GPX4 inhibitors and senolytic compounds and their uses

Abstract

This invention relates to compounds that kill senescent cells, i.e., senolistic compounds, and compounds that inhibit GPX4. Furthermore, this invention provides compounds and methods for treating age-related diseases or disorders, as well as compounds and methods for treating diseases or disorders affected by GPX4.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Applications No. 63 / 505,128, No. 63 / 567,749, and No. 63 / 572,605, filed on 31 May 2023, 20 March 20, 2024, and 1 April 2024, respectively, under 119(e) of the U.S. Patent Act. These applications are incorporated herein by reference in their entirety for all purposes.

[0002] This invention relates to compounds that kill senescent cells, i.e., senolistic compounds and compounds that inhibit GPX4. Furthermore, this invention provides compounds and methods for treating age-related diseases or disorders, as well as compounds and methods for treating diseases or disorders affected by GPX4. [Background technology]

[0003] Aging is a cellular program that forces damaged or old cells to stably cease to replicate. Senescent cells undergo not only cessation of proliferation but also significant phenotypic changes, including chromatin rearrangement, increased beta-galactosidase activity (called senescence-associated beta-galactosidase or SA-β-Gal), and the secretion of several factors, primarily pro-inflammatory, collectively known as the senescence-associated secretory phenotype (SASP).

[0004] Replicational senescence is activated when cells in culture are continuously passaged (or as cells age in an organism). Senescence can also be induced by, for example, oncogene activation, radiation, and exposure to chemotherapy drugs. In addition, several drugs exist that induce senescence, the most representative of which are CDK4 / CDK6 inhibitors such as palbociclib.

[0005] The stable cessation of proliferation, a characteristic of aging, is achieved through the activation of the p16 / Rb and p53 / p21 pathways. Cyclin-dependent kinase inhibitor p16 INK4aFurthermore, p21Cip1 inhibits CDK activity, leading to Rb hypophosphorylation and G1 phase growth arrest (Kuilman et al., Genes Dev 2010, Vol. 24, pp. 2453-2479). In addition, p16 INK4a It is specifically induced during aging and is used alone or in combination with other markers, such as SA-β-Gal activity and the formation of senescence-associated heterochromatin foci (SAHF), to identify senescent cells.

[0006] Senescent cells accumulate with age and are associated with numerous diseases, including cancer, fibrosis, and many age-related conditions. Recent evidence suggests that senescent cells are detrimental in multiple pathological conditions, and their elimination may confer numerous benefits, including improvement of multiple conditions and increased lifespan.

[0007] Senescent cells are present in numerous preneoplastic lesions, fibrous tissues (e.g., liver, kidneys, heart, pancreas), and old tissues. Senescent cells are also associated with a great many other conditions, including neurological conditions (e.g., cerebral aneurysms, Alzheimer's disease, and Parkinson's disease), pulmonary conditions (e.g., idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and cystic fibrosis), ophthalmic conditions (e.g., cataracts, glaucoma, and macular degeneration), musculoskeletal conditions (e.g., sarcopenia, intervertebral disc degeneration, osteoarthritis), cardiovascular conditions (e.g., atherosclerosis, cardiac fibrosis, aortic aneurysm), renal conditions (e.g., kidney disease, transplant complications), as well as other conditions such as diabetes mellitus, mucositis, hypertension, and myelofibrosis (OMF). Senescent cells play a protective role against cancer and limit most types of fibrosis, but the accumulation of senescent cells in aging and numerous other diseases is considered detrimental.

[0008] Evidence for the numerous harmful effects of senescent cells (and the benefits of their selective elimination) has been provided by a series of studies conducted by the van Deursen lab (Baker et al., Nature 2016, Vol. 530, pp. 184-189; Baker et al., Nature 2011, Vol. 479, pp. 232-236; Childs et al., Science 2016, Vol. 354, pp. 472-477). These studies utilized transgenic mice (INK4-ATTAC mice) that specifically express inducible fusion proteins in senescent cells (p16). Ink4a (Utilizing its promoter). Activation of this fusion protein by adding a drug that induces its dimerization leads to the selective death of senescent cells.

[0009] Using the above mouse model, senescent cell clearance increased lifespan by attenuating several age-related conditions (Baker et al., Nature 2016, Vol. 530, pp. 184-189; Baker et al., Nature 2011, Vol. 479, pp. 232-236; Childs et al., Science 2016, Vol. 354, pp. 472-477). Senescent cell clearance delayed tumor formation and attenuated cataract formation, atherosclerosis, and age-related deterioration of other organs, particularly the kidneys, fatty tissue, and heart. The results obtained in INK4-ATTAC mice were partially reproduced in a different mouse model (3MR mice) in which the tk transgene is expressed in senescent cells, enabling selective elimination of senescent cells during ganciclovir treatment (Demaria et al., Dev Cell 2014, Vol. 31, pp. 722-733). Furthermore, the elimination of senescent cells in chemotherapy reduced cancer recurrence and chemotherapy-related side effects. Importantly, the elimination of senescent cells has no side effects other than delaying wound healing when senescent cells are eliminated during the healing process (Baker et al., Nature 2016, Vol. 530, pp. 184-189; Demaria et al., Dev Cell 2014, Vol. 31, pp. 722-733). However, a unified and widely supported hypothesis is that (pro-inflammatory) factors secreted by senescent cells disrupt tissue homeostasis. This suggests that the underlying mechanisms mediated by senescent cells may be responsible for the effects of numerous age-related pathologies.

[0010] Proof-concept studies have led to the identification of compounds (so-called "senolytics") that can selectively eliminate senescent cells. To date, several senolytic compounds have been identified, including dasatinib, quercetin, piperlongmin, and Bcl2 family inhibitors such as ABT-263 and ABT-737. Currently, Bcl2 family inhibitors are the most promising senolytics, having been shown to kill various senescent cells in vivo and demonstrably in transgenic mice. Bcl2 inhibitors were initially developed as a treatment for lymphoma. ABT-737 is a small molecule inhibitor of BCL-2, BCL-XL, and BCL-w, but has low solubility and oral bioavailability. ABT-263 inhibits the same molecules and is better suited for in vivo use, but causes serious thrombocytopenia as a side effect.

[0011] Iron accumulation is another sign observed in a significant number of senescent cell states. For example, replication and stress-induced senescent cell models generated in vitro have shown up to a 30-fold increase in intracellular iron levels (Killea et al., Ann. NYAcad. Sci. 2004, vol. 1019: pp. 365-267; and Masaldan et al., Redox Biol. 2018, pp. 100-115). Senescent cells have been shown to upregulate the expression of transferrin receptors and ferritin subunits, which may contribute to the observation of high levels of ferritin-bound iron accumulation in lysosomes (Masaldan et al., Redox Biol. 2018, pp. 100-115).

[0012] The main sources of oxidative damage to cellular components are reactive oxygen species (ROS) and free radicals produced as byproducts of the respiratory chain, as well as ferrous iron (Fe2), which reacts with the Fenton reaction to produce oxidative intermediates. + +H2O2→Fe3 +(+·OH+OH-). Consistent with this, it has been reported that senescent cells accumulate highly oxidized and covalently cross-linked aggregates such as lipofuscin and neurofibrillary tangles (Flor et al., Cell Death Disc. 2017, Vol. 3: p. 17075; Bae et al., Exp Mol Med. 2022, Vol. 54 (No. 6): pp. 788-800; and Dekhrodi et al., Nat. Aging 2021 (No. 1), Vol. 12: pp. 11107-1116). Furthermore, sources of ferrous and reducing agents may react with bis-allyl hydrogens of polyunsaturated lipids, generating carbon-centered radicals in lipid chains, which may lead to a series of propagation and chain branching reactions. The accumulation of lipid peroxides in the cell membrane can ultimately lead to membrane permeability and cell death, and has been reported to be a specific form of oxidative nonapoptotic cell death called "ferroptosis" (Stockwell, Cell 2022, Vol. 185 (No. 14): pp. 2401-2421).

[0013] Based on current evidence, the biochemical event of lipid peroxidation is a regulated biological process involving oxygen, membrane phospholipids, ferrous iron, glutathione (GSH), the GSH-dependent lipid hydroperoxidase glutathione peroxidase 4 (GPX4), α-tocopherol, and coenzyme Q10 (CoQ10) (Bersuker et al., Nature 2019, Vol. 575: pp. 688-692; Seibt et al., Free Radic Biol Med. 2019, Vol. 133: pp. 133-144; and Polotrack et al., FEBS J. 2022, 289*2: pp. 374-385). In particular, glutathione peroxidase 4 (GPX4) has been established as an important enzymatic regulator of iron-dependent lipid peroxidation and ferroptosis (Malorino et al., Antioxid Redox Signal. 2018, Vol. 29 (No. 1): pp. 61-74). GPX4 contains three catalytic residues of selenocysteine-glutamine-tryptophan that reduce hydroperoxides to non-toxic alcohols. Unlike other members of the glutathione peroxidase family, GPX4 is membrane-bound and reduces phospholipid hydroperoxides to phospholipid hydroxyls, thereby protecting the cell membrane from oxidative damage and negatively regulating ferroptosis (Cozza et al., Free Radic Biol Med. 2017, Vol. 112: pp. 1-11; and Lebrecque et al., Biochemistry 2021, Vol. 60 (No. 37): pp. 2761-2772).

[0014] Ferroptosis acts as a natural tumor suppressor and immune surveillance mechanism and can be induced by agents that bind to GPX4. Induction of ferroptosis by selective inhibition of GPX4 can selectively target cancer cells, including those with mesenchymal characteristics and multidrug resistance (Viswananthan et al., Nature, 2017, Vol. 547: pp. 453-457; Hangauer et al., Nature, 2017, Vol. 561: pp. 247-250; Lui et al., Biochemistry, 2018, Vol. 57, No. 14, pp. 2059-2060).

