WO2024010761A1 - Modulateurs de traduction d'arnm c-myc et leurs utilisations dans le traitement du cancer - Google Patents

Modulateurs de traduction d'arnm c-myc et leurs utilisations dans le traitement du cancer Download PDF

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WO2024010761A1
WO2024010761A1 PCT/US2023/026827 US2023026827W WO2024010761A1 WO 2024010761 A1 WO2024010761 A1 WO 2024010761A1 US 2023026827 W US2023026827 W US 2023026827W WO 2024010761 A1 WO2024010761 A1 WO 2024010761A1
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Prior art keywords
substituted
unsubstituted
branched
linear
ring
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PCT/US2023/026827
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English (en)
Inventor
Boaz Inbal
Aviad MANDABI
Stephen David Penrose
Luba SIMHAEV ISCHAKOV
Iris Alroy
Rina WASSERMANN
Yoni SHEINBERGER
Yaode Wang
Haitang LI
Lothar Willms
Scott Alexander SADLER
Shuyu CHU
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Anima Biotech Inc.
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Priority claimed from US17/856,998 external-priority patent/US20220370431A1/en
Application filed by Anima Biotech Inc. filed Critical Anima Biotech Inc.
Publication of WO2024010761A1 publication Critical patent/WO2024010761A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
    • C07D513/14—Ortho-condensed systems

Definitions

  • 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.
  • 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.
  • 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.
  • 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. 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.
  • 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.
  • 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.
  • 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],
  • MYC modulators 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.
  • 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.
  • the compound is a c-MY C mRNA translation modulator.
  • the compound is a c-MY C mRNA transcription regulator.
  • the compound is a c- MYC inhibitor.
  • the compound is any combination of a c-MYC mRNA translation modulator, c-MY C mRNA transcription regulator and c-MYC inhibitor.
  • This invention further provides a pharmaceutical composition
  • 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.
  • 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.
  • 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.
  • the tumor is cancerous.
  • the subject suffers from cancer.
  • 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.
  • 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.
  • this invention is directed to a compound represented by the structure of formula (I):
  • R 6 is H, F, Cl, Br, I, OH, SH, R 8 -OH, R 8 -SH, -R 8 -O-R 10 (e.g., CH 2 -O-CH 3 , (CH 2 ) 2 -O-CH 3 (CH 2 ) 3 -O-CH 3 , (CH 2 ) 2 -O-CH(CH 3 ) 2 ), R 8 -S-R 10 (e.g., (CH 2 ) 3 -S-(CH 2 ) 2 CH 3 ), R 8 -NHC(O)-R 10 , -O-R 8 - R 10 , R 8 -(substituted or unsubstituted C 3 -C 8 cycloalkyl) (e.g., CH 2 -cyclopropyl, CH 2 -cyclobutanol, CH 2 - difluorocyclopropyl, CH 2 -methylcyclopropyl, CH 2 -dimethylamin
  • 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,
  • R is H, F, Cl, Br, I, OH, SH, COOH, CO(R 10 ) (e.g., C(O)CH 3 ), NH(R 10 ), NH-CH 2 -cyclopropyl, N(R 10 )(R 11 ), CF 3 , CN, NO 2 , C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, iPr, CH 2 -cyclopropyl, CH 2
  • each R 8 is independently [CH 2 ] p wherein p is between 1 and 10 (e.g., 1, 2); R9 is [CH]q, [C]q wherein q is between
  • At least one of X2, X3, and X4 is C(R).
  • X11 is N.
  • X12 is not S.
  • at least one of X2, X3, and X4 is C(R); X11 is N; or X12 is not S.
  • R is not H.
  • 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)); X 5 , X 6 , X 7 , X 8 and X 9 are each independently nitrogen or carbon atoms; wherein if either one of X5, X6,
  • 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
  • R is H, F, Cl, Br, I, OH, SH, COOH, CO(R 10 ) (e.g., C(O)CH 3 ), NH(R 10 ), NH-CH 2 -cyclopropyl, N(R 10 )(R 11 ), CF 3 , CN, NO 2 , C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, iPr, CH 2 -cyclopropyl, CH 2 -OH, CH 2 -CH 2 -OH, CH 2
  • each R 8 is independently [CH 2 ] p wherein p is between 1 and 10 (e.g., 1, 2); R 9 is [CH] q , [C] q wherein
  • 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.
  • At least two of R7’, R7’’, R7’’’ and R7’’’’ are not H and are different than eachother.
  • at least one of X2, X3, and X4 is C(R).
  • X11 is N.
  • X12 is not S.
  • at least one of X2, X3, and X4 is C(R); X11 is N; or X12 is not S.
  • R is not H.
  • 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, pyrrol
  • 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
  • each R 8 is independently [CH 2 ] p wherein p is between 1 and 10 (e.g., 1, 2); R 9 is [CH] q , [C] q wherein q is between 2 and 10; R10 and R11 are each independently H, OH, COOH
  • At least one of X 2 , X 3 , and X 4 is C(R).
  • X 11 is N.
  • X 12 is not S.
  • at least one of X 2 , X 3 , and X 4 is C(R); X 11 is N; or X 12 is not S.
  • R is not H.
  • this invention is directed to a compound represented by the structure of formula I(c): wherein X 2 , X 3 , and X 4 , are each independently CH, C(R) or N (e.g., C(CH 3 ), C(O-CH 2 -cyclopropyl), C(O-CH 2 -methylcyclobutyl), C(NH-CH 2 -cyclopropyl), C(isopropoxy), C(O-CH(CH 3 )-CH 2 -O-CH 3 ), 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 X 2 , X
  • 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, pyrrol
  • 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., (CH2)2-O-CH3), substituted or unsubstituted aryl (e.g., (CH2)2-O-CH3), substituted or unsubstituted aryl (e.g., (CH2)2-O-CH3), substituted or unsubstituted aryl (e.g., (CH2)2-O-CH3), substituted or unsubstituted aryl (e.g., (CH2)2-
  • 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; R 10 and R 11 are each independently H, OH, COOH, C 1 -C 5 substituted or unsubstituted linear or branched
  • At least one of R 7 , R 7 ’, R 7 ’’, R 7 ’’’ and R 7 ’’’’ is not H. In some embodiments, at least two of R 7 , R 7 ’, R 7 ’’, R 7 ’’’ and R 7 ’’’’ are not H. In some embodiments, at least one of R 7 ’, R 7 ’’, R 7 ’’’ and R 7 ’’’’’’’ is not H. In some embodiments, at least two of R 7 ’, R 7 ’’, R 7 ’’’ and R 7 ’’’’’ are not H.
  • At least two of R 7 ’, R 7 ’’, R 7 ’’’ and R 7 ’’’’ are different than eachother. In some embodiments, at least two of R 7 ’, R 7 ’’, R 7 ’’’ and R 7 ’’’’ 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.
  • this invention is directed to a compound represented by the structure of formula I(d): wherein X 2 , X 3 , and X 4 , are each independently CH, C(R) or N (e.g., C(CH 3 ), C(O-CH 2 -cyclopropyl), C(O-CH 2 -methylcyclobutyl), C(NH-CH 2 -cyclopropyl), C(isopropoxy), C(O-CH(CH 3 )-CH 2 -O-CH 3 ), 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;
  • 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
  • R 20 is represented by the following structure: R is H, F, Cl, Br
  • 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, e
  • 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), C 1
  • At least one of X 2 , X 3 , and X 4 is C(R).
  • X 11 is N.
  • X 12 is not S.
  • at least one of X 2 , X 3 , and X 4 is C(R); X 11 is N; or X 12 is not S.
  • R is not H.
  • if R 1 and R 2 are joined to form a C O, then at least one of X 2 , X 3 , X 4 , and X 10 is not CH; [0026]
  • this invention is directed to a compound represented by the structure of formula I(e):
  • 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’
  • 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
  • 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, e
  • each R8 is independently [CH2]p wherein p is between 1 and 10 (e.g., 1, 2);
  • R 9 is [CH] q , [C] q wherein q is between 2 and 10;
  • R 10 and R 11 are each independently H, OH, COOH, C 1 -C 5 substituted or unsubstituted linear or branched alkyl (e.g., methyl, ethyl, CH 2 -cyclopropyl, CH 2 -CH 2 -O-CH 3 ), C 3 -C 8 substituted or unsubstituted cycloalkyl (e.g.,
  • At least one of R 7 ’, R 7 ’’, R 7 ’’’ and R 7 ’’’’ is not H. In some embodiments, at least two of R 7 ’, R 7 ’’, R 7 ’’’ and R 7 ’’’’ are not H. In some embodiments, at least two of R 7 ’, R 7 ’’, R 7 ’’’ and R 7 ’’’’ are different than eachother. In some embodiments, at least two of R 7 ’, R 7 ’’, R 7 ’’’’ and R 7 ’’’’’ are not H and are different than eachother.
  • At least one of X 2 , X 3 , and X 4 is C(R).
  • X 11 is N.
  • X 12 is not S.
  • at least one of X 2 , X 3 , and X 4 is C(R); X 11 is N; or X12 is not S.
  • R is not H.
  • this invention is directed to a compound represented by the structure of formula I(f): wherein X 2 , X 3 , and X 4 , are each independently CH, C(R) or N (e.g., C(CH 3 ), C(O-CH 2 -cyclopropyl), C(O-CH 2 -methylcyclobutyl), C(NH-CH 2 -cyclopropyl), C(isopropoxy), C(O-CH(CH 3 )-CH 2 -O-CH 3 ), 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(C(R) or N (e.g., C(CH 3 ), C(O-CH 2 -cyclopropyl), C(O-CH 2 -methylcyclobutyl), C(NH-CH
  • 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
  • each R 8 is independently [CH 2 ] p wherein p is between 1 and 10 (e.g., 1, 2); R9 is [CH]q, [C]q wherein q is between
  • 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.
  • 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.
  • this invention is directed to a compound represented by the structure of formula I(g): wherein X 2 , X 3 , and X 4 , are each independently CH, C(R) or N (e.g., C(CH 3 ), C(O-CH 2 -cyclopropyl), C(O-CH 2 -methylcyclobutyl), C(NH-CH 2 -cyclopropyl), C(isopropoxy), C(O-CH(CH 3 )-CH 2 -O-CH 3 ), C(CH 2 CH 3 ), C-iPr, C-CH 2 -cyclopropyl, C(OCH 3 ), C(OCH 2 CH 3 ), C(O-(CH 2 ) 2 -O-CH 3 , C(OCHF 2 ), C(Cl), C(C(O)CH3), C(O-CH 2 CH 2 -O-CH 3 ), C(OH)); X 5 , X 6 , X 7
  • R 6 is H, F, Cl, Br, I, OH, SH, R 8 -OH, R 8 -SH, -R 8 -O-R 10 (e.g., CH 2 -O-CH 3 , (CH 2 ) 2 -O-CH 3 (CH 2 ) 3 -O-CH 3 , (CH 2 ) 2 -O-CH(CH 3 ) 2 ), R 8 -S-R 10 (e.g., (CH 2 ) 3 -S-(CH 2 ) 2 CH 3 ), R 8 -NHC(O)-R 10 , -O-R 8 - R 10 , R 8 -(substituted or unsubstituted C 3 -C 8 cycloalkyl) (e.g., CH 2 -cyclopropyl, CH 2 -cyclobutanol, CH 2 - difluorocyclopropyl, CH 2 -methylcyclopropyl, CH 2 -dimethylamin
  • 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,
  • R 30 is H, R 20 , F, Cl, Br, I, OH, SH, alkoxy, N(R) 2 , NH(R 10 ), N(R 10 )(R
  • each R 8 is independently [CH 2 ] p wherein p is between 1 and 10 (e.g., 1, 2);
  • R 9 is [CH] q , [C] q wherein q is between 2 and 10;
  • R 10 and R 11 are each independently H, OH, COOH, C 1 -C 5 substituted or unsubstituted linear or branched alkyl (e.g., methyl, ethyl, CH2-cyclopropyl, CH2-CH2-O-CH3), C3-C8 substituted or unsubstituted or unsubstituted or unsubstituted
  • 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.
  • R 50 is H, R 20 , F, Cl, Br, I, OH, SH, N(R) 2 , NH(R 10 ), N(R 10 )(R 11 ), CF 3 , CN, NO 2 , C 1 -C 5 linear or branched, substituted or unsubstituted alkyl C 1 -C 5 linear or branched alkoxy, C 1 -C 5 linear or branched haloalkyl, -R 8 -R 10 (e.g., (CH 2 ) 2 -O-(CH 2 ) 2 -O-CH 3 ), -R 8 -O-R 10 , -R 8 -R 10 (e.g., (CH 2 ) 2 -O-CH 3 ), -R 8 -O-R 10 , -R 8 -R 10 (e.g., (CH 2 ) 2 -O-CH 3 ), -R 8 -O-R 10 , -R 8 -R 10
  • 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 unsubstit
  • At least one of R7’, R7’’, R7’’’ and R7’’’’ is not H. In some embodiments, at least two of R 7 ’, R 7 ’’, R 7 ’’’ and R 7 ’’’’ are not H. In some embodiments, at least two of R 7 ’, R 7 ’’, R 7 ’’’ and R 7 ’’’’ are different then eachother. In some embodiments, at least two of R 7 ’, R 7 ’’, R 7 ’’’’ and R 7 ’’’’ are not H and are different then eachother. [0037] In some embodiments, at least one of X 2 , X 3 , and X 4 is C(R).
  • X 11 is N. In some embodiments, X 12 is not S. In some embodiments, at least one of X 2 , X 3 , and X 4 is C(R); X 11 is 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):
  • R 6 is H, F, Cl, Br, I, OH, SH, R 8 -OH, R 8 -SH, -R 8 -O-R 10 (e.g., CH 2 -O-CH 3 , (CH 2 ) 2 -O-CH 3 (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-(substit
  • 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,
  • R 30 is H, R 20 , F, Cl, Br, I, OH, SH, alkoxy, N(R) 2 , NH(R 10 ), N(R 10 )(R
  • 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., (CH2)2-O-CH3), substituted or unsubstituted aryl (e.g., (CH2)2-O-CH3), substituted or unsubstituted aryl (e.g., (CH2)2-O-CH3), substituted or unsubstituted aryl (e.g., (CH2)2-O-CH3), substituted or unsubstituted aryl (e.g., (CH2)2-
  • 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; R 10 and R 11 are each independently H, OH, COOH, C 1 -C 5 substituted or unsubstituted linear or branched
  • At least one of R 7 , R 7 ’, R 7 ’’, R 7 ’’’ and R 7 ’’’’ is not H. In some embodiments, at least two of R 7 , R 7 ’, R 7 ’’, R 7 ’’’ and R 7 ’’’’ are not H. In some embodiments, at least one of R 7 ’, R 7 ’’, R 7 ’’’ and R 7 ’’’’’’’ is not H. In some embodiments, at least two of R 7 ’, R 7 ’’, R 7 ’’’ and R 7 ’’’’’ are not H.
  • At least two of R 7 ’, R 7 ’’, R 7 ’’’ and R 7 ’’’ are different then eachother. In some embodiments, at least two of R 7 ’, R 7 ’’, R 7 ’’’ and R 7 ’’’’ are not H and are different then eachother. [0040] In some embodiments, at least one of X 2 , X 3 , and X 4 is C(R). In some embodiments, R is not H.
  • this invention is directed to a compound represented by the structure of formula I(j): wherein X 2 , X 3 , and X 4 , are each independently CH, C(R) or N (e.g., C(CH 3 ), C(O-CH 2 -cyclopropyl), C(O-CH 2 -methylcyclobutyl), C(NH-CH 2 -cyclopropyl), C(isopropoxy), C(O-CH(CH 3 )-CH 2 -O-CH 3 ), C(CH 2 CH 3 ), C-iPr, C-CH 2 -cyclopropyl, C(OCH 3 ), C(OCH 2 CH 3 ), C(O-(CH 2 ) 2 -O-CH 3 , C(OCHF 2 ), C(Cl), C(C(O)CH3), C(O-CH 2 CH 2 -O-CH 3 ), C(OH)); X 5 , X 6 , X 7
  • 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
  • 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,
  • R 30 is H, R 20 , F, Cl, Br, I, OH, SH, alkoxy, N(R) 2 , NH(R 10 ), N(R 10 )(R
  • 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
  • At least one of R 7 , R 7 ’, R 7 ’’, R 7 ’’’ and R 7 ’’’’ is not H. In some embodiments, at least two of R 7 , R 7 ’, R 7 ’’, R 7 ’’’ and R 7 ’’’’ are not H. In some embodiments, at least one of R 7 ’, R 7 ’’, R 7 ’’’ and R 7 ’’’’’’’ is not H. In some embodiments, at least two of R 7 ’, R 7 ’’, R 7 ’’’ and R 7 ’’’’’ are not H.
  • At least two of R 7 ’, R 7 ’’, R 7 ’’’ and R 7 ’’’’ are different than eachother. In some embodiments, at least two of R 7 ’, R 7 ’’, R 7 ’’’ and R 7 ’’’’ are not H and are different than eachother. [0043] In some embodiments, at least one of X 2 , X 3 , and X 4 is C(R). In some embodiments, X 11 is N. In some embodiments, X 12 is not S. In some embodiments, at least one of X 2 , X 3 , and X 4 is C(R); X 11 is N; or X 12 is not S. In some embodiments, R is not H.
  • 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-ar
  • R 6 is H, F, Cl, Br, I, OH, SH, R 8 -OH, R 8 -SH, -R 8 -O-R 10 (e.g., CH 2 -O-CH 3 , (CH 2 ) 2 -O-CH 3 (CH 2 ) 3 -O-CH 3 , (CH 2 ) 2 -O-CH(CH 3 ) 2 ), R 8 -S-R 10 (e.g., (CH 2 ) 3 -S-(CH 2 ) 2 CH 3 ), R 8 -NHC(O)-R 10 , -O-R 8 - R 10 , R 8 -(substituted or unsubstituted C 3 -C 8 cycloalkyl) (e.g., CH 2 -cyclopropyl, CH 2 -cyclobutanol, CH 2 - difluorocyclopropyl, CH 2 -methylcyclopropyl, CH 2 -dimethylamin
  • 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, pyrrol
  • 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-O-CH2-
  • 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 al
  • At least one of R 7 , R 7 ’, R 7 ’’, R 7 ’’’ and R 7 ’’’’ is not H. In some embodiments, at least two of R 7 , R 7 ’, R 7 ’’, R 7 ’’’ and R 7 ’’’’ are not H. In some embodiments, at least one of R 7 ’, R 7 ’’, R 7 ’’’ and R 7 ’’’’’’’ is not H. In some embodiments, at least two of R 7 ’, R 7 ’’, R 7 ’’’ and R 7 ’’’’’ are not H.
  • Ring W is aromatic and at least one of X 2 , X 3 , and X 4 is C(R). In some embodiments, Ring W is aromatic and X 11 is N. In some embodiments, Ring W is aromatic and X 12 is not S.
  • Ring W is aromatic then at least one of X 2 , X 3 , and X 4 is C(R); X 11 is N; or X 12 is 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 X 2 , X 3 , and X 4 is C(R); X 11 is N; or X 12 is not S.
