alkenyl, C1-C5linear or branched, or C3-C8cyclic haloalkyl, C1- C5linear or branched, or C3-C8cyclic alkoxy optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom, C1-C5linear or branched thioalkoxy, C1-C5linear or branched haloalkoxy, C1-C5linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8cycloalkyl, cyclopropyl, cyclohexyl, substituted or unsubstituted 3-8 membered heterocyclic ring, substituted or unsubstituted aryl, phenyl, or substituted or unsubstituted benzyl; each represents a separate embodiment according to this invention. In some embodiments, R7’’’ is cyclopropyl. In some embodiments, R7’’’ is further substituted with at least one substitution selected from: F, Cl, Br, I, C1-C5linear or branched alkyl, OH, alkoxy (e.g., OMe), amide (e.g., C(O)N(R)2, C(O)-pyrrolidine, C(O)- piperidine, N(R)2NH(R10), N(R10)(R11), (e.g., N(CH3)2, NH2), CF3, aryl, phenyl, heteroaryl, substituted or unsubstituted C3-C8cycloalkyl (e.g., cyclobutanol), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g. pyran, oxetane, piperidine, pyrazole, methyl-pyrrazole, triazole, imidazole),halophenyl, (benzyloxy)phenyl, CN and NO2; each represents a separate embodiment according to this invention.

[0121] In some embodiments, R7’’’ of formula I(a), I(c), I(e), and / or I(f)-I(n) is H. In some embodiments, R7’’’ is F. In some embodiments, R7’’’ is Cl. In some embodiments, R7’’’ is Br. In some embodiments, R7’’’ is I. In some embodiments, R7’’’ is CF3. In some embodiments, R7’’’ is C1-C5 linear or branched, substituted or unsubstituted alkyl. In some embodiments, R7’’’ is C1-C5 linear or branched unsubstituted alkyl. In some embodiemnts, the alkyl is isopropyl, methyl, ethyl; each represents a separate embodiment according to this invention. In some embodiments, R7’’’ is C1-C5 linear or branched substituted alkyl. In some embodiments, R7’’’ is isopropyl. In some embodiments, R7’’’ is methyl. In some embodiments, R7’’’ is ethyl. In some embodiments, R7’’’ is C1-C5 linear or branched, or C3-C8 cyclic haloalkyl. In some embodiments, R7’’’ is C1-C5 linear or branched haloalkyl. In some embodiments, the haloalkyl is CHF2. In some embodiments, R7’’’ is C3-C8 cyclic haloalkyl. In some embodiments, R7’’’ is substituted or unsubstituted C3-C8 cycloalkyl. In some embodiments, the cycloalkyl is cyclopropyl. In some embodiments, the cycloalkyl is cyclohexyl. In some embodiments, R7’’’ is substituted or unsubstituted aryl. In some embodiments, R7’’’ is phenyl. In some embodiments, R7’’’ is C1-C5 linear or branched, or C3-C8 cyclic alkoxy. In some embodiments, R7’’’ is methoxy.

[0122] In some embodiments, R7’’’’ of formula I(a), I(c), I(e), and / or I(f)-I(n) is not H.

[0123] In some embodiments, R7’’’’ of formula I(a), I(c), I(e), and / or I(f)-I(n) is H. In some embodiments, R7’’’’ of formula I(i) is F, Cl, Br, I, OH, O-R20, SH, R8-OH, R8-SH, -R8-O-R10, R8-(C3- C8cycloalkyl), R8-(3-8 membered heterocyclic ring), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, NH(R10), N(R10)(R11), R8-N(R10)(R11), R9-R8-N(R10)(R11), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R10, NHCO-N(R10)(R11), COOH, -C(O)Ph, C(O)O-R10, R8-C(O)-R10, C(O)H, C(O)-R10, C1-C5linear or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR, C(O)N(R10)(R11), SO2R, SO2N(R10)(R11), CH(CF3)(NH-R10), C1-C5 linear or branched, substituted or unsubstituted alkyl, C1-C5 linear or branched, substituted or unsubstituted alkenyl, C1-C5 linear or branched, or C3-C8 cyclic haloalkyl, C1- C5linear or branched, or C3-C8cyclic alkoxy optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom, C1-C5linear or branched thioalkoxy, C1-C5linear or branched haloalkoxy, C1-C5linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8cycloalkyl, cyclopropyl, cyclohexyl, substituted or unsubstituted 3-8 membered heterocyclic ring, substituted or unsubstituted aryl, phenyl, or substituted or unsubstituted benzyl; each represents a separate embodiment according to this invention. In some embodiments, R7’’’’ is further substituted with at least one substitution selected from: F, Cl, Br, I, C1-C5linear or branched alkyl, OH, alkoxy (e.g., OMe), amide (e.g., C(O)N(R)2, C(O)-pyrrolidine, C(O)-piperidine, N(R)2NH(R10), N(R10)(R11), (e.g., N(CH3)2, NH2), CF3, aryl, phenyl, heteroaryl, substituted or unsubstituted C3-C8cycloalkyl (e.g., cyclobutanol), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g. pyran, oxetane, piperidine, pyrazole, methyl-pyrrazole, triazole, imidazole), halophenyl, (benzyloxy)phenyl, CN and NO2; each represents a separate embodiment according to this invention.

[0124] In some embodiments, R7’’’’ of formula I(a), I(c), I(e), and / or I(f)-I(n) is H. In some embodiments, R7’’’’ is F. In some embodiments, R7’’’’ is Cl. In some embodiments, R7’’’’ is Br. In some embodiments, R7’’’’ is I. In some embodiments, R7’’’’ is CF3. In some embodiments, R7’’’’ is C1- C5 linear or branched, substituted or unsubstituted alkyl. In some embodiments, R7’’’’ is C1-C5 linear or branched unsubstituted alkyl. In some embodiments, the alkyl is isopropyl, methyl, ethyl; each represents a separate embodiment according to this invention. In some embodiments, R7’’’’ is C1-C5 linear or branched substituted alkyl. In some embodiments, R7’’’’ is isopropyl. I’n some embodiments, R7’’’’ is methyl. In some embodiments, R7’’’’ is ethyl. In some embodiments, R7’’’’ is C1-C5 linear or branched, or C3-C8 cyclic haloalkyl. In some embodiments, R7’’’’ is C1-C5 linear or branched haloalkyl. In some embodiments, the haloalkyl is CHF2. In some embodiments, R7’’’’ is C3-C8 cyclic haloalkyl. In some embodiments, R7’’’’ is substituted or unsubstituted C3-C8 cycloalkyl. In some embodiments, the cycloalkyl is cyclopropyl. In some embodiments, the cycloalkyl is cyclohexyl. In some embodiments, R7’’’’ is substituted or unsubstituted aryl. In some embodiments, R7’’’’ is phenyl. In some embodiments, R7’’’’ is C1-C5 linear or branched, or C3-C8 cyclic alkoxy. In some embodiments, R7’’’’ is methoxy.

[0125] In some embodiments, R7’ and R7’’ of formula I(a), I(c), I(e), and / or I(f)-I(n) are joined to form a 3-8 membered substituted or unsubstituted, saturated, unsaturated or aromatic, carbocyclic or heterocyclic ring. In some embodiments, R7’ and R7’’ are joined to form a 5 membered unsubstituted saturated or unsaturated carbocyclic ring. In some embodiments, R7’ and R7’’ are joined to form a cyclopentane. In some embodiments, R7’ and R7’’ are joined to form 6 membered unsubstituted saturated or unsaturated carbocyclic ring. In some embodiments, R7’ and R7’’ are joined to form a cyclohexane. In some embodiments, R7’ and R7’’ are joined to form a 5 membered substituted saturated or unsaturated carbocyclic ring. In some embodiments, R7’ and R7’’ are joined to form 6 membered substituted saturated or unsaturated carbocyclic ring. In some embodiments, R7’ and R7’’ are joined to form a 6 membered substituted or unsubstituted, aromatic, carbocyclic ring. In some embodiments, R7’ and R7’’ are joined to form a 5 or 6 membered substituted or unsubstituted, aromatic, heterocyclic ring. In some embodiments, R7’ and R7’’ are joined to form a 5 or 6 membered substituted or unsubstituted, heterocyclic ring. In some embodiments, R7’ and R7’’ are joined to form a 6 membered substituted or unsubstituted, heterocyclic ring. In some embodiments, R7’ and R7’’ are joined to form a piperidine. In some embodiments, R7’ and R7’’ are joined to form a tetrahydropyran. In some embodiments, R7’ and R7’’ are joined to form a 5 membered substituted or unsubstituted, heterocyclic ring. In some embodiments, R7’ and R7’’ are joined to form a tetrahydrofuran. In some embodiments, R7’ and R7’’ are joined to form a pyrrolidine.

[0126] In some embodiments, R7’ and R7’’ of formula I(a), I(c), I(e), and / or I(f)-I(n) are different. In some embodiments, R7’ and R7’’ of formula I(a), I(c), I(e), and / or I(f)-I(n) are not H, F, Cl, C1-C5linear or branched, or C3-C8cyclic alkoxy, C1-C5linear or branched haloalkoxy or C1-C5linear or branched, substituted or unsubstituted alkyl; each represents a separate embodiment according to this invention.

