WO2024076635A2 - Suppressors of site iq electron leak and uses thereof - Google Patents
Suppressors of site iq electron leak and uses thereof Download PDFInfo
- Publication number
- WO2024076635A2 WO2024076635A2 PCT/US2023/034468 US2023034468W WO2024076635A2 WO 2024076635 A2 WO2024076635 A2 WO 2024076635A2 US 2023034468 W US2023034468 W US 2023034468W WO 2024076635 A2 WO2024076635 A2 WO 2024076635A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- substituted
- unsubstituted
- membered
- compound
- independently
- Prior art date
Links
- 125000001424 substituent group Chemical group 0.000 claims description 765
- 150000001875 compounds Chemical class 0.000 claims description 206
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 179
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 164
- -1 -CONH2 Chemical group 0.000 claims description 130
- 125000001072 heteroaryl group Chemical group 0.000 claims description 127
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 118
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 113
- 125000003118 aryl group Chemical group 0.000 claims description 100
- 125000000217 alkyl group Chemical group 0.000 claims description 85
- 208000035475 disorder Diseases 0.000 claims description 75
- 229910052739 hydrogen Inorganic materials 0.000 claims description 72
- 239000001257 hydrogen Substances 0.000 claims description 72
- 229910052736 halogen Inorganic materials 0.000 claims description 47
- 206010028980 Neoplasm Diseases 0.000 claims description 45
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 44
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 41
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 38
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 36
- 201000011510 cancer Diseases 0.000 claims description 35
- 150000002367 halogens Chemical group 0.000 claims description 34
- 150000003839 salts Chemical class 0.000 claims description 33
- 229910004727 OSO3H Inorganic materials 0.000 claims description 31
- 229910006074 SO2NH2 Inorganic materials 0.000 claims description 31
- 229910006069 SO3H Inorganic materials 0.000 claims description 31
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 31
- 238000000034 method Methods 0.000 claims description 30
- 229910052757 nitrogen Inorganic materials 0.000 claims description 30
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 claims description 27
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 26
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 24
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 23
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 21
- 150000002431 hydrogen Chemical group 0.000 claims description 21
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 20
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 18
- 239000000651 prodrug Chemical group 0.000 claims description 18
- 229940002612 prodrug Drugs 0.000 claims description 18
- 208000001145 Metabolic Syndrome Diseases 0.000 claims description 17
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 17
- 206010027476 Metastases Diseases 0.000 claims description 15
- 230000009401 metastasis Effects 0.000 claims description 14
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 14
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 14
- 206010022489 Insulin Resistance Diseases 0.000 claims description 11
- 210000000056 organ Anatomy 0.000 claims description 11
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 206010020772 Hypertension Diseases 0.000 claims description 9
- 230000003405 preventing effect Effects 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 208000004476 Acute Coronary Syndrome Diseases 0.000 claims description 5
- 208000009304 Acute Kidney Injury Diseases 0.000 claims description 5
- 201000001320 Atherosclerosis Diseases 0.000 claims description 5
- 206010011878 Deafness Diseases 0.000 claims description 5
- 206010011903 Deafness traumatic Diseases 0.000 claims description 5
- 208000032781 Diabetic cardiomyopathy Diseases 0.000 claims description 5
- 208000002946 Noise-Induced Hearing Loss Diseases 0.000 claims description 5
- 208000001132 Osteoporosis Diseases 0.000 claims description 5
- 208000018737 Parkinson disease Diseases 0.000 claims description 5
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 claims description 5
- 208000033626 Renal failure acute Diseases 0.000 claims description 5
- 206010063837 Reperfusion injury Diseases 0.000 claims description 5
- 208000006011 Stroke Diseases 0.000 claims description 5
- 201000011040 acute kidney failure Diseases 0.000 claims description 5
- 206010000891 acute myocardial infarction Diseases 0.000 claims description 5
- 230000005907 cancer growth Effects 0.000 claims description 5
- 230000000747 cardiac effect Effects 0.000 claims description 5
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 5
- 229960004316 cisplatin Drugs 0.000 claims description 5
- 230000010370 hearing loss Effects 0.000 claims description 5
- 231100000888 hearing loss Toxicity 0.000 claims description 5
- 208000016354 hearing loss disease Diseases 0.000 claims description 5
- 231100000268 induced nephrotoxicity Toxicity 0.000 claims description 5
- 208000012947 ischemia reperfusion injury Diseases 0.000 claims description 5
- 201000008482 osteoarthritis Diseases 0.000 claims description 5
- 238000002054 transplantation Methods 0.000 claims description 5
- 208000024827 Alzheimer disease Diseases 0.000 claims description 4
- 125000002757 morpholinyl group Chemical group 0.000 claims description 4
- 125000003386 piperidinyl group Chemical group 0.000 claims description 4
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 73
- 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 64
- 241001465754 Metazoa Species 0.000 description 61
- 108090000623 proteins and genes Proteins 0.000 description 61
- 102000004169 proteins and genes Human genes 0.000 description 60
- 235000018102 proteins Nutrition 0.000 description 59
- 201000009030 Carcinoma Diseases 0.000 description 57
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 54
- 239000008103 glucose Substances 0.000 description 52
- 239000000126 substance Substances 0.000 description 49
- 150000001413 amino acids Chemical class 0.000 description 45
- 230000000694 effects Effects 0.000 description 45
- 235000001014 amino acid Nutrition 0.000 description 44
- 238000011282 treatment Methods 0.000 description 44
- 201000010099 disease Diseases 0.000 description 43
- 235000009200 high fat diet Nutrition 0.000 description 41
- 210000004027 cell Anatomy 0.000 description 39
- OUUQCZGPVNCOIJ-UHFFFAOYSA-M Superoxide Chemical compound [O-][O] OUUQCZGPVNCOIJ-UHFFFAOYSA-M 0.000 description 38
- 241000699670 Mus sp. Species 0.000 description 35
- 102000004877 Insulin Human genes 0.000 description 32
- 108090001061 Insulin Proteins 0.000 description 32
- 229940125396 insulin Drugs 0.000 description 32
- 238000004519 manufacturing process Methods 0.000 description 32
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 29
- 230000002438 mitochondrial effect Effects 0.000 description 28
- 239000000203 mixture Substances 0.000 description 28
- 125000002947 alkylene group Chemical group 0.000 description 24
- 125000005842 heteroatom Chemical group 0.000 description 24
- 230000003247 decreasing effect Effects 0.000 description 23
- 125000003107 substituted aryl group Chemical group 0.000 description 23
- 210000004369 blood Anatomy 0.000 description 21
- 239000008280 blood Substances 0.000 description 21
- 230000037396 body weight Effects 0.000 description 21
- 230000001413 cellular effect Effects 0.000 description 21
- 125000004474 heteroalkylene group Chemical group 0.000 description 21
- 206010039491 Sarcoma Diseases 0.000 description 20
- 125000004429 atom Chemical group 0.000 description 20
- 208000032839 leukemia Diseases 0.000 description 20
- 125000000547 substituted alkyl group Chemical group 0.000 description 20
- 125000005549 heteroarylene group Chemical group 0.000 description 19
- 125000006588 heterocycloalkylene group Chemical group 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 208000024891 symptom Diseases 0.000 description 18
- 125000000732 arylene group Chemical group 0.000 description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 230000005764 inhibitory process Effects 0.000 description 16
- 230000001629 suppression Effects 0.000 description 16
- 230000007423 decrease Effects 0.000 description 15
- 125000005843 halogen group Chemical group 0.000 description 15
- 230000001225 therapeutic effect Effects 0.000 description 15
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 14
- 230000006870 function Effects 0.000 description 14
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 14
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 14
- 125000005647 linker group Chemical group 0.000 description 14
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 14
- 150000003254 radicals Chemical class 0.000 description 14
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 14
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 13
- 210000003470 mitochondria Anatomy 0.000 description 13
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 12
- 229910052760 oxygen Inorganic materials 0.000 description 12
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 11
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 11
- 229940098773 bovine serum albumin Drugs 0.000 description 11
- 238000002474 experimental method Methods 0.000 description 11
- 230000014509 gene expression Effects 0.000 description 11
- 230000000069 prophylactic effect Effects 0.000 description 11
- 238000011321 prophylaxis Methods 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 229910052717 sulfur Inorganic materials 0.000 description 11
- 102000004190 Enzymes Human genes 0.000 description 10
- 108090000790 Enzymes Proteins 0.000 description 10
- 206010025323 Lymphomas Diseases 0.000 description 10
- 239000013543 active substance Substances 0.000 description 10
- 238000007792 addition Methods 0.000 description 10
- 229910052799 carbon Inorganic materials 0.000 description 10
- 125000002993 cycloalkylene group Chemical group 0.000 description 10
- 235000005911 diet Nutrition 0.000 description 10
- 230000037213 diet Effects 0.000 description 10
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 10
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 10
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 10
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 10
- 150000002632 lipids Chemical class 0.000 description 10
- 230000003211 malignant effect Effects 0.000 description 10
- 201000001441 melanoma Diseases 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 10
- 229920006395 saturated elastomer Polymers 0.000 description 10
- 229910052710 silicon Inorganic materials 0.000 description 10
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 9
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 150000001412 amines Chemical class 0.000 description 9
- 238000003556 assay Methods 0.000 description 9
- 210000000481 breast Anatomy 0.000 description 9
- 230000008859 change Effects 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 239000000460 chlorine Substances 0.000 description 9
- 235000012631 food intake Nutrition 0.000 description 9
- 108090000765 processed proteins & peptides Proteins 0.000 description 9
- 239000003981 vehicle Substances 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 8
- 239000000556 agonist Substances 0.000 description 8
- 239000005557 antagonist Substances 0.000 description 8
- 230000027455 binding Effects 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 235000013305 food Nutrition 0.000 description 8
- 238000007446 glucose tolerance test Methods 0.000 description 8
- 239000010931 gold Substances 0.000 description 8
- 150000002500 ions Chemical class 0.000 description 8
- 239000002105 nanoparticle Substances 0.000 description 8
- 108020004707 nucleic acids Proteins 0.000 description 8
- 150000007523 nucleic acids Chemical class 0.000 description 8
- 102000039446 nucleic acids Human genes 0.000 description 8
- 239000002773 nucleotide Substances 0.000 description 8
- 125000003729 nucleotide group Chemical group 0.000 description 8
- 230000019491 signal transduction Effects 0.000 description 8
- 125000003396 thiol group Chemical group [H]S* 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 7
- 125000006582 (C5-C6) heterocycloalkyl group Chemical group 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 239000010949 copper Substances 0.000 description 7
- 238000000338 in vitro Methods 0.000 description 7
- 238000001727 in vivo Methods 0.000 description 7
- 210000004185 liver Anatomy 0.000 description 7
- 235000004213 low-fat Nutrition 0.000 description 7
- 230000002503 metabolic effect Effects 0.000 description 7
- 108091033319 polynucleotide Proteins 0.000 description 7
- 102000040430 polynucleotide Human genes 0.000 description 7
- 239000002157 polynucleotide Substances 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 125000000041 C6-C10 aryl group Chemical group 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- 238000009825 accumulation Methods 0.000 description 6
- 125000002619 bicyclic group Chemical group 0.000 description 6
- 125000004122 cyclic group Chemical group 0.000 description 6
- 125000000392 cycloalkenyl group Chemical group 0.000 description 6
- 239000003112 inhibitor Substances 0.000 description 6
- 239000011159 matrix material Substances 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- 229910052751 metal Inorganic materials 0.000 description 6
- 239000002184 metal Substances 0.000 description 6
- 230000007170 pathology Effects 0.000 description 6
- 229920000642 polymer Polymers 0.000 description 6
- 230000009467 reduction Effects 0.000 description 6
- 230000029058 respiratory gaseous exchange Effects 0.000 description 6
- 208000011581 secondary neoplasm Diseases 0.000 description 6
- 210000002027 skeletal muscle Anatomy 0.000 description 6
- 125000005717 substituted cycloalkylene group Chemical group 0.000 description 6
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- IFPPZTSKNBSMHN-UHFFFAOYSA-N 2-(3-bromo-4-oxopentyl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CCC(Br)C(=O)C)C(=O)C2=C1 IFPPZTSKNBSMHN-UHFFFAOYSA-N 0.000 description 5
- DPATUMDQWSJANG-UHFFFAOYSA-N 2-(4-oxopentyl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CCCC(=O)C)C(=O)C2=C1 DPATUMDQWSJANG-UHFFFAOYSA-N 0.000 description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 208000027418 Wounds and injury Diseases 0.000 description 5
- 230000001594 aberrant effect Effects 0.000 description 5
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 5
- 150000001721 carbon Chemical group 0.000 description 5
- 238000011260 co-administration Methods 0.000 description 5
- 230000006378 damage Effects 0.000 description 5
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 5
- 125000000524 functional group Chemical group 0.000 description 5
- 208000014674 injury Diseases 0.000 description 5
- 230000003993 interaction Effects 0.000 description 5
- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 description 5
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 5
- 235000015263 low fat diet Nutrition 0.000 description 5
- 229920002521 macromolecule Polymers 0.000 description 5
- 238000004949 mass spectrometry Methods 0.000 description 5
- 206010061289 metastatic neoplasm Diseases 0.000 description 5
- 244000005700 microbiome Species 0.000 description 5
- 125000006606 n-butoxy group Chemical group 0.000 description 5
- 238000001543 one-way ANOVA Methods 0.000 description 5
- 210000003463 organelle Anatomy 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- 229920001184 polypeptide Polymers 0.000 description 5
- 102000004196 processed proteins & peptides Human genes 0.000 description 5
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 5
- 210000003491 skin Anatomy 0.000 description 5
- 150000003384 small molecules Chemical class 0.000 description 5
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 description 4
- NDEGVCVLINMZNW-UHFFFAOYSA-N 2-[2-(2-amino-4-methyl-1,3-thiazol-5-yl)ethyl]isoindole-1,3-dione Chemical compound N1=C(N)SC(CCN2C(C3=CC=CC=C3C2=O)=O)=C1C NDEGVCVLINMZNW-UHFFFAOYSA-N 0.000 description 4
- 208000024172 Cardiovascular disease Diseases 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 229910052688 Gadolinium Inorganic materials 0.000 description 4
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 4
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 4
- 241000700605 Viruses Species 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 125000003342 alkenyl group Chemical group 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- 125000000539 amino acid group Chemical group 0.000 description 4
- 210000003719 b-lymphocyte Anatomy 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 229960002685 biotin Drugs 0.000 description 4
- 239000011616 biotin Substances 0.000 description 4
- 125000003636 chemical group Chemical group 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- 206010012601 diabetes mellitus Diseases 0.000 description 4
- 238000000502 dialysis Methods 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 4
- 229910052737 gold Inorganic materials 0.000 description 4
- 230000012010 growth Effects 0.000 description 4
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 239000007928 intraperitoneal injection Substances 0.000 description 4
- 208000003747 lymphoid leukemia Diseases 0.000 description 4
- 229940049920 malate Drugs 0.000 description 4
- BJEPYKJPYRNKOW-UHFFFAOYSA-L malate(2-) Chemical compound [O-]C(=O)C(O)CC([O-])=O BJEPYKJPYRNKOW-UHFFFAOYSA-L 0.000 description 4
- 238000013227 male C57BL/6J mice Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 description 4
- 208000030159 metabolic disease Diseases 0.000 description 4
- 208000037819 metastatic cancer Diseases 0.000 description 4
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 4
- 201000010879 mucinous adenocarcinoma Diseases 0.000 description 4
- 238000011201 multiple comparisons test Methods 0.000 description 4
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 4
- 239000003642 reactive oxygen metabolite Substances 0.000 description 4
- 241000894007 species Species 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 241000283690 Bos taurus Species 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 3
- 208000003170 Bronchiolo-Alveolar Adenocarcinoma Diseases 0.000 description 3
- 208000009458 Carcinoma in Situ Diseases 0.000 description 3
- 108010078791 Carrier Proteins Proteins 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 208000017604 Hodgkin disease Diseases 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 208000028018 Lymphocytic leukaemia Diseases 0.000 description 3
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical group O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 208000008589 Obesity Diseases 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 102100032891 Superoxide dismutase [Mn], mitochondrial Human genes 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 230000003213 activating effect Effects 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 210000000577 adipose tissue Anatomy 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 235000020958 biotin Nutrition 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052802 copper Inorganic materials 0.000 description 3
- 238000012217 deletion Methods 0.000 description 3
- 230000037430 deletion Effects 0.000 description 3
- 230000002255 enzymatic effect Effects 0.000 description 3
- 230000037406 food intake Effects 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 229930195712 glutamate Natural products 0.000 description 3
- 125000001188 haloalkyl group Chemical group 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000003780 insertion Methods 0.000 description 3
- 230000037431 insertion Effects 0.000 description 3
- 238000007912 intraperitoneal administration Methods 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 208000020816 lung neoplasm Diseases 0.000 description 3
- 150000002739 metals Chemical group 0.000 description 3
- 230000001394 metastastic effect Effects 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- 208000025113 myeloid leukemia Diseases 0.000 description 3
- 235000020824 obesity Nutrition 0.000 description 3
- 230000005298 paramagnetic effect Effects 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 3
- 230000004962 physiological condition Effects 0.000 description 3
- 230000001681 protective effect Effects 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 239000011593 sulfur Substances 0.000 description 3
- 108010045815 superoxide dismutase 2 Proteins 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000032258 transport Effects 0.000 description 3
- 230000009278 visceral effect Effects 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- 102100033350 ATP-dependent translocase ABCB1 Human genes 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 2
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 2
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 206010058354 Bronchioloalveolar carcinoma Diseases 0.000 description 2
- 102000016938 Catalase Human genes 0.000 description 2
- 108010053835 Catalase Proteins 0.000 description 2
- 229910052684 Cerium Inorganic materials 0.000 description 2
- 206010008583 Chloroma Diseases 0.000 description 2
- 208000006332 Choriocarcinoma Diseases 0.000 description 2
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 108020005199 Dehydrogenases Proteins 0.000 description 2
- 238000005698 Diels-Alder reaction Methods 0.000 description 2
- 229910052692 Dysprosium Inorganic materials 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 102000015782 Electron Transport Complex III Human genes 0.000 description 2
- 108010024882 Electron Transport Complex III Proteins 0.000 description 2
- 229910052691 Erbium Inorganic materials 0.000 description 2
- 229910052693 Europium Inorganic materials 0.000 description 2
- 208000002705 Glucose Intolerance Diseases 0.000 description 2
- 206010018429 Glucose tolerance impaired Diseases 0.000 description 2
- 208000032087 Hereditary Leber Optic Atrophy Diseases 0.000 description 2
- 229910052689 Holmium Inorganic materials 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 206010053574 Immunoblastic lymphoma Diseases 0.000 description 2
- 102000004310 Ion Channels Human genes 0.000 description 2
- 108090000862 Ion Channels Proteins 0.000 description 2
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 2
- LRQKBLKVPFOOQJ-YFKPBYRVSA-N L-norleucine Chemical group CCCC[C@H]([NH3+])C([O-])=O LRQKBLKVPFOOQJ-YFKPBYRVSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 2
- 201000000639 Leber hereditary optic neuropathy Diseases 0.000 description 2
- 206010050017 Lung cancer metastatic Diseases 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 229910052765 Lutetium Inorganic materials 0.000 description 2
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 208000037196 Medullary thyroid carcinoma Diseases 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 208000034578 Multiple myelomas Diseases 0.000 description 2
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 229910052779 Neodymium Inorganic materials 0.000 description 2
- 108091005461 Nucleic proteins Proteins 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 description 2
- 229910052777 Praseodymium Inorganic materials 0.000 description 2
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- 208000006265 Renal cell carcinoma Diseases 0.000 description 2
- 208000017442 Retinal disease Diseases 0.000 description 2
- 206010038923 Retinopathy Diseases 0.000 description 2
- 229910052772 Samarium Inorganic materials 0.000 description 2
- 201000001542 Schneiderian carcinoma Diseases 0.000 description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 2
- 241000399119 Spio Species 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical class [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 229910052771 Terbium Inorganic materials 0.000 description 2
- 229910052775 Thulium Inorganic materials 0.000 description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 description 2
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 2
- 208000005946 Xerostomia Diseases 0.000 description 2
- 229910052769 Ytterbium Inorganic materials 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 208000036676 acute undifferentiated leukemia Diseases 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 150000001266 acyl halides Chemical class 0.000 description 2
- 238000011374 additional therapy Methods 0.000 description 2
- 208000009956 adenocarcinoma Diseases 0.000 description 2
- 208000002517 adenoid cystic carcinoma Diseases 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- 125000004450 alkenylene group Chemical group 0.000 description 2
- 150000001345 alkine derivatives Chemical class 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000004419 alkynylene group Chemical group 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 210000001185 bone marrow Anatomy 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 239000013522 chelant Substances 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 239000002872 contrast media Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 238000012937 correction Methods 0.000 description 2
- 238000006352 cycloaddition reaction Methods 0.000 description 2
- 230000007850 degeneration Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- MXFYYFVVIIWKFE-UHFFFAOYSA-N dicyclohexyl-[2-[2,6-di(propan-2-yloxy)phenyl]phenyl]phosphane Chemical group CC(C)OC1=CC=CC(OC(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 MXFYYFVVIIWKFE-UHFFFAOYSA-N 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 206010013781 dry mouth Diseases 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- YCKRFDGAMUMZLT-BJUDXGSMSA-N fluorine-18 atom Chemical compound [18F] YCKRFDGAMUMZLT-BJUDXGSMSA-N 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 229940093181 glucose injection Drugs 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 210000003128 head Anatomy 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 201000001421 hyperglycemia Diseases 0.000 description 2
- 201000004933 in situ carcinoma Diseases 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- WTFXARWRTYJXII-UHFFFAOYSA-N iron(2+);iron(3+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[O-2].[Fe+2].[Fe+3].[Fe+3] WTFXARWRTYJXII-UHFFFAOYSA-N 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 208000017169 kidney disease Diseases 0.000 description 2
- 229910052746 lanthanum Inorganic materials 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000025036 lymphosarcoma Diseases 0.000 description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 2
- 229910052748 manganese Inorganic materials 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000005012 migration Effects 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- 230000005787 mitochondrial ATP synthesis coupled electron transport Effects 0.000 description 2
- 201000006894 monocytic leukemia Diseases 0.000 description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 2
- 201000005962 mycosis fungoides Diseases 0.000 description 2
- 201000005987 myeloid sarcoma Diseases 0.000 description 2
- 210000003739 neck Anatomy 0.000 description 2
- 201000001119 neuropathy Diseases 0.000 description 2
- 230000007823 neuropathy Effects 0.000 description 2
- 229910052759 nickel Inorganic materials 0.000 description 2
- 230000009871 nonspecific binding Effects 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 230000000269 nucleophilic effect Effects 0.000 description 2
- QYSGYZVSCZSLHT-UHFFFAOYSA-N octafluoropropane Chemical compound FC(F)(F)C(F)(F)C(F)(F)F QYSGYZVSCZSLHT-UHFFFAOYSA-N 0.000 description 2
- 238000003305 oral gavage Methods 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 230000010627 oxidative phosphorylation Effects 0.000 description 2
- 201000002528 pancreatic cancer Diseases 0.000 description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 229960004065 perflutren Drugs 0.000 description 2
- 208000033808 peripheral neuropathy Diseases 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 235000021317 phosphate Nutrition 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 208000031223 plasma cell leukemia Diseases 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 125000006413 ring segment Chemical group 0.000 description 2
- 229940080817 rotenone Drugs 0.000 description 2
- JUVIOZPCNVVQFO-UHFFFAOYSA-N rotenone Natural products O1C2=C3CC(C(C)=C)OC3=CC=C2C(=O)C2C1COC1=C2C=C(OC)C(OC)=C1 JUVIOZPCNVVQFO-UHFFFAOYSA-N 0.000 description 2
- 239000011669 selenium Substances 0.000 description 2
- 239000010703 silicon Substances 0.000 description 2
- 208000000649 small cell carcinoma Diseases 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 206010041823 squamous cell carcinoma Diseases 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- 208000013818 thyroid gland medullary carcinoma Diseases 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 229910052722 tritium Inorganic materials 0.000 description 2
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 2
- 238000011144 upstream manufacturing Methods 0.000 description 2
- 229910052720 vanadium Inorganic materials 0.000 description 2
- 210000001835 viscera Anatomy 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- MNULEGDCPYONBU-WMBHJXFZSA-N (1r,4s,5e,5'r,6'r,7e,10s,11r,12s,14r,15s,16s,18r,19s,20r,21e,25s,26r,27s,29s)-4-ethyl-11,12,15,19-tetrahydroxy-6'-[(2s)-2-hydroxypropyl]-5',10,12,14,16,18,20,26,29-nonamethylspiro[24,28-dioxabicyclo[23.3.1]nonacosa-5,7,21-triene-27,2'-oxane]-13,17,23-trio Polymers O([C@@H]1CC[C@@H](/C=C/C=C/C[C@H](C)[C@@H](O)[C@](C)(O)C(=O)[C@H](C)[C@@H](O)[C@H](C)C(=O)[C@H](C)[C@@H](O)[C@H](C)/C=C/C(=O)O[C@H]([C@H]2C)[C@H]1C)CC)[C@]12CC[C@@H](C)[C@@H](C[C@H](C)O)O1 MNULEGDCPYONBU-WMBHJXFZSA-N 0.000 description 1
- MNULEGDCPYONBU-DJRUDOHVSA-N (1s,4r,5z,5'r,6'r,7e,10s,11r,12s,14r,15s,18r,19r,20s,21e,26r,27s)-4-ethyl-11,12,15,19-tetrahydroxy-6'-(2-hydroxypropyl)-5',10,12,14,16,18,20,26,29-nonamethylspiro[24,28-dioxabicyclo[23.3.1]nonacosa-5,7,21-triene-27,2'-oxane]-13,17,23-trione Polymers O([C@H]1CC[C@H](\C=C/C=C/C[C@H](C)[C@@H](O)[C@](C)(O)C(=O)[C@H](C)[C@@H](O)C(C)C(=O)[C@H](C)[C@H](O)[C@@H](C)/C=C/C(=O)OC([C@H]2C)C1C)CC)[C@]12CC[C@@H](C)[C@@H](CC(C)O)O1 MNULEGDCPYONBU-DJRUDOHVSA-N 0.000 description 1
- OVAZCYUQNNFOKS-SCSAIBSYSA-N (2r)-2-(trifluoromethyl)morpholine Chemical compound FC(F)(F)[C@H]1CNCCO1 OVAZCYUQNNFOKS-SCSAIBSYSA-N 0.000 description 1
- XOMRRQXKHMYMOC-NRFANRHFSA-N (3s)-3-hexadecanoyloxy-4-(trimethylazaniumyl)butanoate Chemical compound CCCCCCCCCCCCCCCC(=O)O[C@@H](CC([O-])=O)C[N+](C)(C)C XOMRRQXKHMYMOC-NRFANRHFSA-N 0.000 description 1
- MNULEGDCPYONBU-YNZHUHFTSA-N (4Z,18Z,20Z)-22-ethyl-7,11,14,15-tetrahydroxy-6'-(2-hydroxypropyl)-5',6,8,10,12,14,16,28,29-nonamethylspiro[2,26-dioxabicyclo[23.3.1]nonacosa-4,18,20-triene-27,2'-oxane]-3,9,13-trione Polymers CC1C(C2C)OC(=O)\C=C/C(C)C(O)C(C)C(=O)C(C)C(O)C(C)C(=O)C(C)(O)C(O)C(C)C\C=C/C=C\C(CC)CCC2OC21CCC(C)C(CC(C)O)O2 MNULEGDCPYONBU-YNZHUHFTSA-N 0.000 description 1
- MNULEGDCPYONBU-VVXVDZGXSA-N (5e,5'r,7e,10s,11r,12s,14s,15r,16r,18r,19s,20r,21e,26r,29s)-4-ethyl-11,12,15,19-tetrahydroxy-6'-[(2s)-2-hydroxypropyl]-5',10,12,14,16,18,20,26,29-nonamethylspiro[24,28-dioxabicyclo[23.3.1]nonacosa-5,7,21-triene-27,2'-oxane]-13,17,23-trione Polymers C([C@H](C)[C@@H](O)[C@](C)(O)C(=O)[C@@H](C)[C@H](O)[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@H](C)/C=C/C(=O)OC([C@H]1C)[C@H]2C)\C=C\C=C\C(CC)CCC2OC21CC[C@@H](C)C(C[C@H](C)O)O2 MNULEGDCPYONBU-VVXVDZGXSA-N 0.000 description 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 1
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 description 1
- UKAUYVFTDYCKQA-UHFFFAOYSA-N -2-Amino-4-hydroxybutanoic acid Natural products OC(=O)C(N)CCO UKAUYVFTDYCKQA-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical class C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 150000003923 2,5-pyrrolediones Chemical class 0.000 description 1
- MFYSUUPKMDJYPF-UHFFFAOYSA-N 2-[(4-methyl-2-nitrophenyl)diazenyl]-3-oxo-n-phenylbutanamide Chemical compound C=1C=CC=CC=1NC(=O)C(C(=O)C)N=NC1=CC=C(C)C=C1[N+]([O-])=O MFYSUUPKMDJYPF-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 125000004174 2-benzimidazolyl group Chemical group [H]N1C(*)=NC2=C([H])C([H])=C([H])C([H])=C12 0.000 description 1
- AOYNUTHNTBLRMT-SLPGGIOYSA-N 2-deoxy-2-fluoro-aldehydo-D-glucose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](F)C=O AOYNUTHNTBLRMT-SLPGGIOYSA-N 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- MNULEGDCPYONBU-UHFFFAOYSA-N 4-ethyl-11,12,15,19-tetrahydroxy-6'-(2-hydroxypropyl)-5',10,12,14,16,18,20,26,29-nonamethylspiro[24,28-dioxabicyclo[23.3.1]nonacosa-5,7,21-triene-27,2'-oxane]-13,17,23-trione Polymers CC1C(C2C)OC(=O)C=CC(C)C(O)C(C)C(=O)C(C)C(O)C(C)C(=O)C(C)(O)C(O)C(C)CC=CC=CC(CC)CCC2OC21CCC(C)C(CC(C)O)O2 MNULEGDCPYONBU-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical group [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 description 1
- XVRIEWDDMODMGA-UHFFFAOYSA-N 5-chloropentan-2-one Chemical compound CC(=O)CCCCl XVRIEWDDMODMGA-UHFFFAOYSA-N 0.000 description 1
- CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 206010000871 Acute monocytic leukaemia Diseases 0.000 description 1
- 241000321096 Adenoides Species 0.000 description 1
- 208000009746 Adult T-Cell Leukemia-Lymphoma Diseases 0.000 description 1
- 208000016683 Adult T-cell leukemia/lymphoma Diseases 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 208000035805 Aleukaemic leukaemia Diseases 0.000 description 1
- 208000037540 Alveolar soft tissue sarcoma Diseases 0.000 description 1
- 206010001935 American trypanosomiasis Diseases 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 102000001049 Amyloid Human genes 0.000 description 1
- 108010094108 Amyloid Proteins 0.000 description 1
- 229920000856 Amylose Polymers 0.000 description 1
- 206010073478 Anaplastic large-cell lymphoma Diseases 0.000 description 1
- 201000003076 Angiosarcoma Diseases 0.000 description 1
- 206010003591 Ataxia Diseases 0.000 description 1
- 108090001008 Avidin Proteins 0.000 description 1
- 208000003950 B-cell lymphoma Diseases 0.000 description 1
- 208000028564 B-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- 208000013165 Bowen disease Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 208000011691 Burkitt lymphomas Diseases 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 125000004406 C3-C8 cycloalkylene group Chemical group 0.000 description 1
- 238000011746 C57BL/6J (JAX™ mouse strain) Methods 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- 208000031229 Cardiomyopathies Diseases 0.000 description 1
- 208000002177 Cataract Diseases 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 241000282994 Cervidae Species 0.000 description 1
- 208000024699 Chagas disease Diseases 0.000 description 1
- 108091006146 Channels Proteins 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- 208000005243 Chondrosarcoma Diseases 0.000 description 1
- ACTIUHUUMQJHFO-UHFFFAOYSA-N Coenzym Q10 Natural products COC1=C(OC)C(=O)C(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229910021590 Copper(II) bromide Inorganic materials 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
- SHIBSTMRCDJXLN-UHFFFAOYSA-N Digoxigenin Natural products C1CC(C2C(C3(C)CCC(O)CC3CC2)CC2O)(O)C2(C)C1C1=CC(=O)OC1 SHIBSTMRCDJXLN-UHFFFAOYSA-N 0.000 description 1
- 101001005200 Drosophila melanogaster Protein limb expression 1 homolog Proteins 0.000 description 1
- 201000009051 Embryonal Carcinoma Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 206010057649 Endometrial sarcoma Diseases 0.000 description 1
- 206010014958 Eosinophilic leukaemia Diseases 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 208000032027 Essential Thrombocythemia Diseases 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- 208000001382 Experimental Melanoma Diseases 0.000 description 1
- 208000009331 Experimental Sarcoma Diseases 0.000 description 1
- 201000006850 Familial medullary thyroid carcinoma Diseases 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000008999 Giant Cell Carcinoma Diseases 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 201000010915 Glioblastoma multiforme Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 208000001258 Hemangiosarcoma Diseases 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 208000017662 Hodgkin disease lymphocyte depletion type stage unspecified Diseases 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 101001090050 Homo sapiens Thioredoxin-dependent peroxide reductase, mitochondrial Proteins 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 1
- 208000037147 Hypercalcaemia Diseases 0.000 description 1
- 206010048643 Hypereosinophilic syndrome Diseases 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 206010020843 Hyperthermia Diseases 0.000 description 1
- 210000005131 Hürthle cell Anatomy 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
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- AMDBBAQNWSUWGN-UHFFFAOYSA-N Ioversol Chemical compound OCCN(C(=O)CO)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I AMDBBAQNWSUWGN-UHFFFAOYSA-N 0.000 description 1
- 206010023256 Juvenile melanoma benign Diseases 0.000 description 1
- 239000007836 KH2PO4 Substances 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- 206010023509 Kyphosis Diseases 0.000 description 1
- UKAUYVFTDYCKQA-VKHMYHEASA-N L-homoserine Chemical group OC(=O)[C@@H](N)CCO UKAUYVFTDYCKQA-VKHMYHEASA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical group CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- QEFRNWWLZKMPFJ-ZXPFJRLXSA-N L-methionine (R)-S-oxide Chemical group C[S@@](=O)CC[C@H]([NH3+])C([O-])=O QEFRNWWLZKMPFJ-ZXPFJRLXSA-N 0.000 description 1
- QEFRNWWLZKMPFJ-UHFFFAOYSA-N L-methionine sulphoxide Chemical group CS(=O)CCC(N)C(O)=O QEFRNWWLZKMPFJ-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 208000032004 Large-Cell Anaplastic Lymphoma Diseases 0.000 description 1
- 206010024218 Lentigo maligna Diseases 0.000 description 1
- 206010053180 Leukaemia cutis Diseases 0.000 description 1
- 206010024305 Leukaemia monocytic Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 description 1
- 208000007054 Medullary Carcinoma Diseases 0.000 description 1
- 208000009018 Medullary thyroid cancer Diseases 0.000 description 1
- 208000000172 Medulloblastoma Diseases 0.000 description 1
- 208000035490 Megakaryoblastic Acute Leukemia Diseases 0.000 description 1
- 108010047230 Member 1 Subfamily B ATP Binding Cassette Transporter Proteins 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
- 238000006845 Michael addition reaction Methods 0.000 description 1
- 238000006957 Michael reaction Methods 0.000 description 1
- 108010058682 Mitochondrial Proteins Proteins 0.000 description 1
- 102000006404 Mitochondrial Proteins Human genes 0.000 description 1
- 208000035489 Monocytic Acute Leukemia Diseases 0.000 description 1
- 206010057269 Mucoepidermoid carcinoma Diseases 0.000 description 1
- 206010073148 Multiple endocrine neoplasia type 2A Diseases 0.000 description 1
- 108010085220 Multiprotein Complexes Proteins 0.000 description 1
- 102000007474 Multiprotein Complexes Human genes 0.000 description 1
- 101100173048 Mus musculus Mcat gene Proteins 0.000 description 1
- 208000010428 Muscle Weakness Diseases 0.000 description 1
- 206010028289 Muscle atrophy Diseases 0.000 description 1
- 206010028372 Muscular weakness Diseases 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical class ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 description 1
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- QJGQUHMNIGDVPM-BJUDXGSMSA-N Nitrogen-13 Chemical compound [13N] QJGQUHMNIGDVPM-BJUDXGSMSA-N 0.000 description 1
- 206010029488 Nodular melanoma Diseases 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 229910003849 O-Si Inorganic materials 0.000 description 1
- 208000022873 Ocular disease Diseases 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 229910003872 O—Si Inorganic materials 0.000 description 1
- 206010033701 Papillary thyroid cancer Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 208000027190 Peripheral T-cell lymphomas Diseases 0.000 description 1
- 108010012822 Peroxiredoxin III Proteins 0.000 description 1
- 102000019202 Peroxiredoxin III Human genes 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 206010036524 Precursor B-lymphoblastic lymphomas Diseases 0.000 description 1
- 208000033826 Promyelocytic Acute Leukemia Diseases 0.000 description 1
- 102000004245 Proteasome Endopeptidase Complex Human genes 0.000 description 1
- 108090000708 Proteasome Endopeptidase Complex Proteins 0.000 description 1
- 108010001267 Protein Subunits Proteins 0.000 description 1
- 102000002067 Protein Subunits Human genes 0.000 description 1
- 208000019155 Radiation injury Diseases 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- IGLNJRXAVVLDKE-OIOBTWANSA-N Rubidium-82 Chemical compound [82Rb] IGLNJRXAVVLDKE-OIOBTWANSA-N 0.000 description 1
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 1
- 229910007161 Si(CH3)3 Inorganic materials 0.000 description 1
- 208000003252 Signet Ring Cell Carcinoma Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 206010058907 Spinal deformity Diseases 0.000 description 1
- 241000256248 Spodoptera Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- 206010042553 Superficial spreading melanoma stage unspecified Diseases 0.000 description 1
- 102000019197 Superoxide Dismutase Human genes 0.000 description 1
- 108010012715 Superoxide dismutase Proteins 0.000 description 1
- 208000031673 T-Cell Cutaneous Lymphoma Diseases 0.000 description 1
- 208000031672 T-Cell Peripheral Lymphoma Diseases 0.000 description 1
- 206010042971 T-cell lymphoma Diseases 0.000 description 1
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 208000020982 T-lymphoblastic lymphoma Diseases 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- 102100034769 Thioredoxin-dependent peroxide reductase, mitochondrial Human genes 0.000 description 1
- 208000030886 Traumatic Brain injury Diseases 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 description 1
- 208000008383 Wilms tumor Diseases 0.000 description 1
- 208000012018 Yolk sac tumor Diseases 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Chemical class Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- WXIONIWNXBAHRU-UHFFFAOYSA-N [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-dimethylazanium Chemical compound C1=CN=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 WXIONIWNXBAHRU-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 208000006336 acinar cell carcinoma Diseases 0.000 description 1
- 206010000583 acral lentiginous melanoma Diseases 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 208000020700 acute megakaryocytic leukemia Diseases 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 210000002534 adenoid Anatomy 0.000 description 1
- 208000020990 adrenal cortex carcinoma Diseases 0.000 description 1
- 230000001919 adrenal effect Effects 0.000 description 1
- 201000006966 adult T-cell leukemia Diseases 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 125000005237 alkyleneamino group Chemical group 0.000 description 1
- 125000005238 alkylenediamino group Chemical group 0.000 description 1
- 125000005530 alkylenedioxy group Chemical group 0.000 description 1
- 125000005529 alkyleneoxy group Chemical group 0.000 description 1
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 208000008524 alveolar soft part sarcoma Diseases 0.000 description 1
- 208000006431 amelanotic melanoma Diseases 0.000 description 1
- 230000002707 ameloblastic effect Effects 0.000 description 1
- YVPYQUNUQOZFHG-UHFFFAOYSA-N amidotrizoic acid Chemical compound CC(=O)NC1=C(I)C(NC(C)=O)=C(I)C(C(O)=O)=C1I YVPYQUNUQOZFHG-UHFFFAOYSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 206010002022 amyloidosis Diseases 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 238000013103 analytical ultracentrifugation Methods 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 210000002565 arteriole Anatomy 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 208000016894 basaloid carcinoma Diseases 0.000 description 1
- 201000000450 basaloid squamous cell carcinoma Diseases 0.000 description 1
- 208000003373 basosquamous carcinoma Diseases 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 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
- 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
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000002306 biochemical method Methods 0.000 description 1
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 210000003969 blast cell Anatomy 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 201000009480 botryoid rhabdomyosarcoma Diseases 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 201000010983 breast ductal carcinoma Diseases 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 208000003362 bronchogenic carcinoma Diseases 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- BPKIGYQJPYCAOW-FFJTTWKXSA-I calcium;potassium;disodium;(2s)-2-hydroxypropanoate;dichloride;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Na+].[Na+].[Cl-].[Cl-].[K+].[Ca+2].C[C@H](O)C([O-])=O BPKIGYQJPYCAOW-FFJTTWKXSA-I 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 208000035269 cancer or benign tumor Diseases 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- OKTJSMMVPCPJKN-BJUDXGSMSA-N carbon-11 Chemical compound [11C] OKTJSMMVPCPJKN-BJUDXGSMSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- UHBYWPGGCSDKFX-UHFFFAOYSA-N carboxyglutamic acid Chemical compound OC(=O)C(N)CC(C(O)=O)C(O)=O UHBYWPGGCSDKFX-UHFFFAOYSA-N 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 208000002458 carcinoid tumor Diseases 0.000 description 1
- 238000012754 cardiac puncture Methods 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000007541 cellular toxicity Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 description 1
- 210000003679 cervix uteri Anatomy 0.000 description 1
- 238000009614 chemical analysis method Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000013626 chemical specie Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 208000006990 cholangiocarcinoma Diseases 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000021668 chronic eosinophilic leukemia Diseases 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 235000017471 coenzyme Q10 Nutrition 0.000 description 1
- ACTIUHUUMQJHFO-UPTCCGCDSA-N coenzyme Q10 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UPTCCGCDSA-N 0.000 description 1
- 230000006999 cognitive decline Effects 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 201000011050 comedo carcinoma Diseases 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 235000020940 control diet Nutrition 0.000 description 1
- 230000001054 cortical effect Effects 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 201000011063 cribriform carcinoma Diseases 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 201000007241 cutaneous T cell lymphoma 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
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([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
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 208000016384 diabetic embryopathy Diseases 0.000 description 1
- 208000033679 diabetic kidney disease Diseases 0.000 description 1
- 229960005423 diatrizoate Drugs 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- QONQRTHLHBTMGP-UHFFFAOYSA-N digitoxigenin Natural products CC12CCC(C3(CCC(O)CC3CC3)C)C3C11OC1CC2C1=CC(=O)OC1 QONQRTHLHBTMGP-UHFFFAOYSA-N 0.000 description 1
- SHIBSTMRCDJXLN-KCZCNTNESA-N digoxigenin Chemical compound C1([C@@H]2[C@@]3([C@@](CC2)(O)[C@H]2[C@@H]([C@@]4(C)CC[C@H](O)C[C@H]4CC2)C[C@H]3O)C)=CC(=O)OC1 SHIBSTMRCDJXLN-KCZCNTNESA-N 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- 231100000676 disease causative agent Toxicity 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 150000002019 disulfides Chemical class 0.000 description 1
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000002222 downregulating effect Effects 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000027721 electron transport chain Effects 0.000 description 1
- 238000007336 electrophilic substitution reaction Methods 0.000 description 1
- 230000009881 electrostatic interaction Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 210000000750 endocrine system Anatomy 0.000 description 1
- 208000001991 endodermal sinus tumor Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 210000003020 exocrine pancreas Anatomy 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 230000003328 fibroblastic effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 201000003444 follicular lymphoma Diseases 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- 230000005251 gamma ray Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 230000000762 glandular Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 208000017750 granulocytic sarcoma Diseases 0.000 description 1
- 210000002503 granulosa cell Anatomy 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 201000009277 hairy cell leukemia Diseases 0.000 description 1
- 125000005179 haloacetyl group Chemical group 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 230000002008 hemorrhagic effect Effects 0.000 description 1
- 125000004366 heterocycloalkenyl group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000001794 hormone therapy Methods 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 210000004276 hyalin Anatomy 0.000 description 1
- 150000007857 hydrazones Chemical class 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 229960002591 hydroxyproline Drugs 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
- 208000030915 hypercalcemia disease Diseases 0.000 description 1
- 230000036031 hyperthermia Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000012216 imaging agent Substances 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 230000000984 immunochemical effect Effects 0.000 description 1
- 238000010166 immunofluorescence Methods 0.000 description 1
- 238000003364 immunohistochemistry Methods 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000000415 inactivating effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000012528 insulin ELISA Methods 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- ZCYVEMRRCGMTRW-YPZZEJLDSA-N iodine-125 Chemical compound [125I] ZCYVEMRRCGMTRW-YPZZEJLDSA-N 0.000 description 1
- 229940044173 iodine-125 Drugs 0.000 description 1
- 229960004359 iodixanol Drugs 0.000 description 1
- NBQNWMBBSKPBAY-UHFFFAOYSA-N iodixanol Chemical compound IC=1C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C(I)C=1N(C(=O)C)CC(O)CN(C(C)=O)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I NBQNWMBBSKPBAY-UHFFFAOYSA-N 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 229960001025 iohexol Drugs 0.000 description 1
- NTHXOOBQLCIOLC-UHFFFAOYSA-N iohexol Chemical compound OCC(O)CN(C(=O)C)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I NTHXOOBQLCIOLC-UHFFFAOYSA-N 0.000 description 1
- 229960004647 iopamidol Drugs 0.000 description 1
- XQZXYNRDCRIARQ-LURJTMIESA-N iopamidol Chemical compound C[C@H](O)C(=O)NC1=C(I)C(C(=O)NC(CO)CO)=C(I)C(C(=O)NC(CO)CO)=C1I XQZXYNRDCRIARQ-LURJTMIESA-N 0.000 description 1
- 229960002603 iopromide Drugs 0.000 description 1
- DGAIEPBNLOQYER-UHFFFAOYSA-N iopromide Chemical compound COCC(=O)NC1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)N(C)CC(O)CO)=C1I DGAIEPBNLOQYER-UHFFFAOYSA-N 0.000 description 1
- 229960004537 ioversol Drugs 0.000 description 1
- 229940029407 ioxaglate Drugs 0.000 description 1
- TYYBFXNZMFNZJT-UHFFFAOYSA-N ioxaglic acid Chemical compound CNC(=O)C1=C(I)C(N(C)C(C)=O)=C(I)C(C(=O)NCC(=O)NC=2C(=C(C(=O)NCCO)C(I)=C(C(O)=O)C=2I)I)=C1I TYYBFXNZMFNZJT-UHFFFAOYSA-N 0.000 description 1
- 229960002611 ioxilan Drugs 0.000 description 1
- UUMLTINZBQPNGF-UHFFFAOYSA-N ioxilan Chemical compound OCC(O)CN(C(=O)C)C1=C(I)C(C(=O)NCCO)=C(I)C(C(=O)NCC(O)CO)=C1I UUMLTINZBQPNGF-UHFFFAOYSA-N 0.000 description 1
- 210000004153 islets of langerhan Anatomy 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 210000001865 kupffer cell Anatomy 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229910052747 lanthanoid Inorganic materials 0.000 description 1
- 208000003849 large cell carcinoma Diseases 0.000 description 1
- 210000005240 left ventricle Anatomy 0.000 description 1
- 208000011080 lentigo maligna melanoma Diseases 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 230000000610 leukopenic effect Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 206010024627 liposarcoma Diseases 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 210000005265 lung cell Anatomy 0.000 description 1
- 201000000014 lung giant cell carcinoma Diseases 0.000 description 1
- 201000000966 lung oat cell carcinoma Diseases 0.000 description 1
- 208000037841 lung tumor Diseases 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 210000004324 lymphatic system Anatomy 0.000 description 1
- 201000011649 lymphoblastic lymphoma Diseases 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 201000010953 lymphoepithelioma-like carcinoma Diseases 0.000 description 1
- 210000003563 lymphoid tissue Anatomy 0.000 description 1
- 201000000564 macroglobulinemia Diseases 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 238000002595 magnetic resonance imaging Methods 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 125000005439 maleimidyl group Chemical group C1(C=CC(N1*)=O)=O 0.000 description 1
- 206010061526 malignant mesenchymoma Diseases 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 201000007924 marginal zone B-cell lymphoma Diseases 0.000 description 1
- 208000021937 marginal zone lymphoma Diseases 0.000 description 1
- 208000000516 mast-cell leukemia Diseases 0.000 description 1
- 208000020968 mature T-cell and NK-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 230000000684 melanotic effect Effects 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 230000006371 metabolic abnormality Effects 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
- 229960001252 methamphetamine Drugs 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 229930182817 methionine Chemical group 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-O methylsulfide anion Chemical compound [SH2+]C LSDPWZHWYPCBBB-UHFFFAOYSA-O 0.000 description 1
- 229960004712 metrizoic acid Drugs 0.000 description 1
- GGGDNPWHMNJRFN-UHFFFAOYSA-N metrizoic acid Chemical compound CC(=O)N(C)C1=C(I)C(NC(C)=O)=C(I)C(C(O)=O)=C1I GGGDNPWHMNJRFN-UHFFFAOYSA-N 0.000 description 1
- 230000003228 microsomal effect Effects 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 208000012268 mitochondrial disease Diseases 0.000 description 1
- 230000006686 mitochondrial oxygen consumption Effects 0.000 description 1
- GVZFUVXPTPGOQT-UHFFFAOYSA-M mitoq Chemical compound CS([O-])(=O)=O.O=C1C(OC)=C(OC)C(=O)C(CCCCCCCCCC[P+](C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1C GVZFUVXPTPGOQT-UHFFFAOYSA-M 0.000 description 1
- 108091005601 modified peptides Proteins 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 125000006682 monohaloalkyl group Chemical group 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 125000004572 morpholin-3-yl group Chemical group N1C(COCC1)* 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000020763 muscle atrophy Effects 0.000 description 1
- 201000000585 muscular atrophy Diseases 0.000 description 1
- 208000001611 myxosarcoma Diseases 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229940031182 nanoparticles iron oxide Drugs 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 208000014761 nasopharyngeal type undifferentiated carcinoma Diseases 0.000 description 1
- 201000011216 nasopharynx carcinoma Diseases 0.000 description 1
- 230000017095 negative regulation of cell growth Effects 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 229960005419 nitrogen Drugs 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 201000000032 nodular malignant melanoma Diseases 0.000 description 1
- 208000029809 non-keratinizing sinonasal squamous cell carcinoma Diseases 0.000 description 1
- 230000000683 nonmetastatic effect Effects 0.000 description 1
- 238000001668 nucleic acid synthesis Methods 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229930191479 oligomycin Natural products 0.000 description 1
- MNULEGDCPYONBU-AWJDAWNUSA-N oligomycin A Polymers O([C@H]1CC[C@H](/C=C/C=C/C[C@@H](C)[C@H](O)[C@@](C)(O)C(=O)[C@@H](C)[C@H](O)[C@@H](C)C(=O)[C@@H](C)[C@H](O)[C@@H](C)/C=C/C(=O)O[C@@H]([C@@H]2C)[C@@H]1C)CC)[C@@]12CC[C@H](C)[C@H](C[C@@H](C)O)O1 MNULEGDCPYONBU-AWJDAWNUSA-N 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- QVGXLLKOCUKJST-BJUDXGSMSA-N oxygen-15 atom Chemical compound [15O] QVGXLLKOCUKJST-BJUDXGSMSA-N 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 239000003973 paint Substances 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 201000010198 papillary carcinoma Diseases 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 229960004624 perflexane Drugs 0.000 description 1
- 201000001245 periodontitis Diseases 0.000 description 1
- 210000004303 peritoneum Anatomy 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003003 phosphines Chemical class 0.000 description 1
- 150000008300 phosphoramidites Chemical class 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical class OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
- 125000002743 phosphorus functional group Chemical group 0.000 description 1
- 230000000865 phosphorylative effect Effects 0.000 description 1
- BZQFBWGGLXLEPQ-REOHCLBHSA-N phosphoserine Chemical compound OC(=O)[C@@H](N)COP(O)(O)=O BZQFBWGGLXLEPQ-REOHCLBHSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 210000004224 pleura Anatomy 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 238000002264 polyacrylamide gel electrophoresis Methods 0.000 description 1
- 125000006684 polyhaloalkyl group Polymers 0.000 description 1
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 230000001124 posttranscriptional effect Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 208000025638 primary cutaneous T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 210000001236 prokaryotic cell Anatomy 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000004850 protein–protein interaction Effects 0.000 description 1
- 208000029817 pulmonary adenocarcinoma in situ Diseases 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 239000000941 radioactive substance Substances 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- NPCOQXAVBJJZBQ-UHFFFAOYSA-N reduced coenzyme Q9 Natural products COC1=C(O)C(C)=C(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)C(O)=C1OC NPCOQXAVBJJZBQ-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 201000006845 reticulosarcoma Diseases 0.000 description 1
- 208000029922 reticulum cell sarcoma Diseases 0.000 description 1
- 210000001525 retina Anatomy 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 210000005241 right ventricle Anatomy 0.000 description 1
- 201000007416 salivary gland adenoid cystic carcinoma Diseases 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 208000014212 sarcomatoid carcinoma Diseases 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 208000004259 scirrhous adenocarcinoma Diseases 0.000 description 1
- 206010039722 scoliosis Diseases 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000000276 sedentary effect Effects 0.000 description 1
- 238000003375 selectivity assay Methods 0.000 description 1
- 229910052711 selenium Inorganic materials 0.000 description 1
- 150000007659 semicarbazones Chemical class 0.000 description 1
- 230000001235 sensitizing effect Effects 0.000 description 1
- 230000008786 sensory perception of smell Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 201000008123 signet ring cell adenocarcinoma Diseases 0.000 description 1
- 229910052814 silicon oxide Inorganic materials 0.000 description 1
- 230000009759 skin aging Effects 0.000 description 1
- 206010040882 skin lesion Diseases 0.000 description 1
- 231100000444 skin lesion Toxicity 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 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
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 208000011584 spitz nevus Diseases 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000012289 standard assay Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 208000028210 stromal sarcoma Diseases 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 201000010033 subleukemic leukemia Diseases 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 125000002128 sulfonyl halide group Chemical group 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 208000030457 superficial spreading melanoma Diseases 0.000 description 1
- 239000013595 supernatant sample Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 206010042863 synovial sarcoma Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 1
- 239000012414 tert-butyl nitrite Substances 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 1
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- 125000005309 thioalkoxy group Chemical group 0.000 description 1
- ZCUFMDLYAMJYST-UHFFFAOYSA-N thorium dioxide Chemical compound O=[Th]=O ZCUFMDLYAMJYST-UHFFFAOYSA-N 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 208000030045 thyroid gland papillary carcinoma Diseases 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000759 toxicological effect Toxicity 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 206010044412 transitional cell carcinoma Diseases 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 229940035936 ubiquinone Drugs 0.000 description 1
- 208000022810 undifferentiated (embryonal) sarcoma Diseases 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 208000008662 verrucous carcinoma Diseases 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 230000036642 wellbeing Effects 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
- 229960002555 zidovudine Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
- C07D277/38—Nitrogen atoms
- C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/28—Radicals substituted by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
- C07D277/34—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- Metabolic syndrome is a collection of symptoms that can include high blood pressure, weight gain, high blood glucose concentration, and an increase in blood cholesterol and triglyceride levels. Collectively or in combination, these symptoms are linked to the incidence of diabetes, heart disease, and stroke (3). This linkage is particularly important given that cardiovascular diseases are the leading cause of mortality globally (4), and account for one in every four deaths in the U.S.A. (5). Over-consumption of high-calorie food and drink, and a sedentary way of life compounded with an aging population exacerbate the problem (2,6,7).
