WO2024040045A2 - 2-diarylmethyl-4-aminotetrahydropyran sulfonimidamides as anticancer, antiinflammatory, antifibrotic and neuroprotective agents - Google Patents
2-diarylmethyl-4-aminotetrahydropyran sulfonimidamides as anticancer, antiinflammatory, antifibrotic and neuroprotective agents Download PDFInfo
- Publication number
- WO2024040045A2 WO2024040045A2 PCT/US2023/072200 US2023072200W WO2024040045A2 WO 2024040045 A2 WO2024040045 A2 WO 2024040045A2 US 2023072200 W US2023072200 W US 2023072200W WO 2024040045 A2 WO2024040045 A2 WO 2024040045A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- disease
- pp2a
- compounds
- administering
- Prior art date
Links
- 230000003510 anti-fibrotic effect Effects 0.000 title description 3
- 230000001093 anti-cancer Effects 0.000 title description 2
- 230000003110 anti-inflammatory effect Effects 0.000 title description 2
- 239000004090 neuroprotective agent Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 184
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 106
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 75
- 238000011282 treatment Methods 0.000 claims abstract description 44
- 201000011510 cancer Diseases 0.000 claims abstract description 32
- 230000011664 signaling Effects 0.000 claims abstract description 15
- 230000035945 sensitivity Effects 0.000 claims abstract description 8
- 238000000034 method Methods 0.000 claims description 94
- 239000000203 mixture Substances 0.000 claims description 87
- 201000010099 disease Diseases 0.000 claims description 65
- 229910052739 hydrogen Inorganic materials 0.000 claims description 64
- 208000035475 disorder Diseases 0.000 claims description 40
- 229910052731 fluorine Inorganic materials 0.000 claims description 37
- 239000001257 hydrogen Substances 0.000 claims description 36
- 125000000217 alkyl group Chemical group 0.000 claims description 31
- 150000002431 hydrogen Chemical group 0.000 claims description 22
- 230000008482 dysregulation Effects 0.000 claims description 20
- 229910052736 halogen Inorganic materials 0.000 claims description 20
- 150000002367 halogens Chemical group 0.000 claims description 20
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 19
- 229910052801 chlorine Inorganic materials 0.000 claims description 19
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 17
- 239000007787 solid Substances 0.000 claims description 17
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 16
- 239000002246 antineoplastic agent Substances 0.000 claims description 15
- 229910052717 sulfur Inorganic materials 0.000 claims description 15
- 230000019491 signal transduction Effects 0.000 claims description 14
- 125000006771 (C1-C6) haloalkylthio group Chemical group 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 13
- 229910052794 bromium Inorganic materials 0.000 claims description 13
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 13
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 13
- 208000023275 Autoimmune disease Diseases 0.000 claims description 11
- 102000006478 Protein Phosphatase 2 Human genes 0.000 claims description 11
- 108010058956 Protein Phosphatase 2 Proteins 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 9
- 206010019280 Heart failures Diseases 0.000 claims description 9
- 208000019693 Lung disease Diseases 0.000 claims description 9
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 9
- 125000000623 heterocyclic group Chemical group 0.000 claims description 9
- 208000002874 Acne Vulgaris Diseases 0.000 claims description 8
- 206010000496 acne Diseases 0.000 claims description 8
- 206010012601 diabetes mellitus Diseases 0.000 claims description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
- 210000000056 organ Anatomy 0.000 claims description 8
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 8
- 206010007572 Cardiac hypertrophy Diseases 0.000 claims description 7
- 208000006029 Cardiomegaly Diseases 0.000 claims description 7
- 208000019022 Mood disease Diseases 0.000 claims description 6
- 208000030852 Parasitic disease Diseases 0.000 claims description 6
- 208000036142 Viral infection Diseases 0.000 claims description 6
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 6
- 229940127089 cytotoxic agent Drugs 0.000 claims description 6
- 230000004968 inflammatory condition Effects 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 206010052779 Transplant rejections Diseases 0.000 claims description 5
- 230000001419 dependent effect Effects 0.000 claims description 5
- 208000030159 metabolic disease Diseases 0.000 claims description 5
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 4
- 208000012902 Nervous system disease Diseases 0.000 claims description 4
- 208000025966 Neurological disease Diseases 0.000 claims description 4
- 208000016097 disease of metabolism Diseases 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 230000002503 metabolic effect Effects 0.000 claims description 4
- 230000009385 viral infection Effects 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 2
- 239000005977 Ethylene Substances 0.000 claims description 2
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 34
- 101001059929 Caenorhabditis elegans Forkhead box protein O Proteins 0.000 abstract description 17
- 239000003814 drug Substances 0.000 abstract description 10
- 238000002512 chemotherapy Methods 0.000 abstract description 9
- 229940079593 drug Drugs 0.000 abstract description 9
- 230000001413 cellular effect Effects 0.000 abstract description 8
- 102000040945 Transcription factor Human genes 0.000 abstract description 7
- 108091023040 Transcription factor Proteins 0.000 abstract description 7
- 238000013518 transcription Methods 0.000 abstract description 6
- 230000035897 transcription Effects 0.000 abstract description 6
- 108091000080 Phosphotransferase Proteins 0.000 abstract description 5
- 102000020233 phosphotransferase Human genes 0.000 abstract description 5
- 108010040002 Tumor Suppressor Proteins Proteins 0.000 abstract description 3
- 102000001742 Tumor Suppressor Proteins Human genes 0.000 abstract description 3
- 230000003213 activating effect Effects 0.000 abstract description 3
- 230000001028 anti-proliverative effect Effects 0.000 abstract description 3
- 238000009097 single-agent therapy Methods 0.000 abstract description 3
- 101150022024 MYCN gene Proteins 0.000 abstract description 2
- 231100000590 oncogenic Toxicity 0.000 abstract description 2
- 230000002246 oncogenic effect Effects 0.000 abstract description 2
- 101000741929 Caenorhabditis elegans Serine/threonine-protein phosphatase 2A catalytic subunit Proteins 0.000 abstract 3
- 108700012912 MYCN Proteins 0.000 abstract 1
- 102000055056 N-Myc Proto-Oncogene Human genes 0.000 abstract 1
- 108700026495 N-Myc Proto-Oncogene Proteins 0.000 abstract 1
- 230000005945 translocation Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 52
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 40
- 210000004027 cell Anatomy 0.000 description 40
- -1 cachets Substances 0.000 description 34
- 230000004913 activation Effects 0.000 description 26
- 239000000543 intermediate Substances 0.000 description 26
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 18
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 description 17
- 229940093499 ethyl acetate Drugs 0.000 description 17
- 235000019439 ethyl acetate Nutrition 0.000 description 17
- 150000002500 ions Chemical class 0.000 description 17
- 239000000243 solution Substances 0.000 description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- 210000002950 fibroblast Anatomy 0.000 description 16
- 150000003839 salts Chemical class 0.000 description 16
- 238000003786 synthesis reaction Methods 0.000 description 16
- 230000015572 biosynthetic process Effects 0.000 description 15
- 108090000623 proteins and genes Proteins 0.000 description 15
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 14
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 14
- 239000000460 chlorine Substances 0.000 description 13
- 238000003818 flash chromatography Methods 0.000 description 13
- 230000026731 phosphorylation Effects 0.000 description 12
- 238000006366 phosphorylation reaction Methods 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 11
- 238000009472 formulation Methods 0.000 description 11
- 230000001105 regulatory effect Effects 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- 108010009306 Forkhead Box Protein O1 Proteins 0.000 description 10
- 102100035427 Forkhead box protein O1 Human genes 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 10
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 10
- 150000001412 amines Chemical class 0.000 description 10
- 238000004020 luminiscence type Methods 0.000 description 10
- 230000001225 therapeutic effect Effects 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 241000282414 Homo sapiens Species 0.000 description 9
- 206010025323 Lymphomas Diseases 0.000 description 9
- 102000009572 RNA Polymerase II Human genes 0.000 description 9
- 108010009460 RNA Polymerase II Proteins 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- 210000004072 lung Anatomy 0.000 description 9
- 102000004169 proteins and genes Human genes 0.000 description 9
- 229940124530 sulfonamide Drugs 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 9
- 108010035532 Collagen Proteins 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
- 206010060862 Prostate cancer Diseases 0.000 description 8
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 8
- 208000009956 adenocarcinoma Diseases 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 230000006870 function Effects 0.000 description 8
- 230000001404 mediated effect Effects 0.000 description 8
- 229940073584 methylene chloride Drugs 0.000 description 8
- 210000003289 regulatory T cell Anatomy 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 230000002103 transcriptional effect Effects 0.000 description 8
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 7
- 208000024827 Alzheimer disease Diseases 0.000 description 7
- 206010006187 Breast cancer Diseases 0.000 description 7
- 208000026310 Breast neoplasm Diseases 0.000 description 7
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 7
- 102000008186 Collagen Human genes 0.000 description 7
- 102000045595 Phosphoprotein Phosphatases Human genes 0.000 description 7
- 108700019535 Phosphoprotein Phosphatases Proteins 0.000 description 7
- 206010039491 Sarcoma Diseases 0.000 description 7
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 7
- 229920001436 collagen Polymers 0.000 description 7
- 239000002552 dosage form Substances 0.000 description 7
- 238000001704 evaporation Methods 0.000 description 7
- 230000008020 evaporation Effects 0.000 description 7
- 239000011737 fluorine Substances 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 230000004770 neurodegeneration Effects 0.000 description 7
- 208000005069 pulmonary fibrosis Diseases 0.000 description 7
- 150000003456 sulfonamides Chemical class 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- 238000002560 therapeutic procedure Methods 0.000 description 7
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 6
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 6
- 239000012190 activator Substances 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 6
- 230000006907 apoptotic process Effects 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 208000006673 asthma Diseases 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 230000012010 growth Effects 0.000 description 6
- 150000002430 hydrocarbons Chemical class 0.000 description 6
- 208000015122 neurodegenerative disease Diseases 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 6
- 230000002441 reversible effect Effects 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- 208000024891 symptom Diseases 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 108091005625 BRD4 Proteins 0.000 description 5
- 102100029895 Bromodomain-containing protein 4 Human genes 0.000 description 5
- DPBACUHIFPKXML-UHFFFAOYSA-N COC1=CC(=C(C=C1)CNS(=O)C2=CC=C(C=C2)OC(F)(F)F)OC Chemical group COC1=CC(=C(C=C1)CNS(=O)C2=CC=C(C=C2)OC(F)(F)F)OC DPBACUHIFPKXML-UHFFFAOYSA-N 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 5
- 206010016654 Fibrosis Diseases 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 230000009286 beneficial effect Effects 0.000 description 5
- 230000008901 benefit Effects 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 230000004663 cell proliferation Effects 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 125000000753 cycloalkyl group Chemical group 0.000 description 5
- 238000010511 deprotection reaction Methods 0.000 description 5
- 230000004761 fibrosis Effects 0.000 description 5
- 239000001963 growth medium Substances 0.000 description 5
- 229930195733 hydrocarbon Natural products 0.000 description 5
- 208000032839 leukemia Diseases 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 206010041823 squamous cell carcinoma Diseases 0.000 description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 5
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- 239000004215 Carbon black (E152) Substances 0.000 description 4
- 201000009030 Carcinoma Diseases 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- 208000032612 Glial tumor Diseases 0.000 description 4
- 206010018338 Glioma Diseases 0.000 description 4
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical group C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
- 206010024612 Lipoma Diseases 0.000 description 4
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical group N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
- 210000001744 T-lymphocyte Anatomy 0.000 description 4
- 108010065850 Tristetraprolin Proteins 0.000 description 4
- 241000700605 Viruses Species 0.000 description 4
- 230000001594 aberrant effect Effects 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 4
- 125000001309 chloro group Chemical group Cl* 0.000 description 4
- 230000001086 cytosolic effect Effects 0.000 description 4
- 230000002950 deficient Effects 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical group C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 4
- 230000027928 long-term synaptic potentiation Effects 0.000 description 4
- 102100031622 mRNA decay activator protein ZFP36 Human genes 0.000 description 4
- 201000001441 melanoma Diseases 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 230000007170 pathology Effects 0.000 description 4
- 230000037361 pathway Effects 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 230000001737 promoting effect Effects 0.000 description 4
- 210000002307 prostate Anatomy 0.000 description 4
- 208000016691 refractory malignant neoplasm Diseases 0.000 description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 description 4
- 150000003384 small molecules Chemical class 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 230000000946 synaptic effect Effects 0.000 description 4
- 102000013498 tau Proteins Human genes 0.000 description 4
- 108010026424 tau Proteins Proteins 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 230000000699 topical effect Effects 0.000 description 4
- 238000001890 transfection Methods 0.000 description 4
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 4
- QOWBXWFYRXSBAS-UHFFFAOYSA-N (2,4-dimethoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C(OC)=C1 QOWBXWFYRXSBAS-UHFFFAOYSA-N 0.000 description 3
- 101710137189 Amyloid-beta A4 protein Proteins 0.000 description 3
- 102100022704 Amyloid-beta precursor protein Human genes 0.000 description 3
- 101710151993 Amyloid-beta precursor protein Proteins 0.000 description 3
- 102100032187 Androgen receptor Human genes 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- 108090000695 Cytokines Proteins 0.000 description 3
- 102000004127 Cytokines Human genes 0.000 description 3
- 241000701022 Cytomegalovirus Species 0.000 description 3
- 206010012335 Dependence Diseases 0.000 description 3
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 3
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 3
- 201000008808 Fibrosarcoma Diseases 0.000 description 3
- 102000009562 Forkhead Box Protein O3 Human genes 0.000 description 3
- 108010009307 Forkhead Box Protein O3 Proteins 0.000 description 3
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 3
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 3
- 208000000172 Medulloblastoma Diseases 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 206010049567 Miller Fisher syndrome Diseases 0.000 description 3
- 102100038895 Myc proto-oncogene protein Human genes 0.000 description 3
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical group C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 3
- 238000006434 Ritter amidation reaction Methods 0.000 description 3
- 206010043276 Teratoma Diseases 0.000 description 3
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- DZHSAHHDTRWUTF-SIQRNXPUSA-N amyloid-beta polypeptide 42 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(C)C)C1=CC=CC=C1 DZHSAHHDTRWUTF-SIQRNXPUSA-N 0.000 description 3
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 3
- 108010080146 androgen receptors Proteins 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 208000029560 autism spectrum disease Diseases 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000000481 breast Anatomy 0.000 description 3
- 125000002837 carbocyclic group Chemical group 0.000 description 3
- 229950005499 carbon tetrachloride Drugs 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 230000010261 cell growth Effects 0.000 description 3
- 230000003833 cell viability Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 230000008021 deposition Effects 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 238000003745 diagnosis Methods 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000012091 fetal bovine serum Substances 0.000 description 3
- 206010016629 fibroma Diseases 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 208000005017 glioblastoma Diseases 0.000 description 3
- 208000024908 graft versus host disease Diseases 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 201000011066 hemangioma Diseases 0.000 description 3
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 3
- 235000011167 hydrochloric acid Nutrition 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 230000006698 induction Effects 0.000 description 3
- 230000002757 inflammatory effect Effects 0.000 description 3
- 230000028709 inflammatory response Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 208000020816 lung neoplasm Diseases 0.000 description 3
- 208000010658 metastatic prostate carcinoma Diseases 0.000 description 3
- 238000010172 mouse model Methods 0.000 description 3
- 230000000626 neurodegenerative effect Effects 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 3
- 230000005937 nuclear translocation Effects 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 201000008968 osteosarcoma Diseases 0.000 description 3
- 230000008506 pathogenesis Effects 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 235000021317 phosphate Nutrition 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 238000005086 pumping Methods 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 230000028327 secretion Effects 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 229960005322 streptomycin Drugs 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 239000011593 sulfur Substances 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- 229960003604 testosterone Drugs 0.000 description 3
- 150000003536 tetrazoles Chemical class 0.000 description 3
- 229930192474 thiophene Natural products 0.000 description 3
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical group C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- 102000004899 14-3-3 Proteins Human genes 0.000 description 2
- UHCDBMIOLNKDHG-UHFFFAOYSA-N 4-(trifluoromethoxy)benzenesulfonyl chloride Chemical compound FC(F)(F)OC1=CC=C(S(Cl)(=O)=O)C=C1 UHCDBMIOLNKDHG-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 2
- 230000007730 Akt signaling Effects 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 201000003076 Angiosarcoma Diseases 0.000 description 2
- 102000013918 Apolipoproteins E Human genes 0.000 description 2
- 108010025628 Apolipoproteins E Proteins 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241000701822 Bovine papillomavirus Species 0.000 description 2
- 208000003170 Bronchiolo-Alveolar Adenocarcinoma Diseases 0.000 description 2
- 238000003734 CellTiter-Glo Luminescent Cell Viability Assay Methods 0.000 description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 206010014733 Endometrial cancer Diseases 0.000 description 2
- 206010014759 Endometrial neoplasm Diseases 0.000 description 2
- 102000016359 Fibronectins Human genes 0.000 description 2
- 108010067306 Fibronectins Proteins 0.000 description 2
- 201000011240 Frontotemporal dementia Diseases 0.000 description 2
- 208000035895 Guillain-Barré syndrome Diseases 0.000 description 2
- 208000031886 HIV Infections Diseases 0.000 description 2
- 208000002927 Hamartoma Diseases 0.000 description 2
- 208000001258 Hemangiosarcoma Diseases 0.000 description 2
- 241000711549 Hepacivirus C Species 0.000 description 2
- 102100021454 Histone deacetylase 4 Human genes 0.000 description 2
- 108010025076 Holoenzymes Proteins 0.000 description 2
- 101000899259 Homo sapiens Histone deacetylase 4 Proteins 0.000 description 2
- 241000714260 Human T-lymphotropic virus 1 Species 0.000 description 2
- 241000700588 Human alphaherpesvirus 1 Species 0.000 description 2
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 2
- 241000701806 Human papillomavirus Species 0.000 description 2
- 241000829111 Human polyomavirus 1 Species 0.000 description 2
- 208000023105 Huntington disease Diseases 0.000 description 2
- 206010020880 Hypertrophy Diseases 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 208000007766 Kaposi sarcoma Diseases 0.000 description 2
- 208000018142 Leiomyosarcoma Diseases 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 241000829100 Macaca mulatta polyomavirus 1 Species 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000700560 Molluscum contagiosum virus Species 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 208000034578 Multiple myelomas Diseases 0.000 description 2
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 206010029260 Neuroblastoma Diseases 0.000 description 2
- 201000004404 Neurofibroma Diseases 0.000 description 2
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- 208000018737 Parkinson disease Diseases 0.000 description 2
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 2
- 201000004681 Psoriasis Diseases 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical group C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 241000725643 Respiratory syncytial virus Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 208000000453 Skin Neoplasms Diseases 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- 208000003721 Triple Negative Breast Neoplasms Diseases 0.000 description 2
- 208000008383 Wilms tumor Diseases 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 230000032683 aging Effects 0.000 description 2
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 2
- 208000028004 allergic respiratory disease Diseases 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 230000001363 autoimmune Effects 0.000 description 2
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 2
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 231100000504 carcinogenesis Toxicity 0.000 description 2
- 208000002458 carcinoid tumor Diseases 0.000 description 2
- 230000022131 cell cycle Effects 0.000 description 2
- 230000024245 cell differentiation Effects 0.000 description 2
- 238000001516 cell proliferation assay Methods 0.000 description 2
- 238000012054 celltiter-glo Methods 0.000 description 2
- 230000010094 cellular senescence Effects 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 239000012887 cigarette smoke extract Substances 0.000 description 2
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 238000004891 communication Methods 0.000 description 2
- 239000013058 crude material Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000002939 deleterious effect Effects 0.000 description 2
- 230000030609 dephosphorylation Effects 0.000 description 2
- 238000006209 dephosphorylation reaction Methods 0.000 description 2
- 230000006866 deterioration Effects 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 230000008029 eradication Effects 0.000 description 2
- 210000002744 extracellular matrix Anatomy 0.000 description 2
- 230000003176 fibrotic effect Effects 0.000 description 2
- 229960000556 fingolimod Drugs 0.000 description 2
- KKGQTZUTZRNORY-UHFFFAOYSA-N fingolimod Chemical compound CCCCCCCCC1=CC=C(CCC(N)(CO)CO)C=C1 KKGQTZUTZRNORY-UHFFFAOYSA-N 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 230000005746 immune checkpoint blockade Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000002779 inactivation Effects 0.000 description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Chemical group CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Chemical group C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 208000027866 inflammatory disease Diseases 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 201000010260 leiomyoma Diseases 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 230000004807 localization Effects 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 230000003211 malignant effect Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 206010027191 meningioma Diseases 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- 201000006417 multiple sclerosis Diseases 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000030648 nucleus localization Effects 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 230000002611 ovarian Effects 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 230000029279 positive regulation of transcription, DNA-dependent Effects 0.000 description 2
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000000750 progressive effect Effects 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 230000007115 recruitment Effects 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 238000000611 regression analysis Methods 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- JJLZHSLAFQPNON-UHFFFAOYSA-M sodium;4-(trifluoromethoxy)benzenesulfinate Chemical compound [Na+].[O-]S(=O)C1=CC=C(OC(F)(F)F)C=C1 JJLZHSLAFQPNON-UHFFFAOYSA-M 0.000 description 2
- 230000004960 subcellular localization Effects 0.000 description 2
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 238000007910 systemic administration Methods 0.000 description 2
- IXZDIALLLMRYOU-UHFFFAOYSA-N tert-butyl hypochlorite Chemical compound CC(C)(C)OCl IXZDIALLLMRYOU-UHFFFAOYSA-N 0.000 description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 208000022679 triple-negative breast carcinoma Diseases 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- QRWQFOHBHHIZKG-UHFFFAOYSA-N 1$l^{6},3$l^{6},2-benzodithiazole 1,1,3,3-tetraoxide Chemical compound C1=CC=C2S(=O)(=O)NS(=O)(=O)C2=C1 QRWQFOHBHHIZKG-UHFFFAOYSA-N 0.000 description 1
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 description 1
- 108700020469 14-3-3 Proteins 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 1
- ITJCKQTXCLGXHE-UHFFFAOYSA-N 2-amino-4-(4-heptoxyphenyl)-2-methylbutan-1-ol Chemical compound CCCCCCCOC1=CC=C(CCC(C)(N)CO)C=C1 ITJCKQTXCLGXHE-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- ZSPTYLOMNJNZNG-UHFFFAOYSA-N 3-Buten-1-ol Chemical compound OCCC=C ZSPTYLOMNJNZNG-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- MCSXGCZMEPXKIW-UHFFFAOYSA-N 3-hydroxy-4-[(4-methyl-2-nitrophenyl)diazenyl]-N-(3-nitrophenyl)naphthalene-2-carboxamide Chemical compound Cc1ccc(N=Nc2c(O)c(cc3ccccc23)C(=O)Nc2cccc(c2)[N+]([O-])=O)c(c1)[N+]([O-])=O MCSXGCZMEPXKIW-UHFFFAOYSA-N 0.000 description 1
- PZXJQYIGXNJVCU-UHFFFAOYSA-N 4-(trifluoromethoxy)benzenesulfinyl chloride Chemical compound FC(F)(F)OC1=CC=C(S(Cl)=O)C=C1 PZXJQYIGXNJVCU-UHFFFAOYSA-N 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- BMVWCPGVLSILMU-UHFFFAOYSA-N 5,6-dihydrodibenzo[2,1-b:2',1'-f][7]annulen-11-one Chemical compound C1CC2=CC=CC=C2C(=O)C2=CC=CC=C21 BMVWCPGVLSILMU-UHFFFAOYSA-N 0.000 description 1
- KQROHCSYOGBQGJ-UHFFFAOYSA-N 5-Hydroxytryptophol Chemical compound C1=C(O)C=C2C(CCO)=CNC2=C1 KQROHCSYOGBQGJ-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 102100036732 Actin, aortic smooth muscle Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 208000026872 Addison Disease Diseases 0.000 description 1
- 206010001233 Adenoma benign Diseases 0.000 description 1
- 102100026882 Alpha-synuclein Human genes 0.000 description 1
- 208000037259 Amyloid Plaque Diseases 0.000 description 1
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 1
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 206010003497 Asphyxia Diseases 0.000 description 1
- 206010003571 Astrocytoma Diseases 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 102000008096 B7-H1 Antigen Human genes 0.000 description 1
- 108010074708 B7-H1 Antigen Proteins 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- 208000023328 Basedow disease Diseases 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 206010073106 Bone giant cell tumour malignant Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 102000001805 Bromodomains Human genes 0.000 description 1
- 108050009021 Bromodomains Proteins 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- IREOPUAVDQEJPY-UHFFFAOYSA-N CNS(=O)C1=CC=C(C=C1)OC(F)(F)F Chemical compound CNS(=O)C1=CC=C(C=C1)OC(F)(F)F IREOPUAVDQEJPY-UHFFFAOYSA-N 0.000 description 1
- 102100031625 CTTNBP2 N-terminal-like protein Human genes 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 208000009458 Carcinoma in Situ Diseases 0.000 description 1
- 206010008263 Cervical dysplasia Diseases 0.000 description 1
- 201000005262 Chondroma Diseases 0.000 description 1
- 208000005243 Chondrosarcoma Diseases 0.000 description 1
- 201000009047 Chordoma Diseases 0.000 description 1
- 208000006332 Choriocarcinoma Diseases 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- 208000015943 Coeliac disease Diseases 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 102100033601 Collagen alpha-1(I) chain Human genes 0.000 description 1
- 102100031611 Collagen alpha-1(III) chain Human genes 0.000 description 1
- 102100036213 Collagen alpha-2(I) chain Human genes 0.000 description 1
- 206010048832 Colon adenoma Diseases 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 102100031725 Cortactin-binding protein 2 Human genes 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 102100026810 Cyclin-dependent kinase 7 Human genes 0.000 description 1
- 102100024457 Cyclin-dependent kinase 9 Human genes 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 208000007033 Dysgerminoma Diseases 0.000 description 1
- 208000000471 Dysplastic Nevus Syndrome Diseases 0.000 description 1
- 201000009051 Embryonal Carcinoma Diseases 0.000 description 1
- 102100030013 Endoribonuclease Human genes 0.000 description 1
- 101710199605 Endoribonuclease Proteins 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010014954 Eosinophilic fasciitis Diseases 0.000 description 1
- 206010014967 Ependymoma Diseases 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- 208000004248 Familial Primary Pulmonary Hypertension Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 208000007659 Fibroadenoma Diseases 0.000 description 1