  • 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 X 2 , X 3 , and X 4 , are each independently CH, C(R) or N (e.g., C(CH 3 ), C(O- CH 2 -cyclopropyl), C(O-CH 2 -methylcyclobutyl), C(NH-CH 2 -cyclopropyl), C(isopropoxy), C(O-CH(CH 3 )-CH 2 -O-CH 3 ), C(CH 2 CH 3 ), C-iPr, C-CH 2 -cyclopropyl, C(OCH 3 ), C(OCH 2 CH 3 ), C(O-(CH 2 ) 2 -O-CH 3 , C(OCHF 2 ), C(Cl), C(C(O)CH3), C(O- CH 2 CH 2
  • R 6 is H, F, Cl, Br, I, OH, SH, R 8 -OH, R 8 -SH, -R 8 -O-R 10 (e.g., CH 2 -O-CH 3 , (CH 2 ) 2 -O-CH 3 (CH 2 ) 3 -O-CH 3 , (CH 2 ) 2 -O-CH(CH 3 ) 2 ), R 8 -S-R 10 (e.g., (CH 2 ) 3 -S-(CH 2 ) 2 CH 3 ), R 8 -NHC(O)-R 10 , -O-R 8 - R 10 , R 8 -(substituted or unsubstituted C 3 -C 8 cycloalkyl) (e.g., CH 2 -cyclopropyl, CH 2 -cyclobutanol, CH 2 - difluorocyclopropyl, CH 2 -methylcyclopropyl, CH 2 -dimethylamin
  • 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,
  • R 30 is H, R 20 , F, Cl, Br, I, OH, SH, alkoxy, N(R) 2 , NH(R 10 ), N(R 10 )(R
  • each R 8 is independently [CH 2 ] p wherein p is between 1 and 10 (e.g., 1, 2);
  • R 9 is [CH] q , [C] q wherein q is between 2 and 10;
  • R 10 and R 11 are each independently H, OH, COOH, C 1 -C 5 substituted or unsubstituted linear or branched alkyl (e.g., methyl, ethyl, CH2-cyclopropyl, CH2-CH2-O-CH3), C3-C8 substituted or unsubstituted or unsubstituted or unsubstituted
  • 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).
  • 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.
  • 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 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)
  • 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
  • each R8 is independently [CH2]p wherein p is between 1 and 10 (e.g., 1, 2); R 9 is [CH] q , [C] q wherein q is between 2 and 10; R 10 and R 11 are each independently H, OH, COOH, C 1 -C 5 substituted or unsubstituted linear or
  • At least one of R 7 ’, R 7 ’’, R 7 ’’’ and R 7 ’’’’ is not H. In some embodiments, at least two of R 7 ’, R 7 ’’, R 7 ’’’ and R 7 ’’’’ are not H. In some embodiments, at least two of R 7 ’, R 7 ’’, R 7 ’’’ and R 7 ’’’’ are different then eachother. In some embodiments, at least two of R 7 ’, R 7 ’’, R 7 ’’’’ and R 7 ’’’’’ are not H and are different then eachother.
  • Ring W is aromatic and at least one of X 2 , X 3 , and X 4 is C(R). In some embodiments, Ring W is aromatic and X 11 is N In some embodiments, Ring W is aromatic and X 12 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.
  • 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
  • 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,
  • R is H, F, Cl, Br, I, OH, SH, COOH, CO(R 10 ) (e.g., C(O)CH 3 ), NH(R 10 ), NH-CH 2 -cyclopropyl, N(R 10 )(R 11 ), CF 3 , CN, NO 2 , C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, iPr, CH 2 -cyclopropyl, CH 2
  • 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 unsubstit
  • At least one of R7’, R7’’, R7’’’ and R7’’’’ is not H. In some embodiments, at least two of R 7 ’, R 7 ’’, R 7 ’’’ and R 7 ’’’’ are not H. In some embodiments, at least two of R 7 ’, R 7 ’’, R 7 ’’’ and R 7 ’’’’ are different than eachother. In some embodiments, at least two of R 7 ’, R 7 ’’, R 7 ’’’’ and R 7 ’’’’’ are not H and are different than eachother. [0056] In some embodiments, at least one of X 2 , X 3 , and X 4 is C(R).
  • X 11 is N. In some embodiments, X 12 is not S. In some embodiments, at least one of X 2 , X 3 , and X 4 is C(R); X 11 is N; or X12 is not S. In some embodiments, R is not H.
  • X 2 of formula I and/or I(a)-I(j) is N. In other embodiments, X 2 is a CH. In other embodiments, X 2 is a C(R). In other embodiments, X 2 is C(CH 3 ). In other embodiments, X 2 is C(CH 2 CH 3 ). In other embodiments, X 2 is C-iPr.
  • X 2 is C-CH 2 -cyclopropyl. In other embodiments, X 2 is C(O-CH 2 -cyclopropyl). In other embodiments, X 2 is C(O-CH 2 - methylcyclobutyl). In other embodiments, X 2 is C(O-CH 2 -3-methyloxetane). In other embodiments, X 2 is C(OCH 3 ) In other embodiments, X 2 is C(OCH 2 CH 3 ) In other embodiments, X 2 is C(O-(CH 2 ) 2 -O-CH 3 . In other embodiments, X 2 is C(NH-CH 2 -cyclopropyl).
  • X 2 is C(isopropoxy). In other embodiments, X 2 is C(O-CH(CH 3 )-CH 2 -O-CH 3 ). In other embodiments, X 2 is C(OCHF 2 ). In other embodiments, X 2 is C(Cl). In other embodiments, X 2 is C(C(O)CH 3 ). In other embodiments, X 2 is 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 X 2 is a CH. In other embodiments, if Ring W is aromatic, then X 2 is a C(R).
  • Ring W is aromatic
  • X 2 is C(CH 3 ).
  • X2 is C(CH2CH3).
  • X2 is C-iPr.
  • X2 is C-CH2-cyclopropyl.
  • X2 is C(O-CH2-cyclopropyl).
  • X2 is C(O-CH2-methylcyclobutyl).
  • X2 is C(O-CH2-3-methyloxetane).
  • Ring W is aromatic
  • X2 is C(OCH3)
  • X2 is C(OCH2CH3)
  • X2 is C(O-(CH2)2-O-CH3.
  • X2 is C(NH-CH2-cyclopropyl).
  • if Ring W is aromatic X2 is C(isopropoxy).
  • if Ring W is aromatic X2 is C(O-CH(CH3)-CH2-O-CH3).
  • if Ring W is aromatic X2 is C(OCHF2).
  • 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).
  • X 3 is C-iPr. In other embodiments, X 3 is C-CH 2 -cyclopropyl. In other embodiments, X 3 is C(O-CH 2 -cyclopropyl). In other embodiments, X 3 is C(O-CH 2 -methylcyclobutyl). In other embodiments, X 3 is C(O-CH 2 -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).
  • X 3 is C(isopropoxy). In other embodiments, X 3 is C(O-CH(CH 3 )-CH 2 -O-CH 3 ). In other embodiments, X 3 is C(OCHF 2 ). In other embodiments, X 3 is C(Cl). In other embodiments, X 2 is C(C(O)CH 3 ). In other embodiments, X 3 is 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 X 3 is a CH. In other embodiments, if Ring W is aromatic, then X 3 is a C(R).
  • X 3 is C(CH 3 ). In other embodiments, if Ring W is aromatic, then X 3 is C(CH 2 CH 3 ). In other embodiments, if Ring W is aromatic, then X 3 is C-iPr. In other embodiments, if Ring W is aromatic, then X 3 is C-CH 2 -cyclopropyl. In other embodiments, if Ring W is aromatic, then X 3 is C(O-CH 2 -cyclopropyl). In other embodiments, if Ring W is aromatic, then X 3 is C(O-CH 2 -methylcyclobutyl).
  • Ring W is aromatic
  • X 3 is C(O-CH 2 -3-methyloxetane). In other embodiments, if Ring W is aromatic, then X 3 is C(OCH 3 ) In other embodiments, if Ring W is aromatic, then X 3 is C(OCH 2 CH 3 ). In other embodiments, if Ring W is aromatic then X 3 is C(O-(CH 2 ) 2 -O-CH 3 In other embodiments, if Ring W is aromatic X3 is C(NH-CH2-cyclopropyl). In other embodiments, if Ring W is aromatic X3 is C(isopropoxy).
  • 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.
  • 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.
  • X4 is C(NH-CH2-cyclopropyl). In other embodiments, X4 is C(isopropoxy). In other embodiments, X 4 is C(O-CH(CH 3 )-CH 2 -O-CH 3 ). In other embodiments, X 4 is C(OCHF 2 ). In other embodiments, X 4 is C(Cl). In other embodiments, X 4 is C(C(O)CH 3 ). In other embodiments, X 4 is 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 X 4 is a CH.
  • Ring W is aromatic
  • X4 is a C(R).
  • X4 is C(CH3).
  • X4 is C(CH2CH3).
  • X 4 is C-iPr.
  • Ring W is aromatic
  • X 4 is C-CH 2 -cyclopropyl.
  • X 4 is C(O-CH 2 -cyclopropyl).
  • Ring W is aromatic, then X 4 is C(O-CH 2 -methylcyclobutyl).
  • Ring W is aromatic
  • X 4 is C(O-CH 2 -3-methyloxetane). In other embodiments, if Ring W is aromatic, then X 4 is C(OCH 3 ) In other embodiments, if Ring W is aromatic, then X 4 is C(OCH 2 CH 3 ). In other embodiments, if Ring W is aromatic, then X 4 is C(O-(CH 2 ) 2 -O-CH 3 . In other embodiments, if Ring W is aromatic X 4 is C(NH-CH 2 -cyclopropyl). In other embodiments, if Ring W is aromatic X 4 is C(isopropoxy).
  • Ring W is aromatic X 4 is C(O-CH(CH 3 )-CH 2 -O-CH 3 ). In other embodiments, if Ring W is aromatic X 4 is C(OCHF 2 ). In other embodiments, if Ring W is aromatic X 4 is C(Cl). In other embodiments, if Ring W is aromatic X 4 is C(C(O)CH 3 ). In other embodiments, if Ring W is aromatic X 4 is C(OH). In some embodiments, if Ring W is non-aromatic then X 4 is CH 2 . In some embodiments, if Ring W is non-aromatic then X 4 is CH(R).
  • 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.
  • 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.
  • 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.
  • X 10 of formula I and/or I(a)-I(n) is a nitrogen atom. In other embodiments, X 10 is carbon.
  • X 10 is N. In other embodiments, X 10 is CH. In other embodiments, X 10 is C(R), wherein R is as defined below. In other embodiments, X 10 is C(R), wherein R is an alkyl. In other embodiments, X 10 is C(R), wherein R is a methyl, a substituted methyl, CH 2 -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.
  • X 10 is C(R), wherein R is a substituted alkyl. In other embodiments, X 10 is C(R), wherein R is CH 2 -OH. In other embodiments, X 10 is C(R), wherein R is CH 2 -CH 2 -OH. In other embodiments, X 10 is C(R), wherein R is a cycloalkyl. In other embodiments, X 10 is C(R), wherein R is a cyclopropyl. In other embodiments, X 10 is C(R), wherein R is not methyl. In other embodiments, X 10 is C(R), wherein R is an alkoxy.
  • X 10 is C(R), wherein R is an isopropoxy. In other embodiments, X 10 is C(CH 2 -OH). In other embodiments, X 10 is C(CH 2 -CH 2 -OH). In other embodiments, X 10 is C(R), wherein R is N(H)R 10 ; and R 10 is a substituted alkyl. In other embodiments, X 10 is C(NH-CH 2 -cyclopropyl). In other embodiments, X 10 is C(COOH). In other embodiments, X 10 is C(CH 3 ). In other embodiments, X 10 is C(cyclopropyl). In other embodiments, X 10 is C(isopropoxy).
  • Ring W' is aromatic
  • X12 is not S.
  • X12 is SO2,.
  • X12 is O.
  • X12 is NH.
  • X12 is N(R).
  • X12 is N-CH2-COOH.
  • X12 is N-CH2- CH2-OH.
  • X12 is N-CH3.
  • Ring W' is aromatic
  • Ring W' is non-aromatic
  • 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.
  • 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.
  • 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.
  • X5, X6 , X7, X8 and X9 is nitrogen, then the respective R7’, R7’’, R7, R7’’’, and R7’’’’ substitution is absent.
  • X15 of formula I(k)-I(m) is C.
  • X15 is CH, C(R) or N; each represents a separate embodiment according to this invention.
  • X15 is CH.
  • X15 is C(R).
  • R5 of formula I, I(a), I(d), I(e), I(g) and/or I(i)-I(n) is H.
  • R5 is C1-C5 linear or branched alkyl.
  • R5 is methyl.
  • R5 is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, iso-butyl, pentyl, neopentyl; each represents a separate embodiment according to this invention.
  • R 5 and R 6 of 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, R 5 and R 6 are joined to form a substituted 5-8 membered heterocyclic ring. In some embodiments, R 5 and R 6 are 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.
  • the heterocyclic ring is substituted with at least one substitution selected from: F, Cl, Br, I, CF 3 , R 20 , C 1 -C 5 linear or branched alkyl, C 1 -C 5 linear or branched haloalkyl, OH, alkoxy , R 8 -OH (e.g., CH 2 -OH), OMe, amide , C(O)N(R) 2 , C(O)N(R 10 )(R 11 ), R 8 -C(O)N(R 10 )(R 11 ), C(O)-pyrrolidine, C(O)-piperidine, N(R) 2 , NH(R 10 ), N(R 10 )(R 11 ), N(CH 3 ) 2 , NH 2 , CF 3 , aryl, phenyl, heteroaryl, substituted or unsubstituted C 3 -C 8 cycloalkyl , cyclobutanol
  • R 6 of formula I, I(a), I(d), I(e), I(g), I(i), I(j)-I(l) and/or I(n) is H.
  • R 6 is H, F, Cl, Br, I, OH, SH, R 8 -OH, R 8 -SH, -R 8 -O-R 10 , CH 2 -O-CH 3 , (CH 2 ) 2 -O- CH 3 (CH 2 ) 3 -O-CH 3 , (CH 2 ) 2 -O-CH(CH 3 ) 2 , R 8 -S-R 10 , (CH 2 ) 3 -S-(CH 2 ) 2 CH 3 , R 8 -NHC(O)-R 10 , -O-R 8 -R 10 , R 8 -(substituted or unsubstituted C 3 -C 8 cycloalkyl), CH 2 -cyclopropyl, CH 2 -cyclopropyl, CH 2 -
  • R 6 may be further substituted with at least one substitution selected from: F, Cl, Br, I, C 1 -C 5 linear 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(R 10 ), N(R 10 )(R 11 ), N(CH 3 ) 2 , NH 2 , CF 3 , aryl, phenyl, heteroaryl, substituted or unsubstituted C 3 -C 8 cycloalkyl , cyclobutanol, substituted or unsubstituted 3-8 membered heterocyclic ring pyran, oxetane, piperidine, pyrazole, methyl-pyrrazole, triazole, imidazole, halophenyl, (benzyloxy)
  • R 6 is H. In some embodiments, R 6 is -R 8 -O-R 10 . In some embodiments, R 6 is CH 2 -O-CH 3 . In some embodiments, R 6 is R 8 -S-R 10 . In some embodiments, R 6 is (CH 2 ) 3 -S-(CH 2 ) 2 CH 3 . In some embodiments, R 6 is R 8 -NHC(O)- R 10 . In some embodiments, R 6 is (CH 2 ) 3 -NHC(O)-R 10 In some embodiments, R 6 is (CH 2 )-NHC(O)-R 10 .
  • R6 is R8-(substituted or unsubstituted C3-C8 cycloalkyl).
  • 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.
  • 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).
  • 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).
  • 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, CH 2 -2-oxo-methylpyrrolidine, CH 2 -methyl-azetidine, and CH 2 -azaspir
  • R 6 is NH 2 . In some embodiments, R 6 is NHR. In some embodiments, R 6 is N(R) 2 . In some embodiments, R 6 is NH(R 10 ). In some embodiments, R 6 is N(R 10 )(R 11 ). In some embodiments, R 6 is R 8 -N(R 10 )(R 11 ).
  • R 8 -N(R 10 )(R 11 ) includes but not limited to: (CH 2 ) 3 - N(CH 2 CH 3 ) 2 , (CH 2 ) 3 -N(CH(CH 3 ) 2 ) 2 , (CH 2 ) 3 -piperidine, (CH 2 ) 4 -NH(CH 3 ), (CH 2 ) 3 -NH-CH 3 , (CH 2 ) 3 - NH-CH2CH3, (CH2)3-N(CH2CH3)2, (CH2)2-NH2, (CH2)3-NH2, and (CH2)3-N(CH2CH3)(CH2CF3).
  • R6 is R8-C(O)N(R10)(R11) such as (CH2)2-C(O)-piperidine. In some embodiments, R 6 is C 1 -C 5 linear or branched, substituted or unsubstituted alkyl.
  • C 1 -C 5 linear or branched, substituted or unsubstituted alkyl examples include but not limited to: CH(CH 3 )CH 2 OCH 3 , CH(CH 3 )CH 2 NH 2 , CH(CH 3 )C(O)N(CH 3 ) 2 , CH 2 -CH(OH)Ph, (CH 2 ) 3 N(H)CH 2 CH 3 , CH(CH 3 )(CH 2 ) 2 OH, CH(CH 2 OH)(CH 2 CH 3 ), (CH 2 ) 3 -OCH 3 , (CH 2 ) 2 -OCH 3 , (CH 2 ) 2 -OCH 3 , (CH 2 ) 2 -OCH(CH 3 ) 2 , CH(CH 2 OH)(CH 2 CH(CH 3 ) 2 ), CH 2 CH(CH 3 )(OCH 3 ), CH 2 CH(N(CH 3 ) 2 )(CH 2 CH 3 ), CH(CH 3 )C(O)N(
  • R 6 is methyl. In some embodiments, R 6 is substituted or unsubstituted C 3 -C 8 cycloalkyl. In some embodiments, substituted or unsubstituted C 3 -C 8 cycloalkyl include: cyclopropyl, cyclobutyl, cyclohexyl, methoxycyclopropyl, methylcyclobutyl, cyclopropyl, aminomethyl-cyclobutyl, methoxycyclobutyl and 2,3-dihydro-1H-indeno. In some embodiments, R 6 is R 8 -(substituted or unsubstituted C 3 -C 8 cycloalkyl).
  • R 6 is substituted or unsubstituted saturated, unsaturated or aromatic, single, fused or spiro 3-10 membered heterocyclic ring.
  • the substituted or unsubstituted saturated unsaturated or aromatic single, fused or spiro 3-10 membered heterocyclic 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.
  • 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.
  • 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,
  • 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.
  • 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.
  • the ring may be further substituted by at least one substitution selected from: F, Cl, Br, I, C 1 -C 5 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(R 10 ), N(R 10 )(R 11 ), (e.g., N(CH 3 ) 2 , NH 2 ), CF 3 , aryl, phenyl, heteroaryl, substituted or unsubstituted C 3 -C 8 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.