- R 1 is independently halogen, -CX 1 3 , -CHX 1 2 , -CH 2 X 1 , -OCX 1 3 , -OCH 2 X 1 , -OCHX 1 2, -CN, -SOn1R 1D , -SOv1NR 1A R 1B , ⁇ NR 1C NR 1A R 1B , ⁇ ONR 1A R 1B , -NR 1C C(O)NR 1A R 1B , -N(O)m1, -NR 1A R 1B , -C(O)R 1C , -C(O)OR 1C , -OC(O)R 1C , -OC(O)OR 1C , -C(O)NR 1A R 1B , -OC(O)NR 1A R 1B , -OR 1D , -SR 1D , -NR 1A SO2R 1D , -NR 1A C(O) C(
- R 1A , R 1B , R 1C , and R 1D are independently hydrogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstit
- Each X 1 is independently –Cl, -Br, -I, or –F.
- the symbol n1 is an integer from 0 to 4.
- the synmbols m1 and v1 are independently 1 or 2.
- the symbol z1 is an integer from 0 to 5.
- X is O or NR 2 .
- R 2 is hydrogen or unsubstituted C1-C6 alkyl.
- R 3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or a prodrug moiety.
- R 2 and R 3 substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl.
- R 4 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or a prodrug moiety.
- R 5 and R 6 are independently hydrogen, -OH, unsubstituted C1-C6 alkyl, or unsubstituted 2 to 6 membered heteroalkyl.
- R 5 and R 7 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl; or R 6 and R 7 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl.
- R 7 and R 8 are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO 2 , -SH, -SO 3 H, -OSO 3 H, -SO 2 NH 2 , ⁇ NHNH 2 , ⁇ ONH 2 , ⁇ NHC(O)NHNH 2 , ⁇ NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCBr 3 , -OCF 3 , -OCI 3 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 F,
- R 9 is independently halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ⁇ NHNH2, ⁇ ONH2, ⁇ NHC(O)NHNH2, ⁇ NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH 2 F, -OCH 2 I, -OCHCl 2 , -OCH 2
- FIGS.1A-1C Structure of S1QEL1.719 and potency in vitro.
- FIG.1A Chemical structure.
- FIG.1C Suppression of superoxide/hydrogen peroxide production from site I Q by S1QEL1.719 and inhibition of state 3 respiration on glutamate plus malate under exactly matched conditions. S1QEL1.719 concentrations in panel C are nominal values and uncorrected for binding to BSA.
- FIG.2A Timeline. Diets and S1QEL treatment were introduced at age 15 weeks and continued for two weeks.
- FIG.2B Food consumption during the two weeks was measured crudely by weighing chow.
- FIG.2C Body weight was measured on treatment days 1, 8 and 15.
- FIG.2D The change in body weight for individual animals was calculated as the difference in weight between day 15 and day 1.
- FIG.2E Change in fat mass was measured by EchoMRI and is shown as the difference between day 15 and day 1.
- FIG.2F Lean mass was measured on day 14 using EchoMRI. Dotted lines on graphs represent the mean values for animals fed low-fat chow and high-fat chow.
- FIGS.3A-3E Prophylactic treatment with S1QEL1.719 improves glucose tolerance. Mice were placed for two weeks on a low-fat diet (control, ctrl) or a high-fat diet (HF) and prophylactically gavaged daily from treatment day 1 with vehicle or S1QEL1.719 (HF+719, 30 mg/kg per day, p.o.) (FIG.2A). On treatment days 8 (FIGS.3A-3B) and 15 (FIGS.3C-3D), a glucose tolerance test was conducted by intraperitoneal injection of a 2 g/kg bolus of glucose. FIG.3A, FIG.3C: Concentration of blood glucose, monitored over time.
- FIG.3B, FIG.3D Area under the curve (AUC), calculated from the raw traces in FIG. 3A and FIG.3C for each individual mouse.
- FIG.2A Mice were placed for two weeks on a low-fat diet (control, ctrl) or a high-fat diet (HF) and prophylactically gavaged daily from treatment day 1 with vehicle or S1QEL1.719 (HF+719, 30 mg/kg per day, p.o.) (FIG.2A).
- HF high-fat diet
- FIG. 4C Fasting glucose from (FIG.4A) and (FIG.4B) plotted longitudinally.
- FIG.4F Fasting insulin from (FIG.4D) and (FIG.4E) plotted longitudinally.
- FIGS.5A-5G Therapeutic dosing of S1QEL1.719 starting after six weeks on high- fat diet improves glucose tolerance and decreases plasma insulin concentration. Control twelve-week old mice were maintained on standard chow for the entirety of experiment. Six- week high-fat-fed twelve-week old mice were maintained on a high-fat diet (HF) and therapeutically gavaged daily from treatment day 1 with vehicle or S1QEL1.719 (HF+719, 30 mg/kg per day, p.o.).
- FIG.5A Timeline.
- FIG.5B Food consumption from treatment day 1- 15 was measured crudely by weighing chow.
- FIG.5C The change in body weight for individual animals was calculated as the difference in weight between day 15 and day 1.
- FIG.5D Change in fat mass was measured by EchoMRI and is shown as the difference in fat mass between day 14 and day 1.
- FIG.5E On treatment day 15 a glucose tolerance test was conducted by intraperitoneal injection of a 2 g/kg bolus of glucose and plasma glucose concentration was measured over 120 min.
- FIG.5F On treatment day 15 fasting plasma insulin levels were measured following 7-10 h of food withdrawal.
- FIG.5G Plasma insulin levels were measured following intraperitoneal injection of a 2 g/kg bolus of glucose when conducting the glucose tolerance test.
- alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include mono-, di-, and multivalent radicals.
- the alkyl may include a designated number of carbons (e.g., C 1 -C 10 means one to ten carbons).
- the alkyl is fully saturated. In embodiments, the alkyl is monounsaturated. In embodiments, the alkyl is polyunsaturated. Alkyl is an uncyclized chain. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, methyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
- An unsaturated alkyl group is one having one or more double bonds or triple bonds.
- Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2- isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.
- An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-O-).
- An alkyl moiety may be an alkenyl moiety.
- An alkyl moiety may be an alkynyl moiety.
- An alkenyl includes one or more double bonds.
- An alkynyl includes one or more triple bonds.
- alkylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, -CH 2 CH 2 CH 2 CH 2 -.
- an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred herein.
- a “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
- alkenylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene.
- alkynylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyne.
- the alkylene is fully saturated.
- the alkylene is monounsaturated.
- the alkylene is polyunsaturated.
- An alkenylene includes one or more double bonds.
- An alkynylene includes one or more triple bonds.
- heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
- the heteroatom(s) e.g., N, S, Si, or P
- Heteroalkyl is an uncyclized chain.
- a heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P).
- a heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, or P).
- a heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P).
- a heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P).
- a heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P).
- a heteroalkyl moiety may include up to 8 optionally different heteroatoms (e.g., O, N, S, Si, or P).
- the term “heteroalkenyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one double bond.
- a heteroalkenyl may optionally include more than one double bond and/or one or more triple bonds in additional to the one or more double bonds.
- heteroalkynyl by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one triple bond.
- a heteroalkynyl may optionally include more than one triple bond and/or one or more double bonds in additional to the one or more triple bonds.
- the heteroalkyl is fully saturated.
- the heteroalkyl is monounsaturated.
- the heteroalkyl is polyunsaturated.
- the term “heteroalkylene,” by itself or as part of another substituent means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH 2 -CH 2 -S-CH 2 -CH 2 - and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 -.
- heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)2R'- represents both -C(O)2R'- and -R'C(O)2-.
- heteroalkyl groups include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', -NR'R'', -OR', -SR', and/or -SO 2 R'.
- heteroalkyl is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R'' or the like, it will be understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity.
- heteroalkyl should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R'' or the like.
- heteroalkenylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from a heteroalkene.
- heteroalkynylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from a heteroalkyne.
- the heteroalkylene is fully saturated.
- the heteroalkylene is monounsaturated.
- the heteroalkylene is polyunsaturated.
- a heteroalkenylene includes one or more double bonds.
- a heteroalkynylene includes one or more triple bonds.
- cycloalkyl and heterocycloalkyl by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl,” respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule.
- cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
- heterocycloalkyl examples include, but are not limited to, 1- (1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3- morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.
- the cycloalkyl is fully saturated.
- the cycloalkyl is monounsaturated.
- the cycloalkyl is polyunsaturated.
- the heterocycloalkyl is fully saturated.
- the heterocycloalkyl is monounsaturated.
- the heterocycloalkyl is polyunsaturated.
- cycloalkyl means a monocyclic, bicyclic, or a multicyclic cycloalkyl ring system.
- monocyclic ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups can be saturated or unsaturated, but not aromatic.
- cycloalkyl groups are fully saturated.
- a bicyclic or multicyclic cycloalkyl ring system refers to multiple rings fused together wherein at least one of the fused rings is a cycloalkyl ring and wherein the multiple rings are attached to the parent molecular moiety through any carbon atom contained within a cycloalkyl ring of the multiple rings.
- a cycloalkyl is a cycloalkenyl.
- the term “cycloalkenyl” is used in accordance with its plain ordinary meaning.
- a cycloalkenyl is a monocyclic, bicyclic, or a multicyclic cycloalkenyl ring system.
- a bicyclic or multicyclic cycloalkenyl ring system refers to multiple rings fused together wherein at least one of the fused rings is a cycloalkenyl ring and wherein the multiple rings are attached to the parent molecular moiety through any carbon atom contained within a cycloalkenyl ring of the multiple rings.
- heterocycloalkyl means a monocyclic, bicyclic, or a multicyclic heterocycloalkyl ring system.
- heterocycloalkyl groups are fully saturated.
- a bicyclic or multicyclic heterocycloalkyl ring system refers to multiple rings fused together wherein at least one of the fused rings is a heterocycloalkyl ring and wherein the multiple rings are attached to the parent molecular moiety through any atom contained within a heterocycloalkyl ring of the multiple rings.
- halo or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl.
- halo(C1-C4)alkyl includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
- acyl means, unless otherwise stated, -C(O)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
- aryl means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently.
- a fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring and wherein the multiple rings are attached to the parent molecular moiety through any carbon atom contained within an aryl ring of the multiple rings.
- heteroaryl refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
- heteroaryl includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring and wherein the multiple rings are attached to the parent molecular moiety through any atom contained within a heteroaromatic ring of the multiple rings).
- a 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring.
- a 6,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring.
- a 6,5-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring.
- a heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom.
- Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazoyl benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2- pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imid
- arylene and heteroarylene are selected from the group of acceptable substituents described below.
- a heteroaryl group substituent may be -O- bonded to a ring heteroatom nitrogen.
- Spirocyclic rings are two or more rings wherein adjacent rings are attached through a single atom. The individual rings within spirocyclic rings may be identical or different.
- Individual rings in spirocyclic rings may be substituted or unsubstituted and may have different substituents from other individual rings within a set of spirocyclic rings. Possible substituents for individual rings within spirocyclic rings are the possible substituents for the same ring when not part of spirocyclic rings (e.g., substituents for cycloalkyl or heterocycloalkyl rings).
- Spirocylic rings may be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterocycloalkylene and individual rings within a spirocyclic ring group may be any of the immediately previous list, including having all rings of one type (e.g., all rings being substituted heterocycloalkylene wherein each ring may be the same or different substituted heterocycloalkylene).
- heterocyclic spirocyclic rings means a spirocyclic rings wherein at least one ring is a heterocyclic ring and wherein each ring may be a different ring.
- substituted spirocyclic rings means that at least one ring is substituted and each substituent may optionally be different.
- alkylarylene as an arylene moiety covalently bonded to an alkylene moiety (also referred to herein as an alkylene linker).
- alkylarylene group has the formula: .
- An alkylarylene moiety may be substituted (e.g., with a substituent group) on the alkylene moiety or the arylene linker (e.g., at carbons 2, 3, 4, or 6) with halogen, oxo, -N 3 , -CF3, -CCl3, -CBr3, -CI3, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2CH3, -SO 3 H, -OSO 3 H, -SO 2 NH 2 , ⁇ NHNH 2 , ⁇ ONH 2 , ⁇ NHC(O)NHNH 2 , substituted or unsubstituted C 1 -C 5 alkyl or substituted or unsubstituted 2 to 5 membered heteroalkyl).
- the alkylarylene is unsubstituted.
- Each of the above terms e.g., “alkyl,” “heteroalkyl,” “cycloalkyl,” “heterocycloalkyl,” “aryl,” and “heteroaryl” includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.
- R, R', R'', R'', and R''' each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups.
- aryl e.g., aryl substituted with 1-3 halogens
- substituted or unsubstituted heteroaryl substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups.
- each of the R groups is independently selected as are each R', R'', R''', and R''' group when more than one of these groups is present.
- R' and R'' are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7- membered ring.
- -NR'R'' includes, but is not limited to, 1-pyrrolidinyl and 4- morpholinyl.
- alkyl is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF 3 and -CH 2 CF 3 ) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like).
- haloalkyl e.g., -CF 3 and -CH 2 CF 3
- acyl e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like.
- each of the R groups is independently selected as are each R', R'', R'', and R''' groups when more than one of these groups is present.
- Substituents for rings e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene
- substituents on the ring may be depicted as substituents on the ring rather than on a specific atom of a ring (commonly referred to as a floating substituent).
- the substituent may be attached to any of the ring atoms (obeying the rules of chemical valency) and in the case of fused rings or spirocyclic rings, a substituent depicted as associated with one member of the fused rings or spirocyclic rings (a floating substituent on a single ring), may be a substituent on any of the fused rings or spirocyclic rings (a floating substituent on multiple rings).
- the multiple substituents may be on the same atom, same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent may optionally be different.
- a point of attachment of a ring to the remainder of a molecule is not limited to a single atom (a floating substituent)
- the attachment point may be any atom of the ring and in the case of a fused ring or spirocyclic ring, any atom of any of the fused rings or spirocyclic rings while obeying the rules of chemical valency.
- a ring, fused rings, or spirocyclic rings contain one or more ring heteroatoms and the ring, fused rings, or spirocyclic rings are shown with one more floating substituents (including, but not limited to, points of attachment to the remainder of the molecule), the floating substituents may be bonded to the heteroatoms.
- the ring heteroatoms are shown bound to one or more hydrogens (e.g., a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen) in the structure or formula with the floating substituent, when the heteroatom is bonded to the floating substituent, the substituent will be understood to replace the hydrogen, while obeying the rules of chemical valency.
- Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups.
- Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure.
- the ring-forming substituents are attached to adjacent members of the base structure.
- two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure.
- the ring-forming substituents are attached to a single member of the base structure.
- two ring- forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure.
- the ring-forming substituents are attached to non-adjacent members of the base structure.
- Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)-(CRR')q-U-, wherein T and U are independently -NR-, -O-, -CRR'-, or a single bond, and q is an integer of from 0 to 3.
- two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2)r-B-, wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'-, or a single bond, and r is an integer of from 1 to 4.
- One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
- two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR')s-X'- (C''R''R'')d-, where s and d are independently integers of from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-.
- R, R', R'', and R''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
- heteroatom or “ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), selenium (Se), and silicon (Si).
- heteroatom or “ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).
- a “substituent group,” as used herein, means a group selected from the following moieties: (A) oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F
- a “size-limited substituent” or “ size-limited substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10 aryl, and each substituted or unsubstituted heteroaryl is
- a “lower substituent” or “ lower substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 - C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted phenyl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstitute
- each substituted group described in the compounds herein is substituted with at least one substituent group. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene described in the compounds herein are substituted with at least one substituent group. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent group.
- each substituted or unsubstituted alkyl may be a substituted or unsubstituted C1-C20 alkyl
- each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl
- each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 -C 8 cycloalkyl
- each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl
- each substituted or unsubstituted aryl is a substituted or unsubstituted C6- C 10 aryl
- each substituted or unsubstituted heteroaryl is a substituted or unsubstituted or unsubstituted
- each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C20 alkylene
- each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered heteroalkylene
- each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C 3 -C 8 cycloalkylene
- each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene
- each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C10 arylene
- each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene.
- each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl
- each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl
- each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl
- each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl
- each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 -C 10 aryl
- each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl.
- each substituted or unsubstituted alkylene is a substituted or unsubstituted C 1 -C 8 alkylene
- each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene
- each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7 cycloalkylene
- each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene
- each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C10 arylene
- each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene.
- the compound is a chemical species set forth in the Examples section, figures, or tables below.
- a substituted or unsubstituted moiety e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and/or substituted or unsubstituted heteroarylene) is unsubstituted (e.g., is an unsubstituted alkyl, unsubstituted cycloalkyl, substituted
- a substituted or unsubstituted moiety e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and/or substituted or unsubstituted heteroarylene) is substituted (e.g., is a substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alky
- a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
- is substituted with at least one substituent group wherein if the substituted moiety is substituted with a plurality of substituent groups, each substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of substituent groups, each substituent group is different.
- a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
- is substituted with at least one size-limited substituent group wherein if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group may optionally be different.
- each size-limited substituent group is different.
- a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
- each lower substituent group is different.
- a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
- each substituent group, size-limited substituent group, and/or lower substituent group is different.
- each R substituent or L linker that is described as being “substituted” without reference as to the identity of any chemical moiety that composes the “substituted” group also referred to herein as an “open substitution” on an R substituent or L linker or an “openly substituted” R substituent or L linker
- the recited R substituent or L linker may, in embodiments, be substituted with one or more first substituent groups as defined below.
- the first substituent group is denoted with a corresponding first decimal point numbering system such that, for example, R 1 may be substituted with one or more first substituent groups denoted by R 1.1 , R 2 may be substituted with one or more first substituent groups denoted by R 2.1 , R 3 may be substituted with one or more first substituent groups denoted by R 3.1 , R 4 may be substituted with one or more first substituent groups denoted by R 4.1 , R 5 may be substituted with one or more first substituent groups denoted by R 5.1 , and the like up to or exceeding an R 100 that may be substituted with one or more first substituent groups denoted by R 100.1 .
- R 1A may be substituted with one or more first substituent groups denoted by R 1A.1
- R 2A may be substituted with one or more first substituent groups denoted by R 2A.1
- R 3A may be substituted with one or more first substituent groups denoted by R 3A.1
- R 4A may be substituted with one or more first substituent groups denoted by R 4A.1
- R 5A may be substituted with one or more first substituent groups denoted by R 5A.1 and the like up to or exceeding an R 100A may be substituted with one or more first substituent groups denoted by R 100A.1 .
- L 1 may be substituted with one or more first substituent groups denoted by R L1.1
- L 2 may be substituted with one or more first substituent groups denoted by R L2.1
- L 3 may be substituted with one or more first substituent groups denoted by R L3.1
- L 4 may be substituted with one or more first substituent groups denoted by R L4.1
- L 5 may be substituted with one or more first substituent groups denoted by R L5.1 and the like up to or exceeding an L 100 which may be substituted with one or more first substituent groups denoted by R L100.1 .
- each numbered R group or L group (alternatively referred to herein as R WW or L WW wherein “WW” represents the stated superscript number of the subject R group or L group) described herein may be substituted with one or more first substituent groups referred to herein generally as R WW.1 or R LWW.1 , respectively.
- each first substituent group (e.g., R 1.1 , R 2.1 , R 3.1 , R 4.1 , R 5.1 ... R 100.1 ; R 1A.1 , R 2A.1 , R 3A.1 , R 4A.1 , R 5A.1 ... R 100A.1 ; R L1.1 , R L2.1 , R L3.1 , R L4.1 , R L5.1 ... R L100.1 ) may be further substituted with one or more second substituent groups (e.g., R 1.2 , R 2.2 , R 3.2 , R 4.2 , R 5.2 ... R 100.2 ; R 1A.2 , R 2A.2 , R 3A.2 , R 4A.2 , R 5A.2 ... R 100A.2 ; R L1.2 , R L2.2 , R L3.2 , R L4.2 , R L5.2 ... R L100.2 , respectively).
- each first substituent group which may alternatively be represented herein as R WW.1 as described above, may be further substituted with one or more second substituent groups, which may alternatively be represented herein as R WW.2 .
- each second substituent group e.g., R 1.2 , R 2.2 , R 3.2 , R 4.2 , R 5.2 ... R 100.2 ; R 1A.2 , R 2A.2 , R 3A.2 , R 4A.2 , R 5A.2 ... R 100A.2 ; R L1.2 , R L2.2 , R L3.2 , R L4.2 , R L5.2 ... R L100.2
- may be further substituted with one or more third substituent groups e.g., R 1.3 , R 2.3 , R 3.3 , R 4.3 , R 5.3 ... R 100.3 ; R 1A.3 , R 2A.3 , R 3A.3 , R 4A.3 , R 5A.
- each second substituent group which may alternatively be represented herein as R WW.2 as described above, may be further substituted with one or more third substituent groups, which may alternatively be represented herein as R WW.3 .
- Each of the first substituent groups may be optionally different.
- Each of the second substituent groups may be optionally different.
- Each of the third substituent groups may be optionally different.
- R WW represents a substituent recited in a claim or chemical formula description herein which is openly substituted. “WW” represents the stated superscript number of the subject R group (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.).
- L WW is a linker recited in a claim or chemical formula description herein which is openly substituted.
- WW represents the stated superscript number of the subject L group (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.).
- each R WW may be unsubstituted or independently substituted with one or more first substituent groups, referred to herein as R WW.1 ; each first substituent group, R WW.1 , may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as R WW.2 ; and each second substituent group may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as R WW.3 .
- each L WW linker may be unsubstituted or independently substituted with one or more first substituent groups, referred to herein as R LWW.1 ; each first substituent group, R LWW.1 , may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as R LWW.2 ; and each second substituent group may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as R LWW.3 .
- Each first substituent group is optionally different.
- Each second substituent group is optionally different.
- Each third substituent group is optionally different.
- R WW is phenyl
- the said phenyl group is optionally substituted by one or more R WW.1 groups as defined herein below, e.g., when R WW.1 is R WW.2 -substituted or unsubstituted alkyl, examples of groups so formed include but are not limited to itself optionally substituted by 1 or more R WW.2 , which R WW.2 is optionally substituted by one or more R WW.3 .
- the R WW group is phenyl substituted by R WW.1 , which is methyl
- the methyl group may be further substituted to form groups including but not limited to:
- R WW.1 is independently oxo, halogen, -CX WW.1 3 , -CHX WW.1 2 , -CH 2 X WW.1 , -OCX WW.1 3, -OCH2X WW.1 , -OCHX WW.1 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ⁇ NH2, ⁇ ONH2, ⁇ NHC(O)NHNH2, ⁇ NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, R WW.2 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1
- R WW.1 is independently oxo, halogen, -CX WW.1 3 , , -CH2X WW.1 , -OCX WW.1 3, -OCH2X WW.1 , -OCHX WW.1 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ⁇ NHNH2, ⁇ ONH2, ⁇ NHC(O)NHNH2, ⁇ NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membere
- X WW.1 is independently –F, -Cl, -Br, or –I.
- R WW.2 is independently oxo, halogen, -CX WW.2 3 , -CHX WW.2 2 , -CH 2 X WW.2 , -OCX WW.2 3, -OCH2X WW.2 , -OCHX WW.2 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ⁇ NH2, ⁇ ONH2, ⁇ NHC(O)NHNH2, ⁇ NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, R WW.3 -substituted or unsubstituted alkyl (e.g., C 1
- R WW.2 is independently oxo, halogen, -CX WW.2 3 , -CHX WW.2 2 , -CH 2 X WW.2 , -OCX WW.2 3 , -OCH 2 X WW.2 , -OCHX WW.2 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ⁇ NHNH2, ⁇ ONH2, ⁇ NHC(O)NHNH2, ⁇ NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl
- X WW.2 is independently –F, -Cl, -Br, or –I.
- R WW.3 is independently oxo, halogen, -CX WW.3 3, -CHX WW.3 2, -CH2X WW.3 , -OCX WW.3 3 , -OCH 2 X WW.3 , -OCHX WW.3 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -OSO 3 H, -SO 2 NH 2 , ⁇ NHNH 2 , ⁇ ONH 2 , ⁇ NHC(O)NHNH 2 , ⁇ NHC(O)NH 2 , –NHC(NH)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -N 3 , unsubstituted alkyl
- X WW.3 is independently –F, -Cl, -Br, or –I.
- the openly substituted ring may be independently substituted with one or more first substituent groups, referred to herein as R WW.1 ; each first substituent group, R WW.1 , may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as R WW.2 ; and each second substituent group, R WW.2 , may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as R WW.3 ; and each third substituent group, R WW.3 , is unsubstituted.
- Each first substituent group is optionally different.
- Each second substituent group is optionally different.
- Each third substituent group is optionally different.
- the “WW” symbol in the R WW.1 , R WW.2 and R WW.3 refers to the designated number of one of the two different R WW substituents.
- R WW.1 is R 100A.1
- R WW.2 is R 100A.2
- R WW.3 is R 100A.3 .
- R WW.1 is R 100B.1
- R WW.2 is paragraph are as defined in the preceding paragraphs.
- R LWW.1 is independently oxo, halogen, -CX LWW.1 3, -CHX LWW.1 2, -CH2X LWW.1 , -OCX LWW.1 3 , -OCH 2 X LWW.1 , -OCHX LWW.1 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -OSO3H, -SO2NH2, ⁇ NH2, ⁇ ONH2, ⁇ NHC(O)NHNH2, ⁇ NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)NH2, -NHSO2H, -NHC(O)NH2, -NHSO2H, -NHC(
- R LWW.1 is independently oxo, halogen, -CX LWW.1 3, -CHX LWW.1 2, -CH2X LWW.1 , -OCX LWW.1 3, -OCH2X LWW.1 , -OCHX LWW.1 2, -CN, -OH, -NH2, -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -OSO 3 H, -SO 2 NH 2 , ⁇ NHNH 2 , ⁇ ONH 2 , ⁇ NHC(O)NHNH 2 , ⁇ NHC(O)NH 2 , –NHC(NH)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -N 3 , unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C
- X LWW.1 is independently –F, -Cl, -Br, or –I.
- R LWW.2 is independently oxo, halogen, -CX LWW.2 3 , -CHX LWW.2 2 , -CH 2 X LWW.2 , -OCX LWW.2 3, -OCH2X LWW.2 , -OCHX LWW.2 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ⁇ NH2, ⁇ ONH2, ⁇ NHC(O)NHNH2, ⁇ NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, R LWW.3 -substituted or
- R LWW.2 is independently oxo, halogen, -CX LWW.2 3 , -CHX LWW.2 2 , -CH 2 X LWW.2 , -OCX LWW.2 3 , -OCH 2 X LWW.2 , -OCHX LWW.2 2 , -CN, -OH, -NH 2 , -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ⁇ NHNH2, ⁇ ONH2, ⁇ NHC(O)NHNH2, ⁇ NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C
- X LWW.2 is independently –F, -Cl, -Br, or –I.
- R LWW.3 is independently oxo, halogen, -CX LWW.3 3, -CHX LWW.3 2, -CH2X LWW.3 , -OCX LWW.3 3, -OCH2X LWW.3 , -OCHX LWW.3 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO 3 H, -OSO 3 H, -SO 2 NH 2 , ⁇ NHNH 2 , ⁇ ONH 2 , ⁇ NHC(O)NHNH 2 , ⁇ NHC(O)NH 2 , –NHC(NH)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -N 3 , unsubstit
- X LWW.3 is independently –F, -Cl, -Br, or –I.
- R group R WW group
- R group is hereby defined as independently oxo, halogen, -CX WW 3 , -CHX WW 2 , -CH 2 X WW , -OCX WW 3 , -OCH 2 X WW , -OCHX WW 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -OSO3H, -SO2NH2, ⁇ NH2, ⁇ ONH2, ⁇ NHC(O)NHNH2, ⁇ NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)H, --NHC(O)H, --NHC(O)H, --NHC(O)H,
- X WW is independently –F, -Cl, -Br, or –I.
- WW represents the stated superscript number of the subject R group (e.g., 1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.).
- R WW.1 , R WW.2 , and R WW.3 are as defined above.
- L group is herein defined as independently a bond, –O-, -NH-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, —NHC(NH)NH-, -C(O)O-, -OC(O)-, -S-, -SO2-, -SO2NH-, R LWW.1 - substituted or unsubstituted alkylene (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ), R LWW.1 -substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membere
- R LWW.1 represents the stated superscript number of the subject L group (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.).
- R LWW.1 as well as R LWW.2 and R LWW.3 are as defined above.
- Certain compounds of the present disclosure possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present disclosure.
- the compounds of the present disclosure do not include those that are known in art to be too unstable to synthesize and/or isolate.
- the present disclosure is meant to include compounds in racemic and optically pure forms.
- Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
- the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
- the term “isomers” refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.
- the term “tautomer,” as used herein, refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another. [0081] It will be apparent to one skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure.
- structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.
- structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of this disclosure.
- the compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
- the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.
- radioactive isotopes such as for example tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.
- bioconjugate and “bioconjugate linker” refer to the resulting association between atoms or molecules of bioconjugate reactive groups or bioconjugate reactive moieties. The association can be direct or indirect.
- a conjugate between a first bioconjugate reactive group e.g., –NH2, –COOH, –N- hydroxysuccinimide, or –maleimide
- a second bioconjugate reactive group e.g., sulfhydryl, sulfur-containing amino acid, amine, amine sidechain containing amino acid, or carboxylate
- covalent bond or linker e.g., a first linker of second linker
- indirect e.g., by non-covalent bond (e.g., electrostatic interactions (e.g., ionic bond, hydrogen bond, halogen bond), van der Waals interactions (e.g., dipole-dipole, dipole-induced dipole, London dispersion), ring stacking (pi effects), hydrophobic interactions and the like).
- bioconjugates or bioconjugate linkers are formed using bioconjugate chemistry (i.e., the association of two bioconjugate reactive groups) including, but are not limited to nucleophilic substitutions (e.g., reactions of amines and alcohols with acyl halides, active esters), electrophilic substitutions (e.g., enamine reactions) and additions to carbon-carbon and carbon-heteroatom multiple bonds (e.g., Michael reaction, Diels-Alder addition).
- bioconjugate chemistry i.e., the association of two bioconjugate reactive groups
- nucleophilic substitutions e.g., reactions of amines and alcohols with acyl halides, active esters
- electrophilic substitutions e.g., enamine reactions
- additions to carbon-carbon and carbon-heteroatom multiple bonds e.g., Michael reaction, Diels-Alder addition.
- the first bioconjugate reactive group e.g., maleimide moiety
- the second bioconjugate reactive group e.g., a sulfhydryl
- the first bioconjugate reactive group (e.g., haloacetyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl).
- the first bioconjugate reactive group (e.g., pyridyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl).
- the first bioconjugate reactive group e.g., –N- hydroxysuccinimide moiety
- is covalently attached to the second bioconjugate reactive group (e.g., an amine).
- the first bioconjugate reactive group (e.g., maleimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl).
- the first bioconjugate reactive group (e.g., –sulfo–N-hydroxysuccinimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., an amine).