- 206010053717 Fibrous histiocytoma Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 102000004315 Forkhead Transcription Factors Human genes 0.000 description 1
- 108090000852 Forkhead Transcription Factors Proteins 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 1
- 208000000527 Germinoma Diseases 0.000 description 1
- 208000007569 Giant Cell Tumors Diseases 0.000 description 1
- 201000005409 Gliomatosis cerebri Diseases 0.000 description 1
- 206010018404 Glucagonoma Diseases 0.000 description 1
- 208000009329 Graft vs Host Disease Diseases 0.000 description 1
- 206010018691 Granuloma Diseases 0.000 description 1
- 208000015023 Graves' disease Diseases 0.000 description 1
- 102100034221 Growth-regulated alpha protein Human genes 0.000 description 1
- 206010019629 Hepatic adenoma Diseases 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- 102000006947 Histones Human genes 0.000 description 1
- 108010033040 Histones Proteins 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000723543 Homo sapiens 14-3-3 protein theta Proteins 0.000 description 1
- 101000929319 Homo sapiens Actin, aortic smooth muscle Proteins 0.000 description 1
- 101000897480 Homo sapiens C-C motif chemokine 2 Proteins 0.000 description 1
- 101000940745 Homo sapiens CTTNBP2 N-terminal-like protein Proteins 0.000 description 1
- 101000993285 Homo sapiens Collagen alpha-1(III) chain Proteins 0.000 description 1
- 101000875067 Homo sapiens Collagen alpha-2(I) chain Proteins 0.000 description 1
- 101000941045 Homo sapiens Cortactin-binding protein 2 Proteins 0.000 description 1
- 101000911952 Homo sapiens Cyclin-dependent kinase 7 Proteins 0.000 description 1
- 101000980930 Homo sapiens Cyclin-dependent kinase 9 Proteins 0.000 description 1
- 101001069921 Homo sapiens Growth-regulated alpha protein Proteins 0.000 description 1
- 101000994880 Homo sapiens Inorganic pyrophosphatase 2, mitochondrial Proteins 0.000 description 1
- 101001033788 Homo sapiens Integrator complex subunit 6 Proteins 0.000 description 1
- 101001057504 Homo sapiens Interferon-stimulated gene 20 kDa protein Proteins 0.000 description 1
- 101001055144 Homo sapiens Interleukin-2 receptor subunit alpha Proteins 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102100021042 Immunoglobulin-binding protein 1 Human genes 0.000 description 1
- 102100034415 Inorganic pyrophosphatase 2, mitochondrial Human genes 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 102100039133 Integrator complex subunit 6 Human genes 0.000 description 1
- 208000005045 Interdigitating dendritic cell sarcoma Diseases 0.000 description 1
- 102100026878 Interleukin-2 receptor subunit alpha Human genes 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- 241000710842 Japanese encephalitis virus Species 0.000 description 1
- 208000002260 Keloid Diseases 0.000 description 1
- 206010023421 Kidney fibrosis Diseases 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 239000012097 Lipofectamine 2000 Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 208000002404 Liver Cell Adenoma Diseases 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 208000006644 Malignant Fibrous Histiocytoma Diseases 0.000 description 1
- 208000036626 Mental retardation Diseases 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 102100024193 Mitogen-activated protein kinase 1 Human genes 0.000 description 1
- 101100515472 Mus musculus Mycl gene Proteins 0.000 description 1
- 101710150912 Myc protein Proteins 0.000 description 1
- 101710135898 Myc proto-oncogene protein Proteins 0.000 description 1
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 208000014767 Myeloproliferative disease Diseases 0.000 description 1
- 201000010133 Oligodendroglioma Diseases 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- 208000010191 Osteitis Deformans Diseases 0.000 description 1
- 208000000035 Osteochondroma Diseases 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 208000027067 Paget disease of bone Diseases 0.000 description 1
- 208000002606 Paramyxoviridae Infections Diseases 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 208000000609 Pick Disease of the Brain Diseases 0.000 description 1
- 208000007641 Pinealoma Diseases 0.000 description 1
- 241000224016 Plasmodium Species 0.000 description 1
- 241001505332 Polyomavirus sp. Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 229940122454 Protein phosphatase 2A inhibitor Drugs 0.000 description 1
- 102100033810 RAC-alpha serine/threonine-protein kinase Human genes 0.000 description 1
- 201000000582 Retinoblastoma Diseases 0.000 description 1
- 208000005678 Rhabdomyoma Diseases 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 201000010208 Seminoma Diseases 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 101710113029 Serine/threonine-protein kinase Proteins 0.000 description 1
- 208000000097 Sertoli-Leydig cell tumor Diseases 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000032859 Synucleinopathies Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 241000223777 Theileria Species 0.000 description 1
- 101710150448 Transcriptional regulator Myc Proteins 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 208000015778 Undifferentiated pleomorphic sarcoma Diseases 0.000 description 1
- 208000009311 VIPoma Diseases 0.000 description 1
- 206010047115 Vasculitis Diseases 0.000 description 1
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 description 1
- 241000710886 West Nile virus Species 0.000 description 1
- 206010048214 Xanthoma Diseases 0.000 description 1
- 206010048215 Xanthomatosis Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 238000002679 ablation Methods 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000011481 absorbance measurement Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 208000002718 adenomatoid tumor Diseases 0.000 description 1
- 208000024447 adrenal gland neoplasm Diseases 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000036428 airway hyperreactivity Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 230000000735 allogeneic effect Effects 0.000 description 1
- 230000003281 allosteric effect Effects 0.000 description 1
- 108010029483 alpha 1 Chain Collagen Type I Proteins 0.000 description 1
- 108090000185 alpha-Synuclein Proteins 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 210000002821 alveolar epithelial cell Anatomy 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000003941 amyloidogenesis Effects 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 238000009167 androgen deprivation therapy Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 230000005775 apoptotic pathway Effects 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 239000003886 aromatase inhibitor Substances 0.000 description 1
- 229940046844 aromatase inhibitors Drugs 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- 230000004900 autophagic degradation Effects 0.000 description 1
- 208000001119 benign fibrous histiocytoma Diseases 0.000 description 1
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical group CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- QJCPEOFEBREKQB-UHFFFAOYSA-N benzenesulfinamide Chemical compound NS(=O)C1=CC=CC=C1 QJCPEOFEBREKQB-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- BNBQRQQYDMDJAH-UHFFFAOYSA-N benzodioxan Chemical compound C1=CC=C2OCCOC2=C1 BNBQRQQYDMDJAH-UHFFFAOYSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 208000016738 bone Paget disease Diseases 0.000 description 1
- 201000009480 botryoid rhabdomyosarcoma Diseases 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 201000003149 breast fibroadenoma Diseases 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 208000003362 bronchogenic carcinoma Diseases 0.000 description 1
- 201000002143 bronchus adenoma Diseases 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000006369 cell cycle progression Effects 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000009134 cell regulation Effects 0.000 description 1
- 230000019522 cellular metabolic process Effects 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- 208000019065 cervical carcinoma Diseases 0.000 description 1
- 210000003679 cervix uteri Anatomy 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000011654 childhood malignant neoplasm Diseases 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- VDANGULDQQJODZ-UHFFFAOYSA-N chloroprocaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1Cl VDANGULDQQJODZ-UHFFFAOYSA-N 0.000 description 1
- 229960002023 chloroprocaine Drugs 0.000 description 1
- 208000006990 cholangiocarcinoma Diseases 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 201000005217 chondroblastoma Diseases 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 208000025302 chronic primary adrenal insufficiency Diseases 0.000 description 1
- 208000009060 clear cell adenocarcinoma Diseases 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 229960003920 cocaine Drugs 0.000 description 1
- 230000037319 collagen production Effects 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 208000013044 corticobasal degeneration disease Diseases 0.000 description 1
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 201000010305 cutaneous fibrous histiocytoma Diseases 0.000 description 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 229940043378 cyclin-dependent kinase inhibitor Drugs 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 210000000172 cytosol Anatomy 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 210000003520 dendritic spine Anatomy 0.000 description 1
- 230000002074 deregulated effect Effects 0.000 description 1
- 238000011033 desalting Methods 0.000 description 1
- 230000018514 detection of nutrient Effects 0.000 description 1
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 description 1
- MQYQOVYIJOLTNX-UHFFFAOYSA-N dichloromethane;n,n-dimethylformamide Chemical group ClCCl.CN(C)C=O MQYQOVYIJOLTNX-UHFFFAOYSA-N 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 229940043237 diethanolamine Drugs 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 231100000676 disease causative agent Toxicity 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000007344 dysregulated autophagy Effects 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 229940121647 egfr inhibitor Drugs 0.000 description 1
- 201000009409 embryonal rhabdomyosarcoma Diseases 0.000 description 1
- 210000001671 embryonic stem cell Anatomy 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 238000009261 endocrine therapy Methods 0.000 description 1
- 229940034984 endocrine therapy antineoplastic and immunomodulating agent Drugs 0.000 description 1
- 201000003914 endometrial carcinoma Diseases 0.000 description 1
- 230000002357 endometrial effect Effects 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940095399 enema Drugs 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000001973 epigenetic effect Effects 0.000 description 1
- 230000008556 epithelial cell proliferation Effects 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 102000015694 estrogen receptors Human genes 0.000 description 1
- 108010038795 estrogen receptors Proteins 0.000 description 1
- 229940012017 ethylenediamine Drugs 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 239000000446 fuel Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 208000015419 gastrin-producing neuroendocrine tumor Diseases 0.000 description 1
- 201000000052 gastrinoma Diseases 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 201000003115 germ cell cancer Diseases 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 125000004995 haloalkylthio group Chemical group 0.000 description 1
- 230000007166 healthy aging Effects 0.000 description 1
- 208000024348 heart neoplasm Diseases 0.000 description 1
- 230000037183 heart physiology Effects 0.000 description 1
- 208000018578 heart valve disease Diseases 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 208000006359 hepatoblastoma Diseases 0.000 description 1
- 201000002735 hepatocellular adenoma Diseases 0.000 description 1
- 229940022353 herceptin Drugs 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 239000000833 heterodimer Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 238000001794 hormone therapy Methods 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 230000006951 hyperphosphorylation Effects 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000037451 immune surveillance Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 201000004933 in situ carcinoma Diseases 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 108091006086 inhibitor proteins Proteins 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000015788 innate immune response Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 206010022498 insulinoma Diseases 0.000 description 1
- 102000006495 integrins Human genes 0.000 description 1
- 108010044426 integrins Proteins 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 210000002570 interstitial cell Anatomy 0.000 description 1
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 1
- 230000004068 intracellular signaling Effects 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 208000030776 invasive breast carcinoma Diseases 0.000 description 1
- 201000010985 invasive ductal carcinoma Diseases 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 125000003965 isoxazolidinyl group Chemical group 0.000 description 1
- 210000001117 keloid Anatomy 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 208000022013 kidney Wilms tumor Diseases 0.000 description 1
- 208000003849 large cell carcinoma Diseases 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 206010024627 liposarcoma Diseases 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 230000001050 lubricating effect Effects 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 229940124302 mTOR inhibitor Drugs 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 229940107698 malachite green Drugs 0.000 description 1
- FDZZZRQASAIRJF-UHFFFAOYSA-M malachite green Chemical compound [Cl-].C1=CC(N(C)C)=CC=C1C(C=1C=CC=CC=1)=C1C=CC(=[N+](C)C)C=C1 FDZZZRQASAIRJF-UHFFFAOYSA-M 0.000 description 1
- 201000004593 malignant giant cell tumor Diseases 0.000 description 1
- 201000000289 malignant teratoma Diseases 0.000 description 1
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 210000002418 meninge Anatomy 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 229960001252 methamphetamine Drugs 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- SJFNDMHZXCUXSA-UHFFFAOYSA-M methoxymethyl(triphenyl)phosphanium;chloride Chemical compound [Cl-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(COC)C1=CC=CC=C1 SJFNDMHZXCUXSA-UHFFFAOYSA-M 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 239000007932 molded tablet Substances 0.000 description 1
- 230000002969 morbid Effects 0.000 description 1
- 208000010492 mucinous cystadenocarcinoma Diseases 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 208000009091 myxoma Diseases 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- MXERDVDDPIOSLK-UHFFFAOYSA-N n-methyl-4-(trifluoromethoxy)benzenesulfonamide Chemical compound CNS(=O)(=O)C1=CC=C(OC(F)(F)F)C=C1 MXERDVDDPIOSLK-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004998 naphthylethyl group Chemical group C1(=CC=CC2=CC=CC=C12)CC* 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 201000008026 nephroblastoma Diseases 0.000 description 1
- 201000011682 nervous system cancer Diseases 0.000 description 1
- 208000007538 neurilemmoma Diseases 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 208000004649 neutrophil actin dysfunction Diseases 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000000414 obstructive effect Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid group Chemical group C(CCCCCCC\C=C/CCCCCCCC)(=O)O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 230000005959 oncogenic signaling Effects 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 208000003388 osteoid osteoma Diseases 0.000 description 1
- 208000008798 osteoma Diseases 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 210000003101 oviduct Anatomy 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- AHVQYHFYQWKUKB-UHFFFAOYSA-N oxan-4-amine Chemical compound NC1CCOCC1 AHVQYHFYQWKUKB-UHFFFAOYSA-N 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- LVSJDHGRKAEGLX-UHFFFAOYSA-N oxolane;2,2,2-trifluoroacetic acid Chemical compound C1CCOC1.OC(=O)C(F)(F)F LVSJDHGRKAEGLX-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 208000021255 pancreatic insulinoma Diseases 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000001991 pathophysiological effect Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 208000024724 pineal body neoplasm Diseases 0.000 description 1
- 201000004123 pineal gland cancer Diseases 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 125000005592 polycycloalkyl group Polymers 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000002206 pro-fibrotic effect Effects 0.000 description 1
- 230000003652 pro-growth Effects 0.000 description 1
- 230000001686 pro-survival effect Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 102000003998 progesterone receptors Human genes 0.000 description 1
- 108090000468 progesterone receptors Proteins 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 201000002212 progressive supranuclear palsy Diseases 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 239000003368 psychostimulant agent Substances 0.000 description 1
- 229940127250 psychostimulant medication Drugs 0.000 description 1
- 210000001147 pulmonary artery Anatomy 0.000 description 1
- 208000002815 pulmonary hypertension Diseases 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000022983 regulation of cell cycle Effects 0.000 description 1
- 230000008844 regulatory mechanism Effects 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 230000001718 repressive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 208000029922 reticulum cell sarcoma Diseases 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 230000037390 scarring Effects 0.000 description 1
- 206010039667 schwannoma Diseases 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000009758 senescence Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 208000004548 serous cystadenocarcinoma Diseases 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 210000003625 skull Anatomy 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 230000003956 synaptic plasticity Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 208000001608 teratocarcinoma Diseases 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000014723 transformation of host cell by virus Effects 0.000 description 1
- 206010044412 transitional cell carcinoma Diseases 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 239000013638 trimer Substances 0.000 description 1
- 208000022271 tubular adenoma Diseases 0.000 description 1
- 238000010798 ubiquitination Methods 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 210000003708 urethra Anatomy 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 208000009540 villous adenoma Diseases 0.000 description 1
- 210000003905 vulva Anatomy 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/14—Nitrogen atoms not forming part of a nitro radical
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the invention relates to small molecule modulators of PP2A, comprising 2- diarylmethyl-4-aminotetrahydropyran sulfonimidamides, and their use to treat diseases such as cancer, inflammatory and autoimmune conditions, fibrotic and neurodegenerative diseases.
- BACKGROUND [0003] Protein phosphatase 2A is one of the four major serine threonine phosphatases and is implicated in the negative control of cell growth and division. Protein phosphatase 2A holoenzymes are composed of a structural subunit A and a catalytic subunit C which form a catalytically competent PP2A AC heterodimer.
- PP2A AC heterodimers then associate with a regulatory B subunit, which controls substrate specificity. Regulatory B subunits occur in four families and their expression is cell-type and context dependent.
- the PP2A heterotrimeric protein phosphatase is a ubiquitous and conserved phosphatase with diverse cellular functions.
- proteins of oncogenic signaling cascades such as Raf, MEK, and AKT, and in this role they function as tumor suppressors.
- Recently PP2A AC heterodimers have been shown to interact directly with the INTS6 subunit of the Integrator Complex without any B subunit.
- Integrator associates with RNA Polymerase II (RNAPII) to control it’s transcriptional activity and PP2A AC associated Integrator acts to maintain RNAPII in a paused (i.e. transcriptionally stalled) state.
- RNAPII RNA Polymerase II
- PP2A AC associated Integrator acts to maintain RNAPII in a paused (i.e. transcriptionally stalled) state.
- This non- classical PP2A-Integrator complex thus functions to restrain transcription and this activity also contributes the tumor suppressor property of PP2A in transcriptionally addicted cancers, for example breast, lung, prostate, ovarian cancers glioblastoma, melanoma, leukemia, and others in adults. Also in pediatric cancers such as neuroblastoma and medulloblastoma in children and infants.
- Myc proteins target proliferative and apoptotic pathways vital for progression in cancer and it is overexpressed and deregulated in many human cancers.
- the control of Myc abundance through protein degradation has attracted considerable interest and Ser-62 phosphorylation by a number of kinases has been shown to stabilize the protein.
- PP2A is responsible for Ser-62 dephosphorylation which primes the protein for ubiquitylation and degredation, thus PP2A functions as a negative regulator of Myc.
- the FOXO (Forkhead transcription factors, Class O) proteins are a group of transcription factors involved in control of a variety of physiological, metabolic and developmental pathways.
- FOXO farnesoid endothelial growth factor
- oxidative stress and nutrient deprivation oxidative stress and nutrient deprivation.
- Cellular processes affected by FOXO activity include cell cycle control, differentiation, proliferation, apoptosis and autophagy. Disregulation of FOXO mediated processes has been implicated in a number of pathologies including tumorigenesis, inflammation, fibrosis, diabetes, neurodegenerative and other age related conditions, amongst others.
- Activity of FOXO transcription factors are controlled in part by their sub-cellular localization, in particular their localization to the nucleus from the cytosol, and their subsequent transcriptional activation.
- FOXO1 regulates expression of a number of genes that play critical roles in cell cycle and apoptosis.
- a pivotal regulatory mechanism of FOXO is reversible phosphorylation, catalyzed by kinases and phosphatases. Phosphorylation of FOXO1 is associated with 14-3-3 binding and cytosolic localization, whereas dephosphorylated FOXO1 translocates to the nucleus and is transcriptionally active.
- FOXO3 is regulated in an analogous manner.
- PP2A interacts directly with FOXO1 and dephosphorylates FOXO1.
- Prostate cancer is the second leading cause of cancer death in men in America, behind lung cancer. According to the American Cancer Society, approximately 1 man in 36 will die of prostate cancer. Male hormones, specifically testosterone, fuel the growth of prostate cancer. By reducing the amount and activity of testosterone, the growth of advanced prostate cancer is slowed.
- Endocrine therapy known as androgen ablation
- Androgen deprivation therapy for metastatic prostate cancer results in tumor regression and symptomatic improvement in the majority of patients.
- metastatic prostate cancer inevitably progresses despite castrate levels of serum testosterone.
- CRPC castration-resistant prostate cancer
- Breast cancer can affect both men and women. Breast cancer is the most prevalent cancer in women, after skin cancers, with about 1 in every 8 women expected to develop invasive breast cancer at some point. One subset of breast cancer expresses the androgen receptor (AR), which has been implicated as a therapeutic target in that subset. About 10- 20% of breast cancers — more than one out of every 10 — are found to be triple-negative. "Triple negative breast cancer” refers to a breast cancer that does not contain estrogen receptors, progesterone receptors, or human epidermal growth factor receptor 2 (HER2). This means that the growth of the cancer is not supported by the hormones estrogen and progesterone, nor by the presence of too many HER2 receptors.
- AR androgen receptor
- triple-negative breast cancer does not respond to hormonal therapy (such as tamoxifen or aromatase inhibitors) or therapies that target HER2 receptors, such as Herceptin (chemical name: trastuzumab). While these tumors are often treatable, the chemotherapy is not targeted, and response durations are short. For doctors and researchers, there is intense interest in finding new medications that can treat breast cancer.
- hormonal therapy such as tamoxifen or aromatase inhibitors
- Herceptin chemical name: trastuzumab
- the compounds described herein which are 2-diarylmethyl-4- aminotetrahydropyran sulfonimidamides, exhibit anti-proliferative effects by increasing PP2A activity in cells with suppressed or deficient phosphatase activity and are therefore useful as monotherapy in cancer treatment. Additionally, they can be used in combination with other drugs to restore sensitivity to chemotherapy where resistance has developed. The compounds may also be used in treatment of other diseases characterized by deficient PP2A activity, for example lung fibrosis and Alzheimer’s Disease.
- a genus of 2-diarylmethyl-4-aminotetrahydropyran sulfonimidamide and related compounds has now been found that modulate PP2A activity.
- the compounds deactivate pro- growth and pro-survival kinases such as phospo-ERK and phospho-AKT by promoting their deposphorylation by PP2A; they destabilize oncogenic MYC by promoting PP2A mediated dephoshorylation of MYC, and they promote RNAPII promoter proximal pausing during transcription.
- the invention relates to pharmaceutical compositions comprising the compounds described herein.
- the invention relates to methods and uses of the above-described compounds in medicine, particularly for the treatment of a disease chosen from (a) cancer; (b) diabetes; (c) autoimmune disease; (d) age onset proteotoxic disease (particularly neurodegenerative disease); (e) mood disorder; (f) acne vulgaris; (g) solid organ transplant rejection (graft vs. host disease); (h) pulmonary disease (such as COPD or IPF); (i) cardiac hypertrophy and heart failure; (j) viral or parasitic infection; (k) inflammatory conditions (such as asthma) and (l) organ fibrosis (such as kidney fibrosis).
- a disease chosen from (a) cancer; (b) diabetes; (c) autoimmune disease; (d) age onset proteotoxic disease (particularly neurodegenerative disease); (e) mood disorder; (f) acne vulgaris; (g) solid organ transplant rejection (graft vs. host disease); (h) pulmonary disease (such as
- the invention relates to a method for restoring sensitivity to one or more chemotherapeutic agents in the treatment of cancer. The method includes administering an effective amount of a compound described herein.
- the invention relates to a method for treating a disease or disorder in a patient where the disease or disorder involves the dysregulation of PP2A influenced signaling cascades such as the PI3K-AKT and MAP kinase pathways. These methods include administering to a patient a therapeutically effective amount of a compound described herein.
- the invention in a sixth aspect, relates to a method for treating a disease or disorder in a patient where the disease or disorder involves the dysregulation of a Myc dependent signaling pathway. These methods include administering to a patient a therapeutically effective amount of a compound described herein.
- the invention in a seventh aspect, relates to a method for treating a metabolic disease or disorder in a patient where the disease or disorder involves the dysregulation of the mTOR-PP2A signaling axis. The method includes administering an effective amount of a compound described herein.
- the invention relates to a method for treating disease or disorder in a patient where the disease or disorder involves cellular hyperproliferation or growth due to dysregulation of the PP2A-Integrator-RNAPII axis.
- Fig.1 depicts a general synthetic scheme for preparing compounds described herein, and intermediates useful therefor.
- Fig. 2 depicts a synthetic scheme for preparing Example 1, and intermediates useful therefor.
- Fig. 3 depicts a synthetic scheme for preparing Example 3 and Example 4, and intermediates useful therefor.
- Fig.1 depicts a general synthetic scheme for preparing compounds described herein, and intermediates useful therefor.
- Fig. 2 depicts a synthetic scheme for preparing Example 1, and intermediates useful therefor.
- Fig. 3 depicts a synthetic scheme for preparing Example 3 and Example 4, and intermediates useful therefor.
- Fig. 4 depicts a synthetic scheme for preparing an amine intermediate useful for preparing Example 7, and intermediates useful therefor.
- Fig. 5 depicts another general synthetic scheme for preparing compounds described herein, and intermediates useful therefor.
- Fig. 6 depicts a synthetic scheme for preparing Example 7, and intermediates useful therefor.
- Fig. 7 depicts a synthetic scheme for preparing Example 8, and intermediates useful therefor. DETAILED DESCRIPTION OF THE INVENTION [0028] Substituents are generally defined when introduced and retain that definition throughout the specification and in all independent claims. [0029] In a composition aspect, the invention relates to compounds of formula (I):
- the invention relates to compounds of formula IIa, IIb, IIc or IId:
- the sulfur atom of the sulfonimidamide is also a stable stereogenic chiral center and all of the stereoisomers above, IIa, IIb, IIc and IId may occur as diastereoisomers with either configuration at the sulfur center:
- the compound may be of formula I, IIa, IIb, IIc, IId, IIe or IIf, unless otherwise indicated [0033]
- U and V are carbocyclic aromatic
- B is absent.
- oheptane compounds In still furt her embodiments where Q is -O-, B is -CH 2 CH 2 -, W is carbocyclic aromatic: . [0041] In still furt her embodiments where Q is -O-, B is -CH 2 CH 2 -, W is carbocyclic aromatic: . [0041] In some embodiments, X 1 , X 2 , X 3 , and X 4 are independently selected in each instance from hydrogen, halogen, nitro, cyano, (C1-C6)alkyl optionally substituted with -OH, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )haloalkylthio, -NR 1 R 2 , -OR 1 , -C(O)R 1 , - OC(O)R 1 , -C(O)NR 1 R 2 , -C(O)OR 1 ,
- X 2 and X 4 are each hydrogen.
- X and X are each hydrogen, and X and X 3 are each chosen independently from -H, -F, -Cl, -CF 3 ,-C(CH 3 ) 2 OH, or -C(O)NMe 2 .
- all of X 1 , X 2 , X 3 and X 4 are each hydrogen.
- at least one of X 1 , X 2 , X 3 and X 4 is located at a carbon two positions away from a bridgehead carbon.
- Z 1 and Z 2 are independently selected in each instance from hydrogen, halogen, nitro, cyano, azido, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, (C1-C6)haloalkylthio, -NR 1 R 2 , -NR 1 C(O)R 2 , -NR 1 C(O)OR 6 , -OR 1 , -C(O)R 1 , -OC(O)R 1 , - C(O)NR 1 R 2 , -C(O)OR 1 , -SR 1 , -SO 2 R 1 , -SO 2 NR 1 R 2 , and five membered heterocyclyl.
- Z 1 is H.
- Z 2 is chosen from hydrogen, halogen, and (C1-C6)haloalkoxy.
- Z 2 is chosen from hydrogen, F, Cl, and OCF3.
- Z 2 is in the para position.