[0127] In some embodiments, R7’’ and R7of formula I(a), I(c), I(i), I(j)-I(k) and / or I(n) are joined to form a 3-8 membered substituted or unsubstituted saturated unsaturated or aromatic, carbocyclic orheterocyclic ring. In some embodiments, R7’’ and R7 are joined to form a 5 membered unsubstituted saturated or unsaturated carbocyclic ring. In some embodiments, R7’’ and R7 are joined to form a cyclopentane. In some embodiments, R7’’ and R7 are joined to form 6 membered unsubstituted saturated or unsaturated carbocyclic ring. In some embodiments, R7’’ and R7 are joined to form a cyclohexane. In some embodiments, R7’’ and R7 are joined to form a 5 membered substituted saturated or unsaturated carbocyclic ring. In some embodiments, R7’’ and R7 are joined to form 6 membered substituted saturated or unsaturated carbocyclic ring. In some embodiments, R7’ and R7’’ are joined to form a 6 membered substituted or unsubstituted, aromatic, carbocyclic ring. In some embodiments, R7’’ and R7 are joined to form a 5 or 6 membered substituted or unsubstituted, aromatic, heterocyclic ring. In some embodiments, R7’’ and R7 are joined to form a 5 or 6 membered substituted or unsubstituted, heterocyclic ring. In some embodiments, R7’’ and R7 are joined to form a 6 membered substituted or unsubstituted, heterocyclic ring. In some embodiments, R7’’ and R7 are joined to form a piperidine. In some embodiments, R7’’ and R7 are joined to form a tetrahydropyran. In some embodiments, R7’’ and R7 are joined to form a 5 membered substituted or unsubstituted, heterocyclic ring. In some embodiments, R7’’ and R7 are joined to form a tetrahydrofuran. In some embodiments, R7’’ and R7 are joined to form a pyrrolidine.

[0128] In some embodiments, R7’’ and R7 of formula I(a), I(c), I(i), I(j)-I(k) and / or I(n) are different. In some embodiments, R7’’ and R7 of I(a), I(c), I(i), I(j)-I(k) and / or I(n)are not H, F, Cl, C1-C5 linear or branched, or C3-C8cyclic alkoxy , C1-C5linear or branched haloalkoxy or C1-C5linear or branched, substituted or unsubstituted alkyl; each represents a separate embodiment according to this invention.

[0129] In some embodiments, R7and R7’’’ of formula I(a), I(c), I(i), I(j)-I(k) and / or I(n)are joined to form a 3-8 membered substituted or unsubstituted, saturated, unsaturated or aromatic, carbocyclic or heterocyclic ring. In some embodiments, R7and R7’’’ are joined to form a 5 membered unsubstituted saturated or unsaturated carbocyclic ring. In some embodiments, R7 and R7’’’ are joined to form 6 membered unsubstituted saturated or unsaturated carbocyclic ring. In some embodiments, R7 and R7’’’ are joined to form a 5 membered substituted saturated or unsaturated carbocyclic ring. In some embodiments, R7and R7’’’ are joined to form 6 membered substituted saturated or unsaturated carbocyclic ring. In some embodiments, R7and R7’’’ are joined to form a 6 membered substituted or unsubstituted, aromatic, carbocyclic ring. In some embodiments, R7and R7’’’ are joined to form a 5 or 6 membered substituted or unsubstituted, aromatic, heterocyclic ring. In some embodiments, R7and R7’’’ are joined to form a 5 or 6 membered substituted or unsubstituted, heterocyclic ring. In some embodiments, R7and R7’’’ are joined to form a 6 membered substituted or unsubstituted, heterocyclic ring. In some embodiments, R7and R7’’’ are joined to form a piperidine. In some embodiments, R7and R7’’’ are joined to form a tetrahydrofuran. In some embodiments, R7and R7’’’ are joined to form a tetrahydropyran. In some embodiments, R7and R7’’’ are joined to form a 5 membered substituted or unsubstituted, heterocyclic ring. In some embodiments, R7and R7’’’ are joined to form a pyrrolidine. In some embodiments, R7and R7’’’ are joined to form a cyclopentane. In some embodiments, R7and R7’’’ are joined to form a cyclohexane.

[0130] In some embodiments, R7 and R7’’’ of formula I(a), I(c), I(i), I(j)-I(k) and / or I(n)are different. In some embodiments, R7 and R7’’’ of formula I(i) are not H, F, Cl, C1-C5 linear or branched, or C3-C8 cyclic alkoxy , C1-C5 linear or branched haloalkoxy or C1-C5 linear or branched, substituted or unsubstituted alkyl; each represents a separate embodiment according to this invention.

[0131] In some embodiments, R7’’’ and R7’’’’ of formula I(a), I(c), I(i), I(j)-I(k) and / or I(n)are joined to form a 3-8 membered substituted or unsubstituted, saturated, unsaturated or aromatic, carbocyclic or heterocyclic ring. In some embodiments, R7’’’ and R7’’’’ are joined to form a 5 membered unsubstituted saturated or unsaturated carbocyclic ring. In some embodiments, R7’’’ and R7’’’’ are joined to form 6 membered unsubstituted saturated or unsaturated carbocyclic ring. In some embodiments, R7’’’ and R7’’’’ are joined to form a 5 membered substituted saturated or unsaturated carbocyclic ring. In some embodiments, R7’’’ and R7’’’’ are joined to form 6 membered substituted saturated or unsaturated carbocyclic ring. In some embodiments, R7’’’ and R7’’’’ are joined to form a 6 membered substituted or unsubstituted, aromatic, carbocyclic ring. In some embodiments, R7’’’ and R7’’’’ are joined to form a 5 or 6 membered substituted or unsubstituted, aromatic, heterocyclic ring. In some embodiments, R7’’’ and R7’’’’ are joined to form a 5 or 6 membered substituted or unsubstituted, heterocyclic ring. In some embodiments, R7’’’ and R7’’’’ are joined to form a 6 membered substituted or unsubstituted, heterocyclic ring. In some embodiments, R7’’’ and R7’’’’ are joined to form a piperidine. In some embodiments, R7’’’ and R7’’’’ are joined to form a tetrahydrofuran. In some embodiments, R7’’’ and R7’’’’ are joined to form a tetrahydropyran. In some embodiments, R7’’’ and R7’’’’ are joined to form a 5 membered substituted or unsubstituted, heterocyclic ring. In some embodiments, R7’’’ and R7’’’’ are joined to form a pyrrolidine. In some embodiments, R7’’’ and R7’’’’ are joined to form a cyclopentane. In some embodiments, R7’’’ and R7’’’’ are joined to form a cyclohexane.

[0132] In some embodiments, R7’’’ and R7’’’’ of formula I(a), I(c), and / or I(e)-I(n) are different. In some embodiments, R7’’’ and R7’’’’ of formula I(i) are not H, F, Cl, C1-C5 linear or branched, or C3-C8 cyclic alkoxy , C1-C5 linear or branched haloalkoxy or C1-C5 linear or branched, substituted or unsubstituted alkyl; each represents a separate embodiment according to this invention.

[0133] In some embodiments, at least one of R7’, R7’’, R7’’’ and R7’’’’ of formula I(a), I(c), and / or I(e)-I(n) is not H. In some embodiments, at least two of R7’, R7’’, R7’’’ and R7’’’’ of formula I(a), I(c), and / or I(e)-I(n) are not H. In some embodiments, at least three of R7’, R7’’, R7’’’ and R7’’’’ of formula I(a), I(c), and / or I(e)-I(n) are not H.

[0134] In some embodiments, at least one of R7, R7’, R7’’, R7’’’ and R7’’’’ of formula I(a), I(c), I(i), I(j)-I(k) and / or I(n) is not H. In some embodiments, at least two of R7, R7’, R7’’, R7’’’ and R7’’’’ of formula I(a), I(c), I(i), I(j)-I(k) and / or I(n)are not H. In some embodiments, at least three of R7, R7’, R7’’, R7’’’ and R7’’’’ of formula I(a), I(c), I(i), I(j)-I(k) and / or I(n)are not H.

[0135] In some embodiments, R30of formula I and / or I(a)-I(n) is H, R20, F, Cl, Br, I, OH, SH, alkoxy, N(R)2, NH(R10), N(R10)(R11), CF3, CN, NO2, C1-C5linear or branched, substituted or unsubstituted alkyl, C1-C5linear or branched alkoxy, C1-C5linear or branched haloalkyl, R8-aryl, -R8-O-R8-O-R10, -R8-O- R10, -R8-R10, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; each representsa separate embodiment according to this invention. In some embodiments, R30 is further substituted with at least one substitution selected from: F, Cl, Br, I, C1-C5 linear or branched alkyl, OH, alkoxy (e.g., OMe), amide (e.g., C(O)N(R)2, C(O)-pyrrolidine, C(O)-piperidine, N(R)2 NH(R10), N(R10)(R11), (e.g., N(CH3)2, NH2), CF3, aryl, phenyl, heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclobutanol), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g. pyran, oxetane, piperidine, pyrazole, methyl-pyrrazole, triazole, imidazole), halophenyl, (benzyloxy)phenyl, CN and NO2; each represents a separate embodiment according to this invention. In some embodiments, R30 is H. In some embodiments, R30 is R20.

[0136] In some embodiments, R50 of formula I(b), I(c), I(f), I(h), I(l) and / or I(m) is H, R20, F, Cl, Br, I, OH, SH, N(R)2, NH(R10), N(R10)(R11), CF3, CN, NO2, C1-C5 linear or branched, substituted or unsubstituted alkyl C1-C5 linear or branched alkoxy, C1-C5 linear or branched haloalkyl, -R8-R10 (e.g., (CH2)2-O-CH3), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine); each represents a separate embodiment according to this invention. In some embodiments, R50 is further substituted with at least one substitution selected from: F, Cl, Br, I, C1-C5 linear or branched alkyl, OH, alkoxy (e.g., OMe), amide (e.g., C(O)N(R)2, C(O)-pyrrolidine, C(O)-piperidine, N(R)2 NH(R10), N(R10)(R11), (e.g., N(CH3)2, NH2), CF3, aryl, phenyl, heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclobutanol), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g. pyran, oxetane, piperidine, pyrazole, methyl-pyrrazole, triazole, imidazole), halophenyl, (benzyloxy)phenyl, CN and NO2; each represents a separate embodiment according to this invention. In some embodiments, R50is H. In some embodiments, R50is F. In some embodiments, R50is CF3. In some embodiments, R50is CN.