[0015] Therefore, there is a need to identify more compounds and classes of compounds that possess senolytic properties, as well as compounds that inhibit GPX-4. [Overview of the project]

[0016] In one embodiment, a compound of formula (I) that satisfies these and other needs: [ka] Alternatively, a pharmaceutically acceptable salt, hydrate, or solvate thereof is provided, where R1 is -OR 36, a substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl; R2 is -H, -CN, -CO2R7, -CONR8R9, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl; each R3 and R4 is independently H, -F, or alkyl; n is 1 or 2; R5 is -H, -CO2R 10 , -C(O)R 11 , -CONR 12 R 13, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl; R6 is -H, alkyl , substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, substituted cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl, or X = O or = NR 14 In this case, it does not exist; R 27 This includes hydrogen, halo, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, and -NR. 28 R 29 ,-NCONR 30 R 31 ,-CONR 32 R 33 , -CO2R 34 ,-NCO2R 35 X is = O, = NR 14, or -OR 15 And; R 14 is -OR 16 , -NR 17 R 18 , or -N + R 40 R 41 R 42 And; R7~R 10 , R 12 , R 13 , R 15 , and R 28 ~R 36 These are independently -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl, or R8 and R9, R 12 and R 13 , R 28 and R 29 , R 30 and R 31 , R 32 and R 33 These may, together with the atoms to which they are attached, form a cycloheteralkyl ring or a substituted cycloheteralkyl ring; R 11This is an alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl; 16 is -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, substituted heteroarylalkynyl, or a carbohydrate derivative;R 17 and R 18These are independently -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, substituted heteroarylalkynyl, or carbohydrate derivatives, R 19 CO-, R 20 R 21 NCO-, R 22 OCO- or R 23 It is SO2-, however, all substituents may be substituted with carbohydrate derivatives, R 17 and R 18 Both are R 19 CO-, R 21 R 20 NCO-, R 22 OCO-, R 23 Not SO2-, nor any combination thereof; R 19is an alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, substituted heteroarylalkynyl, or a carbohydrate derivative, or R 19 and R 17 These atoms may, together with the atoms to which they are attached, form a cycloheteralkyl ring or a substituted cycloheteralkyl ring, provided that all substituents are substituted with carbohydrate derivatives; R 20 and R 21 Independently, -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl, or a carbohydrate derivative, or R 20 and R 17These may, together with the atoms to which they are attached, form a cycloheteralkyl ring or a substituted cycloheteralkyl ring which may be substituted with =O, or R 20 and R 21 These atoms may, together with the atoms to which they are attached, form a cycloheteralkyl ring or a substituted cycloheteralkyl ring, provided that all substituents are substituted with carbohydrate derivatives; R 22 This includes alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted aryl Rylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, substituted heteroarylalkynyl, or a carbohydrate derivative, or R 22 and R 17 These atoms may, together with the atoms to which they are attached, form a cycloheteralkyl ring or a substituted cycloheteralkyl ring, provided that all substituents are substituted with carbohydrate derivatives; R 23This is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl, provided that each substituent may be substituted with a carbohydrate derivative, or R 23 and R 17 These atoms may, together with the atoms to which they are attached, form a cycloheteralkyl ring or a substituted cycloheteralkyl ring, provided that all substituents are substituted with carbohydrate derivatives; R 40 , R 41 , and R 42 It is an alkyl group.

[0017] In another embodiment, a compound of formula (II) that satisfies these and other needs: [ka] Or a pharmaceutically acceptable salt, N-oxide, hydrate, or solvate thereof is provided, 100 is -H, -CO2R 107 , -C(O)R 108 ,-CONR 109 R 110Alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl; R 101 is -OR 130 aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl; R 102 -H, -CN, -CO2R 111 ,-CONR 112 R 113, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl; each R 103 and R 104 is independently H, -F, or alkyl, provided that at least one of R 103 and R 104 is -F; q is 1 or 2; R 105 is -H, -CO2R 114 , -C(O)R 115 , -CONR 116 R 117 , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl; each R 106 is independently -H, -CO2R 118 , -C(O)R119 ,-CONR 120 R 121 , -OR 122 , -NR 123 R 124 , -NHR 125 R 126 C(O)R 127 -SO2NR 128 R 129 , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, halo, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl;s is 0, 1, or 2;R 109 ~R 113 , R 116 ~R 118 , R 120 ~R 126 , R 128 ~R 130These are independently -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl;R 107 , R 108 , R 114 , R 115 , R 116 , and R 127 These are independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl.

[0018] Furthermore, derivatives comprising salts, esters, enol ethers, enol esters, solvates, hydrates, metabolites, and prodrugs of the compounds described herein are also provided. In addition, pharmaceutical compositions comprising the compounds provided herein and pharmaceutically acceptable vehicles are provided.

[0019] In yet another embodiment, methods are provided for treating, preventing, or improving symptoms of medical disorders, such as age-related diseases or disorders, and diseases or disorders affected by GPX4. [Brief explanation of the drawing]

[0020] [Figure 1] This figure shows the gel mobility shift of the GPX4 protein in response to treatment of cultured cells with compound 21. [Figure 2] This figure shows the gel mobility shift of the GPX4 protein isolated from mouse skin treated with compound 32. [Figure 3] This figure shows that it is possible to identify competitive binding to the GPX4 protein in cultured human cells by using compounds 32 and 69 and their biotinylated analogues. [Figure 4] This figure shows that compound 32 provided herein induced a marker of cellular lipid peroxidation. [Figure 5] This figure shows that the cell death-inducing activity of compounds 18 and 32 provided herein can be inhibited by anti-ferroptizing agents. [Modes for carrying out the invention]

[0021] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art in which this invention pertains. If there are multiple definitions of a term herein, the definition in this section shall prevail unless otherwise stated.

[0022] Where used herein, unless otherwise specified, the terms “about” and “approximately” indicate, when used in relation to a numerical or range of values, that value or range may deviate to an extent that is reasonable to a person skilled in the art, while still maintaining the particular characteristic. Specifically, where used in this context, the terms “about” and “approximately” indicate that the numerical or range of values ​​may vary by 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% from the stated value or range. Also, the singular “a” and “the” include multiple references unless the context clearly indicates otherwise. For example, a reference to “compound” includes multiple such compounds, and a reference to “assay” includes one or more assays and their equivalents known to a person skilled in the art.

[0023] A dash ("-") that is not between two letters or symbols is used to indicate the attachment point of a substituent. For example, -C(O)NH2 is attached via a carbon atom. Dashes at the beginning or end of a chemical group are for convenience only, and a chemical group can be represented with or without one or more dashes without losing its usual meaning. A wavy line drawn across a line in a structure indicates the attachment point of a group. Unless chemically or structurally necessary, the order of notation or naming of chemical groups neither indicates nor implies direction.

[0024] Prefix “C” u~v The notation indicates that the subsequent group has u to v carbon atoms. It should be understood that u to v carbon atoms include carbon atoms from u+1 to v, from u+2 to v, from u+3 to v, etc., and encompass all possible permutations of u and v atoms, such as u+1 to u+3 to v, from u+1 to u+4 to v, from u+2 to u+4 to v, etc.

[0025] "Characteristics of aging," as used herein, include, but are not limited to, a systemic decline in the immune system, muscle atrophy and weakness, decreased skin elasticity, delayed wound healing, retinal atrophy, reduced lens transparency, hearing loss, osteoporosis, sarcopenia, graying hair, wrinkles, poor vision, frailty, and cognitive impairment.

[0026] "Aging-related diseases or conditions," as used herein, include, but are not limited to, degenerative or functional disorders such as Alzheimer's disease and Parkinson's disease, cataracts, macular degeneration, glaucoma, frailty, muscle weakness, cognitive impairment, atherosclerosis, acute coronary syndrome, myocardial infarction, stroke, hypertension, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), osteoarthritis, type 2 diabetes, obesity, dyslipidemia, coronary artery disease, cerebrovascular disease, periodontal disease, cancer-related impairments such as atrophy and fibrosis of various tissues, and brain and heart injuries. These include harms, as well as treatment-related myelodysplastic syndromes, and disorders associated with accelerated aging and / or defects in DNA damage repair and telomere maintenance, such as progeria syndromes (i.e., Hutchinson-Gilford progeria syndrome, Werner syndrome, Bloom syndrome, Rothumund-Thomson syndrome, Cockayne syndrome, xeroderma pigmentosum, trichorrhizosis, combined xeroderma pigmentosum-Cockayne syndrome, restrictive dermatosis), ataxia telangiectasia, Fanconi anemia, Friedreich ataxia, congenital keratosis, and aplastic anemia.

[0027] "Alkyl" refers to a saturated, branched, or linear monovalent hydrocarbon radical derived by removing one hydrogen atom from a single carbon atom of a parent alkane, either by itself or as part of another substituent. Typical alkyl groups include, but are not limited to, methyl; ethyl; propyl; e.g., propan-1-yl, propan-2-yl; and butyl, e.g., butane-1-yl, butane-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl; and so on. In some embodiments, an alkyl group consists of 1 to 20 carbon atoms (C1 to C2). 20 Alkyl(alkyl) is included. In other embodiments, the alkyl group is composed of 1 to 10 carbon atoms (C1 to C10 It contains alkyl. In yet another embodiment, the alkyl group contains 1 to 6 carbon atoms (C1 to C6 alkyl).

[0028] An "alkenyl" refers to an unsaturated, branched linear group having at least one carbon-carbon double bond, which is derived by removing one hydrogen atom from a single carbon atom of a parent alkene, either by itself or as part of another substituent. The group may be in either a cis or trans conformation with respect to the double bond. Typical alkenyl groups include, but are not limited to, ethenyl; propenyl, e.g., propa-1-en-1-yl, propa-1-en-2-yl, propa-2-en-1-yl(allyl), propa-2-en-2-yl; and butenyl, e.g., buta-1-en-1-yl, buta-1-en-2-yl, 2-methyl-propa-1-en-1-yl, buta-2-en-1-yl, buta-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, etc. In some embodiments, the alkenyl group consists of 2 to 20 carbon atoms (C2-C2). 20 It contains an alkenyl group. In other embodiments, the alkenyl group has 2 to 10 carbon atoms (C2 to C2). 10 It contains an alkenyl group. In yet another embodiment, the alkenyl group contains 2 to 6 carbon atoms (C2 to C6 alkenyl).

[0029] "Alkynyl" refers to an unsaturated branched linear group having at least one carbon-carbon triple bond, which is derived by removing one hydrogen atom from a single carbon atom of the parent alkyne, either by itself or as part of another substituent. Typical alkynyl groups include, but are not limited to, ethynyl; propynyl, e.g., propa-1-in-1-yl, propa-2-in-1-yl, etc.; and butynyl, e.g., buta-1-in-1-yl, buta-1-in-3-yl, buta-3-in-1-yl, etc. In some embodiments, the alkynyl group has 2 to 20 carbon atoms (C2 to C2). 20 It contains an alkynyl group. In other embodiments, the alkynyl group has 2 to 10 carbon atoms (C2 to C2). 10It contains an alkynyl group. In other embodiments, the alkynyl group contains 2 to 6 carbon atoms (C2 to C6 alkynyl).