- the compounds described herein contain asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms which may be defined in terms of absolute stereochemistry as (R)- or (S)-.
- the present invention is meant to include all such possible diastereomers as well as their racemic and optically pure forms.
- Optically active (R)- and (S)- isomers may be prepared using homo-chiral synthons or homo-chiral reagents. Final compounds or intermediates may be resolved in to their enantiomers using conventional techniques such crystallization of amine intermediates with chiral acids or preparative chiral chromatography on final compounds or intermediates.
- racemic cis diastereoisomer with respect to the central ring And racemic trans diastereoisomer with respect to the central ring: And, finally, the structure: conveys no inform ure could be a single enantiomer or a mixture of enantiomers, including a racemic micture, or mixture of diastereoisomers.
- compounds can be single cis enantiomers of formula IIa or formula IIb or single trans enantiomers formula IIc or formula IId, or a mixture of the two. If a mixture, the mixture will most commonly be racemic, but it need not be. Substantially pure single enantiomers of biologically active compounds such as those described herein often exhibit advantages over their racemic mixture. [0047] Various non-limiting embodiments of the present disclosure are described below.
- Q is selected from -O- or NR Q ;
- R im is selected from H or lower alkyl;
- U, V and W are independently cabocyclic aromatic or heteroaromatic rings;
- n 0 or 1;
- X1, X2, X3 and X4 are independently selected in each instance from hydrogen, halogen, nitro, cyano, (C 1 -C 6 )alkyl optionally substituted with -OH, (C 1 -C 6 )haloalkyl, (C1-C6)haloalkoxy, (C1-C6)haloalkylthio, -NR 1 R 2 , -OR 1 , -C(O)R 1 , -OC(O)R 1 , - C
- the compound of formula I is a compound of formula IIa: .
- the compound of formula I is a compound of formula IIb: .
- B is absent.
- B is -(CH2)2-.
- B is a direct bond.
- B is -S-.
- one of U or V is carbocyclic.
- both of U and V are carbocyclic.
- R im is hydrogen.
- R im is methyl.
- W is carbocyclic.
- W is heteroaromatic.
- X 1 , X 2 , X 3 , and X 4 are independently selected in each instance from hydrogen, halogen, nitro, cyano, (C 1 -C 6 )alkyl optionally substituted with -OH, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)haloalkylthio, -NR 1 R 2 , - OR 1 , -C(O)R 1 , -OC(O)R 1 , -C(O)NR 1 R 2 , -C(O)OR 1 , -SR 1 , -SO 2 R 1 , and -SO 2 NR 1 R 2 .
- X 2 and X 4 are each hydrogen.
- X 1 and X 3 are each chosen independently from hydrogen, halogen, nitro, cyano, (C 1 -C 6 )alkyl optionally substituted with -OH, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)haloalkylthio, -NR 1 R 2 , -OR 1 , -C(O)R 1 , - OC(O)R 1 , -C(O)NR 1 R 2 , -C(O)OR 1 , -SR 1 , -SO 2 R 1 , and -SO 2 NR 1 R 2 .
- X 1 and X 3 are each chosen independently from -H, -F, -Cl, -CF 3 , -OMe, or -OCF3. [0068] In some embodiments of the formulae herein, all of X , X , X and X are each hydrogen.
- Z 1 and Z 2 are independently selected in each instance from hydrogen, halogen, nitro, cyano, azido, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C1-C6)haloalkoxy, (C1-C6)haloalkylthio, -NR 1 R 2 , -NR 1 C(O)R 2 , -NR 1 C(O)OR 6 , -OR 1 , - C(O)R 1 , -OC(O)R 1 , -C(O)NR 1 R 2 , -C(O)OR 1 , -SR 1 , -SO 2 R 1 , -SO 2 NR 1 R 2 and five membered hetercyclyl.
- Z 1 and Z 2 are independently selected in each instance from hydrogen, halogen, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and halo(C 1 - C6)alkoxy.
- Z 1 is hydrogen.
- Z 2 is chosen from hydrogen, halogen, and (C1-C6)haloalkoxy.
- Z 2 is chosen from hydrogen, F, Cl, CF3, and trifluoromethoxy.
- Z 2 is trifluoromethoxy.
- one of Z 1 and Z 2 is para to the sulfonyl amide.
- Z 1 is hydrogen
- Z 2 is para to the sulfonyl amide.
- the compounds are provided as a composition.
- the composition is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.
- a disease in a patient wherein the disease is chosen from: (a) cancer (b) diabetes (c) autoimmune disease, such as rheumatoid arthritis or multiple sclerosis (d) age onset proteotoxic disease, particularly neurodegenerative disease (e) mood disorder (f) acne vulgaris (g) solid organ transplant rejection (graft vs. host disease) (h) pulmonary disease, such as COPD or pulmonary fibrosis (i) cardiac hypertrophy and heart failure (j) viral or parasitic infection and (k) inflammatory conditions, such as asthma; the method comprising administering to the patient a therapeutically effective amount of a compound or composition provided herein.
- autoimmune disease such as rheumatoid arthritis or multiple sclerosis (d) age onset proteotoxic disease, particularly neurodegenerative disease (e) mood disorder (f) acne vulgaris (g) solid organ transplant rejection (graft vs. host disease) (h) pulmonary disease, such as COPD or pulmonary fibrosis (i) cardiac hypertrophy and
- said cancer is selected from the group consisting of: ovarian, endometrial, pancreatic, renal cell, breast, prostate, lung, hepatocellular carcinoma, glioma, leukemia, lymphoma, colorectal cancers, and sarcomas.
- said cancer is chemotherapy resistant cancer.
- the methods herein further comprise administering one or more additional cancer chemotherapeutic agents.
- the methods or compounds herein are for treating an age onset proteotoxic disease, particularly neurodegenerative disease, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis.
- the methods or compounds herein are for treating a pulmonary disease.
- the pulmonary disease is COPD, asthma, or pulmonary fibrosis.
- the methods or compounds herein are for treating an inflammatory or autoimmune disease.
- the inflammatory or autoimmune disease is multiple sclerosis.
- Also provided herein are methods for restoring sensitivity to one or more chemotherapeutic agents in the treatment of cancer, the method comprising administering an effective amount of a compound or composition provided herein.
- methods for treating a disease or disorder in a patient where the disease or disorder involves the dysregulation of a Myc dependent signaling pathway the method comprising administering to the patient a therapeutically effective amount of a compound or composition provided herein.
- each instance of lower alkyl is, independently, selected from C1-3 alkyl.
- the compounds herein have a formula: or a pharmaceuticall wherein J 1 is H, F, Cl, Br, or I; J 2 is H, F, Cl, Br, or I; J 3 is H, F, Cl, Br, or I; J 4 is H, F, Cl, Br, or I; J 5 is H or OH; J 6 is H or C 1-6 alkyl; J 7 is H, F, Cl, Br, I, CN, N3 C16 alkyl C16 alkoxyl, C1-6 haloalkyl, C1-6 haloalkoxyl; J 8 is H, F, Cl, Br, I, CN, N3, C1-6 alkyl, C1-6 alkoxyl, C1-6 haloalkyl, C1-6 haloalkoxyl; and J 9 is H and J 10 is H, or J 9 and J 10 together form an ethylene
- J 1 is H or F
- J 2 is H or F
- J 3 is H or F
- J 4 is H or F
- J 5 is H
- J 6 is H or C 1-3 alkyl
- J 7 is H, C1-6 alkoxyl, or C1-6 haloalkoxyl
- J 8 is H, C 1-6 alkoxyl, or C 1-6 haloalkoxyl.
- provided herein are compounds having a formula: or a pharmaceutically acceptable salt thereof, wherein J 2 is H or F; J 3 is H or F; J 6 is H or CH3; and J 8 is OCH 3 or OCF 3 .
- J 2 is H or F
- J 3 is H or F
- J 6 is H or CH3
- J 8 is OCH 3 or OCF 3 .
- compounds having a formula: F 3 or a
- compounds having a formula: , or a pha In some embodiments, provided herein are compounds having a formula: , , or a [00100]
- pharmaceutical compositions comprising a compound disclosed above, or a pharmaceutically acceptable salt form thereof, and a pharmaceutically acceptable carrier or diluent.
- the present invention provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically carriers thereof and optionally one or more other therapeutic ingredients.
- the carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
- Formulations of the compounds and compositions described herein may be administered by a variety of methods: oral (including, but not limited to, capsules, cachets, tablets, powder, granules, solutions, suspensions, emulsions, tablets, or sublingual tablets), buccal, by inhalation (by using, for instance, an inhaler, a nebulizer, an aerosol, a gas, etc.), nasal, topical (including, but not limited to, lotions, creams, ointments, patches (i.e., transdermal), gels, liniments, pastes), ophthalmic, to the ear, rectal (for instance, by using a suppository or an enema), vaginal, or parenteral, depending on the severity and type of the disease being treated.
- oral including, but not limited to, capsules, cachets, tablets, powder, granules, solutions, suspensions, emulsions, tablets, or sublingual tablets
- buccal by inhalation (by
- the compositions are administered orally or intravenously.
- the formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intracranial, intravenous and intraarticular), rectal, vaginal, nasal (inhalation), and topical (including dermal, buccal, sublingual and intraocular) administration.
- the most suitable route may depend upon the condition and disorder of the recipient.
- the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association a compound of formula (I) or a pharmaceutically acceptable salt thereof ("active ingredient”) with the carrier which constitutes one or more accessory ingredients.
- Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
- the active ingredient may also be presented as a bolus, electuary or paste.
- a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
- Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent.
- Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
- the tablets may optionally be coated or scored and may be formulated so as to provide sustained, delayed or controlled release of the active ingredient therein.
- Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient.
- Formulations for parenteral administration also include aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents.
- the formulations may be presented in unit-dose of multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example saline, phosphate-buffered saline (PBS) or the like, immediately prior to use.
- a sterile liquid carrier for example saline, phosphate-buffered saline (PBS) or the like, immediately prior to use.
- Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
- the compounds of this invention can exist in radiolabeled form, i.e., the compounds may contain one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Radioisotopes of hydrogen, carbon, phosphorous, fluorine, and chlorine include 2 H, 3 H, 13 C, 14 C, 15 N, 35 S, 18 F, and 36 Cl, respectively. Compounds that contain those radioisotopes and/or other radioisotopes of other atoms are within the scope of this invention. Tritiated, i.e.
- radiolabeled compounds of formula I of this invention and prodrugs thereof can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabeled compounds can be prepared by carrying out the procedures disclosed in the Examples and Schemes by substituting a readily available radiolabeled reagent for a non-radiolabeled reagent. [00107] In some embodiments, provided herein are kits, comprising a compound or composition described herein, and instructions for use.
- provided herein are methods comprising administering a compound or composition described herein to a subject.
- methods of modulating a protein phosphatase 2A comprising contacting the protein phosphatase 2A with a compound or composition described herein.
- methods of treating a protein phosphatase 2A related disease comprising administering an effective amount of a compound or composition described herein to a subject in need thereof.
- a disease comprising administering an effective amount of a compound or composition described herein to a subject in need thereof, wherein the disease comprises one or more of: (a) cancer; (b) diabetes; (c) autoimmune disease; (d) age onset proteotoxic disease; (e) mood disorder; (f) acne vulgaris; (g) solid organ transplant rejection; (h) pulmonary disease; (i) cardiac hypertrophy; (j) viral infection; (k) an inflammatory condition; (l) heart failure; or (m) parasitic infection.
- the disease comprises one or more of: (a) cancer; (b) diabetes; (c) autoimmune disease; (d) age onset proteotoxic disease; (e) mood disorder; (f) acne vulgaris; (g) solid organ transplant rejection; (h) pulmonary disease; (i) cardiac hypertrophy; (j) viral infection; (k) an inflammatory condition; (l) heart failure; or (m) parasitic infection.
- provided herein are methods of restoring sensitivity to one or more chemotherapeutic agents in the treatment of cancer, comprising administering an effective amount of a compound or composition described herein to a subject in need thereof.
- methods of treating a disease or disorder in a patient where the disease or disorder involves the dysregulation of the PI3K-AKT-FOXO signaling pathway comprising administering an effective amount of a compound or composition described herein to a subject in need thereof.
- provided herein are methods of treating a disease or disorder in a patient where the disease or disorder involves the dysregulation of a Myc dependent signaling pathway, comprising administering an effective amount of a compound or composition described herein to a subject in need thereof.
- methods of treating a metabolic or neurological disease or disorder in a patient wherein the disease or disorder involves the dysregulation of the mTOR-PP2A signaling axis comprising administering an effective amount of a compound or composition described herein to a subject in need thereof.
- the compounds provided herein can be used for treating cancer in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I.
- the cancer is characterized by dysregulation of the PI3K-AKT-FOXO signaling pathway.
- the cancer can be selected from the group consisting of: ovarian, pancreatic, renal cell, breast, prostate, lung, hepatocellular carcinoma, glioma, leukemia, lymphoma, colorectal cancers, and sarcomas.
- the cancer is chemotherapy resistant cancer.
- the method further comprises administering one or more cancer chemotherapeutic agents.
- the one or more cancer chemotherapeutic agents are EGFR inhibitors.
- the cancer is chemotherapy resistant cancer.
- the method further comprises administering one or more cancer chemotherapeutic agents targeting transcriptional dysregulation.
- the one or more cancer chemotherapeutic agents are CDK inhibitors, particularly CDK9 and/or CDK7 inhibitors.
- the cancer is chemotherapy resistant cancer.
- the method further comprises administering one or more cancer chemotherapeutic agents.
- the one or more cancer chemotherapeutic agents are mTOR inhibitors.
- Certain cancers are characterized by dysregulation and overactivation of cellular transcription carried out by RNA polymerase II (RNAPII) as described in Transcriptional Addiction in Cancer. Bradner, J. E., Hnisz, D. and Young, R. A.
- BRD4 a member of the bromodomain and extra-terminal domain (BET) family of epigenetic readers, occupies super-enhancers co-opted in transcriptionally addicted cancer cells, and recruits pTEFb to RNAPII to enable promoter proximal pause release and maintain productive elongation (see, for example, Control of Embryonic Stem Cell Identity by BRD4-Dependent Transcriptional Elongation of Super-Enhancer-Associated Pluripotency Genes. Di Micco, R., et al. October 2014, Cell Reports, Vol. 9, pp. 234-247).
- BRD4 inhibitor (BRD4i) treatment synergizes with PP2A activation in two ways, first by suppressing BRD4 mediated recruitment of pTEFb to paused RNAPII.
- a second mode of synergy with BRD4i treatment is by reversing the activating phosphorylation of BRD4 itself by PP2A complexes (see Phospho-BRD4: transcription plasticity and drug targeting. Chiang, C. 2016, Drug Discov Today: Technol, http://dx.doi.org/10.1016).
- the compounds provided herein can be used for treating cancer in a patient where there is transcriptional dysregulation, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I and a BRD4 inhibitor.
- Cancers characterized by transcriptional addiction include Breast Cancer, Osteosarcoma, Endometrial Cancer, Acute Myeloid Leukemia, Lung Cancer, Prostate Cancer, Melanoma and Ovarian Cancer.
- administration of a compound of formula I can restore sensitivity to one or more chemotherapeutic agents in a patient wherein the patient has developed a resistance to the one or more chemotherapeutic agents.
- cancers that may be treated by the compounds, compositions and methods described herein include, but are not limited to, the following: cardiac cancers, including, for example sarcoma, e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma; myxoma; rhabdomyoma; fibroma; lipoma and teratoma; lung cancers, including, for example, bronchogenic carcinoma, e.g., squamous cell, undifferentiated small cell, undifferentiated large cell, and adenocarcinoma; alveolar and bronchiolar carcinoma; bronchial adenoma; sarcoma; lymphoma; chondromatous hamartoma; and mesothelioma; gastrointestinal cancer, including, for example, cancers of the esophagus, e.g., squamous cell carcinoma, adenos
- Cancers may be solid tumors that may or may not be metastatic. Cancers may also occur, as in leukemia, as a diffuse tissue [00123]
- the compounds described herein can also be administered in combination with existing methods of treating cancers, for example by chemotherapy, irradiation, or surgery.
- a method of treating cancer comprising administering an effective amount of a compound according to formula I to a patient, wherein a therapeutically effective amount of one or more additional cancer chemotherapeutic agents are administered to the patient.
- Also provided herein is a method for treating diabetes in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I.
- autoimmune disease can be, for example, inflammatory bowel disease (IBD).
- IBD inflammatory bowel disease
- Immune responses are constantly and tightly regulated and one important cellular component in maintaining self tolerance (i.e., prevention of autoimmunity) and tolerance of benign commensal gut flora are regulatory T cells (Treg).
- Treg can be subdivided into multiple phenotypes, but the most common are CD4+CD25+ T cells that express the transcription factor Foxp3.
- Foxp3 is a direct transcriptional target of FOXO proteins, particularly FOXO1 and FOXO3.
- Acute immune mediated rejection and chronic immune mediated rejection are key obstacles to successful solid organ transplantation. It is believed that these forms of rejection can be prevented/overcome by amplifying Treg number and or function.
- a common and morbid complication of allogeneic hematopoietic cell transplants (Allo-HCT) used to treat various malignant and non-malignant conditions is graft versus host disease, in which the transplanted immune cells from the donor damage multiple organs in the recipient (most notably skin, gut, and liver).
- compositions of the present invention are useful in treatment of autoimmune and related diseases, by activating FOXO proteins and inducing T cell differentiation to Tregs.
- Compounds may be administered therapeutically to subjects directly, or alternatively, T cells may be collected from a subject and differentiated ex vivo to Tregs as described by Taylor et al. [Blood 99, 3493-3499 (2002)].
- Aspects of the invention include methods for treatment of autoimmune disease characterized by deficiency in Treg function comprising administering a therapeutically useful amount of compound of formula I.
- the method can also include extraction of na ⁇ ve T- cells from a patient, differentiation of T-cells to Tregs ex vivo by treatment with a compound of formula I, optionally supplemented with an HDACi, followed by administration of Tregs to patient with optional separation of compound of formula I from Tregs prior to their administration.
- autoimmune diseases that can be so treated include IBD, solid organ transplant rejection, and GvHD in allo-HCT.
- the compounds can be administered to a patient to treat an autoimmune disorder, for example, Addison’s disease, Amyotrophic Lateral Sclerosis, celiac disease, Crohn's disease, diabetes, eosinophilic fasciitis, Guillain-Barré syndrome (GBS), Graves’ disease, Lupus erythematosus, Miller-Fisher syndrome, psoriasis, rheumatoid arthritis, ulcerative colitis, and vasculitis.
- an autoimmune disorder for example, Addison’s disease, Amyotrophic Lateral Sclerosis, celiac disease, Crohn's disease, diabetes, eosinophilic fasciitis, Guillain-Barré syndrome (GBS), Graves’ disease, Lupus erythematosus, Miller-Fisher syndrome, psoriasis, rheumatoid arthritis, ulcerative colitis, and vasculitis.
- the compound provided herein can be used for treating a disease or disorder in a patient wherein the disease or disorder involves excessive or unregulated cellular proliferation, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I.
- a method for treating a disease or disorder in a patient where the disease or disorder involves the dysregulation of the PI3K-AKT-FOXO signaling pathway the method comprising administering to the patient a therapeutically effective amount of a compound of formula I.
- a method for treating a disease in a patient wherein the disease is characterized by proteotoxicity, including age onset proteotoxicity leading to neurodegeneration comprising administering to the patient a therapeutically effective amount of a compound of formula I.
- Hyperphosphorylated Tau has been implicated as the pathogenic protein in several neurodegenerative diseases and furthermore PP2A has been shown to be an important phosphatase in reversing aberrant phosphorylation of Tau; see for example Ludovic Martin et al., Tau protein phosphatases in Alzheimer’s disease: The leading role of PP2A in Ageing Research Reviews 12 (2013) 39- 49; Miguel Medina and Jesus Avila, Further understanding of tau phosphorylation: implications for therapy in Expert Rev.
- Hyperphosphorylated alpha-Synuclein is a second exemplar of a toxic protein, and again PP2A has been shown to reverse its aberrantly phosphorylated state; see for example Kang-Woo Lee et al., Enhanced Phosphatase Activity Attenuates alpha Synucleinopathy in a Mouse Model in Neurobiology of Disease, May 11, 2011, 31(19) 6963- 6971.
- the disease is selected from the group consisting of: Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration and Pick’s disease.
- a second feature of Alzheimer’s disease is deposition of amyloid plaques and phosphorylation of Amyloid Precursor Protein (APP) at threonine-668 in the cytoplasmic domain of APP is involved in it’s processing to generate toxic amyloid-beta (see T. Zhang et al, Int. J. Mol. Sci. 2020, 21, 209).
- APP Amyloid Precursor Protein
- Activation of PP2A by treatment with compounds of the present invention decreases threonine-668 phosphorylation and suppresses pathological amyloidogenesis contributing to the development of Alzheimer’s disease.
- the compounds provided herein may further be used in a method for treating a mood disorder in a patient by administering to the patient a therapeutically effective amount of a compound of formula I.
- the mood disorder is stress-induced depression.
- Phosphorylation and inactivation of FOXO1 by exclusion from the nucleus has been implicated in acne pathogenesis.
- Modulators of PP2A have also been shown to reduce markers of cellular senescence in human skin models, see Zonari et al, npj Aging (2023) 9:10. Activation of PP2A suppresses senescence associated secretory profile including expression of pro-inflamatory cytokines, for example IL-6, CXCL1 and CCL2, and reduces cellular senescence accumulation.
- pro-inflamatory cytokines for example IL-6, CXCL1 and CCL2
- the compounds may be administered by systemic administration or by topical (transdermal) delivery to affected skin.
- a method for treating age related skin deterioration in a patient by administering to the patient a therapeutically effective amount of a compound of formula I.
- a method for treating pulmonary disease such as COPD.
- Protein phosphatase 2A PP2A
- PP2A Protein phosphatase 2A
- PP2A has shown to be dysregulated in mouse models of COPD, and inhibiting PP2A activity exacerbated inflammatory responses in the lung.
- Idiopathic Pulmonary Fibrosis is a fatal lung disease in which there is progressive and irreversible scaring of the lung associated with changes to alveolar epithelial cells and aberrant fibroblast proliferation and activation.
- the underlying causative agent in IPF is usually unknown (hence idiopathic) and the prognosis after diagnosis is dismal with a median survival time of three years.
- IPF is characterized by a continuous expansion of the fibroblast population and excessive deposition of collagen in the alveolar wall leading to scarred, non- functional airspaces progressive hypoxia and death by asphyxiation.
- ECM extracellular matrix
- signaling via integrins activates PP2A and this suppresses fibroblast growth and proliferation.
- PP2A activation is muted; in these aberrant cells, uncontrolled fibroblast proliferation and collagen secretion occurs. Diminished PP2A signaling in PP2A fibroblasts has several consequences: 1.
- PP2A is known to be the phosphatase responsible for dephosphorylating cytoplasmic FOXO3a and promoting it’s nuclear translocation.
- phospho-Akt is a major kinase responsible for phosphorylation of FOXO3a
- PP2A is the phosphatase responsible for dephosphorylating and deactivating Akt.
- PP2A activation promotes FOXO3a activity in two ways, by suppressing the activity of a major kinase, Akt, that inactivates it, and second by dephosphorylating cytoplasmic phospho-FOXO3a directly to cause nuclear translocation.
- Deficient nuclear FOXO3 protects IPF fibroblasts from polymerized collagen matrix induced apoptosis, therefore PP2A activation will suppress growth of, and will induce apoptosis of IPF fibroblasts. 2.
- PP2A Activation of PP2A will suppress this signaling pathway from TGFb, a known and important pro-fibrotic cytokine. It is reasonable to conjecture that a similar pathway is operative in lung fibroblasts in IPF, thus PP2A activation should be useful there also. 4.
- PP2A negatively regulates Wnt/b-catenin signaling. Wnt3a induces lung epithelial cell proliferation, fibroblast activation and collagen synthesis in IPF. PP2A activation will suppress these processes and thus exert a therapeutic benefit in lung fibrosis and IPF. 5.
- RNAPII pausing in hyperactivated lung fibroblasts in IPF by PP2A activation suppresses the expression of fibrosis related genes such as smooth muscle actin (ACTA2), collagen genes (COL1A1, COL1A2 and COL3A1) and fibronectin (FN1)
- smooth muscle actin ACTA2
- collagen genes COL1A1, COL1A2 and COL3A1
- FN1 fibronectin
- Sattar et al Chemical Activation of Protein Phosphatase 2A Counters TGF ⁇ -Dependent Induction of Extracellular Matrix Proteins in Fibroblasts, Am J Respir Crit Care Med 2022; 205: A1941, poster presented PULMONARY FIBROSIS: ANIMAL AND CELL CULTURE MODELS / Thematic Poster Session / Sunday, May 15, 2022, San Francisco ATS meeting).
- PP2A is involved in several major signaling pathways implicated in the pathogenesis of lung fibrosis and IPF and in all the cases cited above PP2A activation is likely to exert a beneficial therapeutic effect. This implies that a well tolerated, effective, small molecule PP2A activator would constitute a novel therapeutic for lung fibrosis.
- NSCLC non-small cell lung cancer
- PP2A/AKT signaling has been observed in cellular models of idiopathic pulmonary hypertension, where it causes obstructive hyperproliferation and apoptosis resistance of distal pulmonary artery smooth muscle cells. Increasing PP2A activity may reverse this, thus, treatment with compounds of the present invention may be an effective treatment for pulmonary hypertension.
- a method for treating cardiac hypertrophy in a patient by administering to the patient a therapeutically effective amount of a compound of formula I.
- the cardiac hypertrophy is associated with a disease selected from hypertension, myocardial infarction, heart failure, and valvular heart disease.
- Cardiac physiology and hypertrophy are regulated by the phosphorylation status of many proteins, including receptors and ion channels, which is partly controlled by a PP2A-alpha4 intracellular signalling axis.
- Studies indicate that the type 2A protein phosphatases are differentially regulated in both the healthy and hypertrophied myocardium.
- treatment with compounds of the present invention may ameliorate cardiac hypertrophy.
- Examples of parasites that may cause parasitic infections to be treated include, but are not limited to, Plasmodium and Theileria.
- a method for treating inflammatory conditions is provided herein.
- Reduced PP2A activity occurs in animal models of allergic airway disease and patients with severe asthma.
- Treatment with small molecule activators of PP2A such as fingolimod (FTY720) or 2-amino-4-(4-(heptyloxy) phenyl)-2-methylbutan-1-ol (AAL(S)) inhibited the development of inflammation, airway hyperreactivity in mouse models of allergic airway disease.