[0137] In some embodiments, Ring G of formula I(b), I(c), I(f), I(h), I(l) and / or I(m) is absent. In some embodiments, Ring G is a substituted or unsubstituted 3-8 membered carbocyclic or heterocyclic ring. In some embodiments, Ring G is a substituted 3-8 membered carbocyclic ring. In some embodiments, Ring G is a unsubstituted 3-8 membered carbocyclic ring. In some embodiments, Ring G is a unsubstituted 4-7 membered carbocyclic ring. In some embodiments, Ring G is a unsubstituted 3-6 membered carbocyclic ring.In some embodiments, Ring G is cyclobutane. In some embodiments, Ring G is cyclopentane. In some embodiments, Ring G is cyclohexane. In some embodiments, Ring G is a substituted or unsubstituted 3-8 membered heterocyclic ring. In some embodiments, Ring G is a substituted 3-8 membered heterocyclic ring.

[0138] In some embodiments, R of formula I and / or I(a)-I(n) is H, F, Cl, Br, I, OH, SH, COOH, CO(R10), C(O)CH3, NH(R10), NH-CH2-cyclopropyl, N(R10)(R11), CF3, CN, NO2, C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, iPr, CH2-cyclopropyl, CH2-OH, CH2- CH2-OH, CH2-CH2-O-CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), C3-C8substituted or unsubstituted cycloalkyl, cyclopropyl, C1-C5substituted or unsubstituted, linear or branched alkoxy, (e.g., methoxy, ethoxy, O-(CH2CH3), OCHF2, O-(CH2)2-O-CH3, isopropoxy, O-(CH2)-cyclopropyl, O-CH2- methylcyclobutyl, O-CH2-3-methyloxetane, O-CH(CH3)-CH2-O-CH3) C1-C5linear or branched haloalkyl (e.g., CHF2, CF3, CF2CH3CH2CF3CF2CH2CH3CH2CH2CF3,CF2CH(CH3)2,CF(CH3)-CH(CH3)2), R8-aryl (e.g., CH2-Ph), -R8-O-R8-O-R10 (e.g. (CH2)2-O-(CH2)2-O-CH3), -R8-O-R10, O-R8- R10 (e.g. O-(CH2)2-O-CH3, O-(CH2CH3), O-(CH2)-cyclopropyl), -R8-R10 (e.g., (CH2)-cyclopropyl, (CH2)2-O-CH3, (CH2)-OH, (CH2)2-OH, (CH2)-COOH), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine); each represents a separate embodiment according to this invention. In some embodiments, R is further substituted with at least one substitution selected from: F, Cl, Br, I, C1-C5 linear or branched alkyl, OH, alkoxy (e.g., OMe), amide (e.g., C(O)N(R)2, C(O)-pyrrolidine, C(O)-piperidine, N(R)2 NH(R10), N(R10)(R11), (e.g., N(CH3)2, NH2), CF3, aryl, phenyl, heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclobutanol), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g. pyran, oxetane, piperidine, pyrazole, methyl-pyrrazole, triazole, imidazole), halophenyl, (benzyloxy)phenyl, CN and NO2; each represents a separate embodiment according to this invention. In some embodiments, R is H. In some embodiments, R is F, Cl, Br, or I. In some embodiments, R is NH(R10). In some embodiments, R is NH-CH2- cyclopropyl. In some embodiments, R is C1-C5 linear or branched, substituted or unsubstituted alkyl. In some embodiments, R is methyl. In some embodiments, R is ethyl. In some embodiments, R is propyl. In some embodiments, R is isopropyl. In some embodiments, R is butyl. In some embodiments, R is substituted alkyl. In some embodiments, R is CH2-OH. In some embodiments, R is CH2-CH2-OH. In some embodiments, R is C3-C8 substituted or unsubstituted cycloalkyl. In some embodiments, R is cyclopropyl. In some embodiments, R is C1-C5 linear or branched alkoxy. In some embodiments, R is methoxy. In some embodiments, R is ethoxy. In some embodiments, R is propoxy. In some embodiments, R is isopropoxy. In some embodiments, R is O-(CH2)-cyclopropyl. In some embodiments, R is O-CH2- methylcyclobutyl. In some embodiments, R is O-CH(CH3)-CH2-O-CH3. In some embodiments, R is O- (CH2CH3). In some embodiments, R is OCHF2. In some embodiments, R is O-(CH2)2-O-CH3. In some embodiments, R is COOH. In some embodiments, R is O-R8-R10. In some embodiments, R is O-(CH2)2- O-CH3. In some embodiments, R is O-(CH2CH3). In some embodiments, R is -R8-R10. In some embodiments, R is (CH2)-cyclopropyl. In some embodiments, R is (CH2)-OH. In some embodiments, R is (CH2)2-OH. In some embodiments, R is (CH2)-COOH. In some embodiments, R is OH. In some embodiments, R is CO(R10).

[0139] In various embodiments, each R8of compound of formula I and / or I(a)-I(n) is independently CH2. In some embodiments, R8is CH2CH2. In some embodiments, R8is CH2CH2CH2. In some embodiments, R8is CH2CH2CH2CH2.

[0140] In some embodiments, p of formula I and / or I(a)-I(n) is 1. In other embodiments, p is 2. In other embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is between 1 and 3. In some embodiments, p is between 1 and 5. In some embodiments, p is between 1 and 10.

[0141] In some embodiments, R9of formula I and / or I(a)-I(n) is C≡C. In some embodiments, R9is C≡C-C≡C. In some embodiments, R9 is CH=CH. In some embodiments, R9 is CH=CH-CH=CH.

[0142] In some embodiments, q of formula I and / or I(a)-I(n) is 2. In some embodiments, q is 4. In some embodiments, q is 6. In some embodiments, q is 8. In some embodiments, q is between 2 and 6.

[0143] In some embodiments, R10 of formula I and / or I(a)-I(n) is H, OH, COOH, C1-C5 substituted or unsubstituted linear or branched alkyl (e.g., methyl, ethyl, CH2-cyclopropyl, CH2-CH2-O-CH3), C3-C8 substituted or unsubstituted cycloalkyl (e.g., cyclopropyl), C1-C5 substituted or unsubstituted linear or branched haloalky, CH2CF3, C1-C5 linear or branched alkoxy (e.g., O-CH3), R20, C(O)R, or S(O)2R; each represents a separate embodiment according to this invention. In some embodiments, R10 is H. In some embodiments, R10 is OH In some embodiments, R10 is COOH. In some embodiments, R10 is C1-C5 substituted or unsubstituted linear or branched alkyl. In some embodiments, R10 is C1-C5 unsubstituted linear or branched alkyl. In other embodiments, R10 is CH3. In other embodiments, R10 is CH2CH3. In other embodiments, R10 is CH2CH2CH3. In some embodiments, R10 is isopropyl. In some embodiments, R10 is butyl. In some embodiments, R10 is isobutyl. In some embodiments, R10 is t-butyl. In some embodiments, R10 is pentyl. In some embodiments, R10 is isopentyl. In some embodiments, R10 is neopentyl. In some embodiments, R10 is benzyl. In some embodiments, R10 is C1-C5 substituted linear or branched alkyl. In other embodiments, R10 is CH2-CH2-O-CH3. In some embodiments, R10 is C3-C8 substituted or unsubstituted cycloalkyl. In some embodiments, R10 is cyclopropyl. In other embodiments, R10 is CH2CF3. In other embodiments, R10 is C1-C5 substituted or unsubstituted linear or branched haloalkyl. In other embodiments, R10 is C1-C5 linear or branched alkoxy. In other embodiments, R10 is O-CH3. In other embodiments, R10 is R20. In other embodiments, R10 is C(O)R. In other embodiments, R10 is S(O)2R. In some embodiments, R10 is further substituted with at lest one substitution selected from: F, Cl, Br, I, C1-C5linear or branched alkyl, OH, alkoxy (e.g., OMe), amide (e.g., C(O)N(R)2, C(O)-pyrrolidine, C(O)-piperidine, N(R)2NH(R10), N(R10)(R11), (e.g., N(CH3)2, NH2), CF3, aryl, phenyl, heteroaryl, substituted or unsubstituted C3-C8cycloalkyl (e.g., cyclobutanol), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g. pyran, oxetane, piperidine, pyrazole, methyl-pyrrazole, triazole, imidazole), halophenyl, (benzyloxy)phenyl, CN and NO2; each represents a separate embodiment according to this invention.

[0144] In some embodiments, R11 of formula I and / or I(a)-I(n) is H, OH, COOH, C1-C5 substituted or unsubstituted linear or branched alkyl (e.g., methyl, ethyl, CH2-CH2-O-CH3, CH2CF3, C1-C5linear or branched alkoxy (e.g., O-CH3), C(O)R, or S(O)2R; each represents a separate embodiment according to this invention. In some embodiments, R11is H. In some embodiments, R11is OH In some embodiments, R11is COOH. In some embodiments, R11is C1-C5substituted or unsubstituted linear or branched alkyl. In some embodiments, R11is C1-C5unsubstituted linear or branched alkyl. In other embodiments, R11is CH3. In other embodiments, R11is CH2CH3.In other embodiments, R11is CH2CH2CH3. In some embodiments, R11is isopropyl. In some embodiments, R11is butyl. In some embodiments, R11is isobutyl. In some embodiments, R11is t-butyl. In some embodiments, R11is pentyl. In some embodiments, R11is isopentyl. In some embodiments, R11is neopentyl. In some embodiments, R11is benzyl. In some embodiments, R11is C1-C5substituted linear or branched alkyl. In other embodiments, R11is CH2-CH2-O-CH3. In other embodiments, R11is CH2CF3. In other embodiments, R11is C1-C5substituted or unsubstituted linear or branched haloalkyl. In other embodiments, R11is C1-C5linear or branched alkoxy. In other embodiments, R11is O-CH3. In other embodiments, R11is R20. In otherembodiments, R11 is C(O)R. In other embodiments, R11 is S(O)2R. In some embodiments, R11 is further substituted with at lest one substitution selected from: F, Cl, Br, I, C1-C5 linear or branched alkyl, OH, alkoxy (e.g., OMe), amide (e.g., C(O)N(R)2, C(O)-pyrrolidine, C(O)-piperidine, N(R)2 NH(R10), N(R10)(R11), (e.g., N(CH3)2, NH2), CF3, aryl, phenyl, heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclobutanol), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g. pyran, oxetane, piperidine, pyrazole, methyl-pyrrazole, triazole, imidazole), halophenyl, (benzyloxy)phenyl, CN and NO2; each represents a separate embodiment according to this invention.