[0030] "Aryl" refers to a monovalent aromatic hydrocarbon group derived by removing one hydrogen atom from a single carbon atom of a hydrophilic aromatic ring system as defined herein, either by itself or as part of another substituent. Typical aryl groups include, but are not limited to, groups derived from acetantrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluorantene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indan, indene, naphthalene, octacene, octafene, octaene, ovalene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiaden, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. In some embodiments, the aryl group is derived from 6 to 30 carbon atoms (C6 to C6). 30 It contains aryl atoms. In other embodiments, the aryl group contains 6 to 20 carbon atoms (C6 to C6). 20 It contains aryl atoms. In yet another embodiment, the aryl group has 6 to 15 carbon atoms (C6 to C6). 15 It contains aryl atoms. In yet another embodiment, the aryl group contains 6 to 10 carbon atoms (C6 to C6). 10 Includes (Aryl).

[0031] "Arylalkyl" refers to carbon atoms, typically terminal or sp, either by themselves or as part of another substituent. 3 This refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced by an aryl group as defined herein. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethane-1-yl, 1-phenylethen-1-yl, naphthylmethyl, 2-naphthylethane-1-yl, 1-naphthylethen-1-yl, naphthobenzyl, and 2-naphthophenylethane-1-yl. In some embodiments, the arylalkyl group is (C7~C 40) is an arylalkyl, and for example, the alkyl portion of an arylalkyl is (C1~C 10 ) is alkyl, and the aryl portion is (C6~C 30 ) is aryl. In other embodiments, the arylalkyl group is (C7~C 30 ) is an arylalkyl, and for example, the alkyl portion of an arylalkyl is (C1~C 10 ) is alkyl, and the aryl portion is (C6~C 20 ) is aryl. In other embodiments, the arylalkyl group is (C7~C 20 ) is an arylalkyl, for example, the alkyl part of an arylalkyl is (C1~C8)alkyl, and the aryl part is (C6~C 12 )aryl. In yet another embodiment, the arylalkyl group is (C7~C 15 ) is an arylalkyl, for example, the alkyl part of an arylalkyl is (C1~C5)alkyl, and the aryl part is (C6~C 10 ) It is Ariel.

[0032] "Arylalkenyl" refers to an acyclic alkenyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced by an aryl group as defined herein, either by itself or as part of another substituent. In some embodiments, the arylalkenyl group is (C8~C 40 ) is an aryl alkenyl, for example, the alkenyl portion of the aryl alkenyl group is (C2~C 10 ) is an alkenyl, and the aryl portion is (C6~C 30 ) is aryl. In other embodiments, the arylalkenyl group is (C8~C 30 ) is an aryl alkenyl, for example, the alkenyl portion of the aryl alkenyl group is (C2~C 10 ) is an alkenyl, and the aryl portion is (C8~C 20 ) is aryl. In other embodiments, the arylalkenyl group is (C8~C 20 ) is an aryl alkenyl, for example, the alkenyl portion of the aryl alkenyl group is a (C2-C8) alkenyl, and the aryl portion is a (C6-C 12) is aryl. In yet another embodiment, the arylalkenyl group is (C8~C 15 ) is an aryl alkenyl, for example, the alkenyl portion of the aryl alkenyl group is a (C2-C5) alkenyl, and the aryl portion is a (C6-C 10 ) It is Ariel.

[0033] "Arylalkynyl" refers to an acyclic alkynyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced by an aryl group as defined herein, either by itself or as part of another substituent. In some embodiments, the arylalkynyl group is (C8~C 40 ) is an arylalkynyl, for example, the alkynyl portion of the arylalkynyl group is (C2~C 10 ) is an alkynyl, and the aryl portion is (C6~C 30 ) is aryl. In other embodiments, the arylalkynyl group is (C8~C 30 ) is an arylalkynyl, for example, the alkynyl portion of the arylalkynyl group is (C2~C 10 ) is an alkynyl, and the aryl portion is (C6~C 20 ) is aryl. In other embodiments, the arylalkynyl group is (C8~C 20 ) is an arylalkynyl, for example, the alkynyl portion of the arylalkenyl group is (C2~C8)alkynyl, and the aryl portion is (C6~C 12 ) is aryl. In yet another embodiment, the arylalkynyl group is (C8~C 15 ) is an arylalkynyl, for example, the alkynyl portion of the arylalkynyl group is (C2~C5)alkynyl, and the aryl portion is (C6~C 10 ) It is Ariel.

[0034] "Carbohydrate derivatives" are compounds with the general formula C attached to a group of a chemical compound. n H 2n O nThis refers to carbohydrates. In some embodiments, carbohydrate derivatives typically contain five or six carbon atoms. In other embodiments, carbohydrate derivatives are monosaccharides (e.g., glucose, fructose, galactose, ribose). In yet another embodiment, carbohydrate derivatives include disaccharides (e.g., lactose, sucrose, maltose, cellobiose, chitobiose, gentobiose, etc.). In yet another embodiment, carbohydrate derivatives include oligosaccharides (e.g., oligofructose, oligogalactose, raffinose, plantose, veracose, etc.). In yet another embodiment, carbohydrate derivatives include polysaccharides (e.g., cellulose, amylose, starch, chitin, pectin, galactogen, etc.). In yet another embodiment, carbohydrate derivatives include protected carbohydrates such as esters (e.g., acetate esters or benzoic acid esters, etc.), silyl derivatives, or carbohydrates protected with any other known alcohol protecting group.

[0035] "Compound" refers to the compounds encompassed by the structural formulas disclosed herein, and includes any specific compound whose structure is within the formulas disclosed herein. Compounds can be identified by either their chemical structure and / or chemical name. The chemical structure determines the identity of the compound. Compounds described herein may contain one or more chiral centers and / or double bonds, and therefore may exist as stereoisomers such as double bond isomers (i.e., geometric isomers), enantiomers, or diastereomers. Accordingly, the chemical structures illustrated herein include the stereoisomerically pure (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) forms illustrated in the structure. The chemical structures illustrated herein also include enantiomers and stereoisomeric derivatives of the illustrated compounds. Enantiomers and mixtures of stereoisomers can be separated into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques known to those skilled in the art. Compounds may also exist in several tautomeric forms, including enol forms, keto forms, and mixtures thereof. Therefore, the chemical structures illustrated herein encompass all possible tautomeristic forms of the illustrated compounds. The compounds described may also include isotope-labeled compounds in which one or more atoms have atomic masses different from those conventionally found in nature. Examples of isotopes that may be incorporated into the compounds disclosed herein, but are not limited to these, 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17Examples include O. Compounds may exist in solvated forms, including non-solvated and hydrated forms. Generally, compounds may be hydrated or solvated. Certain compounds may exist in multiple crystalline or amorphous forms. Generally, all physical forms are equivalent for the uses envisioned herein and are intended to be within the scope of this disclosure. Furthermore, where substructures of a compound are illustrated, it should be understood that square brackets indicate the point where the substructure attaches to the rest of the molecule.

[0036] "Cycloalkyl" refers to a saturated cyclic monovalent hydrocarbon radical derived by removing one hydrogen atom from a single carbon atom of a parent cycloalkane, either by itself or as part of another substituent. Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclopentenyl; etc. In some embodiments, a cycloalkyl group consists of 3 to 20 carbon atoms (C3 to C3). 15 It contains a cycloalkyl group. In other embodiments, the cycloalkyl group has 3 to 10 carbon atoms (C3 to C3). 10 This includes cycloalkyl groups. In other embodiments, the cycloalkyl group contains 3 to 8 carbon atoms (C3 to C8 cycloalkyl). The term "cyclic monovalent hydrocarbon radical" also includes single radicals and polycyclic hydrocarbon ring systems having 5 to 12 carbon atoms. Examples of polycyclic cycloalkyl rings include norbornyl, pinyl, and adamantyl.

[0037] A "cycloalkenyl" refers to an unsaturated cyclic monovalent hydrocarbon radical derived by removing one hydrogen atom from a single carbon atom of a parent cycloalkene, either by itself or as part of another substituent. Typical cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, and cyclopentenyl; etc. In some embodiments, a cycloalkenyl group consists of 3 to 20 carbon atoms (C3 to C2). 20It contains a cycloalkenyl group. In other embodiments, the cycloalkenyl group has 3 to 10 carbon atoms (C3 to C3). 10 It contains a cycloalkenyl group. In yet another embodiment, the cycloalkenyl group contains 3 to 8 carbon atoms (C3 to C8 cycloalkenyl).

[0038] "Cycloheteroalkyl" means a cycloalkyl group as defined herein, in which one or more carbon atoms (and any optionally associated hydrogen atoms) are replaced, either by themselves or as part of another substituent, by the same or different heteroatoms or heteroatomic groups as defined below by "heteroalkyl". In some embodiments, a cycloheteroalkyl group has 3 to 20 carbon and heteroatoms ( 3~20 It contains a cycloheteralkyl group. In other embodiments, the cycloheteralkyl group contains 3 to 10 carbon atoms and heteroatoms. 3~10 It contains a cycloheteralkyl group. In other embodiments, the cycloheteralkyl group contains 3 to 8 carbon atoms and heteroatoms. 3~8 This includes cycloheteralkyls. Furthermore, the term "cyclic monovalent heteroalkyl radical" includes single radicals and polycyclic heteroalkyl ring systems having 3 to 12 carbon atoms and at least one heteroatom. Exemplary cycloheteralkyls include, for example, azetidine, pyrrolidine, piperazine, piperidine, morpholine, and tetrahydrofuran.

[0039] "Cycloheteralkenyl" refers to a cycloalkenyl group as defined herein, in which one or more carbon atoms (and any optionally associated hydrogen atoms) are replaced, either by themselves or as part of another substituent, by the same or different heteroatoms or heteroatomic groups as defined below in "heteralkenyl". In some embodiments, the cycloheteralkenyl group consists of 3 to 20 carbon and heteroatoms ( 3~20 It contains a cycloheteralkenyl group. In other embodiments, the cycloheteralkenyl group consists of 3 to 10 carbon atoms and heteroatoms. 3~10It contains a cycloheteralkenyl group. In other embodiments, the cycloheteralkenyl group has 3 to 8 carbon atoms and heteroatoms. 3~8 This includes cycloheteralkenyls. Furthermore, the term "cyclic monovalent heteroalkenyl radical" includes single radicals and polycyclic heteroalkenyl ring systems having 2 to 12 carbon atoms and at least one heteroatom.