- FTY720 fingolimod
- AAL(S) 2-amino-4-(4-(heptyloxy) phenyl)-2-methylbutan-1-ol
- compounds of the present invention may be useful in the treatment of asthma.
- TTP tristetraprolin
- PP2A protein phosphatase 2A
- TTP tristetraprolin
- PP2A enzymes are involved in the regulation of cell transcription, cell cycle, and viral transformation.
- the compounds provided herein may further be used in a method for treating a viral infection in a patient by administering to the patient a therapeutically effective amount of a compound of formula I.
- viruses that may cause viral infections to be treated include, but are not limited to: a polyomavirus, such as John Cunningham Virus (JCV), Simian virus 40 (SV40), or BK Virus (BKV); influenza, Human Immunodeficiency Virus type 1 (HIV-1), Human Papilloma Virus (HPV), adenovirus, Epstein-Barr Virus (EBV), Hepatitis C Virus (HCV), Molluscum contagiosum virus (MCV); Human T-lymphotropic virus type 1 HTLV-1), Herpes Simplex Virus type 1 (HSV-1), cytomegalovirus (CMV), hepatitis B virus, Bovine papillomavirus (BPV-1), human T-cell lymphotropic virus type 1, Japanese encephalitis virus, respiratory syncytial virus (RSV), and West Nile virus.
- a polyomavirus such as John Cunningham Virus (JCV), Simian virus 40 (SV40), or B
- Serine/Threonine phosphatases are involved in modulation of synaptic plasticity (D. G. Winder and J. D. Sweatt, Nature Reviews Neuroscience, vol 2, July 2001, pages 461–474). Persistently decreased PP2A activity is associated with maintenance of Long Term Potentiation (LTP) of synapses, thus treatment PP2A activators such as those described here may reverse synaptic LTP.
- Treatment PP2A activators such as those described here may reverse synaptic LTP.
- Psychostimulant drugs of abuse such as cocaine and methamphetamine are associated with deleterious synaptic LTP (L. Mao et al, Neuron 67, September 9, 2010 and A.
- PP2A activators described here may be useful as treatments for psychostimulant abuse.
- Abnormalities in synaptic structure and signaling are linked to autistic spectrum disorder, see for example, Y Chen et al., CTTNBP2, but not CTTNBP2NL, regulates dendritic spinogenesis and synaptic distribution of the striatin-PP2A complex, Molecular Biology of the Cell, 23, November 15, 2012, 4383-4392.
- PP2A has been shown to be important in normal development of dendritic spines, and treatment with compounds of the present invention may ameliorate or reverse autistic spectrum disorder.
- mTOR Mammalian target of rapamycin
- mTOR is a serine/threonineprotein kinase that regulates cell growth, proliferation, and survival: mTOR is frequently activated in human cancers and is a commonly sought anticancer therapeutic target.
- PP2A is a key element in mTOR-AKT signaling during nutritional deprivation, and it has important implications in cell cycle progression and quiescence.
- Dysregulation of cellular metabolism is a feature of cancer, with nutrient transport defects, nutrient sensing defects, dysregulated autophagy and constitutive anabolism being common in tumors; aberrant activation of mTOR is implicated in all of these processes and PP2A activation has been demonstrated to modulate them in vivo.
- PP2A has been shown to be involved in regulatory feedback loops with mTOR, and PP2A activators of the present invention would be expected to affect these processes directly by interacting with mTOR complexes, or indirectly by counterbalancing mTOR’s effects by dephosphorylating its targets.
- Perturbation of the mTOR signaling cascade appears to be a common pathophysiological feature of human neurological disorders, including mental retardation syndromes and autism spectrum disorders, and neurodegenerative conditions such as Alzhiemer’s disease.
- Activation of PP2A has been shown to be effective in animal models of neurodegenerative disease by modulating the PP2A mTOR axis; thus, molecules of the present invention will be useful in treatment of these conditions.
- PP2A activators of the present invention are likely to be useful in the treatment of diseases in which mTOR signaling is dysregulated; these include cancer, diabetes and neurodegenerative conditions.
- Compounds of the present invention may also promote innate immunity to infection and promote healthy aging.
- the compound is selected from a compound of Table 1, or a pharmaceutically acceptable salt thereof.
- Table 1 a pharmaceutically acceptable salt thereof.
- abbreviations and Definitions [00147] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs. A comprehensive list of abbreviations utilized by organic chemists (i.e. persons of ordinary skill in the art) appears in the first issue of each volume of the Journal of Organic Chemistry. The list, which is typically presented in a table entitled “Standard List of Abbreviations” is incorporated herein by reference. In the event that there is a plurality of definitions for terms cited herein, those in this section prevail unless otherwise stated.
- a step of a method or an element of a composition that “comprises”, “has”, “includes” or “contains” one or more features possesses those one or more features, but is not limited to possessing only those one or more features.
- the terms “comprising” and “including” or grammatical variants thereof are to be taken as specifying the stated features, integers, steps or components but do not preclude the addition of one or more additional features, integers, steps, components or groups thereof.
- "X includes a, b and c” means that X includes, but is not limited to, a, b and c. This term encompasses the terms “consisting of” and “consisting essentially of”.
- salts refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases.
- salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids.
- Suitable pharmaceutically acceptable acid addition salts for the compounds of the present invention include acetic, adipic, alginic, ascorbic, aspartic, benzenesulfonic (besylate), benzoic, boric, butyric, camphoric, camphorsulfonic, carbonic, citric, ethanedisulfonic, ethanesulfonic, ethylenediaminetetraacetic, formic, fumaric, glucoheptonic, gluconic, glutamic, hydrobromic, hydrochloric, hydroiodic, hydroxynaphthoic, isethionic, lactic, lactobionic, laurylsulfonic, maleic, malic, mandelic, methanesulfonic, mucic, naphthylenesulfonic, nitric, oleic, pamoic, pantothenic, phosphoric, pivalic, polygalacturonic, salicylic, stearic, succin
- suitable pharmaceutically acceptable base addition salts for the compounds of the present invention include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, arginine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
- Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium cations and carboxylate, sulfonate and phosphonate anions attached to alkyl having from 1 to 20 carbon atoms.
- subject or “subject in need thereof” or “patient” are used interchangeably herein. These terms refer to a patient who has been diagnosed with the underlying disorder to be treated. The subject may currently be experiencing symptoms associated with the disorder or may have experienced symptoms in the past. Additionally, a “subject in need thereof” may be a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological systems of a disease, even though a diagnosis of this disease may not have been made. As a non-limiting example, a "subject in need thereof", for purposes of this application, may include a male who is currently diagnosed with prostate cancer or was diagnosed with prostate cancer in the past, regardless of current symptomatology.
- a “patient,” as used herein, includes both humans and other animals, particularly mammals. Thus the methods are applicable to both human therapy and veterinary applications.
- the patient is a mammal, for example, a primate.
- the patient is a human.
- treatment or “treating are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including, but not limited to, therapeutic benefit.
- Therapeutic benefit includes eradication or amelioration of the underlying disorder being treated; it also includes the eradication or amelioration of one or more of the symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder.
- Treatment can involve administering a compound described herein to a patient diagnosed with a disease, and may involve administering the compound to a patient who does not have active symptoms. Conversely, treatment may involve administering the compositions to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
- the terms “administer”, “administering” or “administration” in reference to a dosage form of the invention refers to the act of introducing the dosage form into the system of subject in need of treatment.
- a dosage form of the invention is given in combination with one or more other active agents (in their respective dosage forms), “administration” and its variants are each understood to include concurrent and/or sequential introduction of the dosage form and the other active agents. Administration of any of the described dosage forms includes parallel administration, co-administration or sequential administration. In some situations, the therapies are administered at approximately the same time, e.g., within about a few seconds to a few hours of one another.
- a “therapeutically effective” amount of the compounds described herein is typically one which is sufficient to achieve the desired effect and may vary according to the nature and severity of the disease condition, and the potency of the compound. It will be appreciated that different concentrations may be employed for prophylaxis than for treatment of an active disease.
- a therapeutic benefit is achieved with the amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder.
- modulate with respect to PP2A refers to activation or potentiation of phosphatase activity by three general effects 1. direct allosteric activation of catalytic activity in PP2A complexes. 2. By promotion of assembly of heterotrimeric B subunit containing trimers, or recruitment of PP2A AC heterodimers to the Integrator-RNAPII complex. 3. By displacement of endogeneous PP2A inhibitors or chaparones, thereby derepressing PP2A activity.
- the term “modulate” with respect to a FOXO transcription factor protein refers to activation of the FOXO transcription factor protein and its biological activities associated with the FOXO pathway. Modulation of FOXO transcription factor proteins includes up- regulation (i.e., agonizing, activation or stimulation).
- the mode of action of a FOXO modulator can be direct, e.g., through binding to the FOXO transcription factor protein as a ligand. The modulation can also be indirect, e.g., through binding to and/or modifying another molecule which otherwise binds to and activates the FOXO transcription factor protein.
- Hydrocarbyl refers to any substituent comprised of hydrogen and carbon as the only elemental constituents.
- Aliphatic hydrocarbons are hydrocarbons that are not aromatic; they may be saturated or unsaturated, cyclic, linear or branched.
- alkyl refers to alkyl groups from 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms.
- alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, s- butyl, t-butyl and the like.
- Cycloalkyl is a subset of hydrocarbon and includes cyclic hydrocarbon groups of from 3 to 8 carbon atoms. Examples of cycloalkyl groups include cy-propyl, cy-butyl, cy- pentyl, norbornyl and the like.
- Alkoxy or alkoxyl refers to groups of from 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms of a straight or branched configuration attached to the parent structure through an oxygen.
- halogen means fluorine, chlorine, bromine or iodine atoms. In one embodiment, halogen may be a fluorine or chlorine atom.
- haloalkyl means alkyl, alkoxy, or alkylthio, respectively, substituted with one or more halogen atoms.
- Heterocycle means an aliphatic or aromatic carbocycle residue in which from one to four carbons is replaced by a heteroatom selected from the group consisting of N, O, and S.
- the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
- a heterocycle may be non- aromatic (heteroaliphatic) or aromatic (heteroaryl).
- heterocycles include pyrrolidine, pyrazole, pyrrole, indole, quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran, benzodioxan, benzodioxole (commonly referred to as methylenedioxyphenyl, when occurring as a substituent), tetrazole, morpholine, thiazole, pyridine, pyridazine, pyrimidine, thiophene, furan, oxazole, oxazoline, isoxazole, dioxane, tetrahydrofuran and the like.
- heterocyclyl residues include piperazinyl, piperidinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, tetrahydrofuryl, tetrahydropyranyl, thienyl (also historically called thiophenyl), benzothienyl, thiamorpholinyl, oxadiazolyl, triazolyl and tetrahydroquinolinyl.
- heteroaryls examples include imidazole, pyridine, indole, thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole.
- examples of heteroaryls include imidazole, pyridine, thiophene, thiazole, furan, pyrimidine, pyrazine, tetrazole and pyrazole.
- the term “optionally substituted” may be used interchangeably with “unsubstituted or substituted”.
- substituted refers to the replacement of one or more hydrogen atoms in a specified group with a specified radical.
- Oxo may also be included among the substituents referred to in “optionally substituted”; it will be appreciated by persons of skill in the art that, because oxo is a divalent radical, there are circumstances in which it will not be appropriate as a substituent (e.g. on phenyl).
- 1, 2, or 3 hydrogen atoms are replaced with a specified radical.
- more than three hydrogen atoms can be replaced by fluorine; indeed, all available hydrogen atoms could be replaced by fluorine. Table 1.
- Sulfonimidamides are isosteres of sulfonamides and their application in medicinal chemistry has been reviewed in Chinthakindi et al, Angew. Chem. Int. Ed. 2017, 56, 4100- 4109. Sulfonimidamides may improve physical and medicinal properties, versus the corresponding sulfonamides, with respect to solubility, lipophilicity, plasma protein binding or permeability. They may also have altered, and potentially beneficial, off-target profile versus the sulfonamides with respect to, for example CYP inhibition or PXR induction resulting in reduced potential for drug-drug inteactions or toxicity.
- Synthesis of sulfonimidamides of the present invention is achieved by reacting an amine intermediate A1, shown in General Synthesis Scheme 1, using a variety of methods disclosed in the scientific literature. See for example Nandi and Arvidsson, Sulfonimidamides: Synthesis and Applications in Preparative Organic Chemistry, Adv. Synth. Catal., 2018, 360, 2976-3001.
- One method is shown in General Synthesis Scheme 1 using an N-(alkyl)benzenesulfinamide sufinamide reagent which is activated with t-butyl hypochlorite in carbontetrachloride and reacted with amine intermediate A1.
- the alkyl group maybe lower alkyl, such as methyl and is thus R im .
- One example is N-(2,4- dimethoxybenzyl)-4-(trifluoromethoxy)benzenesulfinamide where the protecting group is 2,4-dimethoxybenzyl which is conveniently removed by acid treatment, as described in the examples below.
- [00173] General Synthesis Scheme 1 is shown in Fig.1.
- [00174] General synthesis of Amine Intermediates A1.
- the key reaction step is construction of the central tetrahydropyran ring by a modification of the Prins-Ritter conditions reported by Subba Reddy and Ghanty in Synthetic Communications, 2014, 44:17, pages 2545-2554. The main modifications are 1.
- N-(2-(10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)tetrahydro-2H-pyran-4-yl)acetamide is a colorless oil that crystallizes to give a white solid on pumping in vacuo: 0.73 g (2.3 mmole, 45%).
- N-(2-(10,11-dihydro-5H-dibenzo[a,d][7]annulen 5 yl)tetrahydro 2H pyran 4 yl)acetamide 0.86g (2.6 mmole, 1 equivalent) was placed in a 30 mL CEM microwave vial and dissolved in 15 mL dioxane. 5 mL of 6M hydrochloric acid was added and the mixture stirred briefly at room temperature, then heated in microwave at 150°C for 1 hour. The reaction was cooled and made basic by adding 2 g solid potassium hydroxide, then stirred at room temperature for 30 min as two phases form.
- N-(2,4-dimethoxybenzyl)-4-(trifluoromethoxy)benzenesulfinamide is a known compound and is prepared as follows: a mixture of 4-trifluoromethoxybenzenesulfonyl chloride (100 g, 383.7 mmole) and sodium sulfite (106.4 g, 844 mmole) and sodium bicarbonate (70.8 g, 844 mmole) in 1L of water was stirred at 65°C for 18 hours under argon atmosphere. The mixture was concentrated to remove water keeping the temperature below 60°C under vacuume.
- N-((2R,4S)-2-(10,11-dihydro-5H- dibenzo[a,d][7]annulen-5-yl)tetrahydro-2H-pyran-4-yl)-N'-(2,4-dimethoxybenzyl)-4- (trifluoromethoxy)benzenesulfonimidamide is carried out as follows: N (2,4 dimethoxybenzyl)-4-(trifluoromethoxy)benzenesulfinamide (1 equiv) is stirred with t-butyl hypochlorite (1.05 equiv) in carbon tetrachloride at 0°C for 1 hour in the dark.
- the reaction is concentrated to remove carbon tetrachloride keeping the temperature below 5°C, then the residue is dissolved in THF.
- the amine intermediate, 2-(10,11-dihydro-5H- dibenzo[a,d][7]annulen-5-yl)tetrahydro-2H-pyran-4-amine (1.05 equiv) and diisopropylethylamine (3 equiv) are added with stirring and cooling at 0°C, then the mixture is stirred at room temperature over night.
- the reaction is cooled and quenched with water and extracted with ethyl acetate.
- the combined organic is washed with brine, then dried over sodium sulfate.
- Example 1 Deprotection to the final product, Example 1, is carried out by dissolving the 2,4- dimethoxybenzyl protected compound in methylene chloride, cooling to 0°C, then adding adding trifluoroacetic acid to give a 1:1 solvent:acid ratio by volume. Saturated aqueous sodium bicarbonate is added till the mixture is pH 7-8, then the mixture is extracted with dichloromethane. The combined organic extracts are dried over sodium sulfate.
- Example 1 N-(2-(10,11-dihydro-5H-dibenzo[a,d][7]annulen-5- yl)tetrahydro-2H-pyran-4-yl)-4-(trifluoromethoxy)benzenesulfonimidamide, Example 1, as a mixture of diastereoisomers with respect to the sulfur chiral center.
- the amine intermediate from the Prins-Ritter synthesis is predominantly the cis diastereoisomer with respect to the central tetrahydropyran ring and this is depicted as Example 2 in Table 1.
- Example 3 is purified by flash chromatography eluting with ethyl actate-hexane.
- the mixture of diastereoisomers with respect to the sulfur center may be sparable on a flash column.
- Example 1 may also be separable into it’s diastereoisomers by techniques such as HPLC or crystallization. The separate diastereoisomers are depicted as Examples 3 and 4 in Table 1. [00182] Synthesis of Example 3 and Example 4 was carried out as shown in the scheme shown in Fig.3.
- N-(2-(10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)tetrahydro-2H-pyran-4-yl)-4- (trifluoromethoxy)benzenesulfonamide is a known compound and was synthesized as described in WO 2023/023594 as a single cis-diastereoisomer as shown above and labelled sulfonamide intermediate.
- reaction was diluted into 100 mL ethyl acetate then washed with 50 mL 0.1 M hydrochloric acid then 50 mL sat. aq. sodium bicarbonate. The organic was dried over anhydrous sodium sulfate, filetered and evaporated to give a brown oil. Careful flash chromatography eluting with 15% to 25% ethyl acetate separates the 2,4-dimethoxybenzyl protected imidamides as distereoisomers at the sulfur center as glassy foam after pumping in vacuo.
- Example 2 was dried over anhydrous sodium sulfate, then filtered and evaporated to give crude Example 2 as a 1:1 mixture of diastereoisomers at the sulfur center.
- the mixture was further purified by flash chromatography eluting with 30%–40% ethyl acetate in hexane. The diastereoisomers separate to give Example 2 and Example 3 as pale yellow solids after pumping in vacuo.
- Example 9 and Example 10 maybe prepared using the method described above from N-(2-(2,8-difluoro-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl) tetrahydro-2H-pyran-4- yl)-4-(trifluoromethoxy)benzenesulfonamide, as starting material where preparation is given in WO 2023/023594.
- Example 7 is prepared from 2-(bis(4-fluorophenyl)methyl)tetrahydro-2H-pyran-4- amine, synthesized as shown in Fig. 4, by coupling with N-(2,4-dimethoxybenzyl)-4- (trifluoromethoxy)benzenesulfinamide using the method described above for Example 1.
- the Prins-Ritter reaction used in the synthesis of Examples 1 and 7 gives mainly 2,4-cis relative stereochemistry across the central tetrahydropyran ring, see Subba Reddy and Ghanty in Synthetic Communications, 2014, 44:17, pages 2545-2554 and Yadav et al, Tetrahedron Letters 48 (2007) pages 4903-4906.
- Example 7 (Fig. 6). 2-(bis(4 fluorophenyl)methyl)tetrahydro 2H pyran-4-amine (Amine Intermediate A2 in the Fig. 4) was dissolved in 10 mL methylenechloride and 0.41 mL (2.4 mmole, 1.2 equiv) of Hunigs base was added followed by 0.41 mL (0.63g, 2.4 mmol, 1.2 equiv) of 4-trifluoromethoxybenzenesulfonyl chloride.
- N-(2-(bis(4-fluorophenyl)methyl)tetrahydro-2H-pyran-4-yl)-4- (trifluoromethoxy)benzenesulfonamide is a white solid: 400 MHz 1 H NMR in CDCl3 7.84 (m, 2H), 7.27 (m, 2H), 7.17 (m, 2H), 7.07 (m, 2H), 6.93 (m, 4H), 4.62 (d, 1H), 3.96 (m, 1H), 3.84 (m, 1H),, 3.78 (m, 1H), 3.42 (m, 1H), 3.36 (m, 1H), 1.72 (m, 1H), 1.58 (m, 1H), 1.37 (m, 1H), 1.04 (m, 1H).
- the reaction is cooled to 0°C then 2.4-dimethoxybenzylamine is added as a solution in chloroform and the mixture is stirred at between 0°C and room temperature for between 1 and 24 hours.
- the reaction is concentrated and then ether is added and the mixture stirred, then filtered. The filtrate is evaporated to give the crude product which is purified by flash chromatography. Deprotection is carried out by dissolving in dichloromethane, cooling to 0°C, and adding trifluoroacetic acid to give 1:1 CH2Cl2:TFA.
- the reaction is concentrated, then taken up in ethyl acetate and washed with aqueous sodium bicarbonate, then dried over sodium sulfate.
- Example 7 [00194] Alternate conditions used for synthesis of Example 7 were as follows: N-(2-(bis(4- fluorophenyl)methyl)tetrahydro-2H-pyran-4-yl)-4-(trifluoromethoxy)benzenesulfonamide, 0.527 g (1 mmole) and Hunigs base, 0.26 mL (0.19 g, 1.5 mmole, 1.5 equiv) were dissolved in 10 mL dry chloroform in a 35 mL microwave vial.
- Ph 3 PCl 2 0.4g (1.2mmole, 1.2 equiv) was added as a solid in one portion then the vial was sealed and the mixture was stirred and microwaved at 85°C for twelve minutes; mixture darkens on adding Ph 3 PCl 2 .
- the mixture was cooled to room temperature, then 2,4-dimethoxybenzylamine, 0.5 g (3 mmole, 3 equiv) was added and the mixture was stirred overnight at room temperature.
- the reaction was diluted with 100 mL dichloromethane and washed with 50 mL 1% citric acid then 50 mL sat. aq. sodium bicarbonate.
- Example 8 wherein R im is methyl maybe prepared by the route shown in Fig.7.
- N-Methyl-4-(trifluoromethoxy)benzenesulfonamide (1 equiv) in chloroform is added dropwise to a stirred suspension of Ph3PCl2 (1 equiv) in dry chloroform is added triethylamine (1.6 equiv). The mixture is stirred at between 0 and 50°C for between 30 minutes and 8 hours.
- D425 meduloblastoma cells were cultured in improved Dulbecco's modified Eagle's medium (DMEM) Richter's modification supplemented with 20% fetal bovine serum and 1% Penicillin-streptomycin. Incubation was performed at 37°C and 5% CO 2. [00200] D425 cells were seeded at 3000–3500 cells/90 ⁇ L growth medium per well on 96- well tissue culture plates. Cells were incubated overnight to allow them to recover. Next day cells were treated with tested compounds and incubated for 48 hours. [00201] Cell Proliferation assays in triplicate were performed at each concentration. Compounds test range was 1- 30 ⁇ M (0, 5, 10, 15, 20, 25, and 30). The compounds were dissolved in DMSO.
- DMEM Dulbecco's modified Eagle's medium
- Compounds test range was 1- 30 ⁇ M (0, 5, 10, 15, 20, 25, and 30).
- the compounds were dissolved in DMSO.
- a series of dilutions were made in 1% DMSO in growth medium so that the final concentration of DMSO is 0.1% in all of treatments.
- cells were allowed to equilibrate at room temperature for 1/2 to one hour.
- Cell proliferation was measured by Luminescence quantification using Promega CellTiter-Glo Luminescent Cell Viability Assay. To perform the assay, 100 ⁇ L of Celltiter- Glo substrate was added to each well, plates were shake for 2 minutes and allowed to equilibrate for 10 minutes at room temperature. Luminescence intensity was measured using the Spectramax i3x plate reader.
- A172 glioblastoma cells were cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum and 1% Penicillin-streptomycin. Incubation was performed at 37°C and 5% CO 2.
- DMEM Dulbecco's modified Eagle's medium
- A172 cells were seeded at 5x10 5 cells/2.5 ml growth medium (without antibiotics) per well on 6-well tissue culture plates. Cells were incubated overnight to allow them to recover and reattach.
- Malachite Green Phosphatase assays were performed in triplicate using 5ug of total protein per assay and following the manufacture's protocol (Sigma cat # MAK307). The amount of phosphate release in the assay was determined by measuring absorbance at 620 nm using the Spectramax i3x plate reader. [00216] The absorbance intensity data were analyzed using the computer software Graphpad Prism. The phosphate concentration for each sample was determined from the standard curve using phosphate standard concentrations. In order to compare samples, the first set (column A) were there was no transfection performed and no compound added, was designated a baseline; the absorbance measurement in this column was set as 100% phosphatase activity.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A genus of 2-diarylmethyl-4-aminotetrahydropyran derivatives is disclosed, which includes the following genus: The compounds activate cellular PP2A, suppress oncogenic kinase signaling and negatively regulate MYC and MYCN in cancer. The compounds also restrain transcription by activating PP2A-Integrator-RNAPII, and this activity also contributes the tumor suppressor property of PP2A in transcriptionally addicted cancers The compounds also induce FOXO transcription factor translocation to the nucleus by modulating PP2A and, as a consequence, exhibit anti-proliferative effects. They are useful in the treatment of a variety of disorders, including as a monotherapy in cancer treatment, or used in combination with other drugs to restore sensitivity to chemotherapy where resistance has developed.