  • R 6 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 B: wherein m is 0 or 1; and R 12 is R 20 or C 1 -C 5 C(O)-alkyl, and R 13 is R 30 ; or R 12 and R 13 are both H; or R 12 and R 13 are each independently H or substituted or unsubstituted C 1 -C 5 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
  • 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: wherein m is 0 or 1; and R 12 is R 20 or C 1 -C 5 C(O)-alkyl, and R 13 is R 30 ; 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
  • 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.
  • 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.
  • 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, R 12 and R 13 of formula B are joined to form ring B.
  • R 12 and C1 of formula B are joined to form ring C and R 13 is R 30 .
  • C1 and C3 of formula B are joined to form ring D and R 12 and R 13 of formula B are each independently R 30 .
  • R 13 and C2 of formula B are joined to form ring E, m is 1, and R 12 of formula B is R 30 .
  • R 12 and R 13 of formula B are joined to form ring B and C1 and C3 of formula B are joined to form ring D.
  • 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.
  • R 12 of formula Bi is R 20 or C 1 -C 5 C(O)-alkyl
  • R 13 is R 30 .
  • R 12 and R 13 of formula Bi are both H.
  • R 12 and R 13 of formula Bi are each independently H or substituted or unsubstituted C 1 -C 5 alkyl (e.g., ethyl, trifluoroethyl).
  • R 12 and R 13 of formula Bi are each independently H or trifluoroethyl.
  • R 12 and C3 of formula Bi are joined to form ring A and R 13 is R 30 .
  • R 12 and R 13 of formula Bi are joined to form ring B.
  • R 12 and C1 of formula Bi are joined to form ring C and R 13 is R 30 .
  • C1 and C3 of formula Bi are joined to form ring D and R 12 and R 13 of formula Bi are each independently R 30 .
  • R 13 and C2 of formula Bi are joined to form ring E, m is 1, and R 12 of formula Bi is R 30 .
  • R 12 and R 13 of formula Bi are joined to form ring B and C1 and C3 of formula Bi are joined to form ring D.
  • R 6 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 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, pyrazo
  • 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 R 12 and C1 are joined to form ring C and R 13 is R 30 ; or C1 and C3
  • 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.
  • 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.
  • ring A is: pyrrolidine, methylpyrrolidine, or ethylpyrrolidine; each represents a separate embodiment according to this invention.
  • 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 3-8 membered 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.
  • 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.
  • 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-dioxid
  • 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.
  • ring B is 4-fluoropiperidine.
  • 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.
  • 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.
  • 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.
  • ring D of formula Bi is a substituted or unsubstituted C 3 -C 8 cycloalkyl. In some embodiments, ring D, is a substituted C 3 -C 8 cycloalkyl.
  • ring D is an unsubstituted C 3 -C 8 cycloalkyl.
  • ring D is cyclopropane, cyclobutane, cyclopentane, cyclohexane or cycloheptane; each represents a separate embodiment according to this invention.
  • ring E of formula Bi is a substituted or unsubstituted single spiro or fused 3-8 membered heterocyclic ring.
  • ring E is an unsubstituted single 3-8 membered heterocyclic ring.
  • ring E is an unsubstituted spiro 3-8 membered heterocyclic 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.
  • 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.
  • ring E is: pyrrolidine, azetidine, ethylpyrrolidine, oxopyrrolidine, or methylpiperidine; each represents a separate embodiment according to this invention.
  • 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-pyr
  • R 6 may be further substituted with at least one substitution selected from: F, Cl, Br, I, C 1 -C 5 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 (e.g., N(CH 3 ) 2 , NH 2 ), NH(R 10 ), N(R 10 )(R 11 ), CF 3 , aryl, phenyl, heteroaryl, substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g., cyclobutanol), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g.
  • 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.
  • -R8-O-R10 is CH2-O-CH3.
  • R6 is R8-S-R10.
  • R8-S-R10 is (CH2)3-S-(CH2)2CH3.
  • R6 is R8-NHC(O)-R10.
  • R6 is R8-(substituted or unsubstituted C3-C8 cycloalkyl).
  • the R8- (substituted or unsubstituted C3-C8 cycloalkyl) is CH2-cyclobutanol, CH2-difluorocyclopropyl, CH2- methylcyclopropyl, CH2-dimethylamino-cyclohexyl, (CH2)2-cyclopentanole, CH2-cyclohexanol).
  • R6 is R8- (substituted or unsubstituted, saturated, unsaturated or aromatic, single, fused or spiro 3-10 membered heterocyclic ring).
  • R6 is (CH2)3-piperidine.
  • R6 is (CH2)2- NH2.
  • R6 is (CH2)3-NH2.
  • R6 is (CH2)3-4-fluoro-piperidine.
  • 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.
  • R6 is C1-C5 linear or branched, substituted or unsubstituted alkyl. In some embodiments, R6 is C1-C5 linear or branched, substituted alkyl.
  • 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(CH 2 OH)(CH 2 CH 3 ), (CH 2 ) 3 -OCH 3 , (CH 2 ) 2 -OCH 3 , (CH 2 ) 2 -OCH(CH 3 ) 2 , CH(CH 2 OH)(CH 2 CH(CH 3 ) 2 ), CH 2 CH(CH 3 )(OCH 3 ), CH 2 CH(N(CH 3 ) 2 )(CH 2 CH 3 ), CH 2 -OCH 2 -CH 2 -O- CH 3 or benzyl; each represents a separate embodiment according to this invention.
  • R 6 is C 1 -C 5 linear or branched, unsubstituted alkyl.
  • the unsubstituted alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, or neopentyl; each represents a separate embodiment according to this invention.
  • R6 is substituted or unsubstituted C3-C8 cycloalkyl. In some embodiments, R6 is substituted C3-C8 cycloalkyl.
  • the substituted cycloalkyl is methoxycyclopropyl, methylcyclobutyl, aminomethyl-cyclobutyl, or methoxycyclobutyl, 2,3-dihydro-1H-indenol; each represents a separate embodiment according to this invention.
  • R 6 is unsubstituted C 3 -C 8 cycloalkyl.
  • the unsubstituted cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; each represents a separate embodiment according to this invention.
  • R 6 is substituted or unsubstituted 3-8 membered heterocyclic ring.
  • 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.
  • R 6 is piperidine..
  • R 6 is 1-methyl-piperidine..
  • R 6 is tetrahydropyran.
  • R 7 of formula I, I(a)-I(c(, I(i), I(j), I(k) and/or I(n) is H, F, Cl, Br, I, OH, O-R 20 , SH, R 8 -OH, R 8 -SH, SR 10 , -R 8 -O-R 10 , -R 8 -S-R 10 , R 8 -(C 3 -C 8 cycloalkyl), R 8 -(3-8 membered heterocyclic ring), CF 3 , CD 3 , OCD 3 CN NO 2 -CH 2 CN -R 8 CN, NH 2 , NHR, N(R) 2 , NH(R 10 ), N(R10)(R11), R8-N(R10)(R11), R9-R8-N(R10)(R11), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R10,
  • 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.
  • R7 of formula I, I(a)-I(c(, I(i), I(j), I(k) and/or I(n) is H.
  • R 7 is F.
  • R 7 is Cl.
  • R 7 is Br.
  • R 7 is I.
  • R 7 is OH.
  • R 7 is O-R 20 .
  • R 7 is CF 3 . In some embodiments, R 7 is CN. In some embodiments, R 7 is NH 2 . In some embodiments, R 7 is NHR. In some embodiments, R 7 is N(R) 2 . In some embodiments, R 7 is NH(R 10 ). In some embodiments, R 7 is N(R 10 )(R 11 ). In some embodiments, R 7 is NHC(O)-R 10 . 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.
  • R7 is C1-C5 linear or branched C(O)-haloalkyl. In some embodiments, R 7 is -C(O)NH 2 . In some embodiments, R 7 is C(O)NHR. In some embodiments, C(O)NHR is C(O)NH(CH 3 ). In some embodiments, R 7 is C(O)N(R 10 )(R 11 ). In some embodiments, C(O)N(R 10 )(R 11 ) is C(O)NH(CH 3 ), C(O)NH(CH 2 CH 2 OCH 3 ), or C(O)NH(CH 2 CH 2 OH); each represents a separate embodiment according to this invention. In some embodiments, R 7 is SO 2 R.
  • R 7 is C 1 -C 5 linear or branched, substituted or unsubstituted alkyl.
  • 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.
  • R 7 is C 1 -C 5 linear or branched, or C 3 -C 8 cyclic haloalkyl. In some embodiments, R 7 is C 1 -C 5 linear haloalkyl.
  • the haloalkyl is CHF 2 .
  • R 7 is C 1 -C 5 branched haloalkyl.
  • R 7 is C 3 -C 8 cyclic haloalkyl.
  • R 7 is C 1 -C 5 linear or branched, or C 3 -C 8 cyclic alkoxy optionally wherein at least one methylene group (CH 2 ) in the alkoxy is replaced with an oxygen atom.
  • R 7 is C 1 -C 5 linear alkoxy
  • the alkoxy is methoxy.
  • the alkoxy is ethoxy.
  • 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.
  • the cycloalkyl is cyclopropyl, cyclopropanol, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; each represents a separate embodiment according to this invention.
  • 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.
  • 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.
  • morpholine e.g., 2 or 3-morpholine
  • tetrahydrofuran
  • 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, R 7 is R 8 -( unsubstituted fused 3-8 membered heterocyclic ring). In some embodiments, R 7 is R 8 -(unsubstituted spiro 3-8 membered heterocyclic ring). In some embodiments, R 7 is R 8 -(substituted single 3-8 membered heterocyclic ring).
  • R 7 is R 8 -(substituted fused 3-8 membered heterocyclic ring). In some embodiments, R 7 is R 8 -(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, R 7 is phenyl.
  • R 7 may be further substituted with at least one substitution selected from: F, Cl, Br, I, C 1 -C 5 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(R 10 ), N(R 10 )(R 11 ), (e.g., N(CH 3 ) 2 , NH 2 ), CF 3 , aryl, phenyl, heteroaryl, substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g., cyclobutanol), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g.
  • R 7 of formula I, I(a)-I(c(, I(i), I(j), I(k) and/or I(n) is O-R 20 .
  • R 7 is substituted or unsubstituted 4-7 membered heterocyclic ring.
  • R 7 is unsubstituted 4-7 membered heterocyclic ring.
  • R 7 is substituted 4-7 membered heterocyclic ring.
  • 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; each represents a separate embodiment according to this invention.
  • R7 is substituted or unsubstituted aryl.
  • R7 is phenyl.
  • 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.
  • 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.
  • X1 is O.
  • R1 of formula A is H. In other embodiments R1 is F. In other embodiments R1 is CF3.
  • R2 of formula A is H. In other embodiments R2 is F. In other embodiments R2 is CF3.
  • R1 and R2 are joined to form a 3-8 membered heterocyclic ring.
  • R3 of formula A is H.
  • R3 is methyl.
  • R3 is substituted or unsubstituted C1-C5 alkyl.
  • the alkyl is methoxyethylene, methylaminoethylene, aminoethylene; each represents a separate embodiment according to this invention.
  • R3 is substituted or unsubstituted C3-C8 cycloalkyl.
  • the cycloalkyl is cyclopropyl.
  • R 3 is substituted or unsubstituted 5-7 membered heterocyclic ring.
  • the heterocyclic ring is pyrrolidine, methylpyrrolidine, or piperidine; each represents a separate embodiment according to this invention.
  • R 3 is R 20 as defined hereinbelow.
  • R 4 of formula A is H.
  • R 4 is methyl.
  • R4 is substituted or unsubstituted C1-C5 alkyl.
  • the alkyl is methoxyethylene, methylaminoethylene, aminoethylene; each represents a separate embodiment according to this invention.
  • R 4 is substituted or unsubstituted C 3 -C 8 cycloalkyl.
  • the cycloalkyl is cyclopropyl.
  • R 4 is substituted or unsubstituted 5-7 membered heterocyclic ring.
  • the heterocyclic ring is pyrrolidine, methylpyrrolidine, or piperidine; each represents a separate embodiment according to this invention.
  • R 4 is R 20 as defined hereinbelow.
  • R 3 and R 4 of formula A are joined to form a 3-8 membered heterocyclic ring.
  • the heterocyclic ring is imidazole, pyrrolidine, 2-oxopyrrolidine, piperidine, morpholine, or piperazine; each represents a separate embodiment according to this invention.
  • X 1 of formula A is O then R 4 is absent.
  • R 7 of formula I, I(a)-I(c(, I(i), I(j), I(k) and/or I(n) is O-R 20 , 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.
  • substituted or unsubstituted 4-7 membered heterocyclic ring e.g., morpholine, pyran, oxetane, pyrrolidine, imidazole, piperazine, piperidine, dioxazole, triazole, 2-oxopyrrolidine
  • 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
  • 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) 2 NH(R 10 ), N(R 10 )(R 11 ), (e.g., N(CH 3 ) 2 , NH 2 ), CF 3 , aryl, phenyl, heteroaryl, substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g., cyclobutanol), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g.
  • R7’ of formula I and/or I(a)-I(n) is H.
  • R7’ is F.
  • R7’ is Cl.
  • R7’ is Br.
  • R7’ is I.
  • R 7 ’ is CF 3 .
  • R 7 ’ is C 1 -C 5 linear or branched, substituted or unsubstituted alkyl. In some embodiments, R 7 ’ is C 1 -C 5 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, R 7 ’ is C 1 -C 5 linear or branched substituted alkyl. In some embodiments, R 7 ’ is isopropyl. In some embodiments, R 7 ’ is methyl. In some embodiments, R 7 ’ is ethyl.
  • R 7 ’ is C 1 -C 5 linear or branched, or C 3 -C 8 cyclic haloalkyl. In some embodiments, R 7 ’ is C 1 -C 5 linear or branched haloalkyl. In some embodiments, the haloalkyl is CHF 2 . In some embodiments, R 7 ’ is C 3 -C 8 cyclic haloalkyl. In some embodiments, R 7 ’ is substituted or unsubstituted C 3 -C 8 cycloalkyl. In some embodiments, the cycloalkyl is cyclopropyl. In some embodiments, the cycloalkyl is cyclohexyl.
  • R 7 ’ is substituted or unsubstituted aryl. In some embodiments, R 7 ’ is phenyl. In some embodiments, R 7 ’ is C 1 -C 5 linear or branched, or C 3 -C 8 cyclic alkoxy. In some embodiments, R 7 ’ is methoxy. [00114] 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.
  • 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.
  • 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.
  • 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. [00115] In some embodiments, R7 and R7’ of formula I, I(a)-I(c), I(i)-I(k) and/or I(n) are different.
  • 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 C 3 -C 8 cyclic alkoxy , C 1 -C 5 linear or branched haloalkoxy or C 1 -C 5 linear or branched, substituted or unsubstituted alkyl; each represents a separate embodiment according to this invention. [00116] In some embodiments, R 7 ’’ of formula I(a), I(c), I(e), and/or I(f)-I(n) is not H.
  • R 7 ’’ of formula I(a), I(c), I(e), and/or I(f)-I(n) is H.
  • R 7 ’’ of formula I(a), I(c), I(e), and/or I(f)-I(n) is F, Cl, Br, I, OH, O-R 20 , SH, R 8 -OH, R 8 - 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)CF 3 , -OCH 2 Ph, NHC(O)-
  • R 7 ’’ is further substituted with at least one substitution selected from: F, Cl, Br, I, C 1 -C 5 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(R 10 ), N(R 10 )(R 11 ), (e.g., N(CH 3 ) 2 , NH 2 ), CF 3 , aryl, phenyl heteroaryl substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g., cyclobutanol), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g.
  • R7’’ of formula I(a), I(c), I(e), and/or I(f)-I(n) is H.
  • R7’’ is F.
  • R7’’ is Cl.
  • R7’’ is Br.
  • R7’’ is I.
  • R7’’ is CF3.
  • 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.
  • 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.
  • 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. [00119] In some embodiments, R7’’’ of formula I(a), I(c), I(e), and/or I(f)-I(n) is not H. [00120] In some embodiments, R 7 ’’’ of formula I(a), I(c), I(e), and/or I(f)-I(n) is H.
  • R 7 ’’’ of formula I(i) is F, Cl, Br, I, OH, O-R 20 , SH, R 8 -OH, R 8 -SH, -R 8 -O-R 10 , R 8 -(C 3 -C 8 cycloalkyl), R 8 -(3-8 membered heterocyclic ring), CF 3 , CD 3 , OCD 3 , CN, NO 2 , -CH 2 CN, -R 8 CN, NH 2 , NHR, N(R) 2 , NH(R 10 ), N(R 10 )(R 11 ), R 8 -N(R 10 )(R 11 ), R 9 -R 8 -N(R 10 )(R 11 ), B(OH) 2 , -OC(O)CF 3 , -OCH 2 Ph, NHC(O)-R 10 , NHCO-N(R 10 )(R 11 ), COOH, -C(O)
  • R 7 ’’’ is cyclopropyl. In some embodiments, R 7 ’’’ is further substituted with at least one substitution selected from: F, Cl, Br, I, C 1 -C 5 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(R 10 ), N(R 10 )(R 11 ), (e.g., N(CH 3 ) 2 , NH 2 ), CF 3 , aryl, phenyl, heteroaryl, substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g., cyclobutanol), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g.
  • R7’’ of formula I(a), I(c), I(e), and/or I(f)-I(n) is H.
  • R7’’’ is F.
  • R7’’’ is Cl.
  • R7’’’ is Br.
  • R7’’’ is I.
  • R7’’’ is CF3.
  • 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.
  • 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.
  • 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. [00122] In some embodiments, R7’’’’ of formula I(a), I(c), I(e), and/or I(f)-I(n) is not H. [00123] In some embodiments, R7’’’’’ of formula I(a), I(c), I(e), and/or I(f)-I(n) is H.
  • R 7 ’’’ of formula I(i) is F, Cl, Br, I, OH, O-R 20 , SH, R 8 -OH, R 8 -SH, -R 8 -O-R 10 , R 8 -(C 3 - C 8 cycloalkyl), R 8 -(3-8 membered heterocyclic ring), CF 3 , CD 3 , OCD 3 , CN, NO 2 , -CH 2 CN, -R 8 CN, NH 2 , NHR, N(R) 2 , NH(R 10 ), N(R 10 )(R 11 ), R 8 -N(R 10 )(R 11 ), R 9 -R 8 -N(R 10 )(R 11 ), B(OH) 2 , -OC(O)CF 3 , -OCH 2 Ph, NHC(O)-R 10 , NHCO-N(R 10 )(R 11 ), COOH, -C(O)
  • R 7 ’’’’ is further substituted with at least one substitution selected from: F, Cl, Br, I, C 1 -C 5 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(R 10 ), N(R 10 )(R 11 ), (e.g., N(CH 3 ) 2 , NH 2 ), CF 3 , aryl, phenyl, heteroaryl, substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g., cyclobutanol), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g.
  • R7’’’’ of formula I(a), I(c), I(e), and/or I(f)-I(n) is H.
  • R7’’’’ is F.
  • R7’’’’ is Cl.
  • R7’’’’ is Br.
  • R7’’’ is I.
  • R7’’’ is CF3.
  • 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.