[0040] As used herein, "DNA damage therapy" includes, but is not limited to, the following: irradiation, alkylating agents, e.g., nitrogen mustards (e.g., chlorambucil, cyclophosphamide, ifosfamide, melphalan), nitrosoureas (streptozocin, carmustine, lomustine), alkyl sulfonates (e.g., busulfan), triazines (dacarbazine, temozolomide), and ethyleneimines (e.g., thiotepa, altoretamine), platinum-based drugs, e.g., cisplatin, carboplatin, oxalaplatin, etc., antimetabolites, e.g., 5-fluorouracil, 6-mercaptopurine, capecitabine, cladribine, clopharabine, cytarabine, phloxuridine, fludarabine, gemcitabine Antitumor antibiotics such as hydroxyureas, methotrexate, pemetrexed, pentostatin, thioguanine, anthracyclines such as daunorubicin, doxorubicin, epirubicin, idarubicin, etc., actinomycin-D, bleomycin, mitomycin-C, mitoxantrone, topoisomerase inhibitors such as topoisomerase I inhibitors (e.g., topotecan, irinotecan) and topoisomerase II inhibitors (e.g., etoposide, teniposide, mitoxantrone), mitotic inhibitors such as taxanes (e.g., paclitaxel, docetaxel), epothyron (e.g., ixabepyrone), vinca alkaloids (e.g., vinblastine, vincristine, vinorelbine), and estramustine.

[0041] "Halo" refers to a radical -F, -Cl, -Br, or -I, either by itself or as part of another substituent.

[0042] A "heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and optionally any accompanying hydrogen atoms) are replaced, each independently, by the same or different heteroatoms or heteroatomic groups. Typical heteroatoms or heteroatomic groups that can replace carbon atoms include, but are not limited to, -O-, -S-, -N-, -Si-, -NH-, -S(O)-, -S(O)2-, -S(O)NH-, and -S(O)2NH-, as well as combinations thereof. The heteroatoms or heteroatomic groups may be located at any internal position within the alkyl group, alkenyl group, or alkynyl group. Typical heteroatoms that may be included in such groups include, but are not limited to, -O-, -S-, -OO-, -SS-, -OS-, and -NR 501 R 502 ,=NN=,-N=N-,-N=N-NR 503 R 404 ,-PR 505 -, -P(O)2-, -POR 506 -, -OP(O)2-, -SO-, -SO2-, and -SnR 507 R 508 These are some examples, and in the formula, R 501 , R 502 , R 503 , R 504 , R 505 , R 506 , R 507 , and R 508 These are independently hydrogen, alkyl, aryl, substituted aryl, heteroalkyl, heteroaryl, or substituted heteroaryl. In some embodiments, the heteroalkyl group consists of 1 to 20 carbon atoms and heteroatoms. 1~20 It contains a heteroalkyl group. In other embodiments, the heteroalkyl group contains 1 to 10 carbon atoms and a heteroatom. 1~10 It contains a heteroalkyl group. In other embodiments, the heteroalkyl group contains 1 to 6 carbon atoms and a heteroatom ( 1~6 Contains heteroalkyl groups.

[0043] A "heteroalkenyl" refers to an alkenyl group in which one or more carbon atoms (and optionally any accompanying hydrogen atoms) are replaced, each independently, by the same or different heteroatoms or heteroatomic groups. Typical heteroatoms or heteroatomic groups that can replace carbon atoms include, but are not limited to, -O-, -S-, -N-, -Si-, -NH-, -S(O)-, -S(O)2-, -S(O)NH-, and -S(O)2NH-, as well as combinations thereof. The heteroatoms or heteroatomic groups may be located at any internal position of the alkyl group, alkenyl group, or alkynyl group. Typical heteroatomic groups that may be included in such groups include, but are not limited to, -O-, -S-, -OO-, -SS-, -OS-, and -NR 501 R 502 ,=NN=,-N=N-,-N=N-NR 503 R 404 ,-PR 505 -, -P(O)2-, -POR 506 -, -OP(O)2-, -SO-, -SO2-, and -SnR 507 R 508 These are some examples, and in the formula, R 501 , R 502 , R 503 , R 504 , R 505 , R 506 , R 507 , and R 508 These are independently hydrogen, alkyl, aryl, substituted aryl, heteroalkyl, heteroaryl, or substituted heteroaryl. In some embodiments, the heteroalkenyl group consists of 1 to 20 carbon atoms and heteroatoms. 1~20 It contains a heteroalkenyl group. In other embodiments, the heteroalkenyl group consists of 1 to 10 carbon atoms and a heteroatom. 1~10 It contains a heteroalkenyl group. In other embodiments, the heteroalkenyl group consists of 1 to 6 carbon atoms and a heteroatom. 1~6 Contains heteroalkenyls.

[0044] "Heteroaryl" refers to a monovalent heteroaromatic radical derived by removing one hydrogen atom from a single carbon atom of a parent heteroaromatic ring system as defined herein, either by itself or as part of another substituent. Typical heteroaryl groups include, but are not limited to, groups derived from acridine, β-carbolin, chroman, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indidine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenantholidine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, quinazoline, quinoline, quinolidine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, and xanthene. In some embodiments, the heteroaryl group contains 5 to 20 ring atoms (5 to 20-membered heteroaryl). In other embodiments, the heteroaryl group contains 5 to 10 ring atoms (5 to 10-membered heteroaryl). Examples of heteroaryl groups include those derived from furan, thiophene, pyrrole, benzothiophene, benzofuran, benzimidazole, indole, pyridine, pyrazole, quinoline, imidazole, oxazole, isoxazole, and pyrazine.

[0045] "Heteroarylalkyl" refers to carbon atoms, typically terminal or sp, either by themselves or as part of another substituent. 3This refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced by a heteroaryl group. In some embodiments, the heteroarylalkyl group is a 6- to 21-membered heteroarylalkyl group, for example, the alkyl portion of the heteroarylalkyl group is (C1-C6) alkyl and the heteroaryl portion is a 5- to 15-membered heteroaryl group. In other embodiments, the heteroarylalkyl group is a 6- to 13-membered heteroarylalkyl group, for example, the alkyl portion is (C1-C3) alkyl and the heteroaryl portion is a 5- to 10-membered heteroaryl group.

[0046] A "heteroarylalkenyl" refers to an acyclic alkenyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced by a heteroaryl group, either by itself or as part of another substituent. In some embodiments, the heteroarylalkenyl group is a 7- to 21-membered heteroarylalkenyl, for example, the alkyl portion of the heteroarylalkenyl is a (C2-C6) alkenyl and the heteroaryl portion is a 5- to 15-membered heteroaryl. In other embodiments, the heteroarylalkenyl group is a 7- to 13-membered heteroarylalkenyl, for example, the alkenyl portion is a (C2-C3) alkenyl and the heteroaryl portion is a 5- to 10-membered heteroaryl.

[0047] A "heteroarylalkynyl" refers to an acyclic alkynyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced by a heteroaryl group, either by itself or as part of another substituent. In some embodiments, the heteroarylalkynyl group is a 7- to 21-membered heteroarylalkynyl, for example, the alkynyl moiety of the heteroarylalkynyl is a (C2-C6)alkynyl and the heteroaryl moiety is a 5- to 15-membered heteroaryl. In other embodiments, the heteroarylalkynyl group is a 7- to 13-membered heteroarylalkynyl, for example, the alkynyl moiety is a (C2-C3)alkynyl and the heteroaryl moiety is a 5- to 10-membered heteroaryl.

[0048] A “hydrate” refers to a compound described herein in which water is incorporated in stoichiometric proportions into its crystal lattice, resulting in the formation of an adduct. Methods for preparing hydrates include, but are not limited to, storage in a water vapor atmosphere, a water-containing dosage form, or routine pharmaceutical processing steps such as crystallization (i.e., from water or a mixed aqueous solvent), freeze-drying, wet granulation, aqueous film coating, or spray drying. Under certain circumstances, hydrates may also be formed from crystalline solvates upon exposure to water vapor or when anhydrous substances are suspended in water. Hydrates may crystallize in more than one form, resulting in hydrate polymorphism. See, for example, *Polymorphism in Pharmaceutical Solids*, (Brittain, H. ed.), Marcel Dekker, Inc., New York City, NY, 1999, Guillory, K., Chapter 5, pp. 202-205. The above methods for preparing hydrates are well within the knowledge of those skilled in the art, entirely conventional, and require no experiments beyond those typical in the art. Hydrates can be characterized and / or analyzed by methods well known to those skilled in the art, such as single-crystal X-ray diffraction, X-ray powder diffraction, polarized optical microscopy, thermal microscopy, thermogravimetric analysis, differential thermal analysis, differential scanning calorimetry, IR spectroscopy, Raman spectroscopy, and NMR spectroscopy. (Brittain, H., Polymorphism in Pharmaceutical Solids, (ed.), Marcel Dekker, Inc., New York City, 1999, Chapter 6, pp. 205-208). In addition, numerous private companies, such as HOLODIAG, Pharmaparc II, Voie de l'Innovation, 27 100 Val de Reuil, France (http: / / www.holodiag.com), routinely provide services including the preparation and / or characterization of hydrates.

[0049] "N-oxide" refers to a compound containing an NO bond with three additional hydrogen atoms or side chains attached to the nitrogen atom, thereby having a positive charge on the nitrogen. The N-oxides of this disclosure can be synthesized by oxidation procedures well known to those skilled in the art.

[0050] A "philophilic aromatic ring system" refers to an unsaturated or polycyclic ring system that has a conjugated p-electron system. The definition of a "philophilic aromatic ring system" particularly includes condensed ring systems in which one or more rings are aromatic and one or more rings are saturated or unsaturated, such as fluorene, indane, indene, and phenalene. Typical aromatic ring systems include, but are not limited to, acetantrylene, acenaphthylene, acephenantrylene, anthracene, azulene, benzene, chrysene, coronene, fluorantene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octafen, octalen, ovalen, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene.

[0051] A "hetero-aromatic ring system" refers to a ring system in which one or more carbon atoms (and optionally any associated hydrogen atoms) are independently replaced by the same or different heteroatoms. Typical heteroatoms that replace carbon atoms include, but are not limited to, N, P, O, S, and Si. The definition of a "hetero-aromatic ring system" specifically includes fused ring systems in which one or more rings are aromatic and one or more rings are saturated or unsaturated, such as benzodioxane, benzofuran, chroman, chromene, indole, indoline, and xanthene. Typical heteroaromatic ring systems include, but are not limited to, arsindol, carbazole, β-carbolin, chroman, chromene, cinolin, furan, imidazole, indazole, indole, indoline, indoridine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthoridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, quinazoline, quinoline, quinoridine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, and xanthene.

[0052] "Pharmacologically acceptable salts" refer to salts of compounds that have the desired pharmacological activity of the parent compound. Such salts include (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, or acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxy Acid addition salts formed with organic acids such as ethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-octo-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthic acid, salicylic acid, stearic acid, and muconic acid; (2) Salts formed when the acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion, or when it coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, and N-methylglucamine.