Description
2-DIARYLMETHYL-4-AMINOTETRAHYDROPYRAN SULFONIMIDAMIDES AS ANTICANCER, ANTIINFLAMMATORY, ANTIFIBROTIC AND NEUROPROTECTIVE AGENTS RELATED APPLICATIONS [0001] This application claims priority of U.S. Provisional Patent Application No. 63/398,077, filed August 15, 2022, the entire content of which is incorporated herein by reference. FIELD OF THE INVENTION [0002] The invention relates to small molecule modulators of PP2A, comprising 2- diarylmethyl-4-aminotetrahydropyran sulfonimidamides, and their use to treat diseases such as cancer, inflammatory and autoimmune conditions, fibrotic and neurodegenerative diseases. BACKGROUND [0003] Protein phosphatase 2A is one of the four major serine threonine phosphatases and is implicated in the negative control of cell growth and division. Protein phosphatase 2A holoenzymes are composed of a structural subunit A and a catalytic subunit C which form a catalytically competent PP2A AC heterodimer. PP2A AC heterodimers then associate with a regulatory B subunit, which controls substrate specificity. Regulatory B subunits occur in four families and their expression is cell-type and context dependent. The PP2A heterotrimeric protein phosphatase is a ubiquitous and conserved phosphatase with diverse cellular functions. Among the targets of PP2A of the classical B-subunit containing holoenzymes are proteins of oncogenic signaling cascades, such as Raf, MEK, and AKT, and in this role they function as tumor suppressors. [0004] Recently PP2A AC heterodimers have been shown to interact directly with the INTS6 subunit of the Integrator Complex without any B subunit. Integrator associates with RNA Polymerase II (RNAPII) to control it’s transcriptional activity and PP2A AC associated Integrator acts to maintain RNAPII in a paused (i.e. transcriptionally stalled) state. This non- classical PP2A-Integrator complex thus functions to restrain transcription and this activity also contributes the tumor suppressor property of PP2A in transcriptionally addicted cancers, for example breast, lung, prostate, ovarian cancers glioblastoma, melanoma, leukemia, and
others in adults. Also in pediatric cancers such as neuroblastoma and medulloblastoma in children and infants. [0005] Myc proteins (c-myc, Mycn and Mycl) target proliferative and apoptotic pathways vital for progression in cancer and it is overexpressed and deregulated in many human cancers. The control of Myc abundance through protein degradation has attracted considerable interest and Ser-62 phosphorylation by a number of kinases has been shown to stabilize the protein. PP2A is responsible for Ser-62 dephosphorylation which primes the protein for ubiquitylation and degredation, thus PP2A functions as a negative regulator of Myc. [0006] The FOXO (Forkhead transcription factors, Class O) proteins are a group of transcription factors involved in control of a variety of physiological, metabolic and developmental pathways. They are downstream effectors in a number of signaling pathways including insulin and growth factor signaling; they are also regulated by oxidative stress and nutrient deprivation. Cellular processes affected by FOXO activity include cell cycle control, differentiation, proliferation, apoptosis and autophagy. Disregulation of FOXO mediated processes has been implicated in a number of pathologies including tumorigenesis, inflammation, fibrosis, diabetes, neurodegenerative and other age related conditions, amongst others. Activity of FOXO transcription factors are controlled in part by their sub-cellular localization, in particular their localization to the nucleus from the cytosol, and their subsequent transcriptional activation. [0007] FOXO1 regulates expression of a number of genes that play critical roles in cell cycle and apoptosis. A pivotal regulatory mechanism of FOXO is reversible phosphorylation, catalyzed by kinases and phosphatases. Phosphorylation of FOXO1 is associated with 14-3-3 binding and cytosolic localization, whereas dephosphorylated FOXO1 translocates to the nucleus and is transcriptionally active. FOXO3 is regulated in an analogous manner. [0008] PP2A interacts directly with FOXO1 and dephosphorylates FOXO1. Inhibition of PP2A phosphatases rescues FOXO1-mediated cell death by regulating the level of the pro- apoptotic protein BIM. In addition, PP2A directly regulates FOXO3a subcellular localization and transcriptional activation. Without wishing to be held to any particular theory, it may be that the compounds described herein promote apoptosis by acting on FOXO transcription factors via activation of PP2A.
[0009] Prostate cancer is the second leading cause of cancer death in men in America, behind lung cancer. According to the American Cancer Society, approximately 1 man in 36 will die of prostate cancer. Male hormones, specifically testosterone, fuel the growth of prostate cancer. By reducing the amount and activity of testosterone, the growth of advanced prostate cancer is slowed. Endocrine therapy, known as androgen ablation, is the first line of treatment for metastatic prostate cancer. Androgen deprivation therapy for metastatic prostate cancer results in tumor regression and symptomatic improvement in the majority of patients. However, metastatic prostate cancer inevitably progresses despite castrate levels of serum testosterone. Several new therapies have been approved for patients with castration-resistant prostate cancer (CRPC); however, none are curative and tumors ultimately develop resistance. To combat CRPC new approaches and novel therapies are required.
[0010] Breast cancer can affect both men and women. Breast cancer is the most prevalent cancer in women, after skin cancers, with about 1 in every 8 women expected to develop invasive breast cancer at some point. One subset of breast cancer expresses the androgen receptor (AR), which has been implicated as a therapeutic target in that subset. About 10- 20% of breast cancers — more than one out of every 10 — are found to be triple-negative. "Triple negative breast cancer" refers to a breast cancer that does not contain estrogen receptors, progesterone receptors, or human epidermal growth factor receptor 2 (HER2). This means that the growth of the cancer is not supported by the hormones estrogen and progesterone, nor by the presence of too many HER2 receptors. Therefore, triple-negative breast cancer does not respond to hormonal therapy (such as tamoxifen or aromatase inhibitors) or therapies that target HER2 receptors, such as Herceptin (chemical name: trastuzumab). While these tumors are often treatable, the chemotherapy is not targeted, and response durations are short. For doctors and researchers, there is intense interest in finding new medications that can treat breast cancer.
[0011] The compounds described herein, which are 2-diarylmethyl-4- aminotetrahydropyran sulfonimidamides, exhibit anti-proliferative effects by increasing PP2A activity in cells with suppressed or deficient phosphatase activity and are therefore useful as monotherapy in cancer treatment. Additionally, they can be used in combination with other drugs to restore sensitivity to chemotherapy where resistance has developed. The compounds may also be used in treatment of other diseases characterized by deficient PP2A activity, for example lung fibrosis and Alzheimer’s Disease.
SUMMARY OF THE INVENTION [0012] A genus of 2-diarylmethyl-4-aminotetrahydropyran sulfonimidamide and related compounds has now been found that modulate PP2A activity. The compounds deactivate pro- growth and pro-survival kinases such as phospo-ERK and phospho-AKT by promoting their deposphorylation by PP2A; they destabilize oncogenic MYC by promoting PP2A mediated dephoshorylation of MYC, and they promote RNAPII promoter proximal pausing during transcription. The compounds described herein exhibit anti-proliferative effects, and are useful in the treatment of a variety of disorders, including as a monotherapy in cancer treatment, or used in combination with other drugs to restore sensitivity to chemotherapy where resistance has developed. [0013] In a first aspect the invention relates to compounds of formula (I): wherein:
B is absent or is selected from a direct bond, -CH2CH2-, -CH=CH-, O, S, or -NRB- C(O)-; Q is selected from -O- or NRQ; Rim is selected from H or lower alkyl U, V and W are independently cabocyclic aromatic or heteroaromatic rings; n = 0 or 1; X1, X2, X3 and X4 are independently selected in each instance from hydrogen, halogen, nitro, cyano, (C1-C6)alkyl optionally substituted with -OH, (C1-C6)haloalkyl, (C1- C6)haloalkoxy, (C1-C6)haloalkylthio, -NR1R2, -OR1, -C(O)R1, -OC(O)R1, -C(O)NR1R2, - C(O)OR1, -SR1, -SO2R1, and -SO2NR1R2;
Y is H or hydroxyl Z1 and Z2 are independently selected in each instance from hydrogen, halogen, nitro, cyano, azido, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)haloalkylthio, - NR1R2, -NR1C(O)R2, -NR1C(O)OR3, -OR1, -C(O)R1, -OC(O)R1, -C(O)NR1R2, -C(O)OR1, - SR1, -SO2R1, -SO2NR1R2, and five membered heterocyclyl; RB is selected from H, or lower alkyl RQ is selected from H, optionally substituted lower alkyl, aryl R1, R2 and R3 are lower alkyl. [0014] In a second aspect, the invention relates to pharmaceutical compositions comprising the compounds described herein. [0015] In a third aspect, the invention relates to methods and uses of the above-described compounds in medicine, particularly for the treatment of a disease chosen from (a) cancer; (b) diabetes; (c) autoimmune disease; (d) age onset proteotoxic disease (particularly neurodegenerative disease); (e) mood disorder; (f) acne vulgaris; (g) solid organ transplant rejection (graft vs. host disease); (h) pulmonary disease (such as COPD or IPF); (i) cardiac hypertrophy and heart failure; (j) viral or parasitic infection; (k) inflammatory conditions (such as asthma) and (l) organ fibrosis (such as kidney fibrosis). These methods include administering to a patient a therapeutically effective amount of a compound described herein. [0016] In a fourth aspect, the invention relates to a method for restoring sensitivity to one or more chemotherapeutic agents in the treatment of cancer. The method includes administering an effective amount of a compound described herein. [0017] In a fifth aspect, the invention relates to a method for treating a disease or disorder in a patient where the disease or disorder involves the dysregulation of PP2A influenced signaling cascades such as the PI3K-AKT and MAP kinase pathways. These methods include administering to a patient a therapeutically effective amount of a compound described herein. [0018] In a sixth aspect, the invention relates to a method for treating a disease or disorder in a patient where the disease or disorder involves the dysregulation of a Myc dependent signaling pathway. These methods include administering to a patient a therapeutically effective amount of a compound described herein. [0019] In a seventh aspect, the invention relates to a method for treating a metabolic disease or disorder in a patient where the disease or disorder involves the dysregulation of the
mTOR-PP2A signaling axis. The method includes administering an effective amount of a compound described herein. [0020] In an eighth aspect, the invention relates to a method for treating disease or disorder in a patient where the disease or disorder involves cellular hyperproliferation or growth due to dysregulation of the PP2A-Integrator-RNAPII axis. BRIEF DESCRIPTION OF THE DRAWINGS [0021] Fig.1 depicts a general synthetic scheme for preparing compounds described herein, and intermediates useful therefor. [0022] Fig. 2 depicts a synthetic scheme for preparing Example 1, and intermediates useful therefor. [0023] Fig. 3 depicts a synthetic scheme for preparing Example 3 and Example 4, and intermediates useful therefor. [0024] Fig. 4 depicts a synthetic scheme for preparing an amine intermediate useful for preparing Example 7, and intermediates useful therefor. [0025] Fig. 5 depicts another general synthetic scheme for preparing compounds described herein, and intermediates useful therefor. [0026] Fig. 6 depicts a synthetic scheme for preparing Example 7, and intermediates useful therefor. [0027] Fig. 7 depicts a synthetic scheme for preparing Example 8, and intermediates useful therefor. DETAILED DESCRIPTION OF THE INVENTION [0028] Substituents are generally defined when introduced and retain that definition throughout the specification and in all independent claims. [0029] In a composition aspect, the invention relates to compounds of formula (I):
as described ab
[0030] In some embodiments, the invention relates to compounds of formula IIa, IIb, IIc or IId:
[0031] In addition
ran ring the sulfur atom of the sulfonimidamide is also a stable stereogenic chiral center and all of the stereoisomers above, IIa, IIb, IIc and IId may occur as diastereoisomers with either configuration at the sulfur center:
[0032] In the embodiments described herein, the compound may be of formula I, IIa, IIb, IIc, IId, IIe or IIf, unless otherwise indicated
[0033] In some embodiments Q is -O- with n=1, a tetrahydropyran [0034] In some embodiments Q is -NRQ- with n=1, a piperidine [0035] In some embodiments U and V are carbocyclic aromatic [0036] In some embodiments Q is -O- with n=1, Y=H and Rim=H, where U and V are carbocyclic aromatic .
. [0038] In some em
bodiments, B is absent. These embodiments are diarylmethyl compounds:
. [0039] In other emb
, oheptane compounds: . [0040] In still furt
her embodiments where Q is -O-, B is -CH2CH2-, W is carbocyclic aromatic: .
[0041] In some embodiments, X1, X2, X3, and X4 are independently selected in each instance from hydrogen, halogen, nitro, cyano, (C1-C6)alkyl optionally substituted with -OH, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)haloalkylthio, -NR1R2, -OR1, -C(O)R1, - OC(O)R1, -C(O)NR1R2, -C(O)OR1, -SR1, -SO2R1, and -SO2NR1R2. In other embodiments, X2
and X4 are each hydrogen. In still other embodiments, X and X are each hydrogen, and X and X3 are each chosen independently from -H, -F, -Cl, -CF3,-C(CH3)2OH, or -C(O)NMe2. In further embodiments, all of X1, X2, X3 and X4 are each hydrogen. In yet other embodiments, at least one of X1, X2, X3 and X4 is located at a carbon two positions away from a bridgehead carbon. [0042] In some embodiments, Z1 and Z2 are independently selected in each instance from hydrogen, halogen, nitro, cyano, azido, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)haloalkylthio, -NR1R2, -NR1C(O)R2, -NR1C(O)OR6, -OR1, -C(O)R1, -OC(O)R1, - C(O)NR1R2, -C(O)OR1, -SR1, -SO2R1, -SO2NR1R2, and five membered heterocyclyl. In other embodiments, Z1 is H. In still other embodiments, Z2 is chosen from hydrogen, halogen, and (C1-C6)haloalkoxy. In yet other embodiments, Z2 is chosen from hydrogen, F, Cl, and OCF3. In further embodiments, Z2 is in the para position. [0043] In some embodiments: B is absent or -CH2CH2-; Rim is selected from H or Me; Q is selected from -O- with n=1 or 0; U, V and W are carbocyclic aromatic; X2 and X4 are each hydrogen, and X1 and X3 are each chosen independently from -H, -F, -Cl, -CF3,-C(CH3)2OH, -C(O)NMe2; Y is H Z1 is hydrogen; and Z2 is selected in each instance from hydrogen, halogen, trifluoromethyl and (C1- C6)haloalkoxy. [0044] The compounds described herein contain asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms which may be defined in terms of absolute stereochemistry as (R)- or (S)-. The present invention is meant to include all such possible diastereomers as well as their racemic and optically pure forms. Optically active (R)- and (S)- isomers may be prepared using homo-chiral synthons or homo-chiral reagents. Final compounds or intermediates may be resolved in to their enantiomers using conventional techniques such crystallization of amine intermediates with chiral acids or preparative chiral chromatography on final compounds or intermediates. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified
otherwise, it is intended to include both (E)- and (Z) geometric isomers. Likewise, all tautomeric forms are intended to be included. [0045] The graphic representations of racemic, ambiscalemic and scalemic or enantiomerically pure compounds used herein are a modified version of the denotations taken from Maehr J. Chem. Ed. 62, 114-120 (1985): simple lines provide no information about stereochemistry and convey only connectivity; solid and broken wedges are used to denote the absolute configuration of a chiral element; solid and broken bold lines are geometric descriptors indicating the relative configuration shown but not necessarily denoting racemic character; and wedge outlines and dotted or broken lines denote enantiomerically pure compounds of indeterminate absolute configuration. For example, the graphic representations: nd
indicate each single absolute stereochemistry of the stereogenic carbon centers, with the sulfur chirality undefined. For the purpose of the present disclosure, a “pure” or “substantially pure” enantiomer is intended to mean that the enantiomer is at least 95% of the configuration shown and 5% or less of other enantiomers. The graphic representation:
indicates a unknown
bon centers, i.e., it could be either of the two structures shown above, as a substantially pure single stereochemistry. The graphic representations with bold solid and broken lines represent relative stereochemistry in racemic compounds. Thus racemic cis diastereoisomer with respect to the central ring:
And racemic trans diastereoisomer with respect to the central ring:
And, finally, the structure: conveys no inform
ure could be a single enantiomer or a mixture of enantiomers, including a racemic micture, or mixture of diastereoisomers. [0046] In any of these possiblities, compounds can be single cis enantiomers of formula IIa or formula IIb or single trans enantiomers formula IIc or formula IId, or a mixture of the two. If a mixture, the mixture will most commonly be racemic, but it need not be. Substantially pure single enantiomers of biologically active compounds such as those described herein often exhibit advantages over their racemic mixture. [0047] Various non-limiting embodiments of the present disclosure are described below. [0048] Thus, in some embodiments, provided herein are compounds of formula (I): wherein:
B is absent or is selected from a direct bond, -CH2CH2-, -CH=CH-, O, S, or - NRB-C(O)-;
Q is selected from -O- or NRQ; Rim is selected from H or lower alkyl; U, V and W are independently cabocyclic aromatic or heteroaromatic rings; n = 0 or 1; X1, X2, X3 and X4 are independently selected in each instance from hydrogen, halogen, nitro, cyano, (C1-C6)alkyl optionally substituted with -OH, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)haloalkylthio, -NR1R2, -OR1, -C(O)R1, -OC(O)R1, - C(O)NR1R2, -C(O)OR1, -SR1, -SO2R1, and -SO2NR1R2; Y is selected from hydrogen or hydroxyl Z1 and Z2 are independently selected in each instance from hydrogen, halogen, nitro, cyano, azido, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1- C6)haloalkylthio, -NR1R2, -NR1C(O)R2, -NR1C(O)OR3, -OR1, -C(O)R1, -OC(O)R1, - C(O)NR1R2, -C(O)OR1, -SR1, -SO2R1, -SO2NR1R2, and five membered heterocyclyl; RB is selected from H, or lower alkyl RQ is selected from H, optionally substituted lower alkyl, aryl R1, R2 and R3 are lower alkyl. [0049] In some embodiments, the compound of formula I is a compound of formula IIa: .
[0050] In some embodiments, the compound of formula I is a compound of formula IIb: .
[0051] In some embodiments of the formulae herein, B is absent. [0052] In some embodiments of the formulae herein, B is -(CH2)2-. [0053] In some embodiments of the formulae herein, B is a direct bond. [0054] In some embodiments of the formulae herein, B is -S-. [0055] In some embodiments of the formulae herein, Q is -O- with n = 1. [0056] In some embodiments of the formulae herein, Q is -O- with n = 0. [0057] In some embodiments of the formulae herein, Q is -NRQ- with n = 1. [0058] In some embodiments of the formulae herein, one of U or V is carbocyclic. [0059] In some embodiments of the formulae herein, both of U and V are carbocyclic. [0060] In some embodiments of the formulae herein, Rim is hydrogen. [0061] In some embodiments of the formulae herein, Rim is methyl. [0062] In some embodiments of the formulae herein, W is carbocyclic. [0063] In some embodiments of the formulae herein, W is heteroaromatic. [0064] In some embodiments of the formulae herein, X1, X2, X3, and X4 are independently selected in each instance from hydrogen, halogen, nitro, cyano, (C1-C6)alkyl optionally substituted with -OH, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)haloalkylthio, -NR1R2, - OR1, -C(O)R1, -OC(O)R1, -C(O)NR1R2, -C(O)OR1, -SR1, -SO2R1, and -SO2NR1R2. [0065] In some embodiments of the formulae herein, X2 and X4 are each hydrogen. [0066] In some embodiments of the formulae herein, X1 and X3 are each chosen independently from hydrogen, halogen, nitro, cyano, (C1-C6)alkyl optionally substituted with -OH, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)haloalkylthio, -NR1R2, -OR1, -C(O)R1, - OC(O)R1, -C(O)NR1R2, -C(O)OR1, -SR1, -SO2R1, and -SO2NR1R2. [0067] In some embodiments of the formulae herein, X1 and X3 are each chosen independently from -H, -F, -Cl, -CF3, -OMe, or -OCF3.
[0068] In some embodiments of the formulae herein, all of X , X , X and X are each hydrogen. [0069] In some embodiments of the formulae herein, Z1 and Z2 are independently selected in each instance from hydrogen, halogen, nitro, cyano, azido, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)haloalkylthio, -NR1R2, -NR1C(O)R2, -NR1C(O)OR6, -OR1, - C(O)R1, -OC(O)R1, -C(O)NR1R2, -C(O)OR1, -SR1, -SO2R1, -SO2NR1R2 and five membered hetercyclyl. [0070] In some embodiments of the formulae herein, Z1 and Z2 are independently selected in each instance from hydrogen, halogen, halo(C1-C6)alkyl, (C1-C6)alkoxy, and halo(C1- C6)alkoxy. [0071] In some embodiments of the formulae herein, Z1 is hydrogen. [0072] In some embodiments of the formulae herein, Z2 is chosen from hydrogen, halogen, and (C1-C6)haloalkoxy. [0073] In some embodiments of the formulae herein, Z2 is chosen from hydrogen, F, Cl, CF3, and trifluoromethoxy. [0074] In some embodiments of the formulae herein, Z2 is trifluoromethoxy. [0075] In some embodiments of the formulae herein, one of Z1 and Z2 is para to the sulfonyl amide. [0076] In some embodiments of the formulae herein, Z1 is hydrogen Z2 is para to the sulfonyl amide. [0077] In some embodiments, the compounds are provided as a composition. In some embodiments, the composition is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier. [0078] In some embodiments, provided herein are methods for treating a disease in a patient, wherein the disease is chosen from: (a) cancer (b) diabetes (c) autoimmune disease, such as rheumatoid arthritis or multiple sclerosis
(d) age onset proteotoxic disease, particularly neurodegenerative disease (e) mood disorder (f) acne vulgaris (g) solid organ transplant rejection (graft vs. host disease) (h) pulmonary disease, such as COPD or pulmonary fibrosis (i) cardiac hypertrophy and heart failure (j) viral or parasitic infection and (k) inflammatory conditions, such as asthma; the method comprising administering to the patient a therapeutically effective amount of a compound or composition provided herein. [0079] In some embodiments, said cancer is selected from the group consisting of: ovarian, endometrial, pancreatic, renal cell, breast, prostate, lung, hepatocellular carcinoma, glioma, leukemia, lymphoma, colorectal cancers, and sarcomas. [0080] In some embodiments, said cancer is chemotherapy resistant cancer. [0081] In some embodiments, the methods herein further comprise administering one or more additional cancer chemotherapeutic agents. [0082] In some embodiments, the methods or compounds herein are for treating an age onset proteotoxic disease, particularly neurodegenerative disease, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. [0083] In some embodiments, the methods or compounds herein are for treating a pulmonary disease. [0084] In some embodiments, the pulmonary disease is COPD, asthma, or pulmonary fibrosis. [0085] In some embodiments, the methods or compounds herein are for treating an inflammatory or autoimmune disease. [0086] In some embodiments, the inflammatory or autoimmune disease is multiple sclerosis.
[0087] Also provided herein are methods for restoring sensitivity to one or more chemotherapeutic agents in the treatment of cancer, the method comprising administering an effective amount of a compound or composition provided herein. [0088] Also provided herein are methods for treating a disease or disorder in a patient where the disease or disorder involves the dysregulation of the PI3K-AKT-FOXO signaling pathway, the method comprising administering to the patient a therapeutically effective amount of a compound or composition provided herein. [0089] Also provided herein are methods for treating a disease or disorder in a patient where the disease or disorder involves the dysregulation of a Myc dependent signaling pathway, the method comprising administering to the patient a therapeutically effective amount of a compound or composition provided herein. [0090] Also provided herein are methods for treating a metabolic or neurological disease or disorder in a patient wherein the disease or disorder involves the dysregulation of the mTOR- PP2A signaling axis, the method comprising administering to the patient a therapeutically effective amount of a compound or composition provided herein. [0091] In some embodiments, provided herein are compounds having a formula:
or a pharmaceutically acceptable salt thereof, wherein: B is absent or is selected from a direct bond, -CH2CH2-, -CH=CH-, O, S, or -NRB- C(O)-; Q is selected from -O- or NRQ; Rim is selected from hydrogen or lower alkyl;
U, V and W are independently cabocyclic aromatic or heteroaromatic rings; n = 0 or 1; X1, X2, X3 and X4 are independently selected in each instance from hydrogen, halogen, nitro, cyano, (C1-C6)alkyl optionally substituted with -OH, (C1-C6)haloalkyl, (C1- C6)haloalkoxy, (C1-C6)haloalkylthio, -NR1R2, -OR1, -C(O)R1, -OC(O)R1, -C(O)NR1R2, - C(O)OR1, -SR1, -SO2R1, and -SO2NR1R2; Y is selected from hydrogen or hydroxyl; Z1 and Z2 are independently selected in each instance from hydrogen, halogen, nitro, cyano, azido, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)haloalkylthio, - NR1R2, -NR1C(O)R2, -NR1C(O)OR3, -OR1, -C(O)R1, -OC(O)R1, -C(O)NR1R2, -C(O)OR1, - SR1, -SO2R1, -SO2NR1R2, and five membered heterocyclyl; RB is selected from H, or lower alkyl RQ is selected from H, optionally substituted lower alkyl, aryl R1, R2 and R3 are lower alkyl. [0092] In some embodiments of the compounds herein, each instance of lower alkyl is, independently, selected from C1-3 alkyl. [0093] In some embodiments, the compounds herein have a formula: or a pharmaceuticall
wherein J1 is H, F, Cl, Br, or I; J2 is H, F, Cl, Br, or I; J3 is H, F, Cl, Br, or I; J4 is H, F, Cl, Br, or I; J5 is H or OH; J6 is H or C1-6 alkyl; J7 is H, F, Cl, Br, I, CN, N3 C16 alkyl C16 alkoxyl, C1-6 haloalkyl, C1-6 haloalkoxyl;
J8 is H, F, Cl, Br, I, CN, N3, C1-6 alkyl, C1-6 alkoxyl, C1-6 haloalkyl, C1-6 haloalkoxyl; and J9 is H and J10 is H, or J9 and J10 together form an ethylene or ethenylene. [0094] In some embodiments of the compounds herein, J1 is H or F; J2 is H or F; J3 is H or F; J4 is H or F; J5 is H; J6 is H or C1-3 alkyl; J7 is H, C1-6 alkoxyl, or C1-6 haloalkoxyl; and J8 is H, C1-6 alkoxyl, or C1-6 haloalkoxyl. [0095] In some embodiments, provided herein are compounds having a formula: or a pharmaceutically
wherein J2 is H or F; J3 is H or F; J6 is H or CH3; and J8 is OCH3 or OCF3. [0096] In some embodiments, provided herein are compounds having a formula:
or a pharmaceutically acceptable salt thereof, wherein J2 is H or F; J3 is H or F; J6 is H or CH3; and J8 is OCH3 or OCF3. [0097] In some embodiments, provided herein are compounds having a formula: F3 , or a
[0098] In some embodiments, provided herein are compounds having a formula: , or a pha
[0099] In some embodiments, provided herein are compounds having a formula: , , or a
[00100] Also provided herein are pharmaceutical compositions comprising a compound disclosed above, or a pharmaceutically acceptable salt form thereof, and a pharmaceutically acceptable carrier or diluent. [00101] While it may be possible for the compounds of formula I to be administered as the raw chemical, it is preferable to present them as a pharmaceutical composition. According to a further aspect, the present invention provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically carriers thereof and optionally one or more other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. [00102] Formulations of the compounds and compositions described herein may be administered by a variety of methods: oral (including, but not limited to, capsules, cachets,
tablets, powder, granules, solutions, suspensions, emulsions, tablets, or sublingual tablets), buccal, by inhalation (by using, for instance, an inhaler, a nebulizer, an aerosol, a gas, etc.), nasal, topical (including, but not limited to, lotions, creams, ointments, patches (i.e., transdermal), gels, liniments, pastes), ophthalmic, to the ear, rectal (for instance, by using a suppository or an enema), vaginal, or parenteral, depending on the severity and type of the disease being treated. In some embodiments, the compositions are administered orally or intravenously. The formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intracranial, intravenous and intraarticular), rectal, vaginal, nasal (inhalation), and topical (including dermal, buccal, sublingual and intraocular) administration. The most suitable route may depend upon the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association a compound of formula (I) or a pharmaceutically acceptable salt thereof ("active ingredient") with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation. [00103] Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste. [00104] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide sustained, delayed or controlled release of the active ingredient therein. [00105] Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants buffers, bacteriostats and solutes which
render the formulation isotonic with the blood of the intended recipient. Formulations for parenteral administration also include aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. The formulations may be presented in unit-dose of multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example saline, phosphate-buffered saline (PBS) or the like, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. [00106] It will be recognized that the compounds of this invention can exist in radiolabeled form, i.e., the compounds may contain one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Radioisotopes of hydrogen, carbon, phosphorous, fluorine, and chlorine include 2H, 3H, 13C, 14C, 15N, 35S, 18F, and 36Cl, respectively. Compounds that contain those radioisotopes and/or other radioisotopes of other atoms are within the scope of this invention. Tritiated, i.e. 3H, and carbon-14, i.e., 14C, radioisotopes are particularly preferred for their ease in preparation and detectability. Compounds that contain isotopes 11C, 13N, 15O and 18F are well suited for positron emission tomography. Radiolabeled compounds of formula I of this invention and prodrugs thereof can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabeled compounds can be prepared by carrying out the procedures disclosed in the Examples and Schemes by substituting a readily available radiolabeled reagent for a non-radiolabeled reagent. [00107] In some embodiments, provided herein are kits, comprising a compound or composition described herein, and instructions for use. [00108] In some embodiments, provided herein are methods comprising administering a compound or composition described herein to a subject. [00109] In some embodiments, provided herein are methods of modulating a protein phosphatase 2A, comprising contacting the protein phosphatase 2A with a compound or composition described herein. [00110] In some embodiments, provided herein are methods of treating a protein phosphatase 2A related disease, comprising administering an effective amount of a compound or composition described herein to a subject in need thereof.