  • 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.
  • 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. [00125] 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.
  • 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, R 7 ’ and R 7 ’’ are joined to form 6 membered unsubstituted saturated or unsaturated carbocyclic ring. In some embodiments, R 7 ’ and R 7 ’’ are joined to form a cyclohexane. In some embodiments, R 7 ’ and R 7 ’’ are joined to form a 5 membered substituted saturated or unsaturated carbocyclic ring.
  • R 7 ’ and R 7 ’’ are joined to form 6 membered substituted saturated or unsaturated carbocyclic ring. In some embodiments, R 7 ’ and R 7 ’’ 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, R 7 ’ and R 7 ’’ are joined to form a 5 or 6 membered substituted or unsubstituted, heterocyclic ring.
  • R 7 ’ and R 7 ’’ are joined to form a 6 membered substituted or unsubstituted, heterocyclic ring. In some embodiments, R 7 ’ and R 7 ’’ are joined to form a piperidine. In some embodiments, R 7 ’ and R 7 ’’ are joined to form a tetrahydropyran. In some embodiments, R 7 ’ and R 7 ’’ are joined to form a 5 membered substituted or unsubstituted, heterocyclic ring. In some embodiments, R 7 ’ and R 7 ’’ are joined to form a tetrahydrofuran.
  • R 7 ’ and R 7 ’’ are joined to form a pyrrolidine.
  • R 7 ’ and R 7 ’’ of formula I(a), I(c), I(e), and/or I(f)-I(n) are different.
  • R 7 ’ and R 7 ’’ of formula I(a), I(c), I(e), and/or I(f)-I(n) are not H, F, Cl, C 1 -C 5 linear or branched, or C 3 -C 8 cyclic alkoxy, C 1 -C 5 linear or branched haloalkoxy or C 1 -C 5 linear or branched, substituted or unsubstituted alkyl; each represents a separate embodiment according to this invention.
  • R 7 ’’ and R 7 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.
  • R7’’ and R7 are joined to form a 5 membered unsubstituted saturated or unsaturated carbocyclic ring.
  • R7’’ and R7 are joined to form a cyclopentane.
  • R7’’ and R7 are joined to form 6 membered unsubstituted saturated or unsaturated carbocyclic ring.
  • 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.
  • 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.
  • R7’’ and R7 are joined to form a pyrrolidine. [00128] In some embodiments, R7’’ and R7 of formula I(a), I(c), I(i), I(j)-I(k) and/or I(n) are different.
  • 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 C 3 -C 8 cyclic alkoxy , C 1 -C 5 linear or branched haloalkoxy or C 1 -C 5 linear or branched, substituted or unsubstituted alkyl; each represents a separate embodiment according to this invention.
  • R 7 and R 7 ’’ 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.
  • R 7 and R 7 ’’’ are joined to form a 5 membered unsubstituted saturated or unsaturated carbocyclic ring.
  • R7 and R7’’’ are joined to form 6 membered unsubstituted saturated or unsaturated carbocyclic ring.
  • R7 and R7’’ are joined to form a 5 membered substituted saturated or unsaturated carbocyclic ring. In some embodiments, R 7 and R 7 ’’’ are joined to form 6 membered substituted saturated or unsaturated carbocyclic ring. In some embodiments, R 7 and R 7 ’’ are joined to form a 6 membered substituted or unsubstituted, aromatic, carbocyclic ring. In some embodiments, R 7 and R 7 ’’’ are joined to form a 5 or 6 membered substituted or unsubstituted, aromatic, heterocyclic ring.
  • R 7 and R 7 ’’’ are joined to form a 5 or 6 membered substituted or unsubstituted, heterocyclic ring. In some embodiments, R 7 and R 7 ’’’ are joined to form a 6 membered substituted or unsubstituted, heterocyclic ring. In some embodiments, R 7 and R 7 ’’’ are joined to form a piperidine. In some embodiments, R 7 and R 7 ’’’ are joined to form a tetrahydrofuran. In some embodiments, R 7 and R 7 ’’’ are joined to form a tetrahydropyran.
  • R 7 and R 7 ’’’ are joined to form a 5 membered substituted or unsubstituted, heterocyclic ring. In some embodiments, R 7 and R 7 ’’’ are joined to form a pyrrolidine. In some embodiments, R 7 and R 7 ’’’ are joined to form a cyclopentane. In some embodiments, R 7 and R 7 ’’’ are joined to form a cyclohexane. [00130] In some embodiments, R7 and R7’’’ of formula I(a), I(c), I(i), I(j)-I(k) and/or I(n)are different.
  • 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.
  • 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.
  • R7’’’ and R7’’’’ are joined to form a 5 membered unsubstituted saturated or unsaturated carbocyclic ring.
  • R7’’’ and R7’’’’ are joined to form 6 membered unsubstituted saturated or unsaturated carbocyclic ring.
  • 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.
  • 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 R 7 ’’’’ are joined to form a tetrahydropyran.
  • R 7 ’’’ and R 7 ’’’’ are joined to form a 5 membered substituted or unsubstituted, heterocyclic ring. In some embodiments, R 7 ’’’ and R 7 ’’’’ are joined to form a pyrrolidine. In some embodiments, R 7 ’’’ and R 7 ’’’’ are joined to form a cyclopentane. In some embodiments, R 7 ’’’’ and R 7 ’’’’’ are joined to form a cyclohexane. [00132] In some embodiments, R 7 ’’’’’’ of formula I(a), I(c), and/or I(e)-I(n) are different.
  • 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.
  • at least one of R 7 ’, R 7 ’’, R 7 ’’’ and R 7 ’’’’ of formula I(a), I(c), and/or I(e)-I(n) is not H.
  • At least two of R 7 ’, R 7 ’’, R 7 ’’’ and R 7 ’’’ of formula I(a), I(c), and/or I(e)-I(n) are not H. In some embodiments, at least three of R 7 ’, R 7 ’’, R 7 ’’’ and R 7 ’’’’ of formula I(a), I(c), and/or I(e)-I(n) are not H.
  • At least one of R 7 , R 7 ’, R 7 ’’, R 7 ’’’ and R 7 ’’’’ of formula I(a), I(c), I(i), I(j)-I(k) and/or I(n) is not H.
  • at least two of R 7 , R 7 ’, R 7 ’’, R 7 ’’’ and R 7 ’’’’ of formula I(a), I(c), I(i), I(j)-I(k) and/or I(n) are not H.
  • R 30 of formula I and/or I(a)-I(n) is H, R 20 , F, Cl, Br, I, OH, SH, alkoxy, N(R) 2 , NH(R 10 ), N(R 10 )(R 11 ), CF 3 , CN, NO 2 , C 1 -C 5 linear or branched, substituted or unsubstituted alkyl, C 1 -C 5 linear or branched alkoxy, C 1 -C 5 linear or branched haloalkyl, R 8 -aryl, -R 8 -O-R 8 -O-R 10 , -R 8 -O- R 10 , -R 8 -R 10 , substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; each represents a separate embodiment according to this invention.
  • 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.
  • R30 is H. In some embodiments, R30 is R20.
  • 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.
  • 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.
  • R 50 is H. In some embodiments, R 50 is F. In some embodiments, R 50 is CF 3 . In some embodiments, R 50 is CN. [00137] In some embodiments, Ring G of formula I(b), I(c), I(f), I(h), I(l) and/or I(m) is absent.
  • 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.
  • 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.
  • R of formula I and/or I(a)-I(n) is H, F, Cl, Br, I, OH, SH, COOH, CO(R 10 ), C(O)CH 3 , NH(R 10 ), NH-CH 2 -cyclopropyl, N(R 10 )(R 11 ), CF 3 , CN, NO 2 , C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, iPr, CH 2 -cyclopropyl, CH 2 -OH, CH 2 - CH 2 -OH, CH 2 -CH 2 -O-CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH
  • 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.
  • R is H.
  • R is F, Cl, Br, or I.
  • R is NH(R10).
  • R is NH-CH2- cyclopropyl.
  • R is C1-C5 linear or branched, substituted or unsubstituted alkyl.
  • R is methyl.
  • R is ethyl.
  • 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.
  • R is O-(CH 2 )-cyclopropyl. In some embodiments, R is O-CH 2 - methylcyclobutyl. In some embodiments, R is O-CH(CH 3 )-CH 2 -O-CH 3 . In some embodiments, R is O- (CH 2 CH 3 ). In some embodiments, R is OCHF 2 . In some embodiments, R is O-(CH 2 ) 2 -O-CH 3 . In some embodiments, R is COOH. In some embodiments, R is O-R 8 -R 10 . In some embodiments, R is O-(CH 2 ) 2 - O-CH3. In some embodiments, R is O-(CH2CH3).
  • R is -R8-R10. In some embodiments, R is (CH2)-cyclopropyl. In some embodiments, R is (CH2)-OH. In some embodiments, R is (CH 2 ) 2 -OH. In some embodiments, R is (CH 2 )-COOH. In some embodiments, R is OH. In some embodiments, R is CO(R 10 ). [00139] In various embodiments, each R 8 of compound of formula I and/or I(a)-I(n) is independently CH 2 . In some embodiments, R 8 is CH 2 CH 2 . In some embodiments, R 8 is CH 2 CH 2 CH 2 . In some embodiments, R 8 is CH 2 CH 2 CH 2 CH 2 . In some embodiments, R 8 is CH 2 CH 2 CH 2 CH 2 .
  • 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.
  • 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.
  • C1-C5 substituted or unsubstituted linear or branched alkyl e.g., methyl, ethyl, CH2-cyclopropyl, CH2-CH2-O-CH3
  • 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 is isopropyl. In some embodiments, R10 is butyl. In some embodiments, R10 is isobutyl. In some embodiments, R10 is t-butyl.
  • 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.
  • 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.
  • R10 is further substituted with at lest one substitution selected from: F, Cl, Br, I, C 1 -C 5 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(R 10 ), N(R 10 )(R 11 ), (e.g., N(CH 3 ) 2 , NH 2 ), CF 3 , aryl, phenyl, heteroaryl, substituted or unsubstituted C 3 -C 8 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 NO 2 ; each represents a separate embodiment according to this invention.
  • 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, CH 2 -CH 2 -O-CH 3 , CH 2 CF 3 , C 1 -C 5 linear or branched alkoxy (e.g., O-CH 3 ), C(O)R, or S(O) 2 R; each represents a separate embodiment according to this invention.
  • R 11 is H.
  • R 11 is OH
  • R 11 is COOH.
  • R 11 is C 1 -C 5 substituted or unsubstituted linear or branched alkyl. In some embodiments, R 11 is C 1 -C 5 unsubstituted linear or branched alkyl. In other embodiments, R 11 is CH 3 . In other embodiments, R 11 is CH 2 CH 3. In other embodiments, R 11 is CH 2 CH 2 CH 3 . In some embodiments, R 11 is isopropyl. In some embodiments, R 11 is butyl. In some embodiments, R 11 is isobutyl. In some embodiments, R 11 is t-butyl. In some embodiments, R 11 is pentyl. In some embodiments, R 11 is isopentyl.
  • R 11 is neopentyl. In some embodiments, R 11 is benzyl. In some embodiments, R 11 is C 1 -C 5 substituted linear or branched alkyl. In other embodiments, R 11 is CH 2 -CH 2 -O-CH 3 . In other embodiments, R 11 is CH 2 CF 3 . In other embodiments, R 11 is C 1 -C 5 substituted or unsubstituted linear or branched haloalkyl. In other embodiments, R 11 is C 1 -C 5 linear or branched alkoxy. In other embodiments, R 11 is O-CH 3 . In other embodiments, R 11 is R 20 . In other embodiments, R11 is C(O)R.
  • R11 is S(O)2R.
  • 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.
  • 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.
  • R10 and R11 are joined to form a piperazine ring.
  • R10 and R11 are joined to form a piperidine ring.
  • 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.
  • 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.
  • n of formula I, I(b) and/or I(d) is 1 or 2.
  • R 1 of formula I(d)-I(h), I(l)-I(m) and/or A is H.
  • R1 is F.
  • R1 is CF3.
  • R1 is Cl.
  • R1 is Br.
  • R1 is I.
  • R1 is OH.
  • R1 is SH.
  • R 1 is substituted or unsubstituted C 1 -C 5 alkyl.
  • R 1 is C 1 -C 5 linear or branched, or C 3 -C 8 cyclic haloalkyl.
  • R 1 is substituted or unsubstituted C 1 -C 5 linear or branched, or C 3 -C 8 cyclic alkoxy.
  • R 2 of formula I(d)-I(h), I(l)-I(m) and/or A is H.
  • R 2 is F.
  • R 2 is CF 3 .
  • R 2 is Cl.
  • R 2 is Br.
  • R 2 is I.
  • R 2 is OH.
  • R 2 is SH.
  • R 2 is substituted or unsubstituted C 1 -C 5 alkyl.
  • the carbocyclic ring is cyclopropyl.
  • R 1 and R 2 are joined to form a 3-8 membered heterocyclic ring.
  • the heterocyclic ring is oxetane.
  • X2, X3, X4, and X10 is not CH.
  • R3 of formula I(d)-I(h), I(l)-I(m) and/or A is H.
  • R3 is methyl.
  • R3 is substituted or unsubstituted C1-C5 alkyl.
  • the alkyl is methoxyethylene, methylaminoethylene, aminoethylene; each represents a separate embodiment according to this invention.
  • R3 is -R8-O-R10.
  • R3 is (CH2)2-O-CH3.
  • R3 is R8-N(R10)(R11).
  • R3 is (CH2)2-NH(CH3)).
  • R3 is substituted or unsubstituted C3-C8 cycloalkyl.
  • the cycloalkyl is cyclopropyl.
  • R3 is substituted or unsubstituted 5-7 membered heterocyclic ring.
  • R3 is pyrrolidine. In some embodiments, R3 is methylpyrrolidine. In some embodiments, R3 is piperidine. In some embodiments, R3 is R20 as defined hereinbelow. [00151] 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.
  • 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, R 4 is substituted or unsubstituted 5-7 membered heterocyclic ring. In some embodiments, R 4 is pyrrolidine. In some embodiments, R 4 is methylpyrrolidine. In some embodiments, R 4 is piperidine. In some embodiments, R 4 is R 20 as defined hereinbelow.
  • R 2 and R 4 of formula I(d)-I(h), I(l)-I(m) and/or A are joined to form Ring F as defined hereinbelow.
  • R2 and R4 are joined to form a substituted or unsubstituted, saturated or unsaturated, 4-8 membered heterocyclic or carbocyclic ring.
  • R 2 and R 4 are joined to form a substituted or unsubstituted, unsaturated, 4-8 membered heterocyclic ring.
  • R 2 and R 4 are 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.
  • R 2 and R 4 are joined to form pyrrolidine.
  • R 2 and R 4 are joined to form 1-methylpyrrolidine.
  • R 2 and R 4 are joined to form pyrrolidin-2-one.
  • R 2 and R 4 are joined to form pyrrolidin-3-ol. In some embodiments, R 2 and R 4 are joined to form morpholine. In some embodiments, R 2 and R 4 are joined to form piperidine. In some embodiments, if Ring F is aromatic, then R 1 is absent. In some embodiments, if Ring F is aromatic, then R 3 is absent. In some embodiments, if Ring F is aromatic, then R 1 and/or R 3 are absent. [00153] In some embodiments, R 3 and R 4 of formula I(d)-I(h), I(l)-I(m) and/or A are joined to form a 3-8 membered heterocyclic ring.
  • the heterocyclic ring is pyrrolidine, pyrrolidone, 2-oxopyrrolidine, piperidine, morpholine, piperazine, imidazole; each represents a separate embodiment according to this invention.
  • 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.
  • R1 and R2 are joined to form a cyclopropyl ring.
  • R1 and R2 are joined to form an oxetane ring.
  • Ring F of formula I(d)-I(h), I(l)-I(m) and/or A is absent.
  • Ring F is a substituted or unsubstituted, saturated or unsaturated, 4-8 membered heterocyclic ring.
  • Ring F is a substituted, saturated, 4-8 membered heterocyclic ring.
  • Ring F is a substituted unsaturated, 4-8 membered heterocyclic ring.
  • Ring F is an unsubstituted, saturated, 4-8 membered heterocyclic ring.
  • Ring F is an unsubstituted, unsaturated, 4-8 membered heterocyclic ring.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Ring F is 6,7-dihydro- 5H-pyrazolo[5,1-b][1,3]oxazine.
  • 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 X 2 , X 3 , and X 4 , are each independently CH, C(R) or N; each represent a separate embodiment according to this invention.
  • 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.
  • X15 is C.
  • 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.
  • Ring W is non-aromatic
  • Ring W is non-aromatic
  • Ring W' is aromatic.
  • Ring W is non-aromatic
  • Ring W' is non-aromatic.
  • Ring W is aromatic, and Ring W' is non-aromatic.
  • Ring W is aromatic, and Ring W' is aromatic.
  • Ring W' of formula I(k)-I(m) may be either aromatic or non-aromatic ring.
  • Ring W' is aromatic.
  • X 12 is N-CH 2 -COOH, N-CH 2 -CH 2 -OH, N-CH 3 , N-CH 2 CH 3 , N-iPr, N- cyclopropyl, N-CH 2 -cyclopropyl; each represents a separate embodiment according to this invention.
  • X 12 is SO 2 .
  • X 12 is O.
  • X 12 is NH.
  • X 12 is N(R).
  • 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:
  • 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.
  • 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. [00164] 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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, -NH 3 .
  • 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.
  • 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 CF 3 , CF 2 CF 3 , CF 2 CH 3, CH 2 CF 3 , CF 2 CH 2 CH 3 , CH 2 CH 2 CF 3 , CF 2 CH(CH 3 ) 2 and CF(CH 3 )-CH(CH 3 ) 2 .
  • 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.
  • 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 -CH 2 -O-CH 3 , -CH 2 -O-CH(CH 3 ) 2 , -CH 2 -O- C(CH 3 ) 3, -CH 2 -CH 2 -O-CH 3 , -CH 2 -CH 2 -O-CH(CH 3 ) 2 , -CH 2 -CH 2 -O-C(CH 3 ) 3 .
  • 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.
  • the cycloalkyl is a 3-10 membered ring. In some embodiments the cycloalkyl is a 3-12 membered ring. In some embodiments the cycloalkyl is a 6 membered ring. In some embodiments the cycloalkyl is a 5-7 membered ring. In some embodiments the cycloalkyl is a 3-8 membered ring.
  • the cycloalkyl group may be unsubstituted or substituted by a halogen, alkyl, 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.
  • the cycloalkyl ring may be fused to another saturated or unsaturated cycloalkyl or heterocyclic 3-8 membered ring. In some embodiments, the cycloalkyl ring is a saturated ring. In some embodiments, the cycloalkyl ring is an unsaturated ring.
  • Non limiting examples of a cycloalkyl group comprise cyclohexyl, cyclohexenyl, cyclopropyl, cyclopropenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclobutyl, cyclobutenyl, cycloctyl, cycloctadienyl (COD), cycloctaene (COE) etc.
  • a “heterocycle” or “heterocyclic” group refers, in various embodiments, to a ring structure comprising in addition to carbon atoms, sulfur, oxygen, nitrogen or any combination thereof, as part of the ring.