[0145] In some embodiments, R10 and R11 of formula I and / or I(a)-I(n) are joined to form a substituted or unsubstituted 3-8 membered heterocyclic ring. In other embodiments, R10 and R11 are joined to form a piperazine ring. In other embodiments, R10 and R11 are joined to form a piperidine ring. In some embodiments, substitutions include: F, Cl, Br, I, C1-C5 linear or branched alkyl, OH, alkoxy , OMe, amide , C(O)N(R)2, C(O)-pyrrolidine, C(O)-piperidine, N(R)2, NH(R10), N(R10)(R11), N(CH3)2, NH2, CF3, aryl, phenyl, heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl , cyclobutanol, substituted or unsubstituted 3-8 membered heterocyclic ring pyran, oxetane, piperidine, pyrazole, methyl-pyrrazole, triazole, imidazole, halophenyl, (benzyloxy)phenyl, CN, and NO2; each represents a separate embodiment according to this invention.

[0146] In some embodiments, n of formula I, I(b) and / or I(d) is an integer between 0 and 4. In some embodiments, n of formula I, I(b) and / or I(d) is an integer between 1 and 4. In some embodiments, n of formula I, I(b) and / or I(d) is 0. In some embodiments, n of formula I, I(b) and / or I(d) is 1. In some embodiments, n of formula I, I(b) and / or I(d) is 2. In some embodiments, n of formula I, I(b) and / or I(d) is 3. In some embodiments, n of formula I, I(b) and / or I(d) is 4. In some embodiments, n of formula I, I(b) and / or I(d) is 1 or 2.

[0147] In some embodiments, R1of formula I(d)-I(h), I(l)-I(m) and / or A is H. In other embodiments R1 is F. In other embodiments R1 is CF3. In other embodiments R1 is Cl. In other embodiments R1 is Br. In other embodiments R1 is I. In other embodiments R1 is OH. In other embodiments R1 is SH. In other embodiments R1is substituted or unsubstituted C1-C5alkyl. In other embodiments R1is C1-C5linear or branched, or C3-C8cyclic haloalkyl. In other embodiments R1is substituted or unsubstituted C1-C5linear or branched, or C3-C8cyclic alkoxy.

[0148] In some embodiments, R2of formula I(d)-I(h), I(l)-I(m) and / or A is H. In other embodiments R2is F. In other embodiments R2is CF3. In other embodiments R2is Cl. In other embodiments R2is Br. In other embodiments R2is I. In other embodiments R2is OH. In other embodiments R2is SH. In other embodiments R2is substituted or unsubstituted C1-C5alkyl. In other embodiments R2is C1-C5linear or branched, or C3-C8cyclic haloalkyl. In other embodiments R2is substituted or unsubstituted C1-C5linear or branched, or C3-C8cyclic alkoxy.

[0149] In some embodiments, R1and R2of formula I(d)-I(h), I(l)-I(m) and / or A are joined to form C=O. In other embodiments, R1and R2are joined to form a 3-8 membered carbocyclic or heterocyclic ring. In other embodiments, R1and R2are joined to form a a 3-8 membered carbocyclic ring. In some embodiments, the carbocyclic ring is cyclopropyl. In other embodiments, R1and R2are joined to forma 3-8 membered heterocyclic ring. In some embodiments, the heterocyclic ring is oxetane. In some embodiments, if R1 and R2 are joined to form a C=O, then at least one of X2, X3, X4, and X10 is not CH.

[0150] In some embodiments, R3 of formula I(d)-I(h), I(l)-I(m) and / or A is H. In some embodiments, R3 is methyl. In some embodiments, R3 is substituted or unsubstituted C1-C5 alkyl. In some embodiments, the alkyl is methoxyethylene, methylaminoethylene, aminoethylene; each represents a separate embodiment according to this invention. In some embodiments, R3 is -R8-O-R10. In some embodiments, R3 is (CH2)2-O-CH3. In some embodiments, R3 is R8-N(R10)(R11). In some embodiments, R3 is (CH2)2-NH(CH3)). In some embodiments, R3 is substituted or unsubstituted C3-C8 cycloalkyl. In some embodiments, the cycloalkyl is cyclopropyl. In some embodiments, R3 is substituted or unsubstituted 5-7 membered heterocyclic ring. In some embodiments, R3 is pyrrolidine. In some embodiments, R3 is methylpyrrolidine. In some embodiments, R3 is piperidine. In some embodiments, R3 is R20 as defined hereinbelow.

[0151] In some embodiments, R4 of formula I(d)-I(h), I(l)-I(m) and / or A is H. In some embodiments, R4 is methyl. In some embodiments, R4 is substituted or unsubstituted C1-C5 alkyl. In some embodiments, the alkyl is methoxyethylene, methylaminoethylene, aminoethylene; each represents a separate embodiment according to this invention. In some embodiments, R4 is -R8-O-R10. In some embodiments, R4 is (CH2)2-O-CH3. In some embodiments, R4 is R8-N(R10)(R11). In some embodiments, R4 is (CH2)2-NH(CH3)). In some embodiments, R4 is substituted or unsubstituted C3-C8 cycloalkyl. In some embodiments, the cycloalkyl is cyclopropyl. In some embodiments, R4is substituted or unsubstituted 5-7 membered heterocyclic ring. In some embodiments, R4is pyrrolidine. In some embodiments, R4is methylpyrrolidine. In some embodiments, R4is piperidine. In some embodiments, R4is R20as defined hereinbelow.

[0152] In some embodiments, R2and R4of formula I(d)-I(h), I(l)-I(m) and / or A are joined to form Ring F as defined hereinbelow. In some embodiments, R2 and R4 are joined to form a substituted or unsubstituted, saturated or unsaturated, 4-8 membered heterocyclic or carbocyclic ring. In some embodiments, R2and R4are joined to form a substituted or unsubstituted, unsaturated, 4-8 membered heterocyclic ring. In some embodiments, R2and R4are joined to form pyrrolidine, 1-methylpyrrolidine, pyrrolidin-2-one, pyrrolidin-3-ol, morpholine, pyridine, piperidine, tetrahydrofurane, tetrahydrothiophene, cyclopropyl, oxetane, imidazole, pyrimidine, triazole, oxadiazole, pyrazole; each represents a separate embodiment according to this invention. In some embodiments, R2and R4are joined to form pyrrolidine. In some embodiments, R2and R4are joined to form 1-methylpyrrolidine. In some embodiments, R2and R4are joined to form pyrrolidin-2-one. In some embodiments, R2and R4are joined to form pyrrolidin-3-ol. In some embodiments, R2and R4are joined to form morpholine. In some embodiments, R2and R4are joined to form piperidine. In some embodiments, if Ring F is aromatic, then R1is absent. In some embodiments, if Ring F is aromatic, then R3is absent. In some embodiments, if Ring F is aromatic, then R1and / or R3are absent.

[0153] In some embodiments, R3and R4of formula I(d)-I(h), I(l)-I(m) and / or A are joined to form a 3-8 membered heterocyclic ring. In some embodiments, the heterocyclic ring is pyrrolidine, pyrrolidone,2-oxopyrrolidine, piperidine, morpholine, piperazine, imidazole; each represents a separate embodiment according to this invention.

[0154] In some embodiments, R1 and R2 of formula I(d)-I(h), I(l)-I(m) and / or A are joined to form a 3-8 membered carbocyclic or heterocyclic ring. In some embodiments, R1 and R2 are joined to form a cyclopropyl ring. In some embodiments, R1 and R2 are joined to form an oxetane ring.