[00111] In some embodiments, provided herein are methods of treating a disease, comprising administering an effective amount of a compound or composition described herein to a subject in need thereof, wherein the disease comprises one or more of: (a) cancer; (b) diabetes; (c) autoimmune disease; (d) age onset proteotoxic disease; (e) mood disorder; (f) acne vulgaris; (g) solid organ transplant rejection; (h) pulmonary disease; (i) cardiac hypertrophy; (j) viral infection; (k) an inflammatory condition; (l) heart failure; or (m) parasitic infection. [00112] In some embodiments, provided herein are methods of restoring sensitivity to one or more chemotherapeutic agents in the treatment of cancer, comprising administering an effective amount of a compound or composition described herein to a subject in need thereof. [00113] In some embodiments, provided herein are methods of treating a disease or disorder in a patient where the disease or disorder involves the dysregulation of the PI3K-AKT-FOXO signaling pathway, comprising administering an effective amount of a compound or composition described herein to a subject in need thereof. [00114] In some embodiments, provided herein are methods of treating a disease or disorder in a patient where the disease or disorder involves the dysregulation of a Myc dependent signaling pathway, comprising administering an effective amount of a compound or composition described herein to a subject in need thereof. [00115] In some embodiments, provided herein are methods of treating a metabolic or neurological disease or disorder in a patient wherein the disease or disorder involves the dysregulation of the mTOR-PP2A signaling axis, comprising administering an effective amount of a compound or composition described herein to a subject in need thereof.
[00116] The compounds provided herein can be used for treating cancer in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I. In some embodiments, the cancer is characterized by dysregulation of the PI3K-AKT-FOXO signaling pathway. For example, the cancer can be selected from the group consisting of: ovarian, pancreatic, renal cell, breast, prostate, lung, hepatocellular carcinoma, glioma, leukemia, lymphoma, colorectal cancers, and sarcomas. [00117] In some embodiments, the cancer is chemotherapy resistant cancer. In some embodiments, the method further comprises administering one or more cancer chemotherapeutic agents. In some embodiments, the one or more cancer chemotherapeutic agents are EGFR inhibitors. [00118] In some embodiments, the cancer is chemotherapy resistant cancer. In some embodiments, the method further comprises administering one or more cancer chemotherapeutic agents targeting transcriptional dysregulation. In some embodiments, the one or more cancer chemotherapeutic agents are CDK inhibitors, particularly CDK9 and/or CDK7 inhibitors. [00119] In some embodiments, the cancer is chemotherapy resistant cancer. In some embodiments, the method further comprises administering one or more cancer chemotherapeutic agents. In some embodiments, the one or more cancer chemotherapeutic agents are mTOR inhibitors. [00120] Certain cancers are characterized by dysregulation and overactivation of cellular transcription carried out by RNA polymerase II (RNAPII) as described in Transcriptional Addiction in Cancer. Bradner, J. E., Hnisz, D. and Young, R. A. February 2017, Cell, Vol. 168, pp. 629-643. BRD4, a member of the bromodomain and extra-terminal domain (BET) family of epigenetic readers, occupies super-enhancers co-opted in transcriptionally addicted cancer cells, and recruits pTEFb to RNAPII to enable promoter proximal pause release and maintain productive elongation (see, for example, Control of Embryonic Stem Cell Identity by BRD4-Dependent Transcriptional Elongation of Super-Enhancer-Associated Pluripotency Genes. Di Micco, R., et al. October 2014, Cell Reports, Vol. 9, pp. 234-247). Therefore BRD4 inhibitor (BRD4i) treatment synergizes with PP2A activation in two ways, first by suppressing BRD4 mediated recruitment of pTEFb to paused RNAPII. A second mode of synergy with BRD4i treatment is by reversing the activating phosphorylation of BRD4 itself by PP2A complexes (see Phospho-BRD4: transcription plasticity and drug targeting.
Chiang, C. 2016, Drug Discov Today: Technol, http://dx.doi.org/10.1016). The compounds provided herein can be used for treating cancer in a patient where there is transcriptional dysregulation, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I and a BRD4 inhibitor. Cancers characterized by transcriptional addiction include Breast Cancer, Osteosarcoma, Endometrial Cancer, Acute Myeloid Leukemia, Lung Cancer, Prostate Cancer, Melanoma and Ovarian Cancer. [00121] In some embodiments, administration of a compound of formula I can restore sensitivity to one or more chemotherapeutic agents in a patient wherein the patient has developed a resistance to the one or more chemotherapeutic agents. More particularly, cancers that may be treated by the compounds, compositions and methods described herein include, but are not limited to, the following: cardiac cancers, including, for example sarcoma, e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma; myxoma; rhabdomyoma; fibroma; lipoma and teratoma; lung cancers, including, for example, bronchogenic carcinoma, e.g., squamous cell, undifferentiated small cell, undifferentiated large cell, and adenocarcinoma; alveolar and bronchiolar carcinoma; bronchial adenoma; sarcoma; lymphoma; chondromatous hamartoma; and mesothelioma; gastrointestinal cancer, including, for example, cancers of the esophagus, e.g., squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma; cancers of the stomach, e.g., carcinoma, lymphoma, and leiomyosarcoma; cancers of the pancreas, e.g., ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, and vipoma; cancers of the small bowel, e.g., adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, and fibroma; cancers of the large bowel, e.g., adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, and leiomyoma; genitourinary tract cancers, including, for example, cancers of the kidney, e.g., adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, and leukemia; cancers of the bladder and urethra, e.g., squamous cell carcinoma, transitional cell carcinoma, and adenocarcinoma; cancers of the prostate, e.g., adenocarcinoma, and sarcoma; cancer of the testis, e.g., seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, and lipoma;
liver cancers, including, for example, hepatoma, e.g., hepatocellular carcinoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma; hepatocellular adenoma; and hemangioma; bone cancers, including, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochrondroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; nervous system cancers, including, for example, cancers of the skull, e.g., osteoma, hemangioma, granuloma, xanthoma, and osteitis deformans; cancers of the meninges, e.g., meningioma, meningiosarcoma, and gliomatosis; cancers of the brain, e.g., astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, and congenital tumors; and cancers of the spinal cord, e.g., neurofibroma, meningioma, glioma, and sarcoma; gynecological cancers, including, for example, cancers of the uterus, e.g., endometrial carcinoma; cancers of the cervix, e.g., cervical carcinoma, and pre tumor cervical dysplasia; cancers of the ovaries, e.g., ovarian carcinoma, including serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granulosa thecal cell tumors, Sertoli Leydig cell tumors, dysgerminoma, and malignant teratoma; cancers of the vulva, e.g., squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, and melanoma; cancers of the vagina, e.g., clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma, and embryonal rhabdomyosarcoma; and cancers of the fallopian tubes, e.g., carcinoma; hematologic cancers, including, for example, cancers of the blood, e.g., acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, and myelodysplastic syndrome, Hodgkin's lymphoma, non Hodgkin's lymphoma (malignant lymphoma) and Waldenström's macroglobulinemia; skin cancers, including, for example, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and adrenal gland cancers, including, for example, neuroblastoma. [00122] Cancers may be solid tumors that may or may not be metastatic. Cancers may also occur, as in leukemia, as a diffuse tissue
[00123] The compounds described herein can also be administered in combination with existing methods of treating cancers, for example by chemotherapy, irradiation, or surgery. Thus, there is further provided a method of treating cancer comprising administering an effective amount of a compound according to formula I to a patient, wherein a therapeutically effective amount of one or more additional cancer chemotherapeutic agents are administered to the patient. [00124] Also provided herein is a method for treating diabetes in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I. [00125] Further provided herein is a method for treating an autoimmune disease in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I. The autoimmune disease can be, for example, inflammatory bowel disease (IBD). Immune responses are constantly and tightly regulated and one important cellular component in maintaining self tolerance (i.e., prevention of autoimmunity) and tolerance of benign commensal gut flora are regulatory T cells (Treg). Treg can be subdivided into multiple phenotypes, but the most common are CD4+CD25+ T cells that express the transcription factor Foxp3. Foxp3 is a direct transcriptional target of FOXO proteins, particularly FOXO1 and FOXO3. Thus activation of FOXO proteins in naïve T- cells promotes and directs differentiation to maintain a population of Treg cells. [00126] Acute immune mediated rejection and chronic immune mediated rejection are key obstacles to successful solid organ transplantation. It is believed that these forms of rejection can be prevented/overcome by amplifying Treg number and or function. Similarly, a common and morbid complication of allogeneic hematopoietic cell transplants (Allo-HCT) used to treat various malignant and non-malignant conditions, is graft versus host disease, in which the transplanted immune cells from the donor damage multiple organs in the recipient (most notably skin, gut, and liver). Increasing experimental and clinical data indicate that Tregs can be harnessed to prevent and or treat this disease process. [00127] Thus compounds of the present invention are useful in treatment of autoimmune and related diseases, by activating FOXO proteins and inducing T cell differentiation to Tregs. Compounds may be administered therapeutically to subjects directly, or alternatively, T cells may be collected from a subject and differentiated ex vivo to Tregs as described by Taylor et al. [Blood 99, 3493-3499 (2002)].
[00128] Aspects of the invention include methods for treatment of autoimmune disease characterized by deficiency in Treg function comprising administering a therapeutically useful amount of compound of formula I. The method can also include extraction of naïve T- cells from a patient, differentiation of T-cells to Tregs ex vivo by treatment with a compound of formula I, optionally supplemented with an HDACi, followed by administration of Tregs to patient with optional separation of compound of formula I from Tregs prior to their administration. As stated above, autoimmune diseases that can be so treated include IBD, solid organ transplant rejection, and GvHD in allo-HCT. [00129] In some embodiments, the compounds can be administered to a patient to treat an autoimmune disorder, for example, Addison’s disease, Amyotrophic Lateral Sclerosis, celiac disease, Crohn's disease, diabetes, eosinophilic fasciitis, Guillain-Barré syndrome (GBS), Graves’ disease, Lupus erythematosus, Miller-Fisher syndrome, psoriasis, rheumatoid arthritis, ulcerative colitis, and vasculitis. In some embodiments, the compound provided herein can be used for treating a disease or disorder in a patient wherein the disease or disorder involves excessive or unregulated cellular proliferation, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I. Also provided herein is a method for treating a disease or disorder in a patient where the disease or disorder involves the dysregulation of the PI3K-AKT-FOXO signaling pathway, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I. [00130] Further provided herein is a method for treating a disease in a patient wherein the disease is characterized by proteotoxicity, including age onset proteotoxicity leading to neurodegeneration, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I. Hyperphosphorylated Tau has been implicated as the pathogenic protein in several neurodegenerative diseases and furthermore PP2A has been shown to be an important phosphatase in reversing aberrant phosphorylation of Tau; see for example Ludovic Martin et al., Tau protein phosphatases in Alzheimer’s disease: The leading role of PP2A in Ageing Research Reviews 12 (2013) 39- 49; Miguel Medina and Jesus Avila, Further understanding of tau phosphorylation: implications for therapy in Expert Rev. Neurotherapy, 15(1), 115-112 (2015) and Michael Voronkov et al., Phosphoprotein phosphatase 2A: a novel druggable target for Alzheimer’s disease in Future Med Chem.2011 May, 3(7) 821-833. Hyperphosphorylated alpha-Synuclein is a second exemplar of a toxic protein, and again PP2A has been shown to reverse its aberrantly phosphorylated state; see
for example Kang-Woo Lee et al., Enhanced Phosphatase Activity Attenuates alpha Synucleinopathy in a Mouse Model in Neurobiology of Disease, May 11, 2011, 31(19) 6963- 6971. In some embodiments, the disease is selected from the group consisting of: Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration and Pick’s disease. [00131] A second feature of Alzheimer’s disease is deposition of amyloid plaques and phosphorylation of Amyloid Precursor Protein (APP) at threonine-668 in the cytoplasmic domain of APP is involved in it’s processing to generate toxic amyloid-beta (see T. Zhang et al, Int. J. Mol. Sci. 2020, 21, 209). Activation of PP2A by treatment with compounds of the present invention decreases threonine-668 phosphorylation and suppresses pathological amyloidogenesis contributing to the development of Alzheimer’s disease. [00132] The compounds provided herein may further be used in a method for treating a mood disorder in a patient by administering to the patient a therapeutically effective amount of a compound of formula I. In some embodiments, the mood disorder is stress-induced depression. [00133] Phosphorylation and inactivation of FOXO1 by exclusion from the nucleus has been implicated in acne pathogenesis. These effects may be mediated by direct transcriptional inactivation of FOXO1 target genes or indirectly by loss of repressive interaction with other nuclear transcription factors such as the androgen receptor which contribute to acne pathogenesis, see Melnik, British Journal of Dermatology (2010) 162, pp 1398-1400, DOI: 10.1111/j.1365-2133.2010.09754.x, and Teng et al Cells (2021) 10, 1219, doi.org/10.3390/cells10051219. The compounds provided herein are there fore useful in the treatment of acne vulgaris via PP2A mediated nuclear localization of FOXO1 and deactivation of Akt signaling. The compounds may be administered by systemic administration or by topical(transdermal) delivery to affected skin. Also provided herein is a method for treating acne vulgaris in a patient by administering to the patient a therapeutically effective amount of a compound of formula I. [00134] Modulators of PP2A have also been shown to reduce markers of cellular senescence in human skin models, see Zonari et al, npj Aging (2023) 9:10. Activation of PP2A suppresses senescence associated secretory profile including expression of pro-inflamatory cytokines, for example IL-6, CXCL1 and CCL2, and reduces cellular senescence
accumulation. Thus compounds of the present invention are likely to useful as agents to slow or prevent age related skin deterioration. The compounds may be administered by systemic administration or by topical (transdermal) delivery to affected skin. Also provided herein is a method for treating age related skin deterioration in a patient by administering to the patient a therapeutically effective amount of a compound of formula I. [00135] Further provided herein is a method for treating pulmonary disease such as COPD. Protein phosphatase 2A (PP2A) is a primary serine-threonine phosphatase that modulates inflammatory responses in asthma and COPD. PP2A has shown to be dysregulated in mouse models of COPD, and inhibiting PP2A activity exacerbated inflammatory responses in the lung. Conversely, increasing PP2A activity via PP2A protein transfection down regulated cytokine expression and prevented the induction of proteases following cigarette smoke extract (CSE) treatment. Thus, increasing PP2A activity by treatment with compounds of the present invention may ameliorate or reverse the pathology underlying lung diseases such as COPD. [00136] Idiopathic Pulmonary Fibrosis is a fatal lung disease in which there is progressive and irreversible scaring of the lung associated with changes to alveolar epithelial cells and aberrant fibroblast proliferation and activation. The underlying causative agent in IPF is usually unknown (hence idiopathic) and the prognosis after diagnosis is dismal with a median survival time of three years. IPF is characterized by a continuous expansion of the fibroblast population and excessive deposition of collagen in the alveolar wall leading to scarred, non- functional airspaces progressive hypoxia and death by asphyxiation. In normal lung tissue fibroblasts interact with the extracellular matrix (ECM) and signaling via integrins activates PP2A and this suppresses fibroblast growth and proliferation. In IPF fibroblasts this signaling is defective and PP2A activation is muted; in these aberrant cells, uncontrolled fibroblast proliferation and collagen secretion occurs. Diminished PP2A signaling in PP2A fibroblasts has several consequences: 1. Excessive phosphorylation of the transcription factor FOXO3a, which leads to exit of phospho-FOXO3a from the nucleus to the cytoplasm where it is sequestered by 14-3-3 proteins. PP2A is known to be the phosphatase responsible for dephosphorylating cytoplasmic FOXO3a and promoting it’s nuclear translocation. Activated, phospho-Akt is a major kinase responsible for phosphorylation of FOXO3a and PP2A is the phosphatase responsible for dephosphorylating and deactivating Akt. Thus PP2A activation promotes FOXO3a activity in two ways, by suppressing the activity of a major kinase, Akt, that inactivates it, and second by dephosphorylating cytoplasmic phospho-FOXO3a directly
to cause nuclear translocation. Deficient nuclear FOXO3 protects IPF fibroblasts from polymerized collagen matrix induced apoptosis, therefore PP2A activation will suppress growth of, and will induce apoptosis of IPF fibroblasts. 2. Low PP2A activity in IPF fibroblasts results in HDAC4 hyperphosphorylation and decreases it’s nuclear localization, thus the histones of it’s target genes remain acetylated and transcriptionally active which drives excessive collagen secretion from IPF fibroblasts. Thus PP2A activation, by promoting HDAC4 nuclear translocation, will suppress excessive the excessive collagen secretion characteristic of IPF and other systemic fibrotic diseases.3. Activated phosph-ERK is a direct target of PP2A, which it dephosphorylates and deactivates. In scleroderma fibroblasts TGFb reduces PP2A activity and promotes ERK signaling and excessive collagen production. Activation of PP2A will suppress this signaling pathway from TGFb, a known and important pro-fibrotic cytokine. It is reasonable to conjecture that a similar pathway is operative in lung fibroblasts in IPF, thus PP2A activation should be useful there also. 4. PP2A negatively regulates Wnt/b-catenin signaling. Wnt3a induces lung epithelial cell proliferation, fibroblast activation and collagen synthesis in IPF. PP2A activation will suppress these processes and thus exert a therapeutic benefit in lung fibrosis and IPF. 5. Promotion of RNAPII pausing in hyperactivated lung fibroblasts in IPF by PP2A activation suppresses the expression of fibrosis related genes such as smooth muscle actin (ACTA2), collagen genes (COL1A1, COL1A2 and COL3A1) and fibronectin (FN1) (see Sattar et al, Chemical Activation of Protein Phosphatase 2A Counters TGFβ-Dependent Induction of Extracellular Matrix Proteins in Fibroblasts, Am J Respir Crit Care Med 2022; 205: A1941, poster presented PULMONARY FIBROSIS: ANIMAL AND CELL CULTURE MODELS / Thematic Poster Session / Sunday, May 15, 2022, San Francisco ATS meeting). Therefore compounds of the present invention exert a useful therapeutic effect in IPF by suppression of these genes and reducing excesive collagen deposition and scarring in IPF. In summary, PP2A is involved in several major signaling pathways implicated in the pathogenesis of lung fibrosis and IPF and in all the cases cited above PP2A activation is likely to exert a beneficial therapeutic effect. This implies that a well tolerated, effective, small molecule PP2A activator would constitute a novel therapeutic for lung fibrosis. [00137] Tumor associated fibrosis in non-small cell lung cancer (NSCLC) impairs immune surveillance and diminishes the effectiveness of immune checkpoint blockade in treatment of NSCLC, see Herzog et al, Science Translational Medicine, 15 eadh8005 (2023). Compounds of the present invention, which activate the tumor suppressor PP2A and, which display antifibrotic effects as described in paragraph [00136] above are therefore likely to be
particularly useful in treatment of NSCLC. Compounds of the present invention may also be used in combination with PD-1/PD-L1 checkpoint blockade where resistance to this therapy is manifest because of tumor fibrosis. [00138] Impaired PP2A/AKT signaling has been observed in cellular models of idiopathic pulmonary hypertension, where it causes obstructive hyperproliferation and apoptosis resistance of distal pulmonary artery smooth muscle cells. Increasing PP2A activity may reverse this, thus, treatment with compounds of the present invention may be an effective treatment for pulmonary hypertension. [00139] Further provided herein is a method for treating cardiac hypertrophy in a patient by administering to the patient a therapeutically effective amount of a compound of formula I. In some embodiments, the cardiac hypertrophy is associated with a disease selected from hypertension, myocardial infarction, heart failure, and valvular heart disease. Cardiac physiology and hypertrophy are regulated by the phosphorylation status of many proteins, including receptors and ion channels, which is partly controlled by a PP2A-alpha4 intracellular signalling axis. Studies indicate that the type 2A protein phosphatases are differentially regulated in both the healthy and hypertrophied myocardium. The data suggest that pressure overload-induced hypertrophy is associated with (1) altered expression of type 2A protein phosphatases and their regulatory subunits and (2) an increase in expression of their non-catalytic inhibitor protein alpha4. Thus, treatment with compounds of the present invention may ameliorate cardiac hypertrophy. Also, significant reduction in endosomal PP2A activity has been observed in heart failure samples versus controls, suggesting that inhibited resensitization of beta-adrenergic receptors occurs in human heart failure. These studies suggest that resensitization of beta adrenergic receptors is inhibited in human heart failure and targeting the PP2A inhibitor SET to derepress and activate PP2A may provide preservation of receptor function and beneficial cardiac remodeling. Thus, treatment with compounds of the present invention may have a beneficial effect in heart failure. [00140] Further provided herein is a method for treating a parasitic infection in a patient by administering to the patient a therapeutically effective amount of a compound of formula I. Examples of parasites that may cause parasitic infections to be treated include, but are not limited to, Plasmodium and Theileria. [00141] Further provided herein is a method for treating inflammatory conditions. Reduced PP2A activity occurs in animal models of allergic airway disease and patients with severe asthma. Treatment with small molecule activators of PP2A such as fingolimod (FTY720) or
2-amino-4-(4-(heptyloxy) phenyl)-2-methylbutan-1-ol (AAL(S)) inhibited the development of inflammation, airway hyperreactivity in mouse models of allergic airway disease. Thus, compounds of the present invention may be useful in the treatment of asthma. Dephosphorylation of tristetraprolin (TTP) functions as an “off-switch” in inflammatory responses, and it’s activity can be promoted by compounds that stimulate PP2A activity. Therapeutic efficacy of protein phosphatase 2A (PP2A)-activating drugs, to target tristetraprolin (TTP), in models of rheumatoid arthritis has been demonstrated in vitro and in vivo. Thus, treatment with compounds of the present invention may be useful in chronic inflammatory conditions such as rheumatoid arthritis. [00142] PP2A enzymes are involved in the regulation of cell transcription, cell cycle, and viral transformation. Many viruses, including cytomegalovirus, parainfluenza, DNA tumor viruses, and HIV-1, utilize different approaches to exploit PPA2 in order to modify, control, or inactivate cellular activities of the host [Garcia et al., Microbes and Infection, 2, 2000, 401−407]. Therefore, the compounds provided herein may further be used in a method for treating a viral infection in a patient by administering to the patient a therapeutically effective amount of a compound of formula I. Examples of viruses that may cause viral infections to be treated include, but are not limited to: a polyomavirus, such as John Cunningham Virus (JCV), Simian virus 40 (SV40), or BK Virus (BKV); influenza, Human Immunodeficiency Virus type 1 (HIV-1), Human Papilloma Virus (HPV), adenovirus, Epstein-Barr Virus (EBV), Hepatitis C Virus (HCV), Molluscum contagiosum virus (MCV); Human T-lymphotropic virus type 1 HTLV-1), Herpes Simplex Virus type 1 (HSV-1), cytomegalovirus (CMV), hepatitis B virus, Bovine papillomavirus (BPV-1), human T-cell lymphotropic virus type 1, Japanese encephalitis virus, respiratory syncytial virus (RSV), and West Nile virus. [00143] Serine/Threonine phosphatases, including PP2A, are involved in modulation of synaptic plasticity (D. G. Winder and J. D. Sweatt, Nature Reviews Neuroscience, vol 2, July 2001, pages 461–474). Persistently decreased PP2A activity is associated with maintenance of Long Term Potentiation (LTP) of synapses, thus treatment PP2A activators such as those described here may reverse synaptic LTP. Psychostimulant drugs of abuse such as cocaine and methamphetamine are associated with deleterious synaptic LTP (L. Mao et al, Neuron 67, September 9, 2010 and A. Stipanovich et al, Nature vol 453, 2008, pages 879–884), which may underlie the pathology of addiction and relapse therefore PP2A activators described here may be useful as treatments for psychostimulant abuse.