- bioconjugate reactive moieties used for bioconjugate chemistries herein include, for example: (a) carboxyl groups and various derivatives thereof including, but not limited to, N-hydroxysuccinimide esters, N-hydroxybenztriazole esters, acid halides, acyl imidazoles, thioesters, p-nitrophenyl esters, alkyl, alkenyl, alkynyl and aromatic esters; (b) hydroxyl groups which can be converted to esters, ethers, aldehydes, etc.; (c) haloalkyl groups wherein the halide can be later displaced with a nucleophilic group such as, for example, an amine, a carboxylate anion, thiol anion, carbanion, or an alkoxide ion, thereby resulting in the covalent attachment of a new group at the site of the halogen atom; (d) dienophile groups which are capable of participating in Die
- bioconjugate reactive groups can be chosen such that they do not participate in, or interfere with, the chemical stability of the conjugate described herein.
- a reactive functional group can be protected from participating in the crosslinking reaction by the presence of a protecting group.
- the bioconjugate comprises a molecular entity derived from the reaction of an unsaturated bond, such as a maleimide, and a sulfhydryl group.
- an analog is used in accordance with its plain ordinary meaning within Chemistry and Biology and refers to a chemical compound that is structurally similar to another compound (i.e., a so-called “reference” compound) but differs in composition, e.g., in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or the replacement of one functional group by another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Accordingly, an analog is a compound that is similar or comparable in function and appearance but not in structure or origin to a reference compound.
- the terms “a” or “an”, as used in herein means one or more.
- substituted with a[n] means the specified group may be substituted with one or more of any or all of the named substituents.
- a group such as an alkyl or heteroaryl group
- the group may contain one or more unsubstituted C1-C20 alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls.
- R-substituted where a moiety is substituted with an R substituent, the group may be referred to as “R-substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. Where a particular R group is present in the description of a chemical genus (such as Formula (I)), a Roman alphabetic symbol may be used to distinguish each appearance of that particular R group. For example, where multiple R 13 substituents are present, each R 13 substituent may be distinguished as R 13.A , R 13.B , R 13.C , R 13.D , etc., wherein each of R 13.A , R 13.B , R 13.C , R 13.D , etc.
- a group may be substituted by one or more of a number of substituents
- substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and/or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, and several known physiological conditions.
- a heterocycloalkyl or heteroaryl is attached to the remainder of the molecule via a ring heteroatom in compliance with principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable compounds.
- salts are meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
- base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
- pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
- acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
- Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p- tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and the like.
- inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic,
- salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19).
- Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
- the compounds of the present disclosure may exist as salts, such as with pharmaceutically acceptable acids.
- the present disclosure includes such salts.
- Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, proprionates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid, and quaternary ammonium salts (e.g., methyl iodide, ethyl iodide, and the like). These salts may be prepared by methods known to those skilled in the art.
- the neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
- the parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents.
- the present disclosure provides compounds, which are in a prodrug form.
- Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure.
- Prodrugs of the compounds described herein may be converted in vivo after administration.
- prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment, such as, for example, when contacted with a suitable enzyme or chemical reagent.
- Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.
- a polypeptide, or a cell is “recombinant” when it is artificial or engineered, or derived from or contains an artificial or engineered protein or nucleic acid (e.g., non-natural or not wild type).
- a polynucleotide that is inserted into a vector or any other heterologous location, e.g., in a genome of a recombinant organism, such that it is not associated with nucleotide sequences that normally flank the polynucleotide as it is found in nature is a recombinant polynucleotide.
- a protein expressed in vitro or in vivo from a recombinant polynucleotide is an example of a recombinant polypeptide.
- a polynucleotide sequence that does not appear in nature for example a variant of a naturally occurring gene, is recombinant.
- compositions described herein are administered at the same time, just prior to, or just after the administration of one or more additional therapies.
- the compounds of the invention can be administered alone or can be co-administered to the patient.
- Co-administration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound).
- the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation).
- a “cell” as used herein, refers to a cell carrying out metabolic or other function sufficient to preserve or replicate its genomic DNA.
- a cell can be identified by well-known methods in the art including, for example, presence of an intact membrane, staining by a particular dye, ability to produce progeny or, in the case of a gamete, ability to combine with a second gamete to produce a viable offspring.
- Cells may include prokaryotic and eukaroytic cells.
- Prokaryotic cells include but are not limited to bacteria.
- Eukaryotic cells include but are not limited to yeast cells and cells derived from plants and animals, for example mammalian, insect (e.g., spodoptera) and human cells. Cells may be useful when they are naturally nonadherent or have been treated not to adhere to surfaces, for example by trypsinization.
- treating refers to any indicia of success in the treatment or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient’s physical or mental well-being.
- the treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation. For example, the certain methods presented herein successfully treat cancer by decreasing the incidence of cancer and or causing remission of cancer.
- treating cancer includes slowing the rate of growth or spread of cancer cells, reducing metastasis, or reducing the growth of metastatic tumors.
- the term “treating” and conjugations thereof, include prevention of an injury, pathology, condition, or disease.
- treating is preventing.
- treating does not include preventing.
- the treating or treatment is no prophylactic treatment.
- An “effective amount” is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g., achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce signaling pathway, reduce one or more symptoms of a disease or condition.
- an “effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a “therapeutically effective amount” when referred to in this context.
- a “reduction” of a symptom or symptoms means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s).
- a “prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms.
- the full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses.
- a prophylactically effective amount may be administered in one or more administrations.
- An “activity decreasing amount,” as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme relative to the absence of the antagonist.
- a “function disrupting amount,” as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist.
- An “activity increasing amount,” as used herein, refers to an amount of agonist required to increase the activity of an enzyme relative to the absence of the agonist.
- a “function increasing amount,” as used herein, refers to the amount of agonist required to increase the function of an enzyme or protein relative to the absence of the agonist.
- Control or “control experiment” is used in accordance with its plain ordinary meaning and refers to an experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment except for omission of a procedure, reagent, or variable of the experiment.
- control is used as a standard of comparison in evaluating experimental effects.
- a control is the measurement of the activity (e.g., signaling pathway) of a protein in the absence of a compound as described herein (including embodiments, examples, figures, or Tables).
- Contacting is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g., chemical compounds including biomolecules, or cells) to become sufficiently proximal to react, interact or physically touch. It should be appreciated; however, the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents which can be produced in the reaction mixture.
- the term “contacting” may include allowing two species to react, interact, or physically touch, wherein the two species may be a compound as described herein and a cellular component (e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, virus, lipid droplet, vesicle, small molecule, protein complex, protein aggregate, or macromolecule).
- a cellular component e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, virus, lipid droplet, vesicle, small molecule, protein complex, protein aggregate, or macromolecule.
- contacting includes allowing a compound described herein to interact with a cellular component (e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, virus, lipid droplet, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule) that is involved in a signaling pathway.
- a cellular component e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, virus, lipid droplet, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule
- the terms “agonist,” “activator,” “upregulator,” etc. refer to a substance capable of detectably increasing the expression or activity of a given gene or protein.
- the agonist can increase expression or activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% in comparison to a control in the absence of the agonist.
- expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or higher than the expression or activity in the absence of the agonist.
- the term “inhibition,” “inhibit,” “inhibiting” and the like in reference to a cellular component-inhibitor interaction means negatively affecting (e.g., decreasing) the activity or function of the cellular component (e.g., decreasing the signaling pathway stimulated by a cellular component (e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule)), relative to the activity or function of the cellular component in the absence of the inhibitor.
- a cellular component e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule
- inhibition means negatively affecting (e.g., decreasing) the concentration or levels of the cellular component relative to the concentration or level of the cellular component in the absence of the inhibitor.
- inhibition refers to reduction of a disease or symptoms of disease.
- inhibition refers to a reduction in the activity of a signal transduction pathway or signaling pathway (e.g., reduction of a pathway involving the cellular component).
- inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating the signaling pathway or enzymatic activity or the amount of a cellular component.
- inhibitor refers to a substance capable of detectably decreasing the expression or activity of a given gene or protein.
- the antagonist can decrease expression or activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% in comparison to a control in the absence of the antagonist.
- expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or lower than the expression or activity in the absence of the antagonist.
- the term modulator refers to a composition that increases or decreases the level of a target molecule or the function of a target molecule or the physical state of the target of the molecule (e.g., a target may be a cellular component (e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule)) relative to the absence of the composition.
- a target may be a cellular component (e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule)) relative to the absence of the composition.
- the term “expression” includes any step involved in the production of the polypeptide including, but not limited to, transcription, post-transcriptional modification, translation, post-translational modification, and secretion. Expression can be detected using conventional techniques for detecting protein (e.g., ELISA, Western blotting, flow cytometry, immunofluorescence, immunohistochemistry, etc.).
- modulate is used in accordance with its plain ordinary meaning and refers to the act of changing or varying one or more properties. “Modulation” refers to the process of changing or varying one or more properties.
- to modulate means to change by increasing or decreasing a property or function of the target molecule or the amount of the target molecule.
- “Patient”, “patient in need thereof”, “subject”, or “subject in need thereof” refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein.
- Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals.
- a patient is human.
- a patient in need thereof is human.
- a subject is human.
- a subject in need thereof is human.
- Disease or “condition” refer to a state of being or health status of a patient or subject capable of being treated with the compounds or methods provided herein.
- the disease is a disease related to (e.g., caused by) a cellular component (e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule).
- a cellular component e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule.
- the disease is an age-related disorder (e.g., ischemia reperfusion injury, acute coronary syndrome, stroke, acute kidney injury, acute myocardial infarction, organ transplantation, metabolic syndrome, insulin resistance, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), noise-induced hearing loss, age-induced hearing loss, cisplatin-induced nephrotoxicity, Alzheimer s disease, Parkinson’s disease, cardiac hypertension, pulmonary arterial hypertension, diabetic cardiomyopathy, Type 2 diabetes, cancer growth, incidence, and metastasis, atherosclerosis, osteoarthritis, or osteoporosis).
- age-related disorder e.g., ischemia reperfusion injury, acute coronary syndrome, stroke, acute kidney injury, acute myocardial infarction, organ transplantation, metabolic syndrome, insulin resistance, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), noise-induced hearing loss, age-induced hearing loss, cis
- a metabolic disorder refers to a disorder characterized by one or more abnormal metabolic processes in a subject.
- a metabolic disorder may be associated with, related to, or may be diabetes (e.g., type 1 diabetes or type 2 diabetes), insulin resistance, metabolic syndrome, obesity, hyperlipidemia, hyperglycemia, high serum triglycerides, and/or high blood pressure.
- a metabolic disorder may be associated with, related to, or may be a diabetes associated disease selected from nephropathy, retinopathy, neuropathy, cardiovascular disease, or inflammation.
- a metabolic disorder may be associated with, related to, or may be nephropathy, retinopathy, neuropathy, cardiovascular disease, or inflammation.
- cancer refers to all types of cancer, neoplasm or malignant tumors found in mammals (e.g., humans), including leukemia, lymphoma, carcinomas and sarcomas.
- exemplary cancers that may be treated with a compound or method provided herein include cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head and neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus, medulloblastoma, colorectal cancer, or pancreatic cancer.
- Additional examples include, Hodgkin’s Disease, Non-Hodgkin’s Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer.
- leukemia refers broadly to progressive, malignant diseases of the blood- forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood- leukemic or aleukemic (subleukemic).
- Exemplary leukemias that may be treated with a compound or method provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross’ leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia,
- lymphoma refers to a group of cancers affecting hematopoietic and lymphoid tissues. It begins in lymphocytes, the blood cells that are found primarily in lymph nodes, spleen, thymus, and bone marrow. Two main types of lymphoma are non-Hodgkin lymphoma and Hodgkin’s disease. Hodgkin’s disease represents approximately 15% of all diagnosed lymphomas. This is a cancer associated with Reed- Sternberg malignant B lymphocytes. Non-Hodgkin’s lymphomas (NHL) can be classified based on the rate at which cancer grows and the type of cells involved.
- B-cell lymphomas that may be treated with a compound or method provided herein include, but are not limited to, small lymphocytic lymphoma, Mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, extranodal (MALT) lymphoma, nodal (monocytoid B-cell) lymphoma, splenic lymphoma, diffuse large cell B-lymphoma, Burkitt’s lymphoma, lymphoblastic lymphoma, immunoblastic large cell lymphoma, or precursor B-lymphoblastic lymphoma.
- Exemplary T- cell lymphomas that may be treated with a compound or method provided herein include, but are not limited to, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, anaplastic large cell lymphoma, mycosis fungoides, and precursor T-lymphoblastic lymphoma.
- the term “sarcoma” generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance.
- Sarcomas that may be treated with a compound or method provided herein include a chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms’ tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing’s sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemo
- melanoma is taken to mean a tumor arising from the melanocytic system of the skin and other organs.
- Melanomas that may be treated with a compound or method provided herein include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman’s melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma, or superficial spreading melanoma.
- carcinoma refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases.
- exemplary carcinomas that may be treated with a compound or method provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid
- the terms “metastasis,” “metastatic,” and “metastatic cancer” can be used interchangeably and refer to the spread of a proliferative disease or disorder, e.g., cancer, from one organ or another non-adjacent organ or body part. “Metastatic cancer” is also called “Stage IV cancer.” Cancer occurs at an originating site, e.g., breast, which site is referred to as a primary tumor, e.g., primary breast cancer. Some cancer cells in the primary tumor or originating site acquire the ability to penetrate and infiltrate surrounding normal tissue in the local area and/or the ability to penetrate the walls of the lymphatic system or vascular system circulating through the system to other sites and tissues in the body.
- a second clinically detectable tumor formed from cancer cells of a primary tumor is referred to as a metastatic or secondary tumor.
- the metastatic tumor and its cells are presumed to be similar to those of the original tumor.
- the secondary tumor at the site of the breast consists of abnormal lung cells and not abnormal breast cells.
- the secondary tumor in the breast is referred to a metastatic lung cancer.
- metastatic cancer refers to a disease in which a subject has or had a primary tumor and has one or more secondary tumors.
- non- metastatic cancer or subjects with cancer that is not metastatic refers to diseases in which subjects have a primary tumor but not one or more secondary tumors.
- metastatic lung cancer refers to a disease in a subject with or with a history of a primary lung tumor and with one or more secondary tumors at a second location or multiple locations, e.g., in the breast.
- the terms “cutaneous metastasis” and “skin metastasis” refer to secondary malignant cell growths in the skin, wherein the malignant cells originate from a primary cancer site (e.g., breast).
- a primary cancer site e.g., breast
- cancerous cells from a primary cancer site may migrate to the skin where they divide and cause lesions. Cutaneous metastasis may result from the migration of cancer cells from breast cancer tumors to the skin.
- visceral metastasis refers to secondary malignant cell growths in the interal organs (e.g., heart, lungs, liver, pancreas, intestines) or body cavities (e.g., pleura, peritoneum), wherein the malignant cells originate from a primary cancer site (e.g., head and neck, liver, breast).
- a primary cancer site e.g., head and neck, liver, breast.
- a primary cancer site e.g., head and neck, liver, breast
- Visceral metastasis may result from the migration of cancer cells from liver cancer tumors or head and neck tumors to internal organs.
- drug is used in accordance with its common meaning and refers to a substance which has a physiological effect (e.g., beneficial effect, is useful for treating a subject) when introduced into or to a subject (e.g., in or on the body of a subject or patient).
- a drug moiety is a radical of a drug.
- a “detectable agent,” “detectable compound,” “detectable label,” or “detectable moiety” is a substance (e.g., element), molecule, or composition detectable by spectroscopic, photochemical, biochemical, immunochemical, chemical, magnetic resonance imaging, or other physical means.
- detectable agents include 18 F, 32 P, 33 P, 45 Ti, 47 Sc, 52 Fe, 59 Fe, 62 Cu, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 77 As, 86 Y, 90 Y, 89 Sr, 89 Zr, 94 Tc, 94 Tc, 99m Tc, 99 Mo, 105 Pd, 105 Rh, 111 Ag, 111 In, 123 I, 124 I, 125 I, 131 I, 142 Pr, 143 Pr, 149 Pm, 153 Sm, 154-158 Gd, 161 Tb, 166 Dy, 166 Ho, 169 Er, 175 Lu, 177 Lu, 186 Re, 188 Re, 189 Re, 194 Ir, 198 Au, 199 Au, 211 At, 211 Pb, 212 Bi, 212 Pb, 213 Bi, 223 Ra, 225 Ac, Cr, V, Mn, Fe, Co, Ni, Cu, La, Ce, Pr, Nd, Pm, S
- Radioactive substances e.g., radioisotopes
- Radioactive substances include, but are not limited to, 18 F, 32 P, 33 P, 45 Ti, 47 Sc, 52 Fe, 59 Fe, 62 Cu, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 77 As, 86 Y, 90 Y, 89 Sr, 89 Zr, 94 Tc, 94 Tc, 99m Tc, 99 Mo, 105 Pd, 105 Rh, 111 Ag, 111 In, 123 I, 124 I, 125 I, 131 I, 142 Pr, 143 Pr, 149 Pm, 153 Sm, 154-158 Gd, 161 Tb, 166 Dy, 166 Ho, 169 Er, 175 Lu, 177 Lu, 186 Re, 188 Re, 189 Re, 194 Ir, 198 Au, 199 Au, 211 At, 211 Pb, 212 Bi, 212
- Paramagnetic ions that may be used as additional imaging agents in accordance with the embodiments of the disclosure include, but are not limited to, ions of transition and lanthanide metals (e.g., metals having atomic numbers of 21-29, 42, 43, 44, or 57-71). These metals include ions of Cr, V, Mn, Fe, Co, Ni, Cu, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, and Lu.
- transition and lanthanide metals e.g., metals having atomic numbers of 21-29, 42, 43, 44, or 57-71.
- These metals include ions of Cr, V, Mn, Fe, Co, Ni, Cu, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, and Lu.
- “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient.
- Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like.
- preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
- auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
- auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
- auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents,
- Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
- the term “about” means a range of values including the specified value, which a person of ordinary skill in the art would consider reasonably similar to the specified value. In embodiments, about means within a standard deviation using measurements generally acceptable in the art. In embodiments, about means a range extending to +/- 10% of the specified value. In embodiments, about includes the specified value.
- administering is used in accordance with its plain and ordinary meaning and includes oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini- osmotic pump, to a subject.
- Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal).
- Parenteral administration includes, e.g., intravenous, intramuscular, intra- arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial.
- Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.
- co-administer it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies, for example cancer therapies such as chemotherapy, hormonal therapy, radiotherapy, or immunotherapy.
- the compounds of the invention can be administered alone or can be co-administered to the patient.
- Co- administration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound).
- compositions of the present invention can be delivered by transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.
- the compounds described herein can be used in combination with one another, with other active agents known to be useful in treating a disease associated with cells expressing a disease associated cellular component, or with adjunctive agents that may not be effective alone, but may contribute to the efficacy of the active agent.
- co-administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent.
- Co- administration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order.
- co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition including both active agents.
- the active agents can be formulated separately.
- the active and/or adjunctive agents may be linked or conjugated to one another.
- compound utilized in the pharmaceutical compositions of the present invention may be administered at the initial dosage of about 0.001 mg/kg to about 1000 mg/kg daily.
- the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound or drug being employed. For example, dosages can be empirically determined considering the type and stage of disease (e.g., age-related disorder) diagnosed in a particular patient.
- the dose administered to a patient should be sufficient to affect a beneficial therapeutic response in the patient over time.
- the size of the dose will also be determined by the existence, nature, and extent of any adverse side effects that accompany the administration of a compound in a particular patient. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.
- a disease e.g., a protein associated disease, disease associated with a cellular component
- the disease e.g., age-related disorder
- a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function or the disease or a symptom of the disease may be treated by modulating (e.g., inhibiting or activating) the substance (e.g., cellular component).
- modulating e.g., inhibiting or activating
- aberrant refers to different from normal. When used to describe enzymatic activity, aberrant refers to activity that is greater or less than a normal control or the average of normal non-diseased control samples. Aberrant activity may refer to an amount of activity that results in a disease, wherein returning the aberrant activity to a normal or non-disease-associated amount (e.g., by administering a compound or using a method as described herein), results in reduction of the disease or one or more disease symptoms.
- electrophilic as used herein refers to a chemical group that is capable of accepting electron density.
- an “electrophilic substituent,” “electrophilic chemical moiety,” or “electrophilic moiety” refers to an electron-poor chemical group, substituent, or moiety (monovalent chemical group), which may react with an electron-donating group, such as a nucleophile, by accepting an electron pair or electron density to form a bond.
- an electron-donating group such as a nucleophile
- Nucleophilic refers to a chemical group that is capable of donating electron density.
- isolated when applied to a nucleic acid or protein, denotes that the nucleic acid or protein is essentially free of other cellular components with which it is associated in the natural state.
- amino acid refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids.
- Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, ⁇ - carboxyglutamate, and O-phosphoserine.
- Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an ⁇ carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid.
- Amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid.
- non-naturally occurring amino acid and “unnatural amino acid” refer to amino acid analogs, synthetic amino acids, and amino acid mimetics which are not found in nature.
- Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single-letter codes.
- polypeptide “peptide,” and “protein” are used interchangeably herein to refer to a polymer of amino acid residues, wherein the polymer may in embodiments be conjugated to a moiety that does not consist of amino acids.
- amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymers.
- An amino acid or nucleotide base “position” is denoted by a number that sequentially identifies each amino acid (or nucleotide base) in the reference sequence based on its position relative to the N-terminus (or 5'-end).
- the amino acid residue number in a test sequence determined by simply counting from the N-terminus will not necessarily be the same as the number of its corresponding position in the reference sequence.
- the amino acid residue number in a test sequence determined by simply counting from the N-terminus will not necessarily be the same as the number of its corresponding position in the reference sequence.
- that insertion will not correspond to a numbered amino acid position in the reference sequence.
- protein complex is used in accordance with its plain ordinary meaning and refers to a protein which is associated with an additional substance (e.g., another protein, protein subunit, or a compound). Protein complexes typically have defined quaternary structure. The association between the protein and the additional substance may be a covalent bond. In embodiments, the association between the protein and the additional substance (e.g., compound) is via non-covalent interactions. In embodiments, a protein complex refers to a group of two or more polypeptide chains. Proteins in a protein complex are linked by non-covalent protein–protein interactions. A non-limiting example of a protein complex is the proteasome.
- protein aggregate is used in accordance with its plain ordinary meaning and refers to an aberrant collection or accumulation of proteins (e.g., misfolded proteins). Protein aggregates are often associated with diseases (e.g., amyloidosis). Typically, when a protein misfolds as a result of a change in the amino acid sequence or a change in the native environment which disrupts normal non-covalent interactions, and the misfolded protein is not corrected or degraded, the unfolded/misfolded protein may aggregate. There are three main types of protein aggregates that may form: amorphous aggregates, oligomers, and amyloid fibrils. In embodiments, protein aggregates are termed aggresomes.
- mitochondrial site I Q refers to a site of superoxide/hydrogen peroxide production associate with the mitochondrial electron transport chain.
- selective or “selectivity” or the like in reference to a compound or agent refers to the compound’s or agent’s ability to cause an increase or decrease in activity of a particular molecular target (e.g., protein, enzyme, etc.) preferentially over one or more different molecular targets (e.g., a compound having selectivity toward mitochondrial site 1Q would preferentially inhibit mitochondrial site 1 Q over other mitochondrial sites).
- a particular molecular target e.g., protein, enzyme, etc.
- a compound having selectivity toward mitochondrial site 1Q would preferentially inhibit mitochondrial site 1 Q over other mitochondrial sites.
- a “suppressor of site I Q electron leak” or “S1QEL” refers to a compound (e.g., compound described herein) having selectivity towards mitochondrial site IQ.
- S1QEL a compound having selectivity towards mitochondrial site IQ.
- R 1 is independently halogen, -CX 1 3 , -CHX 1 2 , -CH 2 X 1 , -OCX 1 3 , -OCH 2 X 1 , -OCHX 1 2, -CN, -SOn1R 1D , -SOv1NR 1A R 1B , ⁇ NR 1C NR 1A R 1B , ⁇ ONR 1A R 1B , -NR 1C C(O)NR 1A R 1B , -N(O)m1, -NR 1A R 1B , -C(O)R 1C , -C(O)OR 1C , -OC(O)R 1C , -OC(O)OR 1C , -C(O)NR 1A R 1B , -OC(O)NR 1A R 1B , -OR 1D , -SR 1D , -NR 1A SO2R 1D , -NR 1A C(O) C(
- R 1A , R 1B , R 1C , and R 1D are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C 1 -C 2 ), substituted or unsubstituted heteroalkyl (e.
- Each X 1 is independently –Cl, -Br, -I, or –F.
- the symbol n1 is an integer from 0 to 4.
- the synmbols m1 and v1 are independently 1 or 2.
- the symbol z1 is an integer from 0 to 5.
- X is O or NR 2 .
- R 2 is hydrogen or unsubstituted C1-C6 alkyl.
- R 3 is hydrogen, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1- C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), or a prodrug moiety.
- R 2 and R 3 substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
- R 4 is hydrogen, substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 - C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), or a prodrug moiety.
- R 5 and R 6 are independently hydrogen, -OH, unsubstituted C 1 -C 6 alkyl, or unsubstituted 2 to 6 membered heteroalkyl.
- R 5 and R 7 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 , or C 5 -C 6 ) or substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered); or R 6 and R 7 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 , or C 5 -C 6 ) or substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered,
- R 7 and R 8 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ⁇ NHNH2, ⁇ ONH2, ⁇ NHC(O)NHNH2, ⁇ NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI 3 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 F,
- R 9 is independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO 3 H, -OSO 3 H, -SO 2 NH 2 , ⁇ NHNH 2 , ⁇ ONH 2 , ⁇ NHC(O)NHNH 2 , ⁇ NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCBr 3 , -OCF 3 , -OCI 3 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I,
- the compound has the formula: Ring A, n, X, R 3 , R 4 , R 5 , and R 6 are as described herein, including in embodiments.
- R 1.1 , R 1.2 , and R 1.3 are independently hydrogen or any value of R 1 as described herein, including in embodiments.
- the compound has the formula: Ring A and n are as described herein, including in embodiments.
- R 1.2 is –NR 1A C(O)R 1B , -NR 1A SO2R 1C , -NR 1A C(O)OR 1B , -OR 1A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein R 1A , R 1B , and R 1C are as described herein, including in embodiments.
- R 1.1 and R 1.3 are hydrogen.
- R 1.1 and R 1.2 substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl; or R 1.2 and R 1.3 substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl.
- X is O and R 3 is hydrogen; or X is NR 2 and R 2 and R 3 substituents are joined to form a substituted or unsubstituted heterocycloalkyl.
- R 4 is hydrogen.
- R 5 is hydrogen.
- R 6 is hydrogen, -OH, or unsubstituted 2 to 6 membered heteroalkyl.
- R 5 and R 7 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl; or R 6 and R 7 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl.
- R 7 is hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
- R 8 is substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
- the compound has the formula: Ring A, n, R 1.1 , R 1.2 , R 1.3 , R 5 and R 6 are as described herein, including in embodiments.
- the compound has the formula: Ring A, n, R 1.1 , R 1.2 , R 1.3 , R 5 and R 6 are as described herein, including in embodiments.
- the compound has the formula: Ring A, n, R 1.1 , R 1.2 , R 1.3 , R 5 and R 6 are as described herein, including in embodiments.
- Ring B is cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), aryl (e.g., C 6 -C 10 or phenyl), or heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
- cycloalkyl e.g., C3-C8, C3-C6, C4-C6, or C5-C6
- heterocycloalkyl e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4
- R 10 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -OSO 3 H, -SO 2 NH 2 , ⁇ NHNH 2 , ⁇ ONH 2 , ⁇ NHC(O)NHNH 2 , ⁇ NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCBr 3 , -OCF 3 , -OCI 3 , -OCH 2 Cl, -
- the symbol z10 is an integer from 0 to 11.
- the compound has the formula: Ring A, Ring B, n, R 1.1 , R 1.2 , R 1.3 , R 5 , R 6 , R 10 , and z10 are as described herein, including in embodiments.
- the compound has the formula: Ring A, Ring B, n, R 1.1 , R 1.2 , R 1.3 , R 5 , R 6 , R 10 , and z10 are as described herein, including in embodiments.
- Ring , wherein R 7 and R 8 are as described herein, including in embodiments.
- Ring , wherein R 8 is as described herein, including in embodiments.
- Ring A is , wherein R 7 , R 8 , R 9 , and z9 are as described herein, including in embodiments.
- Ring , wherein R 8 , R 9 , and z9 are as described herein, including in embodiments.
- Ring , wherein R 7 , R 8 , R 9 , and z9 are as described herein, including in embodiments.
- Ring , wherein R 8 , R 9 , and z9 are as described herein, including in embodiments.
- Ring B is C 3 -C 8 cycloalkyl.
- Ring B is 3 to 8 membered heterocycloalkyl. In embodiments, Ring B is phenyl. In embodiments, Ring B is 5 to 6 membered heteroaryl. In embodiments, Ring B is pyrrolidinyl, piperidinyl, or morpholinyl. In embodiments, Ring B is pyrrolidinyl. In embodiments, Ring B is piperidinyl. In embodiments, Ring B is morpholinyl. [0182] In embodiments, n is 0. In embodiments, n is 1. In embodiments, n is 2.
- a substituted R 1 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 1 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R 1 is substituted, it is substituted with at least one substituent group.
- R 1 when R 1 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 1 is substituted, it is substituted with at least one lower substituent group.
- a substituted ring formed when two R 1 substituents are joined e.g., substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
- is substituted with at least one substituent group, size-limited substituent group, or lower substituent group wherein if the substituted ring formed when two R 1 substituents are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
- a substituted R 1.1 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 1.1 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
- R 1.1 when R 1.1 is substituted, it is substituted with at least one substituent group.
- R 1.1 when R 1.1 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 1.1 is substituted, it is substituted with at least one lower substituent group.
- a substituted R 1.2 e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
- R 1.2 is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 1.2 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
- R 1.2 when R 1.2 is substituted, it is substituted with at least one substituent group. In embodiments, when R 1.2 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 1.2 is substituted, it is substituted with at least one lower substituent group.
- a substituted R 1.3 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 1.3 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R 1.3 is substituted, it is substituted with at least one substituent group.
- R 1.1 , R 1.2 , and R 1.3 are independently hydrogen, halogen, -CX 1 3 , -CHX 1 2, -CH2X 1 , -OCX 1 3, -OCH2X 1 , -OCHX 1 2, -CN, -SOn1R 1D , -SOv1NR 1A R 1B , ⁇ NR 1C NR 1A R 1B , ⁇ ONR 1A R 1B , -NR 1C C(O)NR 1A R 1B , -N(O)m1, -NR 1A R 1B , -C(O)R 1C , -C(O)OR 1C , -OC(O)R 1C , -OC(O)OR 1C ,
- R 1 is independently halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ⁇ NHNH2, ⁇ ONH2, ⁇ NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH 2 F, -OCH 2 I, -OCHCl 2 , -OCHBr 2 ,
- R 1 is independently halogen. In embodiments, R 1 is independently –F. In embodiments, R 1 is independently –Cl. In embodiments, R 1 is independently –Br. In embodiments, R 1 is independently –I. In embodiments, R 1 is independently -CCl3. In embodiments, R 1 is independently -CBr 3 . In embodiments, R 1 is independently -CF 3 . In embodiments, R 1 is independently -CI3. In embodiments, R 1 is independently -CH2Cl. In embodiments, R 1 is independently -CH2Br. In embodiments, R 1 is independently -CH2F. In embodiments, R 1 is independently -CH 2 I.
- R 1 is independently -CHCl 2 . In embodiments, R 1 is independently -CHBr 2 . In embodiments, R 1 is independently -CHF 2 . In embodiments, R 1 is independently -CHI2. In embodiments, R 1 is independently –CN. In embodiments, R 1 is independently –OH. In embodiments, R 1 is independently -NH2. In embodiments, R 1 is independently –COOH. In embodiments, R 1 is independently -CONH 2 . In embodiments, R 1 is independently -NO2. In embodiments, R 1 is independently –SH. In embodiments, R 1 is independently -SO3H. In embodiments, R 1 is independently -OSO3H.
- R 1 is independently -SO 2 NH 2 . In embodiments, R 1 is independently ⁇ NHNH 2 . In embodiments, R 1 is independently ⁇ ONH 2 . In embodiments, R 1 is independently ⁇ NHC(O)NH 2 . In embodiments, R 1 is independently -NHSO 2 H. In embodiments, R 1 is independently -NHC(O)H. In embodiments, R 1 is independently -NHC(O)OH. In embodiments, R 1 is independently –NHOH. In embodiments, R 1 is independently -OCCl 3 . In embodiments, R 1 is independently -OCBr3. In embodiments, R 1 is independently -OCF3. In embodiments, R 1 is independently -OCI3.
- R 1 is independently -OCH2Cl. In embodiments, R 1 is independently -OCH 2 Br. In embodiments, R 1 is independently -OCH2F. In embodiments, R 1 is independently -OCH2I. In embodiments, R 1 is independently -OCHCl2. In embodiments, R 1 is independently -OCHBr2. In embodiments, R 1 is independently -OCHF2. In embodiments, R 1 is independently -OCHI2. In embodiments, R 1 is independently unsubstituted C 1 -C 4 alkyl. In embodiments, R 1 is independently unsubstituted methyl. In embodiments, R 1 is independently unsubstituted ethyl.
- R 1 is independently unsubstituted propyl. In embodiments, R 1 is independently unsubstituted n-propyl. In embodiments, R 1 is independently unsubstituted isopropyl. In embodiments, R 1 is independently unsubstituted butyl. In embodiments, R 1 is independently unsubstituted n-butyl. In embodiments, R 1 is independently unsubstituted isobutyl. In embodiments, R 1 is independently unsubstituted tert-butyl. In embodiments, R 1 is independently unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 1 is independently unsubstituted methoxy.
- R 1 is independently unsubstituted ethoxy. In embodiments, R 1 is independently unsubstituted propoxy. In embodiments, R 1 is independently unsubstituted n-propoxy. In embodiments, R 1 is independently unsubstituted isopropoxy. In embodiments, R 1 is independently unsubstituted butoxy. In embodiments, R 1 is independently unsubstituted n-butoxy. In embodiments, R 1 is independently unsubstituted isobutoxy. In embodiments, R 1 is independently unsubstituted tert-butoxy.
- R 1 is independently –NR 1A C(O)R 1B , wherein R 1A and R 1B are as described herein, including in embodiments.
- R 1 is independently –NR 1A C(O)R 1B , wherein R 1A and R 1B are independently hydrogen or unsubstituted C 1 -C 4 alkyl.
- R 1 is independently –NHC(O)CH 3 , -NCH 3 C(O)CH 3 , -OH, -OCH 3 , or –NHSO2CH3.
- R 1 is independently –NHC(O)CH3.
- R 1 is independently -NCH3C(O)CH3.
- R 1 is independently –OH. In embodiments, R 1 is independently -OCH 3 . In embodiments, R 1 is independently –NHSO2CH3. [0192] In embodiments, two R 1 substituents are joined to form a substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. [0193] In embodiments, R 1.2 is –NR 1A C(O)R 1B , wherein R 1A and R 1B are as described herein, including in embodiments.
- R 1.2 is –NR 1A C(O)R 1B , wherein R 1A and R 1B are independently hydrogen or unsubstituted C1-C4 alkyl.
- R 1.2 is –NHC(O)CH3, -NCH3C(O)CH3, -OH, -OCH3, or –NHSO2CH3.
- R 1.2 is –NHC(O)CH3.
- R 1.2 is -NCH3C(O)CH3.
- R 1.2 is –OH.
- R 1.2 is -OCH3.
- R 1.2 is –NHSO2CH3.
- a substituted R 1A (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 1A is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R 1A is substituted, it is substituted with at least one substituent group.
- R 1A when R 1A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 1A is substituted, it is substituted with at least one lower substituent group.
- a substituted R 1B e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
- R 1B is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 1B is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
- R 1B when R 1B is substituted, it is substituted with at least one substituent group. In embodiments, when R 1B is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 1B is substituted, it is substituted with at least one lower substituent group.
- a substituted ring formed when R 1A and R 1B substituents bonded to the same nitrogen atom are joined e.g., substituted heterocycloalkyl and/or substituted heteroaryl
- at least one substituent group, size-limited substituent group, or lower substituent group e.g., substituted heterocycloalkyl and/or substituted heteroaryl
- the substituted ring formed when R 1A and R 1B substituents bonded to the same nitrogen atom are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
- when the substituted ring formed when R 1A and R 1B substituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R 1A and R 1B substituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R 1A and R 1B substituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.
- a substituted R 1C (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 1C is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R 1C is substituted, it is substituted with at least one substituent group.
- R 1C when R 1C is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 1C is substituted, it is substituted with at least one lower substituent group.
- a substituted R 1D e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
- R 1D is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 1D is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
- R 1D when R 1D is substituted, it is substituted with at least one substituent group. In embodiments, when R 1D is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 1D is substituted, it is substituted with at least one lower substituent group.
- R 1A is independently hydrogen. In embodiments, R 1A is independently unsubstituted C 1 -C 4 alkyl. In embodiments, R 1A is independently unsubstituted methyl. In embodiments, R 1A is independently unsubstituted ethyl. In embodiments, R 1A is independently unsubstituted propyl.
- R 1A is independently unsubstituted n-propyl. In embodiments, R 1A is independently unsubstituted isopropyl. In embodiments, R 1A is independently unsubstituted butyl. In embodiments, R 1A is independently unsubstituted n-butyl. In embodiments, R 1A is independently unsubstituted isobutyl. In embodiments, R 1A is independently unsubstituted tert-butyl. [0200] In embodiments, R 1B is independently hydrogen. In embodiments, R 1B is independently unsubstituted C1-C4 alkyl. In embodiments, R 1B is independently unsubstituted methyl.
- R 1B is independently unsubstituted ethyl. In embodiments, R 1B is independently unsubstituted propyl. In embodiments, R 1B is independently unsubstituted n-propyl. In embodiments, R 1B is independently unsubstituted isopropyl. In embodiments, R 1B is independently unsubstituted butyl. In embodiments, R 1B is independently unsubstituted n-butyl. In embodiments, R 1B is independently unsubstituted isobutyl. In embodiments, R 1B is independently unsubstituted tert-butyl. [0201] In embodiments, R 1C is independently hydrogen.
- R 1C is independently unsubstituted C 1 -C 4 alkyl. In embodiments, R 1C is independently unsubstituted methyl. In embodiments, R 1C is independently unsubstituted ethyl. In embodiments, R 1C is independently unsubstituted propyl. In embodiments, R 1C is independently unsubstituted n-propyl. In embodiments, R 1C is independently unsubstituted isopropyl. In embodiments, R 1C is independently unsubstituted butyl. In embodiments, R 1C is independently unsubstituted n-butyl. In embodiments, R 1C is independently unsubstituted isobutyl.
- R 1C is independently unsubstituted tert-butyl.
- R 1D is independently hydrogen. In embodiments, R 1D is independently unsubstituted C1-C4 alkyl. In embodiments, R 1D is independently unsubstituted methyl. In embodiments, R 1D is independently unsubstituted ethyl. In embodiments, R 1D is independently unsubstituted propyl. In embodiments, R 1D is independently unsubstituted n-propyl. In embodiments, R 1D is independently unsubstituted isopropyl. In embodiments, R 1D is independently unsubstituted butyl.
- R 1D is independently unsubstituted n-butyl. In embodiments, R 1D is independently unsubstituted isobutyl. In embodiments, R 1D is independently unsubstituted tert-butyl.
- z1 is 0. In embodiments, z1 is 1. In embodiments, z1 is 2. In embodiments, z1 is 3. In embodiments, z1 is 4. In embodiments, z1 is 5. [0205] In embodiments, X is O. In embodiments, X is NR 2 , wherein R 2 is as described herein, including in embodiments. In embodiments, X is NH. [0206] In embodiments, R 2 is hydrogen. In embodiments, R 2 is unsubstituted C1-C6 alkyl. In embodiments, R 2 is unsubstituted methyl. In embodiments, R 2 is unsubstituted ethyl.
- R 2 is unsubstituted propyl. In embodiments, R 2 is unsubstituted n-propyl. In embodiments, R 2 is unsubstituted isopropyl. In embodiments, R 2 is unsubstituted butyl. In embodiments, R 2 is unsubstituted n-butyl. In embodiments, R 2 is unsubstituted isobutyl. In embodiments, R 2 is unsubstituted tert-butyl. In embodiments, R 2 is unsubstituted pentyl. In embodiments, R 2 is unsubstituted hexyl.
- a substituted R 3 (e.g., substituted alkyl and/or substituted heteroalkyl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 3 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
- R 3 when R 3 is substituted, it is substituted with at least one substituent group.
- R 3 when R 3 is substituted, it is substituted with at least one size-limited substituent group.
- R 3 when R 3 is substituted, it is substituted with at least one lower substituent group.
- R 3 is hydrogen. In embodiments, R 3 is substituted or unsubstituted C1-C4 alkyl. In embodiments, R 3 is unsubstituted C1-C4 alkyl. In embodiments, R 3 is unsubstituted methyl. In embodiments, R 3 is unsubstituted ethyl. In embodiments, R 3 is unsubstituted propyl. In embodiments, R 3 is unsubstituted n-propyl. In embodiments, R 3 is unsubstituted isopropyl. In embodiments, R 3 is unsubstituted butyl.
- R 3 is unsubstituted n-butyl. In embodiments, R 3 is unsubstituted isobutyl. In embodiments, R 3 is unsubstituted tert-butyl. [0209] In embodiments, R 3 is a prodrug moiety. In embodiments, R 3 is a substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R 3 is .
- a substituted ring formed when R 2 and R 3 substituents are joined is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R 2 and R 3 substituents are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
- when the substituted ring formed when R 2 and R 3 substituents are joined is substituted, it is substituted with at least one substituent group.
- R 2 and R 3 substituents when the substituted ring formed when R 2 and R 3 substituents are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R 2 and R 3 substituents are joined is substituted, it is substituted with at least one lower substituent group. [0211] In embodiments, R 2 and R 3 substituents are joined to form a substituted or unsubstituted 3 to 8 membered heterocycloalkyl.
- a substituted R 4 (e.g., substituted alkyl and/or substituted heteroalkyl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 4 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
- R 4 when R 4 is substituted, it is substituted with at least one substituent group.
- R 4 when R 4 is substituted, it is substituted with at least one size-limited substituent group.
- R 4 when R 4 is substituted, it is substituted with at least one lower substituent group.
- R 4 is hydrogen. In embodiments, R 4 is substituted or unsubstituted C1-C4 alkyl. In embodiments, R 4 is unsubstituted C1-C4 alkyl. In embodiments, R 4 is unsubstituted methyl. In embodiments, R 4 is unsubstituted ethyl. In embodiments, R 4 is unsubstituted propyl. In embodiments, R 4 is unsubstituted n-propyl. In embodiments, R 4 is unsubstituted isopropyl. In embodiments, R 4 is unsubstituted butyl.
- R 4 is unsubstituted n-butyl. In embodiments, R 4 is unsubstituted isobutyl. In embodiments, R 4 is unsubstituted tert-butyl. [0214] In embodiments, R 4 is a prodrug moiety. In embodiments, R 4 is a substituted or O unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R 4 is . [0215] In embodiments, R 5 is hydrogen, -OH, unsubstituted C 1 -C 6 alkyl, or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R 5 is hydrogen. In embodiments, R 5 is –OH.
- R 5 is unsubstituted C1-C6 alkyl. In embodiments, R 5 is unsubstituted methyl. In embodiments, R 5 is unsubstituted ethyl. In embodiments, R 5 is unsubstituted propyl. In embodiments, R 5 is unsubstituted n-propyl. In embodiments, R 5 is unsubstituted isopropyl. In embodiments, R 5 is unsubstituted butyl. In embodiments, R 5 is unsubstituted n- butyl. In embodiments, R 5 is unsubstituted isobutyl. In embodiments, R 5 is unsubstituted tert-butyl.