[0155] In some embodiments, Ring F of formula I(d)-I(h), I(l)-I(m) and / or A is absent. In some embodiments, Ring F is a substituted or unsubstituted, saturated or unsaturated, 4-8 membered heterocyclic ring. In some embodiments, Ring F is a substituted, saturated, 4-8 membered heterocyclic ring. In some embodiments, Ring F is a substituted unsaturated, 4-8 membered heterocyclic ring. In some embodiments, Ring F is an unsubstituted, saturated, 4-8 membered heterocyclic ring. In some embodiments, Ring F is an unsubstituted, unsaturated, 4-8 membered heterocyclic ring. In some embodiments, Ring F is pyrrolidine. In some embodiments, Ring F is 1-methylpyrrolidine. In some embodiments, Ring F is pyrrolidine-2-one. In some embodiments, Ring F is pyrrolidin-3-ol. In some embodiments, Ring F is morpholine. In some embodiments, Ring F is piperidine. In some embodiments, Ring F is tetrahydrofurane. In some embodiments, Ring F is tetrahydrothiophene. In some embodiments, Ring F is cyclopropyl. In some embodiments, Ring F is oxetane. In some embodiments, Ring F is piperazine. In some embodiments, Ring F is morpholine. In some embodiments, Ring F is a pyridinyl. In other embodiments, Ring F is 2-pyridinyl. In other embodiments, Ring F is pyrimidine. In other embodiments, Ring F is imidazole. In other embodiments, Ring F is pyridazine. In other embodiments, Ring F is pyrazine. In other embodiments, Ring F is pyrazole. In other embodiments, Ring F is thiazole. In other embodiments, Ring F is isothiazolyl. In other embodiments, Ring F is thiadiazolyl. In other embodiments, Ring F is triazolyl. In other embodiments, Ring F is thiazolyl. In other embodiments, Ring F is oxazolyl. In other embodiments, Ring F is isoxazolyl. In other embodiments, Ring F is pyrrolyl. In other embodiments, Ring F is oxadiazolyl. In other embodiments, Ring F is 1,2,3-, 1,2,4-, 1,2,5- or 1,3,4- oxadiazolyl; each is a separate embodiment according to this invention. In other embodiments, Ring F is oxazolonyl. In other embodiments, Ring F is oxazolidonyl. In other embodiments, Ring F is thiazolonyl. In other embodiments, Ring F is isothiazolinonyl. In other embodiments, Ring F is isoxazolidinonyl. In other embodiments, Ring F is imidazolidinonyl. In other embodiments, Ring F is pyrazolonyl. In other embodiments, Ring F is 2H-pyrrol-2-onyl. In other embodiments, Ring F is triazolopyrimidine. In other embodiments, Ring F is 3H-[1,2,3]triazolo[4,5-d]pyrimidine, 1H-[1,2,3]triazolo[4,5-d]pyrimidine, [1,2,4]triazolo[4,3-c]pyrimidine, [1,2,4]triazolo[4,3-a]pyrimidine, [1,2,3]triazolo[1,5-a]pyrimidine, [1,2,3]triazolo[1,5-c]pyrimidine, [1,2,4]triazolo[1,5-a]pyrimidine or [1,2,4]triazolo[1,5-c]pyrimidine; each is a separate embodiment according to this invention. In other embodiments, Ring F is 6,7-dihydro- 5H-pyrazolo[5,1-b][1,3]oxazine.

[0156] In some embodiments, Ring W of formula I(k)-I(m) may be either aromatic or non-aromatic ring. In some embodiments, Ring W is aromatic. In some embodiments, if Ring W is aromatic, then X2, X3, and X4, are each independently CH, C(R) or N; each represent a separate embodiment accordingto this invention. In some embodiments, if Ring W is aromatic, then X2, X3, and X4, are each independently C(CH3), C(O-CH2-cyclopropyl), C(O-CH2-methylcyclobutyl), C(NH-CH2-cyclopropyl), C(isopropoxy), C(O-CH(CH3)-CH2-O-CH3), C(CH2CH3), C-iPr, C-CH2-cyclopropyl, C(OCH3), C(OCH2CH3), C(O-(CH2)2-O-CH3, C(OCHF2), C(Cl), C(C(O)CH3), C(O-CH2CH2-O-CH3), or C(OH); each represent a separate embodiment according to this invention. In some embodiments, if Ring W is aromatic, then X15 is C. In some embodiments, if Ring W is aromatic, then X2, X3, and X4, are each independently C(CH3), C(O-CH2-cyclopropyl), C(O-CH2-methylcyclobutyl), C(NH-CH2-cyclopropyl), C(isopropoxy), C(O-CH(CH3)-CH2-O-CH3), C(CH2CH3), C-iPr, C-CH2-cyclopropyl, C(OCH3), C(OCH2CH3), C(O-(CH2)2-O-CH3, C(OCHF2), C(Cl), C(C(O)CH3), C(O-CH2CH2-O-CH3), or C(OH); each represent a separate embodiment according to this invention and X15 is C.

[0157] In some embodiments, Ring W is non-aromatic. In some embodiments, Ring W is a saturated ring. In some embodiments, Ring W is unsaturated, non-aromatic ring. In some embodiments, if Ring W is non-aromatic, then X2, X3, and X4, are each independently CH2, CH(R), C(R)2, NH, N(R), O, S, S=O or SO2; each represents a separate embodiment according to this invention. In some embodiments, if Ring W is non-aromatic, then X15 is CH, C(R) or N; each represents a separate embodiment according to this invention. In some embodiments, if Ring W is non-aromatic, then X2, X3, and X4, are each independently CH2, CH(R), C(R)2, NH, N(R), O, S, S=O or SO2; each represents a separate embodiment according to this invention, and X15 is CH, C(R) or N; each represents a separate embodiment according to this invention.

[0158] In some embodiments, Ring W is non-aromatic, and Ring W' is aromatic. In some embodiments, Ring W is non-aromatic, and Ring W' is non-aromatic. In some embodiments, Ring W is aromatic, and Ring W' is non-aromatic. In some embodiments, Ring W is aromatic, and Ring W' is aromatic. In some embodiments, if both Ring W and Ring W' are aromatic, then at least one of X2, X3, and X4 is C(R); X11 is N; or X12 is not S.

[0159] In some embodiments, Ring W' of formula I(k)-I(m) may be either aromatic or non-aromatic ring. In some embodiments, Ring W' is aromatic. In some embodiments, if Ring W' is aromatic, then X12is S, SO2, O, NH, N(R), N-OH, CH=CH, CH=CH(R), C(R)=CH, N=CH, N=C(R), CH=N or C(R)=N; each represents a separate embodiment according to this invention. In some embodiments, if Ring W' is aromatic, then X12is N-CH2-COOH, N-CH2-CH2-OH, N-CH3, N-CH2CH3, N-iPr, N- cyclopropyl, N-CH2-cyclopropyl; each represents a separate embodiment according to this invention. In some embodiments, if Ring W' is aromatic, then X12is SO2. In some embodiments, if Ring W' is aromatic, then X12is O. In some embodiments, if Ring W' is aromatic, then X12is NH. In some embodiments, if Ring W' is aromatic, then X12is N(R). In some embodiments, if Ring W' is aromatic, then X12is N-CH3. In some embodiments, if Ring W' is aromatic, then X12is N-CH2CH3. In some embodiments, if Ring W' is aromatic, then X12is N-iPr. In some embodiments, if Ring W' is aromatic, then X12is N-cyclopropyl. In some embodiments, if Ring W' is aromatic, then X12is N-CH2- cyclopropyl. In some embodiments, if Ring W' is aromatic, then X12is CH=CH. In some embodiments,if Ring W' is aromatic, then X12 is CH=CH(R). In some embodiments, if Ring W' is aromatic, then X12 is C(R)=CH.

[0160] In some embodiments, Ring W' is non-aromatic. In some embodiments, Ring W' is a saturated ring. In some embodiments, Ring W' is unsaturated, non-aromatic ring. In some embodiments, if Ring W' is non-aromatic, then X12 is CH=CH, CH=CH(R), C(R)=CH, OCH2, CH2O, SCH2, CH2S, CH=N, C(R)=N, N=CH, N=C(R); each represents a separate embodiment according to this invention. In some embodiments, if Ring W' is non-aromatic, then X12 is CH=CH. In some embodiments, if Ring W' is non-aromatic, then X12 is OCH2. In some embodiments, if Ring W' is non-aromatic, then X12 is CH=N. In some embodiments, if Ring W' is non-aromatic, then X12 is N=CH.

[0161] In various embodiments, this invention is directed to the compounds presented in Table 1, pharmaceutical compositions and / or method of use thereof, each represents a separate embodiment according to this invention: Table 1:

[0162] It is well understood that in structures presented in this invention wherein the carbon atom has less than 4 bonds, H atoms are present to complete the valence of the carbon. It is well understood that in structures presented in this invention wherein the nitrogen atom has less than 3 bonds, H atoms are present to complete the valence of the nitrogen.

[0163] In some embodiments, this invention is directed to the compounds listed hereinabove, pharmaceutical compositions and / or method of use thereof, wherein the compound is pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (deuterated analog), PROTAC, pharmaceutical product or any combination thereof. In some embodiments, the compounds are c-MYC mRNA translation modulators. In some embodiments, the compounds are c-MYC mRNA translation inhibitors. In some embodiments, the compounds are c-MYC inhibitors. In various embodiments, the compounds are c-MYC mRNA transcription regulators. In various embodiments, the compounds are any combination of c-MYC mRNA translation modulators, c- MYC mRNA transcription regulators and c-MYC inhibitors.

[0164] As used herein, the term “alkyl” can be any straight- or branched-chain alkyl group containing up to about 30 carbons unless otherwise specified. In various embodiments, an alkyl includes C1-C5 carbons. In some embodiments, an alkyl includes C1-C6 carbons. In some embodiments, an alkyl includes C1-C5 carbons. In some embodiments, an alkyl includes C1-C8 carbons. In some embodiments, an alkyl includes C1-C10 carbons. In some embodiments, an alkyl is a C1-C12 carbons. In some embodiments, an alkyl is a C1-C20 carbons. In some embodiments, branched alkyl is an alkyl substituted by alkyl side chains of 1 to 5 carbons. In various embodiments, the alkyl group may be unsubstituted. In some embodiments, the alkyl group may be substituted by a halogen, haloalkyl, hydroxyl, alkoxy, carbonyl, amido, alkylamido, dialkylamido, cyano, nitro, CO2H, amino, alkylamino, dialkylamino, carboxyl, thio, thioalkyl, C1-C5 linear or branched haloalkoxy, CF3, phenyl, halophenyl, (benzyloxy)phenyl, -CH2CN, NH2, NH-alkyl, N(alkyl)2, -OC(O)CF3, -OCH2Ph, -NHCO-alkyl, - C(O)Ph, C(O)O-alkyl, C(O)H, -C(O)NH2 or any combination thereof.

[0165] The alkyl group can be a sole substituent, or it can be a component of a larger substituent, such as in an alkoxy, alkoxyalkyl, haloalkyl, arylalkyl, alkylamino, dialkylamino, alkylamido, alkylurea, etc.Preferred alkyl groups are methyl, ethyl, and propyl, and thus halomethyl, dihalomethyl, trihalomethyl, haloethyl, dihaloethyl, trihaloethyl, halopropyl, dihalopropyl, trihalopropyl, methoxy, ethoxy, propoxy, arylmethyl, arylethyl, arylpropyl, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, methylamido, acetamido, propylamido, halomethylamido, haloethylamido, halopropylamido, methyl-urea, ethyl-urea, propyl-urea, 2, 3, or 4-CH2-C6H4-Cl, C(OH)(CH3)(Ph), etc.