[00144] Abnormalities in synaptic structure and signaling are linked to autistic spectrum disorder, see for example, Y Chen et al., CTTNBP2, but not CTTNBP2NL, regulates dendritic spinogenesis and synaptic distribution of the striatin-PP2A complex, Molecular Biology of the Cell, 23, November 15, 2012, 4383-4392. PP2A has been shown to be important in normal development of dendritic spines, and treatment with compounds of the present invention may ameliorate or reverse autistic spectrum disorder. [00145] Further provided herein is a method for treating a disease or disorder in which the disease or disorder involves the dysregulation of the mTOR-PP2A signaling axis. Mammalian target of rapamycin (mTOR) is a serine/threonineprotein kinase that regulates cell growth, proliferation, and survival: mTOR is frequently activated in human cancers and is a commonly sought anticancer therapeutic target. PP2A is a key element in mTOR-AKT signaling during nutritional deprivation, and it has important implications in cell cycle progression and quiescence. Dysregulation of cellular metabolism is a feature of cancer, with nutrient transport defects, nutrient sensing defects, dysregulated autophagy and constitutive anabolism being common in tumors; aberrant activation of mTOR is implicated in all of these processes and PP2A activation has been demonstrated to modulate them in vivo. PP2A has been shown to be involved in regulatory feedback loops with mTOR, and PP2A activators of the present invention would be expected to affect these processes directly by interacting with mTOR complexes, or indirectly by counterbalancing mTOR’s effects by dephosphorylating its targets. Perturbation of the mTOR signaling cascade appears to be a common pathophysiological feature of human neurological disorders, including mental retardation syndromes and autism spectrum disorders, and neurodegenerative conditions such as Alzhiemer’s disease. Activation of PP2A has been shown to be effective in animal models of neurodegenerative disease by modulating the PP2A mTOR axis; thus, molecules of the present invention will be useful in treatment of these conditions. PP2A activators of the present invention are likely to be useful in the treatment of diseases in which mTOR signaling is dysregulated; these include cancer, diabetes and neurodegenerative conditions. Compounds of the present invention may also promote innate immunity to infection and promote healthy aging. [00146] In some embodiments of the compounds, compositions, or methods provided herein, the compound is selected from a compound of Table 1, or a pharmaceutically acceptable salt thereof. Abbreviations and Definitions
[00147] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs. A comprehensive list of abbreviations utilized by organic chemists (i.e. persons of ordinary skill in the art) appears in the first issue of each volume of the Journal of Organic Chemistry. The list, which is typically presented in a table entitled “Standard List of Abbreviations” is incorporated herein by reference. In the event that there is a plurality of definitions for terms cited herein, those in this section prevail unless otherwise stated. [00148] The following abbreviations and terms have the indicated meanings throughout: Ac = acetyl Aq = aqueous Boc = t-butyloxy carbonyl Bu = butyl c- = cyclo cat = catalyst Cbz = carboxybenzyl DBA = dibenzylideneacetone DCM = dichloromethane = methylene chloride = CH2Cl2 DMF = N,N-dimethylformamide eq. or equiv. = equivalent(s) Et = ethyl GC = gas chromatography h = hour(s) KHMDS = Potassium bis(trimethylsilyl)amide Lg = leaving group Ln = chiral ligands mCPBA = meta-Chloroperoxybenzoic acid Me = methyl mesyl = methanesulfonyl min. = minute(s) Ms = mesylate NMO or NMMO = N-methylmorpholine oxide Pg = protecting group Ph = phenyl RT = room temperature sat’d or sat. = saturated t- or tert = tertiary Tf = triflate TFA = trifluoroacetic acid THF = tetrahydrofuran tosyl = p-toluenesulfonyl [00149] Throughout this specification the terms and substituents retain their definitions.
[00150] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms “comprise” (and any form of comprise, such as “comprises” and “comprising”), “have” (and any form of have, such as “has” and “having”), “include” (and any form of include, such as “includes” and “including”), and “contain” (and any form contain, such as “contains” and “containing”) are open-ended linking verbs. As a result, a method or composition that “comprises”, “has”, “includes” or “contains” one or more steps or elements possesses those one or more steps or elements, but is not limited to possessing only those one or more steps or elements. Likewise, a step of a method or an element of a composition that “comprises”, “has”, “includes” or “contains” one or more features possesses those one or more features, but is not limited to possessing only those one or more features. The terms “comprising” and “including” or grammatical variants thereof are to be taken as specifying the stated features, integers, steps or components but do not preclude the addition of one or more additional features, integers, steps, components or groups thereof. For example, "X includes a, b and c" means that X includes, but is not limited to, a, b and c. This term encompasses the terms “consisting of” and “consisting essentially of”. [00151] The phrase “consisting essentially of” or grammatical variants thereof when used herein are to be taken as specifying the stated features, integers, steps or components but do not preclude the addition of one or more additional features, integers, steps, components or groups thereof, but only if the additional features, integers, steps, components or groups thereof do not materially alter the basic and novel characteristics of the claimed composition or method. [00152] Unless otherwise specified, the phrase "such as" is intended to be open-ended. For example, "X can be a halogen, such as fluorine or chlorine" means that X can be, but is not limited to, fluorine or chlorine. [00153] As used herein, and as would be understood by the person of skill in the art, the recitation of “a compound”—unless expressly further limited—is intended to include salts of that compound. In a particular embodiment, the term “compound of formula” refers to the compound or a pharmaceutically acceptable salt thereof. [00154] The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and
organic acids and bases. When the compounds of the present invention are basic, salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Suitable pharmaceutically acceptable acid addition salts for the compounds of the present invention include acetic, adipic, alginic, ascorbic, aspartic, benzenesulfonic (besylate), benzoic, boric, butyric, camphoric, camphorsulfonic, carbonic, citric, ethanedisulfonic, ethanesulfonic, ethylenediaminetetraacetic, formic, fumaric, glucoheptonic, gluconic, glutamic, hydrobromic, hydrochloric, hydroiodic, hydroxynaphthoic, isethionic, lactic, lactobionic, laurylsulfonic, maleic, malic, mandelic, methanesulfonic, mucic, naphthylenesulfonic, nitric, oleic, pamoic, pantothenic, phosphoric, pivalic, polygalacturonic, salicylic, stearic, succinic, sulfuric, tannic, tartaric acid, teoclatic, p-toluenesulfonic, and the like. When the compounds contain an acidic side chain, suitable pharmaceutically acceptable base addition salts for the compounds of the present invention include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, arginine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium cations and carboxylate, sulfonate and phosphonate anions attached to alkyl having from 1 to 20 carbon atoms. [00155] The terms "subject" or "subject in need thereof" or “patient” are used interchangeably herein. These terms refer to a patient who has been diagnosed with the underlying disorder to be treated. The subject may currently be experiencing symptoms associated with the disorder or may have experienced symptoms in the past. Additionally, a "subject in need thereof" may be a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological systems of a disease, even though a diagnosis of this disease may not have been made. As a non-limiting example, a "subject in need thereof", for purposes of this application, may include a male who is currently diagnosed with prostate cancer or was diagnosed with prostate cancer in the past, regardless of current symptomatology. [00156] A “patient,” as used herein, includes both humans and other animals, particularly mammals. Thus the methods are applicable to both human therapy and veterinary applications. In some embodiments, the patient is a mammal, for example, a primate. In some embodiments, the patient is a human.
[00157] As used herein, the terms “treatment” or “treating are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including, but not limited to, therapeutic benefit. Therapeutic benefit includes eradication or amelioration of the underlying disorder being treated; it also includes the eradication or amelioration of one or more of the symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder. [00158] Treatment can involve administering a compound described herein to a patient diagnosed with a disease, and may involve administering the compound to a patient who does not have active symptoms. Conversely, treatment may involve administering the compositions to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. [00159] The terms “administer”, “administering” or “administration” in reference to a dosage form of the invention refers to the act of introducing the dosage form into the system of subject in need of treatment. When a dosage form of the invention is given in combination with one or more other active agents (in their respective dosage forms), “administration” and its variants are each understood to include concurrent and/or sequential introduction of the dosage form and the other active agents. Administration of any of the described dosage forms includes parallel administration, co-administration or sequential administration. In some situations, the therapies are administered at approximately the same time, e.g., within about a few seconds to a few hours of one another. [00160] A “therapeutically effective” amount of the compounds described herein is typically one which is sufficient to achieve the desired effect and may vary according to the nature and severity of the disease condition, and the potency of the compound. It will be appreciated that different concentrations may be employed for prophylaxis than for treatment of an active disease. A therapeutic benefit is achieved with the amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder. [00161] The term modulate with respect to PP2A refers to activation or potentiation of phosphatase activity by three general effects 1. direct allosteric activation of catalytic activity
in PP2A complexes. 2. By promotion of assembly of heterotrimeric B subunit containing trimers, or recruitment of PP2A AC heterodimers to the Integrator-RNAPII complex. 3. By displacement of endogeneous PP2A inhibitors or chaparones, thereby derepressing PP2A activity. These effects are not mutually exclusive though their relative importance may depend on cell or tissue type and specific disease state or pathology. [00162] The term “modulate” with respect to a FOXO transcription factor protein refers to activation of the FOXO transcription factor protein and its biological activities associated with the FOXO pathway. Modulation of FOXO transcription factor proteins includes up- regulation (i.e., agonizing, activation or stimulation). The mode of action of a FOXO modulator can be direct, e.g., through binding to the FOXO transcription factor protein as a ligand. The modulation can also be indirect, e.g., through binding to and/or modifying another molecule which otherwise binds to and activates the FOXO transcription factor protein. [00163] “Hydrocarbon” (e.g., (C1-C8)hydrocarbon) includes alkyl, cycloalkyl, polycycloalkyl, alkenyl, alkynyl, aryl and combinations thereof. Examples include benzyl, phenethyl, cyclohexylmethyl, adamantyl, norbornyl, and naphthylethyl. Hydrocarbyl (or hydrocarbon) refers to any substituent comprised of hydrogen and carbon as the only elemental constituents. Aliphatic hydrocarbons are hydrocarbons that are not aromatic; they may be saturated or unsaturated, cyclic, linear or branched. Examples of aliphatic hydrocarbons include isopropyl, 2-butenyl, 2-butynyl, cyclopentyl, norbornyl, etc. Aromatic hydrocarbons include benzene (phenyl), naphthalene (naphthyl), anthracene, etc. [00164] Unless otherwise specified, alkyl (or alkylene) is intended to include linear or branched saturated hydrocarbon structures and combinations thereof. Alkyl refers to alkyl groups from 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, s- butyl, t-butyl and the like. [00165] Cycloalkyl is a subset of hydrocarbon and includes cyclic hydrocarbon groups of from 3 to 8 carbon atoms. Examples of cycloalkyl groups include cy-propyl, cy-butyl, cy- pentyl, norbornyl and the like. [00166] Alkoxy or alkoxyl refers to groups of from 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms of a straight or branched configuration attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy and the like. Lower-alkoxy refers to groups containing one to four
carbons. For the purpose of this application, alkoxy and lower alkoxy include methylenedioxy and ethylenedioxy. [00167] The term "halogen" means fluorine, chlorine, bromine or iodine atoms. In one embodiment, halogen may be a fluorine or chlorine atom. [00168] The terms "haloalkyl," "haloalkoxy," or “haloalkylthio” mean alkyl, alkoxy, or alkylthio, respectively, substituted with one or more halogen atoms. [00169] Heterocycle means an aliphatic or aromatic carbocycle residue in which from one to four carbons is replaced by a heteroatom selected from the group consisting of N, O, and S. The nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. Unless otherwise specified, a heterocycle may be non- aromatic (heteroaliphatic) or aromatic (heteroaryl). Examples of heterocycles include pyrrolidine, pyrazole, pyrrole, indole, quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran, benzodioxan, benzodioxole (commonly referred to as methylenedioxyphenyl, when occurring as a substituent), tetrazole, morpholine, thiazole, pyridine, pyridazine, pyrimidine, thiophene, furan, oxazole, oxazoline, isoxazole, dioxane, tetrahydrofuran and the like. Examples of heterocyclyl residues include piperazinyl, piperidinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, tetrahydrofuryl, tetrahydropyranyl, thienyl (also historically called thiophenyl), benzothienyl, thiamorpholinyl, oxadiazolyl, triazolyl and tetrahydroquinolinyl. Examples of heteroaryls include imidazole, pyridine, indole, thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole. In some embodiments, examples of heteroaryls include imidazole, pyridine, thiophene, thiazole, furan, pyrimidine, pyrazine, tetrazole and pyrazole. [00170] As used herein, the term “optionally substituted” may be used interchangeably with “unsubstituted or substituted”. The term “substituted” refers to the replacement of one or more hydrogen atoms in a specified group with a specified radical. “Oxo” may also be included among the substituents referred to in “optionally substituted”; it will be appreciated by persons of skill in the art that, because oxo is a divalent radical, there are circumstances in which it will not be appropriate as a substituent (e.g. on phenyl). In one embodiment, 1, 2, or 3 hydrogen atoms are replaced with a specified radical. In the case of alkyl and cycloalkyl,
more than three hydrogen atoms can be replaced by fluorine; indeed, all available hydrogen atoms could be replaced by fluorine. Table 1. Examples Example Number Synthesis Scheme Structure r r
5 2 1
8 ur r
[00171] Preparation of compounds can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. Suitable groups for that purpose are discussed in standard textbooks in the field of chemistry, such as Protective Groups in Organic Synthesis by T.W.Greene and P.G.M.Wuts [John Wiley & Sons, New York, 1999], in Protecting Group Chemistry, 1st Ed., Oxford University Press, 2000; and in March’s Advanced Organic chemistry: Reactions, Mechanisms, and Structure, 5th Ed., Wiley-Interscience Publication, 2001. [00172] Sulfonimidamides are isosteres of sulfonamides and their application in medicinal chemistry has been reviewed in Chinthakindi et al, Angew. Chem. Int. Ed. 2017, 56, 4100- 4109. Sulfonimidamides may improve physical and medicinal properties, versus the corresponding sulfonamides, with respect to solubility, lipophilicity, plasma protein binding or permeability. They may also have altered, and potentially beneficial, off-target profile
versus the sulfonamides with respect to, for example CYP inhibition or PXR induction resulting in reduced potential for drug-drug inteactions or toxicity. Synthesis of sulfonimidamides of the present invention is achieved by reacting an amine intermediate A1, shown in General Synthesis Scheme 1, using a variety of methods disclosed in the scientific literature. See for example Nandi and Arvidsson, Sulfonimidamides: Synthesis and Applications in Preparative Organic Chemistry, Adv. Synth. Catal., 2018, 360, 2976-3001. One method is shown in General Synthesis Scheme 1 using an N-(alkyl)benzenesulfinamide sufinamide reagent which is activated with t-butyl hypochlorite in carbontetrachloride and reacted with amine intermediate A1. In some instances the alkyl group maybe lower alkyl, such as methyl and is thus Rim. In other instances the alkyl group maybe removable and it functions as a protecting group to yield Rim = H after deprotection. One example is N-(2,4- dimethoxybenzyl)-4-(trifluoromethoxy)benzenesulfinamide where the protecting group is 2,4-dimethoxybenzyl which is conveniently removed by acid treatment, as described in the examples below. [00173] General Synthesis Scheme 1 is shown in Fig.1. [00174] General synthesis of Amine Intermediates A1. The key reaction step is construction of the central tetrahydropyran ring by a modification of the Prins-Ritter conditions reported by Subba Reddy and Ghanty in Synthetic Communications, 2014, 44:17, pages 2545-2554. The main modifications are 1. Use of methyl enol ether as aldehyde equivalent, 2. Microwave heating and 3. Stoichiometric benzenesulfonimide acid catalyst. The reaction is reported to give cis-relative stereochemistry as the major product, as depicted for Example 2. [00175] Synthesis Scheme 2. Example 1: Synthetic route to N-(2-(10,11-dihydro-5H- dibenzo[a,d][7]annulen-5-yl)tetrahydro-2H-pyran-4-yl)-4- (trifluoromethoxy)benzenesulfonimidamide is shown in Scheme 2 in Fig.2. [00176] An oven dried two-neck round bottomed flask equipped with a pressure equalizing addition funnel was cooled to room temperature while flushing with argon and (methoxymethyl)triphenylphosphonium chloride, 34.3 g (100 mmole, 2 equivalents) was added, and the solid suspended in 200 mL dry THF. The suspension was stirred and cooled to 0oC in ice, then 40 mL of 2.5M n-butyllithium solution (100 mmole, 2 equivalents) in hexanes was added dropwise. The deep red solution was stirred at 0oC for 10 minutes, then a solution of dibenzosuberone, 10.4 g (50 mmole, 1 equivalent) in 50 mL dry THF was added from the addition funnel and the solution was stirred at 0oC for 5 hours, then at room
temperature overnight. White precipitate forms after about five hours. The reaction was cooled in ice then quenched with aqueous ammonium chloride (2.6g, 50 mmole in 10 mL water), stirred briefly, then filtered through a pad of Celite to remove bulk of precipitate, which was washed with 50 mL ethyl acetate. The filtrate was evaporated to give an orange oil. 100 mL ethyl acetate was added, then 50 mL hexanes (till solution was slightly cloudy) and the mixture was left to stand in a fridge at 4oC overnight. The mixture was filtered through a 2 cm pad of silica gel, which was washed with ethyl acetate. The filtrate was evaporated to give a pale yellow oil which was purified by flash chromatography eluting with 2% ethyl acetate in hexane, to give 4.87g (41%) of the product, 5-(methoxymethylene)- 10,11-dihydro-5H-dibenzo[a,d][7]annulene, as a colorless oil. 300 MHz 1H NMR in CDCl3 7.46–7.11 (overlapping m, 8H), 6.37 (s, 1H), 3.73 (s, 3H), 3.16 (br s, 4H). TLC-MS ESI +ve ion, 278.9 [M+CH3CN+H]+. [
00177] 5-(Methoxymethylene)-10,11-dihydro-5H-dibenzo[a,d][7]annulene, 1.26g (5 mmole, 1 equivalent), 3-buten-1-ol, 0.53 mL (0.46 g, 6.4 mmole, 1.2 equivalent), and 1,3,2- Benzodithiazole-1,1,3,3-tetraoxide, 1.1 g (5 mmole, 1 equivalent) were placed in a 30 mL CEM microwave vial. Dry acetonitrile, 15 mL, was added and the mixture was stirred briefly at room temperature to give a clear homogeneous solution. The mixture was stirred and heated at 150°C for 1 hour. Reaction was diluted into 100 mL ethyl acetate and the organic was washed once with 1M aqueous potassium carbonate, once with saturated brine then dried over anhydrous sodium sulfate. Filtration and evaporation gives crude product which was purified by flash chromatography, eluting with 60 to 70% ethyl acetate hexane. The product, N-(2-(10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)tetrahydro-2H-pyran-4-yl)acetamide, is a colorless oil that crystallizes to give a white solid on pumping in vacuo: 0.73 g (2.3 mmole, 45%). 300 MHz 1H NMR in CDCl37.21–7.05 (overlapping m, 8H), 5.32 (br d, 1H), 4.11 (m, 1H), 3.98-3.90 (overlapping m, 2H), 3.83 (m, 1H), 3.50-3.33 (overlapping m, 3H), 2.98-2.81 (overlapping m, 2H) 1.89 (s, 3H), 1.85 (m, 1H), 1.63 (m, 1H), 1.35 (m, 1H), 1.02 (m, 1H). TLC-MS ESI +ve ion, 336.2 [M+H]+.
[00178] N-(2-(10,11-dihydro-5H-dibenzo[a,d][7]annulen 5 yl)tetrahydro 2H pyran 4 yl)acetamide, 0.86g (2.6 mmole, 1 equivalent) was placed in a 30 mL CEM microwave vial and dissolved in 15 mL dioxane. 5 mL of 6M hydrochloric acid was added and the mixture stirred briefly at room temperature, then heated in microwave at 150°C for 1 hour. The reaction was cooled and made basic by adding 2 g solid potassium hydroxide, then stirred at room temperature for 30 min as two phases form. The reaction was diluted into 100 mL ethyl actate, washed with water once, then saturated brine and dried over anhydrous sodium sulfate. Filtration and evaporation gives the crude Amine Intermediate, 2-(10,11-dihydro-5H- dibenzo[a,d][7]annulen-5-yl)tetrahydro-2H-pyran-4-amine, which was carried into the next step without further purification. The Prins-Ritter reaction give predominantly the cis diastereoisomer. [00179] N-(2,4-dimethoxybenzyl)-4-(trifluoromethoxy)benzenesulfinamide is a known compound and is prepared as follows: a mixture of 4-trifluoromethoxybenzenesulfonyl chloride (100 g, 383.7 mmole) and sodium sulfite (106.4 g, 844 mmole) and sodium bicarbonate (70.8 g, 844 mmole) in 1L of water was stirred at 65°C for 18 hours under argon atmosphere. The mixture was concentrated to remove water keeping the temperature below 60°C under vacuume. Then the residue was stirred with 1 L methanol at 15–25°C and the reaction mixture was filtered and concentrated to yield sodium 4- (trifluoromethoxy)benzenesulfinate. To a mixture of sodium 4- (trifluoromethoxy)benzenesulfinate (20 g, 80.6 mmole) and DMF (0.2 mL, catalytic) in 200 mL methylene chloride was added oxaloyl chloride (15.4 g, 121.3 mmole) with stirring and cooling to keep the temperature below 20°C. The mixture was stirred for an additional one hour at room temperature then evaporated to give crude 4-(trifluoromethoxy)benzenesulfinic chloride which was then redissolved in 200 mL methylene chloride. 2,4- dimethoxybenzylamine (20.2 g, 121.3 mmole) and triethylamine (24.6 g, 248.1 mmole) was added and the mixture stirred at 15-25°C for 18 hours. The reaction was quenched with 100 mL water and the organic layer separated. The aqueous was back extracted with 100 mL methylene chloride. The combined organic was washed with brine and dried over sodium sulfate. Filteration and evaporation gives the crude product, N-(2,4-dimethoxybenzyl)-4- (trifluoromethoxy)benzenesulfinamide which is purified by flash chromatography, eluting with 10-20% ethyl acetate hexane. [00180] Coupling to give the protected intermediate, N-((2R,4S)-2-(10,11-dihydro-5H- dibenzo[a,d][7]annulen-5-yl)tetrahydro-2H-pyran-4-yl)-N'-(2,4-dimethoxybenzyl)-4-
(trifluoromethoxy)benzenesulfonimidamide is carried out as follows: N (2,4 dimethoxybenzyl)-4-(trifluoromethoxy)benzenesulfinamide (1 equiv) is stirred with t-butyl hypochlorite (1.05 equiv) in carbon tetrachloride at 0°C for 1 hour in the dark. The reaction is concentrated to remove carbon tetrachloride keeping the temperature below 5°C, then the residue is dissolved in THF. The amine intermediate, 2-(10,11-dihydro-5H- dibenzo[a,d][7]annulen-5-yl)tetrahydro-2H-pyran-4-amine (1.05 equiv) and diisopropylethylamine (3 equiv) are added with stirring and cooling at 0°C, then the mixture is stirred at room temperature over night. The reaction is cooled and quenched with water and extracted with ethyl acetate. The combined organic is washed with brine, then dried over sodium sulfate. Filtration and evaporation gives the crude 2,4-dimethoxybenzyl protected compound which is purified by flash chromatography, eluting with ethyl acetate hexane. [00181] Deprotection to the final product, Example 1, is carried out by dissolving the 2,4- dimethoxybenzyl protected compound in methylene chloride, cooling to 0°C, then adding adding trifluoroacetic acid to give a 1:1 solvent:acid ratio by volume. Saturated aqueous sodium bicarbonate is added till the mixture is pH 7-8, then the mixture is extracted with dichloromethane. The combined organic extracts are dried over sodium sulfate. Filtration and evaporation gives the crude product, N-(2-(10,11-dihydro-5H-dibenzo[a,d][7]annulen-5- yl)tetrahydro-2H-pyran-4-yl)-4-(trifluoromethoxy)benzenesulfonimidamide, Example 1, as a mixture of diastereoisomers with respect to the sulfur chiral center. The amine intermediate from the Prins-Ritter synthesis is predominantly the cis diastereoisomer with respect to the central tetrahydropyran ring and this is depicted as Example 2 in Table 1. This material is purified by flash chromatography eluting with ethyl actate-hexane. The mixture of diastereoisomers with respect to the sulfur center, may be sparable on a flash column. Example 1 may also be separable into it’s diastereoisomers by techniques such as HPLC or crystallization. The separate diastereoisomers are depicted as Examples 3 and 4 in Table 1. [00182] Synthesis of Example 3 and Example 4 was carried out as shown in the scheme shown in Fig.3. [00183] N-(2-(10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)tetrahydro-2H-pyran-4-yl)-4- (trifluoromethoxy)benzenesulfonamide is a known compound and was synthesized as described in WO 2023/023594 as a single cis-diastereoisomer as shown above and labelled sulfonamide intermediate. The intermediate sulfonamide, 1.03 g (2 mmole, 1 equiv) and Hunigs base, 0.68 mL (0.52 g, 4 mmole, 2 equiv) were dissolved in 10 mL dry chloroform in
a 35 mL microwave vial. Ph3PCl2, 1.0 g (3 mmole, 1.5 equiv) was added as a solid in one portion and the mixture was stirred and microwaved at 85°C for twenty minutes and then cooled to room temperature. 2,4-dimethoxybenzylamine, 1.34 g (8 mmole, 4 equiv) was added and the mixture stirred at room temerature overnight. the reaction was diluted into 100 mL ethyl acetate then washed with 50 mL 0.1 M hydrochloric acid then 50 mL sat. aq. sodium bicarbonate. The organic was dried over anhydrous sodium sulfate, filetered and evaporated to give a brown oil. Careful flash chromatography eluting with 15% to 25% ethyl acetate separates the 2,4-dimethoxybenzyl protected imidamides as distereoisomers at the sulfur center as glassy foam after pumping in vacuo. Less polar Isomer 1: 400 MHz 1H NMR in CDCl37.80 (m, 2H), 7.22 (m, 1H) 7.21- 7.07 (overlapping m, 10H), 6.80 (br d, 1H [NH proton]), 6.29- 6.27 (overlapping m 2H), 4.07 (m, 1H), 4.01- 3.81 (overlapping m, 4H), 3.76 (s, 3H), 3.65 (s, 3H), 3.50 (m, 2H) 3.39 (m, 1H), 3.30 (m, 1H), 2.93 (m, 2H), 1.78 (m, 1H), 1.64 (overlapping m, 2H), 1.35 (m, 1H). TLC-MS APCI +ve ion, 667.2 [M+H]+ and APCI - ve ion, 665.4 [M-H]- . More polar Isomer 2: 400 MHz 1H NMR in CDCl37.76 (m, 2H), 7.20 (m, 1H) 7.15- 7.02 (overlapping m, 10H), 6.88 (br d, 1H [NH proton]), 6.29- 6.27 (overlapping m 2H), 4.04-3.98 (overlapping m, 2H), 3.96- 3.91 (overlapping m, 2H), 3.80 (m, 1H), 3.74 (s, 3H), 3.68 (s, 3H), 3.50 (m, 2H) 3.32 (m, 2H), 2.89 (m, 2H), 1.77 (m, 1H), 1.72- 1.59 (overlapping m, 2H), 1.29 (m, 1H). TLC-MS APCI +ve ion, 667.2 [M+H]+ and APCI - ve ion, 665.4 [M-H]-. [00184] A 1:1 mixture of the 2,4-dimethoxybenzyl protected imidamides, 0.69 g (approximately 1 mmole) was dissolved in 10 mL methylene chloride. The solution was cooled in ice and 10 mL trifluoroacetic was added, then the mixture was stirred at room temerature overnight. The reaction was diluted into 100 mL ethyl acetate and washed with an ice-cold solution of 9 g potassium carbonate in 100 mL water. The organic was dried over anhydrous sodium sulfate, then filtered and evaporated to give crude Example 2 as a 1:1 mixture of diastereoisomers at the sulfur center. The mixture was further purified by flash chromatography eluting with 30%–40% ethyl acetate in hexane. The diastereoisomers separate to give Example 2 and Example 3 as pale yellow solids after pumping in vacuo. Configuration at the sulfur center is undetermined and the less polar, first eluting isomer is assigned as Example 3: 400 MHz 1H NMR in CDCl37.93 (m, 2H), 7.23 (m, 2H) 7.15-6.94 (overlapping m, 8H), 3.96 (m, 1H), 3.85 (m, 1H), 3.80-3.68 (overlapping m, 3H [includes broad NH, 2H]), 3.49-3.18 (overlapping m, 4H), 2.93-2.85 (overlapping m, 2H) 1.51-1.43 (overlappimg m, 2H), 1.31 (m, 1H), 1.00 (m, 1H). TLC-MS APCI +ve ion, 517.2 [M+H]+
and APCI -ve ion, 515.2 [M-H]-. The more polar, second eluting isomer is assigned as Example 4: 400 MHz 1H NMR in CDCl37.88 (m, 2H), 7.20 (m, 2H) 7.18- 7.01 (overlapping m, 8H), 3.91 (m, 2H), 3.69 (m, 1H), 3.34 (m, 2H), 3.23 (m, 2H), 3.00 (broad NH, 2H ), 2.91 (m 1H), 2.82 (m, 1H), 1.71 (m, 1H), 1.40 (m, 1H), 1.27 (m, 1H), 0.90 (m, 1H). TLC-MS APCI +ve ion, 517.2 [M+H]+ and APCI -ve ion, 515.2 [M-H]-. [00185] Example 9 and Example 10 maybe prepared using the method described above from N-(2-(2,8-difluoro-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl) tetrahydro-2H-pyran-4- yl)-4-(trifluoromethoxy)benzenesulfonamide, as starting material where preparation is given in WO 2023/023594. [00186] Example 7 is prepared from 2-(bis(4-fluorophenyl)methyl)tetrahydro-2H-pyran-4- amine, synthesized as shown in Fig. 4, by coupling with N-(2,4-dimethoxybenzyl)-4- (trifluoromethoxy)benzenesulfinamide using the method described above for Example 1. [00187] The Prins-Ritter reaction used in the synthesis of Examples 1 and 7 gives mainly 2,4-cis relative stereochemistry across the central tetrahydropyran ring, see Subba Reddy and Ghanty in Synthetic Communications, 2014, 44:17, pages 2545-2554 and Yadav et al, Tetrahedron Letters 48 (2007) pages 4903-4906. Compounds with 2,4-trans stereochemistry may be accessed by inversion of the 4-amino stereocenter on the tetrahydropyran using one of the several methods developed by Fiksdahl, see for example Sørbye et al, Tetrahedron: Asymmetry 9 (1998) pages 681-689, or Said and Fiksdahl, Tetrahedron: Asymmetry 12 (2001) 1947-1951. The 2,4-trans amine intermediates may be used in the synthesis of compounds such as Example 5 shown in Table 1. [00188] Compounds wherein Rim = lower alkyl, for example methyl, as depicted for Example 6 above are prepared from N-methyl-4-(trifluoromethoxy)benzenesulfinamide and coupling to amine intermediates as described above. [00189] Compounds wherein Y=H maybe prepared via the route shown in General Scheme 2, show in Fig.5. [00190] Conditions in Scheme 2 are adapted from those published in Chen and Gibson, RSC Adv. 2015, 5, 4171–4174 or Chinthakindi et al, Eur. J. Org. Chem., 2018, 10.1002/ejoc.201801541 and use of these conditions in the syntheses of Example 7 and Example 8 are described.