- R 5 is unsubstituted pentyl. In embodiments, R 5 is unsubstituted hexyl. In embodiments, R 5 is unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R 5 is unsubstituted methoxy. In embodiments, R 5 is unsubstituted ethoxy. In embodiments, R 5 is unsubstituted propoxy. In embodiments, R 5 is unsubstituted n-propoxy. In embodiments, R 5 is unsubstituted isopropoxy. In embodiments, R 5 is unsubstituted butoxy. In embodiments, R 5 is unsubstituted n-butoxy.
- R 5 is unsubstituted isobutoxy. In embodiments, R 5 is unsubstituted tert-butoxy.
- R 6 is hydrogen, -OH, unsubstituted C 1 -C 6 alkyl, or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R 6 is hydrogen. In embodiments, R 6 is –OH. In embodiments, R 6 is unsubstituted C1-C6 alkyl. In embodiments, R 6 is unsubstituted methyl. In embodiments, R 6 is unsubstituted ethyl. In embodiments, R 6 is unsubstituted propyl.
- R 6 is unsubstituted n-propyl. In embodiments, R 6 is unsubstituted isopropyl. In embodiments, R 6 is unsubstituted butyl. In embodiments, R 6 is unsubstituted n- butyl. In embodiments, R 6 is unsubstituted isobutyl. In embodiments, R 6 is unsubstituted tert-butyl. In embodiments, R 6 is unsubstituted pentyl. In embodiments, R 6 is unsubstituted hexyl. In embodiments, R 6 is unsubstituted 2 to 6 membered heteroalkyl.
- R 6 is unsubstituted methoxy. In embodiments, R 6 is unsubstituted ethoxy. In embodiments, R 6 is unsubstituted propoxy. In embodiments, R 6 is unsubstituted n-propoxy. In embodiments, R 6 is unsubstituted isopropoxy. In embodiments, R 6 is unsubstituted butoxy. In embodiments, R 6 is unsubstituted n-butoxy. In embodiments, R 6 is unsubstituted isobutoxy. In embodiments, R 6 is unsubstituted tert-butoxy. , wherein R 7 and R 8 are as described herein, including in embodiments.
- R 7 and R 8 are as described herein, including in embodiments. In embodiments, wherein R 7 and R 8 are as described herein, including in embodiments. In embodiments, , wherein R 7 and R 8 are as described herein, including in embodiments. In embodiments, , wherein R 7 and R 8 are as described herein, including in embodiments. In embodiments, , wherein R 8 is as described herein, including in embodiments. In embodiments, , wherein R 8 is as described herein, including in embodiments.
- a substituted R 7 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 7 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R 7 is substituted, it is substituted with at least one substituent group.
- R 7 when R 7 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 7 is substituted, it is substituted with at least one lower substituent group.
- R 7 is hydrogen. In embodiments, R 7 is unsubstituted C 1 -C 6 alkyl. In embodiments, R 7 is unsubstituted methyl. In embodiments, R 7 is unsubstituted ethyl. In embodiments, R 7 is unsubstituted propyl. In embodiments, R 7 is unsubstituted n-propyl. In embodiments, R 7 is unsubstituted isopropyl.
- R 7 is unsubstituted butyl. In embodiments, R 7 is unsubstituted n-butyl. In embodiments, R 7 is unsubstituted isobutyl. In embodiments, R 7 is unsubstituted tert-butyl. In embodiments, R 7 is unsubstituted pentyl. In embodiments, R 7 is unsubstituted hexyl.
- a substituted ring formed when R 5 and R 7 substituents are joined is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R 5 and R 7 substituents are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
- the substituted ring formed when R 5 and R 7 substituents are joined is substituted, it is substituted with at least one substituent group.
- R 5 and R 7 substituents when the substituted ring formed when R 5 and R 7 substituents are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R 5 and R 7 substituents are joined is substituted, it is substituted with at least one lower substituent group. [0221] In embodiments, R 5 and R 7 substituents are joined to form a substituted or unsubstituted C3-C8 cycloalkyl or substituted or unsubstituted 3 to 8 membered heterocycloalkyl.
- a substituted ring formed when R 6 and R 7 substituents are joined is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R 6 and R 7 substituents are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
- when the substituted ring formed when R 6 and R 7 substituents are joined is substituted, it is substituted with at least one substituent group.
- R 6 and R 7 substituents when the substituted ring formed when R 6 and R 7 substituents are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R 6 and R 7 substituents are joined is substituted, it is substituted with at least one lower substituent group. [0223] In embodiments, R 6 and R 7 substituents are joined to form a substituted or unsubstituted C3-C8 cycloalkyl or substituted or unsubstituted 3 to 8 membered heterocycloalkyl.
- a substituted R 8 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 8 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R 8 is substituted, it is substituted with at least one substituent group.
- R 8 when R 8 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 8 is substituted, it is substituted with at least one lower substituent group. [0225] In embodiments, R 8 is substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl. In embodiments, R 8 is substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, or substituted or unsubstituted phenyl.
- R 8 is –OCH2CF3.
- R 8 is , wherein Ring B, R 10 , and z10 are as described herein, including in embodiments. In embodiments, .
- a substituted R 9 e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
- R 9 when R 9 is substituted, it is substituted with at least one substituent group. In embodiments, when R 9 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 9 is substituted, it is substituted with at least one lower substituent group.
- R 9 is independently halogen. In embodiments, R 9 is independently –F. In embodiments, R 9 is independently –Cl. In embodiments, R 9 is independently –Br. In embodiments, R 9 is independently –I. In embodiments, R 9 is independently -CCl 3 . In embodiments, R 9 is independently -CBr3. In embodiments, R 9 is independently -CF3. In embodiments, R 9 is independently -CI3.
- R 9 is independently -CH2Cl. In embodiments, R 9 is independently -CH 2 Br. In embodiments, R 9 is independently -CH 2 F. In embodiments, R 9 is independently -CH 2 I. In embodiments, R 9 is independently -CHCl 2 . In embodiments, R 9 is independently -CHBr2. In embodiments, R 9 is independently -CHF2. In embodiments, R 9 is independently -CHI2. In embodiments, R 9 is independently –CN. In embodiments, R 9 is independently –OH. In embodiments, R 9 is independently -NH 2 . In embodiments, R 9 is independently –COOH. In embodiments, R 9 is independently -CONH2. In embodiments, R 9 is independently -NO2.
- R 9 is independently –SH. In embodiments, R 9 is independently -SO 3 H. In embodiments, R 9 is independently -OSO 3 H. In embodiments, R 9 is independently -SO2NH2. In embodiments, R 9 is independently ⁇ NHNH2. In embodiments, R 9 is independently ⁇ ONH2. In embodiments, R 9 is independently ⁇ NHC(O)NH 2 . In embodiments, R 9 is independently -NHSO 2 H. In embodiments, R 9 is independently -NHC(O)H. In embodiments, R 9 is independently -NHC(O)OH. In embodiments, R 9 is independently –NHOH. In embodiments, R 9 is independently -OCCl3. In embodiments, R 9 is independently -OCBr3.
- R 9 is independently -OCF3. In embodiments, R 9 is independently -OCI 3 . In embodiments, R 9 is independently -OCH 2 Cl. In embodiments, R 9 is independently -OCH2Br. In embodiments, R 9 is independently -OCH2F. In embodiments, R 9 is independently -OCH2I. In embodiments, R 9 is independently -OCHCl 2 . In embodiments, R 9 is independently -OCHBr 2 . In embodiments, R 9 is independently -OCHF 2 . In embodiments, R 9 is independently -OCHI 2 . In embodiments, R 9 is independently unsubstituted C1-C4 alkyl. In embodiments, R 9 is independently unsubstituted methyl.
- R 9 is independently unsubstituted ethyl. In embodiments, R 9 is independently unsubstituted propyl. In embodiments, R 9 is independently unsubstituted n-propyl. In embodiments, R 9 is independently unsubstituted isopropyl. In embodiments, R 9 is independently unsubstituted butyl. In embodiments, R 9 is independently unsubstituted n-butyl. In embodiments, R 9 is independently unsubstituted isobutyl. In embodiments, R 9 is independently unsubstituted tert-butyl. In embodiments, R 9 is independently unsubstituted 2 to 4 membered heteroalkyl.
- R 9 is independently unsubstituted methoxy. In embodiments, R 9 is independently unsubstituted ethoxy. In embodiments, R 9 is independently unsubstituted propoxy. In embodiments, R 9 is independently unsubstituted n-propoxy. In embodiments, R 9 is independently unsubstituted isopropoxy. In embodiments, R 9 is independently unsubstituted butoxy. In embodiments, R 9 is independently unsubstituted n-butoxy. In embodiments, R 9 is independently unsubstituted isobutoxy. In embodiments, R 9 is independently unsubstituted tert-butoxy.
- a substituted R 10 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 10 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R 10 is substituted, it is substituted with at least one substituent group.
- R 10 when R 10 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 10 is substituted, it is substituted with at least one lower substituent group.
- a substituted ring formed when two R 10 substituents are joined e.g., substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
- each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
- R 10 when the substituted ring formed when two R 10 substituents are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when two R 10 substituents are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when two R 10 substituents are joined is substituted, it is substituted with at least one lower substituent group.
- R 10 is independently oxo. In embodiments, R 10 is independently halogen. In embodiments, R 10 is independently –F. In embodiments, R 10 is independently –Cl. In embodiments, R 10 is independently –Br. In embodiments, R 10 is independently –I.
- R 10 is independently -CCl3. In embodiments, R 10 is independently -CBr3. In embodiments, R 10 is independently -CF3. In embodiments, R 10 is independently -CI3. In embodiments, R 10 is independently -CH2Cl. In embodiments, R 10 is independently -CH2Br. In embodiments, R 10 is independently -CH 2 F. In embodiments, R 10 is independently -CH 2 I. In embodiments, R 10 is independently -CHCl2. In embodiments, R 10 is independently -CHBr2. In embodiments, R 10 is independently -CHF2. In embodiments, R 10 is independently -CHI 2 . In embodiments, R 10 is independently –CN. In embodiments, R 10 is independently –OH.
- R 10 is independently -NH 2 . In embodiments, R 10 is independently –COOH. In embodiments, R 10 is independently -CONH2. In embodiments, R 10 is independently -NO2. In embodiments, R 10 is independently –SH. In embodiments, R 10 is independently -SO 3 H. In embodiments, R 10 is independently -OSO 3 H. In embodiments, R 10 is independently -SO2NH2. In embodiments, R 10 is independently ⁇ NHNH2. In embodiments, R 10 is independently ⁇ ONH2. In embodiments, R 10 is independently ⁇ NHC(O)NH2. In embodiments, R 10 is independently -NHSO2H. In embodiments, R 10 is independently -NHC(O)H.
- R 10 is independently -NHC(O)OH. In embodiments, R 10 is independently –NHOH. In embodiments, R 10 is independently -OCCl3. In embodiments, R 10 is independently -OCBr 3 . In embodiments, R 10 is independently -OCF 3 . In embodiments, R 10 is independently -OCI 3 . In embodiments, R 10 is independently -OCH2Cl. In embodiments, R 10 is independently -OCH2Br. In embodiments, R 10 is independently -OCH2F. In embodiments, R 10 is independently -OCH2I. In embodiments, R 10 is independently -OCHCl 2 . In embodiments, R 10 is independently -OCHBr2.
- R 10 is independently -OCHF2. In embodiments, R 10 is independently -OCHI2. In embodiments, R 10 is independently unsubstituted C1-C4 alkyl. In embodiments, R 10 is independently unsubstituted methyl. In embodiments, R 10 is independently unsubstituted ethyl. In embodiments, R 10 is independently unsubstituted propyl. In embodiments, R 10 is independently unsubstituted n-propyl. In embodiments, R 10 is independently unsubstituted isopropyl. In embodiments, R 10 is independently unsubstituted butyl. In embodiments, R 10 is independently unsubstituted n-butyl.
- R 10 is independently unsubstituted isobutyl. In embodiments, R 10 is independently unsubstituted tert-butyl. In embodiments, R 10 is independently unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 10 is independently unsubstituted methoxy. In embodiments, R 10 is independently unsubstituted ethoxy. In embodiments, R 10 is independently unsubstituted propoxy. In embodiments, R 10 is independently unsubstituted n- propoxy. In embodiments, R 10 is independently unsubstituted isopropoxy. In embodiments, R 10 is independently unsubstituted butoxy.
- R 10 is independently unsubstituted n-butoxy. In embodiments, R 10 is independently unsubstituted isobutoxy. In embodiments, R 10 is independently unsubstituted tert-butoxy. [0232] In embodiments, R 10 is independently halogen, -CF3, unsubstituted C1-C6 alkyl, or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R 10 is independently –F, -Cl, -CF 3 , unsubstituted methyl, or unsubstituted methoxy.
- two R 10 substituents are joined to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.
- z10 is 0. In embodiments, z10 is 1. In embodiments, z10 is 2. In embodiments, z10 is 3. In embodiments, z10 is 4. In embodiments, z10 is 5. In embodiments, z10 is 6. In embodiments, z10 is 7. In embodiments, z10 is 8. In embodiments, z10 is 9.
- z10 is 10. In embodiments, z10 is 11. [0235]
- R 1 when R 1 is substituted, R 1 is substituted with one or more first substituent groups denoted by R 1.1 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 1.1 substituent group when an R 1.1 substituent group is substituted, the R 1.1 substituent group is substituted with one or more second substituent groups denoted by R 1.2 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 1.2 substituent group when an R 1.2 substituent group is substituted, the R 1.2 substituent group is substituted with one or more third substituent groups denoted by R 1.3 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 1 , R 1.1 , R 1.2 , and R 1.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 1 , R 1.1 , R 1.2 , and R 1.3 , respectively.
- R 1 substituents when two R 1 substituents are optionally joined to form a moiety that is substituted (e.g., a substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R 1.1 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 1.1 substituent group when an R 1.1 substituent group is substituted, the R 1.1 substituent group is substituted with one or more second substituent groups denoted by R 1.2 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 1.2 substituent group when an R 1.2 substituent group is substituted, the R 1.2 substituent group is substituted with one or more third substituent groups denoted by R 1.3 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 1 , R 1.1 , R 1.2 , and R 1.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 1 , R 1.1 , R 1.2 , and R 1.3 , respectively.
- R 1.1 when R 1.1 is substituted, R 1.1 is substituted with one or more first substituent groups denoted by R 1.1.1 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 1.1.1 substituent group when an R 1.1.1 substituent group is substituted, the R 1.1.1 substituent group is substituted with one or more second substituent groups denoted by R 1.1.2 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 1.1.2 substituent group when an R 1.1.2 substituent group is substituted, the R 1.1.2 substituent group is substituted with one or more third substituent groups denoted by R 1.1.3 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 1.1 , R 1.1.1 , R 1.1.2 , and R 1.1.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R , respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 1.1 , R 1.1.1 , R 1.1.2 , and R 1.1.3 , respectively.
- R 1.2 when R 1.2 is substituted, R 1.2 is substituted with one or more first substituent groups denoted by R 1.2.1 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 1.2.1 substituent group when an R 1.2.1 substituent group is substituted, the R 1.2.1 substituent group is substituted with one or more second substituent groups denoted by R 1.2.2 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 1.2.2 substituent group when an R 1.2.2 substituent group is substituted, the R 1.2.2 substituent group is substituted with one or more third substituent groups denoted by R 1.2.3 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 1.2 , R 1.2.1 , R 1.2.2 , and R 1.2.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R , respectively, as explained in the definitions section above in the description of first substituent group(s) , wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 1.2 , R 1.2.1 , R 1.2.2 , and R 1.2.3 , respectively.
- R 1.3 when R 1.3 is substituted, R 1.3 is substituted with one or more first substituent groups denoted by R 1.3.1 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 1.3.1 substituent group when an R 1.3.1 substituent group is substituted, the R 1.3.1 substituent group is substituted with one or more second substituent groups denoted by R 1.3.2 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 1.3.2 substituent group when an R 1.3.2 substituent group is substituted, the R 1.3.2 substituent group is substituted with one or more third substituent groups denoted by R 1.3.3 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 1.3 , R 1.3.1 , R 1.3.2 , and R 1.3.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 1.3 , R 1.3.1 , R 1.3.2 , and R 1.3.3 , respectively.
- R 1A when R 1A is substituted, R 1A is substituted with one or more first substituent groups denoted by R 1A.1 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 1A.1 substituent group when an R 1A.1 substituent group is substituted, the R 1A.1 substituent group is substituted with one or more second substituent groups denoted by R 1A.2 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 1A.2 substituent group when an R 1A.2 substituent group is substituted, the R 1A.2 substituent group is substituted with one or more third substituent groups denoted by R 1A.3 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 1A , R 1A.1 , R 1A.2 , and R 1A.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 1A , R 1A.1 , R 1A.2 , and R 1A.3 , respectively.
- R 1B when R 1B is substituted, R 1B is substituted with one or more first substituent groups denoted by R 1B.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R 1B.1 substituent group is substituted, the R 1B.1 substituent group is substituted with one or more second substituent groups denoted by R 1B.2 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 1B.2 substituent group when an R 1B.2 substituent group is substituted, the R 1B.2 substituent group is substituted with one or more third substituent groups denoted by R 1B.3 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 1B , R 1B.1 , R 1B.2 , and R 1B.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 1B , R 1B.1 , R 1B.2 , and R 1B.3 , respectively.
- R 1A and R 1B substituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R 1A.1 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 1A.1 when an R 1A.1 substituent group is substituted, the R 1A.1 substituent group is substituted with one or more second substituent groups denoted by R 1A.2 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 1A.2 substituent group when an R 1A.2 substituent group is substituted, the R 1A.2 substituent group is substituted with one or more third substituent groups denoted by R 1A.3 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 1A.1 , R 1A.2 , and R 1A.3 have values corresponding to the values of R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R WW.1 , R WW.2 , and R WW.3 correspond to R 1A.1 , R 1A.2 , and R 1A.3 , respectively.
- R 1A and R 1B substituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R 1B.1 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 1B.1 when an R 1B.1 substituent group is substituted, the R 1B.1 substituent group is substituted with one or more second substituent groups denoted by R 1B.2 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 1B.2 substituent group when an R 1B.2 substituent group is substituted, the R 1B.2 substituent group is substituted with one or more third substituent groups denoted by R 1B.3 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 1B.1 , R 1B.2 , and R 1B.3 have values corresponding to the values of R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of first substituent group(s) , wherein R WW.1 , R WW.2 , and R WW.3 correspond to R 1B.1 , R 1B.2 , and R 1B.3 , respectively.
- R 1C when R 1C is substituted, R 1C is substituted with one or more first substituent groups denoted by R 1C.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R 1C.1 substituent group is substituted, the R 1C.1 substituent group is substituted with one or more second substituent groups denoted by R 1C.2 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 1C.2 substituent group when an R 1C.2 substituent group is substituted, the R 1C.2 substituent group is substituted with one or more third substituent groups denoted by R 1C.3 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 1C , R 1C.1 , R 1C.2 , and R 1C.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 1C , R 1C.1 , R 1C.2 , and R 1C.3 , respectively.
- R 1D when R 1D is substituted, R 1D is substituted with one or more first substituent groups denoted by R 1D.1 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 1D.1 when an R 1D.1 substituent group is substituted, the R 1D.1 substituent group is substituted with one or more second substituent groups denoted by R 1D.2 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 1D.2 substituent group when an R 1D.2 substituent group is substituted, the R 1D.2 substituent group is substituted with one or more third substituent groups denoted by R 1D.3 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 1D , R 1D.1 , R 1D.2 , and R 1D.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 1D , R 1D.1 , R 1D.2 , and R 1D.3 , respectively.
- R 3 when R 3 is substituted, R 3 is substituted with one or more first substituent groups denoted by R 3.1 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 3.1 substituent group when an R 3.1 substituent group is substituted, the R 3.1 substituent group is substituted with one or more second substituent groups denoted by R 3.2 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 3.2 substituent group when an R 3.2 substituent group is substituted, the R 3.2 substituent group is substituted with one or more third substituent groups denoted by R 3.3 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 3 , R 3.1 , R 3.2 , and R 3.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 3 , R 3.1 , R 3.2 , and R 3.3 , respectively.
- R 2 and R 3 substituents are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl)
- the moiety is substituted with one or more first substituent groups denoted by R 2.1 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 2.1 substituent group when an R 2.1 substituent group is substituted, the R 2.1 substituent group is substituted with one or more second substituent groups denoted by R 2.2 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 2.2 substituent group when an R 2.2 substituent group is substituted, the R 2.2 substituent group is substituted with one or more third substituent groups denoted by R 2.3 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 2.1 , R 2.2 , and R 2.3 have values corresponding to the values of R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R WW.1 , R WW.2 , and R WW.3 correspond to R 2.1 , R 2.2 , and R 2.3 , respectively.
- R 2 and R 3 substituents are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl)
- the moiety is substituted with one or more first substituent groups denoted by R 3.1 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 3.1 substituent group when an R 3.1 substituent group is substituted, the R 3.1 substituent group is substituted with one or more second substituent groups denoted by R 3.2 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 3.2 substituent group when an R 3.2 substituent group is substituted, the R 3.2 substituent group is substituted with one or more third substituent groups denoted by R 3.3 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 3.1 , R 3.2 , and R 3.3 have values corresponding to the values of R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R WW.1 , R WW.2 , and R WW.3 correspond to R 3.1 , R 3.2 , and R 3.3 , respectively.
- R 4 when R 4 is substituted, R 4 is substituted with one or more first substituent groups denoted by R 4.1 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 4.1 substituent group when an R 4.1 substituent group is substituted, the R 4.1 substituent group is substituted with one or more second substituent groups denoted by R 4.2 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 4.2 substituent group when an R 4.2 substituent group is substituted, the R 4.2 substituent group is substituted with one or more third substituent groups denoted by R 4.3 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 4 , R 4.1 , R 4.2 , and R 4.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 4 , R 4.1 , R 4.2 , and R 4.3 , respectively.
- R 7 when R 7 is substituted, R 7 is substituted with one or more first substituent groups denoted by R 7.1 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 7.1 substituent group when an R 7.1 substituent group is substituted, the R 7.1 substituent group is substituted with one or more second substituent groups denoted by R 7.2 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 7.2 substituent group when an R 7.2 substituent group is substituted, the R 7.2 substituent group is substituted with one or more third substituent groups denoted by R 7.3 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 7 , R 7.1 , R 7.2 , and R 7.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 7 , R 7.1 , R 7.2 , and R 7.3 , respectively.
- R 5 and R 7 substituents are optionally joined to form a moiety that is substituted (e.g., a substituted cycloalkyl or substituted heterocycloalkyl), the moiety is substituted with one or more first substituent groups denoted by R 5.1 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 5.1 substituent group when an R 5.1 substituent group is substituted, the R 5.1 substituent group is substituted with one or more second substituent groups denoted by R 5.2 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 5.2 substituent group when an R 5.2 substituent group is substituted, the R 5.2 substituent group is substituted with one or more third substituent groups denoted by R 5.3 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 5.1 , R 5.2 , and R 5.3 have values corresponding to the values of R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R WW.1 , R WW.2 , and R WW.3 correspond to R 5.1 , R 5.2 , and R 5.3 , respectively.
- R 5 and R 7 substituents are optionally joined to form a moiety that is substituted (e.g., a substituted cycloalkyl or substituted heterocycloalkyl), the moiety is substituted with one or more first substituent groups denoted by R 7.1 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 7.1 when an R 7.1 substituent group is substituted, the R 7.1 substituent group is substituted with one or more second substituent groups denoted by R 7.2 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 7.2 substituent group when an R 7.2 substituent group is substituted, the R 7.2 substituent group is substituted with one or more third substituent groups denoted by R 7.3 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 7.1 , R 7.2 , and R 7.3 have values corresponding to the values of R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R WW.1 , R WW.2 , and R WW.3 correspond to R 7.1 , R 7.2 , and R 7.3 , respectively.
- R 6 and R 7 substituents are optionally joined to form a moiety that is substituted (e.g., a substituted cycloalkyl or substituted heterocycloalkyl), the moiety is substituted with one or more first substituent groups denoted by R 6.1 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 6.1 when an R 6.1 substituent group is substituted, the R 6.1 substituent group is substituted with one or more second substituent groups denoted by R 6.2 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 6.2 substituent group when an R 6.2 substituent group is substituted, the R 6.2 substituent group is substituted with one or more third substituent groups denoted by R 6.3 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 6.1 , R 6.2 , and R 6.3 have values corresponding to the values of R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R WW.1 , R WW.2 , and R WW.3 correspond to R 6.1 , R 6.2 , and R 6.3 , respectively.
- R 6 and R 7 substituents are optionally joined to form a moiety that is substituted (e.g., a substituted cycloalkyl or substituted heterocycloalkyl), the moiety is substituted with one or more first substituent groups denoted by R 7.1 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 7.1 when an R 7.1 substituent group is substituted, the R 7.1 substituent group is substituted with one or more second substituent groups denoted by R 7.2 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 7.2 substituent group when an R 7.2 substituent group is substituted, the R 7.2 substituent group is substituted with one or more third substituent groups denoted by R 7.3 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 7.1 , R 7.2 , and R 7.3 have values corresponding to the values of R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R WW.1 , R WW.2 , and R WW.3 correspond to R 7.1 , R 7.2 , and R 7.3 , respectively.
- R 8 when R 8 is substituted, R 8 is substituted with one or more first substituent groups denoted by R 8.1 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 8.1 substituent group when an R 8.1 substituent group is substituted, the R 8.1 substituent group is substituted with one or more second substituent groups denoted by R 8.2 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 8.2 substituent group when an R 8.2 substituent group is substituted, the R 8.2 substituent group is substituted with one or more third substituent groups denoted by R 8.3 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 8 , R 8.1 , R 8.2 , and R 8.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 8 , R 8.1 , R 8.2 , and R 8.3 , respectively.
- R 9 when R 9 is substituted, R 9 is substituted with one or more first substituent groups denoted by R 9.1 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 9.1 substituent group when an R 9.1 substituent group is substituted, the R 9.1 substituent group is substituted with one or more second substituent groups denoted by R 9.2 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 9.2 substituent group when an R 9.2 substituent group is substituted, the R 9.2 substituent group is substituted with one or more third substituent groups denoted by R 9.3 as explained in the definitions section above in the description of first substituent group(s)”.
- R 9 , R 9.1 , R 9.2 , and R 9.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 9 , R 9.1 , R 9.2 , and R 9.3 , respectively.
- R 10 when R 10 is substituted, R 10 is substituted with one or more first substituent groups denoted by R 10.1 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 10.1 substituent group when an R 10.1 substituent group is substituted, the R 10.1 substituent group is substituted with one or more second substituent groups denoted by R 10.2 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 10.2 substituent group when an R 10.2 substituent group is substituted, the R 10.2 substituent group is substituted with one or more third substituent groups denoted by R 10.3 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 10 , R 10.1 , R 10.2 , and R 10.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 10 , R 10.1 , R 10.2 , and R 10.3 , respectively.
- R 10 substituents when two R 10 substituents are optionally joined to form a moiety that is substituted (e.g., a substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R 10.1 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 10.1 when an R 10.1 substituent group is substituted, the R 10.1 substituent group is substituted with one or more second substituent groups denoted by R 10.2 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 10.2 substituent group when an R 10.2 substituent group is substituted, the R 10.2 substituent group is substituted with one or more third substituent groups denoted by R 10.3 as explained in the definitions section above in the description of “first substituent group(s)”.
- R 10 , R 10.1 , R 10.2 , and R 10.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 10 , R 10.1 , R 10.2 , and R 10.3 , respectively.
- the compound has the formula: In embodiments, the compound has the formula: In embodiments, the compound has the formula: . embodiments, the compound has the formula: embodiments, the compound has the formula: . In embodiments, the compound has the formula: . In embodiments, the compound has the formula: . In embodiments, the compound has the formula: . In embodiments, the compound has the formula: . In embodiments, the compound has the formula: . In embodiments, the compound has the formula: embodiments, the compound has the formula: . embodiments, the compound has the formula:
- the compound has the formula: embodiments, the compound has the formula: . In embodiments, the compound has the formula: .
- the compound has the formula: .
- the compound is useful as a comparator compound. In embodiments, the comparator compound can be used to assess the activity of a test compound as set forth in an assay described herein (e.g., in the examples section, figures, or tables).
- the compound is a compound as described herein, including in embodiments. In embodiments the compound is a compound described herein (e.g., in the examples section, figures, tables, or claims). III.
- compositions including a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
- the pharmaceutical composition includes an effective amount of the compound.
- the pharmaceutical composition includes a therapeutically effective amount of the compound.
- the compound is a compound of formula (I), (II), (III), (IV), (V), or (VI).
- the compound is a compound of formula (I), (II), (III), (IV), (V), or (VI), including embodiments thereof. IV.
- a method of treating or preventing an age-related disorder in a subject including administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.
- the compound is [0266] In embodiments, the compound is not: , .
- the age-related disorder is ischemia reperfusion injury, acute coronary syndrome, stroke, acute kidney injury, acute myocardial infarction, organ transplantation, metabolic syndrome, insulin resistance, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), noise-induced hearing loss, age-induced hearing loss, cisplatin-induced nephrotoxicity, Alzheimer’s disease, Parkinson’s disease, cardiac hypertension, pulmonary arterial hypertension, diabetic cardiomyopathy, Type 2 diabetes, cancer growth, cancer incidence, cancer metastasis, atherosclerosis, osteoarthritis, or osteoporosis.
- the age-related disorder is ischemia reperfusion injury.
- the age-related disorder is acute coronary syndrome. In embodiments, the age- related disorder is stroke. In embodiments, the age-related disorder is acute kidney injury. In embodiments, the age-related disorder is acute myocardial infarction. In embodiments, the age-related disorder is organ transplantation. In embodiments, the age-related disorder is metabolic syndrome. In embodiments, the age-related disorder is insulin resistance. In embodiments, the age-related disorder is non-alcoholic steatohepatitis (NASH). In embodiments, the age-related disorder is non-alcoholic fatty liver disease (NAFLD). In embodiments, the age-related disorder is noise-induced hearing loss. In embodiments, the age-related disorder is age-induced hearing loss.
- NASH non-alcoholic steatohepatitis
- NAFLD non-alcoholic fatty liver disease
- the age-related disorder is cisplatin-induced nephrotoxicity. In embodiments, the age-related disorder is Alzheimer’s disease. In embodiments, the age-related disorder is Parkinson’s disease. In embodiments, the age-related disorder is cardiac hypertension. In embodiments, the age-related disorder is pulmonary arterial hypertension. In embodiments, the age-related disorder is right ventricle hypertension. In embodiments, the age-related disorder is left ventricle hypertension. In embodiments, the age-related disorder is diabetic cardiomyopathy. In embodiments, the age- related disorder is diabetic nephropathy. In embodiments, the age-related disorder is diabetic embryopathy. In embodiments, the age-related disorder is diabetes. In embodiments, the age-related disorder is Type 2 diabetes.
- the age-related disorder is pancreatic dysfunction. In embodiments, the age-related disorder is hyperglycemia. In embodiments, the age-related disorder is cancer growth. In embodiments, the age-related disorder is cancer incidence. In embodiments, the age-related disorder is cancer metastasis. In embodiments, the age-related disorder is cancer (e.g., breast cancer, lung cancer, melanoma, pancreatic cancer, prostate cancer). In embodiments, the age-related disorder is atherosclerosis. In embodiments, the age-related disorder is osteoarthritis. In embodiments, the age-related disorder is osteoporosis. In embodiments, the age-related disorder is inflammation (e.g., macrophage activation).
- inflammation e.g., macrophage activation
- the age-related disorder is an ocular disease (e.g., retina disease). In embodiments, the age-related disorder is glaucoma. In embodiments, the age-related disorder is cataract. In embodiments, the age-related disorder is drug-induced toxicity, wherein the drug is, for example, acetaminophen, anthracyclines, AZT, NRTIs, platinum anti-cancer drugs, or methamphetamine. In embodiments, the age-related disorder is alcohol-induced toxicity. In embodiments, the age- related disorder is obesity. In embodiments, the age-related disorder is inflammatory bowel disease. In embodiments, the age-related disorder is hyposalivation. In embodiments, the age-related disorder is dry mouth.
- the age-related disorder is an ocular disease (e.g., retina disease). In embodiments, the age-related disorder is glaucoma. In embodiments, the age-related disorder is cataract. In embodiments, the age-related disorder is drug-induced toxicity, wherein the
- the age-related disorder is xerostomia. In embodiments, the age-related disorder is cognitive decline. In embodiments, the age- related disorder is cardiomyopathy. In embodiments, the age-related disorder is muscle weakness. In embodiments, the age-related disorder is muscle atrophy. In embodiments, the age-related disorder is radiation injury. In embodiments, the age-related disorder is cardiovascular disease. In embodiments, the age-related disorder is brain trauma. In embodiments, the age-related disorder is skin aging. In embodiments, the age-related disorder is mitochondrial disease. In embodiments, the age-related disorder is amyotrophic lateral sclerosis. In embodiments, the age-related disorder is periodontitis. In embodiments, the age-related disorder is hyperthermia.
- the age-related disorder is Friedrich’s Ataxia.
- the age-related disorder is a spinal deformity (e.g., scoliosis, kyphosis).
- the age-related disorder is Chagas’ disease.
- the age-related disorder is epilepsy.
- the age-related disorder is loss of olfaction.
- the age-related disorder is Leber’s hereditary optic neuropathy (LHON).
- the age-related disorder is Huntington’s disease. .
- n is an integer from 0 to 2;
- R 1 is independently halogen, -CX 1 3, -CHX 1 2, -CH2X 1 , -OCX 1 3, -OCH2X 1 , -OCHX 1 2, -CN, -SO n1 R 1D , -SO v1 NR 1A R 1B , ⁇ NR 1C NR 1A R 1B , ⁇ ONR 1A R 1B , -NR 1C C(O)NR 1A R 1B , -N(O) m1 , -NR 1A R 1B , -C(O)R 1C , -C(O)OR 1C , -OC(O)R 1C , -OC(O)OR 1C , -C(O)NR 1A R 1B , -OC(O)NR 1A R 1B , -OR 1D , -SR 1D ,
- Embodiment P2 The compound of embodiment P1, having the formula: R 1.2 is –NR 1A C(O)R 1B , -NR 1A SO2R 1C , -NR 1A C(O)OR 1B , -OR 1A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 1.1 and R 1.3 are hydrogen; R 1.1 and R 1.2 substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl; or R 1.2 and R 1.3 substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl; X is O and R 3 is hydrogen; or X is NR 2
- Embodiment P3 The compound of one of embodiments P1 to P2, wherein R 3 is a prodrug moiety.
- Embodiment P4. The compound of one of embodiments P1 to P2, wherein R 3 is .
- Embodiment P5. The compound of one of embodiments P1 to P4, wherein R 4 is a prodrug moiety.
- Embodiment P6 The compound of one of embodiments P1 to P4, wherein R 4 is [0276] Embodiment P8.
- Embodiment P10 The compound of one of embodiments P1 to P8, wherein R 8 is substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, or substituted or unsubstituted phenyl.
- Embodiment P11 The compound of one of embodiments P1 to P8, wherein R 8 is substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, or substituted or unsubstituted phenyl.
- Embodiment P12 The compound of embodiment P2, having the formula: wherein Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 10 is independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -OSO3H, -SO2NH2, ⁇ NHNH2, ⁇ ONH2, ⁇ NHC(O)NHNH2, ⁇ NHC(O)NH2, -NHSO2H
- Embodiment P13 The compound of one of embodiments P2 to P12, wherein R 1.2 is –NR 1A C(O)R 1B .
- Embodiment P14 The compound of embodiment P13, wherein R 1A and R 1B are independently hydrogen or unsubstituted C1-C4 alkyl.
- Embodiment P15 The compound of one of embodiments P2 to P12, wherein R 1.2 is –NHC(O)CH3, -NCH3C(O)CH3, -OH, -OCH3, or –NHSO2CH3.
- Embodiment P16 Embodiment P16.
- Embodiment P17 The compound of one of embodiments P1 to P12, wherein .
- Embodiment P18 The compound of one of embodiments P1 to P17, wherein R 6 is hydrogen, -OH, or –OCH3.
- Embodiment P19 The compound of one of embodiments P1 to P17, wherein R 6 is hydrogen.
- Embodiment P20 The compound of one of embodiments P1 to P19, wherein [0289] Embodiment P21. The compound of one of embodiments P1 to P19, wherein Ring .
- Embodiment P22 The compound of one of embodiments P1 to P21, wherein R 7 is unsubstituted C 1 -C 6 alkyl.
- Embodiment P23 The compound of one of embodiments P1 to P21, wherein R 7 is unsubstituted methyl.
- Embodiment P24 The compound of one of embodiments P12 to P23, wherein Ring B is 3 to 8 membered heterocycloalkyl or phenyl.
- Embodiment P25 The compound of one of embodiments P12 to P23, wherein Ring B is 3 to 8 membered heterocycloalkyl.
- Embodiment P26 The compound of one of embodiments P12 to P23, wherein Ring B is 3 to 8 membered heterocycloalkyl.
- Embodiment P27 The compound of one of embodiments P12 to P23, wherein Ring B is pyrrolidinyl, piperidinyl, or morpholinyl.
- Embodiment P28 The compound of one of embodiments P12 to P23, wherein R 10 is independently halogen, -CF3, unsubstituted C1-C6 alkyl, or unsubstituted 2 to 6 membered heteroalkyl.
- Embodiment P28 The compound of one of embodiments P12 to P23, wherein R 10 is independently –F, -Cl, -CF 3 , unsubstituted methyl, or unsubstituted methoxy.
- Embodiment P29 The compound of one of embodiments P12 to P23, wherein R 10 is independently –F, -Cl, -CF 3 , unsubstituted methyl, or unsubstituted methoxy.
- Embodiment P33 A pharmaceutical composition comprising a compound of one of embodiments P1 to P32 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
- Embodiment P34 A method of treating or preventing an age-related disorder in a subject, said method comprising administering to the subject a therapeutically effective amount of a compound of one of embodiments P1 to P32, or a pharmaceutically acceptable salt thereof.
- Embodiment P35 A pharmaceutical composition comprising a compound of one of embodiments P1 to P32 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
- the age-related disorder is ischemia reperfusion injury, acute coronary syndrome, stroke, acute kidney injury, acute myocardial infarction, organ transplantation, metabolic syndrome, insulin resistance, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), noise- induced hearing loss, age-induced hearing loss, cisplatin-induced nephrotoxicity, Alzheimer’s disease, Parkinson’s disease, cardiac hypertension, pulmonary arterial hypertension, diabetic cardiomyopathy, Type 2 diabetes, cancer growth, cancer incidence, cancer metastasis, atherosclerosis, osteoarthritis, or osteoporosis.
- NASH non-alcoholic steatohepatitis
- NAFLD non-alcoholic fatty liver disease
- noise- induced hearing loss age-induced hearing loss
- cisplatin-induced nephrotoxicity Alzheimer’s disease
- Parkinson’s disease cardiac hypertension, pulmonary arterial hypertension, diabetic cardiomyopathy, Type 2 diabetes
- cancer growth cancer incidence, cancer metastasis, athe
- S1QEL1.719 prevented superoxide/hydrogen peroxide production at site IQ of mitochondrial complex I in vitro with a binding-corrected IC 50 of 52 nM. At 50-fold higher concentrations it did not inhibit superoxide/hydrogen peroxide production from other sites.
- the IC50 for inhibition of complex I electron flow was 500-fold higher than the IC50 for suppression of site IQ.
- S1QEL1.719 was used to test the metabolic effects of suppressing the activity of site I Q in vivo. C57BL/6J male mice fed a high-fat chow for two or eight weeks had increased body fat, decreased glucose tolerance, and increased fasting insulin concentrations, classic symptoms of metabolic syndrome.
- AUC area under the curve
- BSA bovine serum albumin
- fu fraction unbound
- HPMC hydroxypropyl methylcellulose
- ROS reactive oxygen species
- site I Q the site of superoxide and/or hydrogen peroxide production in mitochondrial complex I functionally associated with the ubiquinone (Q) binding site
- S1QEL suppressor of site I Q electron leak
- site III Qo the site of superoxide production in mitochondrial complex III at the outer Q- binding site, S3QEL, suppressor of site IIIQo electron leak.
- Numerous mechanisms and pathways have been suggested to initiate metabolic syndrome and the eventual development of specific diseases.
- sites I Q and IIIQo are important contributors to cytosolic hydrogen peroxide levels, and site IQ dominates the production of superoxide/hydrogen peroxide in the mitochondrial matrix (23-25).
- S1QELs and S3QELs are not well suited for systemic in vivo use because of their poor solubility and bioavailability, although they can be added to the diet to affect gut cell function in flies (26,29) and mice (29).
- S1QEL712 a S1QEL1 with improved properties that enable its successful intraperitoneal administration to neonatal mice, and showed that it protected against systemic pathologies caused by the elevated matrix superoxide levels resulting from SOD2 knockout (30).
- S1QEL712 a potent, selective and orally-bioavailable S1QEL1: S1QEL1.719 (also referred to herein as 719 or S1QEL719).
- S1QEL1.719 The synthesis of S1QEL1.719 is described in the supplementary materials (Scheme 1). Its properties include: MW, 499.51, calculated logD 7.4 (distribution coefficient at pH 7.4), 2.3; aqueous solubility, 1.5 ⁇ M (pH 7.4), 987 ⁇ M (pH 1); MDCK-MDR1 (Madin Darby canine kidney cells overexpressing MDR1, which encodes P-gp) apparent permeability Papp, 32 x 10 -6 cm/sec; scaled Cl int , mic (mouse) (intrinsic microsomal clearance), 12 L/hr/kg.
- These exposure values were 2-3 fold greater than the IC 50 of 52 nM for suppression of superoxide/H2O2 production from site IQ and 200-300 fold less than the IC50 of 30 ⁇ M for inhibition of respiration on complex I substrates, determined below using isolated rat skeletal muscle mitochondria in vitro.
- mice For the therapeutic study, ten-week-old male C57BL/6J mice that had been fed a high-fat diet from six weeks of age were purchased from The Jackson Laboratory and acclimated in-house on equivalent high-fat chow for two weeks before the study. During the study, animals were housed in groups of 4 per cage. A total of 24 animals per group was used for the prophylactic study, and a total of 12 animals per group was used for the therapeutic study. At 15 or 12 weeks of age respectively, mice were randomized into groups based on weight, ensuring an equal mean weight distribution between groups.
- mice were fed either a control semi-purified diet, D12450J, containing corn starch (10% of total kcal from fat) or a high-fat diet, D12492, otherwise the same but with corn starch replaced by lard (60% of total kcal from fat).
- Therapeutic study control animals were fed standard vivarium chow throughout the study because the Jackson Laboratory does not supply animals pre-fed the semi-purified diet (D12450J). Diets were from Research Diets and were gamma-irradiated.
- mice were maintained on the experimental diets for two weeks and gavaged (per os; p.o.) daily from day 1 during the afternoon with 500 ⁇ l of either HPMC vehicle or 30 mg/kg S1QEL1.719 suspended in HPMC.
- Food consumption was measured semi-quantitatively: food provided to the cage on day 1 was weighed, and food remaining at day 8 was weighed and discarded and the amount consumed calculated by difference. The sequence was repeated for days 8-15. The food weight differences were added and divided by the number of mice in the cage to determine the total food consumption per mouse over two weeks.
- the animal protocol was approved by the Institutional Animal Care and Use Committee of the Buck Institute (License/protocol No.
- Body weight and composition Body weight was measured every week (treatment days 1, 8 and 15) using a table balance. Body composition was measured on day 1 and on day 14 using an EchoMRI-100TM analyzer (EchoRMI-100TM company, Texas, U.S.A.) to measure fat and lean mass (EchoMRI ACQ-SYS (acquisition system) version 2018).