[0053] "Preventing" or "preventing" means reducing the risk of developing a disease or disorder (i.e., preventing at least one clinical symptom of a disease from developing in a patient who may be exposed to or susceptible to the disease but has not yet experienced or presented symptoms of the disease). The application of therapeutic agents for the prevention or prevention of a disease or disorder is known as preventive action. In some embodiments, the compounds provided herein offer superior preventive effects due to lower long-term side effects over extended periods.

[0054] As used herein, "prodrug" refers to a derivative of a drug molecule that requires conversion in the body to release the active drug. Prodrugs are often, though not always, pharmacologically inactive until they are converted to the parent drug.

[0055] As used herein, "promoiety" refers to a form of protecting group that, when used to shield a functional group within a drug molecule, converts the drug into a prodrug. Typically, the promoiety attaches to the drug via a bond that is cleaved in vivo by enzymatic or non-enzymatic means.

[0056] A "protecting group" refers to a group of atoms that, when attached to a reactive functional group in a molecule, shield, reduce, or prevent the reactivity of the functional group during chemical synthesis. Examples of protecting groups can be found in Green et al., "Protective Groups in Organic Chemistry" (Wiley, 2nd edition, 1991) and Harrison et al., "Compendium of Synthetic Organic Methods," Volumes 1-8 (John Wiley and Sons, 1971-1996). Representative amino protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilyl-ethanesulfonyl ("SES"), trityl groups and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("FMOC"), and nitro-veratryloxycarbonyl ("NVOC"). Representative hydroxy protecting groups include, but are not limited to, those in which the hydroxyl group is either acylated or alkylated, such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers, and allyl ethers.

[0057] As used herein, “senescence” or “senescent cells” refers to a state in which cells have acquired one or more markers of senescence in response to some cellular stress. Such markers typically include permanent departure from the cell cycle, expression of the bioactive secretome of inflammatory factors, methylation changes, senescence-associated heterochromatin foci (SAHF), expression of oxidative stress markers, expression of DNA damage markers, protein and lipid modifications, morphological features of senescence, lysosome / vacuole changes, and expression of senescence-associated β-galactosidase (Galluzzi et al. (eds.), Cell Senescence: Methods and Protocols, Methods in Molecular Biology, Vol. 965, DOI 10.1007 / 978-1-62703-239-1_4, (Copyright) Springer Science+Business Media, LLC 2013).

[0058] When used herein, “senolytic agent” refers to an agent that “selectively” (preferentially or to a greater degree) destroys, kills, removes, or promotes the selective destruction of senescent cells. In other words, a senolytic agent destroys or kills senescent cells in a manner that is biologically, clinically, and / or statistically significant compared to its ability to destroy or kill non-senescent cells. A senolytic agent is used in an amount and duration sufficient to selectively kill established senescent cells, but is insufficient to kill non-senescent cells in a clinically significant or biologically significant manner. In certain embodiments, the senolytic agents described herein modify at least one signaling pathway to induce (i.e., initiate, stimulate, induce, activate, or promote) the death of senescent cells, resulting in death.

[0059] A “solvate” refers to a compound described herein in which a solvent is incorporated into the crystal lattice in a stoichiometric proportion, resulting in the formation of an adduct. Methods for preparing solvates include, but are not limited to, storage in a solvent-containing atmosphere, a solvent-containing dosage form, or routine pharmaceutical processing steps such as crystallization (i.e., from a solvent or mixed solvent) or vapor diffusion. Solvates may also be formed from other crystalline solvates or hydrates under certain circumstances upon exposure to a solvent or when a substance is suspended in a solvent. Solvates may crystallize in more than one form, resulting in solvate polymorphism. See, for example, (Polymorphism in Pharmaceutical Solids, (Brittain, H. ed.), Marcel Dekker, Inc., New York City, NY, 1999, Guillory, K., Chapter 5, pp. 202-205). The above methods for preparing solvates are well within the knowledge of those skilled in the art, entirely conventional, and require no experiments beyond those typical in the art. Solvates can be characterized and / or analyzed by methods well known to those skilled in the art, such as single-crystal X-ray diffraction, X-ray powder diffraction, polarized optical microscopy, thermal microscopy, thermogravimetric analysis, differential thermal analysis, differential scanning calorimetry, IR spectroscopy, Raman spectroscopy, and NMR spectroscopy. (Brittain, H., Polymorphism in Pharmaceutical Solids, (ed.), Marcel Dekker, Inc., New York City, 1999, Chapter 6, pp. 205-208). In addition, numerous private companies, such as HOLODIAG, Pharmaparc II, Voie de l'Innovation, 27 100 Val de Reuil, France (http: / / www.holodiag.com), routinely provide services including the preparation and / or characterization of solvates.

[0060] When used to modify a particular group or radical, "substituted" means that one or more hydrogen atoms of that particular group or radical are replaced, each independently of the other, by the same or different substituents. A useful substituent for substituting the saturated carbon atoms of a given group or radical is R a Hello, -O - ,=O,-OR b , -SR b , -S - ,=S,-NR c R c ,=NR b 、=N-OR b , trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, -N-OR b , -N-NR c R c , -NR b S(O)2R b , =N2, -N3, -S(O)2R b -S(O)2NR b R b -S(O)2O - -S(O)2OR b -OS(O)2R b -OS(O)2O - -OS(O)2OR b -OS(O)2NR c NR c ,-P(O)(O - )2, -P(O)(OR b )(O - ), -P(O)(OR b )(OR b ), -C(O)R b -C(O)NR b -OR b -C(S)R b -C(NR b )R b ,-C(O)O - , -C(O)OR b , -C(S)OR b -C(O)NR c R c -C(NR b )NR c R c -OC(O)Rb ,-OC(S)R b ,-OC(O)O - , -OC(O)OR b -OC(O)NR c R c -OC(NCN)NR c R c -OC(S)OR b , -NR b C(O)R b , -NR b C(S)R b , -NR b C(O)O - , -NR b C(O)OR b , -NR b C(NCN)OR b , -NR b S(O)2NR c R c , -NR b C(S)OR b , -NR b C(O)NR c R c , -NR b C(S)NR c R c , -NR b C(S)NR b C(O)R a , -NR b S(O)2OR b , -NR b S(O)2R b , -NR b C(NCN)NR c R c , -NR b C(NR b )R b , and -NR b C(NR b )NR c R c These are listed, and in the formula, each R aEach R is independently a substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, or substituted heteroaryl; each R b Each R is independently hydrogen, substituted alkyl, substituted alkenyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl; each R c R is independent b Alternatively, two R c These, together with the nitrogen atom to which they are bonded, form a cycloheteroalkyl or cycloheteroalkenyl condensed with an aryl group which may optionally contain 4, 5, 6, or 7-membered cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl ring, or 1 to 4 additional heteroatoms, either the same or different, selected from the group consisting of O, N, and S. In certain examples, -NR c R c It is intended to include -NH2, -NH-alkyl, N-pyrrolidinyl, and N-morpholinyl. In other embodiments, useful substituents for substituting the saturated carbon atom of the specified group or radical include R a Hello, -OR b , -NR c R c , trihalomethyl, -CN, -NR b S(O)2R b , -C(O)R b -C(O)NR b -ORb , -C(O)OR b -C(O)NR c R c -OC(O)R b , -OC(O)OR b -OS(O)2NR c NR c -OC(O)NR c R c , and -NR b C(O)OR b These are listed, and in the formula, R a , R b , and R c This is as previously defined. In yet another embodiment, a substituent useful for substituting a saturated carbon atom of a given group or radical is R a Hello, -OR b , -NR c R c , trihalomethyl, -CN, -C(O)R b , -C(O)OR b -C(O)NR c R c -OC(O)R b -OC(O)NR c R c , and -NR b C(O)OR b These are listed, and in the formula, R a , R b , and R c This is as previously defined.

[0061] Useful substituents for substituting the unsaturated carbon atom of a specified group or radical include -R a Hello, -O - , -OR b , -SR b , -S - , -NR c R c Trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, -N3, -S(O)2O - -S(O)2OR b -OS(O)2R b -OS(O)2OR b -OS(O)2O- 、-P(O)(O - )2、-P(O)(OR b )(O - )、-P(O)(OR b )(OR b )、-C(O)R b 、-C(S)R b 、-C(NR b )R b 、-C(O)O - 、-C(O)OR b 、-C(S)OR b 、-C(O)NR c R c 、-C(NR b )NR c R c 、-OC(O)R b 、-OC(S)R b 、-OC(O)O - 、-OC(O)OR b 、-OC(S)OR b 、-OC(O)NR c R c 、-OS(O)2NR c NR c 、-NR b C(O)R b 、-NR b C(S)R b 、-NR b C(O)O - 、-NR b C(O)OR b 、-NR b S(O)2OR a 、-NR b S(O)2R a 、-NR b C(S)OR b 、-NR b C(O)NR c R c 、-NR b C(NR b )R b 、-NR b C(NR b )NR c R c 、および-C(NR b )NR b C(NR b )NR c Rc These are listed, and in the formula, R a , R b , and R c This is as previously defined. In other embodiments, useful substituents for substituting an unsaturated carbon atom of a given group or radical include -R a Hello, -OR b , -SR b , -NR c R c , trihalomethyl, -CN, -S(O)2OR b , -C(O)R b , -C(O)OR b -C(O)NR c R c -OC(O)R b , -OC(O)OR b -OS(O)2NR c NR c , -NR b C(O)R b , and -NR b C(O)OR b These are listed, and in the formula, R a , R b , and R c This is as previously defined. In yet another embodiment, a substituent useful for substituting an unsaturated carbon atom of a given group or radical is -R a Hello, -OR b , -NR c R c , trihalomethyl, -S(O)2OR b , -C(O)R b , -C(O)OR b -C(O)NR c R c -OC(O)R b , -NR b C(O)R b , and -NR b C(O)OR b These are listed, and in the formula, R a , R b , and R c This is as previously defined.