[00191] Synthesis of Example 7 (Fig. 6). 2-(bis(4 fluorophenyl)methyl)tetrahydro 2H pyran-4-amine (Amine Intermediate A2 in the Fig. 4) was dissolved in 10 mL methylenechloride and 0.41 mL (2.4 mmole, 1.2 equiv) of Hunigs base was added followed by 0.41 mL (0.63g, 2.4 mmol, 1.2 equiv) of 4-trifluoromethoxybenzenesulfonyl chloride. The mixture was stirred at room temperature overnight then diluted into 100mL ethyl acetate and the organic was washed with 1M HCl(aq), 1x50 mL, followed by water, 1x50 mL then dried over anhydrous magnesium sulfate. Filtration and evaporation give crude Sulfonamide Intermediate, which was purified by flash chromatography eluting with 20% ethylacetate in hexane. [00192] N-(2-(bis(4-fluorophenyl)methyl)tetrahydro-2H-pyran-4-yl)-4- (trifluoromethoxy)benzenesulfonamide, is a white solid: 400 MHz 1H NMR in CDCl3 7.84 (m, 2H), 7.27 (m, 2H), 7.17 (m, 2H), 7.07 (m, 2H), 6.93 (m, 4H), 4.62 (d, 1H), 3.96 (m, 1H), 3.84 (m, 1H),, 3.78 (m, 1H), 3.42 (m, 1H), 3.36 (m, 1H), 1.72 (m, 1H), 1.58 (m, 1H), 1.37 (m, 1H), 1.04 (m, 1H). TLC-MS APCI -ve ion 526.5 [M-H]-. [00193] To a stirred suspension of Ph3PCl2 (1 equiv) in dry chloroform is added triethylamine (1.6 equiv). The mixture is stirred at room temperature for 20 minutes then cooled to 0°C. The Sulfonamide Intermediate, N-(2-(bis(4-fluorophenyl)methyl)tetrahydro- 2H-pyran-4-yl)-4-(trifluoromethoxy)benzenesulfonamide, is added dropwise with stirring as solution in chloroform. The mixture is stirred at between 0°C and 50°C for 10 to 60 minutes. The reaction is cooled to 0°C then 2.4-dimethoxybenzylamine is added as a solution in chloroform and the mixture is stirred at between 0°C and room temperature for between 1 and 24 hours. The reaction is concentrated and then ether is added and the mixture stirred, then filtered. The filtrate is evaporated to give the crude product which is purified by flash chromatography. Deprotection is carried out by dissolving in dichloromethane, cooling to 0°C, and adding trifluoroacetic acid to give 1:1 CH2Cl2:TFA. The reaction is concentrated, then taken up in ethyl acetate and washed with aqueous sodium bicarbonate, then dried over sodium sulfate. Filtration and evaporation gives crude material with is purified by flash chromatography to give Example 7. [00194] Alternate conditions used for synthesis of Example 7 were as follows: N-(2-(bis(4- fluorophenyl)methyl)tetrahydro-2H-pyran-4-yl)-4-(trifluoromethoxy)benzenesulfonamide, 0.527 g (1 mmole) and Hunigs base, 0.26 mL (0.19 g, 1.5 mmole, 1.5 equiv) were dissolved in 10 mL dry chloroform in a 35 mL microwave vial. Ph3PCl2, 0.4g (1.2mmole, 1.2 equiv)
was added as a solid in one portion then the vial was sealed and the mixture was stirred and microwaved at 85°C for twelve minutes; mixture darkens on adding Ph3PCl2. The mixture was cooled to room temperature, then 2,4-dimethoxybenzylamine, 0.5 g (3 mmole, 3 equiv) was added and the mixture was stirred overnight at room temperature. The reaction was diluted with 100 mL dichloromethane and washed with 50 mL 1% citric acid then 50 mL sat. aq. sodium bicarbonate. The organic solution was dried over sodium sulfate and evaporated to give a brown oil which was purified by flash chromatography eluting with 20% ethyl acetate/hexane.300 MHz 1H NMR in CDCl3 is consistent with 1:1 mixture of diastereoismers at sulfur chiral center, for example each methoxy singlet of 2,4-methoxybenzyl occurs is doubled to give four singlets at 3.76 and 3.74 ppm and 3.68 and 3.67 ppm. TLC-MS APCI +ve ion, 677.2 [M+H]+ and APCI -ve ion, 675.3 [M-H]- is consistent with 2,4- dimethoxybenzyl protected intermediate: [00195] The above compoun
was eprotecte y ssoving 0.64 g in 10 mL methylene chloride with cooling to 0°C. 10 mL trifluoroacetic was added and the mixture stirred at 0°C for 5 minutes, then room temperature for 7 hours, a deep purple color developed. The reaction was diluted into 100 mL ethyl acetate and washed with a solution of 8.3 g potassium carbonate in 100 mL water. The organic solution was dried over anhydrous sodium sulfate, filtered then evaporated to give a crude residue which was purified by flash chromatography eluting with 30% ethyl acetate in hexane. Example 7 separates on chromatography into two diastereoisomers at the sulfur center. Less polar isomer, 7-isomer1: 400 MHz 1H NMR in CDCl3 7.97 (m, 2H), 7.42 (m, 2H) 7.23 (m, 2H), 7.09 (m, 2H), 6.97- 6.89 (overlapping m 4H), 3.92 (m, 1H), 3.90 (m, 1H), 3.84 (overlapping m, 2H), 3.42 (m, 1H), 3.34 (m, 1H) 3.06 (br singlet, 2H [NH protons]), 1.64 (m, 1H), 1.56 (m, 1H), 1.31 (m, 1H), 1.06 (m, 1H). MS ESI +ve ion, 527.0 [M+H]+, MS ESI -ve ion, 525.0 [M-H]-. More polar isomer, 7-isomer2: 400 MHz 1H NMR in CDCl37.93 (m, 2H), 7.22 (m, 2H), 7.15 (m, 2H), 7.04 (m, 2H), 6.96- 6.80 (overlapping m 4H), 3.96 (m, 1H), 3.80 (m, 1H), 3.75 (m, 1H), 3.40 (overlapping m, 2H), 3.02 (br singlet, 2H [NH protons]), 1.75 (m, 1H), 1.43-1.34 (overlapping m, 2H), 0.95 (m, 1H). MS ESI +ve ion, 527.0 [M+H]+, MS ESI -ve ion, 525.1 [M-H]-.
[00196] Example 8 wherein Rim is methyl maybe prepared by the route shown in Fig.7. [00197] N-Methyl-4-(trifluoromethoxy)benzenesulfonamide (1 equiv) in chloroform is added dropwise to a stirred suspension of Ph3PCl2 (1 equiv) in dry chloroform is added triethylamine (1.6 equiv). The mixture is stirred at between 0 and 50°C for between 30 minutes and 8 hours. The mixture is cooled to 0°C then a solution of 2-(bis(4- fluorophenyl)methyl)tetrahydro-2H-pyran-4-amine in chloroform is added. The mixture is stirred at between 0 and 50°C for between 30 minutes and 24 hours. The reaction is diluted into ethyl acetate and washed with aqueous sodium bicarbonate. The organic is dried over sodium sulfate, filtered and concentrated to give crude product. The crude material is purified by flash chromatography to give Example 8. [00198] Cancer Cell Viability Inhibition [00199] D425 medulloblastoma cells were purchased from SigmaAldrich. D425 meduloblastoma cells were cultured in improved Dulbecco's modified Eagle's medium (DMEM) Richter's modification supplemented with 20% fetal bovine serum and 1% Penicillin-streptomycin. Incubation was performed at 37°C and 5% CO2. [00200] D425 cells were seeded at 3000–3500 cells/90 µL growth medium per well on 96- well tissue culture plates. Cells were incubated overnight to allow them to recover. Next day cells were treated with tested compounds and incubated for 48 hours. [00201] Cell Proliferation assays in triplicate were performed at each concentration. Compounds test range was 1- 30 µM (0, 5, 10, 15, 20, 25, and 30). The compounds were dissolved in DMSO. A series of dilutions were made in 1% DMSO in growth medium so that the final concentration of DMSO is 0.1% in all of treatments. [00202] After treatment, cells were allowed to equilibrate at room temperature for one hour. Cell proliferation was measured by Luminescence quantification using Promega CellTiter- Glo Luminescent Cell Viability Assay. To perform the assay, 90 µL of Celltiter-Glo substrate was added to each well, plates were shake for 2 minutes and allowed to equilibrate for 10 minutes at room temperature. Luminescence intensity was measured using the Spectramax i3x plate reader. [00203] The Luminescence intensity data were analyzed using the computer software Graphpad Prism. In the absence of the compound, the luminescence intensity (Lt) in each
data set was defined as 100% cell viability. The percent cell in the presence of each compound was calculated according to the following equation: %Cell= L/Lt, were L= the luminescence intensity in the presence of the compound. [00204] The values of % cell versus a series of compound concentrations (0, 5, 10, 15, 20, 25, and 30 µM) were then plotted using Nonlinear regression analysis of Sigmoidal dose- response curve. IC50 value was determined by the concentration causing a half-maximal percent activity. [00205] IC50 for example compounds, determined by the method above are given in Table 2. Table 2. Example IC50 for D425 cell growth (μM) Note 7-isomer1 14.3 n = 3 3 3 3 [00206] A172 gl
fied Eagle's medium (DMEM) supplemented with 10% fetal bovine serum and 1% Penicillin-streptomycin. Incubation was performed at 37°C and 5% CO2. [00207] A172 cells were seeded at 3000–3500 cells/90 µL growth medium per well on 96- well tissue culture plates. Cells were incubated overnight to allow them to recover and reattach. Next day cells were treated with tested compounds and incubated for 48-72 hours. [00208] Cell Proliferation assays in triplicate were performed at each concentration. Compounds test range was 1- 30 µM (0, 5, 10, 15, 20, 25, and 30). The compounds were dissolved in DMSO. A series of dilutions were made in 1% DMSO in growth medium so that the final concentration of DMSO is 0.1% in all of treatments. [00209] After treatment, cells were allowed to equilibrate at room temperature for 1/2 to one hour. Cell proliferation was measured by Luminescence quantification using Promega CellTiter-Glo Luminescent Cell Viability Assay. To perform the assay, 100 µL of Celltiter- Glo substrate was added to each well, plates were shake for 2 minutes and allowed to equilibrate for 10 minutes at room temperature. Luminescence intensity was measured using the Spectramax i3x plate reader.
[00210] The Luminescence intensity data were analyzed using the computer software Graphpad Prism. In the absence of the compound, the luminescence intensity (Lt) in each data set was defined as 100% cell viability. The percent cell in the presence of each compound was calculated according to the following equation: %Cell= L/Lt, were L= the luminescence intensity in the presence of the compound. [00211] The values of % cell versus a series of compound concentrations (0, 5, 10, 15, 20, 25, and 30 µM) were then plotted using Nonlinear regression analysis of Sigmoidal dose- response curve. IC50 value was determined by the concentration causing a half-maximal percent activity. [00212] Cellular in vitro phosphatase activation assay was performed using the method of Theendakara et al, Molecular and Cellular Neuroscience, 83 (2017), pages 83-91 which is described below: [00213] A172 glioblastoma cells were cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum and 1% Penicillin-streptomycin. Incubation was performed at 37°C and 5% CO2. [00214] A172 cells were seeded at 5x105 cells/2.5 ml growth medium (without antibiotics) per well on 6-well tissue culture plates. Cells were incubated overnight to allow them to recover and reattach. Next day, when the cells were at about 75% confluence, transfection was performed with 2-2.5 ug of ApoE cDNA following the manufacture's protocol: Lipofectamine 2000 from Invitrogen (Cat # 12566014) or Neuroporter transfection kit form Sigma (Cat# NPT01). After 24 hrs. the cells were treated with 5 μM test compounds and incubated for an additional 24 hours. [00215] After 24hrs, cells were washed twice with imidazole buffer and lysed using NP-40 Lysis buffer. The lysate was cleared up from small molecules including endogenous phosphates using desalting spin columns. Malachite Green Phosphatase assays were performed in triplicate using 5ug of total protein per assay and following the manufacture's protocol (Sigma cat # MAK307). The amount of phosphate release in the assay was determined by measuring absorbance at 620 nm using the Spectramax i3x plate reader. [00216] The absorbance intensity data were analyzed using the computer software Graphpad Prism. The phosphate concentration for each sample was determined from the standard curve
using phosphate standard concentrations. In order to compare samples, the first set (column A) were there was no transfection performed and no compound added, was designated a baseline; the absorbance measurement in this column was set as 100% phosphatase activity. [00217] Phosphatase activation, determined by the method above are given in Table 3. Table 3. Example % increase from ApoE transfected cell at Note 5μM test compound concentration 3 [00218] Whi f illustration, the
foregoing descriptions and examples should not be deemed to be a limitation on the scope of the invention. Accordingly, various modifications, adaptations, and alternatives may occur to one skilled in the art without departing from the spirit and scope of the present invention.
Claims
CLAIMS What is claimed is: 1. A compound, having a formula: or a pharmaceuticall
, wherein: B is absent or is selected from a direct bond, -CH2CH2-, -CH=CH-, O, S, or -NRB- C(O)-; Q is selected from -O- or NRQ; Rim is selected from hydrogen or lower alkyl; U, V and W are independently cabocyclic aromatic or heteroaromatic rings; n = 0 or 1; X1, X2, X3 and X4 are independently selected in each instance from hydrogen, halogen, nitro, cyano, (C1-C6)alkyl optionally substituted with -OH, (C1-C6)haloalkyl, (C1- C6)haloalkoxy, (C1-C6)haloalkylthio, -NR1R2, -OR1, -C(O)R1, -OC(O)R1, -C(O)NR1R2, - C(O)OR1, -SR1, -SO2R1, and -SO2NR1R2; Y is selected from hydrogen or hydroxyl; Z1 and Z2 are independently selected in each instance from hydrogen, halogen, nitro, cyano, azido, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)haloalkylthio, - NR1R2, -NR1C(O)R2, -NR1C(O)OR3, -OR1, -C(O)R1, -OC(O)R1, -C(O)NR1R2, -C(O)OR1, - SR1, -SO2R1, -SO2NR1R2, and five membered heterocyclyl; RB is selected from H, or lower alkyl RQ is selected from H, optionally substituted lower alkyl, aryl R1, R2 and R3 are lower alkyl.
2. The compound of claim 1, wherein each instance of lower alkyl is, independently, selected from C1-3 alkyl.
3. The compound of claim 1, having a formula: or a pharmaceuticall
wherein J1 is H, F, Cl, Br, or I; J2 is H, F, Cl, Br, or I; J3 is H, F, Cl, Br, or I; J4 is H, F, Cl, Br, or I; J5 is H or OH; J6 is H or C1-6 alkyl; J7 is H, F, Cl, Br, I, CN, N3, C1-6 alkyl, C1-6 alkoxyl, C1-6 haloalkyl, C1-6 haloalkoxyl; J8 is H, F, Cl, Br, I, CN, N3, C1-6 alkyl, C1-6 alkoxyl, C1-6 haloalkyl, C1-6 haloalkoxyl; and J9 is H and J10 is H, or J9 and J10 together form an ethylene or ethenylene.
4. The compound of claim 3, wherein J1 is H or F; J2 is H or F; J3 is H or F; J4 is H or F; J5 is H; J6 is H or C1-3 alkyl; J7 is H, C1-6 alkoxyl, or C1-6 haloalkoxyl; and J8 is H, C1-6 alkoxyl, or C1-6 haloalkoxyl.
7. The compound of claim 3, selected from ,
F F F F3 , or a p
8. The compound of claim 3, selected from , or a pha
9. The compound of claim 3, selected from ,
F F , or a
10. A composition, comprising the compound of one of claims 1–9. 11. The composition of claim 10, which is a pharmaceutical composition including a pharmaceutically acceptable carrier. 12. A method, comprising administering the compound of one of claims 1–9, or the compositon of one of claims 10–11, to a subject. 13. A method of modulating a protein phosphatase 2A, comprising contacting the protein phosphatase 2A with the compound of one of claims 1–9. 14. A method of treating a protein phosphatase 2A related disease, comprising administering an effective amount of the compound of one of claims 1–9, or the composition of one of claims 10–11, to a subject in need thereof. 15. A method of treating a disease, comprising administering an effective amount of the compound of one of claims 1–9, or the composition of one of claims 10–11, to a subject in need thereof, wherein the disease comprises one or more of: (a) cancer; (b) diabetes; (c) autoimmune disease; (d) age onset proteotoxic disease; (e) mood disorder; (f) acne vulgaris; (g) solid organ transplant rejection; (h) pulmonary disease;
(i) cardiac hypertrophy; (j) viral infection; (k) an inflammatory condition; (l) heart failure; or (m) parasitic infection. 16. A method for restoring sensitivity to one or more chemotherapeutic agents in the treatment of cancer, comprising administering an effective amount of the compound of one of claims 1–9, or the composition of one of claims 10–11, to a subject in need thereof. 17. A method for treating a disease or disorder in a patient where the disease or disorder involves the dysregulation of the PI3K-AKT-FOXO signaling pathway, comprising administering an effective amount of the compound of one of claims 1–9, or the composition of one of claims 10–11, to a subject in need thereof. 18. A method for treating a disease or disorder in a patient where the disease or disorder involves the dysregulation of a Myc dependent signaling pathway, comprising administering an effective amount of the compound of one of claims 1–9, or the composition of one of claims 10–11, to a subject in need thereof. 19. A method for treating a metabolic or neurological disease or disorder in a patient wherein the disease or disorder involves the dysregulation of the mTOR-PP2A signaling axis, comprising administering an effective amount of the compound of one of claims 1–9, or the composition of one of claims 10–11, to a subject in need thereof. 20. A kit, comprising the compound of one of claims 1–9, or the composition of one of claims 10–11, and instructions for use. 21. A method, comprising one or more synthetic steps for preparing the compound of one of claims 1–9.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US202263398077P | 2022-08-15 | 2022-08-15 | |
US63/398,077 | 2022-08-15 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2024040045A2 true WO2024040045A2 (en) | 2024-02-22 |
WO2024040045A3 WO2024040045A3 (en) | 2024-04-11 |
Family
ID=89942366
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2023/072200 WO2024040045A2 (en) | 2022-08-15 | 2023-08-15 | 2-diarylmethyl-4-aminotetrahydropyran sulfonimidamides as anticancer, antiinflammatory, antifibrotic and neuroprotective agents |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2024040045A2 (en) |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060122263A1 (en) * | 2003-03-28 | 2006-06-08 | Dutta Aloke K | Tri-substituted 2-benzhydryl-5-benzlamino-tetrahydro-pyran-4-ol and 6-benzhydryl-4-benzylamino-tetrahydro-pyran-3-ol analogues, and novel 3,6-disubstituted pyran derivatives |
WO2017044575A1 (en) * | 2015-09-09 | 2017-03-16 | Icahn School Of Medicine At Mount Sinai | Constrained benzhydryl sulfonamides as anticancer and neuroprotective agents |
EP4110762A1 (en) * | 2020-02-28 | 2023-01-04 | Rappta Therapeutics Oy | Tricyclic modulators of pp2a |
WO2021188949A1 (en) * | 2020-03-20 | 2021-09-23 | Atux Iskay Llc | 3-diarylmethylenes and uses thereof |
-
2023
- 2023-08-15 WO PCT/US2023/072200 patent/WO2024040045A2/en unknown
Also Published As
Publication number | Publication date |
---|---|
WO2024040045A3 (en) | 2024-04-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2017254523B2 (en) | Compounds and compositions for treating conditions associated with NLRP activity | |
US10221158B2 (en) | Heterocyclic constrained tricyclic sulfonamides as anti-cancer agents | |
US9937186B2 (en) | Sulfonamides derived from tricyclyl-2-aminocycloalkanols as anticancer agents | |
US10011611B2 (en) | Histone deacetylase inhibitors and methods for use thereof | |
EA017714B1 (en) | Tgr5 modulators and methods of use thereof | |
WO2021150695A1 (en) | Constrained n-substituted tetrahydrobenzoazepine sulfonamides as anticancer and neuroprotective agents | |
WO2017044575A1 (en) | Constrained benzhydryl sulfonamides as anticancer and neuroprotective agents | |
CN105120854B (en) | New salicyclic acid derivatives, its pharmaceutically acceptable salt, its composition and its application method | |
US20110212911A1 (en) | Transcription factor inhibitors and related compositions, formulations and methods | |
JP2018518480A (en) | ROR gamma (RORγ) modulator | |
WO2022174525A1 (en) | Compound, preparation method therefor and use thereof | |
CN111620815B (en) | Chiral chloroquine, hydroxychloroquine and derivatives thereof, and preparation methods and applications thereof | |
Tang et al. | Novel cytisine derivatives exert anti-liver fibrosis effect via PI3K/Akt/Smad pathway | |
JP2021534215A (en) | Aromatic molecules for use in the treatment of pathological symptoms | |
WO2021188949A1 (en) | 3-diarylmethylenes and uses thereof | |
JP2022507117A (en) | A novel compound for the treatment of respiratory diseases | |
US20170183297A1 (en) | Omega-3 analogues | |
WO2024040045A2 (en) | 2-diarylmethyl-4-aminotetrahydropyran sulfonimidamides as anticancer, antiinflammatory, antifibrotic and neuroprotective agents | |
WO2019185033A1 (en) | Amide pyrazole compound used as fgfr irreversible inhibitor | |
WO2021150697A1 (en) | N-substituted-3-tricyclyl piperidine derivatives as anticancer and neuroprotective agents | |
WO2023023594A9 (en) | 2‑diarylmethyl‑4‑aminotetrahydropyran derivatives and related compounds as anticancer, antiinflammatory, antifibrotic and neuroprotective agents | |
JP2009537551A (en) | Pyrimidine low molecular weight ligands for modulating hormone receptors | |
JP2021534212A (en) | Aromatic molecules for use in the treatment of pathological conditions | |
BRPI0708098A2 (en) | 4-benzoylaminophenyl) -6,7-dimethoxy-2-methylaminoquinazoline derivatives | |
WO2021150700A1 (en) | N-substituted-3-tricyclyl piperidine derivatives as anticancer and neuroprotective agents |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 23855605 Country of ref document: EP Kind code of ref document: A2 |