  • heterocycle or heteroaromatic ring refers in various embodiments, to an aromatic ring structure comprising in addition to carbon atoms, sulfur, oxygen, nitrogen or any combination thereof, as part of the ring.
  • the heterocycle or heteroaromatic ring is a 3-10 membered ring.
  • the heterocycle or heteroaromatic ring is a 3-12 membered ring.
  • the heterocycle or heteroaromatic ring is a 6 membered ring.
  • the heterocycle or heteroaromatic ring is a 5-7 membered ring.
  • the heterocycle or heteroaromatic ring is a 3-8 membered ring.
  • the heterocycle group or heteroaromatic ring may be unsubstituted or substituted by a halogen, alkyl, haloalkyl, hydroxyl, alkoxy, carbonyl, amido, alkylamido, dialkylamido, cyano, nitro, CO 2 H, amino, alkylamino, dialkylamino, carboxyl, thio, thioalkyl, C 1 -C 5 linear or branched haloalkoxy, 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.
  • the heterocycle ring or heteroaromatic ring may be fused to another saturated or unsaturated cycloalkyl or heterocyclic 3-8 membered ring.
  • the heterocyclic ring is a saturated ring.
  • the heterocyclic ring is an unsaturated ring.
  • Non limiting examples of a heterocyclic ring or heteroaromatic ring systems comprise pyridine, piperidine, morpholine, piperazine, thiophene, pyrrole, benzodioxole, benzofuran-2(3H)-one, benzo[d][1,3]dioxole, indole, oxazole, isoxazole, imidazole and 1-methylimidazole, furane, triazole, pyrimidine, pyrazine, oxacyclobutane (1 or 2- oxacyclobutane), naphthalene, tetrahydrothiophene 1,1-dioxide, thiazole, benzimidazole, piperidine, 1- methylpiperidine, isoquinoline, 1,3-dihydroisobenzofuran, benzofuran, 3-methyl-4H-1,2,4-triazole, oxadiazolyl, 5-methyl-1,2,
  • heterocyclic ring refers to substituted or unsubstituted, 3 to 8 membered, saturated, unsaturated or aromatic, single, fused or spiro rings, which comprise at least one heteroatom selected from: N, O or S.
  • the heterocyclic ring may be substituted, unsubstitutied, saturated, unsaturated, aromatic, single, fused or spiro ring; each represent a separate embodiment according to this invention.
  • the heterocyclic ring(s) may be 3-10; 3- 9; 3-8; 3-7; 3-6; 3-5; 4-6; 4-7; 4-8; 4-9; 5-6; 5-7; 5-8; 5-10 or 5-9 membered ring(s); each represents a separate embodiment according to this invention.
  • heterocyclic rings include, but ot limited to: pyran, tetrahydropyran, pyrrazole, imidazole, furan, tetrahydrofuran, dioxane, azetidine, pyridine, pyridazine, pyrimidine, piperidine, piperazine, triazole, oxadiazole, tetrahydrofuran (THF), tetrahydrofurane, morpholine, thiomorpholine 1,1-dioxide, oxa-azaspirodecane, azaspiroheptane, 5- azaspiro[2.4]heptane, 2-azaspiro[3.3]heptane, oxa-azaspiroheptane, 2-oxa-6-azaspiro[3.3]heptane pyrrol, pyrrolidine, pyrrolidine-2-one, 2-oxo-pyrrolidine, pyrrolidinone, quin
  • the heterocyclic ring may be further substituted with at least one group selected from: F, Cl, Br, I, CF3, R20 as defined hereinbelow, C1-C5 linear or branched alkyl (e.g., methyl, ethyl, propyl), alkyleneamine (e.g., CH2-NH2), C1-C5 linear or branched haloalkyl, OH, alkoxy (e.g., OCH3), alkylene- OH (e.g., CH2-OH), amide, alkylene-amide (e.g., CH2-C(O)NH2), C(O)-heterocyclic ring, amine (e.g., NH 2 ), alkylamine (e.g., NH(CH 3 )), dialkylamine (e.g., N(CH 3 ) 2 ), CF 3 , aryl, phenyl, halophenyl, heteroaryl, C 3 -
  • “single or fused saturated, unsaturated or aromatic heterocyclic ring” or “saturated, unsaturated, aromatic, single, fused or spiro heterocyclic ring” can be any such ring(s), which comprise at least one heteroatom selected from: N, O or S, including but not limited to: pyridinyl, (2-, 3-, and 4-pyridinyl), quinolinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, 1-methylimidazole, pyrazolyl, pyrrolyl, furanyl, thiophene-yl, quinolinyl, isoquinolinyl, 2,3-dihydroindenyl, indenyl, tetrahydronaph
  • the heterocyclic ring according to this invention includes: pyran, tetrahydropyran, pyrrazole, imidazole, furan, tetrahydrofuran, dioxane, oxetane, azetidine, pyridine, pyridazine, pyrimidine, piperidine, piperazine, triazole, oxadiazole, tetrahydrofuran (THF), tetrahydrofurane, morpholine, thiomorpholine 1,1-dioxide, oxa-azaspirodecane, azaspiroheptane, 5-azaspiro[2.4]heptane, 2-azaspiro[3.3]heptane, oxa-azaspiroheptane, pyrrol, pyrrolidine, pyrrolidine-2-one, 2-oxo-pyrrolidine, pyrrolidinone, quinuclidine, aze
  • the heterocyclic ring may be further substituted with at least one group selected from: F, Cl, Br, I, CF3, R20 as defined hereinbelow, C1-C5 linear or branched alkyl (e.g., methyl, ethyl, propyl), alkyleneamine (e.g., CH2-NH2), C1-C5 linear or branched haloalkyl, OH, alkoxy (e.g., OCH3), alkylene-OH (e.g., CH2-OH), amide, alkylene-amide (e.g., CH2-C(O)NH2), C(O)-heterocyclic ring, amine (e.g., NH 2 ), alkylamine (e.g., NH(CH 3 )), dialkylamine (e.g., N(CH 3 ) 2 ), CF 3 , aryl, phenyl, halophenyl, heteroaryl, C 3 -C
  • this invention provides a compound of this invention or its isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (deuterated analog), PROTAC, polymorph, or crystal or combinations thereof.
  • this invention provides an isomer of the compound of this invention.
  • this invention provides a metabolite of the compound of this invention.
  • this invention provides a pharmaceutically acceptable salt of the compound of this invention.
  • this invention provides a pharmaceutical product of the compound of this invention.
  • this invention provides a tautomer of the compound of this invention.
  • this invention provides a hydrate of the compound of this invention. In some embodiments, this invention provides an N-oxide of the compound of this invention. In some embodiments, this invention provides a reverse amide analog of the compound of this invention. In some embodiments, “reverse amide analog” refers to acyclic amides or amides of acyclic amines. In some embodiments, this invention provides a prodrug of the compound of this invention. In some embodiments, this invention provides an isotopic variant (including but not limited to deuterated analog) of the compound of this invention. In some embodiments, this invention provides a PROTAC (Proteolysis targeting chimera) of the compound of this invention.
  • PROTAC Proteolysis targeting chimera
  • this invention provides a polymorph of the compound of this invention. In some embodiments, this invention provides a crystal of the compound of this invention. In some embodiments, this invention provides composition comprising a compound of this invention, as described herein, or, In some embodiments, a combination of an isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (deuterated analog), PROTAC, polymorph, or crystal of the compound of this invention.
  • the term “isomer” includes, but is not limited to, stereoisomers including optical isomers and analogs, structural isomers and analogs, conformational isomers and analogs, and the like.
  • the isomer is a stereoisomer.
  • the isomer is an optical isomer.
  • Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
  • asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are included in this invention. [00179] In various embodiments, this invention encompasses the use of various stereoisomers of the compounds of the invention. It will be appreciated by those skilled in the art that the compounds of the present invention may contain at least one chiral center. Accordingly, the compounds used in the methods of the present invention may exist in, and be isolated in, optically-active or racemic forms.
  • the compounds according to this invention may further exist as stereoisomers which may be also optically- active isomers (e.g., enantiomers such as (R) or (S)), as enantiomerically enriched mixtures, racemic mixtures, or as single diastereomers, diastereomeric mixtures, or any other stereoisomers, including but not limited to: (R)(R), (R)(S), (S)(S), (S)(R), (R)(R)(R), (R)(R)(S), (R)(S)(R), (S)(R)(R), (R)(S)(R), (S)(R)(S), (S)(R)(S), (S)(S)(R)(R) or (S)(S)(S)(S) stereoisomers.
  • enantiomers such as (R) or (S)
  • the present invention encompasses any racemic, optically-active, polymorphic, or stereroisomeric form, or mixtures thereof, which form possesses properties useful in the treatment of the various conditions described herein.
  • optically active forms for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase.
  • the compounds of the present invention can also be present in the form of a racemic mixture, containing substantially equivalent amounts of stereoisomers.
  • the compounds of the present invention can be prepared or otherwise isolated, using known procedures, to obtain a stereoisomer substantially free of its corresponding stereoisomer (i.e., substantially pure).
  • substantially pure it is intended that a stereoisomer is at least about 80% pure, more preferably at least about 95% pure, even more preferably at least about 98% pure, most preferably at least about 99% pure.
  • the compound according to the invention comprises a substantially pure stereoisomer.
  • the substantially pure stereoisomer is at least 70%; 75%; 80%; 85%; 90%; 93%; 95%; 97%; 98%; 99%; 99.5% pure; each represents a separate embodiment according to this invention.
  • the compound comprises a single stereoisomer in a purity of >80%; >85%; >90%; >91%; >92%; >93%; >94%; >95%; >96%; >97%; >98%; >99%; >99.5% enantiomeric excess (ee); each represents a separate embodiment according to this invention.
  • the compound comprises a single stereoisomer in a purity >80%; >85%; >90%; >91%; >92%; >93%; >94%; >95%; >96%; >97%; >98%; >99%; >99.5% enantiomeric ratio (er); each represents a separate embodiment according to this invention.
  • the compound comprises a single stereoisomer in a purity higher than 80%; 85%; 90%; 91%; 92%; 93%; 94%; 95%; 96%; 97%; 98%; 99%; 99.5%; each represents a separate embodiment according to this invention.
  • the compound is a substantially pure single enantiomer.
  • the compound comprises a mixture of enantiomers.
  • the compound is a racemate.
  • the compound has two chiral centers.
  • the compound comprises a mixture of stereoisomers.
  • the compound comprises a mixture of 2, 3, or 4 stereoisomers; each represents a separate embodiment according to this invention.
  • the compound is a single stereoisomer. In various embodiments, the compound is a substantially pure single stereoisomer. In various embodiments, the substantially pure stereoisomer has at least 80%, 85%, 90%, 95%, 97%, 98%, 99% purity; each represents a separate embodiment according to this invention. In various embodiments, the compound is the substantially pure RR stereoisomer. In various embodiments, the compound is the substantially pure SS stereoisomer. In various embodiments, the compound is the substantially pure RS stereoisomer. In various embodiments, the compound is the substantially pure SR stereoisomer.
  • Compounds of the present invention can also be in the form of a hydrate, which means that the compound further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
  • a chemical functional group e.g., alkyl or aryl
  • substituted it is herein defined that one or more substitutions are possible.
  • the term “substituted” according to this invention refers to but is not limited to at least one group selected from: halogen, substituted or unsubstituted C 1 -C 5 linear or branched alkyl (e.g., methyl, ethyl, propyl, isopropyl, CH(Me)CH 2 -OMe), OH, C 1 -C 5 linear or branched alkyl-OH (e.g., C(CH 3 ) 2 CH 2 -OH, CH 2 CH 2 -OH), linear, branched or cyclic alkoxy (e.g., OMe, oxetane), amide (e.g., C(O)N(R) 2 , C(O)- pyrrolidine, C(O)-piperidine, N(R) 2 , NH(R 10 ), N(R 10 )(R 11 ), (e.g., N(CH 3 ) 2 , NH 2
  • Compounds of the present invention may exist in the form of one or more of the possible tautomers and depending on the conditions it may be possible to separate some or all of the tautomers into individual and distinct entities. It is to be understood that all of the possible tautomers, including all additional enol and keto tautomers and/or isomers are hereby covered.
  • the invention includes “pharmaceutically acceptable salts” of the compounds of this invention, which may be produced, by reaction of a compound of this invention with an acid or base. Certain compounds, particularly those possessing acid or basic groups, can also be in the form of a salt, preferably a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt refers to those salts that retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable.
  • the salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like
  • organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fuma
  • Suitable pharmaceutically acceptable salts of amines of the compounds of this invention may be prepared from an inorganic acid or from an organic acid.
  • examples of inorganic salts of amines are bisulfates, borates, bromides, chlorides, hemisulfates, hydrobromates, hydrochlorates, 2-hydroxyethylsulfonates (hydroxyethanesulfonates), iodates, iodides, isethionates, nitrates, persulfates, phosphate, sulfates, sulfamates, sulfanilates, sulfonic acids (alkylsulfonates, arylsulfonates, halogen substituted alkylsulfonates, halogen substituted arylsulfonates), sulfonates and thiocyanates.
  • examples of organic salts of amines may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are acetates, arginines, aspartates, ascorbates, adipates, anthranilates, alkane carboxylates, substituted alkane carboxylates, alginates, benzenesulfonates, benzoates, bisulfates, butyrates, bicarbonates, bitartrates, citrates, camphorates, camphorsulfonates, cyclohexylsulfamates, cyclopentanepropionates, calcium edetates, camsylates, carbonates, clavulanates, cinnamates, dicarboxylates, digluconates, dodecylsulfonates, dihydrochlorides, decanoates, enant
  • examples of inorganic salts of carboxylic acids or hydroxyls may be selected from ammonium, alkali metals to include lithium, sodium, potassium, cesium; alkaline earth metals to include calcium, magnesium, aluminium; zinc, barium, cholines, quaternary ammoniums.
  • examples of organic salts of carboxylic acids or hydroxyl may be selected from arginine, organic amines to include aliphatic organic amines, alicyclic organic amines, aromatic organic amines, benzathines, t-butylamines, benethamines (N-benzylphenethylamine), dicyclohexylamines, dimethylamines, diethanolamines, ethanolamines, ethylenediamines, hydrabamines, imidazoles, lysines, methylamines, meglumines, N-methyl-D-glucamines, N,N’- dibenzylethylenediamines, nicotinamides, organic amines, ornithines, pyridines, picolies, piperazines, procain, tris(hydroxymethyl)methylamines, triethylamines, triethanolamines, trimethylamines, tromethamines and ureas.
  • the salts may be formed by conventional means, such as by reacting the free base or free acid form of the product with one or more equivalents of the appropriate acid or base in a solvent or medium in which the salt is insoluble or in a solvent such as water, which is removed in vacuo or by freeze drying or by exchanging the ions of a existing salt for another ion or suitable ion-exchange resin.
  • Pharmaceutical composition [00194] Another aspect of the present invention relates to a pharmaceutical composition including a pharmaceutically acceptable carrier and a compound according to the aspects of the present invention.
  • the pharmaceutical composition can contain one or more of the above-identified compounds of the present invention.
  • the pharmaceutical composition of the present invention will include a compound of the present invention or its pharmaceutically acceptable salt, as well as a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier refers to any suitable adjuvants, carriers, excipients, or stabilizers, and can be in solid or liquid form such as, tablets, capsules, powders, solutions, suspensions, or emulsions.
  • the composition will contain from about 0.01 to 99 percent, preferably from about 20 to 75 percent of active compound(s), together with the adjuvants, carriers and/or excipients. While individual needs may vary, determination of optimal ranges of effective amounts of each component is within the skill of the art.
  • Typical dosages comprise about 0.01 to about 100 mg/kg body wt.
  • the preferred dosages comprise about 0.1 to about 100 mg/kg body wt.
  • the most preferred dosages comprise about 1 to about 100 mg/kg body wt.
  • Treatment regimen for the administration of the compounds of the present invention can also be determined readily by those with ordinary skill in art. That is, the frequency of administration and size of the dose can be established by routine optimization, preferably while minimizing any side effects.
  • the solid unit dosage forms can be of the conventional type.
  • the solid form can be a capsule and the like, such as an ordinary gelatin type containing the compounds of the present invention and a carrier, for example, lubricants and inert fillers such as, lactose, sucrose, or cornstarch.
  • these compounds are tabulated with conventional tablet bases such as lactose, sucrose, or cornstarch in combination with binders like acacia, cornstarch, or gelatin, disintegrating agents, such as cornstarch, potato starch, or alginic acid, and a lubricant, like stearic acid or magnesium stearate.
  • conventional tablet bases such as lactose, sucrose, or cornstarch in combination with binders like acacia, cornstarch, or gelatin
  • disintegrating agents such as cornstarch, potato starch, or alginic acid
  • a lubricant like stearic acid or magnesium stearate.
  • the tablets, capsules, and the like can also contain a binder such as gum tragacanth, acacia, corn starch, or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose, or saccharin.
  • a binder such as gum tragacanth, acacia, corn starch, or gelatin
  • excipients such as dicalcium phosphate
  • a disintegrating agent such as corn starch, potato starch, alginic acid
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, lactose, or saccharin.
  • a liquid carrier such as a fatty oil.
  • Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets can be coated with
  • a syrup can contain, in addition to active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye, and flavoring such as cherry or orange flavor.
  • these active compounds can be incorporated with excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups, and the like.
  • Such compositions and preparations should contain at least 0.1% of active compound.
  • the percentage of the compound in these compositions can, of course, be varied and can conveniently be between about 2% to about 60% of the weight of the unit.
  • the amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained.
  • compositions according to the present invention are prepared so that an oral dosage unit contains between about 1 mg and 800 mg of active compound.
  • the active compounds of the present invention may be orally administered, for example, with an inert diluent, or with an assimilable edible carrier, or they can be enclosed in hard- or soft-shell capsules, or they can be compressed into tablets, or they can be incorporated directly with the food of the diet.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form should be sterile and should be fluid to the extent that easy syringability exists.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • the compounds or pharmaceutical compositions of the present invention may also be administered in injectable dosages by solution or suspension of these materials in a physiologically acceptable diluent with a pharmaceutical adjuvant, carrier or excipient.
  • Such adjuvants, carriers and/or excipients include, but are not limited to, sterile liquids, such as water and oils, with or without the addition of a surfactant and other pharmaceutically and physiologically acceptable components.
  • sterile liquids such as water and oils
  • Illustrative oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, or mineral oil.
  • water, saline, aqueous dextrose and related sugar solution, and glycols, such as propylene glycol or polyethylene glycol are preferred liquid carriers, particularly for injectable solutions.
  • These active compounds may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils.
  • oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, or mineral oil.
  • water, saline, aqueous dextrose and related sugar solution, and glycols such as, propylene glycol or polyethylene glycol are preferred liquid carriers, particularly for injectable solutions.
  • these preparations contain a preservative to prevent the growth of microorganisms.
  • the compounds of the present invention in solution or suspension may be packaged in a pressurized aerosol container together with suitable propellants, for example, hydrocarbon propellants like propane, butane, or isobutane with conventional adjuvants.