[0062] Useful substituents for substituting the nitrogen atom of heteroalkyl and cycloheteralkyl groups include, but are not limited to, -R a , -O - , -OR b , -SR b , -S - , -NR c R c , trihalomethyl, -CF3, -CN, -NO, -NO2, -S(O)2R b -S(O)2O - -S(O)2OR b -OS(O)2R b -OS(O)2O - -OS(O)2OR b ,-P(O)(O - )2, -P(O)(OR b )(O - ), -P(O)(OR b )(OR b ), -C(O)R b ,-C(S)R b -C(NR b )R b , -C(O)OR b , -C(S)OR b -C(O)NR c R c -C(NR b )NR c R c -OC(O)R b ,-OC(S)R b , -OC(O)OR b , -OC(S)OR b , -NR b C(O)R b , -NR b C(S)R b , -NR b C(O)OR b , -NR b C(S)OR b , -NR b C(O)NR c R c , -NR b C(NR b )R b , -NR b C(NR b )NRc R c , and -C(NR b )NR b C(NR b )NR c R c These are listed, and in the formula, R a , R b , and R c This is as previously defined. In some embodiments, useful substituents for substituting the nitrogen atom of heteroalkyl and cycloheteralkyl groups include R a Hello, -OR b , -NR c R c , trihalomethyl, -CN, -S(O)2OR b -OS(O)2R b , -C(O)R b -C(NR b )R b , -C(O)OR b -C(O)NR c R c -OC(O)R b , -OC(O)OR b -OS(O)2NR c NR c , -NR b C(O)R b , and -NR b C(O)OR b These are listed, and in the formula, R a , R b , and R c This is as previously defined. In yet another embodiment, useful substituents for substituting the nitrogen atom of heteroalkyl and cycloheteralkyl groups include R a Hello, -OR b , -NR c R c , trihalomethyl, -CN, -S(O)2OR b , -C(O)R b -C(NR b )R b , -C(O)OR b -C(O)NR c R c -OC(O)R b , -NR bC(O)R b , and -NR b C(O)OR b These are listed, and in the formula, R a , R b , and R c This is as previously defined.

[0063] The substituents in the above list that are useful for substituting other specific groups or atoms will be obvious to those skilled in the art.

[0064] Substituents used to replace a particular group may typically be further substituted with one or more of the same or different groups selected from the various groups specified above.

[0065] "Subject," "individual," or "patient" are used synonymously herein and refer to vertebrates, preferably mammals. Mammals include, but are not limited to, mice, rodents, monkeys, humans, domestic animals, sporting animals, and pets. In some embodiments, the subject, individual, or patient is a member of the species Homo sapiens. In other embodiments, the subject, individual, or patient includes all mammals other than Homo sapiens.

[0066] In some embodiments, “to treat” or “to cure” any disease or disorder means to improve the disease or disorder (i.e., to stop or reduce the onset of at least one of the disease or its clinical symptoms). Treatment can also be considered to include preemptive or prophylactic administration to improve, stop or prevent the onset of at least one of the disease or its clinical symptoms. In further characteristics, the treatment given is less likely to have long-term side effects over several years. In other embodiments, “to treat” or “to cure” means to improve at least one physical parameter that the patient does not perceive. In yet another embodiment, “to treat” or “to cure” means to inhibit the disease or disorder, either physically (e.g., stabilization of recognizable symptoms), physiologically (e.g., stabilization of physical parameters), or both. In yet another embodiment, “to treat” or “to cure” means to delay the onset of the disease or disorder.

[0067] The "therapeutic dose" refers to the amount of a compound sufficient to treat a disease when administered to a patient. The therapeutic dose will vary depending on the compound, the disease and its severity, the age and weight of the patient being treated, absorption, distribution, metabolism, and excretion.

[0068] A "vehicle" refers to a diluent, excipient, or carrier used to administer a compound to a target. In some embodiments, the vehicle is pharmaceutically acceptable.

[0069] compound In one embodiment, a compound of formula (I) that satisfies these and other needs: [ka] Alternatively, a pharmaceutically acceptable salt, hydrate, or solvate thereof is provided, where R1 is -OR 36, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl; R2 is -H, -CN, -CO2R7, -CONR8R9, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted aryl R3 and R4 are arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl; each R3 and R4 is independently H, -F, or alkyl; n is 1 or 2; R5 is -H, -CO2R 10 , -C(O)R 11 ,-CONR 12 R 13, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl; R6 is -H, alkyl , substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, substituted cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl, or X = O or = NR 14 In this case, it does not exist; R 27 This includes hydrogen, halo, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, and -NR. 28 R 29 ,-NCONR 30 R 31 ,-CONR 32 R 33 , -CO2R 34 ,-NCO2R 35 X is = O, = NR 14, or -OR 15 And; R 14 is -OR 16 , -NR 17 R 18 , or -N + R 40 R 41 R 42 And; R7~R 10 , R 12 , R 13 , R 15 , and R 28 ~R 36 These are independently -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl, or R8 and R9, R 12 and R 13 , R 28 and R 29 , R 30 and R 31 , R 32 and R 33 These may, together with the atoms to which they are attached, form a cycloheteralkyl ring or a substituted cycloheteralkyl ring; R 11This is an alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl; 16 is -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, substituted heteroarylalkynyl, or a carbohydrate derivative;R 17 and R 18These are independently -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, substituted heteroarylalkynyl, or carbohydrate derivatives, R 19 CO-, R 20 R 21 NCO-, R 22 OCO-, or R 23 It is SO2-, however, all substituents may be substituted with carbohydrate derivatives, R 17 and R 18 Both are R 19 CO-, R 21 R 20 NCO-, R 22 OCO-, R 23 Not SO2-, nor any combination thereof; R 19is an alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, substituted heteroarylalkynyl, or a carbohydrate derivative, or R 19 and R 17 These atoms may, together with the atoms to which they are attached, form a cycloheteralkyl ring or a substituted cycloheteralkyl ring, provided that all substituents are substituted with carbohydrate derivatives; R 20 and R 21 Independently, -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl, or a carbohydrate derivative, or R 20 and R 17These may, together with the atoms to which they are attached, form a cycloheteralkyl ring or a substituted cycloheteralkyl ring which may be substituted with =O, or R 20 and R 21 These atoms may, together with the atoms to which they are attached, form a cycloheteralkyl ring or a substituted cycloheteralkyl ring, provided that all substituents are substituted with carbohydrate derivatives; R 22 These include alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, and arylalkyl. , substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, substituted heteroarylalkynyl, or a carbohydrate derivative, or R 22 and R 17 These atoms may, together with the atoms to which they are attached, form a cycloheteralkyl ring or a substituted cycloheteralkyl ring, provided that all substituents are substituted with carbohydrate derivatives; R 23is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl, wherein each substituent may be substituted with a carbohydrate derivative, or R 23 and R 17 These atoms may, together with the atoms to which they are attached, form a cycloheteralkyl ring or a substituted cycloheteralkyl ring, provided that all substituents are substituted with carbohydrate derivatives; R 40 , R 41 , and R 42 It is an alkyl group.

[0070] In some embodiments, when X = O and n is 1, R1 is neither phenyl nor substituted phenyl, with the exception that R1 has -OR at the para position. 25 It may also be a phenyl substituted with, where R1 is -OR at the para position. 25 It may also be a phenyl substituted with R 25 is a cycloalkyl, substituted cycloalkyl, or alkyl, cycloalkyl, substituted cycloalkyl, or R 43 It is SO2-, and in the formula R 43 It is alkyl or CF3.

[0071] In other embodiments, X = O, n = 1, R3 and R4 = -F, R 27If R1 is -H, then R1 is neither phenyl nor substituted phenyl, and as an exception, R1 is -OR at the para position. 25 It may also be a phenyl substituted with R 25 is a cycloalkyl, substituted cycloalkyl, or alkyl, cycloalkyl, substituted cycloalkyl, or R 43 It is SO2-, and in the formula R 43 It is alkyl or CF3.

[0072] In other embodiments, X = O, n = 1, R3 and R4 are -H, and R 27 When R1 is -H, R1 is neither phenyl nor substituted phenyl, with the exception that R1 may be a phenyl whose para position is substituted with a cycloalkyl or substituted cycloalkyl.

[0073] In yet another embodiment, when X is =O and n is 1, R1 is neither phenyl, nor substituted phenyl, nor -OH, nor alkyl, nor alkenyl, nor heteroaryl. In yet another embodiment, when X is =O and n is 1, R1 is neither phenyl, nor substituted phenyl, nor alkyl, nor alkenyl, nor heteroaryl. In yet another embodiment, when X is =O and n is 1, R1 is neither phenyl, nor substituted phenyl, nor alkyl, nor alkenyl. In yet another embodiment, when X is =O and n is 1, R1 is neither phenyl, nor substituted phenyl, nor heteroaryl. In yet another embodiment, when X is =O and n is 1, R1 is -OR at the para position. 25 If it is a phenyl substituted with R 25 It is neither -H, nor alkyl, nor substituted alkyl, nor aryl-substituted aryl, nor arylalkyl, nor substituted arylalkyl.

[0074] In some embodiments, when X is = O, n is 1, and R1 is phenyl, the para position of the phenyl group can be alkyl or alkenyl, R 24 Whether it's CO-, cycloalkyl, cycloheteroalkyl, -CN, R25 O-, -N(R 26 )2, -CON(R 26 )2, -S(O) x R 26 However, -(CH2)p-CH2-Y is not substituted; Y is -H, -OR 26 -SCH3, -CF3, or -N(R 26 ) is 2; x is 0, 1, or 2; p is an integer from 1 to 18; R 24 is, -(C1~C 12 ) alkyl; R 25 R is -H, alkyl, substituted alkyl, aryl-substituted aryl, arylalkyl, or substituted arylalkyl; 26 is -H, alkyl, or cycloalkyl; R1 is [ka] In other embodiments, neither of the above applies, where X = O, n is 1, R3 and R4 are -F, and R 27 If R1 is -H and R1 is phenyl, then the para position of the phenyl group can be alkyl or alkenyl, R 24 Whether it's CO-, cycloalkyl, cycloheteroalkyl, -CN, R 25 O-, -N(R 26 )2, -CON(R 26 )2, -S(O) x R 26 However, -(CH2)p-CH2-Y is not substituted; Y is -H, -OR 26 -SCH3, -CF3, or -N(R 26 ) is 2; x is 0, 1, or 2; p is an integer from 1 to 18; R 24 is, -(C1~C 12 ) alkyl; R 25 R is -H, alkyl, substituted alkyl, aryl-substituted aryl, arylalkyl, or substituted arylalkyl; 26 is -H, alkyl, or cycloalkyl; R1 is [ka] Neither of the above.

[0075] In some embodiments, when X is =O and n is 1, R1 is neither phenyl nor substituted phenyl. In other embodiments, when X is =O, n is 1, and R3 and R4 are -F, R1 is neither phenyl nor substituted phenyl. In some embodiments, when X is =O and n is 1, R 3 and R 4 If R is -F, 1 teeth, [ka] Except for phenyl substituted with , it is neither phenyl nor substituted phenyl. In some embodiments, X is = O, n is 1, and R 3 and R 4 If R is -H, 1 teeth, [ka] Except for substituted phenyl, it is neither phenyl nor substituted phenyl. In some embodiments, when X = O and n is 1, R 1 teeth, [ka] or [ka] Except for substituted phenyl compounds, it is neither phenyl nor substituted phenyl.