[0166] As used herein, the term “aryl” refers to any aromatic ring that is directly bonded to another group and can be either substituted or unsubstituted. The aryl group can be a sole substituent, or the aryl group can be a component of a larger substituent, such as in an arylalkyl, arylamino, arylamido, etc. In some embodiments, the term aryl according to this invention, includes also heteroaryl. Exemplary aryl groups include, without limitation, phenyl, tolyl, xylyl, furanyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, thiazolyl, oxazolyl, isooxazolyl, pyrazolyl, imidazolyl, thiophene-yl, pyrrolyl, indolyl, phenylmethyl, phenylethyl, phenylamino, phenylamido, 3-methyl-4H-1,2,4-triazolyl, oxadiazolyl, 5-methyl-1,2,4-oxadiazolyl, isothiazolyl, thiadiazolyl, triazolyl, etc. Substitutions include but are not limited to: F, Cl, Br, I, C1-C5 linear or branched alkyl, C1-C5 linear or branched haloalkyl, C1-C5 linear or branched alkoxy, C1-C5 linear or branched haloalkoxy, CF3, phenyl, halophenyl, CN, NO2, -CH2CN, NH2, NH-alkyl, N(alkyl)2, hydroxyl, -OC(O)CF3, -OCH2Ph, -NHCO-alkyl, COOH, - C(O)Ph, C(O)O-alkyl, C(O)H, -C(O)NH2 or any combination thereof.

[0167] As used herein, the term "alkoxy" refers to an ether group substituted by an alkyl group as defined above. Alkoxy refers both to linear and to branched alkoxy groups. Nonlimiting examples of alkoxy groups are methoxy, ethoxy, propoxy, iso-propoxy, tert-butoxy.

[0168] As used herein, the term "aminoalkyl" refers to an amine group substituted by an alkyl group as defined above. Aminoalkyl refers to monoalkylamine, dialkylamine or trialkylamine. Nonlimiting examples of aminoalkyl groups are -N(Me)2, -NHMe, -NH3.

[0169] A “haloalkyl” group refers, in some embodiments, to an alkyl group as defined above, which is substituted by one or more halogen atoms, e.g. by F, Cl, Br or I. The term “haloalkyl” include but is not limited to fluoroalkyl, i.e., to an alkyl group bearing at least one fluorine atom. Nonlimiting examples of haloalkyl groups are CF3, CF2CF3, CF2CH3,CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2and CF(CH3)-CH(CH3)2.

[0170] A “halophenyl” group refers, in some embodiments, to a phenyl substitutent which is substituted by one or more halogen atoms, e.g. by F, Cl, Br or I. In one embodiment, the halophenyl is 4- chlorophenyl.

[0171] An “alkoxyalkyl” group refers, in some embodiments, to an alkyl group as defined above, which is substituted by alkoxy group as defined above, e.g. by methoxy, ethoxy, propoxy, i-propoxy, t- butoxy etc. Nonlimiting examples of alkoxyalkyl groups are -CH2-O-CH3, -CH2-O-CH(CH3)2, -CH2-O- C(CH3)3,-CH2-CH2-O-CH3, -CH2-CH2-O-CH(CH3)2, -CH2-CH2-O-C(CH3)3.

[0172] A “cycloalkyl” or "carbocyclic" group refers, in various embodiments, to a ring structure comprising carbon atoms as ring atoms, which may be either saturated or unsaturated, substituted or unsubstituted, single or fused. In some embodiments the cycloalkyl is a 3-10 membered ring. In someembodiments the cycloalkyl is a 3-12 membered ring. In some embodiments the cycloalkyl is a 6 membered ring. In some embodiments the cycloalkyl is a 5-7 membered ring. In some embodiments the cycloalkyl is a 3-8 membered ring. In some embodiments, the c...

Claims

WHAT IS CLAIMED:

1. A compound represented by the structure of formula I(k):I(k) wherein Ring W may be either aromatic or non-aromatic ring, wherein if ring W is aromatic then X2, X3, and X4, are each independently CH, C(R) or N (e.g., C(CH3), C(O- CH2-cyclopropyl), C(O-CH2-methylcyclobutyl), C(O-CH2-3-methyloxetane), C(NH- CH2-cyclopropyl), C(isopropoxy), C(O-CH(CH3)-CH2-O-CH3), C(CH2CH3), C-iPr, C- CH2-cyclopropyl, C(OCH3), C(OCH2CH3), C(O-(CH2)2-O-CH3, C(OCHF2), C(Cl), C(C(O)CH3), C(O-CH2CH2-O-CH3), C(OH)); X15is C; and wherein if ring W is non-aromatic then X2, X3, and X4, are each independently CH2, CH(R), C(R)2, NH, N(R), O, S, S=O or SO2(e.g., CH2); X15is CH, C(R) or N (e.g., CH, N); X5, X6, X7, X8and X9are each independently nitrogen or carbon atoms; wherein if either one of X5, X6, X7, X8 and X9 is nitrogen, then the respective R7’, R7’’, R7, R7’’’, and R7’’’’ substitution is absent; X10 is N, CH, C(R), or C=O; wherein if X10 is C=O then X11 is N (e.g., C(CH2-OH), C(CH2- CH2-OH), C(NH-CH2-cyclopropyl), C(COOH), C(CH3), C(cyclopropyl), C(isopropoxy)); X11 is N or C; wherein if X11 is N then X10 is C=O; Ring W’ may be either aromatic or non-aromatic ring, wherein if ring W’ is aromatic thenX12 is S, SO2, O, NH, N(R), N-OH, CH=CH, CH=CH(R), C(R)=CH, N=CH, N=C(R), CH=N or C(R)=N (e.g., N-CH2-COOH, N-CH2-CH2-OH, N-CH3, N-CH2CH3, N-iPr, N-cyclopropyl, N-CH2-cyclopropyl); wherein if ring W’ is non-aromatic then X12 is CH=CH, CH=CH(R), C(R)=CH, OCH2, SCH2, CH=N, C(R)=N, N=CH, N=C(R); wherein if both Ring W and Ring W' are aromatic, then at least one of X2, X3, and X4 is C(R); X11 is N; or X12 is not S; R5 is H or C1-C5 linear or branched alkyl (e.g. methyl); R6 is H, F, Cl, Br, I, OH, SH, R8-OH, R8-SH, -R8-O-R10 (e.g., CH2-O-CH3, (CH2)2-O-CH3 (CH2)3-O-CH3, (CH2)2-O-CH(CH3)2), R8-S-R10 (e.g., (CH2)3-S-(CH2)2CH3), R8-NHC(O)-R10, -O-R8- R10, R8-(substituted or unsubstituted C3-C8 cycloalkyl) (e.g., CH2-cyclopropyl, CH2-cyclobutanol, CH2- difluorocyclopropyl, CH2-methylcyclopropyl, CH2-dimethylamino-cyclohexyl, (CH2)2-cyclopentanole, CH2-cyclohexanol), R8-(substituted or unsubstituted, saturated, unsaturated or aromatic, single, fused or spiro 3-10 membered heterocyclic ring) (e.g., (CH2)3-piperidine, (CH2)3-4-fluoro-piperidine, (CH2)3- pyran, (CH2)2-pyrrazole, (CH2)2-imidazole, CH2-tetrahydrofurane, CH2-dioxane, CH2-oxetane, CH2- piperidine, CH2-triazole, CH2-1-oxa-8-azaspiro[4.5]decane, (CH2)3-diazabicyclo[2.2.1]heptane, CH2- methyl-THF, CH2-ethyl-piperidine, CH2-oxa-azaspirodecane, (CH2)3-dimethylpyrazole, CH2-2-oxo- methylpyrrolidine, CH2-methyl-azetidine, CH2-azaspiroheptane), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, NH(R10), N(R10)(R11), R8-N(R10)(R11) (e.g., (CH2)2-NH2, (CH2)3- N(CH2CH3)2, (CH2)3-N(CH(CH3)2)2, (CH2)3-piperidine, (CH2)3-4-fluoro-piperidine, (CH2)3-4-cyano- piperidine, (CH2)4-NH(CH3), (CH2)3-NH-CH3, (CH2)3-NH-CH2CH3, (CH2)3-N(CH2CH3)2, (CH2)3-NH2, (CH2)3-N(CH2CH3)(CH2CF3)), R9-R8-N(R10)(R11) (e.g., (CH2)2-C(O)-piperidine), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R10, NHCO-N(R10)(R11), COOH, -C(O)Ph, C(O)O-R10, R8-C(O)-R10, C(O)H, C(O)- R10 (e.g., C(O)CH3), C1-C5 linear or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR, C(O)N(R10)(R11), SO2R, SO2N(R10)(R11), CH(CF3)(NH-R10), C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., CH(CH3)CH2OCH3, CH(CH3)CH2NH2, CH(CH3)C(O)N(CH3)2, CH2-CH(OH)Ph, (CH2)3N(H)CH2CH3, CH(CH3)(CH2)2OH, CH(CH2OH)(CH2CH3), (CH2)3-OCH3, (CH2)2-OCH3, (CH2)2-OCH(CH3)2, CH(CH2OH)(CH2CH(CH3)2), CH2CH(CH3)(OCH3), CH2CH(N(CH3)2)(CH2CH3), benzyl, methyl, ethyl, CH2-OCH2-CH2-O-CH3, CH(CH3)C(O)N(CH3)2), C1-C5linear or branched, substituted or unsubstituted alkenyl, C1-C5linear or branched, or C3-C8cyclic haloalkyl, substituted or unsubstituted C1-C5linear or branched, or C3-C8cyclic alkoxy (e.g. methoxy, O-(CH2)2-O-CH3), optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom, C1-C5linear or branched thioalkoxy, C1-C5linear or branched haloalkoxy, C1-C5linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclohexyl, methoxycyclopropyl, methylcyclobutyl, aminomethyl-cyclobutyl, methoxycyclobutyl, 2,3-dihydro-1H- indenol), R8-(substituted or unsubstituted C3-C8cycloalkyl), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., piperidine, 1-methyl-piperidine, azetidine, pyrrolidine, pyrrolidinone,quinuclidine, tetrahydropyran, azaspiro[3.3]heptane, imidazole, trifluoromethyl-oxetane, hydroxy-etrahydrofurane, azepan-2-one, azabicyclohexane), substituted or unsubstituted aryl, substituted or unsubstituted R8-aryl (e.g., benzyl), substituted or unsubstituted benzyl; or R6 and R5 are joined to form a substituted or unsubstituted 5-8 membered heterocyclic ring e.g., azepane, piperazine, 2-(piperazin-1-yl)acetamide; or R6 is represented by the structure of formula B or Bi:wherein m is 0 or 1; and R12is R20or C1-C5C(O)-alkyl, and R13is R30; or R12and R13are both H; R12 and R13 are each independently H or substituted or unsubstituted C1-C5 alkyl (e.g., ethyl, trifluoroethyl); R12 and C3 are joined to form ring A and R13 is R30; or R12 and R13 are joined to form ring B; or R12 and C1 are joined to form ring C and R13 is R30; or C1 and C3 are joined to form ring D and R12 and R13 are each independently R30; or R13 and C2 are joined to form ring E, m is 1, and R12 is R30; or R12 and R13 are joined to form ring B and C1 and C3 are joined to form ring D; wherein Ring A, C and E are each independently a substituted or unsubstituted single spiro or fused 3-8 membered heterocyclic ring (e.g., A: pyrrolidine, methylpyrrolidine, ethylpyrrolidine); C: piperidine, pyrrolidine, methyl-2-oxopyrrolidine, pyran- pyrrolidine, methyl-azetidine, azabicyclooctane, 2-azabicyclo[2.1.1]hexane, 2- azaspiro[3.3]heptane; E: pyrrolidine, azetidine, ethylpyrrolidine, oxopyrrolidine, methylpiperidine;Ring B is a substituted or unsubstituted single, spiro or fused 3-8 membered heterocyclic ring (B: piperidine, piperidin-2-one, 4-fluoropiperidin-2-one, piperidine- 4-carbonitrile, 4-fluoropiperidine, 4-fluoro-2-methylpiperidine, methyl-piperidin, fluoropiperidine, difluoropiperidine, pyrrolidine, piperazine, methylpyrrolidine, thiomorpholine 1,1-dioxide, 2-oxa-6-azaspiro[3.3]heptane, methyl-piperazine, dimethyl-pyrazole, imidazole, 2-methyl-2,5-diazabicyclo[2.2.1]heptane, hydroxymethyl-pyrrolidine, diazabicyclo[2.2.1]heptane, 6-fluoro-3- azabicyclo[3.1.1]heptane; and Ring D is a substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclobutane, cyclohexane); R7 is H, F, Cl, Br, I, OH, O-R20, SH, R8-OH, R8-SH, SR10, -R8-O-R10, -R8-S-R10, R8-(C3-C8 cycloalkyl), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, NH(R10), N(R10)(R11), R8- N(R10)(R11), R9-R8-N(R10)(R11), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R10, NHCO-N(R10)(R11), COOH, -C(O)Ph, C(O)O-R10, R8-C(O)-R10, C(O)H, C(O)-R10, C1-C5 linear or branched C(O)-haloalkyl, C(O)NH2, C(O)NHR (e.g., C(O)NH(CH3)), C(O)N(R10)(R11) (e.g., C(O)NH(CH3), C(O)NH(CH2CH2OCH3), C(O)NH(CH2CH2OH)), SO2R, SO2N(R10)(R11), CH(CF3)(NH-R10), C1-C5inear or branched, substituted or unsubstituted alkyl (e.g., methylimidazole, methyl, ethyl), C1-C5 linear or branched, substituted or unsubstituted alkenyl, C1-C5 linear or branched, or C3-C8 cyclic haloalkyl e.g., CHF2), C1-C5linear or branched, or C3-C8cyclic alkoxy (e.g. methoxy, ethoxy), optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom, C1-C5linear or branched thioalkyl, C1-C5linear or branched thioalkoxy, C1-C5linear or branched haloalkoxy, C1-C5inear or branched alkoxyalkyl, substituted or unsubstituted C3-C8cycloalkyl (e.g., cyclopropyl, cyclopropanol, cyclohexyl), substituted or unsubstituted 4-7 membered heterocyclic ring (e.g., morpholine (e.g., 2 or 3-morpholine), tetrahydrofuran, tetrahydropyran, oxetane, oxetan-3-ol, pyrrolidine, pyrrolidine-3-ol, 1-methylpyrrolidine, pyrrolidin-2-one, pyrrolidinone, imidazole, pyrazole, piperazine, piperidine, piperidine-4-ol, piperidine-4-carbonitrile, 4-fluoropiperidine, oxadiazole,riazole, 2-oxopyrrolidine, pyridine, 1-methylpyridine), R8-(substituted or unsubstituted single, fused or piro 3-8 membered heterocyclic ring), substituted or unsubstituted aryl, substituted or unsubstituted benzyl; R7’, R7’’, R7’’’ and R7’’’’ are each independently H, F, Cl, Br, I, OH, O-R20, SH, R8-OH, R8- SH, -R8-O-R10, R8-(C3-C8cycloalkyl), R8-(3-8 membered heterocyclic ring), CF3, CD3, OCD3, CN, NO2, CH2CN, -R8CN, NH2, NHR, N(R)2, NH(R10), N(R10)(R11), R8-N(R10)(R11), R9-R8-N(R10)(R11), B(OH)2, OC(O)CF3, -OCH2Ph, NHC(O)-R10, NHCO-N(R10)(R11), COOH, -C(O)Ph, C(O)O-R10, R8-C(O)-R10, C(O)H, C(O)-R10, C1-C5linear or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR, C(O)N(R10)(R11), SO2R, SO2N(R10)(R11), CH(CF3)(NH-R10), C1-C5linear or branched, substituted or unsubstituted alkyl e.g., isopropyl, methyl, ethyl), C1-C5linear or branched, substituted or unsubstituted alkenyl, C1-C5inear or branched, or C3-C8cyclic haloalkyl (e.g., CHF2), C1-C5linear or branched, or C3-C8cyclic alkoxy (e.g. methoxy), optionally wherein at least one methylene group (CH2) in the alkoxy is replacedwith an oxygen atom, C1-C5 linear or branched thioalkoxy, C1-C5 linear or branched haloalkoxy, C1-C5inear or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclohexyl), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., morpholine, pyran, oxetane, pyrrolidine, imidazole, piperazine, piperidine, dioxazole, 2-oxopyrrolidine), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted benzyl; or R7’ and R7’’ are joined to form a 3-8 membered substituted or unsubstituted, saturated, unsaturated or aromatic, carbocyclic or heterocyclic ring (e.g., cyclopentyl, cyclohexyl, piperidine,etrahydrofuran, tetrahydropyran, pyrrolidine); or R7’’ and R7 are joined to form a 3-8 membered substituted or unsubstituted carbocyclic or heterocyclic ring (e.g., cyclopentyl, cyclohexyl, piperidine, tetrahydrofuran, tetrahydropyran, pyrrolidine); or R7 and R7’’’ are joined to form a 3-8 membered substituted or unsubstituted carbocyclic or heterocyclic ring (e.g., cyclopentyl, cyclohexyl, piperidine, tetrahydrofuran, tetrahydropyran, pyrrolidine); or R7’’’ and R7’’’’ are joined to form a 3-8 membered substituted or unsubstituted carbocyclic or heterocyclic ring (e.g., cyclopentyl, cyclohexyl, piperidine, tetrahydrofuran, tetrahydropyran, pyrrolidine); R20 is represented by the following structure:R30is H, R20, F, Cl, Br, I, OH, SH, alkoxy, N(R)2, NH(R10), N(R10)(R11), CF3, CN, NO2, C1-C5inear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH2-CH2-O-CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), C1-C5linear or branched alkoxy, C1-C5linear or branched haloalkyl (e.g., CHF2, CF3, CF2CH3, CH2CF3,CF2CH2CH3,CH2CH2CF3,CF2CH(CH3)2,CF(CH3)-CH(CH3)2), R8-aryl e.g., CH2-Ph), -R8-O-R8-O-R10(e.g. (CH2)2-O-(CH2)2-O-CH3), -R8-O-R10, -R8-R10(e.g., (CH2)2-O- CH3), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine); R is H, F, Cl, Br, I, OH, SH, COOH, CO(R10), C(O)CH3, NH(R10), NH-CH2-cyclopropyl, N(R10)(R11), CF3, CN, NO2, C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, iPr, CH2-cyclopropyl, CH2-OH, CH2-CH2-OH, CH2-CH2-O-CH2-CH2-O-CH3, CH2-O-CH2-CH2- O-CH3), C3-C8substituted or unsubstituted cycloalkyl, cyclopropyl, substituted or unsubstituted C1-C5inear or branched alkoxy, (e.g., methoxy, ethoxy, O-(CH2CH3), OCHF2, O-(CH2)2-O-CH3, isopropoxy, O-(CH2)-cyclopropyl, O-CH2-methylcyclobutyl, O-CH2-3-methyloxetane, O-CH(CH3)-CH2-O-CH3) C1-C5linear or branched haloalkyl (e.g., CHF2, CF3, CF2CH3, CH2CF3,CF2CH2CH3,CH2CH2CF3,CF2CH(CH3)2,CF(CH3)-CH(CH3)2), R8-aryl (e.g., CH2-Ph), -R8-O-R8-O-R10(e.g. (CH2)2-O-(CH2)2-O- CH3), -R8-O-R10, O-R8-R10 (e.g. O-(CH2)2-O-CH3, O-(CH2CH3), O-(CH2)-cyclopropyl), -R8-R10 (e.g.,CH2)-cyclopropyl, (CH2)2-O-CH3, (CH2)-OH, (CH2)2-OH, (CH2)-COOH), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine); each R8 is independently [CH2]p wherein p is between 1 and 10 (e.g., 1, 2); R9 is [CH]q, [C]q wherein q is between 2 and 10; R10 and R11 are each independently H, OH, COOH, C1-C5 substituted or unsubstituted linear or branched alkyl (e.g., methyl, ethyl, CH2-cyclopropyl, CH2-CH2-O-CH3), C3-C8 substituted or unsubstituted cycloalkyl (e.g., cyclopropyl), C1-C5 substituted or unsubstituted linear or branched haloalky (e.g., CH2CF3), C1-C5 linear or branched alkoxy (e.g., O-CH3), R20, C(O)R, or S(O)2R; or R10 and R11 are joined to form a substituted or unsubstituted 3-8 membered heterocyclic ing (e.g., piperazine, piperidine), n is an integer between 0 and 4 (e.g., 1, 2); or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, pharmaceutical product or any combination thereof.2.The compound of claim 1, wherein R5 is H or CH3.3.The compound of claims 1 or 2, wherein R6 is H, C1-C5 linear or branched, substituted or unsubstituted alkyl (preferably methyl), substituted or unsubstituted 3-8 membered heterocyclic ring (preferably substituted or unsubstituted piperidine or tetrahydropyran), R8-N(R10)(R11) (preferably (CH2)2-NH2, (CH2)3-NH2, (CH2)3-piperidine or (CH2)3-4-fluoro-piperidine), or R6is represented by the structure of formula Bi.