  • suitable propellants for example, hydrocarbon propellants like propane, butane, or isobutane with conventional adjuvants.
  • the materials of the present invention also may be administered in a non-pressurized form such as in a nebulizer or atomizer.
  • the compounds of this invention are administered in combination with an anti-cancer therapy. Examples of such therapies include but are not limited to: chemotherapy, immunotherapy, radiotherapy, biological therapy, surgical intervention, and combinations thereof.
  • the compound is administered in combination with an anti-cancer agent by administering the compounds as herein described, alone or in combination with other agents.
  • administering can be accomplished in any manner effective for delivering the compounds or the pharmaceutical compositions to the cancerous cells.
  • Exemplary modes of administration include, without limitation, administering the compounds or compositions orally, topically, transdermally, parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, intraocularly, intraarterially, intralesionally, or by application to mucous membranes, such as, that of the nose, throat, and bronchial tubes.
  • Biological Activity [00207]
  • the invention provides compounds and compositions, including any embodiment described herein, for use in any of the methods of this invention.
  • compositions may further comprise additional active ingredients, whose activity is useful for the particular application for which the compound of this invention is being administered.
  • the invention relates to the treatment, inhibition, and reduction of cancer, employing the use of a compound according to this invention or a pharmaceutically acceptable salt thereof.
  • this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting cancer in a subject, comprising administering a compound according to this invention, 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.
  • the compound is a c-MYC mRNA translation modulator.
  • the compound is a c-MYC mRNA translation inhibitor.
  • the compound is a c- MYC inhibitor.
  • the compound is a c-MYC mRNA transcription regulator.
  • the compound is any combination of a c-MYC mRNA translation modulator, a c- MYC mRNA transcription regulator and a c-MYC inhibitor.
  • the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to this invention.
  • the cancer is early cancer. In some embodiments, the cancer is advanced cancer. In some embodiments, the cancer is invasive cancer. In some embodiments, the cancer is metastatic cancer. In some embodiments, the cancer is drug resistant cancer.
  • the cancer is selected from the following list: bladder cancer (urothelial carcinoma), myelodysplasia, breast cancer, cervix cancer, endometrium cancer, esophagus cancer, head and neck cancer (squamous cell carcinoma), kidney cancer (e.g., renal cell carcinoma, clear cell renal cell carcinoma), liver cancer (hepatocellular carcinoma), lung cancer (e.g., metastatic, non-small cell, NSCLC, squamous cell carcinoma, small cell (SCLC)), metastatic cacner (e.g., to brain), nasopharynx cancer, solid tumor cancer, stomach cancer, adrenocortical carcinoma, Glioblastoma multiforme, acute myeloid leukemia, chronic lymphocytic leukemia, lymphoma (e.g., Hodgkin's (classical), diffuse large B-cell, primary central nervous system), malignant melanoma, uveal melanoma, mening
  • bladder cancer urotheli
  • squamous cell biliary cancer
  • bladder cancer muscle invasive urothelial carcinoma
  • colorectal cancer metastatic colorectal cancer
  • fallopian tube cancer gastroesophageal junction cacner (e.g., adenocarcinoma), larynx cancer (e.g., squamous cell), merkel cell cancer, mouth cancer, ovary cancer (e.g., epithelial), pancreas cacner (e.g., adenocarcinoma, metastatic), penis cancer (e.g., squamous cell carcinoma), peritoneum cancer, prostate cancer (e.g., castration-resistant, metastatic), rectum cancer, skin cancer (e.g., basal cell carcinoma, squamous cell carcinoma), small intestine cacner (e.g., adenocarcinoma), testicle cancer, thymus cancer, anaplastic thyroid cancer, cholangiocarcinoma, chordoma
  • the cancer is selected from a list including but not limited to: 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.
  • the cancer may be selected from solid tumors and non-solid tumors.
  • this invention is directed to a method for suppressing, reducing or inhibiting tumor growth in a subject, comprising administering a compound of this invention, to a subject under conditions effective to suppress, reduce or inhibit tumor growth in said subject.
  • the tumor may be a solid tumor or a non-solid tumor.
  • the solid tumor cancer is selected from a list including but not limited to: breast cancer, ovarian carcinoma, prostate cancer, colon cancer, gastric cancer, glioblastoma, medulloblastoma, melanoma, non-small cell lung carcinoma, esophageal squamous cell carcinoma, osteosarcoma, bladder cancer, pancreatic cancer, lung adenocarcinoma, BRAF V600E thyroid cancer, choroid plexus carcinoma, colitis-associated cancer, epithelial ovarian cancer, colorectal cancer, pancreatic cancer and uterine cancer.
  • the non-solid tumors include but not limited to: hematological malignancies including leukemia, lymphoma or myeloma and inherited cancers such as retinoblastoma and Wilm’s tumor.
  • the non-solid tumor cancer is selected from a list including but not limited to: acute myeloid leukemia, chronic myelogenous leukemia, Hodgkin’s and Burkitt’s lymphoma, diffuse large Bcell lymphoma, primary central nervous system lymphoma, glioblastoma, medulloblastoma, germinal center-derived lymphomas, myeloma, retinoblastoma and Wilm’s tumor.
  • this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting cancer comprising administering a compound of this invention to a subject suffering from cancer under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit the cancer.
  • the cancer is early cancer.
  • the cancer is advanced cancer.
  • the cancer is invasive cancer.
  • the cancer is metastatic cancer.
  • the cancer is drug resistant cancer.
  • the compound is a c- MYC mRNA translation modulator.
  • the compound is a c-MYC mRNA translation inhibitor.
  • the compound is a c-MYC mRNA transcription regulator. In some embodiments, the compound is selective to c-MYC. In some embodiments, the compound reduces the amount of c-Myc protein in a cell. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to this invention. [00219] In various embodiments, this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting breast cancer comprising administering a compound of this invention to a subject suffering from breast cancer under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit the breast cancer. In some embodiments, the breast cancer is early breast cancer.
  • the breast cancer is advanced breast cancer. In some embodiments, the breast cancer is invasive breast cancer. In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, the breast cancer is drug resistant breast cancer. In some embodiments, the compound is a c-MYC mRNA translation modulator. In some embodiments, the compound is a c-MYC mRNA translation inhibitor. In some embodiments, the compound is a c-MYC mRNA transcription regulator. In some embodiments, the compound is selective to c-MYC. In some embodiments, the compound reduces the amount of c-Myc protein in a cell. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to this invention.
  • this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting ovarian carcinoma comprising administering a compound of this invention to a subject suffering from ovarian carcinoma under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit the ovarian carcinoma.
  • the ovarian carcinoma is early ovarian carcinoma.
  • the ovarian carcinoma is advanced ovarian carcinoma.
  • the ovarian carcinoma is invasive ovarian carcinoma.
  • the ovarian carcinoma is metastatic ovarian carcinoma.
  • the ovarian carcinoma is drug resistant ovarian carcinoma.
  • the compound is a c-MYC mRNA translation modulator. In some embodiments, the compound is a c-MYC mRNA translation inhibitor. In some embodiments, the compound is a c-MYC mRNA transcription regulator. In some embodiments, the compound is selective to c-MYC. In some embodiments, the compound reduces the amount of c-Myc protein in a cell. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to this invention.
  • this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting acute myeloid leukemia comprising administering a compound of this invention to a subject suffering from acute myeloid leukemia under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit the acute myeloid leukemia.
  • the acute myeloid leukemia is early acute myeloid leukemia.
  • the acute myeloid leukemia is advanced acute myeloid leukemia.
  • the acute myeloid leukemia is invasive acute myeloid leukemia.
  • the acute myeloid leukemia is metastatic acute myeloid leukemia.
  • the acute myeloid leukemia is drug resistant acute myeloid leukemia.
  • the compound is a c-MYC mRNA translation modulator. In some embodiments, the compound is a c-MYC mRNA translation inhibitor. In some embodiments, the compound is a c-MYC mRNA transcription regulator. In some embodiments, the compound is selective to c-MYC. In some embodiments, the compound reduces the amount of c-Myc protein in a cell. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to this invention.
  • this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting chronic myelogenous leukemia comprising administering a compound of this invention to a subject suffering from chronic myelogenous leukemia under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit the chronic myelogenous leukemia.
  • the chronic myelogenous leukemia is early chronic myelogenous leukemia.
  • the chronic myelogenous leukemia is advanced chronic myelogenous leukemia.
  • the chronic myelogenous leukemia is invasive chronic myelogenous leukemia.
  • the chronic myelogenous leukemia is metastatic chronic myelogenous leukemia. In some embodiments, the chronic myelogenous leukemia is drug resistant chronic myelogenous leukemia.
  • the compound is a c-MYC mRNA translation modulator. In some embodiments, the compound is a c-MYC mRNA translation inhibitor. In some embodiments, the compound is a c-MYC mRNA transcription regulator. In some embodiments, the compound is selective to c-MYC. In some embodiments, the compound reduces the amount of c- Myc protein in a cell.
  • this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting Hodgkin’s and/or Burkitt’s lymphoma comprising administering a compound of this invention to a subject suffering from Hodgkin’s and/or Burkitt’s lymphoma under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit the Hodgkin’s and/or Burkitt’s lymphoma.
  • the Hodgkin’s and/or Burkitt’s lymphoma is early Hodgkin’s and/or Burkitt’s lymphoma. In some embodiments, the Hodgkin’s and/or Burkitt’s lymphoma is advanced Hodgkin’s and/or Burkitt’s lymphoma. In some embodiments, the Hodgkin’s and/or Burkitt’s lymphoma is invasive Hodgkin’s and/or Burkitt’s lymphoma. In some embodiments, the Hodgkin’s and/or Burkitt’s lymphoma is metastatic Hodgkin’s and/or Burkitt’s lymphoma.
  • the Hodgkin’s and/or Burkitt’s lymphoma is drug resistant Hodgkin’s and/or Burkitt’s lymphoma.
  • the compound is a c-MYC mRNA translation modulator. In some embodiments, the compound is a c-MYC mRNA translation inhibitor. In some embodiments, the compound is a c-MYC mRNA transcription regulator. In some embodiments, the compound is selective to c-MYC. In some embodiments, the compound reduces the amount of c-Myc protein in a cell. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to this invention.
  • this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting diffuse large Bcell lymphoma comprising administering a compound of this invention to a subject suffering from diffuse large Bcell lymphoma under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit the diffuse large Bcell lymphoma.
  • the diffuse large Bcell lymphoma is early diffuse large Bcell lymphoma.
  • the diffuse large Bcell lymphoma is advanced diffuse large Bcell lymphoma.
  • the diffuse large Bcell lymphoma is invasive diffuse large Bcell lymphoma.
  • the diffuse large Bcell lymphoma is metastatic diffuse large Bcell lymphoma. In some embodiments, the diffuse large Bcell lymphoma is drug resistant diffuse large Bcell lymphoma. In some embodiments, the compound is a c-MYC mRNA translation modulator. In some embodiments, the compound is a c-MYC mRNA translation inhibitor. In some embodiments, the compound is a c-MYC mRNA transcription regulator. In some embodiments, the compound is selective to c-MYC. In some embodiments, the compound reduces the amount of c-Myc protein in a cell. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to this invention.
  • this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting prostate cancer comprising administering a compound of this invention to a subject suffering from prostate cancer under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit the prostate cancer.
  • the prostate cancer is early prostate cancer.
  • the prostate cancer is advanced prostate cancer.
  • the prostate cancer is invasive prostate cancer.
  • the prostate cancer is metastatic prostate cancer.
  • the prostate cancer is drug resistant prostate cancer.
  • the compound is a c-MYC mRNA translation modulator.
  • the compound is a c-MYC mRNA translation inhibitor. In some embodiments, the compound is a c-MYC mRNA transcription regulator. In some embodiments, the compound is selective to c-MYC. In some embodiments, the compound reduces the amount of c- Myc protein in a cell. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to this invention.
  • this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting colon cancer comprising administering a compound of this invention to a subject suffering from colon cancer under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit the colon cancer.
  • the colon cancer is early colon cancer.
  • the colon cancer is advanced colon cancer.
  • the colon cancer is invasive colon cancer.
  • the colon cancer is metastatic colon cancer.
  • the colon cancer is drug resistant colon cancer.
  • the compound is a c-MYC mRNA translation modulator.
  • the compound is a c-MYC mRNA translation inhibitor. In some embodiments, the compound is a c-MYC mRNA transcription regulator. In some embodiments, the compound is selective to c-MYC. In some embodiments, the compound reduces the amount of c-Myc protein in a cell. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to this invention.
  • this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting gastric cancer comprising administering a compound of this invention to a subject suffering from gastric cancer under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit the gastric cancer.
  • the gastric cancer is early gastric cancer.
  • the gastric cancer is advanced gastric cancer.
  • the gastric cancer is invasive gastric cancer.
  • the gastric cancer is metastatic gastric cancer.
  • the gastric cancer is drug resistant gastric cancer.
  • the compound is a c-MYC mRNA translation modulator.
  • the compound is a c-MYC mRNA translation inhibitor. In some embodiments, the compound is a c-MYC mRNA transcription regulator. In some embodiments, the compound is selective to c-MYC. In some embodiments, the compound reduces the amount of c-Myc protein in a cell. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to this invention.
  • this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting lymphoma comprising administering a compound of this invention to a subject suffering from lymphoma under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit the lymphoma.
  • the lymphoma is early lymphoma.
  • the lymphoma is advanced lymphoma.
  • the lymphoma is invasive lymphoma.
  • the lymphoma is metastatic lymphoma.
  • the lymphoma is drug resistant lymphoma.
  • the lymphoma is primary central nervous system lymphoma. In some embodiments, the lymphoma is germinal center-derived lymphoma. In some embodiments, the lymphoma is Hodgkin’s lymphoma. In some embodiments, the lymphoma is Burkitt’s lymphoma. In some embodiments, the lymphoma is diffuse large B-cell lymphoma. In some embodiments, the compound is a c-MYC mRNA translation modulator. In some embodiments, the compound is a c-MYC mRNA translation inhibitor. In some embodiments, the compound is a c-MYC mRNA transcription regulator. In some embodiments, the compound is selective to c-MYC.
  • the compound reduces the amount of c-Myc protein in a cell.
  • the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to this invention.
  • this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting glioblastoma comprising administering a compound of this invention to a subject suffering from glioblastoma under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit the glioblastoma.
  • the glioblastoma is early glioblastoma.
  • the glioblastoma is advanced glioblastoma. In some embodiments, the glioblastoma is invasive glioblastoma. In some embodiments, the glioblastoma is metastatic glioblastoma. In some embodiments, the glioblastoma is drug resistant glioblastoma. In some embodiments, the compound is a c-MYC mRNA translation modulator. In some embodiments, the compound is a c-MYC mRNA translation inhibitor. In some embodiments, the compound is a c-MYC mRNA transcription regulator. In some embodiments, the compound is selective to c-MYC.
  • the compound reduces the amount of c-Myc protein in a cell.
  • the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to this invention.
  • this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting medulloblastoma comprising administering a compound of this invention to a subject suffering from medulloblastoma under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit the medulloblastoma.
  • the medulloblastoma is early medulloblastoma.
  • the medulloblastoma is advanced medulloblastoma. In some embodiments, the medulloblastoma is invasive medulloblastoma. In some embodiments, the medulloblastoma is metastatic medulloblastoma. In some embodiments, the medulloblastoma is drug resistant medulloblastoma. In some embodiments, the compound is a c-MYC mRNA translation modulator. In some embodiments, the compound is a c-MYC mRNA translation inhibitor. In some embodiments, the compound is a c-MYC mRNA transcription regulator. In some embodiments, the compound is selective to c-MYC.
  • the compound reduces the amount of c-Myc protein in a cell.
  • the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to this invention.
  • this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting melanoma comprising administering a compound of this invention to a subject suffering from melanoma under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit the melanoma.
  • the melanoma is early melanoma.
  • the melanoma is advanced melanoma.
  • the melanoma is invasive melanoma. In some embodiments, the melanoma is metastatic melanoma. In some embodiments, the melanoma is drug resistant melanoma. In some embodiments, the compound is a c-MYC mRNA translation modulator. In some embodiments, the compound is a c-MYC mRNA translation inhibitor. In some embodiments, the compound is a c- MYC mRNA transcription regulator. In some embodiments, the compound is selective to c-MYC. In some embodiments, the compound reduces the amount of c-Myc protein in a cell.
  • the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to this invention.
  • this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting non-small cell lung carcinoma comprising administering a compound of this invention to a subject suffering from non-small cell lung carcinoma under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit the non-small cell lung carcinoma.
  • the non-small cell lung carcinoma is early non-small cell lung carcinoma.
  • the non-small cell lung carcinoma is advanced non-small cell lung carcinoma.
  • the non-small cell lung carcinoma is invasive non-small cell lung carcinoma.
  • the non-small cell lung carcinoma is metastatic non-small cell lung carcinoma. In some embodiments, the non-small cell lung carcinoma is drug resistant non-small cell lung carcinoma. In some embodiments, the compound is a c-MYC mRNA translation modulator. In some embodiments, the compound is a c-MYC mRNA translation inhibitor. In some embodiments, the compound is a c-MYC mRNA transcription regulator. In some embodiments, the compound is selective to c-MYC. In some embodiments, the compound reduces the amount of c- Myc protein in a cell. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to this invention.
  • this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting esophageal squamous cell carcinoma comprising administering a compound of this invention to a subject suffering from esophageal squamous cell carcinoma under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit the esophageal squamous cell carcinoma.
  • the esophageal squamous cell carcinoma is early esophageal squamous cell carcinoma.
  • the esophageal squamous cell carcinoma is advanced esophageal squamous cell carcinoma.
  • the esophageal squamous cell carcinoma is invasive esophageal squamous cell carcinoma. In some embodiments, the esophageal squamous cell carcinoma is metastatic esophageal squamous cell carcinoma. In some embodiments, the esophageal squamous cell carcinoma is drug resistant esophageal squamous cell carcinoma.
  • the compound is a c-MYC mRNA translation modulator. In some embodiments, the compound is a c-MYC mRNA translation inhibitor. In some embodiments, the compound is a c-MYC mRNA transcription regulator. In some embodiments, the compound is selective to c-MYC.
  • the compound reduces the amount of c- Myc protein in a cell.
  • the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to this invention.
  • this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting osteosarcoma comprising administering a compound of this invention to a subject suffering from osteosarcoma under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit the osteosarcoma.
  • the osteosarcoma is early osteosarcoma.
  • the osteosarcoma is advanced osteosarcoma.
  • the osteosarcoma is invasive osteosarcoma. In some embodiments, the osteosarcoma is metastatic osteosarcoma. In some embodiments, the osteosarcoma is drug resistant osteosarcoma. In some embodiments, the compound is a c-MYC mRNA translation modulator. In some embodiments, the compound is a c-MYC mRNA translation inhibitor. In some embodiments, the compound is a c-MYC mRNA transcription regulator. In some embodiments, the compound is selective to c-MYC. In some embodiments, the compound reduces the amount of c-Myc protein in a cell.
  • the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to this invention.
  • this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting bladder cancer comprising administering a compound of this invention to a subject suffering from bladder cancer under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit the bladder cancer.