- EchoMRI-100TM analyzer EchoMRI-100TM company, Texas, U.S.A.
- Glucose and insulin Basal fasting glucose, plasma fasting insulin levels, and glucose tolerance were assessed on treatment days 8 and 15 (prophylactic study) or day 15 (therapeutic study). Mice were fasted for 7-10 h then baseline blood glucose and plasma insulin were measured.15 ⁇ L of blood was taken from each mouse by tail bleed and placed on ice. A small amount was used for measurement of blood glucose as described below. The remaining blood was centrifuged at 10,000 g for 5 min to isolate plasma. Plasma insulin levels were quantified using an ultrasensitive mouse insulin ELISA (Crystal Chem). [0318] For the glucose tolerance test, a bolus of glucose was given by intraperitoneal injection using a 27-gauge needle and syringe.
- Glucose is often given disproportionately based on body weight (33,34). Each animal received the same volume and concentration of glucose (2 g glucose/kg based on the mean total body weight of the whole cohort at that timepoint). This protocol ensured that, despite differences in total body weight, each animal received the same glucose challenge per lean body weight, which was not significantly different between groups (FIG.2F). This protocol is important because glucose is taken up mostly by muscle, and very little by fat tissue. Blood glucose was measured by tail bleed at 15, 30, 60, and 120 min after glucose injection using a Contour next EZ blood glucose- monitoring meter. For insulin measurements during the glucose tolerance tests in the therapeutic study, blood samples for glucose and plasma insulin assay were taken at 15, 30, 60, and 120 min after glucose injection.
- S1QEL1.719 had no significant effect on superoxide/hydrogen peroxide production from sites III Qo , I F plus upstream dehydrogenases, IIF, PF and GQ. At these concentrations it had no effect on state 3, state 4 or uncoupled respiration on different substrates (26) (5 mM glutamate plus 5 mM malate, 5 mM succinate plus 4 ⁇ M rotenone, 27 mM glycerol 3-phosphate plus 4 ⁇ M rotenone, 15–60 ⁇ M palmitoylcarnitine plus 1 mM malate). However, S1QEL1.719 does inhibit complex I at higher concentrations.
- the nominal IC 50 for inhibition of state 3 (phosphorylating) respiration divided by the nominal IC 50 for suppression of superoxide/hydrogen peroxide production under closely-matched conditions of 5 ⁇ g mitochondrial protein in 20 ⁇ L of medium (220 mM mannitol, 70 mM sucrose, 10 mM KH 2 PO 4 , 5 mM MgCl 2 , 2 mM HEPES, 1 mM EGTA, 0.2% (w/v) fatty acid free BSA), followed by mitochondrial centrifugation for 20 min at 2000 x g for plate attachment was calculated for each mitochondrial preparation and these values were averaged to give a ratio of 500 ⁇ 114 (SEM, n 6).
- S1QEL1.719 was also selective against a standard non- mitochondrial panel of off-target receptors, channels and transporters (Table 1). These results show that S1QEL1.719 is a potent and specific suppressor of superoxide/hydrogen peroxide production by site IQ, but indicate that at high concentrations it can also inhibit electron transport, with potentially confounding consequences. [0325] Effects of two-week high-fat diet with and without prophylactic S1QEL1.719 treatment on food consumption, body weight and body composition. [0326] Fifteen-week-old male C57BL/6J mice were placed for two weeks on either a control diet containing 10% kcal as fat or a high-fat diet containing 60% kcal as fat (FIG. 2A).
- mice on the high-fat diet were gavaged daily from treatment day 1 with either HPMC vehicle or 30 mg/kg S1QEL1.719 suspended in HPMC (FIG.2A).
- animals fed high-fat chow had significantly decreased food consumption compared to animals fed low-fat chow, presumably because of the difference in caloric density of the two diets.
- Prophylactic treatment with S1QEL1.719 did not affect food intake on the high-fat diet (FIG.2B). Feeding the high-fat diet resulted in a longitudinal increase in average body weight over two weeks compared to the low-fat diet (FIG.2C).
- FIG.2F shows that there were no significant differences in lean body weight between low-fat and high-fat-fed animals, or with S1QEL1.719 treatment of high-fat-fed animals, although there were trends for the decreased fat accumulation in S1QEL1.719-treated animals (FIG.2E) to be offset by a non-significant increase in lean body weight (FIG.2F) and a non-significant decrease in change in total body weight (FIG.2D).
- prophylactic treatment of high-fat-fed mice with S1QEL1.719 had no effect on food intake or body weight, but attenuated the increase in fat mass.
- FIG. 3A shows the total area under the curve (AUC) from the raw trace in FIG.3A. There was a significant increase in the AUC in high-fat animals compared to controls.
- FIG.3A Prophylactic treatment of high-fat-fed animals with S1QEL1.719 resulted in a significant improvement in the removal of the glucose bolus (FIG.3A) resulting in a significant 36% decrease in AUC compared to the untreated high-fat animals (FIG.3B). This effect was maintained after two weeks of high-fat feeding (FIG.3C), with a significant 32% decrease in AUC achieved by S1QEL1.719 treatment (FIG.3D).
- FIG.3E plots the AUC of the glucose tolerance test longitudinally, showing a large difference between control and high-fat fed animals and a striking ability of prophylactic treatment with S1QEL1.719 to maintain the AUC close to control values.
- FIG. 4A shows longitudinal fasting blood glucose levels, which were similar between untreated and treated high-fat fed animals.
- FIGS.2A-2F, FIGS.3A-3E, and FIGS.4A-4F show that prophylactic S1QEL1.719 treatment protected mice against metabolic effects when dosed daily from treatment day 1 of a high-fat diet.
- S1QEL1.719 protected when dosed therapeutically i.e.
- mice Male C57BL/6J mice raised on the high-fat diet containing 60% kcal as fat from six weeks of age were purchased at ten weeks of age and maintained on the high-fat diet for a further two weeks before treatment with S1QEL or vehicle. Control mice raised on standard chow were purchased at ten weeks of age and maintained on standard chow for the entirety of the study. At twelve weeks of age, mice on the high-fat diet were therapeutically gavaged daily from treatment day 1 with either HPMC vehicle or 30 mg/kg S1QEL1.719 suspended in HPMC.
- mice treated therapeutically with S1QEL1.719 required less plasma insulin to clear the glucose bolus than did untreated animals (FIG.5G) and had improved glucose tolerance (FIG.5E), suggesting that S1QEL1.719 may act by improving insulin sensitivity.
- the model of acute two-week high-fat feeding of wild-type mice enables rapid testing of compounds for efficacy against aspects of the metabolic syndrome.
- prophylactically dosing a novel bioavailable S1QEL decreases body fat accumulation, improves glucose tolerance, and protects against elevated fasting plasma insulin level in this model.
- S1QEL1.719 treatment is also protective when given therapeutically starting after six weeks of high-fat feeding.
- This high specificity strongly suggests that superoxide/hydrogen peroxide production from site I Q drives high-fat feeding-induced glucose intolerance, insulin resistance, and obesity, and S1QEL1.719 works by suppressing the activity of site IQ.
- reaction mixture was stirred at 85 °C for 96 h.
- the reaction mixture was diluted with dichloromethane (100 mL).
- the brown orange slurry was filtered through celite.
- the filtrate was concentrated under reduced pressure.
- the residue was purified by flash column (eluted with 0-40% petroleum ether/ethyl acetate) to give tert-butyl (R)-(2-(4-methyl- 2-(2-(trifluoromethyl)morpholino)thiazol-5-yl)ethyl)carbamate (8) (11 g, 14.74 mmol, 44.8% yield) as a light-yellow solid.
Abstract
Described herein, inter alia, are suppressors of site IQ electron leak (SIQELs) and uses thereof.
Description
SUPPRESSORS OF SITE IQ ELECTRON LEAK AND USES THEREOF CROSS-REFERENCES TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application No.63/413,479, filed October 5, 2022, which is incorporated herein by reference in its entirety and for all purposes. STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT [0002] This invention was made with government support under grant nos. R01 AG033542, GM084432, R01 GM100196, and R01 HL127891 awarded by The National Institutes of Health. The government has certain rights in the invention. BACKGROUND [0003] The prevalence of metabolic syndrome is a global problem (1,2). Metabolic syndrome is a collection of symptoms that can include high blood pressure, weight gain, high blood glucose concentration, and an increase in blood cholesterol and triglyceride levels. Collectively or in combination, these symptoms are linked to the incidence of diabetes, heart disease, and stroke (3). This linkage is particularly important given that cardiovascular diseases are the leading cause of mortality globally (4), and account for one in every four deaths in the U.S.A. (5). Over-consumption of high-calorie food and drink, and a sedentary way of life compounded with an aging population exacerbate the problem (2,6,7). Although diet and exercise have been shown to prevent and reverse symptoms of metabolic syndrome, lifestyle changes are difficult to implement, and pharmaceutical intervention would be helpful. Disclosed herein, inter alia, are solutions to these and other problems in the art. BRIEF SUMMARY [0004] In an aspect is provided a compound, or a pharmaceutically acceptable salt thereof, having the formula:
[0005]
[0006] The symbol n is an integer from 0 to 2. [0007] R1 is independently halogen, -CX1 3, -CHX1 2, -CH2X1, -OCX1 3, -OCH2X1, -OCHX12, -CN, -SOn1R1D, -SOv1NR1AR1B, ^NR1CNR1AR1B, ^ONR1AR1B, -NR1CC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)OR1C, -OC(O)R1C, -OC(O)OR1C, -C(O)NR1AR1B, -OC(O)NR1AR1B, -OR1D, -SR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0008] R1A, R1B, R1C, and R1D are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. [0009] Each X1 is independently –Cl, -Br, -I, or –F. The symbol n1 is an integer from 0 to 4. The synmbols m1 and v1 are independently 1 or 2. [0010] The symbol z1 is an integer from 0 to 5. [0011] X is O or NR2. [0012] R2 is hydrogen or unsubstituted C1-C6 alkyl. [0013] R3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or a prodrug moiety.
[0014] R2 and R3 substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl. [0015] R4 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or a prodrug moiety. [0016] R5 and R6 are independently hydrogen, -OH, unsubstituted C1-C6 alkyl, or unsubstituted 2 to 6 membered heteroalkyl. [0017] R5 and R7 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl; or R6 and R7 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl. [0018] R7 and R8 are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0019] R9 is independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0020] The symbol z9 is an integer from 0 to 2. [0021] In embodiments, the compound is not:
,
. [0022] In an aspect is provided a pharmaceutical composition including a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
[0023] In an aspect is provided a method of treating or preventing an age-related disorder in a subject, the method including administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. BRIEF DESCRIPTION OF THE DRAWINGS [0024] FIGS.1A-1C. Structure of S1QEL1.719 and potency in vitro. FIG.1A: Chemical structure. FIG.1B: Suppression of superoxide/hydrogen peroxide production from site IQ in mitochondria isolated from rat skeletal muscle based on S1QEL1.719 concentration in the supernatant (measured by mass spectrometry) after correction for binding to BSA (fraction unbound, fu = 0.856, determined by equilibrium dialysis). The fully corrected unbound IC50 value was 52 ± 17 nM (mean ^ SEM of n = 6 independent biological replicates). FIG.1C: Suppression of superoxide/hydrogen peroxide production from site IQ by S1QEL1.719 and inhibition of state 3 respiration on glutamate plus malate under exactly matched conditions. S1QEL1.719 concentrations in panel C are nominal values and uncorrected for binding to BSA. The nominal IC50 for suppression of site IQ was 67 ± 10 nM; the nominal IC50 for inhibition of respiration was 30 ± 5 µM (censoring the high point at 1 µM S1QEL1.719 made little difference to this estimate). Data are means ^ SEM (n = 6 independent biological replicates). Values of IC50 (concentrations causing 50% inhibition or suppression) in FIGS. 1B-1C were determined by curve-fitting using Prism 7 ([Inhibitor] vs. normalized response- Variable slope). Most of the error bars in FIGS.1B-1C are smaller than the points they are associated with. [0025] FIGS.2A-2F. Effect of two weeks on a high fat diet with and without prophylactic S1QEL1.719 treatment on chow consumption, body weight, and body composition of mice. Mice were placed for two weeks on a low-fat diet (control, ctrl) or a high-fat diet (HF) and prophylactically gavaged daily from treatment day 1 with vehicle or S1QEL1.719 (HF+719, 30 mg/kg per day, p.o.). FIG.2A: Timeline. Diets and S1QEL treatment were introduced at age 15 weeks and continued for two weeks. FIG.2B: Food consumption during the two weeks was measured crudely by weighing chow. FIG.2C: Body weight was measured on treatment days 1, 8 and 15. FIG.2D: The change in body weight for individual animals was calculated as the difference in weight between day 15 and day 1. FIG.2E: Change in fat mass was measured by EchoMRI and is shown as the difference between day 15 and day 1. FIG.2F: Lean mass was measured on day 14 using EchoMRI. Dotted lines on graphs represent the mean values for animals fed low-fat chow and high-fat chow. For FIG.2B, data
are means ± SEM of n = 8 cages. For FIGS.2C-2D, data are means ± SEM of n = 28 animals. For FIGS.2E-2F, data are means ± SEM of n = 16 animals. **P<0.01, ****P<0.0001 by one-way ANOVA with Dunnett's multiple comparisons test. ns = not significant. [0026] FIGS.3A-3E. Prophylactic treatment with S1QEL1.719 improves glucose tolerance. Mice were placed for two weeks on a low-fat diet (control, ctrl) or a high-fat diet (HF) and prophylactically gavaged daily from treatment day 1 with vehicle or S1QEL1.719 (HF+719, 30 mg/kg per day, p.o.) (FIG.2A). On treatment days 8 (FIGS.3A-3B) and 15 (FIGS.3C-3D), a glucose tolerance test was conducted by intraperitoneal injection of a 2 g/kg bolus of glucose. FIG.3A, FIG.3C: Concentration of blood glucose, monitored over time. FIG.3B, FIG.3D: Area under the curve (AUC), calculated from the raw traces in FIG. 3A and FIG.3C for each individual mouse. FIG.3E: AUCs from (B) and (D) plotted longitudinally. Dotted lines represent the mean values for control and high-fat chow fed animals. Data are means ± SEM of n = 28 animals per group. **P<0.002, ****P<0.0001 by one-way ANOVA with Dunnett's multiple comparisons test. [0027] FIGS.4A-4F. Prophylactic treatment with S1QEL1.719 does not affect fasting glucose level but protects against elevated fasting insulin level. Mice were placed for two weeks on a low-fat diet (control, ctrl) or a high-fat diet (HF) and prophylactically gavaged daily from treatment day 1 with vehicle or S1QEL1.719 (HF+719, 30 mg/kg per day, p.o.) (FIG.2A). On treatment days 8 (FIG.4A, FIG.4D) and 15 (FIG.4B, FIG.4E), blood glucose and plasma insulin levels were measured following 7-10 h of food withdrawal. FIG. 4C: Fasting glucose from (FIG.4A) and (FIG.4B) plotted longitudinally. FIG.4F: Fasting insulin from (FIG.4D) and (FIG.4E) plotted longitudinally. Data are means ± SEM of n = 28 animals per group. *P<0.03, **P<0.007, ***P<0.0002 by one-way ANOVA with Dunnett's multiple comparisons test. ns = not significant. [0028] FIGS.5A-5G. Therapeutic dosing of S1QEL1.719 starting after six weeks on high- fat diet improves glucose tolerance and decreases plasma insulin concentration. Control twelve-week old mice were maintained on standard chow for the entirety of experiment. Six- week high-fat-fed twelve-week old mice were maintained on a high-fat diet (HF) and therapeutically gavaged daily from treatment day 1 with vehicle or S1QEL1.719 (HF+719, 30 mg/kg per day, p.o.). FIG.5A: Timeline. FIG.5B: Food consumption from treatment day 1- 15 was measured crudely by weighing chow. FIG.5C: The change in body weight for
individual animals was calculated as the difference in weight between day 15 and day 1. FIG.5D: Change in fat mass was measured by EchoMRI and is shown as the difference in fat mass between day 14 and day 1. FIG.5E: On treatment day 15 a glucose tolerance test was conducted by intraperitoneal injection of a 2 g/kg bolus of glucose and plasma glucose concentration was measured over 120 min. FIG.5F: On treatment day 15 fasting plasma insulin levels were measured following 7-10 h of food withdrawal. FIG.5G: Plasma insulin levels were measured following intraperitoneal injection of a 2 g/kg bolus of glucose when conducting the glucose tolerance test. For FIG.5B, data are means ± SEM of n = 6 cages. For FIGS.5C-5G, data are means ± SEM of n = 12 animals. **P<0.01, ***P<0.0001 by one- way ANOVA with Dunnett's multiple comparisons test. ns = not significant. DETAILED DESCRIPTION I. Definitions [0029] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts. [0030] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-. [0031] The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include mono-, di-, and multivalent radicals. The alkyl may include a designated number of carbons (e.g., C1-C10 means one to ten carbons). In embodiments, the alkyl is fully saturated. In embodiments, the alkyl is monounsaturated. In embodiments, the alkyl is polyunsaturated. Alkyl is an uncyclized chain. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, methyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2- isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. An alkoxy is an alkyl attached to the
remainder of the molecule via an oxygen linker (-O-). An alkyl moiety may be an alkenyl moiety. An alkyl moiety may be an alkynyl moiety. An alkenyl includes one or more double bonds. An alkynyl includes one or more triple bonds. [0032] The term “alkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred herein. A “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms. The term “alkenylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene. The term “alkynylene” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyne. In embodiments, the alkylene is fully saturated. In embodiments, the alkylene is monounsaturated. In embodiments, the alkylene is polyunsaturated. An alkenylene includes one or more double bonds. An alkynylene includes one or more triple bonds. [0033] The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) (e.g., N, S, Si, or P) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Heteroalkyl is an uncyclized chain. Examples include, but are not limited to: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -S-CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. A heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety
may include up to 8 optionally different heteroatoms (e.g., O, N, S, Si, or P). The term “heteroalkenyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one double bond. A heteroalkenyl may optionally include more than one double bond and/or one or more triple bonds in additional to the one or more double bonds. The term “heteroalkynyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one triple bond. A heteroalkynyl may optionally include more than one triple bond and/or one or more double bonds in additional to the one or more triple bonds. In embodiments, the heteroalkyl is fully saturated. In embodiments, the heteroalkyl is monounsaturated. In embodiments, the heteroalkyl is polyunsaturated. [0034] Similarly, the term “heteroalkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)2R'- represents both -C(O)2R'- and -R'C(O)2-. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', -NR'R'', -OR', -SR', and/or -SO2R'. Where “heteroalkyl” is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R'' or the like, it will be understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R'' or the like. The term “heteroalkenylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from a heteroalkene. The term “heteroalkynylene” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from a heteroalkyne. In embodiments, the heteroalkylene is fully saturated. In embodiments, the heteroalkylene is monounsaturated. In embodiments, the heteroalkylene is polyunsaturated. A heteroalkenylene includes one or more double bonds. A heteroalkynylene includes one or more triple bonds.
[0035] The terms cycloalkyl and heterocycloalkyl, by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl,” respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1- (1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3- morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. A “cycloalkylene” and a “heterocycloalkylene,” alone or as part of another substituent, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively. In embodiments, the cycloalkyl is fully saturated. In embodiments, the cycloalkyl is monounsaturated. In embodiments, the cycloalkyl is polyunsaturated. In embodiments, the heterocycloalkyl is fully saturated. In embodiments, the heterocycloalkyl is monounsaturated. In embodiments, the heterocycloalkyl is polyunsaturated. [0036] In embodiments, the term “cycloalkyl” means a monocyclic, bicyclic, or a multicyclic cycloalkyl ring system. In embodiments, monocyclic ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups can be saturated or unsaturated, but not aromatic. In embodiments, cycloalkyl groups are fully saturated. A bicyclic or multicyclic cycloalkyl ring system refers to multiple rings fused together wherein at least one of the fused rings is a cycloalkyl ring and wherein the multiple rings are attached to the parent molecular moiety through any carbon atom contained within a cycloalkyl ring of the multiple rings. [0037] In embodiments, a cycloalkyl is a cycloalkenyl. The term “cycloalkenyl” is used in accordance with its plain ordinary meaning. In embodiments, a cycloalkenyl is a monocyclic, bicyclic, or a multicyclic cycloalkenyl ring system. A bicyclic or multicyclic cycloalkenyl ring system refers to multiple rings fused together wherein at least one of the fused rings is a cycloalkenyl ring and wherein the multiple rings are attached to the parent molecular moiety through any carbon atom contained within a cycloalkenyl ring of the multiple rings. [0038] In embodiments, the term “heterocycloalkyl” means a monocyclic, bicyclic, or a multicyclic heterocycloalkyl ring system. In embodiments, heterocycloalkyl groups are fully
saturated. A bicyclic or multicyclic heterocycloalkyl ring system refers to multiple rings fused together wherein at least one of the fused rings is a heterocycloalkyl ring and wherein the multiple rings are attached to the parent molecular moiety through any atom contained within a heterocycloalkyl ring of the multiple rings. [0039] The terms “halo” or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “halo(C1-C4)alkyl” includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. [0040] The term “acyl” means, unless otherwise stated, -C(O)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0041] The term “aryl” means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently. A fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring and wherein the multiple rings are attached to the parent molecular moiety through any carbon atom contained within an aryl ring of the multiple rings. The term “heteroaryl” refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. Thus, the term “heteroaryl” includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring and wherein the multiple rings are attached to the parent molecular moiety through any atom contained within a heteroaromatic ring of the multiple rings). A 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Likewise, a 6,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring. A heteroaryl
group can be attached to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazoyl benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2- pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4- oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2- thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. An “arylene” and a “heteroarylene,” alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. A heteroaryl group substituent may be -O- bonded to a ring heteroatom nitrogen. [0042] Spirocyclic rings are two or more rings wherein adjacent rings are attached through a single atom. The individual rings within spirocyclic rings may be identical or different. Individual rings in spirocyclic rings may be substituted or unsubstituted and may have different substituents from other individual rings within a set of spirocyclic rings. Possible substituents for individual rings within spirocyclic rings are the possible substituents for the same ring when not part of spirocyclic rings (e.g., substituents for cycloalkyl or heterocycloalkyl rings). Spirocylic rings may be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterocycloalkylene and individual rings within a spirocyclic ring group may be any of the immediately previous list, including having all rings of one type (e.g., all rings being substituted heterocycloalkylene wherein each ring may be the same or different substituted heterocycloalkylene). When referring to a spirocyclic ring system, heterocyclic spirocyclic rings means a spirocyclic rings wherein at least one ring is a heterocyclic ring and wherein each ring may be a different ring. When referring to a spirocyclic ring system, substituted spirocyclic rings means that at least one ring is substituted and each substituent may optionally be different.
[0043] The symbol denotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula. [0044] The term “oxo,” as used herein, means an oxygen that is double bonded to a carbon atom. [0045] The term “alkylarylene” as an arylene moiety covalently bonded to an alkylene moiety (also referred to herein as an alkylene linker). In embodiments, the alkylarylene group has the formula:
. [0046] An alkylarylene moiety may be substituted (e.g., with a substituent group) on the alkylene moiety or the arylene linker (e.g., at carbons 2, 3, 4, or 6) with halogen, oxo, -N3, -CF3, -CCl3, -CBr3, -CI3, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2CH3, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, substituted or unsubstituted C1-C5 alkyl or substituted or unsubstituted 2 to 5 membered heteroalkyl). In embodiments, the alkylarylene is unsubstituted. [0047] Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “cycloalkyl,” “heterocycloalkyl,” “aryl,” and “heteroaryl”) includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below. [0048] Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to, -OR', =O, =NR', =N-OR', -NR'R'', -SR', halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'C(O)NR''R''', -NR''C(O)2R', -NRC(NR'R''R''')=NR'''', -NRC(NR'R'')=NR''', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NRSO2R', -NR'NR''R''', -ONR'R'', -NR'C(O)NR''NR'''R'''', -CN, -NO2, -NR'SO2R'', -NR'C(O)R'', -NR'C(O)OR'', -NR'OR'', in a number ranging from zero to (2m'+1), where m' is the total number of carbon atoms in such radical. R, R', R'', R''', and R'''' each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,
substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R', R'', R''', and R'''' group when more than one of these groups is present. When R' and R'' are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7- membered ring. For example, -NR'R'' includes, but is not limited to, 1-pyrrolidinyl and 4- morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term “alkyl” is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3 and -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like). [0049] Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are varied and are selected from, for example: -OR', -NR'R'', -SR', halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'C(O)NR''R''', -NR''C(O)2R', -NR-C(NR'R''R''')=NR'''', -NR-C(NR'R'')=NR''', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NRSO2R', -NR'NR''R''', -ONR'R'', -NR'C(O)NR''NR'''R'''', -CN, -NO2, -R', -N3, -CH(Ph)2, fluoro(C1-C4)alkoxy, and fluoro(C1-C4)alkyl, -NR'SO2R'', -NR'C(O)R'', -NR'C(O)OR'', -NR'OR'', in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R', R'', R''', and R'''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R', R'', R''', and R'''' groups when more than one of these groups is present. [0050] Substituents for rings (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) may be depicted as substituents on the ring rather than on a specific atom of a ring (commonly referred to as a floating substituent). In such a case, the substituent may be attached to any of the ring atoms (obeying the rules of chemical valency) and in the case of fused rings or spirocyclic rings, a substituent depicted as associated with one member of the fused rings or spirocyclic rings (a floating substituent on a single ring), may be a substituent on any of the fused rings or
spirocyclic rings (a floating substituent on multiple rings). When a substituent is attached to a ring, but not a specific atom (a floating substituent), and a subscript for the substituent is an integer greater than one, the multiple substituents may be on the same atom, same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent may optionally be different. Where a point of attachment of a ring to the remainder of a molecule is not limited to a single atom (a floating substituent), the attachment point may be any atom of the ring and in the case of a fused ring or spirocyclic ring, any atom of any of the fused rings or spirocyclic rings while obeying the rules of chemical valency. Where a ring, fused rings, or spirocyclic rings contain one or more ring heteroatoms and the ring, fused rings, or spirocyclic rings are shown with one more floating substituents (including, but not limited to, points of attachment to the remainder of the molecule), the floating substituents may be bonded to the heteroatoms. Where the ring heteroatoms are shown bound to one or more hydrogens (e.g., a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen) in the structure or formula with the floating substituent, when the heteroatom is bonded to the floating substituent, the substituent will be understood to replace the hydrogen, while obeying the rules of chemical valency. [0051] Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring- forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure. [0052] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)-(CRR')q-U-, wherein T and U are independently -NR-, -O-, -CRR'-, or a single bond, and q is an integer of from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2)r-B-, wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'-, or a single bond, and r is
an integer of from 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR')s-X'- (C''R''R''')d-, where s and d are independently integers of from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituents R, R', R'', and R''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. [0053] As used herein, the terms “heteroatom” or “ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), selenium (Se), and silicon (Si). In embodiments, the terms “heteroatom” or “ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si). [0054] A “substituent group,” as used herein, means a group selected from the following moieties: (A) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, –OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and (B) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6
membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from: (i) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, –OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6- C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and (ii) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C6- C10 aryl, C10 aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from: (a) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, –OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8
membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and (b) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C6- C10 aryl, C10 aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from: oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, –OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0055] A “size-limited substituent” or “ size-limited substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20
membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl. [0056] A “lower substituent” or “ lower substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3- C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted phenyl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 6 membered heteroaryl. [0057] In some embodiments, each substituted group described in the compounds herein is substituted with at least one substituent group. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene described in the compounds herein are substituted with at least one substituent group. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent group. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent group. [0058] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl may be a substituted or unsubstituted C1-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6- C10 aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C20 alkylene, each substituted or
unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C10 arylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene. [0059] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10 aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl. In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C8 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C10 arylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene. In some embodiments, the compound is a chemical species set forth in the Examples section, figures, or tables below. [0060] In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and/or substituted or unsubstituted heteroarylene) is unsubstituted (e.g., is an unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkylene, unsubstituted heteroalkylene, unsubstituted
cycloalkylene, unsubstituted heterocycloalkylene, unsubstituted arylene, and/or unsubstituted heteroarylene, respectively). In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and/or substituted or unsubstituted heteroarylene) is substituted (e.g., is a substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene, respectively). [0061] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one substituent group, wherein if the substituted moiety is substituted with a plurality of substituent groups, each substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of substituent groups, each substituent group is different. [0062] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one size-limited substituent group, wherein if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group is different. [0063] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene,
substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one lower substituent group, wherein if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group is different. [0064] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group is different. [0065] In a recited claim or chemical formula description herein, each R substituent or L linker that is described as being “substituted” without reference as to the identity of any chemical moiety that composes the “substituted” group (also referred to herein as an “open substitution” on an R substituent or L linker or an “openly substituted” R substituent or L linker), the recited R substituent or L linker may, in embodiments, be substituted with one or more first substituent groups as defined below. [0066] The first substituent group is denoted with a corresponding first decimal point numbering system such that, for example, R1 may be substituted with one or more first substituent groups denoted by R1.1, R2 may be substituted with one or more first substituent groups denoted by R2.1, R3 may be substituted with one or more first substituent groups denoted by R3.1, R4 may be substituted with one or more first substituent groups denoted by R4.1, R5 may be substituted with one or more first substituent groups denoted by R5.1, and the like up to or exceeding an R100 that may be substituted with one or more first substituent groups denoted by R100.1. As a further example, R1A may be substituted with one or more first substituent groups denoted by R1A.1, R2A may be substituted with one or more first
substituent groups denoted by R2A.1, R3A may be substituted with one or more first substituent groups denoted by R3A.1, R4A may be substituted with one or more first substituent groups denoted by R4A.1, R5A may be substituted with one or more first substituent groups denoted by R5A.1 and the like up to or exceeding an R100A may be substituted with one or more first substituent groups denoted by R100A.1. As a further example, L1 may be substituted with one or more first substituent groups denoted by RL1.1, L2 may be substituted with one or more first substituent groups denoted by RL2.1, L3 may be substituted with one or more first substituent groups denoted by RL3.1, L4 may be substituted with one or more first substituent groups denoted by RL4.1, L5 may be substituted with one or more first substituent groups denoted by RL5.1 and the like up to or exceeding an L100 which may be substituted with one or more first substituent groups denoted by RL100.1. Thus, each numbered R group or L group (alternatively referred to herein as RWW or LWW wherein “WW” represents the stated superscript number of the subject R group or L group) described herein may be substituted with one or more first substituent groups referred to herein generally as RWW.1 or RLWW.1, respectively. In turn, each first substituent group (e.g., R1.1, R2.1, R3.1, R4.1, R5.1 … R100.1; R1A.1, R2A.1, R3A.1, R4A.1, R5A.1 … R100A.1; RL1.1, RL2.1, RL3.1, RL4.1, RL5.1 … RL100.1) may be further substituted with one or more second substituent groups (e.g., R1.2, R2.2, R3.2, R4.2, R5.2… R100.2; R1A.2, R2A.2, R3A.2, R4A.2, R5A.2 … R100A.2; RL1.2, RL2.2, RL3.2, RL4.2, RL5.2 … RL100.2, respectively). Thus, each first substituent group, which may alternatively be represented herein as RWW.1 as described above, may be further substituted with one or more second substituent groups, which may alternatively be represented herein as RWW.2. [0067] Finally, each second substituent group (e.g., R1.2, R2.2, R3.2, R4.2, R5.2 … R100.2; R1A.2, R2A.2, R3A.2, R4A.2, R5A.2 … R100A.2; RL1.2, RL2.2, RL3.2, RL4.2, RL5.2 … RL100.2) may be further substituted with one or more third substituent groups (e.g., R1.3, R2.3, R3.3, R4.3, R5.3 … R100.3; R1A.3, R2A.3, R3A.3, R4A.3, R5A.3 … R100A.3; RL1.3, RL2.3, RL3.3, RL4.3, RL5.3 … RL100.3; respectively). Thus, each second substituent group, which may alternatively be represented herein as RWW.2 as described above, may be further substituted with one or more third substituent groups, which may alternatively be represented herein as RWW.3. Each of the first substituent groups may be optionally different. Each of the second substituent groups may be optionally different. Each of the third substituent groups may be optionally different. [0068] Thus, as used herein, RWW represents a substituent recited in a claim or chemical formula description herein which is openly substituted. “WW” represents the stated
superscript number of the subject R group (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). Likewise, LWW is a linker recited in a claim or chemical formula description herein which is openly substituted. Again, “WW” represents the stated superscript number of the subject L group (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). As stated above, in embodiments, each RWW may be unsubstituted or independently substituted with one or more first substituent groups, referred to herein as RWW.1; each first substituent group, RWW.1, may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as RWW.2; and each second substituent group may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as RWW.3. Similarly, each LWW linker may be unsubstituted or independently substituted with one or more first substituent groups, referred to herein as RLWW.1; each first substituent group, RLWW.1, may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as RLWW.2; and each second substituent group may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as RLWW.3. Each first substituent group is optionally different. Each second substituent group is optionally different. Each third substituent group is optionally different. For example, if RWW is phenyl, the said phenyl group is optionally substituted by one or more RWW.1 groups as defined herein below, e.g., when RWW.1 is RWW.2-substituted or unsubstituted alkyl, examples of groups so formed include but are not limited to itself optionally substituted by 1 or more RWW.2, which RWW.2 is optionally substituted by one or more RWW.3. By way of example when the RWW group is phenyl substituted by RWW.1, which is methyl, the methyl group may be further substituted to form groups including but not limited to:
. [0069] RWW.1 is independently oxo, halogen, -CXWW.1 3, -CHXWW.1 2, -CH2XWW.1, -OCXWW.13, -OCH2XWW.1, -OCHXWW.12, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, RWW.2-substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), RWW.2-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), RWW.2-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), RWW.2-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), RWW.2-substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or RWW.2-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, RWW.1 is independently oxo, halogen, -CXWW.1 3,
, -CH2XWW.1, -OCXWW.13, -OCH2XWW.1, -OCHXWW.12, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl
(e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XWW.1 is independently –F, -Cl, -Br, or –I. [0070] RWW.2 is independently oxo, halogen, -CXWW.2 3, -CHXWW.2 2, -CH2XWW.2, -OCXWW.23, -OCH2XWW.2, -OCHXWW.22, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, RWW.3-substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), RWW.3-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), RWW.3-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), RWW.3-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), RWW.3-substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or RWW.3-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, RWW.2 is independently oxo, halogen, -CXWW.2 3, -CHXWW.2 2, -CH2XWW.2, -OCXWW.2 3, -OCH2XWW.2, -OCHXWW.2 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XWW.2 is independently –F, -Cl, -Br, or –I. [0071] RWW.3 is independently oxo, halogen, -CXWW.33, -CHXWW.32, -CH2XWW.3, -OCXWW.3 3, -OCH2XWW.3, -OCHXWW.3 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),
unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XWW.3 is independently –F, -Cl, -Br, or –I. [0072] Where two different RWW substituents are joined together to form an openly substituted ring (e.g., substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl or substituted heteroaryl), in embodiments the openly substituted ring may be independently substituted with one or more first substituent groups, referred to herein as RWW.1; each first substituent group, RWW.1, may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as RWW.2; and each second substituent group, RWW.2, may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as RWW.3; and each third substituent group, RWW.3, is unsubstituted. Each first substituent group is optionally different. Each second substituent group is optionally different. Each third substituent group is optionally different. In the context of two different RWW substituents joined together to form an openly substituted ring, the “WW” symbol in the RWW.1, RWW.2 and RWW.3 refers to the designated number of one of the two different RWW substituents. For example, in embodiments where R100A and R100B are optionally joined together to form an openly substituted ring, RWW.1 is R100A.1, RWW.2 is
R100A.2, and RWW.3 is R100A.3. Alternatively, in embodiments where R100A and R100B are optionally joined together to form an openly substituted ring, RWW.1 is R100B.1, RWW.2 is
paragraph are as defined in the preceding paragraphs. [0073] RLWW.1 is independently oxo, halogen, -CXLWW.13, -CHXLWW.12, -CH2XLWW.1, -OCXLWW.1 3, -OCH2XLWW.1, -OCHXLWW.1 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, RLWW.2-substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), RLWW.2-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), RLWW.2-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), RLWW.2-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), RLWW.2-substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or RLWW.2-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6
membered). In embodiments, RLWW.1 is independently oxo, halogen, -CXLWW.13, -CHXLWW.12, -CH2XLWW.1, -OCXLWW.13, -OCH2XLWW.1, -OCHXLWW.12, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XLWW.1 is independently –F, -Cl, -Br, or –I. [0074] RLWW.2 is independently oxo, halogen, -CXLWW.2 3, -CHXLWW.2 2, -CH2XLWW.2, -OCXLWW.23, -OCH2XLWW.2, -OCHXLWW.22, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, RLWW.3-substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), RLWW.3-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), RWW.3-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), RLWW.3-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), RLWW.3-substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or RLWW.3-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, RLWW.2 is independently oxo, halogen, -CXLWW.2 3, -CHXLWW.2 2, -CH2XLWW.2, -OCXLWW.2 3, -OCH2XLWW.2, -OCHXLWW.2 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XLWW.2 is independently –F, -Cl, -Br, or –I.
[0075] RLWW.3 is independently oxo, halogen, -CXLWW.33, -CHXLWW.32, -CH2XLWW.3, -OCXLWW.33, -OCH2XLWW.3, -OCHXLWW.32, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XLWW.3 is independently –F, -Cl, -Br, or –I. [0076] In the event that any R group recited in a claim or chemical formula description set forth herein (RWW substituent) is not specifically defined in this disclosure, then that R group (RWW group) is hereby defined as independently oxo, halogen, -CXWW 3, -CHXWW 2, -CH2XWW, -OCXWW 3, -OCH2XWW, -OCHXWW 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, RWW.1-substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), RWW.1-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), RWW.1-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), RWW.1-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), RWW.1-substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or RWW.1-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XWW is independently –F, -Cl, -Br, or –I. Again, “WW” represents the stated superscript number of the subject R group (e.g., 1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). RWW.1, RWW.2, and RWW.3 are as defined above. [0077] In the event that any L linker group recited in a claim or chemical formula description set forth herein (i.e., an LWW substituent) is not explicitly defined, then that L group (LWW group) is herein defined as independently a bond, –O-, -NH-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, –NHC(NH)NH-, -C(O)O-, -OC(O)-, -S-, -SO2-, -SO2NH-, RLWW.1- substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), RLWW.1-substituted
or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), RLWW.1-substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), RLWW.1-substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), RLWW.1-substituted or unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl), or RLWW.1- substituted or unsubstituted heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). Again, “WW” represents the stated superscript number of the subject L group (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). RLWW.1, as well as RLWW.2 and RLWW.3 are as defined above. [0078] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include those that are known in art to be too unstable to synthesize and/or isolate. The present disclosure is meant to include compounds in racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. [0079] As used herein, the term “isomers” refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms. [0080] The term “tautomer,” as used herein, refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another. [0081] It will be apparent to one skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure.
[0082] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure. [0083] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13C- or 14C-enriched carbon are within the scope of this disclosure. [0084] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I), or carbon-14 (14C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. [0085] It should be noted that throughout the application that alternatives are written in Markush groups, for example, each amino acid position that contains more than one possible amino acid. It is specifically contemplated that each member of the Markush group should be considered separately, thereby comprising another embodiment, and the Markush group is not to be read as a single unit. [0086] As used herein, the terms “bioconjugate” and “bioconjugate linker” refer to the resulting association between atoms or molecules of bioconjugate reactive groups or bioconjugate reactive moieties. The association can be direct or indirect. For example, a conjugate between a first bioconjugate reactive group (e.g., –NH2, –COOH, –N- hydroxysuccinimide, or –maleimide) and a second bioconjugate reactive group (e.g., sulfhydryl, sulfur-containing amino acid, amine, amine sidechain containing amino acid, or carboxylate) provided herein can be direct, e.g., by covalent bond or linker (e.g., a first linker of second linker), or indirect, e.g., by non-covalent bond (e.g., electrostatic interactions (e.g., ionic bond, hydrogen bond, halogen bond), van der Waals interactions (e.g., dipole-dipole, dipole-induced dipole, London dispersion), ring stacking (pi effects), hydrophobic interactions and the like). In embodiments, bioconjugates or bioconjugate linkers are formed using bioconjugate chemistry (i.e., the association of two bioconjugate reactive groups)
including, but are not limited to nucleophilic substitutions (e.g., reactions of amines and alcohols with acyl halides, active esters), electrophilic substitutions (e.g., enamine reactions) and additions to carbon-carbon and carbon-heteroatom multiple bonds (e.g., Michael reaction, Diels-Alder addition). These and other useful reactions are discussed in, for example, March, ADVANCED ORGANIC CHEMISTRY, 3rd Ed., John Wiley & Sons, New York, 1985; Hermanson, BIOCONJUGATE TECHNIQUES, Academic Press, San Diego, 1996; and Feeney et al., MODIFICATION OF PROTEINS; Advances in Chemistry Series, Vol.198, American Chemical Society, Washington, D.C., 1982. In embodiments, the first bioconjugate reactive group (e.g., maleimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., haloacetyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., pyridyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., –N- hydroxysuccinimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., an amine). In embodiments, the first bioconjugate reactive group (e.g., maleimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., –sulfo–N-hydroxysuccinimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., an amine). [0087] Useful bioconjugate reactive moieties used for bioconjugate chemistries herein include, for example: (a) carboxyl groups and various derivatives thereof including, but not limited to, N-hydroxysuccinimide esters, N-hydroxybenztriazole esters, acid halides, acyl imidazoles, thioesters, p-nitrophenyl esters, alkyl, alkenyl, alkynyl and aromatic esters; (b) hydroxyl groups which can be converted to esters, ethers, aldehydes, etc.; (c) haloalkyl groups wherein the halide can be later displaced with a nucleophilic group such as, for example, an amine, a carboxylate anion, thiol anion, carbanion, or an alkoxide ion, thereby resulting in the covalent attachment of a new group at the site of the halogen atom; (d) dienophile groups which are capable of participating in Diels-Alder reactions such as, for example, maleimido or maleimide groups; (e) aldehyde or ketone groups such that subsequent derivatization is possible via formation of carbonyl derivatives such as, for example, imines, hydrazones, semicarbazones or oximes, or via such mechanisms as Grignard addition or alkyllithium addition; (f) sulfonyl halide groups for subsequent reaction with amines, for example, to form sulfonamides; (g) thiol groups, which can be converted to
disulfides, reacted with acyl halides, or bonded to metals such as gold, or react with maleimides; (h) amine or sulfhydryl groups (e.g., present in cysteine), which can be, for example, acylated, alkylated or oxidized; (i) alkenes, which can undergo, for example, cycloadditions, acylation, Michael addition, etc.; (j) epoxides, which can react with, for example, amines and hydroxyl compounds; (k) phosphoramidites and other standard functional groups useful in nucleic acid synthesis; (l) metal silicon oxide bonding; (m) metal bonding to reactive phosphorus groups (e.g., phosphines) to form, for example, phosphate diester bonds; (n) azides coupled to alkynes using copper catalyzed cycloaddition click chemistry; and (o) biotin conjugate can react with avidin or streptavidin to form an avidin- biotin complex or streptavidin-biotin complex. [0088] The bioconjugate reactive groups can be chosen such that they do not participate in, or interfere with, the chemical stability of the conjugate described herein. Alternatively, a reactive functional group can be protected from participating in the crosslinking reaction by the presence of a protecting group. In embodiments, the bioconjugate comprises a molecular entity derived from the reaction of an unsaturated bond, such as a maleimide, and a sulfhydryl group. [0089] “Analog,” “analogue,” or “derivative” is used in accordance with its plain ordinary meaning within Chemistry and Biology and refers to a chemical compound that is structurally similar to another compound (i.e., a so-called “reference” compound) but differs in composition, e.g., in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or the replacement of one functional group by another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Accordingly, an analog is a compound that is similar or comparable in function and appearance but not in structure or origin to a reference compound. [0090] The terms “a” or “an”, as used in herein means one or more. In addition, the phrase “substituted with a[n]”, as used herein, means the specified group may be substituted with one or more of any or all of the named substituents. For example, where a group, such as an alkyl or heteroaryl group, is “substituted with an unsubstituted C1-C20 alkyl, or unsubstituted 2 to 20 membered heteroalkyl”, the group may contain one or more unsubstituted C1-C20 alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls. [0091] Moreover, where a moiety is substituted with an R substituent, the group may be referred to as “R-substituted.” Where a moiety is R-substituted, the moiety is substituted
with at least one R substituent and each R substituent is optionally different. Where a particular R group is present in the description of a chemical genus (such as Formula (I)), a Roman alphabetic symbol may be used to distinguish each appearance of that particular R group. For example, where multiple R13 substituents are present, each R13 substituent may be distinguished as R13.A, R13.B, R13.C, R13.D, etc., wherein each of R13.A, R13.B, R13.C, R13.D, etc. is defined within the scope of the definition of R13 and optionally differently. Where an R moiety, group, or substituent as disclosed herein is attached through the representation of a single bond and the R moiety, group, or substituent is oxo, a person having ordinary skill in the art will immediately recognize that the oxo is attached through a double bond in accordance with the normal rules of chemical valency. [0092] Descriptions of compounds of the present disclosure are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and/or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, and several known physiological conditions. For example, a heterocycloalkyl or heteroaryl is attached to the remainder of the molecule via a ring heteroatom in compliance with principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable compounds. [0093] The term “pharmaceutically acceptable salts” is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric,
sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p- tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. [0094] Thus, the compounds of the present disclosure may exist as salts, such as with pharmaceutically acceptable acids. The present disclosure includes such salts. Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, proprionates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid, and quaternary ammonium salts (e.g., methyl iodide, ethyl iodide, and the like). These salts may be prepared by methods known to those skilled in the art. [0095] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents. [0096] In addition to salt forms, the present disclosure provides compounds, which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure. Prodrugs of the compounds described herein may be converted in vivo after administration. Additionally, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment, such as, for example, when contacted with a suitable enzyme or chemical reagent. [0097] Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms.