4. The compound of claim 3, wherein R12and R13of formula Bi are joined to form a substituted or unsubstituted piperidine ring, or wherein R10 and R11 are joined to form a substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., piperidine or 4-fluoro-piperidine).

5. The compound of any one of the preceiding claims, wherein R7is H, C(O)N(R10)(R11) (preferably C(O)NH(CH3)), C1-C5linear or branched, substituted or unsubstituted alkyl (preferably methyl), substituted or unsubstituted C3-C8cycloalkyl (preferably cyclopropanol), substituted or unsubstituted 4-7 membered heterocyclic ring (preferably morpholine, pyrrolidine, pyrrolidine-3-ol, piperidine, piperidine-4-ol, tetrahydrofuran, oxetane, oxetan-3-ol, pyridine, or 1-methylpyridine), or substituted or unsubstituted aryl.

6. The compound of any one of the preceiding claims, wherein R7' is H or F.

7. The compound of any one of the preceiding claims, wherein Ring W is aromatic and one of X2, X3and X4is C(R); preferably wherein R is alkoxy, more preferably methoxy.

8. The compounds of any one of the preceiding claims, wherein X12is O, NH, N(R), CH=N, N=CH, CH=CH, OCH2, or N-OH; preferably wherein R is C1-C5linear or branched, substituted orunsubstituted alkyl, substituted or unsubstituted C1-C5 linear or branched alkoxy, O-R8-R10, OH, NH(R10), haloalkoxy or cycloalkyl.

9. The compound of any one of the preceiding claims, wherein R is CH2-COOH, CH2-CH2-OH, CH3, CH2CH3, iPr, cyclopropyl or CH2-cyclopropyl.

10. The compound of any one of the preceiding claims, wherein X4 is C(R) and R is alkoxy, preferably methoxy.

11. The compound of any one of the preceiding claims, selected from the following:

12. The compound according to claim 1, represented by the structure of formula I(l):wherein Ring F is absent or is a substituted or unsubstituted, saturated or unsaturated, 3-8 membered heterocyclic or carbocyclic ring (e.g., pyrrolidine, 1-methylpyrrolidine, pyrrolidine-3-ol, pyrrolidin-2- one, pyridine, piperidine, piperidine-4-ol, tetrahydrofurane, morpholine, tetrahydrothiophene, cyclopropyl, oxetane, oxetan-3-ol, imidazole, pyrimidine, triazole, oxadiazole, pyrazole); R1and R2are each independently H, F, Cl, Br, I, OH, SH, or CF3, substituted or unsubstituted C1-C5alkyl, C1-C5linear or branched, or C3-C8cyclic haloalkyl, substituted or unsubstituted C1-C5linear or branched, or C3-C8cyclic alkoxy; or R1and R2are joined to form a 3-8 membered carbocyclic or heterocyclic ring (e.g., cyclopropyl, oxetane); or R2and R4are joined to form Ring F as defined above (e.g., pyrrolidine, pyrrolidin-2-one, piperidine, morpholine, pyridine, pyrimidine, triazole, oxadiazole, pyrazole, tetrahydrofurane), whereinf Ring F is aromatic, then R1and / or R3are absent; R3and R4are each independently H, Me, substituted or unsubstituted C1-C5alkyl (e.g., methoxyethylene, methylaminoethyl, aminoethyl), -R8-O-R10(e.g., (CH2)2-O-CH3), R8-N(R10)(R11) e.g., (CH2)2-NH(CH3)), substituted or unsubstituted C3-C8cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted 5-7 membered heterocyclic ring (e.g., pyrrolidine, methylpyrrolidine, piperidine), or R20;or R3 and R4 are joined to form a 3-8 membered heterocyclic ring (e.g., pyrrolidine, , pyrrolidone, 2-oxopyrrolidine, piperidine, morpholine, piperazine, imidazole); andX14 is S, O, N or CH, wherein if X14 is CH then Ring F is not absent and if X14 is S or O then R3 is absent.

13. The compound of claims 1 or 12, represented by the structure of formula I(m):( ) wherein X13 is CH2, CH(R) (e.g., CH-CH3), C(R)2, or C=O; Ring G is absent or is a substituted or unsubstituted 3-8 membered carbocyclic or heterocyclic ing (e.g., cyclobutane, cyclopentane, cyclohexane); R50 is H, R20, F, Cl, Br, I, OH, SH, N(R)2, NH(R10), N(R10)(R11), CF3, CN, NO2, C1-C5 linear or branched, substituted or unsubstituted alkyl C1-C5 linear or branched alkoxy, C1-C5 linear or branched haloalkyl, -R8-R10 (e.g., (CH2)2-O-CH3), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine). 14.The compound of any one of claims 12 or 13, wherein X14 is O or N. 15.The compound of any one of claims 12-14, wherein R1 is H, or wherein R1 and R2 are joined to form a 3-8 membered carbocyclic or heterocyclic ring (e.g., cyclopropyl, oxetane, pyrrolidine).

16. The compound of any one of claims 12-15, wherein R3is H, substituted or unsubstituted C1-C5alkyl or absent.

17. The compound of any one of claims 12-16, wherein R2and R4are joined to form Ring F (preferably pyrrolidine, piperidine, tetrahydrofurane, pyrrolidin-2-one, pyrrolidin-3-ol, morpholine).

18. A compound represented by any one of the following structures:

19. The compound of any one of the preceiding claims, wherein the compound is a substantially pure single stereoisomer.

20. The compound according to any one of the preceiding claims, wherein the compound is a c-MYC mRNA translation modulator, a c-MYC mRNA transcription regulator, a c-MYC inhibitor or any combination thereof.

21. A pharmaceutical composition comprising the compound of any one of the preceiding claims and a pharmaceutically acceptable carrier.

22. The compound according to any one of claims 1-21, for use in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting cancer in a subject.

23. The compound of claim 22, wherein the cancer is selected from the list of: breast cancer, ovarian carcinoma, acute myeloid leukemia, chronic myelogenous leukemia, Hodgkin’s and Burkitt’s lymphoma, diffuse large Bcell lymphoma, prostate cancer, colon cancer, gastric cancer, primary central nervous system lymphoma, glioblastoma, medulloblastoma, melanoma, non-small cell lung carcinoma, germinal center-derived lymphomas, esophageal squamous cell carcinoma, osteosarcoma, bladder cancer, pancreatic cancer, lung adenocarcinoma, BRAF V600E thyroid cancer, choroid plexus carcinoma, colitis-associated cancer, epithelial ovarian cancer, colorectal cancer, pancreatic cancer and uterine cancer; wherein the cancer is early cancer, advanced cancer, invasive cancer, metastatic cancer, drug resistant cancer or any combination thereof; wherein the subject has been previously treated with chemotherapy, immunotherapy, radiotherapy, biological therapy, surgical intervention, or any combination thereof; wherein the compound is administered in combination with an anti-cancer therapy; or any combination thereof.

24. The compound of claim 23, wherein the anti-cancer therapy is chemotherapy, immunotherapy, radiotherapy, biological therapy, surgical intervention, or any combination thereof.

25. The compound according to any one of claims 1-21, for use in suppressing, reducing or inhibiting tumor growth in a subject.

26. A method of modulating c-MYC mRNA translation, or regulating c-MYC mRNA transcription in a cell, comprising contacting a compound according to any one of claims 1-22 with a cell, thereby modulating c-MYC mRNA translation, or regulating c-MYC mRNA transcription in said cell.

27. The method of claim 26, wherein said method is carried out (a) by regulating c-MYC mRNA splicing (inclusion or exclusion of untranslated region or alternative usage of exons); (b) by regulation of c-MYC mRNA modifications; (c) by regulation of the interaction of RNA binding protein with c-MYC mRNA thereby changing mRNA localization; (d) by regulating c-MYC mRNA localization in the cytoplasm; (e) by regulating ribosomes or ribosome accessory factor to c-MYC mRNA; (f) by reducing the amount of c-MYC protein in the cell; or any combination thereof.

Images