  • the bladder cancer is early bladder cancer.
  • the bladder cancer is advanced bladder cancer.
  • the bladder cancer is invasive bladder cancer.
  • the bladder cancer is metastatic bladder cancer.
  • the bladder cancer is drug resistant bladder cancer.
  • the compound is a c-MYC mRNA translation modulator. In some embodiments, the compound is a c-MYC mRNA translation inhibitor. In some embodiments, the compound is a c-MYC mRNA transcription regulator. In some embodiments, the compound is selective to c-MYC. In some embodiments, the compound reduces the amount of c-Myc protein in a cell. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to this invention.
  • this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting pancreatic cancer comprising administering a compound of this invention to a subject suffering from pancreatic cancer under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit the pancreatic cancer.
  • the pancreatic cancer is early pancreatic cancer.
  • the pancreatic cancer is advanced pancreatic cancer.
  • the pancreatic cancer is invasive pancreatic cancer.
  • the pancreatic cancer is metastatic pancreatic cancer.
  • the pancreatic cancer is drug resistant pancreatic cancer.
  • the compound is a c-MYC mRNA translation modulator. In some embodiments, the compound is a c-MYC mRNA translation inhibitor. In some embodiments, the compound is a c-MYC mRNA transcription regulator. In some embodiments, the compound is selective to c-MYC. In some embodiments, the compound reduces the amount of c-Myc protein in a cell. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to this invention.
  • this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting lung adenocarcinoma comprising administering a compound of this invention to a subject suffering from lung adenocarcinoma under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit the lung adenocarcinoma.
  • the lung adenocarcinoma is early lung adenocarcinoma.
  • the lung adenocarcinoma is advanced lung adenocarcinoma.
  • the lung adenocarcinoma is invasive lung adenocarcinoma.
  • the lung adenocarcinoma is metastatic lung adenocarcinoma. In some embodiments, the lung adenocarcinoma is drug resistant lung adenocarcinoma. In some embodiments, the compound is a c- MYC mRNA translation modulator. In some embodiments, the compound is a c-MYC mRNA translation inhibitor. In some embodiments, the compound is a c-MYC mRNA transcription regulator. In some embodiments, the compound is selective to c-MYC. In some embodiments, the compound reduces the amount of c-Myc protein in a cell.
  • the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to this invention.
  • this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting thyroid cancer comprising administering a compound of this invention to a subject suffering from thyroid cancerunder conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit the thyroid cancer.
  • the thyroid cancer is early thyroid cancer.
  • the thyroid cancer is advanced thyroid cancer.
  • the thyroid cancer is invasive thyroid cancer.
  • the thyroid cancer is metastatic thyroid cancer.
  • the thyroid cancer is drug resistant thyroid cancer.
  • the thyroid cancer is BRAF V600E thyroid cancer.
  • the compound is a c-MYC mRNA translation modulator.
  • the compound is a c-MYC mRNA translation inhibitor.
  • the compound is a c-MYC mRNA transcription regulator.
  • the compound is selective to c-MYC.
  • the compound reduces the amount of c-Myc protein in a cell.
  • the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to this invention.
  • this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting choroid plexus carcinoma comprising administering a compound of this invention to a subject suffering from choroid plexus carcinoma under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit the choroid plexus carcinoma.
  • the choroid plexus carcinoma is early choroid plexus carcinoma.
  • the choroid plexus carcinoma is advanced choroid plexus carcinoma.
  • the choroid plexus carcinoma is invasive choroid plexus carcinoma.
  • the choroid plexus carcinoma is metastatic choroid plexus carcinoma.
  • the choroid plexus carcinoma is drug resistant choroid plexus carcinoma.
  • the compound is a c-MYC mRNA translation modulator. In some embodiments, the compound is a c-MYC mRNA translation inhibitor. In some embodiments, the compound is a c-MYC mRNA transcription regulator. In some embodiments, the compound is selective to c-MYC. In some embodiments, the compound reduces the amount of c-Myc protein in a cell. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to this invention.
  • this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting colitis-associated cancer comprising administering a compound of this invention to a subject suffering from colitis-associated cancer under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit the colitis-associated cancer.
  • the colitis-associated cancer is early colitis-associated cancer.
  • the colitis-associated cancer is advanced colitis-associated cancer.
  • the colitis-associated cancer is invasive colitis-associated cancer.
  • the colitis-associated cancer is metastatic colitis-associated cancer.
  • the colitis-associated cancer is drug resistant colitis-associated cancer.
  • the compound is a c-MYC mRNA translation modulator. In some embodiments, the compound is a c-MYC mRNA translation inhibitor. In some embodiments, the compound is a c-MYC mRNA transcription regulator. In some embodiments, the compound is selective to c-MYC. In some embodiments, the compound reduces the amount of c-Myc protein in a cell. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to this invention.
  • this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting ovarian cancer comprising administering a compound of this invention to a subject suffering from ovarian cancer under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit the ovarian cancer.
  • the ovarian cancer is early ovarian cancer.
  • the ovarian cancer is advanced ovarian cancer .
  • the ovarian cancer is invasive ovarian cancer.
  • the ovarian cancer is metastatic ovarian cancer.
  • the ovarian cancer is drug resistant ovarian cancer.
  • the ovarian cancer is epithelial ovarian cancer.
  • the compound is a c-MYC mRNA translation modulator.
  • the compound is a c-MYC mRNA translation inhibitor.
  • the compound is a c-MYC mRNA transcription regulator.
  • the compound is selective to c-MYC.
  • the compound reduces the amount of c-Myc protein in a cell.
  • the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to this invention.
  • this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting colorectal cancer comprising administering a compound of this invention to a subject suffering from colorectal cancer under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit the colorectal cancer.
  • the colorectal cancer is early colorectal cancer.
  • the colorectal cancer is advanced colorectal cancer.
  • the colorectal cancer is invasive colorectal cancer.
  • the colorectal cancer is metastatic colorectal cancer.
  • the colorectal cancer is drug resistant colorectal cancer.
  • the compound is a c-MYC mRNA translation modulator. In some embodiments, the compound is a c-MYC mRNA translation inhibitor. In some embodiments, the compound is a c-MYC mRNA transcription regulator. In some embodiments, the compound is selective to c-MYC. In some embodiments, the compound reduces the amount of c-Myc protein in a cell. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to this invention.
  • this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting uterine cancer comprising administering a compound of this invention to a subject suffering from uterine cancer under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit the uterine cancer.
  • the uterine cancer is early uterine cancer.
  • the uterine cancer is advanced uterine cancer.
  • the uterine cancer is invasive uterine cancer.
  • the uterine cancer is metastatic uterine cancer.
  • the uterine cancer is drug resistant uterine cancer.
  • the compound is a c-MYC mRNA translation modulator. In some embodiments, the compound is a c-MYC mRNA translation inhibitor. In some embodiments, the compound is a c-MYC mRNA transcription regulator. In some embodiments, the compound is selective to c-MYC. In some embodiments, the compound reduces the amount of c-Myc protein in a cell. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to this invention.
  • this invention provides methods for increasing the survival of a subject suffering from metastatic cancer comprising the step of administering to said subject a compound of this invention and/or an isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, polymorph, or crystal of said compound, or any combination thereof.
  • the compound is a c-MYC mRNA translation modulator.
  • the compound is a c- MYC mRNA translation inhibitor.
  • the compound is a c-MYC mRNA transcription regulator.
  • the compound is selective to c-MYC. In some embodiments, the compound reduces the amount of c-Myc protein in a cell.
  • the cancer is breast cancer, ovarian carcinoma, acute myeloid leukemia, chronic myelogenous leukemia, Hodgkin’s and Burkitt’s lymphoma, diffuse large Bcell lymphoma, prostate cancer, colon cancer, gastric cancer, primary central nervous system lymphoma, glioblastoma, medulloblastoma, melanoma, non- small cell lung carcinoma, germinal center-derived lymphomas, esophageal squamous cell carcinoma, osteosarcoma, bladder cancer, pancreatic cancer, lung adenocarcinoma, thyroid cancer, choroid plexus carcinoma, colitis-associated cancer, colorectal cancer, or uterine cancer; each represents a separate embodiment according to this invention.
  • this invention provides methods for treating, suppressing, reducing the severity, reducing the risk, or inhibiting advanced cancer comprising the step of administering to said subject a compound of this invention and/or an isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, polymorph, or crystal of said compound, or any combination thereof.
  • the compound is a c-MYC mRNA translation modulator.
  • the compound is a c-MYC mRNA translation inhibitor.
  • the compound is a c-MYC mRNA transcription regulator. In some embodiments, the compound is selective to c-MYC. In some embodiments, the compound reduces the amount of c-Myc protein in a cell.
  • the cancer is breast cancer, ovarian carcinoma, acute myeloid leukemia, chronic myelogenous leukemia, Hodgkin’s and Burkitt’s lymphoma, diffuse large Bcell lymphoma, prostate cancer, colon cancer, gastric cancer, primary central nervous system lymphoma, glioblastoma, medulloblastoma, melanoma, non-small cell lung carcinoma, germinal center-derived lymphomas, esophageal squamous cell carcinoma, osteosarcoma, bladder cancer, pancreatic cancer, lung adenocarcinoma, thyroid cancer, choroid plexus carcinoma, colitis-associated cancer, colorectal cancer, or uterine cancer; each represents a separate embodiment according to
  • the compounds of the present invention are useful in the treatment, reducing the severity, reducing the risk of developing, or inhibition of early cancer, metastatic cancer, advanced cancer, drug resistant cancer, and various forms of cancer.
  • the cancer is breast cancer, ovarian carcinoma, acute myeloid leukemia, chronic myelogenous leukemia, Hodgkin’s and Burkitt’s lymphoma, diffuse large Bcell lymphoma, prostate cancer, colon cancer, gastric cancer, primary central nervous system lymphoma, glioblastoma, medulloblastoma, melanoma, non-small cell lung carcinoma, germinal center- derived lymphomas, esophageal squamous cell carcinoma, osteosarcoma, bladder cancer, pancreatic cancer, lung adenocarcinoma, thyroid cancer, choroid plexus carcinoma, colitis-associated cancer, colorectal cancer, or uterine cancer; each represents a separate embodiment accordin g to this invention.
  • Preferred compounds of the present invention are selectively disruptive to cancer cells, causing ablation of cancer cells but preferably not normal cells. Significantly, harm to normal cells is minimized because the cancer cells are susceptible to disruption at much lower concentrations of the compounds of the present invention.
  • the cancer is invasive. In some embodiments the cancer is metastatic cancer. In some embodiments the cancer is advanced cancer. In some embodiments the cancer is drug resistant cancer. [00248] In various embodiments “metastatic cancer” refers to a cancer that spread (metastasized) from its original site to another area of the body. Virtually all cancers have the potential to spread. Whether metastases develop depends on the complex interaction of many tumor cell factors, including the type of cancer, the degree of maturity (differentiation) of the tumor cells, the location and how long the cancer has been present, as well as other incompletely understood factors. Metastases spread in three ways - by local extension from the tumor to the surrounding tissues, through the bloodstream to distant sites or through the lymphatic system to neighboring or distant lymph nodes.
  • drug-resistant cancer refers to cancer cells that acquire resistance to chemotherapy. Cancer cells can acquire resistance to chemotherapy by a range of mechanisms, including the mutation or overexpression of the drug target, inactivation of the drug, or elimination of the drug from the cell. Tumors that recur after an initial response to chemotherapy may be resistant to multiple drugs (they are multidrug resistant). In the conventional view of drug resistance, one or several cells in the tumor population acquire genetic changes that confer drug resistance.
  • the reasons for drug resistance are: a) some of the cells that are not killed by the chemotherapy mutate (change) and become resistant to the drug. Once they multiply, there may be more resistant cells than cells that are sensitive to the chemotherapy; b) Gene amplification. A cancer cell may produce hundreds of copies of a particular gene.
  • This gene triggers an overproduction of protein that renders the anticancer drug ineffective; c) cancer cells may pump the drug out of the cell as fast as it is going in using a molecule called p-glycoprotein; d) cancer cells may stop taking in the drugs because the protein that transports the drug across the cell wall stops working; e) the cancer cells may learn how to repair the DNA breaks caused by some anti-cancer drugs; f) cancer cells may develop a mechanism that inactivates the drug.
  • P-gp P-glycoprotein
  • This protein is a clinically important transporter protein belonging to the ATP-binding cassette family of cell membrane transporters.
  • resistant cancer refers to drug-resistant cancer as described herein above. In some embodiments “resistant cancer” refers to cancer cells that acquire resistance to any treatment such as chemotherapy, radiotherapy or biological therapy.
  • this invention is directed to treating, suppressing, reducing the severity, reducing the risk of developing, or inhibiting cancer in a subject, wherein the subject has been previously treated with chemotherapy, radiotherapy or biological therapy.
  • “Chemotherapy” refers to chemical treatment for cancer such as drugs that kill cancer cells directly. Such drugs are referred as "anti-cancer” drugs or "antineoplastics.”
  • Today's therapy uses more than 100 drugs to treat cancer. Chemotherapy is used to control tumor growth when cure is not possible; to shrink tumors before surgery or radiation therapy; to relieve symptoms (such as pain); and to destroy microscopic cancer cells that may be present after the known tumor is removed by surgery (called adjuvant therapy).
  • Radiotherapy also referred herein as “Radiation therapy” refers to high energy x-rays and similar rays (such as electrons) to treat disease. Many people with cancer will have radiotherapy as part of their treatment. This can be given either as external radiotherapy from outside the body using x-rays or from within the body as internal radiotherapy. Radiotherapy works by destroying the cancer cells in the treated area. Although normal cells can also be damaged by the radiotherapy, they can usually repair themselves. Radiotherapy treatment can cure some cancers and can also reduce the chance of a cancer coming back after surgery. It may be used to reduce cancer symptoms.
  • Bio therapy refers to substances that occur naturally in the body to destroy cancer cells. There are several types of treatment including: monoclonal antibodies, cancer growth inhibitors, vaccines and gene therapy. Biological therapy is also known as immunotherapy.
  • the pharmaceutical composition can also contain, or can be administered in conjunction with, other therapeutic agents or treatment regimen presently known or hereafter developed for the treatment of various types of cancer. Examples of other therapeutic agents or treatment regimen include, without limitation, radiation therapy, immunotherapy, chemotherapy, surgical intervention, and combinations thereof.
  • the compound according to this invention is administered in combination with an anti-cancer therapy.
  • anti-cancer therapy examples include but are not limited to: chemotherapy, immunotherapy, radiotherapy, biological therapy, surgical intervention, and combinations thereof.
  • the compound is administered in combination with an anti-cancer agent by administering the compounds as herein described, alone or in combination with other agents.
  • the composition for cancer treatment of the present invention can be used together with existing chemotherapy drugs or be made as a mixture with them.
  • Such a chemotherapy drug includes, for example, alkylating agents, nitrosourea agents, antimetabolites, antitumor antibiotics, alkaloids derived from plant, topoisomerase inhibitors, hormone therapy medicines, hormone antagonists, aromatase inhibitors, P-glycoprotein inhibitors, platinum complex derivatives, other immunotherapeutic drugs, and other anticancer agents. Further, they can be used together with hypoleukocytosis (neutrophil) medicines that are cancer treatment adjuvant, thrombopenia medicines, antiemetic drugs, and cancer pain medicines for patient's QOL recovery or be made as a mixture with them.
  • hypoleukocytosis neurotrophil
  • this invention 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/or by the structures listed in Table 1, as defined herein above, with a cell, thereby modulating c-MYC mRNA translation in said cell.
  • the method is carried out by regulating c-MYC mRNA splicing.
  • the method is carried out by inclusion or exclusion of untranslated region or alternative usage of exons.
  • the method is carried out by regulation of c-MYC mRNA modifications.
  • the method is carried out by regulation of the interaction of RNA binding protein with c-MYC mRNA thereby changing mRNA localization. In some embodiments, the method is carried out by regulating c-MYC mRNA localization in the cytoplasm. In some embodiments, the method is carried out by regulating ribosomes or ribosome accessory factor to c-MYC mRNA. In some embodiments, the method is carried out by reducing the amount of c-MYC protein in the cell.
  • 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/or by the structures listed in Table 1, as defined herein above, with a cell, thereby regulating c-MYC mRNA transcription in said cell.
  • the method is carried out by regulating c-MYC mRNA splicing.
  • the method is carried out by inclusion or exclusion of untranslated region or alternative usage of exons.
  • the method is carried out by regulation of c-MYC mRNA modifications.
  • the method is carried out by regulation of the interaction of RNA binding protein with c-MYC mRNA thereby changing mRNA localization. In some embodiments, the method is carried out by regulating c-MYC mRNA localization in the cytoplasm. In some embodiments, the method is carried out by regulating ribosomes or ribosome accessory factor to c-MYC mRNA. In some embodiments, the method is carried out by reducing the amount of c-MYC protein in the cell. [00261] In various embodiments, this invention is directed to a method of destroying a cancerous cell comprising providing a compound of this invention and contacting the cancerous cell with the compound under conditions effective to destroy the contacted cancerous cell.
  • the cells to be destroyed can be located either in vivo or ex vivo (i.e., in culture).
  • a still further aspect of the present invention relates to a method of treating or preventing a cancerous condition that includes providing a compound of the present invention and then administering an effective amount of the compound to a patient in a manner effective to treat or prevent a cancerous condition.
  • the patient to be treated is characterized by the presence of a precancerous condition, and the administering of the compound is effective to prevent development of the precancerous condition into the cancerous condition. This can occur by destroying the precancerous cell prior to or concurrent with its further development into a cancerous state.
  • the patient to be treated is characterized by the presence of a cancerous condition, and the administering of the compound is effective either to cause regression of the cancerous condition or to inhibit growth of the cancerous condition, i.e., stopping its growth altogether or reducing its rate of growth.
  • This preferably occurs by destroying cancer cells, regardless of their location in the patient body. That is, whether the cancer cells are located at a primary tumor site or whether the cancer cells have metastasized and created secondary tumors within the patient body.
  • subject or patient refers to any mammalian patient, including without limitation, humans and other primates, dogs, cats, horses, cows, sheep, pigs, rats, mice, and other rodents.
  • the subject is male. In some embodiments, the subject is female. In some embodiments, while the methods as described herein may be useful for treating either males or females. [00266]
  • administering the compounds of the present invention they can be administered systemically or, alternatively, they can be administered directly to a specific site where cancer cells or precancerous cells are present. Thus, administering can be accomplished in any manner effective for delivering the compounds or the pharmaceutical compositions to the cancer cells or precancerous cells.
  • Exemplary modes of administration include, without limitation, administering the compounds or compositions orally, topically, transdermally, parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, intraocularly, intraarterially, intralesionally, or by application to mucous membranes, such as, that of the nose, throat, and bronchial tubes.
  • Splitting patterns are designated as s (singlet), d (doublet), dd (doublet of doublets), t (triplet), dt (doublet of triplets), q (quartet), m (multiplet) and br s (broad singlet).
  • the initial step involved a cyclization reaction between modified ⁇ -bromoketone analogues 19 and corresponding 2-aminobenzo[d]thiazole 21 affording substituted tricyclic benzo[d]imidazo[2,1- b]thiazole intermediates 22.