In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure. [0098] A polypeptide, or a cell is “recombinant” when it is artificial or engineered, or derived from or contains an artificial or engineered protein or nucleic acid (e.g., non-natural or not wild type). For example, a polynucleotide that is inserted into a vector or any other heterologous location, e.g., in a genome of a recombinant organism, such that it is not associated with nucleotide sequences that normally flank the polynucleotide as it is found in nature is a recombinant polynucleotide. A protein expressed in vitro or in vivo from a recombinant polynucleotide is an example of a recombinant polypeptide. Likewise, a polynucleotide sequence that does not appear in nature, for example a variant of a naturally occurring gene, is recombinant. [0099] “Co-administer” is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies. The compounds of the invention can be administered alone or can be co-administered to the patient. Co-administration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). Thus, the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation). [0100] A “cell” as used herein, refers to a cell carrying out metabolic or other function sufficient to preserve or replicate its genomic DNA. A cell can be identified by well-known methods in the art including, for example, presence of an intact membrane, staining by a particular dye, ability to produce progeny or, in the case of a gamete, ability to combine with a second gamete to produce a viable offspring. Cells may include prokaryotic and eukaroytic cells. Prokaryotic cells include but are not limited to bacteria. Eukaryotic cells include but are not limited to yeast cells and cells derived from plants and animals, for example mammalian, insect (e.g., spodoptera) and human cells. Cells may be useful when they are naturally nonadherent or have been treated not to adhere to surfaces, for example by trypsinization. [0101] The terms “treating” or “treatment” refers to any indicia of success in the treatment or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of
degeneration or decline; making the final point of degeneration less debilitating; improving a patient’s physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation. For example, the certain methods presented herein successfully treat cancer by decreasing the incidence of cancer and or causing remission of cancer. In some embodiments of the compositions or methods described herein, treating cancer includes slowing the rate of growth or spread of cancer cells, reducing metastasis, or reducing the growth of metastatic tumors. The term “treating” and conjugations thereof, include prevention of an injury, pathology, condition, or disease. In embodiments, treating is preventing. In embodiments, treating does not include preventing. In embodiments, the treating or treatment is no prophylactic treatment. [0102] An “effective amount” is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g., achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce signaling pathway, reduce one or more symptoms of a disease or condition. An example of an “effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a “therapeutically effective amount” when referred to in this context. A “reduction” of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). A “prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms. The full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. An “activity decreasing amount,” as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme relative to the absence of the antagonist. A “function disrupting amount,” as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. An “activity increasing amount,” as used herein, refers to an amount of agonist required to increase the activity of an enzyme relative to the absence of the agonist. A “function increasing amount,” as used herein, refers to the
amount of agonist required to increase the function of an enzyme or protein relative to the absence of the agonist. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols.1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). [0103] “Control” or “control experiment” is used in accordance with its plain ordinary meaning and refers to an experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment except for omission of a procedure, reagent, or variable of the experiment. In some instances, the control is used as a standard of comparison in evaluating experimental effects. In some embodiments, a control is the measurement of the activity (e.g., signaling pathway) of a protein in the absence of a compound as described herein (including embodiments, examples, figures, or Tables). [0104] “Contacting” is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g., chemical compounds including biomolecules, or cells) to become sufficiently proximal to react, interact or physically touch. It should be appreciated; however, the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents which can be produced in the reaction mixture. [0105] The term “contacting” may include allowing two species to react, interact, or physically touch, wherein the two species may be a compound as described herein and a cellular component (e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, virus, lipid droplet, vesicle, small molecule, protein complex, protein aggregate, or macromolecule). In some embodiments contacting includes allowing a compound described herein to interact with a cellular component (e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, virus, lipid droplet, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule) that is involved in a signaling pathway. [0106] As defined herein, the term “activation,” “activate,” “activating” and the like in reference to a protein refers to conversion of a protein into a biologically active derivative
from an initial inactive or deactivated state. The terms reference activation, or activating, sensitizing, or up-regulating signal transduction or enzymatic activity or the amount of a protein decreased in a disease. [0107] The terms “agonist,” “activator,” “upregulator,” etc. refer to a substance capable of detectably increasing the expression or activity of a given gene or protein. The agonist can increase expression or activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% in comparison to a control in the absence of the agonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or higher than the expression or activity in the absence of the agonist. [0108] As defined herein, the term “inhibition,” “inhibit,” “inhibiting” and the like in reference to a cellular component-inhibitor interaction means negatively affecting (e.g., decreasing) the activity or function of the cellular component (e.g., decreasing the signaling pathway stimulated by a cellular component (e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule)), relative to the activity or function of the cellular component in the absence of the inhibitor. In embodiments, inhibition means negatively affecting (e.g., decreasing) the concentration or levels of the cellular component relative to the concentration or level of the cellular component in the absence of the inhibitor. In some embodiments, inhibition refers to reduction of a disease or symptoms of disease. In some embodiments, inhibition refers to a reduction in the activity of a signal transduction pathway or signaling pathway (e.g., reduction of a pathway involving the cellular component). Thus, inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating the signaling pathway or enzymatic activity or the amount of a cellular component. [0109] The terms “inhibitor,” “repressor,” “antagonist,” or “downregulator” interchangeably refer to a substance capable of detectably decreasing the expression or activity of a given gene or protein. The antagonist can decrease expression or activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% in comparison to a control in the absence of the antagonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or lower than the expression or activity in the absence of the antagonist.
[0110] The term modulator refers to a composition that increases or decreases the level of a target molecule or the function of a target molecule or the physical state of the target of the molecule (e.g., a target may be a cellular component (e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule)) relative to the absence of the composition. [0111] The term “expression” includes any step involved in the production of the polypeptide including, but not limited to, transcription, post-transcriptional modification, translation, post-translational modification, and secretion. Expression can be detected using conventional techniques for detecting protein (e.g., ELISA, Western blotting, flow cytometry, immunofluorescence, immunohistochemistry, etc.). [0112] The term “modulate” is used in accordance with its plain ordinary meaning and refers to the act of changing or varying one or more properties. “Modulation” refers to the process of changing or varying one or more properties. For example, as applied to the effects of a modulator on a target protein, to modulate means to change by increasing or decreasing a property or function of the target molecule or the amount of the target molecule. [0113] “Patient”, “patient in need thereof”, “subject”, or “subject in need thereof” refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals. In embodiments, a patient is human. In embodiments, a patient in need thereof is human. In embodiments, a subject is human. In embodiments, a subject in need thereof is human. [0114] “Disease” or “condition” refer to a state of being or health status of a patient or subject capable of being treated with the compounds or methods provided herein. In some embodiments, the disease is a disease related to (e.g., caused by) a cellular component (e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule). In embodiments, the disease is an age-related disorder (e.g., ischemia reperfusion injury, acute coronary syndrome, stroke, acute kidney injury, acute myocardial infarction, organ transplantation, metabolic syndrome, insulin resistance, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), noise-induced hearing
loss, age-induced hearing loss, cisplatin-induced nephrotoxicity, Alzheimer s disease, Parkinson’s disease, cardiac hypertension, pulmonary arterial hypertension, diabetic cardiomyopathy, Type 2 diabetes, cancer growth, incidence, and metastasis, atherosclerosis, osteoarthritis, or osteoporosis). [0115] The term “metabolic disorder” refers to a disorder characterized by one or more abnormal metabolic processes in a subject. In embodiments, a metabolic disorder may be associated with, related to, or may be diabetes (e.g., type 1 diabetes or type 2 diabetes), insulin resistance, metabolic syndrome, obesity, hyperlipidemia, hyperglycemia, high serum triglycerides, and/or high blood pressure. In embodiments, a metabolic disorder may be associated with, related to, or may be a diabetes associated disease selected from nephropathy, retinopathy, neuropathy, cardiovascular disease, or inflammation. In embodiments, a metabolic disorder may be associated with, related to, or may be nephropathy, retinopathy, neuropathy, cardiovascular disease, or inflammation. [0116] As used herein, the term “cancer” refers to all types of cancer, neoplasm or malignant tumors found in mammals (e.g., humans), including leukemia, lymphoma, carcinomas and sarcomas. Exemplary cancers that may be treated with a compound or method provided herein include cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head and neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus, medulloblastoma, colorectal cancer, or pancreatic cancer. Additional examples include, Hodgkin’s Disease, Non-Hodgkin’s Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer. [0117] The term “leukemia” refers broadly to progressive, malignant diseases of the blood- forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or
chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood- leukemic or aleukemic (subleukemic). Exemplary leukemias that may be treated with a compound or method provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross’ leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling’s leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia. [0118] As used herein, the term “lymphoma” refers to a group of cancers affecting hematopoietic and lymphoid tissues. It begins in lymphocytes, the blood cells that are found primarily in lymph nodes, spleen, thymus, and bone marrow. Two main types of lymphoma are non-Hodgkin lymphoma and Hodgkin’s disease. Hodgkin’s disease represents approximately 15% of all diagnosed lymphomas. This is a cancer associated with Reed- Sternberg malignant B lymphocytes. Non-Hodgkin’s lymphomas (NHL) can be classified based on the rate at which cancer grows and the type of cells involved. There are aggressive (high grade) and indolent (low grade) types of NHL. Based on the type of cells involved, there are B-cell and T-cell NHLs. Exemplary B-cell lymphomas that may be treated with a compound or method provided herein include, but are not limited to, small lymphocytic lymphoma, Mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, extranodal (MALT) lymphoma, nodal (monocytoid B-cell) lymphoma, splenic lymphoma, diffuse large cell B-lymphoma, Burkitt’s lymphoma, lymphoblastic lymphoma, immunoblastic large cell lymphoma, or precursor B-lymphoblastic lymphoma. Exemplary T- cell lymphomas that may be treated with a compound or method provided herein include, but
are not limited to, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, anaplastic large cell lymphoma, mycosis fungoides, and precursor T-lymphoblastic lymphoma. [0119] The term “sarcoma” generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance. Sarcomas that may be treated with a compound or method provided herein include a chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms’ tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing’s sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen’s sarcoma, Kaposi’s sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma. [0120] The term “melanoma” is taken to mean a tumor arising from the melanocytic system of the skin and other organs. Melanomas that may be treated with a compound or method provided herein include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman’s melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma, or superficial spreading melanoma. [0121] The term “carcinoma” refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases. Exemplary carcinomas that may be treated with a compound or method provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse,
carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher’s carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signet-ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, or carcinoma villosum. [0122] As used herein, the terms "metastasis," "metastatic," and "metastatic cancer" can be used interchangeably and refer to the spread of a proliferative disease or disorder, e.g., cancer, from one organ or another non-adjacent organ or body part. “Metastatic cancer” is also called “Stage IV cancer.” Cancer occurs at an originating site, e.g., breast, which site is referred to as a primary tumor, e.g., primary breast cancer. Some cancer cells in the primary tumor or originating site acquire the ability to penetrate and infiltrate surrounding normal tissue in the local area and/or the ability to penetrate the walls of the lymphatic system or vascular system circulating through the system to other sites and tissues in the body. A second clinically detectable tumor formed from cancer cells of a primary tumor is referred to as a metastatic or secondary tumor. When cancer cells metastasize, the metastatic tumor and its cells are presumed to be similar to those of the original tumor. Thus, if lung cancer metastasizes to the breast, the secondary tumor at the site of the breast consists of abnormal
lung cells and not abnormal breast cells. The secondary tumor in the breast is referred to a metastatic lung cancer. Thus, the phrase metastatic cancer refers to a disease in which a subject has or had a primary tumor and has one or more secondary tumors. The phrases non- metastatic cancer or subjects with cancer that is not metastatic refers to diseases in which subjects have a primary tumor but not one or more secondary tumors. For example, metastatic lung cancer refers to a disease in a subject with or with a history of a primary lung tumor and with one or more secondary tumors at a second location or multiple locations, e.g., in the breast. [0123] The terms “cutaneous metastasis” and “skin metastasis” refer to secondary malignant cell growths in the skin, wherein the malignant cells originate from a primary cancer site (e.g., breast). In cutaneous metastasis, cancerous cells from a primary cancer site may migrate to the skin where they divide and cause lesions. Cutaneous metastasis may result from the migration of cancer cells from breast cancer tumors to the skin. [0124] The term “visceral metastasis” refers to secondary malignant cell growths in the interal organs (e.g., heart, lungs, liver, pancreas, intestines) or body cavities (e.g., pleura, peritoneum), wherein the malignant cells originate from a primary cancer site (e.g., head and neck, liver, breast). In visceral metastasis, cancerous cells from a primary cancer site may migrate to the internal organs where they divide and cause lesions. Visceral metastasis may result from the migration of cancer cells from liver cancer tumors or head and neck tumors to internal organs. [0125] The term “drug” is used in accordance with its common meaning and refers to a substance which has a physiological effect (e.g., beneficial effect, is useful for treating a subject) when introduced into or to a subject (e.g., in or on the body of a subject or patient). A drug moiety is a radical of a drug. [0126] A “detectable agent,” “detectable compound,” “detectable label,” or “detectable moiety” is a substance (e.g., element), molecule, or composition detectable by spectroscopic, photochemical, biochemical, immunochemical, chemical, magnetic resonance imaging, or other physical means. For example, detectable agents include 18F, 32P, 33P, 45Ti, 47Sc, 52Fe, 59Fe, 62Cu, 64Cu, 67Cu, 67Ga, 68Ga, 77As, 86Y, 90Y, 89Sr, 89Zr, 94Tc, 94Tc, 99mTc, 99Mo, 105Pd, 105Rh, 111Ag, 111In, 123I, 124I, 125I, 131I, 142Pr, 143Pr, 149Pm, 153Sm, 154-158Gd, 161Tb, 166Dy, 166Ho, 169Er, 175Lu, 177Lu, 186Re, 188Re, 189Re, 194Ir, 198Au, 199Au, 211At, 211Pb, 212Bi, 212Pb, 213Bi, 223Ra, 225Ac, Cr, V, Mn, Fe, Co, Ni, Cu, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er,
Tm, Yb, Lu, 32P, fluorophore (e.g., fluorescent dyes), modified oligonucleotides (e.g., moieties described in PCT/US2015/022063, which is incorporated herein by reference), electron-dense reagents, enzymes (e.g., as commonly used in an ELISA), biotin, digoxigenin, paramagnetic molecules, paramagnetic nanoparticles, ultrasmall superparamagnetic iron oxide ("USPIO") nanoparticles, USPIO nanoparticle aggregates, superparamagnetic iron oxide ("SPIO") nanoparticles, SPIO nanoparticle aggregates, monochrystalline iron oxide nanoparticles, monochrystalline iron oxide, nanoparticle contrast agents, liposomes or other delivery vehicles containing Gadolinium chelate ("Gd-chelate") molecules, Gadolinium, radioisotopes, radionuclides (e.g., carbon-11, nitrogen-13, oxygen-15, fluorine-18, rubidium- 82), fluorodeoxyglucose (e.g., fluorine-18 labeled), any gamma ray emitting radionuclides, positron-emitting radionuclide, radiolabeled glucose, radiolabeled water, radiolabeled ammonia, biocolloids, microbubbles (e.g., including microbubble shells including albumin, galactose, lipid, and/or polymers; microbubble gas core including air, heavy gas(es), perfluorcarbon, nitrogen, octafluoropropane, perflexane lipid microsphere, perflutren, etc.), iodinated contrast agents (e.g., iohexol, iodixanol, ioversol, iopamidol, ioxilan, iopromide, diatrizoate, metrizoate, ioxaglate), barium sulfate, thorium dioxide, gold, gold nanoparticles, gold nanoparticle aggregates, fluorophores, two-photon fluorophores, or haptens and proteins or other entities which can be made detectable, e.g., by incorporating a radiolabel into a peptide or antibody specifically reactive with a target peptide. [0127] Radioactive substances (e.g., radioisotopes) that may be used as imaging and/or labeling agents in accordance with the embodiments of the disclosure include, but are not limited to, 18F, 32P, 33P, 45Ti, 47Sc, 52Fe, 59Fe, 62Cu, 64Cu, 67Cu, 67Ga, 68Ga, 77As, 86Y, 90Y, 89Sr, 89Zr, 94Tc, 94Tc, 99mTc, 99Mo, 105Pd, 105Rh, 111Ag, 111In, 123I, 124I, 125I, 131I, 142Pr, 143Pr, 149Pm, 153Sm, 154-158Gd, 161Tb, 166Dy, 166Ho, 169Er, 175Lu, 177Lu, 186Re, 188Re, 189Re, 194Ir, 198Au, 199Au, 211At, 211Pb, 212Bi, 212Pb, 213Bi, 223Ra and 225Ac. Paramagnetic ions that may be used as additional imaging agents in accordance with the embodiments of the disclosure include, but are not limited to, ions of transition and lanthanide metals (e.g., metals having atomic numbers of 21-29, 42, 43, 44, or 57-71). These metals include ions of Cr, V, Mn, Fe, Co, Ni, Cu, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, and Lu. [0128] “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present invention without causing a
significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present invention. [0129] The term “preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration. [0130] As used herein, the term “about” means a range of values including the specified value, which a person of ordinary skill in the art would consider reasonably similar to the specified value. In embodiments, about means within a standard deviation using measurements generally acceptable in the art. In embodiments, about means a range extending to +/- 10% of the specified value. In embodiments, about includes the specified value. [0131] As used herein, the term “administering” is used in accordance with its plain and ordinary meaning and includes oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini- osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra- arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. By “co-administer” it is meant that a
composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies, for example cancer therapies such as chemotherapy, hormonal therapy, radiotherapy, or immunotherapy. The compounds of the invention can be administered alone or can be co-administered to the patient. Co- administration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). Thus, the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation). The compositions of the present invention can be delivered by transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols. [0132] The compounds described herein can be used in combination with one another, with other active agents known to be useful in treating a disease associated with cells expressing a disease associated cellular component, or with adjunctive agents that may not be effective alone, but may contribute to the efficacy of the active agent. [0133] In some embodiments, co-administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent. Co- administration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition including both active agents. In other embodiments, the active agents can be formulated separately. In another embodiment, the active and/or adjunctive agents may be linked or conjugated to one another. [0134] In therapeutic use for the treatment of a disease, compound utilized in the pharmaceutical compositions of the present invention may be administered at the initial dosage of about 0.001 mg/kg to about 1000 mg/kg daily. A daily dose range of about 0.01 mg/kg to about 500 mg/kg, or about 0.1 mg/kg to about 200 mg/kg, or about 1 mg/kg to about 100 mg/kg, or about 10 mg/kg to about 50 mg/kg, can be used. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound or drug being employed. For example, dosages can be empirically determined considering the type and stage of disease (e.g., age-related disorder) diagnosed in a particular patient. The dose administered to a patient, in the context of the present invention, should be sufficient to affect a beneficial therapeutic response in the
patient over time. The size of the dose will also be determined by the existence, nature, and extent of any adverse side effects that accompany the administration of a compound in a particular patient. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired. [0135] The term “associated” or “associated with” in the context of a substance or substance activity or function associated with a disease (e.g., a protein associated disease, disease associated with a cellular component) means that the disease (e.g., age-related disorder) is caused by (in whole or in part), or a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function or the disease or a symptom of the disease may be treated by modulating (e.g., inhibiting or activating) the substance (e.g., cellular component). As used herein, what is described as being associated with a disease, if a causative agent, could be a target for treatment of the disease. [0136] The term “aberrant” as used herein refers to different from normal. When used to describe enzymatic activity, aberrant refers to activity that is greater or less than a normal control or the average of normal non-diseased control samples. Aberrant activity may refer to an amount of activity that results in a disease, wherein returning the aberrant activity to a normal or non-disease-associated amount (e.g., by administering a compound or using a method as described herein), results in reduction of the disease or one or more disease symptoms. [0137] The term “electrophilic” as used herein refers to a chemical group that is capable of accepting electron density. An “electrophilic substituent,” “electrophilic chemical moiety,” or “electrophilic moiety” refers to an electron-poor chemical group, substituent, or moiety (monovalent chemical group), which may react with an electron-donating group, such as a nucleophile, by accepting an electron pair or electron density to form a bond. [0138] “Nucleophilic” as used herein refers to a chemical group that is capable of donating electron density. [0139] The term “isolated,” when applied to a nucleic acid or protein, denotes that the nucleic acid or protein is essentially free of other cellular components with which it is
associated in the natural state. It can be, for example, in a homogeneous state and may be in either a dry or aqueous solution. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. A protein that is the predominant species present in a preparation is substantially purified. [0140] The term “amino acid” refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, γ- carboxyglutamate, and O-phosphoserine. Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an α carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid. The terms “non-naturally occurring amino acid” and “unnatural amino acid” refer to amino acid analogs, synthetic amino acids, and amino acid mimetics which are not found in nature. [0141] Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single-letter codes. [0142] The terms “polypeptide,” “peptide,” and “protein” are used interchangeably herein to refer to a polymer of amino acid residues, wherein the polymer may in embodiments be conjugated to a moiety that does not consist of amino acids. The terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymers. [0143] An amino acid or nucleotide base “position” is denoted by a number that sequentially identifies each amino acid (or nucleotide base) in the reference sequence based on its position relative to the N-terminus (or 5'-end). Due to deletions, insertions, truncations,
fusions, and the like that must be taken into account when determining an optimal alignment, in general the amino acid residue number in a test sequence determined by simply counting from the N-terminus will not necessarily be the same as the number of its corresponding position in the reference sequence. For example, in a case where a variant has a deletion relative to an aligned reference sequence, there will be no amino acid in the variant that corresponds to a position in the reference sequence at the site of deletion. Where there is an insertion in an aligned reference sequence, that insertion will not correspond to a numbered amino acid position in the reference sequence. In the case of truncations or fusions there can be stretches of amino acids in either the reference or aligned sequence that do not correspond to any amino acid in the corresponding sequence. [0144] The terms “numbered with reference to” or “corresponding to,” when used in the context of the numbering of a given amino acid or polynucleotide sequence, refers to the numbering of the residues of a specified reference sequence when the given amino acid or polynucleotide sequence is compared to the reference sequence. [0145] An amino acid residue in a protein “corresponds” to a given residue when it occupies the same essential structural position within the protein as the given residue. [0146] The term “protein complex” is used in accordance with its plain ordinary meaning and refers to a protein which is associated with an additional substance (e.g., another protein, protein subunit, or a compound). Protein complexes typically have defined quaternary structure. The association between the protein and the additional substance may be a covalent bond. In embodiments, the association between the protein and the additional substance (e.g., compound) is via non-covalent interactions. In embodiments, a protein complex refers to a group of two or more polypeptide chains. Proteins in a protein complex are linked by non-covalent protein–protein interactions. A non-limiting example of a protein complex is the proteasome. [0147] The term “protein aggregate” is used in accordance with its plain ordinary meaning and refers to an aberrant collection or accumulation of proteins (e.g., misfolded proteins). Protein aggregates are often associated with diseases (e.g., amyloidosis). Typically, when a protein misfolds as a result of a change in the amino acid sequence or a change in the native environment which disrupts normal non-covalent interactions, and the misfolded protein is not corrected or degraded, the unfolded/misfolded protein may aggregate. There are three
main types of protein aggregates that may form: amorphous aggregates, oligomers, and amyloid fibrils. In embodiments, protein aggregates are termed aggresomes. [0148] The term “mitochondrial site IQ” or “S1Q” refers to a site of superoxide/hydrogen peroxide production associate with the mitochondrial electron transport chain. [0149] The term “selective” or “selectivity” or the like in reference to a compound or agent refers to the compound’s or agent’s ability to cause an increase or decrease in activity of a particular molecular target (e.g., protein, enzyme, etc.) preferentially over one or more different molecular targets (e.g., a compound having selectivity toward mitochondrial site 1Q would preferentially inhibit mitochondrial site 1Q over other mitochondrial sites). In embodiments, a “suppressor of site IQ electron leak” or “S1QEL” refers to a compound (e.g., compound described herein) having selectivity towards mitochondrial site IQ. II. Compounds [0150] In an aspect is provided a compound, or a pharmaceutically acceptable salt thereof, having the formula:
[0152] The symbol n is an integer from 0 to 2. [0153] R1 is independently halogen, -CX1 3, -CHX1 2, -CH2X1, -OCX1 3, -OCH2X1, -OCHX12, -CN, -SOn1R1D, -SOv1NR1AR1B, ^NR1CNR1AR1B, ^ONR1AR1B, -NR1CC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)OR1C, -OC(O)R1C, -OC(O)OR1C, -C(O)NR1AR1B, -OC(O)NR1AR1B, -OR1D, -SR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -SF5, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1- C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5
membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); two R1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0154] R1A, R1B, R1C, and R1D are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0155] Each X1 is independently –Cl, -Br, -I, or –F. [0156] The symbol n1 is an integer from 0 to 4. [0157] The synmbols m1 and v1 are independently 1 or 2. [0158] The symbol z1 is an integer from 0 to 5. [0159] X is O or NR2. [0160] R2 is hydrogen or unsubstituted C1-C6 alkyl.
[0161] R3 is hydrogen, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1- C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), or a prodrug moiety. [0162] R2 and R3 substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). [0163] R4 is hydrogen, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1- C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), or a prodrug moiety. [0164] R5 and R6 are independently hydrogen, -OH, unsubstituted C1-C6 alkyl, or unsubstituted 2 to 6 membered heteroalkyl. [0165] R5 and R7 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6) or substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered); or R6 and R7 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6) or substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). [0166] R7 and R8 are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0167] R9 is independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6- C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0168] The symbol z9 is an integer from 0 to 2. [0169] In embodiments, the compound is not: ,
,
. [0170] In embodiments, the compound has the formula:
Ring A, n, X, R3, R4, R5, and R6 are as described herein, including in embodiments. R1.1, R1.2, and R1.3 are independently hydrogen or any value of R1 as described herein, including in embodiments. [0171] In embodiments, the compound has the formula:
Ring A and n are as described herein, including in embodiments. R1.2 is –NR1AC(O)R1B, -NR1ASO2R1C, -NR1AC(O)OR1B, -OR1A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein R1A, R1B, and R1C are as described herein, including in embodiments. R1.1 and R1.3 are hydrogen. R1.1 and R1.2 substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl; or R1.2 and R1.3 substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl. X is O and R3 is hydrogen; or X is NR2 and R2 and R3 substituents are
joined to form a substituted or unsubstituted heterocycloalkyl. R4 is hydrogen. R5 is hydrogen. R6 is hydrogen, -OH, or unsubstituted 2 to 6 membered heteroalkyl. R5 and R7 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl; or R6 and R7 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl. R7 is hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. R8 is substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0172] In embodiments, the compound has the formula:
Ring A, n, R1.1, R1.2, R1.3, R5 and R6 are as described herein, including in embodiments. [0173] In embodiments, the compound has the formula:
Ring A, n, R1.1, R1.2, R1.3, R5 and R6 are as described herein, including in embodiments. [0174] In embodiments, the compound has the formula:
Ring A, n, R1.1, R1.2, R1.3, R5 and R6 are as described herein, including in embodiments.
[0175] Ring B is cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), aryl (e.g., C6-C10 or phenyl), or heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0176] R10 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6- C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); two R10 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0177] The symbol z10 is an integer from 0 to 11. [0178] In embodiments, the compound has the formula:
Ring A, Ring B, n, R1.1, R1.2, R1.3, R5, R6, R10, and z10 are as described herein, including in embodiments. [0179] In embodiments, the compound has the formula:
Ring A, Ring B, n, R1.1, R1.2, R1.3, R5, R6, R10, and z10 are as described herein, including in embodiments. [0180] In embodiments, Ring
, wherein R7 and R8 are as described herein, including in embodiments. In embodiments, Ring
, wherein R8 is as described herein, including in embodiments. In embodiments, Ring A is
, wherein R7, R8, R9, and z9 are as described herein, including in embodiments. In embodiments, Ring
, wherein R8, R9, and z9 are as described herein, including in embodiments. In embodiments, Ring
, wherein R7, R8, R9, and z9 are as described herein, including in embodiments. In embodiments, Ring
, wherein R8, R9, and z9 are as described herein, including in embodiments. [0181] In embodiments, Ring B is C3-C8 cycloalkyl. In embodiments, Ring B is 3 to 8 membered heterocycloalkyl. In embodiments, Ring B is phenyl. In embodiments, Ring B is 5 to 6 membered heteroaryl. In embodiments, Ring B is pyrrolidinyl, piperidinyl, or morpholinyl. In embodiments, Ring B is pyrrolidinyl. In embodiments, Ring B is piperidinyl. In embodiments, Ring B is morpholinyl.
[0182] In embodiments, n is 0. In embodiments, n is 1. In embodiments, n is 2. [0183] In embodiments, a substituted R1 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R1 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R1 is substituted, it is substituted with at least one substituent group. In embodiments, when R1 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R1 is substituted, it is substituted with at least one lower substituent group. [0184] In embodiments, a substituted ring formed when two R1 substituents are joined (e.g., substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when two R1 substituents are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when two R1 substituents are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when two R1 substituents are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when two R1 substituents are joined is substituted, it is substituted with at least one lower substituent group. [0185] In embodiments, a substituted R1.1 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R1.1 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R1.1 is substituted, it is substituted with at least one substituent group. In embodiments, when R1.1 is substituted, it is
substituted with at least one size-limited substituent group. In embodiments, when R1.1 is substituted, it is substituted with at least one lower substituent group. [0186] In embodiments, a substituted R1.2 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R1.2 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R1.2 is substituted, it is substituted with at least one substituent group. In embodiments, when R1.2 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R1.2 is substituted, it is substituted with at least one lower substituent group. [0187] In embodiments, a substituted R1.3 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R1.3 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R1.3 is substituted, it is substituted with at least one substituent group. In embodiments, when R1.3 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R1.3 is substituted, it is substituted with at least one lower substituent group. [0188] In embodiments, R1.1, R1.2, and R1.3 are independently hydrogen, halogen, -CX1 3, -CHX12, -CH2X1, -OCX13, -OCH2X1, -OCHX12, -CN, -SOn1R1D, -SOv1NR1AR1B, ^NR1CNR1AR1B, ^ONR1AR1B, -NR1CC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)OR1C, -OC(O)R1C, -OC(O)OR1C, -C(O)NR1AR1B, -OC(O)NR1AR1B, -OR1D, -SR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -SF5, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-
C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0189] In embodiments, R1 is independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0190] In embodiments, R1 is independently halogen. In embodiments, R1 is independently –F. In embodiments, R1 is independently –Cl. In embodiments, R1 is independently –Br. In embodiments, R1 is independently –I. In embodiments, R1 is independently -CCl3. In embodiments, R1 is independently -CBr3. In embodiments, R1 is independently -CF3. In embodiments, R1 is independently -CI3. In embodiments, R1 is independently -CH2Cl. In embodiments, R1 is independently -CH2Br. In embodiments, R1 is independently -CH2F. In embodiments, R1 is independently -CH2I. In embodiments, R1 is independently -CHCl2. In embodiments, R1 is independently -CHBr2. In embodiments, R1 is independently -CHF2. In embodiments, R1 is independently -CHI2. In embodiments, R1 is independently –CN. In embodiments, R1 is independently –OH. In embodiments, R1 is independently -NH2. In embodiments, R1 is independently –COOH. In embodiments, R1 is independently -CONH2. In embodiments, R1 is independently -NO2. In embodiments, R1 is independently –SH. In embodiments, R1 is independently -SO3H. In embodiments, R1 is independently -OSO3H. In embodiments, R1 is independently -SO2NH2. In embodiments, R1 is independently ^NHNH2. In embodiments, R1 is independently ^ONH2. In embodiments, R1 is independently ^NHC(O)NH2. In embodiments, R1 is independently -NHSO2H. In embodiments, R1 is independently -NHC(O)H. In embodiments, R1 is independently -NHC(O)OH. In embodiments, R1 is independently –NHOH. In embodiments, R1 is independently -OCCl3. In embodiments, R1 is independently -OCBr3. In embodiments, R1 is independently -OCF3. In embodiments, R1 is independently -OCI3. In embodiments, R1 is independently -OCH2Cl. In embodiments, R1 is independently -OCH2Br. In embodiments, R1 is independently -OCH2F. In embodiments, R1 is independently -OCH2I. In embodiments, R1
is independently -OCHCl2. In embodiments, R1 is independently -OCHBr2. In embodiments, R1 is independently -OCHF2. In embodiments, R1 is independently -OCHI2. In embodiments, R1 is independently unsubstituted C1-C4 alkyl. In embodiments, R1 is independently unsubstituted methyl. In embodiments, R1 is independently unsubstituted ethyl. In embodiments, R1 is independently unsubstituted propyl. In embodiments, R1 is independently unsubstituted n-propyl. In embodiments, R1 is independently unsubstituted isopropyl. In embodiments, R1 is independently unsubstituted butyl. In embodiments, R1 is independently unsubstituted n-butyl. In embodiments, R1 is independently unsubstituted isobutyl. In embodiments, R1 is independently unsubstituted tert-butyl. In embodiments, R1 is independently unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R1 is independently unsubstituted methoxy. In embodiments, R1 is independently unsubstituted ethoxy. In embodiments, R1 is independently unsubstituted propoxy. In embodiments, R1 is independently unsubstituted n-propoxy. In embodiments, R1 is independently unsubstituted isopropoxy. In embodiments, R1 is independently unsubstituted butoxy. In embodiments, R1 is independently unsubstituted n-butoxy. In embodiments, R1 is independently unsubstituted isobutoxy. In embodiments, R1 is independently unsubstituted tert-butoxy. [0191] In embodiments, R1 is independently –NR1AC(O)R1B, wherein R1A and R1B are as described herein, including in embodiments. In embodiments, R1 is independently –NR1AC(O)R1B, wherein R1A and R1B are independently hydrogen or unsubstituted C1-C4 alkyl. In embodiments, R1 is independently –NHC(O)CH3, -NCH3C(O)CH3, -OH, -OCH3, or –NHSO2CH3. In embodiments, R1 is independently –NHC(O)CH3. In embodiments, R1 is independently -NCH3C(O)CH3. In embodiments, R1 is independently –OH. In embodiments, R1 is independently -OCH3. In embodiments, R1 is independently –NHSO2CH3. [0192] In embodiments, two R1 substituents are joined to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. [0193] In embodiments, R1.2 is –NR1AC(O)R1B, wherein R1A and R1B are as described herein, including in embodiments. In embodiments, R1.2 is –NR1AC(O)R1B, wherein R1A and R1B are independently hydrogen or unsubstituted C1-C4 alkyl. In embodiments, R1.2 is –NHC(O)CH3, -NCH3C(O)CH3, -OH, -OCH3, or –NHSO2CH3. In embodiments, R1.2 is
–NHC(O)CH3. In embodiments, R1.2 is -NCH3C(O)CH3. In embodiments, R1.2 is –OH. In embodiments, R1.2 is -OCH3. In embodiments, R1.2 is –NHSO2CH3. [0194] In embodiments, a substituted R1A (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R1A is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R1A is substituted, it is substituted with at least one substituent group. In embodiments, when R1A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R1A is substituted, it is substituted with at least one lower substituent group. [0195] In embodiments, a substituted R1B (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R1B is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R1B is substituted, it is substituted with at least one substituent group. In embodiments, when R1B is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R1B is substituted, it is substituted with at least one lower substituent group. [0196] In embodiments, a substituted ring formed when R1A and R1B substituents bonded to the same nitrogen atom are joined (e.g., substituted heterocycloalkyl and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R1A and R1B substituents bonded to the same nitrogen atom are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when R1A and R1B substituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R1A
and R1B substituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R1A and R1B substituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group. [0197] In embodiments, a substituted R1C (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R1C is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R1C is substituted, it is substituted with at least one substituent group. In embodiments, when R1C is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R1C is substituted, it is substituted with at least one lower substituent group. [0198] In embodiments, a substituted R1D (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R1D is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R1D is substituted, it is substituted with at least one substituent group. In embodiments, when R1D is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R1D is substituted, it is substituted with at least one lower substituent group. [0199] In embodiments, R1A is independently hydrogen. In embodiments, R1A is independently unsubstituted C1-C4 alkyl. In embodiments, R1A is independently unsubstituted methyl. In embodiments, R1A is independently unsubstituted ethyl. In embodiments, R1A is independently unsubstituted propyl. In embodiments, R1A is independently unsubstituted n-propyl. In embodiments, R1A is independently unsubstituted isopropyl. In embodiments, R1A is independently unsubstituted butyl. In embodiments, R1A is independently unsubstituted n-butyl. In embodiments, R1A is independently unsubstituted isobutyl. In embodiments, R1A is independently unsubstituted tert-butyl.
[0200] In embodiments, R1B is independently hydrogen. In embodiments, R1B is independently unsubstituted C1-C4 alkyl. In embodiments, R1B is independently unsubstituted methyl. In embodiments, R1B is independently unsubstituted ethyl. In embodiments, R1B is independently unsubstituted propyl. In embodiments, R1B is independently unsubstituted n-propyl. In embodiments, R1B is independently unsubstituted isopropyl. In embodiments, R1B is independently unsubstituted butyl. In embodiments, R1B is independently unsubstituted n-butyl. In embodiments, R1B is independently unsubstituted isobutyl. In embodiments, R1B is independently unsubstituted tert-butyl. [0201] In embodiments, R1C is independently hydrogen. In embodiments, R1C is independently unsubstituted C1-C4 alkyl. In embodiments, R1C is independently unsubstituted methyl. In embodiments, R1C is independently unsubstituted ethyl. In embodiments, R1C is independently unsubstituted propyl. In embodiments, R1C is independently unsubstituted n-propyl. In embodiments, R1C is independently unsubstituted isopropyl. In embodiments, R1C is independently unsubstituted butyl. In embodiments, R1C is independently unsubstituted n-butyl. In embodiments, R1C is independently unsubstituted isobutyl. In embodiments, R1C is independently unsubstituted tert-butyl. [0202] In embodiments, R1D is independently hydrogen. In embodiments, R1D is independently unsubstituted C1-C4 alkyl. In embodiments, R1D is independently unsubstituted methyl. In embodiments, R1D is independently unsubstituted ethyl. In embodiments, R1D is independently unsubstituted propyl. In embodiments, R1D is independently unsubstituted n-propyl. In embodiments, R1D is independently unsubstituted isopropyl. In embodiments, R1D is independently unsubstituted butyl. In embodiments, R1D is independently unsubstituted n-butyl. In embodiments, R1D is independently unsubstituted isobutyl. In embodiments, R1D is independently unsubstituted tert-butyl.
. [0204] In embodiments, z1 is 0. In embodiments, z1 is 1. In embodiments, z1 is 2. In embodiments, z1 is 3. In embodiments, z1 is 4. In embodiments, z1 is 5. [0205] In embodiments, X is O. In embodiments, X is NR2, wherein R2 is as described herein, including in embodiments. In embodiments, X is NH. [0206] In embodiments, R2 is hydrogen. In embodiments, R2 is unsubstituted C1-C6 alkyl. In embodiments, R2 is unsubstituted methyl. In embodiments, R2 is unsubstituted ethyl. In embodiments, R2 is unsubstituted propyl. In embodiments, R2 is unsubstituted n-propyl. In embodiments, R2 is unsubstituted isopropyl. In embodiments, R2 is unsubstituted butyl. In embodiments, R2 is unsubstituted n-butyl. In embodiments, R2 is unsubstituted isobutyl. In embodiments, R2 is unsubstituted tert-butyl. In embodiments, R2 is unsubstituted pentyl. In embodiments, R2 is unsubstituted hexyl. [0207] In embodiments, a substituted R3 (e.g., substituted alkyl and/or substituted heteroalkyl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R3 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R3 is substituted, it is substituted with at least one substituent group. In embodiments, when R3 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R3 is substituted, it is substituted with at least one lower substituent group.