[0076] In yet another embodiment, when X is =O and n is 1, R1 is neither phenyl, nor substituted phenyl, nor -OH, nor alkyl, nor alkenyl, nor heteroaryl. In yet another embodiment, when X is =O and n is 1, R1 is neither phenyl, nor substituted phenyl, nor alkyl, nor alkenyl, nor heteroaryl. In yet another embodiment, when X is =O and n is 1, R1 is neither phenyl, nor substituted phenyl, nor alkyl, nor alkenyl. In yet another embodiment, when X is =O and n is 1, R1 is neither phenyl, nor substituted phenyl, nor heteroaryl. In yet another embodiment, when X is =O, n is 1 and R1 is phenyl, the para position of the phenyl group is not substituted with -OH.

[0077] In some embodiments, when X is = O, n is 1, and R1 is phenyl, the para position of the phenyl group can be alkyl or alkenyl, R 24 Whether it's CO-, cycloalkyl, cycloheteroalkyl, -CN, R 25 O-, -N(R 26 )2, -CON(R 26 )2, -S(O) x R 26 However, -(CH2)p-CH2-Y is not substituted; Y is -H, -OR 26 -SCH3, -CF3, or -N(R 26 ) is 2; x is 0, 1, or 2; p is an integer from 1 to 18; R 24 is, -(C1~C 12 ) alkyl; R 25 R is -H, alkyl, substituted alkyl, aryl-substituted aryl, arylalkyl, or substituted arylalkyl; 26 is -H, alkyl, or cycloalkyl; R1 is [ka] Neither of the above.

[0078] In some embodiments, R1 R2 is a substituted aryl, heteroaryl, or substituted heteroaryl. In other embodiments, R2 is -H, -CN, -CO2R7, -CONR8R9, alkyl, alkenyl, aryl, substituted aryl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, or substituted heteroaryl. In yet another embodiment, R3 and R4 are independently H or -F. In yet another embodiment, R3 and R4 are independently H or -F, provided that at least one of R3 and R4 is -F. In yet another embodiment, R5 is -H, -CO2R 10 , -C(O)R 11 ,-CONR 12 R 13 In yet another embodiment, R6 is -H, alkyl, alkenyl, aryl, substituted aryl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, or substituted heteroaryl. In yet another embodiment, R 27 This is hydrogen, halo, -NR 28 R 29 ,-CONR 32 R 33 , or -CO2R 34 In further embodiments, R7~R 10 , R 12 , R 13 , R 15 , R 16 , and R 28 ~R 36 In other embodiments, R is independently -H, alkyl, alkenyl, aryl, substituted aryl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, or substituted heteroaryl. 11R is independently an alkyl, alkenyl, aryl, substituted aryl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, or substituted heteroaryl. In further embodiments, R 17 and R 18 These are independently -H, alkyl, alkenyl, aryl, substituted aryl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, substituted heteroaryl, carbohydrate derivatives, R 19 CO-, R 20 R 21 NCO-, R 22 OCO-, or R 23 In another embodiment, R 19 is an alkyl, alkenyl, aryl, substituted aryl, arylalkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, substituted heteroalkenyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or carbohydrate derivative, or R 19 and R 17 These may, together with the atoms to which they are attached, form a cycloheteralkyl ring or a substituted cycloheteralkyl ring, wherein the substituents may all be substituted with carbohydrate derivatives. In further embodiments, R 20 and R 21 Independently, are alkyl, alkenyl, aryl, substituted aryl, arylalkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, substituted heteroalkenyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or carbohydrate derivatives, or R 20 and R 21These may, together with the atoms to which they are bonded, form a cycloheteralkyl ring or a substituted cycloheteralkyl ring, wherein the substituents may all be substituted with carbohydrate derivatives. In further embodiments, R 22 is an alkyl, alkenyl, aryl, substituted aryl, arylalkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, substituted heteroalkenyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or carbohydrate derivative, or R 22 and R 17 These may, together with the atoms to which they are attached, form a cycloheteralkyl ring or a substituted cycloheteralkyl ring, wherein the substituents may all be substituted with carbohydrate derivatives. In further embodiments, R 23 is an alkyl, alkenyl, aryl, substituted aryl, arylalkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, substituted heteroalkenyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or carbohydrate derivative, wherein any substituent may be substituted with a carbohydrate derivative, or R 23 and R 17 These atoms may, together with the atoms to which they are attached, form a cycloheteralkyl ring or a substituted cycloheteralkyl ring, wherein any substituent may be substituted with a carbohydrate derivative.

[0079] In some embodiments, R 1R2 is a substituted aryl, heteroaryl, or substituted heteroaryl, where R2 is -H, -CN, -CO2R7, -CONR8R9, alkyl, alkenyl, aryl, substituted aryl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, or substituted heteroaryl; each R3 and R4 is independently H or -F, provided that at least one of R3 and R4 is -F; R5 is -H, -CO2R 10 , -C(O)R 11 ,-CONR 12 R 13 R6 is -H, alkyl, alkenyl, aryl, substituted aryl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, or substituted heteroaryl; R 27 This is hydrogen, halo, -NR 28 R 29 ,-CONR 32 R 33 , or -CO2R 34 And; R7~R 10 , R 12 , R 13 , R 15 , and R 28 ~R 36 R is independently -H, alkyl, alkenyl, aryl, substituted aryl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, or substituted heteroaryl; 11 R is independently an alkyl, alkenyl, aryl, substituted aryl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, or substituted heteroaryl; 16R is -H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, substituted heteroaryl, or a carbohydrate derivative; 17 and R 18 These are independently -H, alkyl, alkenyl, aryl, substituted aryl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, substituted heteroaryl, carbohydrate derivatives, R 19 CO-, R 20 R 21 NCO-, R 22 OCO-, or R 23 SO2- and R 19 is an alkyl, alkenyl, aryl, substituted aryl, arylalkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, substituted heteroalkenyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or carbohydrate derivative, or R 19 and R 17 These atoms may, together with the atoms to which they are attached, form a cycloheteralkyl ring or a substituted cycloheteralkyl ring, provided that all substituents are substituted with carbohydrate derivatives; R 20 and R 21 Independently, are alkyl, alkenyl, aryl, substituted aryl, arylalkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, substituted heteroalkenyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or carbohydrate derivatives, or R 20 and R 21 These atoms may, together with the atoms to which they are attached, form a cycloheteralkyl ring or a substituted cycloheteralkyl ring, provided that all substituents are substituted with carbohydrate derivatives; R 22is an alkyl, alkenyl, aryl, substituted aryl, arylalkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, substituted heteroalkenyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or carbohydrate derivative, or R 22 and R 17 These atoms may, together with the atoms to which they are attached, form a cycloheteralkyl ring or a substituted cycloheteralkyl ring, provided that all substituents are substituted with carbohydrate derivatives; R 23 is an alkyl, alkenyl, aryl, substituted aryl, arylalkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, substituted heteroalkenyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or carbohydrate derivative, wherein each substituent may be substituted with a carbohydrate derivative, or R 23 and R 17 These atoms may, together with the atoms to which they are attached, form a cycloheteralkyl ring or a substituted cycloheteralkyl ring, provided that all substituents are substituted with carbohydrate derivatives.

[0080] In some embodiments, R1 is a substituted aryl or substituted phenyl. In other embodiments, R1 is [ka] And; R 36 is alkyl, substituted alkyl, -SO2R 39 , arylalkyl, substituted arylalkyl; R 39 is alkyl or substituted alkyl; R 37 is alkyl; R 38 is alkyl or substituted alkyl. In yet another embodiment, R 36R is -CH3, -CH2CF3, -SO2CF3, -CH2(CH3)-cyclobutyl, or -CH2Ph, where Ph is where the para position is substituted with -SO2CF3; R 37 is -CH3; R 38 is CF3 or cyclopropyl. In yet another embodiment, R1 is [ka] And; R 36 is alkyl, substituted alkyl, -SO2R 39 , arylalkyl, substituted arylalkyl; R 39 is alkyl or substituted alkyl; R 38 is alkyl or substituted alkyl. In yet another embodiment, R 36 R is -CH3, -CH2CF3, -SO2CF3, or -CH2(CH3)-cyclobutyl; 37 is -CH3; R 38 It is CF3 or cyclopropyl.

[0081] In some embodiments, n is 1 and R3 and R4 are -F. In other embodiments, R2 is -H. In yet another embodiment, R5 is -H. In yet another embodiment, X is =O. In yet another embodiment, X is -OR 15 In other embodiments, R 15 is -H or alkyl. In yet another embodiment, X is =NR 14 In another embodiment, R 14 is -OR 16 That is the case.

[0082] In some embodiments, R 16 In other embodiments, R 16 is alkyl. In yet another embodiment, R 16 is (C1~C4)alkyl. In further embodiments, R 16 It is -CH2CH3.

[0083] In some embodiments, R 16 is a substituted alkyl group. In other embodiments, R 16 -CH2CF3, -CH2CO2H, -CH2CH2OCH3, -CH2(CH3)2OH, -CH2C(O)N(CH3)2, -CH2CN, -CH2CH2OSi(CH3)3, -CH2CH2OH, -CH2CH2OCH2CH2OH, -CH2CH2OCH2CH2OCH2CH2OCH3, [ka] That is the case.

[0084] In some embodiments, R 16 is a heteroaryl compound. In other embodiments, R 16 teeth, [ka] That is the case.

[0085] In some embodiments, R 16 is a cycloheteralkyl. In other embodiments, R 16 teeth, [ka] That is the case.

[0086] In some embodiments, R 16 is a carbohydrate derivative. In other embodiments, R 16 teeth, [ka] That is the case.

[0087] In some embodiments, R 14 -NR 17 R 18 In other embodiments, R 17 The group is -H, methyl, alkyl, cyclopropyl, cycloalkyl, or -C(O)CH3.

[0088] In some embodiments, R 18 is -H or methyl.

[0089] In some embodiments, R 18 is a substituted arylalkyl. In other embodiments, R 18 R is an arylalkyl substituted with a carbohydrate derivative. In yet another embodiment, R 18 teeth, [ka] That is the case.

[0090] In some embodiments, R 17 is -H, methyl, alkyl, cyclopropyl, cycloalkyl, or -C(O)CH3, and R 18 is a carbohydrate derivative. In other embodiments, R 18 teeth, [ka] That is the case.