  • the carboxylic esters 22 were hydrolyzed under basic conditions such as aqueous lithium hydroxide to afford carboxylic acids 23.
  • Intermediates 25 were deprotected under acidic conditions such as hydrogen chloride in dioxane solution to generate final compounds 26.
  • Cross-coupling partners to introduce R 2 include various boronic acid / esters (Suzuki-Miyaura coupling) or various organostannane reagents (Stille coupling) to furnish the final compounds with various right-hand sides (RHS), Structure I (Scheme 6).
  • RHS right-hand sides
  • Scheme 7 Second generation synthesis of benzo[d]imidazo[2,1-b]thiazole compounds, Structure II.
  • the first step of the synthesis involves bromination of the ⁇ -carbonyl position of various substituted aryl methyl ketones 6 (Scheme 7), using pyridinium tribromide in the presence of HBr in acetic acid affording substituted phenacyl bromide intermediates 7 (Scheme 7).
  • These intermediates 7 facilitate ready diversification of the right-hand side (RHS) of the final compounds, Structure II.
  • the first step involves a “one-pot” alkylation and intramolecular cyclization reaction between substituted phenacyl bromide intermediates 7 (as in Scheme 7) and 2-amino-6- bromobenzothiazole 10 (Scheme 8) at elevated temperature affording 7-bromo-2-aryl- lbenzo[d]imidazo[2,1-b]thiazole intermediates 11 (Scheme 8).
  • the bromo heterocyclic intermediate 11 (Scheme 8) is employed as the key starting material for the final palladium-catalyzed aminocarbonylation reaction at elevated temperature.
  • Various primary ⁇ secondary amines are used in this final palladium-catalyzed aminocarbonylation reaction to provide a variety of left-hand side (LHS) amides, Structure II (Scheme 8).
  • LHS left-hand side
  • the first step of the synthesis proceeds via a Curtius Rearrangement, using diphenyl phosphoryl azide (DPPA) and tert-butanol in the presence of triethylamine at elevated temperature affording N-Boc amine intermediate 10 (Scheme 9).
  • DPPA diphenyl phosphoryl azide
  • tert-butanol in the presence of triethylamine at elevated temperature affording N-Boc amine intermediate 10 (Scheme 9).
  • N-Boc deprotection of intermediate 10 (Scheme 9) using a mixture of TFA in DCM enabled ready access to the 7-amino-2-aryl-lbenzo[d]imidazo[2,1- b]thiazole intermediate 11 (Scheme 9).
  • the fourth ⁇ -bromoketone analogues 28 were synthesized following the same synthetic sequence as in Scheme 10 using starting materials 26.
  • Scheme 17. General synthesis of benzo[d]imidazo[2,1-b]oxazole analogues 34.
  • 2-aminophenol compounds 29, were cyclized by reaction with cyanic bromide. A subsequent bromination reaction was performed to generate intermediates 31. This was followed by another cyclization with ⁇ -bromoketone analogues 8 at elevated temperature to generate intermediates 32. The bromide of intermediates 32 was converted to various amides via aminocarbonylation reaction to generate intermediates 33.
  • the N-Boc protecting group was removed using 4 N hydrochloride in 1,4-dioxane to produce the final benzo[d]imidazo[2,1-b]oxazole analogues 34 as a free base or a hydrochloride salt.
  • a Suzuki cross-coupling reaction of 80 with aromatic boronic acids or borates produced the final benzo[d]imidazo[2,1-b]thiazole analogues 81 as a free base or as the hydrochloride salt.
  • Scheme 30 General synthesis of benzo[d]imidazo[2,1-b]thiazole analogues 84. [00298] Final compounds 84 were synthesized from compounds 70 following the same synthetic sequence as in Scheme 26.
  • Scheme 31 General synthesis of benzo[d]imidazo[2,1-b]thiazole analogues 86.
  • An amide coupling reaction was performed on acids 83 with various amines to generate amides 85.
  • Scheme 34 General synthesis of imidazo[2,1-b]thiazole analogues 100. [00302] A cyclisation reaction with ketone 95 and thiourea gave 2-aminothiazole 96. The final compounds 100 were isolated as the free base or as the hydrochloride salt, following the same synthetic sequence applied in Scheme 26.
  • Scheme 35 General synthesis of imidazo[2,1-b]thiazole analogues 101. [00303] The N-Boc of compounds 98 was removed to generate compounds 101 as the free base or as a hydrochloride salt.
  • Scheme 37 General synthesis of benzo[d]imidazo[2,1-b]thiazole analogues 110.
  • Compounds 110 were synthesized from commercial available 5-methoxybenzo[d]thiazol-2- amine, 108, following the same synthetic sequence as in Scheme 26. The compounds were isolated as the free base or as the hydrochloride salt.
  • Scheme 38 General synthesis of benzo[d]imidazo[2,1-b]thiazole analogues 111.
  • Methyl group of compounds 109 was removed by tribromoborane to generate compounds 111 as the free base or as the hydrochloride salt.
  • the final compounds 139 were synthesized from intermediates 137 following the same synthetic sequence as in Scheme 26. The compounds were isolated as the free base or as the hydrochloride salt.
  • Scheme 44 General synthesis of imidazo[2,1-b]thiazole analogues 144. [00312] The final compounds 144 were synthesized from compounds 140 following the same synthetic sequence as in Scheme 26. The compounds were isolated as the free base or as the hydrochloride salt.
  • Scheme 49 Another alternative synthesis of benzo[d]imidazo[2,1-b]thiazole analogues 54.
  • ⁇ -bromoketone analogues 8 were synthesized from building blocks 1, following the same synthetic sequence described in Scheme 10.
  • the final compounds 54 were synthesized from ⁇ -bromoketone analogues 8 following the same synthetic sequence outlined in Scheme 26.
  • the compounds were isolated as the free base or as the hydrochloride salt.
  • Scheme 50 General synthesis of benzo[d]imidazo[2,1-b]thiazole analogues 173.
  • Benzyl alcohol intermediates 170 were synthesized from building blocks 1, following the same synthetic sequence described in Scheme 10.
  • Scheme 55 General synthesis of right-hand side fragment bromobenzene analogue 184.
  • Condensation reaction was performed on commercially available carboxylic acids, 2R/2S-1- (1,1-Dimethylethyl)-4-oxo-1,2-pyrrolidinedicarboxylate with 2-hydroxyisoindoline-1,3-dione to generate activated ester intermediate 182. It was followed by a cross-coupling reaction with compound 1 to generate ketone analogue 183. The ketone 183 was reduced to the cis alcohol intermediate 184.
  • Scheme 56 General synthesis of right-hand side fragment bromobenzene analogue 190.
  • the reaction solution was stirred for 16 h at 90°C under a nitrogen atmosphere.
  • the solution was cooled to room temperature and purified directly by reverse phase flash column chromatography with the following conditions; Column: Spherical C18, 20 - 40 um, 330 g; Mobile Phase A: water (plus 10 mmol ammonium bicarbonate); Mobile Phase B: acetonitrile; Flow rate: 80 mL/min; Gradient: 65% - 85% B in 20 min; Detector: UV 254 nm.
  • the reaction mixture was stirred for 16 h at 90°C.
  • the mixture was cooled to room temperature, diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL).
  • the combined organic layers were washed with water (3 x 20 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure.
  • N-methoxy-N-methylpropionamide (2.72 g, 23.22 mmol) was then added dropwise over 5 min. The resulting solution was stirred for 1 h. The solution was allowed to warm up to 0°C and quenched with water (100 mL). The resulting mixture was concentrated under reduced pressure to remove the organic solvent. The aqueous mixture was then extracted with ethyl acetate (2 x 200 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure.
  • the reaction solution was stirred for 2 h at room temperature.
  • the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL).
  • the combined organic layers were washed with brine (200 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (25% of ethyl acetate in petroleum ether) to afford 1-bromo-2-(2-methoxyethoxy)-4-nitrobenzene as a light yellow solid. Yield 5.10 g (81%).
  • the filtered cake was washed with ethyl acetate (3 x 50 mL).
  • the combined filtrate was concentrated under reduced pressure.
  • the residue was diluted with water (50 mL) and adjusted the pH to 7 with an aqueous solution of saturated sodium bicarbonate.
  • the resulting mixture was extracted with ethyl acetate (3 x 100 mL).
  • the combined organic phase was washed with brine (200 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford 4-bromo-3-(2-methoxyethoxy)aniline as an orange oil. Yield (2.20 g, 82%).
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was basified to pH 7 with an aqueous solution of saturated sodium bicarbonate.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by reverse phase flash column chromatography with the following conditions; column, C18 silica gel, 20-40 um, 120 g; Mobile phase A: water (10 mmol/L ammonium bicarbonate); Mobile phase B: acetonitrile; Gradient: 30% - 50% B in 25 min; Flow rate: 60 mL/min; Detector, UV 254 nm.
  • the reaction mixture was cooled to room temperature and quenched with ice/water (10 mL).
  • the pH of the aqueous solution was adjusted to 9 with 3 N aqueous sodium hydroxide.
  • Methanol (10 mL) was added, followed by di-tert-butyl dicarbonate (400 mg, 1.833 mmol) as a single portion.
  • the reaction solution was stirred for an additional 2 h at room temperature.
  • the pH was readjusted to 5 with 1 N aqueous hydrochloric acid.
  • the solution was concentrated under reduced pressure to remove methanol and the resulting solid collected by vacuum filtration.
  • tert-butyl 2-oxopyrrolidine-1-carboxylate (7.50 g, 40.49 mmol) was added portion wise over 5 min.
  • the reaction solution was warmed to room temperature and stirred for an additional 16 h.
  • the reaction was quenched with saturated aqueous ammonium chloride (200 mL).
  • the resulting mixture was extracted with ethyl acetate (3 ⁇ 200 mL).
  • the combined organic layers were washed with brine (300 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure.
  • the reaction mixture was heated to 60°C and stirred for an additional 5 h.
  • the reaction mixture was cooled to room temperature and concentrated under reduced pressure.
  • the residue was triturated with ethyl acetate (200 mL) for 30 min. After filtration, the filtrate was concentrated under reduced pressure again.
  • the residue was dissolved in methanol (100 mL).
  • the reaction solution was stirred for an additional 2 h at room temperature.
  • the reaction mixture was concentrated under reduced pressure.
  • the reaction mixture was stirred for 4 h at 70°C.
  • the mixture was cooled to room temperature, diluted with water (500 mL) and extracted with ethyl acetate (3 ⁇ 300 mL).
  • the combined organic layers were washed with brine (300 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (25% ethyl acetate in petroleum ether) to afford tert-butyl 4-(4-bromo-3- fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate as a white oil. Yield 16.00 g (90%).
  • reaction solution was stirred for an additional 30 min.
  • the reaction solution was purified directly by reverse phase flash chromatography using the following conditions; Column: Spherical C18, 20 - 40 um, 330 g; Mobile Phase A: water (plus 10 mM ammonium bicarbonate); Mobile Phase B: acetonitrile; Flow rate: 60 mL/min; Gradient: 60% - 80% B in 20 min; UV Detector: 254 nm.
  • the reaction mixture was diluted with brine (800 mL) and extracted with ethyl acetate (4 ⁇ 600 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1%-20% ethyl acetate in petroleum ether) to afford tert-butyl 2-(4-bromo-3-fluorophenyl)-4-oxopyrrolidine-1-carboxylate as a yellow oil. Yield 8.50 g (32%).
  • A549 cells are incubated with active compounds and metabolically labelled with fluorescent methionine for a 4 hour pulse (click-chemistry modified methionine). Cells are fixed and newly synthesized proteins detected by using click-chemistry with a fluorescent detector. [00517] A549 cells are incubated with compounds for 24 hours and c-Myc protein is detected by immunofluorescence.
  • A549 cells are incubated with compounds for 4 hours and c-Myc mRNA is visualized by micrscopy using c-Myc mRNA specific fluorescent-tagged probes.
  • A549 human non-small cell lung carcinoma cells are treated for 24 hours with increasing compound concentration, cells are fixed and stained with a nuclei stain (DAPI) and anti-c-Myc fluorescent antibody.
  • DAPI nuclei stain
  • the c-Myc signal is quantified by image analysis, and data is exported and analyzed using TIBCO Spotfire® (TIBCO Corporation). Dose response curves are generated and fitted with logaristic regression to calculate potency (EC 50 values).
  • EXAMPLE 5 In vivo activity of compounds of the invention A549 xenograft model in nude mice.
  • NMRI nude female mice of 6-8 weeks of age are acclimated after shipping for > 4 days.
  • A549 cells 5 x 10 6 in 100 ul Matrigel:PBS (50:50), are subcutaneously injected into flanks of mice. When the tumor size reaches 80 to 200 mm 3 , mice are grouped with similar average tumor size in each group, 10 animals per group.
  • Compounds are dissolved in 10% DMSO, 10% Solutol, 80% water. Compounds are given i.p. for 49 days at 3 mg/kg twice a week. Caliper measurement of tumor size are done twice a week.
  • Positive hits are re-screened in the specific PSM assay, using tRNAgln and tRNAser. Hits are scored using Anima’s proprietary algorithms, and compounds, which selectively inhibit c-Myc synthesis in specific PSM assay, are selected as confirmed hits. These compounds are purchased as powder to confirm activity. Re-purchased hits are tested in the specific PSM assay (tRNAgln-tRNAser) and anti-c-Myc immunofluorescence, and in counter assays to eliminate global translation modulators: (1) bulk tRNA and (2) metabolic labeling using Click-ITTM AHA (L-Azidohomoalanine).
  • A549 cells (ATCC ® CCL-185 TM ) are maintained in DMEM low glucose medium (Biological Industries, Cat. 01-050-1A), containing 10% fetal bovine serum, 1% L-glutamine and 1% penicillin- streptomycin solution.
  • SK-N-F1 cells (ATCC ® CRL-2142 TM ) are maintained in DMEM high glucose medium (Biological Industries, Cat. 01-055-1A), containing 10% fetal bovine serum, 2% L-glutamine, 1% penicillin-streptomycin solution, 1% sodium pyruvate and 1% non-essential amino acids.
  • tRNA isoacceptor isolation and labeling [00524]
  • the specific tRNAgln (TTG) and tRNAser (CGA) are isolated for from baker’s yeast (Roche) using biotinylated oligos complimentary to sequences encompassing the D-loop and anti-codon.
  • the biotinylated oligos are mixed with total yeast tRNA and heat up to 82°C for 10 min, followed by addition of TMA buffer (20mM Tris, pH 7.6,1.8M tetramethylammonium chloride, 0.2mM EDTA). The mixture is incubated at 68°C for 10 min, and annealed by slow cooling to 37°C.
  • tRNA:DNA oligo mixture then is incubated with streptavidin linked agarose beads at room temperature for 30 min while shaking. Unbound tRNA and tRNA:DNA complexes are removed by centrifugation and beads are washed with 10mM Tris- HCl (pH 7.6). The target tRNA is eluted from the resin by incubation at 45°C or 55°C for 7 min followed by centrifugation and collection of the supernatant to clean tubes. [00525] The purity of the isolated tRNA isoacceptors is confirmed using fluorescent polarization assay. Purified tRNA is annealed to a complementary oligo tagged at the 3’-end with Cy3.
  • the annealed purified tRNA isoacceptor FP signal is compared to the signal derived from annealing of a tRNA isoacceptor oligo annealed to the same Cy3-oligo. Samples with more than 80% purity are selected for labeling.
  • the dihydrouridines of the target tRNAs or total yeast tRNA are labeled as described in U.S. Pat. No.8,785,119. Labeled tRNAs are purified by reverse phase HPLC and eluted with an ethanol gradient.
  • Protein synthesis monitoring (PSM) Assays [00527] Cy3 and Cy5 Labeled tRNA, bulk or specific, are transfected with 0.4 ⁇ l HiPerFect (Qiagen) per 384 well. First, HiPerFect is mixed with DMEM and incubated for 5 min; next, 6 nanograms Cy3- labeled tRNAgln and 6 ng Cy5-labled tRNAser (or 9 ng each Cy3 and Cy5-labelled bulk tRNA) are diluted in 1xPBS and then added to the HiPerFect:DMEM cocktail and incubated at room temperature for 10 min. The transfection mixture is dispersed automatically into 384-well black plates.
  • HiPerFect Qiagen
  • Cells are then seeded at 3,500 cells per well in complete culture medium and incubated at 37°C, 5% CO2. Forty-eight hours after transfection compounds are added at a final concentration of 30 ⁇ M. Four hours post-treatment, cells are fixed with 4% paraformaldehyde and images are captured with Operetta microscope (Perkin Elmer) using x20 high NA objective lens. Metabolic labeling assay [00528] A549 cells are seeded at 3,200 cells per well in complete culture medium. Plates are incubated at 37°C, 5% CO2 overnight. After 48 hours of incubation, the growth medium is aspirated, and cells are washed three times with HBSS.
  • Metabolic labeling medium DMEM (-Cys -Met), containing 10% dialyzed FBS, 1% pencillin-streptomycin and 1% L-glutamine is added to the cells for 30 min. Then medium is replaced by metabolic labeling medium containing 25 ⁇ M L-Azidohomoalanine (AHA, ThermoFisher) and tested compounds at a final concentration of 30 ⁇ M, and cells are incubated for 4 hours at 37°C, 5% CO2. Cells are washed by HBSS at 37°C for 15 min before fixing with 4% paraformaldehyde.
  • AHA L-Azidohomoalanine
  • FISH Fluorescent In Situ Hybridization
  • RNA FISH experiments Following RNA FISH experiments, images of cells are taken with Operetta (Perkin Elmer, USA), a wide-field fluorescence microscope at x63 magnification. After acquisition, the images are transferred to Columbus software for image analysis. In Columbus, cells are identified by their nucleus, using the “Find Nuceli” module, cytoplasm is detected based on the FISH-channel, and single mRNAs in the cytoplasm and transcription sites in the nucleus are detected using “Find Spots” module. Subsequently, fluorescent signals are collected for each channel in the identified regions: nucleus, cytoplasm and spots. Data is exported to a data analysis and visualization software, Tibco Spotfire, USA. A549 xenograft model in nude mice.
  • NMRI nude female mice of 6-8 weeks of age are acclimated after shipping for > 4 days.
  • A549 cells 5 x 10 6 in 100 ul Matrigel:PBS (50:50), are subcutaneously injected into flanks of mice. When the tumor size reached 80 to 200 mm 3 , mice are grouped with similar average tumor size in each group, 10 animals per group.
  • Compounds are dissolved in 10% DMSO, 10% Solutol, 80% water. Compounds are given i.p. for 49 days at 3 mg/kg twice a week. Caliper measurement of tumor size is done twice a week.

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Abstract

La présente invention concerne de nouveaux modulateurs de traduction d'ARNm c-MYC, une composition et des procédés de préparation de ceux-ci, et leurs utilisations dans le traitement du cancer.
PCT/US2023/026827 2022-07-03 2023-07-02 Modulateurs de traduction d'arnm c-myc et leurs utilisations dans le traitement du cancer WO2024010761A1 (fr)

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