[0208] In embodiments, R3 is hydrogen. In embodiments, R3 is substituted or unsubstituted C1-C4 alkyl. In embodiments, R3 is unsubstituted C1-C4 alkyl. In embodiments, R3 is unsubstituted methyl. In embodiments, R3 is unsubstituted ethyl. In embodiments, R3 is unsubstituted propyl. In embodiments, R3 is unsubstituted n-propyl. In embodiments, R3 is unsubstituted isopropyl. In embodiments, R3 is unsubstituted butyl. In embodiments, R3 is unsubstituted n-butyl. In embodiments, R3 is unsubstituted isobutyl. In embodiments, R3 is unsubstituted tert-butyl. [0209] In embodiments, R3 is a prodrug moiety. In embodiments, R3 is a substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R3 is
. [0210] In embodiments, a substituted ring formed when R2 and R3 substituents are joined (e.g., substituted heterocycloalkyl) is substituted with at least one substituent group, size- limited substituent group, or lower substituent group; wherein if the substituted ring formed when R2 and R3 substituents are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when R2 and R3 substituents are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R2 and R3 substituents are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R2 and R3 substituents are joined is substituted, it is substituted with at least one lower substituent group. [0211] In embodiments, R2 and R3 substituents are joined to form a substituted or unsubstituted 3 to 8 membered heterocycloalkyl. [0212] In embodiments, a substituted R4 (e.g., substituted alkyl and/or substituted heteroalkyl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R4 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R4 is substituted, it is substituted with at least one substituent group. In embodiments, when R4 is substituted, it is
substituted with at least one size-limited substituent group. In embodiments, when R4 is substituted, it is substituted with at least one lower substituent group. [0213] In embodiments, R4 is hydrogen. In embodiments, R4 is substituted or unsubstituted C1-C4 alkyl. In embodiments, R4 is unsubstituted C1-C4 alkyl. In embodiments, R4 is unsubstituted methyl. In embodiments, R4 is unsubstituted ethyl. In embodiments, R4 is unsubstituted propyl. In embodiments, R4 is unsubstituted n-propyl. In embodiments, R4 is unsubstituted isopropyl. In embodiments, R4 is unsubstituted butyl. In embodiments, R4 is unsubstituted n-butyl. In embodiments, R4 is unsubstituted isobutyl. In embodiments, R4 is unsubstituted tert-butyl. [0214] In embodiments, R4 is a prodrug moiety. In embodiments, R4 is a substituted or O unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R4 is
. [0215] In embodiments, R5 is hydrogen, -OH, unsubstituted C1-C6 alkyl, or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R5 is hydrogen. In embodiments, R5 is –OH. In embodiments, R5 is unsubstituted C1-C6 alkyl. In embodiments, R5 is unsubstituted methyl. In embodiments, R5 is unsubstituted ethyl. In embodiments, R5 is unsubstituted propyl. In embodiments, R5 is unsubstituted n-propyl. In embodiments, R5 is unsubstituted isopropyl. In embodiments, R5 is unsubstituted butyl. In embodiments, R5 is unsubstituted n- butyl. In embodiments, R5 is unsubstituted isobutyl. In embodiments, R5 is unsubstituted tert-butyl. In embodiments, R5 is unsubstituted pentyl. In embodiments, R5 is unsubstituted hexyl. In embodiments, R5 is unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R5 is unsubstituted methoxy. In embodiments, R5 is unsubstituted ethoxy. In embodiments, R5 is unsubstituted propoxy. In embodiments, R5 is unsubstituted n-propoxy. In embodiments, R5 is unsubstituted isopropoxy. In embodiments, R5 is unsubstituted butoxy. In embodiments, R5 is unsubstituted n-butoxy. In embodiments, R5 is unsubstituted isobutoxy. In embodiments, R5 is unsubstituted tert-butoxy. [0216] In embodiments, R6 is hydrogen, -OH, unsubstituted C1-C6 alkyl, or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R6 is hydrogen. In embodiments, R6 is –OH. In embodiments, R6 is unsubstituted C1-C6 alkyl. In embodiments, R6 is unsubstituted methyl. In embodiments, R6 is unsubstituted ethyl. In embodiments, R6 is unsubstituted propyl. In embodiments, R6 is unsubstituted n-propyl. In embodiments, R6 is unsubstituted
isopropyl. In embodiments, R6 is unsubstituted butyl. In embodiments, R6 is unsubstituted n- butyl. In embodiments, R6 is unsubstituted isobutyl. In embodiments, R6 is unsubstituted tert-butyl. In embodiments, R6 is unsubstituted pentyl. In embodiments, R6 is unsubstituted hexyl. In embodiments, R6 is unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R6 is unsubstituted methoxy. In embodiments, R6 is unsubstituted ethoxy. In embodiments, R6 is unsubstituted propoxy. In embodiments, R6 is unsubstituted n-propoxy. In embodiments, R6 is unsubstituted isopropoxy. In embodiments, R6 is unsubstituted butoxy. In embodiments, R6 is unsubstituted n-butoxy. In embodiments, R6 is unsubstituted isobutoxy. In embodiments, R6 is unsubstituted tert-butoxy.
, wherein R7 and R8 are as described herein, including in embodiments. In embodiments,
, wherein R7 and R8 are as described herein, including in embodiments. In embodiments,
, wherein R7 and R8 are as described herein, including in embodiments. In embodiments,
, wherein R7 and R8 are as described herein, including in embodiments. In embodiments,
, wherein R8 is as described herein, including in embodiments. In embodiments,
, wherein R8 is as described herein, including in embodiments. [0218] In embodiments, a substituted R7 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R7 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R7 is substituted, it is substituted with at least one substituent group. In embodiments, when R7 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R7 is substituted, it is substituted with at least one lower substituent group. [0219] In embodiments, R7 is hydrogen. In embodiments, R7 is unsubstituted C1-C6 alkyl. In embodiments, R7 is unsubstituted methyl. In embodiments, R7 is unsubstituted ethyl. In embodiments, R7 is unsubstituted propyl. In embodiments, R7 is unsubstituted n-propyl. In embodiments, R7 is unsubstituted isopropyl. In embodiments, R7 is unsubstituted butyl. In embodiments, R7 is unsubstituted n-butyl. In embodiments, R7 is unsubstituted isobutyl. In embodiments, R7 is unsubstituted tert-butyl. In embodiments, R7 is unsubstituted pentyl. In embodiments, R7 is unsubstituted hexyl. [0220] In embodiments, a substituted ring formed when R5 and R7 substituents are joined (e.g., substituted cycloalkyl and/or substituted heterocycloalkyl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R5 and R7 substituents are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when R5 and R7 substituents are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R5 and R7 substituents are joined is substituted, it is substituted with at least one size-limited substituent
group. In embodiments, when the substituted ring formed when R5 and R7 substituents are joined is substituted, it is substituted with at least one lower substituent group. [0221] In embodiments, R5 and R7 substituents are joined to form a substituted or unsubstituted C3-C8 cycloalkyl or substituted or unsubstituted 3 to 8 membered heterocycloalkyl. [0222] In embodiments, a substituted ring formed when R6 and R7 substituents are joined (e.g., substituted cycloalkyl and/or substituted heterocycloalkyl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R6 and R7 substituents are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when R6 and R7 substituents are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R6 and R7 substituents are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R6 and R7 substituents are joined is substituted, it is substituted with at least one lower substituent group. [0223] In embodiments, R6 and R7 substituents are joined to form a substituted or unsubstituted C3-C8 cycloalkyl or substituted or unsubstituted 3 to 8 membered heterocycloalkyl. [0224] In embodiments, a substituted R8 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R8 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R8 is substituted, it is substituted with at least one substituent group. In embodiments, when R8 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R8 is substituted, it is substituted with at least one lower substituent group.
[0225] In embodiments, R8 is substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl. In embodiments, R8 is substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, or substituted or unsubstituted phenyl. In embodiments, R8 is –OCH2CF3. [0226] In embodiments, R8 is
, wherein Ring B, R10, and z10 are as described herein, including in embodiments. In embodiments,
. [0227] In embodiments, a substituted R9 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R9 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R9 is substituted, it is substituted with at least one substituent group. In embodiments, when R9 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R9 is substituted, it is substituted with at least one lower substituent group.
[0228] In embodiments, R9 is independently halogen. In embodiments, R9 is independently –F. In embodiments, R9 is independently –Cl. In embodiments, R9 is independently –Br. In embodiments, R9 is independently –I. In embodiments, R9 is independently -CCl3. In embodiments, R9 is independently -CBr3. In embodiments, R9 is independently -CF3. In embodiments, R9 is independently -CI3. In embodiments, R9 is independently -CH2Cl. In embodiments, R9 is independently -CH2Br. In embodiments, R9 is independently -CH2F. In embodiments, R9 is independently -CH2I. In embodiments, R9 is independently -CHCl2. In embodiments, R9 is independently -CHBr2. In embodiments, R9 is independently -CHF2. In embodiments, R9 is independently -CHI2. In embodiments, R9 is independently –CN. In embodiments, R9 is independently –OH. In embodiments, R9 is independently -NH2. In embodiments, R9 is independently –COOH. In embodiments, R9 is independently -CONH2. In embodiments, R9 is independently -NO2. In embodiments, R9 is independently –SH. In embodiments, R9 is independently -SO3H. In embodiments, R9 is independently -OSO3H. In embodiments, R9 is independently -SO2NH2. In embodiments, R9 is independently ^NHNH2. In embodiments, R9 is independently ^ONH2. In embodiments, R9 is independently ^NHC(O)NH2. In embodiments, R9 is independently -NHSO2H. In embodiments, R9 is independently -NHC(O)H. In embodiments, R9 is independently -NHC(O)OH. In embodiments, R9 is independently –NHOH. In embodiments, R9 is independently -OCCl3. In embodiments, R9 is independently -OCBr3. In embodiments, R9 is independently -OCF3. In embodiments, R9 is independently -OCI3. In embodiments, R9 is independently -OCH2Cl. In embodiments, R9 is independently -OCH2Br. In embodiments, R9 is independently -OCH2F. In embodiments, R9 is independently -OCH2I. In embodiments, R9 is independently -OCHCl2. In embodiments, R9 is independently -OCHBr2. In embodiments, R9 is independently -OCHF2. In embodiments, R9 is independently -OCHI2. In embodiments, R9 is independently unsubstituted C1-C4 alkyl. In embodiments, R9 is independently unsubstituted methyl. In embodiments, R9 is independently unsubstituted ethyl. In embodiments, R9 is independently unsubstituted propyl. In embodiments, R9 is independently unsubstituted n-propyl. In embodiments, R9 is independently unsubstituted isopropyl. In embodiments, R9 is independently unsubstituted butyl. In embodiments, R9 is independently unsubstituted n-butyl. In embodiments, R9 is independently unsubstituted isobutyl. In embodiments, R9 is independently unsubstituted tert-butyl. In embodiments, R9 is independently unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R9 is independently unsubstituted methoxy. In embodiments, R9 is independently unsubstituted
ethoxy. In embodiments, R9 is independently unsubstituted propoxy. In embodiments, R9 is independently unsubstituted n-propoxy. In embodiments, R9 is independently unsubstituted isopropoxy. In embodiments, R9 is independently unsubstituted butoxy. In embodiments, R9 is independently unsubstituted n-butoxy. In embodiments, R9 is independently unsubstituted isobutoxy. In embodiments, R9 is independently unsubstituted tert-butoxy. [0229] In embodiments, a substituted R10 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R10 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R10 is substituted, it is substituted with at least one substituent group. In embodiments, when R10 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R10 is substituted, it is substituted with at least one lower substituent group. [0230] In embodiments, a substituted ring formed when two R10 substituents are joined (e.g., substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when two R10 substituents are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when two R10 substituents are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when two R10 substituents are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when two R10 substituents are joined is substituted, it is substituted with at least one lower substituent group. [0231] In embodiments, R10 is independently oxo. In embodiments, R10 is independently halogen. In embodiments, R10 is independently –F. In embodiments, R10 is independently –Cl. In embodiments, R10 is independently –Br. In embodiments, R10 is independently –I. In embodiments, R10 is independently -CCl3. In embodiments, R10 is independently -CBr3.
In embodiments, R10 is independently -CF3. In embodiments, R10 is independently -CI3. In embodiments, R10 is independently -CH2Cl. In embodiments, R10 is independently -CH2Br. In embodiments, R10 is independently -CH2F. In embodiments, R10 is independently -CH2I. In embodiments, R10 is independently -CHCl2. In embodiments, R10 is independently -CHBr2. In embodiments, R10 is independently -CHF2. In embodiments, R10 is independently -CHI2. In embodiments, R10 is independently –CN. In embodiments, R10 is independently –OH. In embodiments, R10 is independently -NH2. In embodiments, R10 is independently –COOH. In embodiments, R10 is independently -CONH2. In embodiments, R10 is independently -NO2. In embodiments, R10 is independently –SH. In embodiments, R10 is independently -SO3H. In embodiments, R10 is independently -OSO3H. In embodiments, R10 is independently -SO2NH2. In embodiments, R10 is independently ^NHNH2. In embodiments, R10 is independently ^ONH2. In embodiments, R10 is independently ^NHC(O)NH2. In embodiments, R10 is independently -NHSO2H. In embodiments, R10 is independently -NHC(O)H. In embodiments, R10 is independently -NHC(O)OH. In embodiments, R10 is independently –NHOH. In embodiments, R10 is independently -OCCl3. In embodiments, R10 is independently -OCBr3. In embodiments, R10 is independently -OCF3. In embodiments, R10 is independently -OCI3. In embodiments, R10 is independently -OCH2Cl. In embodiments, R10 is independently -OCH2Br. In embodiments, R10 is independently -OCH2F. In embodiments, R10 is independently -OCH2I. In embodiments, R10 is independently -OCHCl2. In embodiments, R10 is independently -OCHBr2. In embodiments, R10 is independently -OCHF2. In embodiments, R10 is independently -OCHI2. In embodiments, R10 is independently unsubstituted C1-C4 alkyl. In embodiments, R10 is independently unsubstituted methyl. In embodiments, R10 is independently unsubstituted ethyl. In embodiments, R10 is independently unsubstituted propyl. In embodiments, R10 is independently unsubstituted n-propyl. In embodiments, R10 is independently unsubstituted isopropyl. In embodiments, R10 is independently unsubstituted butyl. In embodiments, R10 is independently unsubstituted n-butyl. In embodiments, R10 is independently unsubstituted isobutyl. In embodiments, R10 is independently unsubstituted tert-butyl. In embodiments, R10 is independently unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R10 is independently unsubstituted methoxy. In embodiments, R10 is independently unsubstituted ethoxy. In embodiments, R10 is independently unsubstituted propoxy. In embodiments, R10 is independently unsubstituted n- propoxy. In embodiments, R10 is independently unsubstituted isopropoxy. In embodiments,
R10 is independently unsubstituted butoxy. In embodiments, R10 is independently unsubstituted n-butoxy. In embodiments, R10 is independently unsubstituted isobutoxy. In embodiments, R10 is independently unsubstituted tert-butoxy. [0232] In embodiments, R10 is independently halogen, -CF3, unsubstituted C1-C6 alkyl, or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R10 is independently –F, -Cl, -CF3, unsubstituted methyl, or unsubstituted methoxy. [0233] In embodiments, two R10 substituents are joined to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. [0234] In embodiments, z10 is 0. In embodiments, z10 is 1. In embodiments, z10 is 2. In embodiments, z10 is 3. In embodiments, z10 is 4. In embodiments, z10 is 5. In embodiments, z10 is 6. In embodiments, z10 is 7. In embodiments, z10 is 8. In embodiments, z10 is 9. In embodiments, z10 is 10. In embodiments, z10 is 11. [0235] In embodiments, when R1 is substituted, R1 is substituted with one or more first substituent groups denoted by R1.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1.1 substituent group is substituted, the R1.1 substituent group is substituted with one or more second substituent groups denoted by R1.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1.2 substituent group is substituted, the R1.2 substituent group is substituted with one or more third substituent groups denoted by R1.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1, R1.1, R1.2, and R1.3 have values corresponding to the values of RWW, RWW.1, RWW.2,
respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R1, R1.1, R1.2, and R1.3, respectively. [0236] In embodiments, when two R1 substituents are optionally joined to form a moiety that is substituted (e.g., a substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R1.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1.1 substituent group is substituted, the R1.1
substituent group is substituted with one or more second substituent groups denoted by R1.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1.2 substituent group is substituted, the R1.2 substituent group is substituted with one or more third substituent groups denoted by R1.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1, R1.1, R1.2, and R1.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R1, R1.1, R1.2, and R1.3, respectively. [0237] In embodiments, when R1.1 is substituted, R1.1 is substituted with one or more first substituent groups denoted by R1.1.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1.1.1 substituent group is substituted, the R1.1.1 substituent group is substituted with one or more second substituent groups denoted by R1.1.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1.1.2 substituent group is substituted, the R1.1.2 substituent group is substituted with one or more third substituent groups denoted by R1.1.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1.1, R1.1.1, R1.1.2, and R1.1.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and R
, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R1.1, R1.1.1, R1.1.2, and R1.1.3, respectively. [0238] In embodiments, when R1.2 is substituted, R1.2 is substituted with one or more first substituent groups denoted by R1.2.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1.2.1 substituent group is substituted, the R1.2.1 substituent group is substituted with one or more second substituent groups denoted by R1.2.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1.2.2 substituent group is substituted, the R1.2.2 substituent group is substituted with one or more third substituent groups denoted by R1.2.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1.2, R1.2.1, R1.2.2, and R1.2.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and R , respectively, as explained in the definitions
section above in the description of first substituent group(s) , wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R1.2, R1.2.1, R1.2.2, and R1.2.3, respectively. [0239] In embodiments, when R1.3 is substituted, R1.3 is substituted with one or more first substituent groups denoted by R1.3.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1.3.1 substituent group is substituted, the R1.3.1 substituent group is substituted with one or more second substituent groups denoted by R1.3.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1.3.2 substituent group is substituted, the R1.3.2 substituent group is substituted with one or more third substituent groups denoted by R1.3.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1.3, R1.3.1, R1.3.2, and R1.3.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R1.3, R1.3.1, R1.3.2, and R1.3.3, respectively. [0240] In embodiments, when R1A is substituted, R1A is substituted with one or more first substituent groups denoted by R1A.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1A.1 substituent group is substituted, the R1A.1 substituent group is substituted with one or more second substituent groups denoted by R1A.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1A.2 substituent group is substituted, the R1A.2 substituent group is substituted with one or more third substituent groups denoted by R1A.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1A, R1A.1, R1A.2, and R1A.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R1A, R1A.1, R1A.2, and R1A.3, respectively. [0241] In embodiments, when R1B is substituted, R1B is substituted with one or more first substituent groups denoted by R1B.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1B.1 substituent group is substituted, the R1B.1 substituent group is substituted with one or more second substituent groups denoted by R1B.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1B.2 substituent group is substituted,
the R1B.2 substituent group is substituted with one or more third substituent groups denoted by R1B.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1B, R1B.1, R1B.2, and R1B.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R1B, R1B.1, R1B.2, and R1B.3, respectively. [0242] In embodiments, when R1A and R1B substituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R1A.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1A.1 substituent group is substituted, the R1A.1 substituent group is substituted with one or more second substituent groups denoted by R1A.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1A.2 substituent group is substituted, the R1A.2 substituent group is substituted with one or more third substituent groups denoted by R1A.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1A.1, R1A.2, and R1A.3 have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3 correspond to R1A.1, R1A.2, and R1A.3, respectively. [0243] In embodiments, when R1A and R1B substituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R1B.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1B.1 substituent group is substituted, the R1B.1 substituent group is substituted with one or more second substituent groups denoted by R1B.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1B.2 substituent group is substituted, the R1B.2 substituent group is substituted with one or more third substituent groups denoted by R1B.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1B.1, R1B.2, and R1B.3 have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the
description of first substituent group(s) , wherein RWW.1, RWW.2, and RWW.3 correspond to R1B.1, R1B.2, and R1B.3, respectively. [0244] In embodiments, when R1C is substituted, R1C is substituted with one or more first substituent groups denoted by R1C.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1C.1 substituent group is substituted, the R1C.1 substituent group is substituted with one or more second substituent groups denoted by R1C.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1C.2 substituent group is substituted, the R1C.2 substituent group is substituted with one or more third substituent groups denoted by R1C.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1C, R1C.1, R1C.2, and R1C.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R1C, R1C.1, R1C.2, and R1C.3, respectively. [0245] In embodiments, when R1D is substituted, R1D is substituted with one or more first substituent groups denoted by R1D.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1D.1 substituent group is substituted, the R1D.1 substituent group is substituted with one or more second substituent groups denoted by R1D.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1D.2 substituent group is substituted, the R1D.2 substituent group is substituted with one or more third substituent groups denoted by R1D.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1D, R1D.1, R1D.2, and R1D.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R1D, R1D.1, R1D.2, and R1D.3, respectively. [0246] In embodiments, when R3 is substituted, R3 is substituted with one or more first substituent groups denoted by R3.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3.1 substituent group is substituted, the R3.1 substituent group is substituted with one or more second substituent groups denoted by R3.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3.2 substituent group is substituted,
the R3.2 substituent group is substituted with one or more third substituent groups denoted by R3.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R3, R3.1, R3.2, and R3.3 have values corresponding to the values of RWW, RWW.1, RWW.2,
respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R3, R3.1, R3.2, and R3.3, respectively. [0247] In embodiments, when R2 and R3 substituents are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl), the moiety is substituted with one or more first substituent groups denoted by R2.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2.1 substituent group is substituted, the R2.1 substituent group is substituted with one or more second substituent groups denoted by R2.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2.2 substituent group is substituted, the R2.2 substituent group is substituted with one or more third substituent groups denoted by R2.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R2.1, R2.2, and R2.3 have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3 correspond to R2.1, R2.2, and R2.3, respectively. [0248] In embodiments, when R2 and R3 substituents are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl), the moiety is substituted with one or more first substituent groups denoted by R3.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3.1 substituent group is substituted, the R3.1 substituent group is substituted with one or more second substituent groups denoted by R3.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3.2 substituent group is substituted, the R3.2 substituent group is substituted with one or more third substituent groups denoted by R3.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R3.1, R3.2, and R3.3 have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3 correspond to R3.1, R3.2, and R3.3, respectively.
[0249] In embodiments, when R4 is substituted, R4 is substituted with one or more first substituent groups denoted by R4.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4.1 substituent group is substituted, the R4.1 substituent group is substituted with one or more second substituent groups denoted by R4.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4.2 substituent group is substituted, the R4.2 substituent group is substituted with one or more third substituent groups denoted by R4.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4, R4.1, R4.2, and R4.3 have values corresponding to the values of RWW, RWW.1, RWW.2,
respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R4, R4.1, R4.2, and R4.3, respectively. [0250] In embodiments, when R7 is substituted, R7 is substituted with one or more first substituent groups denoted by R7.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R7.1 substituent group is substituted, the R7.1 substituent group is substituted with one or more second substituent groups denoted by R7.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R7.2 substituent group is substituted, the R7.2 substituent group is substituted with one or more third substituent groups denoted by R7.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R7, R7.1, R7.2, and R7.3 have values corresponding to the values of RWW, RWW.1, RWW.2,
respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R7, R7.1, R7.2, and R7.3, respectively. [0251] In embodiments, when R5 and R7 substituents are optionally joined to form a moiety that is substituted (e.g., a substituted cycloalkyl or substituted heterocycloalkyl), the moiety is substituted with one or more first substituent groups denoted by R5.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5.1 substituent group is substituted, the R5.1 substituent group is substituted with one or more second substituent groups denoted by R5.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5.2 substituent group is substituted, the R5.2 substituent group is substituted with one or more
third substituent groups denoted by R5.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R5.1, R5.2, and R5.3 have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3 correspond to R5.1, R5.2, and R5.3, respectively. [0252] In embodiments, when R5 and R7 substituents are optionally joined to form a moiety that is substituted (e.g., a substituted cycloalkyl or substituted heterocycloalkyl), the moiety is substituted with one or more first substituent groups denoted by R7.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R7.1 substituent group is substituted, the R7.1 substituent group is substituted with one or more second substituent groups denoted by R7.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R7.2 substituent group is substituted, the R7.2 substituent group is substituted with one or more third substituent groups denoted by R7.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R7.1, R7.2, and R7.3 have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3 correspond to R7.1, R7.2, and R7.3, respectively. [0253] In embodiments, when R6 and R7 substituents are optionally joined to form a moiety that is substituted (e.g., a substituted cycloalkyl or substituted heterocycloalkyl), the moiety is substituted with one or more first substituent groups denoted by R6.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R6.1 substituent group is substituted, the R6.1 substituent group is substituted with one or more second substituent groups denoted by R6.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R6.2 substituent group is substituted, the R6.2 substituent group is substituted with one or more third substituent groups denoted by R6.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R6.1, R6.2, and R6.3 have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3 correspond to R6.1, R6.2, and R6.3, respectively.
[0254] In embodiments, when R6 and R7 substituents are optionally joined to form a moiety that is substituted (e.g., a substituted cycloalkyl or substituted heterocycloalkyl), the moiety is substituted with one or more first substituent groups denoted by R7.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R7.1 substituent group is substituted, the R7.1 substituent group is substituted with one or more second substituent groups denoted by R7.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R7.2 substituent group is substituted, the R7.2 substituent group is substituted with one or more third substituent groups denoted by R7.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R7.1, R7.2, and R7.3 have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3 correspond to R7.1, R7.2, and R7.3, respectively. [0255] In embodiments, when R8 is substituted, R8 is substituted with one or more first substituent groups denoted by R8.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R8.1 substituent group is substituted, the R8.1 substituent group is substituted with one or more second substituent groups denoted by R8.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R8.2 substituent group is substituted, the R8.2 substituent group is substituted with one or more third substituent groups denoted by R8.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R8, R8.1, R8.2, and R8.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R8, R8.1, R8.2, and R8.3, respectively. [0256] In embodiments, when R9 is substituted, R9 is substituted with one or more first substituent groups denoted by R9.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R9.1 substituent group is substituted, the R9.1 substituent group is substituted with one or more second substituent groups denoted by R9.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R9.2 substituent group is substituted, the R9.2 substituent group is substituted with one or more third substituent groups denoted by
R9.3 as explained in the definitions section above in the description of first substituent group(s)”. In the above embodiments, R9, R9.1, R9.2, and R9.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R9, R9.1, R9.2, and R9.3, respectively. [0257] In embodiments, when R10 is substituted, R10 is substituted with one or more first substituent groups denoted by R10.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10.1 substituent group is substituted, the R10.1 substituent group is substituted with one or more second substituent groups denoted by R10.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10.2 substituent group is substituted, the R10.2 substituent group is substituted with one or more third substituent groups denoted by R10.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R10, R10.1, R10.2, and R10.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R10, R10.1, R10.2, and R10.3, respectively. [0258] In embodiments, when two R10 substituents are optionally joined to form a moiety that is substituted (e.g., a substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R10.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10.1 substituent group is substituted, the R10.1 substituent group is substituted with one or more second substituent groups denoted by R10.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10.2 substituent group is substituted, the R10.2 substituent group is substituted with one or more third substituent groups denoted by R10.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R10, R10.1, R10.2, and R10.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R10, R10.1, R10.2, and R10.3, respectively.
[0259] In embodiments, the compound has the formula:
In embodiments, the compound has the formula:
In embodiments, the compound has the formula:
. embodiments, the compound has the formula:
embodiments, the compound has the formula:
. In embodiments, the compound has the
embodiments, the compound has the formula:
. In embodiments, the compound has the formula:
. In embodiments, the compound has the formula:
. In embodiments, the compound has the formula:
embodiments, the compound has the formula:
. embodiments, the compound has the formula:
embodiments, the compound has the formula:
embodiments, the compound has the formula:
. In embodiments, the compound has the formula:
. [0260] In embodiments, the compound is useful as a comparator compound. In embodiments, the comparator compound can be used to assess the activity of a test compound as set forth in an assay described herein (e.g., in the examples section, figures, or tables). [0261] In embodiments, the compound is a compound as described herein, including in embodiments. In embodiments the compound is a compound described herein (e.g., in the examples section, figures, tables, or claims). III. Pharmaceutical compositions [0262] In an aspect is provided a pharmaceutical composition including a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [0263] In embodiments, the pharmaceutical composition includes an effective amount of the compound. In embodiments, the pharmaceutical composition includes a therapeutically effective amount of the compound. In embodiments, the compound is a compound of formula (I), (II), (III), (IV), (V), or (VI). In embodiments, the compound is a compound of formula (I), (II), (III), (IV), (V), or (VI), including embodiments thereof. IV. Methods of use [0264] In an aspect is provided a method of treating or preventing an age-related disorder in a subject, the method including administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.
[0265] In embodiments, the compound is
[0266] In embodiments, the compound is not:
,
. [0267] In embodiments, the the age-related disorder is ischemia reperfusion injury, acute coronary syndrome, stroke, acute kidney injury, acute myocardial infarction, organ transplantation, metabolic syndrome, insulin resistance, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), noise-induced hearing loss, age-induced hearing loss, cisplatin-induced nephrotoxicity, Alzheimer’s disease, Parkinson’s disease,
cardiac hypertension, pulmonary arterial hypertension, diabetic cardiomyopathy, Type 2 diabetes, cancer growth, cancer incidence, cancer metastasis, atherosclerosis, osteoarthritis, or osteoporosis. [0268] In embodiments, the age-related disorder is ischemia reperfusion injury. In embodiments, the age-related disorder is acute coronary syndrome. In embodiments, the age- related disorder is stroke. In embodiments, the age-related disorder is acute kidney injury. In embodiments, the age-related disorder is acute myocardial infarction. In embodiments, the age-related disorder is organ transplantation. In embodiments, the age-related disorder is metabolic syndrome. In embodiments, the age-related disorder is insulin resistance. In embodiments, the age-related disorder is non-alcoholic steatohepatitis (NASH). In embodiments, the age-related disorder is non-alcoholic fatty liver disease (NAFLD). In embodiments, the age-related disorder is noise-induced hearing loss. In embodiments, the age-related disorder is age-induced hearing loss. In embodiments, the age-related disorder is cisplatin-induced nephrotoxicity. In embodiments, the age-related disorder is Alzheimer’s disease. In embodiments, the age-related disorder is Parkinson’s disease. In embodiments, the age-related disorder is cardiac hypertension. In embodiments, the age-related disorder is pulmonary arterial hypertension. In embodiments, the age-related disorder is right ventricle hypertension. In embodiments, the age-related disorder is left ventricle hypertension. In embodiments, the age-related disorder is diabetic cardiomyopathy. In embodiments, the age- related disorder is diabetic nephropathy. In embodiments, the age-related disorder is diabetic embryopathy. In embodiments, the age-related disorder is diabetes. In embodiments, the age-related disorder is Type 2 diabetes. In embodiments, the age-related disorder is pancreatic dysfunction. In embodiments, the age-related disorder is hyperglycemia. In embodiments, the age-related disorder is cancer growth. In embodiments, the age-related disorder is cancer incidence. In embodiments, the age-related disorder is cancer metastasis. In embodiments, the age-related disorder is cancer (e.g., breast cancer, lung cancer, melanoma, pancreatic cancer, prostate cancer). In embodiments, the age-related disorder is atherosclerosis. In embodiments, the age-related disorder is osteoarthritis. In embodiments, the age-related disorder is osteoporosis. In embodiments, the age-related disorder is inflammation (e.g., macrophage activation). In embodiments, the age-related disorder is an ocular disease (e.g., retina disease). In embodiments, the age-related disorder is glaucoma. In embodiments, the age-related disorder is cataract. In embodiments, the age-related disorder is drug-induced toxicity, wherein the drug is, for example, acetaminophen,
anthracyclines, AZT, NRTIs, platinum anti-cancer drugs, or methamphetamine. In embodiments, the age-related disorder is alcohol-induced toxicity. In embodiments, the age- related disorder is obesity. In embodiments, the age-related disorder is inflammatory bowel disease. In embodiments, the age-related disorder is hyposalivation. In embodiments, the age-related disorder is dry mouth. In embodiments, the age-related disorder is xerostomia. In embodiments, the age-related disorder is cognitive decline. In embodiments, the age- related disorder is cardiomyopathy. In embodiments, the age-related disorder is muscle weakness. In embodiments, the age-related disorder is muscle atrophy. In embodiments, the age-related disorder is radiation injury. In embodiments, the age-related disorder is cardiovascular disease. In embodiments, the age-related disorder is brain trauma. In embodiments, the age-related disorder is skin aging. In embodiments, the age-related disorder is mitochondrial disease. In embodiments, the age-related disorder is amyotrophic lateral sclerosis. In embodiments, the age-related disorder is periodontitis. In embodiments, the age-related disorder is hyperthermia. In embodiments, the age-related disorder is Friedrich’s Ataxia. In embodiments, the age-related disorder is a spinal deformity (e.g., scoliosis, kyphosis). In embodiments, the age-related disorder is Chagas’ disease. In embodiments, the age-related disorder is epilepsy. In embodiments, the age-related disorder is loss of olfaction. In embodiments, the age-related disorder is Leber’s hereditary optic neuropathy (LHON). In embodiments, the age-related disorder is Huntington’s disease. . Embodiments [0269] Embodiment P1. A compound, or a pharmaceutically acceptable salt thereof, having the formula:
n is an integer from 0 to 2; R1 is independently halogen, -CX13, -CHX12, -CH2X1, -OCX13, -OCH2X1, -OCHX12, -CN, -SOn1R1D, -SOv1NR1AR1B, ^NR1CNR1AR1B, ^ONR1AR1B, -NR1CC(O)NR1AR1B, -N(O)m1,
-NR1AR1B, -C(O)R1C, -C(O)OR1C, -OC(O)R1C, -OC(O)OR1C, -C(O)NR1AR1B, -OC(O)NR1AR1B, -OR1D, -SR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A, R1B, R1C, and R1D are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X1 is independently –Cl, -Br, -I, or –F; n1 is an integer from 0 to 4; m1 and v1 are independently 1 or 2; z1 is an integer from 0 to 5; X is O or NR2; R2 is hydrogen or unsubstituted C1-C6 alkyl; R3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or a prodrug moiety; R2 and R3 substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl; R4 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or a prodrug moiety;
R5 and R6 are independently hydrogen, -OH, unsubstituted C1-C6 alkyl, or unsubstituted 2 to 6 membered heteroalkyl; R5 and R7 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl; or R6 and R7 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl; R7 and R8 are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R9 is independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and z9 is an integer from 0 to 2; wherein the compound is not:
,
. [0270] Embodiment P2. The compound of embodiment P1, having the formula:
R1.2 is –NR1AC(O)R1B, -NR1ASO2R1C, -NR1AC(O)OR1B, -OR1A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1.1 and R1.3 are hydrogen; R1.1 and R1.2 substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl; or R1.2 and R1.3 substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl; X is O and R3 is hydrogen; or X is NR2 and R2 and R3 substituents are joined to form a substituted or unsubstituted heterocycloalkyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen, -OH, or unsubstituted 2 to 6 membered heteroalkyl; R5 and R7 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl; or R6 and R7 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl; R7 is hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; and R8 is substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0271] Embodiment P3. The compound of one of embodiments P1 to P2, wherein R3 is a prodrug moiety. [0272] Embodiment P4. The compound of one of embodiments P1 to P2, wherein R3 is
.
[0273] Embodiment P5. The compound of one of embodiments P1 to P4, wherein R4 is a prodrug moiety. [0274] Embodiment P6. The compound of one of embodiments P1 to P4, wherein R4 is
[0276] Embodiment P8. The compound of embodiment P2, having the formula:
[0277] Embodiment P9. The compound of one of embodiments P1 to P8, wherein R8 is substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl. [0278] Embodiment P10. The compound of one of embodiments P1 to P8, wherein R8 is substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, or substituted or unsubstituted phenyl. [0279] Embodiment P11. The compound of one of embodiments P1 to P8, wherein R8 is –OCH2CF3. [0280] Embodiment P12. The compound of embodiment P2, having the formula:
wherein Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R10 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R10 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and z10 is an integer from 0 to 11. [0281] Embodiment P13. The compound of one of embodiments P2 to P12, wherein R1.2 is –NR1AC(O)R1B. [0282] Embodiment P14. The compound of embodiment P13, wherein R1A and R1B are independently hydrogen or unsubstituted C1-C4 alkyl. [0283] Embodiment P15. The compound of one of embodiments P2 to P12, wherein R1.2 is –NHC(O)CH3, -NCH3C(O)CH3, -OH, -OCH3, or –NHSO2CH3. [0284] Embodiment P16. The compound of one of embodiments P2 to P12, wherein R1.2 is –NHC(O)CH3.
[0285] Embodiment P17. The compound of one of embodiments P1 to P12, wherein
. [0286] Embodiment P18. The compound of one of embodiments P1 to P17, wherein R6 is hydrogen, -OH, or –OCH3. [0287] Embodiment P19. The compound of one of embodiments P1 to P17, wherein R6 is hydrogen. [0288] Embodiment P20. The compound of one of embodiments P1 to P19, wherein
[0289] Embodiment P21. The compound of one of embodiments P1 to P19, wherein Ring
. [0290] Embodiment P22. The compound of one of embodiments P1 to P21, wherein R7 is unsubstituted C1-C6 alkyl. [0291] Embodiment P23. The compound of one of embodiments P1 to P21, wherein R7 is unsubstituted methyl. [0292] Embodiment P24. The compound of one of embodiments P12 to P23, wherein Ring B is 3 to 8 membered heterocycloalkyl or phenyl. [0293] Embodiment P25. The compound of one of embodiments P12 to P23, wherein Ring B is 3 to 8 membered heterocycloalkyl.
[0294] Embodiment P26. The compound of one of embodiments P12 to P23, wherein Ring B is pyrrolidinyl, piperidinyl, or morpholinyl. [0295] Embodiment P27. The compound of one of embodiments P12 to P23, wherein R10 is independently halogen, -CF3, unsubstituted C1-C6 alkyl, or unsubstituted 2 to 6 membered heteroalkyl. [0296] Embodiment P28. The compound of one of embodiments P12 to P23, wherein R10 is independently –F, -Cl, -CF3, unsubstituted methyl, or unsubstituted methoxy. [0297] Embodiment P29. The compound of one of embodiments P12 to P23, wherein z10 is 0. [0298] Embodiment P30. The compound of one of embodiments P12 to P28, wherein z10 is 1. [0299] Embodiment P31. The compound of one of embodiments P12 to P28, wherein z10 is 2.
,
. [0301] Embodiment P33. A pharmaceutical composition comprising a compound of one of embodiments P1 to P32 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [0302] Embodiment P34. A method of treating or preventing an age-related disorder in a subject, said method comprising administering to the subject a therapeutically effective amount of a compound of one of embodiments P1 to P32, or a pharmaceutically acceptable salt thereof. [0303] Embodiment P35. The method of embodiment P34, wherein the age-related disorder is ischemia reperfusion injury, acute coronary syndrome, stroke, acute kidney injury, acute myocardial infarction, organ transplantation, metabolic syndrome, insulin resistance, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), noise- induced hearing loss, age-induced hearing loss, cisplatin-induced nephrotoxicity, Alzheimer’s disease, Parkinson’s disease, cardiac hypertension, pulmonary arterial hypertension, diabetic cardiomyopathy, Type 2 diabetes, cancer growth, cancer incidence, cancer metastasis, atherosclerosis, osteoarthritis, or osteoporosis. [0304] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent
applications cited herein are hereby incorporated by reference in their entirety for all purposes. EXAMPLES Example 1: Suppression of superoxide/hydrogen peroxide production at mitochondrial site IQ decreases fat accumulation, improves glucose tolerance and normalizes fasting insulin concentration in mice fed a high-fat diet [0305] We developed S1QEL1.719, a novel bioavailable S1QEL (suppressor of site IQ electron leak). S1QEL1.719 prevented superoxide/hydrogen peroxide production at site IQ of mitochondrial complex I in vitro with a binding-corrected IC50 of 52 nM. At 50-fold higher concentrations it did not inhibit superoxide/hydrogen peroxide production from other sites. The IC50 for inhibition of complex I electron flow was 500-fold higher than the IC50 for suppression of site IQ. S1QEL1.719 was used to test the metabolic effects of suppressing the activity of site IQ in vivo. C57BL/6J male mice fed a high-fat chow for two or eight weeks had increased body fat, decreased glucose tolerance, and increased fasting insulin concentrations, classic symptoms of metabolic syndrome. Daily prophylactic or therapeutic oral treatment of high-fat-fed animals with S1QEL1.719 decreased fat accumulation, strongly protected against decreased glucose tolerance and prevented or reversed the increase in fasting insulin level. Free exposures in plasma and liver at Cmax were 2-3 fold the IC50 for suppression of superoxide/hydrogen peroxide production at site IQ and substantially below levels that inhibit electron flow through complex I. These results show that the production of superoxide/hydrogen peroxide from mitochondrial site IQ in vivo is necessary for the induction and maintenance of glucose intolerance caused by a high-fat diet in mice. They raise the possibility that oral administration of S1QELs may be beneficial in metabolic syndrome. [0306] Abbreviations [0307] AUC, area under the curve; BSA, bovine serum albumin; fu, fraction unbound; HPMC, hydroxypropyl methylcellulose; ROS, reactive oxygen species; site IQ, the site of superoxide and/or hydrogen peroxide production in mitochondrial complex I functionally associated with the ubiquinone (Q) binding site; S1QEL, suppressor of site IQ electron leak; site IIIQo, the site of superoxide production in mitochondrial complex III at the outer Q- binding site, S3QEL, suppressor of site IIIQo electron leak.
[0308] Numerous mechanisms and pathways have been suggested to initiate metabolic syndrome and the eventual development of specific diseases. In particular, there is a wealth of literature connecting metabolic syndrome to increased mitochondrial reactive oxygen species (ROS) (8-11). The most compelling evidence comes from genetic manipulations in mice. Expression or overexpression of enzymes that determine the superoxide and hydrogen peroxide concentrations in the mitochondrial matrix (superoxide dismutase 2, SOD2; peroxiredoxin 3, PRDX3; mitochondria-targeted catalase, mCAT) are all strongly protective (8,12-14). The same outcome can be achieved pharmacologically by the use of mitochondria- targeted superoxide dismutase/catalase mimetics, particularly mitoTEMPO (8,15). Further support comes from the use of less specific mitochondria-targeted antioxidants; mitoQ, mitoVitE, and the peptide SS-31 (8,16-19). These lines of evidence strongly implicate mitochondria as the source of superoxide/hydrogen peroxide, but they do not identify the specific site or sites of superoxide/hydrogen peroxide production within the mitochondria that drives the development of metabolic syndrome. [0309] Eleven different sites of superoxide/hydrogen peroxide production associated with the mitochondrial electron transport chain have been identified (20,21). Of these, site IQ in complex I, site IIIQo in complex III, and site IIF in complex II have the greatest maximum capacities to generate superoxide/hydrogen peroxide in vitro. Under simulated physiological conditions these three sites plus site IF in complex I contribute the most to mitochondrial generation of superoxide and hydrogen peroxide (22,23). In a range of cell types, sites IQ and IIIQo are important contributors to cytosolic hydrogen peroxide levels, and site IQ dominates the production of superoxide/hydrogen peroxide in the mitochondrial matrix (23-25). These considerations make site IQ a potentially important source of the mitochondrial superoxide and hydrogen peroxide that drive the development of metabolic syndrome. Brand and colleagues have identified compounds that specifically suppress superoxide/hydrogen peroxide production from site IQ (Suppressors of Site IQ Electron Leak, S1QELs) (26) and site IIIQo (Suppressors of Site IIIQo Electron Leak, S3QELs) (27) without inhibiting the electron transport chain or affecting oxidative phosphorylation. S1QELs and S3QELs have profound protective effects in cell and organ models (26-28), demonstrating the biological importance of superoxide/hydrogen peroxide production from sites IQ and IIIQo (28). [0310] Existing S1QELs and S3QELs are not well suited for systemic in vivo use because of their poor solubility and bioavailability, although they can be added to the diet to affect gut
cell function in flies (26,29) and mice (29). We recently introduced S1QEL712, a S1QEL1 with improved properties that enable its successful intraperitoneal administration to neonatal mice, and showed that it protected against systemic pathologies caused by the elevated matrix superoxide levels resulting from SOD2 knockout (30). We describe herein, inter alia, a potent, selective and orally-bioavailable S1QEL1: S1QEL1.719 (also referred to herein as 719 or S1QEL719). We use it in acute two-week and longer-term eight-week high-fat- feeding mouse models (31,32) to determine whether suppression of superoxide/hydrogen peroxide production from mitochondrial site IQ can protect against the early metabolic effects of a high fat diet. We test both prophylactic treatment from the start of two-week high-fat feeding and therapeutic treatment beginning after six weeks of high-fat feeding. [0311] Materials and Methods [0312] Reagents: Amplex UltraRed was from Thermo Fisher Scientific (Waltham, MA). Oligomycin was from Cayman Chemical (Ann Arbor, MI). Other reagents were from Sigma Aldrich (St. Louis, MO). [0313] Synthesis, properties and in vivo exposure of S1QEL1.719: The synthesis of S1QEL1.719 is described in the supplementary materials (Scheme 1). Its properties include: MW, 499.51, calculated logD7.4 (distribution coefficient at pH 7.4), 2.3; aqueous solubility, 1.5 µM (pH 7.4), 987 µM (pH 1); MDCK-MDR1 (Madin Darby canine kidney cells overexpressing MDR1, which encodes P-gp) apparent permeability Papp, 32 x 10-6 cm/sec; scaled Clint, mic (mouse) (intrinsic microsomal clearance), 12 L/hr/kg. It has suitable solubility, permeability and metabolic stability for oral administration dosed as a suspension in 0.5% w/v hydroxypropyl methylcellulose (HPMC). Total unbound exposures in mice dosed prophylactically on the high-fat diet described below, measured by mass spectrometry 2 h after oral gavage of 30 mg S1QEL1.719/kg body weight, were 110 ^ 4 nM (SEM, n = 16 animals) in plasma and 186 ^ 31 nmol/g (SEM, n = 12 animals) in liver (plasma fraction unbound (fu) = 0.04, liver fu = 0.07; fu values determined by equilibrium dialysis). Total unbound exposures in mice dosed therapeutically on the high-fat diet described below, measured by mass spectrometry 2 h after oral gavage of 30 mg S1QEL1.719/kg body weight, were 86 ^ 5 nM (SEM, n = 12 animals) in plasma and 104 ^ 7 nmol/g (SEM, n = 12 animals) in liver. These exposure values (near Cmax) were 2-3 fold greater than the IC50 of 52 nM for suppression of superoxide/H2O2 production from site IQ and 200-300 fold less than the IC50 of 30 µM for inhibition of respiration on complex I substrates, determined below using
isolated rat skeletal muscle mitochondria in vitro. A dose-depedent increase in blood lactate level was observed after 2 hours of oral dosing of S1QEL1.719 in C57BL/6J mice fed a standard vivarium chow. The S1QEL1.719 exposures achieved in the HF fed animals of this study overlap with exposures that caused a blood lactate increase, and therefore could affect the interpretation of the results. However, it is not known if this effect is seen in animals fed a HF diet. [0314] Mitochondrial assays: Except where noted, mitochondrial studies were carried out as detailed in Wong et al. (30). Mitochondria were prepared from skeletal muscles of female Wistar rats aged 8-10 weeks fed chow ad libitum with free access to water. The animal protocol was approved by the Institutional Animal Care and Use Committee of the Buck Institute (License/protocol No. A10233) in accordance with the National Institutes of Health guide for the care and use of laboratory animals (NIH Publications No.8023, revised 1978). The rates of mitochondrial superoxide/hydrogen peroxide production were assessed by 96- well microplate-based assays. The concentrations of S1QEL1.719 giving half-maximal inhibition of superoxide/hydrogen peroxide production from site IQ (IC50) in isolated mitochondria were established by titration (30). For most experiments, concentrations are given as the nominal amounts added. For the binding-corrected measurement of IC50, mitochondria in exactly parallel incubations to the IC50 determinations were centrifuged and the total S1QEL1.719 in the supernatant was measured by mass spectrometry, then corrected for binding to the 0.3% w/v bovine serum albumin (BSA) present in the medium (fu was measured using equilibrium dialysis). The high specificity of S1QEL1.719 for site IQ was confirmed using a panel of six selectivity assays of the rates of superoxide/hydrogen peroxide production from sites IQ, IIIQo, IF plus upstream dehydrogenases, IIF, PF and GQ (26,27). Measurements of mitochondrial oxygen consumption with several different substrates confirmed no inhibition of electron transport or oxidative phosphorylation at 10-fold and 50- fold the nominal IC50 for superoxide/hydrogen peroxide production from site IQ. Similarly, S1QEL1.719 at concentrations up to 50-fold this IC50 had no effect on the growth of HEK293 cells, confirming no general cell toxicity. [0315] Mice: For the prophylactic study, 13-week-old male C57BL/6J mice were purchased from The Jackson Laboratory and acclimated in-house on standard vivarium chow for two weeks before the study. For the therapeutic study, ten-week-old male C57BL/6J mice that had been fed a high-fat diet from six weeks of age were purchased from The Jackson
Laboratory and acclimated in-house on equivalent high-fat chow for two weeks before the study. During the study, animals were housed in groups of 4 per cage. A total of 24 animals per group was used for the prophylactic study, and a total of 12 animals per group was used for the therapeutic study. At 15 or 12 weeks of age respectively, mice were randomized into groups based on weight, ensuring an equal mean weight distribution between groups. From treatment day 1, mice were fed either a control semi-purified diet, D12450J, containing corn starch (10% of total kcal from fat) or a high-fat diet, D12492, otherwise the same but with corn starch replaced by lard (60% of total kcal from fat). Therapeutic study control animals were fed standard vivarium chow throughout the study because the Jackson Laboratory does not supply animals pre-fed the semi-purified diet (D12450J). Diets were from Research Diets and were gamma-irradiated. Mice were maintained on the experimental diets for two weeks and gavaged (per os; p.o.) daily from day 1 during the afternoon with 500 µl of either HPMC vehicle or 30 mg/kg S1QEL1.719 suspended in HPMC. Food consumption was measured semi-quantitatively: food provided to the cage on day 1 was weighed, and food remaining at day 8 was weighed and discarded and the amount consumed calculated by difference. The sequence was repeated for days 8-15. The food weight differences were added and divided by the number of mice in the cage to determine the total food consumption per mouse over two weeks. The animal protocol was approved by the Institutional Animal Care and Use Committee of the Buck Institute (License/protocol No. A10233) in accordance with the National Institutes of Health guide for the care and use of laboratory animals. To assess exposures to S1QEL1.719, animals were gavaged 2 h prior to take-down on day 16, when cardiac puncture was performed and tissue and plasma were collected for analysis. [0316] Body weight and composition: Body weight was measured every week (treatment days 1, 8 and 15) using a table balance. Body composition was measured on day 1 and on day 14 using an EchoMRI-100™ analyzer (EchoRMI-100™ company, Texas, U.S.A.) to measure fat and lean mass (EchoMRI ACQ-SYS (acquisition system) version 2018). [0317] Glucose and insulin: Basal fasting glucose, plasma fasting insulin levels, and glucose tolerance were assessed on treatment days 8 and 15 (prophylactic study) or day 15 (therapeutic study). Mice were fasted for 7-10 h then baseline blood glucose and plasma insulin were measured.15 µL of blood was taken from each mouse by tail bleed and placed on ice. A small amount was used for measurement of blood glucose as described below. The
remaining blood was centrifuged at 10,000 g for 5 min to isolate plasma. Plasma insulin levels were quantified using an ultrasensitive mouse insulin ELISA (Crystal Chem). [0318] For the glucose tolerance test, a bolus of glucose was given by intraperitoneal injection using a 27-gauge needle and syringe. Glucose is often given disproportionately based on body weight (33,34). Each animal received the same volume and concentration of glucose (2 g glucose/kg based on the mean total body weight of the whole cohort at that timepoint). This protocol ensured that, despite differences in total body weight, each animal received the same glucose challenge per lean body weight, which was not significantly different between groups (FIG.2F). This protocol is important because glucose is taken up mostly by muscle, and very little by fat tissue. Blood glucose was measured by tail bleed at 15, 30, 60, and 120 min after glucose injection using a Contour next EZ blood glucose- monitoring meter. For insulin measurements during the glucose tolerance tests in the therapeutic study, blood samples for glucose and plasma insulin assay were taken at 15, 30, 60, and 120 min after glucose injection. [0319] Data analysis: [0320] Data are expressed as mean ^ SEM and were analyzed by one-way ANOVA with inter-group differences detected by Dunnett’s multiple comparisons post-test and deemed significant (*) when p <0.05. Values of IC50 were determined by curve-fitting using Prism 7 ([Inhibitor] vs. normalized response-Variable slope). [0321] Potency and selectivity of S1QEL1.719 in mitochondria isolated from rat skeletal muscle. [0322] We examined the structure-activity relationships of a wide range of S1QEL1 (26) analogs to identify compounds that could be used for oral dosing in mice. A suitable compound was S1QEL1.719 (structure shown in FIG.1A). [0323] Under our standard assay conditions (30) in vitro using mitochondria isolated from rat skeletal muscle, the nominal IC50 for suppression of site IQ by S1QEL1.719 was 86 ± 8 nM (SEM, n = 19 mitochondrial preparations). This value was based on the nominal amounts of S1QEL1.719 added to the assay, as other IC50 values have been in our previous studies (26,30). However, we found that the nominal IC50 value for S1QEL1.719 varied with the experimental conditions (data not shown). For example, it appeared to depend on the concentration of mitochondria in the assay, presumably because of non-specific binding to
mitochondria, components of the medium such as BSA, and the various surfaces it was exposed to. For this reason, we withdrew supernatant samples in experiments parallel to the standard IC50 assay and measured the total supernatant concentration of S1QEL1.719 by mass spectrometry. We also used equilibrium dialysis to measure the binding of S1QEL1.719 to the 0.3% w/v BSA present in the medium and enable correction for the fraction of S1QEL1.719 that was bound to BSA (FIG.1B). Using the measured amounts of S1QEL1.719 in the mitochondrial supernatant, and correcting for its binding to BSA in the medium (fraction unbound (fu) = 0.856), the fully-corrected unbound IC50 value was 52 ± 17 nM (SEM, n = 6). These experiments show that the binding of this S1QEL to mitochondria and assay components caused the nominal IC50 to overestimate the true binding-corrected IC50. In subsequent experiments S1QEL1.719 was kept in non-dilute stocks in glass vials and made up regularly from powdered stocks in an attempt to minimize losses caused by non- specific binding. [0324] The specificity of S1QEL1.719 was tested in a standard panel of mitochondrial specificity assays using mitochondria isolated from rat skeletal muscle (26,27). At concentrations of 10-fold and 50-fold its nominal IC50 for site IQ, S1QEL1.719 had no significant effect on superoxide/hydrogen peroxide production from sites IIIQo, IF plus upstream dehydrogenases, IIF, PF and GQ. At these concentrations it had no effect on state 3, state 4 or uncoupled respiration on different substrates (26) (5 mM glutamate plus 5 mM malate, 5 mM succinate plus 4 μM rotenone, 27 mM glycerol 3-phosphate plus 4 μM rotenone, 15–60 μM palmitoylcarnitine plus 1 mM malate). However, S1QEL1.719 does inhibit complex I at higher concentrations. S1QEL1.719 inhibited coupled state 3 respiration of glutamate plus malate (a surrogate measure of complex I electron flow) with a mean nominal IC50 of 30 ± 5 µM (FIG.1C), 500-fold higher than the mean nominal IC50 for suppression of site IQ of 67 ± 10 nM under the matched conditions (FIG.1C). The nominal IC50 for inhibition of state 3 (phosphorylating) respiration divided by the nominal IC50 for suppression of superoxide/hydrogen peroxide production under closely-matched conditions of 5 µg mitochondrial protein in 20 µL of medium (220 mM mannitol, 70 mM sucrose, 10 mM KH2PO4, 5 mM MgCl2, 2 mM HEPES, 1 mM EGTA, 0.2% (w/v) fatty acid free BSA), followed by mitochondrial centrifugation for 20 min at 2000 x g for plate attachment was calculated for each mitochondrial preparation and these values were averaged to give a ratio of 500 ^ 114 (SEM, n = 6). S1QEL1.719 was also selective against a standard non- mitochondrial panel of off-target receptors, channels and transporters (Table 1). These results
show that S1QEL1.719 is a potent and specific suppressor of superoxide/hydrogen peroxide production by site IQ, but indicate that at high concentrations it can also inhibit electron transport, with potentially confounding consequences. [0325] Effects of two-week high-fat diet with and without prophylactic S1QEL1.719 treatment on food consumption, body weight and body composition. [0326] Fifteen-week-old male C57BL/6J mice were placed for two weeks on either a control diet containing 10% kcal as fat or a high-fat diet containing 60% kcal as fat (FIG. 2A). Mice on the high-fat diet were gavaged daily from treatment day 1 with either HPMC vehicle or 30 mg/kg S1QEL1.719 suspended in HPMC (FIG.2A). [0327] As expected, animals fed high-fat chow had significantly decreased food consumption compared to animals fed low-fat chow, presumably because of the difference in caloric density of the two diets. Prophylactic treatment with S1QEL1.719 did not affect food intake on the high-fat diet (FIG.2B). Feeding the high-fat diet resulted in a longitudinal increase in average body weight over two weeks compared to the low-fat diet (FIG.2C). The individual 2-week weight changes showed that this increase was significant, and was not significantly affected by treatment with S1QEL1.719 (FIG.2D). Analysis of body composition using EchoMRI revealed that high-fat fed mice accumulated an average of nearly 4 g of fat over two weeks, significantly more than their low-fat fed counterparts, which accumulated less than 1.5 g. Prophylactic treatment with S1QEL1.719 significantly decreased the fat gain of high-fat-fed animals, to only 2 g (FIG.2E). FIG.2F shows that there were no significant differences in lean body weight between low-fat and high-fat-fed animals, or with S1QEL1.719 treatment of high-fat-fed animals, although there were trends for the decreased fat accumulation in S1QEL1.719-treated animals (FIG.2E) to be offset by a non-significant increase in lean body weight (FIG.2F) and a non-significant decrease in change in total body weight (FIG.2D). Overall, prophylactic treatment of high-fat-fed mice with S1QEL1.719 had no effect on food intake or body weight, but attenuated the increase in fat mass. [0328] Effect of prophylactic treatment with S1QEL1.719 on glucose tolerance. [0329] Feeding a high-fat chow to mice for as little as three days is known to increase blood glucose level substantially and decrease the ability to clear elevated blood glucose (31). We determined whether suppression of superoxide/hydrogen peroxide production from site IQ
could improve glucose tolerance after acute feeding of a high-fat chow. A glucose tolerance test was performed after one and two weeks of high-fat feeding. [0330] After one week of high-fat feeding, there was a significantly decreased ability of high-fat fed animals to clear a bolus of glucose compared to control low-fat fed animals (FIG. 3A). FIG.3B shows the total area under the curve (AUC) from the raw trace in FIG.3A. There was a significant increase in the AUC in high-fat animals compared to controls. Prophylactic treatment of high-fat-fed animals with S1QEL1.719 resulted in a significant improvement in the removal of the glucose bolus (FIG.3A) resulting in a significant 36% decrease in AUC compared to the untreated high-fat animals (FIG.3B). This effect was maintained after two weeks of high-fat feeding (FIG.3C), with a significant 32% decrease in AUC achieved by S1QEL1.719 treatment (FIG.3D). FIG.3E plots the AUC of the glucose tolerance test longitudinally, showing a large difference between control and high-fat fed animals and a striking ability of prophylactic treatment with S1QEL1.719 to maintain the AUC close to control values. [0331] Prophylactic suppression of superoxide/hydrogen peroxide production at site IQ protects against elevation of fasting plasma insulin level. [0332] Following 7-10 h of food withdrawal, fasting blood glucose levels were measured in mice after one and two weeks of either control or high-fat feeding. Fasting blood glucose level was not significantly different between groups after one week (FIG.4A). However, after two weeks on high-fat chow, fasting blood glucose was significantly higher than the control value (FIG.4B). Prophylactic treatment with S1QEL1.719 did not significantly affect fasting blood glucose level after one or two weeks of high-fat feeding (FIGS.4A-4B). FIG. 4C shows longitudinal fasting blood glucose levels, which were similar between untreated and treated high-fat fed animals. [0333] After one week of high-fat feeding, there was a significant 94% increase in fasting plasma insulin level compared to control (FIG.4D). Treatment with S1QEL1.719 caused a significant 77% decrease when compared to untreated high-fat-fed animals (FIG.4D). After two weeks of feeding, we observed the same effect. High-fat fed animals had a significant 89% increase in fasting insulin levels, whereas S1QEL1.719 treatment caused a significant 92% decrease in insulin level compared to untreated high-fat-diet animals (FIG.4E). Longitudinally, fasting insulin level was elevated in high-fat untreated animals over two
weeks. In comparison, both control and S1QEL1.719-treated animals had consistently lower (and indistinguishable) fasting insulin levels over two weeks (FIG.4F). [0334] Therapeutic dosing of S1QEL1.719 starting after six weeks on a high-fat diet improves glucose tolerance and lowers plasma insulin concentration. [0335] FIGS.2A-2F, FIGS.3A-3E, and FIGS.4A-4F show that prophylactic S1QEL1.719 treatment protected mice against metabolic effects when dosed daily from treatment day 1 of a high-fat diet. Next, we investigated whether S1QEL1.719 protected when dosed therapeutically, i.e. dosed only after mice were fed a high-fat diet for six weeks prior to treatment, then fed the high-fat diet for a further two weeks (FIG.5A). [0336] Male C57BL/6J mice raised on the high-fat diet containing 60% kcal as fat from six weeks of age were purchased at ten weeks of age and maintained on the high-fat diet for a further two weeks before treatment with S1QEL or vehicle. Control mice raised on standard chow were purchased at ten weeks of age and maintained on standard chow for the entirety of the study. At twelve weeks of age, mice on the high-fat diet were therapeutically gavaged daily from treatment day 1 with either HPMC vehicle or 30 mg/kg S1QEL1.719 suspended in HPMC. Two-week therapeutic treatment with S1QEL1.719 did not affect food intake on the high-fat diet (FIG.5B). Continued feeding of the high-fat diet resulted in a further increase in average body weight between days 1 and 15 compared to the low-fat diet (FIG.5C). The two- week therapeutic daily dosing of S1QEL1.719 did not significantly affect change in body weight (FIG.5C). Analysis of body composition using EchoMRI revealed that high-fat fed mice accumulated an extra ~2 g of fat over two weeks, significantly more than their low-fat fed counterparts, which accumulated less than 0.15 g. Treatment with S1QEL1.719 significantly decreased the fat gain of high-fat-fed animals, to a similar level as control animals (FIG.5D), akin to what was seen with prophylactic S1QEL1.719 dosing (FIG.2E). [0337] On day 15, after a total of eight weeks of high-fat feeding, there was a significantly decreased ability of high-fat fed animals to clear a bolus of glucose compared to control low- fat fed animals (FIG.5E). Therapeutic treatment of high-fat-fed animals with S1QEL1.719 for the final two weeks resulted in a significant improvement in the removal of the glucose bolus on treatment day 15 (FIG.5E) resulting in a significant 20% decrease in AUC compared to the untreated high-fat-diet animals (not shown). On day 15, following 7-10 h of food withdrawal, fasting plasma insulin was significantly increased in high-fat-diet animals
compared to controls, and significantly decreased by 40% with S1QEL1.719 therapeutic treatment compared to untreated high-fat animals (FIG.5F). [0338] Considering that S1QEL1.719 decreased fasting plasma insulin when dosed prophylactically (FIGS.4D-4F) or therapeutically (FIG.5F), we investigated whether the improvement in glucose tolerance might be due to improved insulin sensitivity, resulting in lower insulin levels being needed to clear glucose during the test. During a glucose tolerance test, plasma insulin was measured at each time-point (0, 10, 30, 60, and 120 min). After the glucose bolus, high-fat fed animals had a higher concentration of plasma insulin compared to control animals (FIG.5G), consistent with expectations that mice fed the high-fat diet were less sensitive to insulin, and required twice the plasma concentration to clear the glucose bolus. In comparison, mice treated therapeutically with S1QEL1.719 required less plasma insulin to clear the glucose bolus than did untreated animals (FIG.5G) and had improved glucose tolerance (FIG.5E), suggesting that S1QEL1.719 may act by improving insulin sensitivity. [0339] The model of acute two-week high-fat feeding of wild-type mice (31,32) enables rapid testing of compounds for efficacy against aspects of the metabolic syndrome. Here, we show that prophylactically dosing a novel bioavailable S1QEL (S1QEL1.719) decreases body fat accumulation, improves glucose tolerance, and protects against elevated fasting plasma insulin level in this model. S1QEL1.719 treatment is also protective when given therapeutically starting after six weeks of high-fat feeding. Oral dosing of 30 mg S1QEL1.719/kg body weight achieved in vivo exposures that were 2-3 fold above the in vitro IC50 for suppressing superoxide/hydrogen peroxide production specifically from site IQ in mitochondrial complex I, but two orders of magnitude lower than the concentrations needed for off-target inhibition of electron transport through complex I, for inhibition of cell growth, or for inhibition of a wide panel of off-target receptors, ion channels and transporters. This high specificity strongly suggests that superoxide/hydrogen peroxide production from site IQ drives high-fat feeding-induced glucose intolerance, insulin resistance, and obesity, and S1QEL1.719 works by suppressing the activity of site IQ. This is consistent with the growing realization that site IQ is the major source of superoxide and hydrogen peroxide in the mitochondrial matrix under many conditions (23-25) and suggests that the activity or effect of superoxide/hydrogen peroxide production at site IQ is exacerbated under high-fat feeding. Suppression of superoxide/hydrogen peroxide production in the mitochondrial matrix from
site IQ may improve glucose tolerance and fasting plasma insulin levels by improving insulin sensitivity (as suggested by the decreased insulin levels during glucose challenge) and by decreasing body fat accumulation, which is known to aid in driving insulin resistance (35,36). S1QELs may be a new therapeutic for treating metabolic syndrome. Example 2: Experimental methods [0340] Scheme 1. Synthesis of S1QEL1.719
[0341] A mixture of 5-chloropentan-2-one (100 g, 829 mmol), isoindoline-1,3-dione (1) (61.0 g, 415 mmol) and potassium carbonate (86 g, 622 mmol) in dimethyl formamide (1 L) was stirred and heated to 80 °C for 12 h. The mixture was poured into ice water (1 L), then
extracted with ethyl acetate (2 x 1 L). The organic phase was dried with sodium sulfate and concentrated under reduced pressure to give 2-(4-oxopentyl)isoindoline-1,3-dione (2) (66.7 g, 273.8 mmol, 67% yield) as a brown solid.1H NMR (400 MHz, DMSO-d6) δ ppm 1.71 - 1.82 (m, 2 H) 2.01 - 2.07 (m, 3 H) 2.72 - 2.74 (m, 1 H) 2.88 - 2.90 (m, 1 H) 3.29 - 3.35 (m, 1 H) 3.51 - 3.58 (m, 2 H) 7.77 - 7.90 (m, 4 H); MS (ESI+) m/z 232 (M+H)+. [0342] To a solution of 2-(4-oxopentyl)isoindoline-1,3-dione (2) (10 g, 43.2 mmol) in tetrachloro carbon (100 mL) was added Br2 (2.67 mL, 51.9 mmol) at 20 °C. Then the reaction mixture was stirred at 20 °C for 4 h. The reaction mixture was concentrated under reduced pressure. The residue was triturated with methyl tertiary butyl ether (50 mL) for 1 h, filtered, and the solid was collected and concentrated under reduced pressure to give 2-(3-bromo-4- oxopentyl)isoindoline-1,3-dione (3) (10 g, 23.22 mmol, 53.7% yield) as a pale yellow solid, which was used for the next step directly. MS (ESI+) m/z 311 (M+H)+. [0343] To a solution of 2-(3-bromo-4-oxopentyl)isoindoline-1,3-dione (3) (5 g, 16.12 mmol) in ethanol (50 mL) was added thiourea (2.454 g, 32.2 mmol) at 20 °C. The reaction mixture was stirred at 80 °C for 12 h. The mixture was concentrated under reduced pressure. The residue was treated with water (50 mL) and filtered. The cake was collected and dried by high vacuum to give 2-(2-(2-amino-4-methylthiazol-5-yl)ethyl)isoindoline-1,3-dione (4) (3.33 g, 9.85 mmol, 61.1% yield) as a crude white solid, which was used for the next step directly. MS (ESI+) m/z 288 (M+H)+. [0344] To a solution of 2-(2-(2-amino-4-methylthiazol-5-yl)ethyl)isoindoline-1,3-dione (4) (3.3 g, 11.48 mmol) copper(II) bromide (2.82 g, 12.63 mmol) in acetonitrile (30 mL) was added tert-butyl nitrite (1.421 g, 13.78 mmol) at 0 °C under N2. Then the reaction was stirred at 20 °C for 4 h. The reaction mixture was quenched by addition of water (200 mL) at 0 °C. The mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic phases were washed with brine (3 x 100 mL), and dried over sodium sulfate. It was filtered and concentrated under reduced pressure. The residue was triturated with methyl tertiary butyl ether (50 mL) for 1 h, filtered, and the solid was collected and dried under reduced pressure to give 2-(2-(2-bromo-4-methylthiazol-5-yl)ethyl)isoindoline-1,3-dione (5) (1.8g, 4.87 mmol, 42.4% yield) as a crude yellow solid, which was used for the next step directly. MS (ESI+) m/z 352 (M+H)+. [0345] A solution of 2-(2-(2-bromo-4-methylthiazol-5-yl)ethyl)isoindoline-1,3-dione (5) (1 g, 2.85 mmol) in aqueous HBr (0.155 mL, 2.85 mmol) was stirred at 100 °C for 12 h. The
mixture was concentrated under reduced pressure to give 2-(2-bromo-4-methylthiazol-5- yl)ethan-1-amine hydrobromide (6) (0.6 g, 2.306 mmol, 81% yield) as a crude black solid, which was used for the next step directly. MS (ESI+) m/z 222 (M+H)+. [0346] To a solution of 2-(2-bromo-4-methylthiazol-5-yl)ethan-1-amine hydrobromide (6) (50 g, 166 mmol) in dimethyl formamide (500 mL) was added di-tert-butyl dicarbonate (54.2 g, 248 mmol) and triethylamine (81 mL, 579 mmol) dropwise at 20 °C. The reaction mixture was stirred at 20 °C for 12 h. The mixture was diluted with water (1 L), and extracted with ethyl acetate (3 x 200 mL). The combined organic layer was washed with saturated brine (3 x 200 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column (petroleum ether:ethyl acetate = 20:1 to 10:1) to give tert-butyl (2-(2-bromo-4-methylthiazol-5-yl)ethyl)carbamate (7) (23 g, 37.9 mmol, 22.92% yield) as a colorless oil.1H NMR (400 MHz, DMSO-d6) δ ppm 1.28 - 1.40 (m, 9 H) 2.22 - 2.26 (m, 3 H) 2.79 - 2.86 (m, 2 H) 3.04 - 3.11 (m, 2 H) 3.30 - 3.36 (m, 7 H) 6.97 (br t, J=5.32 Hz, 1 H); MS (ESI+) m/z 322 (M+H)+. [0347] A suspension of tert-butyl (2-(2-bromo-4-methylthiazol-5-yl)ethyl)carbamate (7) (2.4g, 7.32 mmol), (R)-2-(trifluoromethyl)morpholine, hydrochloric acid (1.753 g, 9.15 mmol) and cesium carbonate (7.87 g, 24.16 mmol) in 1,4-dioxane (30 mL) was degassed with nitrogen for 5 min and then treated with methanesulfonato(2-dicyclohexylphosphino-2',6'-di- iso-propoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (RuPhos Gen 4, 0.612 g, 0.732 mmol). The reaction mixture was stirred at 85 °C for 96 h. The reaction mixture was diluted with dichloromethane (100 mL). The brown orange slurry was filtered through celite. The filtrate was concentrated under reduced pressure. The residue was purified by flash column (eluted with 0-40% petroleum ether/ethyl acetate) to give tert-butyl (R)-(2-(4-methyl- 2-(2-(trifluoromethyl)morpholino)thiazol-5-yl)ethyl)carbamate (8) (11 g, 14.74 mmol, 44.8% yield) as a light-yellow solid.1H NMR (400 MHz, Chloroform-d) δ ppm 1.45 (s, 8 H) 1.40 - 1.49 (m, 1 H) 1.57 (s, 3 H) 2.18 (s, 3 H) 2.81 (br t, J=6.44 Hz, 2 H) 3.04 - 3.34 (m, 4 H) 3.65 (dd, J=12.69, 1.31 Hz, 1 H) 3.78 (td, J=11.69, 2.88 Hz, 1 H) 3.97 - 4.15 (m, 3 H) 4.62 (br s, 1 H); MS (ESI+) m/z 396 (M+H)+. [0348] To a solution of (R)-tert-butyl (2-(4-methyl-2-(2- (trifluoromethyl)morpholino)thiazol-5-yl)ethyl)carbamate (8) (2.7 g, 6.83 mmol) in dichloromethane (22.76 mL) was added hydrogen chloride in dioxane (8.53 mL, 34.1 mmol) dropwise. The reaction mixture was stirred for 1 h at 20 °C. It was concentrated under
reduced pressure to give (R)-2-(4-methyl-2-(2-(trifluoromethyl)morpholino)thiazol-5- yl)ethanamine hydrochloride (9). The material was used in the subsequent step without further purification.1H NMR (400 MHz, DMSO-d6) δ ppm 8.28 (s, 2H), 4.48 (ddd, J = 10.2, 6.6, 3.1 Hz, 1H), 4.21 (d, J = 12.7 Hz, 1H), 4.15 - 4.04 (m, 1H), 3.79 (td, J = 9.0, 4.6 Hz, 2H), 3.43 - 3.27 (m, 2H), 3.05 - 2.86 (m, 4H), 2.23 (s, 3H); MS (ESI+) m/z 332 (M+H)+. [0349] To a solution of 2-((3-acetamidophenyl)amino)-2-oxoacetic acid (1.969 g, 8.86 mmol) in dimethyl formamide (28.1 mL) were added 2,6-lutidine (3.93 mL, 33.8 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (3.53 g, 9.28 mmol). The reaction mixture was stirred then (R)-2-(4- methyl-2-(2-(trifluoromethyl)morpholino)thiazol-5-yl)ethanamine hydrochloride (9) (2.8 g, 8.44 mmol) was added. The reaction mixture was stirred for 1 h at 20 °C. Water (150 mL) was added to form a white solid. The solid was filtered and was washed with water (75 mL) three times. The wet solid was stirred with methanol/dichloromethane/ethyl acetate (1:5:5) mixture then it was concentrated until 30-50 mL of solvent was left. It was triturated with heptane. The white solid was filtered and washed with dichloromethane (50 mL) to give (R)- N1-(3-acetamidophenyl)-N2-(2-(4-methyl-2-(2-(trifluoromethyl)morpholino)thiazol-5- yl)ethyl)oxalamide (S1QEL1.719) (3.5 g, 7.01 mmol, 83% yield) as white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 10.55 (s, 1H), 9.96 (s, 1H), 9.02 (t, J = 6.1 Hz, 1H), 8.08 (t, J = 2.0 Hz, 1H), 7.45 - 7.32 (m, 2H), 7.23 (t, J = 8.1 Hz, 1H), 4.43 - 4.29 (m, 1H), 4.07 - 3.99 (m, 1H), 3.95 - 3.86 (m, 1H), 3.72 (td, J = 11.6, 2.9 Hz, 1H), 3.57 - 3.48 (m, 1H), 3.31 (s, 2H), 3.10 (ddd, J = 12.7, 11.6, 3.6 Hz, 1H), 3.01 (dd, J = 12.3, 10.6 Hz, 1H), 2.84 (t, J = 7.1 Hz, 2H), 2.10 (s, 3H), 2.03 (s, 3H); MS (ESI+) m/z 500 (M+H)+. [0350] Table 1. Activity of S1QEL1.719 against GPCRs, ion channels and transporters, performed at Eurofins Discovery – CEREP (Celle L’Evescault, France). No off-target inhibition reached 60% at 10 µM SIQEL719, 200 x the on-target IC50 for suppression of superoxide/hydrogen peroxide production by site IQ.
Example 3: Biological activity [0351] Table 2. Biological activity
REFERENCES [0352] 1. Hirode, G. & Wong, R. J.2011-2016. JAMA 323, 2526–2528 (2020). 2. Saklayen, M. G. Curr. Hypertens. Rep.20, 12 (2018). 3. Alberti, K. G. M. M. et al. Circulation 120, 1640–1645 (2009). 4. McNamara, K., Alzubaidi, H. & Jackson, J. K.
Integr. Pharm. Res. Pract.8, 1–11 (2019). 5. Benjamin, E. J. et al. Circulation 139, 56–528 (2019). 6. Rodgers, J. L. et al. J. Cardiovasc. Dev. Dis.6, 19 (2019). 7. Yazdanyar, A. & Newman, A. B. Clin. Geriatr. Med.25, 563–577 (2009). 8. Brand, M. D. Crit. Rev. Biochem. Mol. Biol.55, 592–661 (2020). 9. Forrester, S. J., Kikuchi, D. S., Hernandes, M. S., Xu, Q. & Griendling, K. K. Circ. Res.122, 877–902 (2018). 10. Bhatti, J. S., Bhatti, G. K. & Reddy, P. H. Biochim. Biophys. Acta - Mol. Basis Dis.1863, 1066–1077 (2017). 11. James, A. M., Collins, Y., Logan, A. & Murphy, M. P. Trends Endocrinol. Metab.23, 429–34 (2012). 12. Liu, Y. et al. Biochem. Biophys. Res. Commun.438, 78–83 (2013). 13. Chen, L. et al. Aging Cell 7, 866–78 (2008). 14. Lee, H.-Y. et al. Diabetes 66, 2072–2081 (2017). 15. Jeong, E. M. et al. J. Am. Heart Assoc.5, (2016). 16. Mercer, J. R. et al. Free Radic. Biol. Med.52, 841–849 (2012). 17. Feillet-Coudray, C. et al. Free Radic. Res.48, 1232–1246 (2014). 18. Mao, G. et al. J. Nutr.140, 1425–1431 (2010). 19. Anderson, E. J. et al. J. Clin. Invest.119, 573–81 (2009). 20. Brand, M. D. Free Radic. Biol. Med.100, 14–31 (2016). 21. Wong, H.- S., Dighe, P. A., Mezera, V., Monternier, P.-A. & Brand, M. D. J. Biol. Chem.292, 16804– 16809 (2017). 22. Goncalves, R. L. S., Quinlan, C. L., Perevoshchikova, I. V., Hey- Mogensen, M. & Brand, M. D. J. Biol. Chem.290, 209–227 (2015). 23. Goncalves, R. L. S., Watson, M. A., Wong, H. S., Orr, A. L. & Brand, M. D. Redox Biol.28, 101341 (2020). 24. Fang, J., Wong, H.-S. & Brand, M. D. Redox Biol.37, 101722 (2020). 25. Wong, H.-S., Benoit, B. & Brand, M. D. Free Radic. Biol. Med.130, 140–150 (2019). 26. Brand, M. D. et al. Cell Metab.24, 582–592 (2016). 27. Orr, A. L. et al. Nat. Chem. Biol.11, (2015). 28. Watson, M. A., Wong, H.-S. & Brand, M. D. Biochem. Soc. Trans.47, 1461–1469 (2019). 29. Watson, M. A. et al. Aging Cell (2021). In press. doi: 10.1111/acel.13476. 30. Wong, H.- S. et al. Free Radic. Biol. Med.164, 223–232 (2021). 31. Williams, L. M. et al. PLoS One 9, e106159 (2014). 32. Paglialunga, S., Ludzki, A., Root-McCaig, J. & Holloway, G. P. Diabetologia 58, 1071–1080 (2015). 33. McGuinness, O. P., Ayala, J. E., Laughlin, M. R. & Wasserman, D. H. Am. J. Physiol. Endocrinol. Metab.297, E849-55 (2009). 34. Andrikopoulos, S., Blair, A. R., Deluca, N., Fam, B. C. & Proietto, J. Am. J. Physiol. Endocrinol. Metab.295, E1323-32 (2008). 35. Goodpaster, B. H., Kelley, D. E., Wing, R. R., Meier, A. & Thaete, F. L. Diabetes 48, 839–47 (1999). 36. Gabriely, I. et al. Diabetes 51, 2951–8 (2002). 37. Orr, A. L. et al. Free Radic. Biol. Med.65, 1047–1059 (2013). 38. Wong, H. S., Monternier, P. A. & Brand, M. D. Free Radic. Biol. Med.143, 545–559 (2019). 39. Fang, J. et al. Free Radic. Biol. Med.188, 92–102 (2022).
Claims
WHAT IS CLAIMED IS: 1. A compound, or a pharmaceutically acceptable salt thereof, having the formula:
n is an integer from 0 to 2; R1 is independently halogen, -CX13, -CHX12, -CH2X1, -OCX13, -OCH2X1, -OCHX1 2, -CN, -SOn1R1D, -SOv1NR1AR1B, ^NR1CNR1AR1B, ^ONR1AR1B, -NR1CC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)OR1C, -OC(O)R1C, -OC(O)OR1C, -C(O)NR1AR1B, -OC(O)NR1AR1B, -OR1D, -SR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A, R1B, R1C, and R1D are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X1 is independently –Cl, -Br, -I, or –F; n1 is an integer from 0 to 4; m1 and v1 are independently 1 or 2; z1 is an integer from 0 to 5;
X is O or NR2; R2 is hydrogen or unsubstituted C1-C6 alkyl; R3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or a prodrug moiety; R2 and R3 substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl; R4 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or a prodrug moiety; R5 and R6 are independently hydrogen, -OH, unsubstituted C1-C6 alkyl, or unsubstituted 2 to 6 membered heteroalkyl; R5 and R7 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl; or R6 and R7 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl; R7 and R8 are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R9 is independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and z9 is an integer from 0 to 2; wherein the compound is not:
R1.2 is –NR1AC(O)R1B, -NR1ASO2R1C, -NR1AC(O)OR1B, -OR1A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1.1 and R1.3 are hydrogen; R1.1 and R1.2 substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl; or R1.2 and R1.3 substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl; X is O and R3 is hydrogen; or X is NR2 and R2 and R3 substituents are joined to form a substituted or unsubstituted heterocycloalkyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen, -OH, or unsubstituted 2 to 6 membered heteroalkyl; R5 and R7 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl; or R6 and R7 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl; R7 is hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; and R8 is substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 3. The compound of claim 1, wherein R3 is a prodrug moiety. O 4. The compound of claim 1, wherein R3 is
. 5. The compound of claim 1, wherein R4 is a prodrug moiety. O 6. The compound of claim 1, wherein R4 is
. 7. The compound of claim 2, having the formula:
8. The compound of claim 2, having the formula:
9. The compound of claim 1, wherein R8 is substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl. 10. The compound of claim 1, wherein R8 is substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, or substituted or unsubstituted phenyl. 11. The compound of claim 1, wherein R8 is –OCH2CF3. 12. The compound of claim 2, having the formula:
wherein Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R10 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R10 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and z10 is an integer from 0 to 11. 13. The compound of claim 2, wherein R1.2 is –NR1AC(O)R1B. 14. The compound of claim 13, wherein R1A and R1B are independently hydrogen or unsubstituted C1-C4 alkyl. 15. The compound of claim 2, wherein R1.2 is –NHC(O)CH3, -NCH3C(O)CH3, -OH, -OCH3, or –NHSO2CH3. 16. The compound of claim 2, wherein R1.2 is –NHC(O)CH3.
. 18. The compound of claim 1, wherein R6 is hydrogen, -OH, or –OCH3. 19. The compound of claim 1, wherein R6 is hydrogen. 20. The compound of claim 1, wherein
21. The compound of claim 1, wherein Ring A is
. 22. The compound of claim 1, wherein R7 is unsubstituted C1-C6 alkyl. 23. The compound of claim 1, wherein R7 is unsubstituted methyl. 24. The compound of claim 12, wherein Ring B is 3 to 8 membered heterocycloalkyl or phenyl. 25. The compound of claim 12, wherein Ring B is 3 to 8 membered heterocycloalkyl. 26. The compound of claim 12, wherein Ring B is pyrrolidinyl, piperidinyl, or morpholinyl. 27. The compound of claim 12, wherein R10 is independently halogen, -CF3, unsubstituted C1-C6 alkyl, or unsubstituted 2 to 6 membered heteroalkyl. 28. The compound of claim 12, wherein R10 is independently –F, -Cl, -CF3, unsubstituted methyl, or unsubstituted methoxy. 29. The compound of claim 12, wherein z10 is 0. 30. The compound of claim 12, wherein z10 is 1. 31. The compound of claim 12, wherein z10 is 2.
32. The compound of claim 1, having the formula: ,
. 33. A pharmaceutical composition comprising a compound of one of claims 1 to 32 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
34. A method of treating or preventing an age-related disorder in a subject, said method comprising administering to the subject a therapeutically effective amount of a compound of one of claims 1 to 32, or a pharmaceutically acceptable salt thereof. 35. The method of claim 34, wherein the age-related disorder is ischemia reperfusion injury, acute coronary syndrome, stroke, acute kidney injury, acute myocardial infarction, organ transplantation, metabolic syndrome, insulin resistance, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), noise-induced hearing loss, age-induced hearing loss, cisplatin-induced nephrotoxicity, Alzheimer’s disease, Parkinson’s disease, cardiac hypertension, pulmonary arterial hypertension, diabetic cardiomyopathy, Type 2 diabetes, cancer growth, cancer incidence, cancer metastasis, atherosclerosis, osteoarthritis, or osteoporosis.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US202263413479P | 2022-10-05 | 2022-10-05 | |
US63/413,479 | 2022-10-05 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2024076635A2 true WO2024076635A2 (en) | 2024-04-11 |
Family
ID=90608662
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2023/034468 WO2024076635A2 (en) | 2022-10-05 | 2023-10-04 | Suppressors of site iq electron leak and uses thereof |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2024076635A2 (en) |
-
2023
- 2023-10-04 WO PCT/US2023/034468 patent/WO2024076635A2/en unknown
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11891402B2 (en) | Compositions and methods for treating cancer | |
AU2017358901B2 (en) | Compounds and methods for modulating interleukin-2-inducible T-cell kinase | |
AU2013323426A1 (en) | Modulation of ire1 | |
AU2020270487B2 (en) | PCNA inhibitors | |
EP3350181B1 (en) | Her3 ligands and uses thereof | |
ES2762193T3 (en) | Protein tyrosine phosphatase 1 agonists containing Src-2 homology domain and treatment methods using the same | |
WO2014145642A9 (en) | Nrf2 small molecule inhibitors for cancer therapy | |
WO2019183600A1 (en) | Methods and compounds for targeted autophagy | |
US20180346499A1 (en) | Pct/us2016/063408 | |
Abdelaal et al. | Reversing oncogenic transformation with iron chelation | |
JP6933644B2 (en) | Androgen receptor antagonist | |
WO2020047518A1 (en) | Ire1 kinase inhibitors and uses thereof | |
BR112019022015A2 (en) | SMALL MOLECULE INHIBITORS OF BCL-2 ASSOCIATED DEATH PROMOTER | |
WO2024076635A2 (en) | Suppressors of site iq electron leak and uses thereof | |
WO2021163192A1 (en) | Myc inhibitors and uses thereof | |
WO2024016000A2 (en) | Eif4a inhibitors and uses thereof | |
US20210009551A1 (en) | Compounds and methods for treating fibrosis or cancer | |
WO2021133742A1 (en) | Stabilization of mhc complexes | |
WO2016085825A1 (en) | Estrogen receptor modulators | |
WO2024044649A2 (en) | GTPase INHIBITORS AND USES THEREOF | |
WO2005041953A1 (en) | Bisindolyl maleimides useful for treating prostate cancer and akt-mediated diseases | |
EP3765442A1 (en) | Amphiphilic thiol compounds and uses thereof | |
WO2023141635A2 (en) | Her3 ligands and uses thereof | |
WO2017205611A1 (en) | Estrogen receptor modulator combinations | |
KR20100015086A (en) | Composition for prevention or treatment of cancer or cardiovascular disease containing thioxo-thiazolidin-one derivatives or pharmaceutically acceptable salts thereof inhibiting erk2 as an active ingredient |