[0091] In some embodiments, R 17 is -H, methyl, alkyl, cyclopropyl, cycloalkyl, or -C(O)CH3, and R 18 is an arylalkyl substituted with -H, a substituted arylalkyl, or a carbohydrate derivative. In other embodiments, R 18 is -H, a substituted arylalkyl, an arylalkyl substituted with a carbohydrate derivative, or a carbohydrate derivative. In further embodiments, R 17 R is -H, methyl, alkyl, substituted alkyl, cyclopropyl, substituted cyclopropyl, cycloalkyl, or substituted cycloalkyl, 18 R 19 It is CO-.

[0092] In some embodiments, R 18 R 19 In other embodiments, R 19is alkyl. In yet another embodiment, R 19 These are -CH3, -CH(CH3)2, -CH2CH(CH3)2, -C(CH3)3-, or -CH2CH2CH3.

[0093] In some embodiments, R 19 is a substituted alkyl group. In other embodiments, R 19 -CH2NH2, -CH2NHBoc, -CH2OCH3, -CH2OH, -CH2N(CH3)2, -CH2CN, or [ka] That is the case.

[0094] In some embodiments, R 19 is a cycloalkyl or substituted cycloalkyl. In other embodiments, R 19 These are cyclopropyl and substituted cyclopropyl.

[0095] In some embodiments, R 19 is a heteroaryl or substituted heteroaryl. In other embodiments, R 19 teeth, [ka] or [ka] That is the case.

[0096] In some embodiments, R 19 is a heteroarylalkyl. In other embodiments, R 19 teeth, [ka] That is the case.

[0097] In some embodiments, R 19 is a cycloalkyl group. In other embodiments, R 19 teeth, [ka] That is the case.

[0098] In some embodiments, R 19 is a cycloheteralkyl. In other embodiments, R 19 teeth, [ka] That is the case.

[0099] In some embodiments, R 19 and R 17 These, together with the atoms to which they are attached, form a cycloheteralkyl ring. In other embodiments, R 19 and R 17 They, together with the atoms to which they are attached, [ka] It forms.

[0100] In some embodiments, R 17 R is -H, methyl, alkyl, substituted alkyl, cyclopropyl, substituted cyclopropyl, cycloalkyl, or substituted cycloalkyl, 18 R 20 R 21 It is NCO-.

[0101] In some embodiments, R 18 R 20 R 21 In other embodiments, R 20 is hydrogen or alkyl, and R 21 is a cycloalkyl or substituted cycloalkyl. In yet another embodiment, R 20 is hydrogen or alkyl, and R 21 It is cyclopropyl or substituted cyclopropyl.

[0102] In some embodiments, R 20is hydrogen or alkyl, and R 21 It is hydrogen or alkyl.

[0103] In some embodiments, R 20 is hydrogen or alkyl, and R 21 It is a substituted alkyl group.

[0104] In some embodiments, R 20 is hydrogen or alkyl, and R 21 is a carbohydrate derivative. In other embodiments, R 21 teeth, [ka] That is the case.

[0105] In some embodiments, R 17 R is -H, methyl, alkyl, cyclopropyl, cycloalkyl, -C(O)CH3, 18 is, -R 19 CO- and R 19 is alkyl, substituted alkyl, heteroaryl, substituted heteroaryl, substituted heteroarylalkyl, cycloalkyl, cycloheteroalkyl, or R 19 and R 17 These atoms, together with the atoms to which they are attached, form a cycloheteralkyl ring.

[0106] In some embodiments, R 18 is, -R 19 CO- and R 19 is alkyl, substituted alkyl, heteroaryl, substituted heteroaryl, substituted heteroarylalkyl, cycloalkyl, cycloheteroalkyl, or R 19 and R 17 These may, together with the atoms to which they are attached, form a cycloheteralkyl ring.

[0107] In some embodiments, R 18 R 22 In other embodiments, R 22R is an arylalkyl substituted with a carbohydrate derivative. In yet another embodiment, R 22 teeth, [ka] That is the case.

[0108] In some embodiments, R 22 is a carbohydrate derivative. In other embodiments, R 22 teeth, [ka] That is the case.

[0109] In some embodiments, R 22 is alkyl. In other embodiments, R 22 This is -CH3, -C2H5, or -C(CH3)3.

[0110] In some embodiments, R 22 is a substituted alkyl group. In other embodiments, R 22 These are -CH2CH2OH, -CH2CH2OSi(CH3)3, or -CH2CF3.

[0111] In some embodiments, R 22 and R 17 These, together with the atoms to which they are attached, form a cycloheteralkyl ring. In other embodiments, R 22 and R 17 They, together with the atoms to which they are attached, [ka] or [ka] It forms.

[0112] In some embodiments, R 17 R is -H, methyl, alkyl, cyclopropyl, cycloalkyl, -C(O)CH3,18 is R 22 OCO-, and R 22 is arylalkyl substituted with a carbohydrate derivative, a carbohydrate derivative, alkyl, substituted alkyl, or R 22 and R 17 together with the atoms to which they are attached form a cycloheteroalkyl ring.

[0113] In some embodiments, R 18 is R 22 OCO-, and R 22 is arylalkyl substituted with a carbohydrate derivative, a carbohydrate derivative, alkyl, substituted alkyl, or R 22 and R 17 together with the atoms to which they are attached form a cycloheteroalkyl ring.

[0114] In some embodiments, R 18 is R 20 R 21 NCO-. In other embodiments, R 20 and R 17 together with the atoms to which they are attached form a cycloheteroalkyl ring or a substituted cycloheteroalkyl ring optionally substituted with =O. In still other embodiments, R 20 and R 17 together with the atoms to which they are attached

Chemical formula

[0115] In some embodiments, R 20 and R 21 together with the atoms to which they are attached form a cycloheteroalkyl ring or a substituted cycloheteroalkyl ring. In other embodiments, R 20 and R 21 together with the atoms to which they are attached

Chemical formula

[0116] In some embodiments, R 20 In other embodiments, R 20 teeth, [ka] That is the case.

[0117] In some embodiments, R 20 is alkyl. In other embodiments, R 20 This is -CH(CH3)2.

[0118] In some embodiments, R 20 is a substituted alkyl group. In other embodiments, R 20 teeth, [ka] That is the case.

[0119] In some embodiments, R 20 is a cycloalkyl group. In other embodiments, R 20 teeth, [ka] That is the case.

[0120] In some embodiments, R 20 is a cycloheteralkyl. In other embodiments, R 20 teeth, [ka] That is the case.

[0121] In some embodiments, R 17 R is -H, methyl, alkyl, cyclopropyl, cycloalkyl, -C(O)CH3, 18 R 20 R 21 NCO- and R 20These are alkyl, substituted alkyl, aryl, cycloalkyl, and cycloheteroalkyl, and R 20 and R 17 They, together with the atoms to which they are attached, form a cycloheteralkyl ring or a substituted cycloheteralkyl ring which may be substituted with =O, or R 20 and R 21 These atoms, together with the atoms to which they are attached, form a cycloheteralkyl ring or a substituted cycloheteralkyl ring.

[0122] In some embodiments, R 18 R 20 R 21 NCO- and R 20 These are alkyl, substituted alkyl, aryl, cycloalkyl, and cycloheteroalkyl, and R 20 and R 17 They, together with the atoms to which they are attached, form a cycloheteralkyl ring or a substituted cycloheteralkyl ring which may be substituted with =O, or R 20 and R 21 These atoms, together with the atoms to which they are attached, form a cycloheteralkyl ring or a substituted cycloheteralkyl ring.

[0123] In some embodiments, R 18 R 23 It is SO2-.

[0124] In some embodiments, R 23 is alkyl. In other embodiments, R 23 This is either -CH2CH2CH3 or -CH(CH3)2.

[0125] In some embodiments, R 23 is a substituted alkyl group. In other embodiments, R 23 -CH2CH2OCH3, -CH2CN, -CH2SO3CH3, [ka] , [ka] , Alternatively, it is -CH2CF3.

[0126] In some embodiments, R 23 is a substitution aryl. In other embodiments, R 23 teeth, [ka] or [ka] That is the case.

[0127] In some embodiments, R 23 is a heteroaryl or substituted heteroaryl. In other embodiments, R 23 teeth, [ka] or [ka] That is the case.

[0128] In some embodiments, R 23 is a cycloalkyl group. In other embodiments, R 23 teeth, [ka] or [ka] That is the case.

[0129] In some embodiments, R 23 is a cycloheteralkyl. In other embodiments, R 23 teeth, [ka] It is.

[0130] In some embodiments, R 17 is -H, methyl, alkyl, cyclopropyl, cycloalkyl, -C(O)CH3, and R 18 is R 23 SO2-, and R 23 is alkyl, substituted alkyl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or cycloheteroalkyl. In other embodiments, R 18 is R 23 SO2-, and R 23 is alkyl, substituted alkyl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or cycloheteroalkyl.

[0131] In some embodiments, R 16 is -H, alkyl, substituted alkyl, heteroarylalkyl, or cycloheteroalkyl, and R 17 is -H, methyl, alkyl, cyclopropyl, cycloalkyl, -C(O)CH3, and R 18 is -H, substituted arylalkyl, arylalkyl substituted with a carbohydrate derivative, carbohydrate derivative, -R 19 CO-, R 20 R 21 NCO-, R 22 OCO-, or R 23 SO2-.

[0132] In some embodiments, R 19 is alkyl, substituted alkyl, heteroaryl, substituted heteroaryl, substituted heteroarylalkyl, cycloalkyl, cycloheteroalkyl, or R 19 and R 17 may together with the atom to which they are attached form a cycloheteroalkyl ring; R 20 is alkyl, substituted alkyl, aryl, cycloalkyl, cycloheteroalkyl, or R 20 and R 17They, together with the atoms to which they are attached, form a cycloheteralkyl ring or a substituted cycloheteralkyl ring which may be substituted with =O, or R 20 and R 21 They, together with the atoms to which they are attached, form a cycloheteralkyl ring or a substituted cycloheteralkyl ring; R 22 is an arylalkyl substituted with a carbohydrate derivative, a carbohydrate derivative, an alkyl, a substituted alkyl, or R 22 and R 17 They, together with the atoms to which they are attached, form a cycloheteralkyl ring; R 23 These are alkyl, substituted alkyl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or cycloheteroalkyl.

[0133] In another embodiment, the compound of formula (II): [ka] Or a pharmaceutically acceptable salt, hydrate, or solvate thereof is provided, R 100 is -H, -CO2R 107 , -C(O)R 108 ,-CONR 109 R 110 Alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl; R 101is -OR 130 aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl; R 102 -H, -CN, -CO2R 111 ,-CONR 112 R 113 Alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl; each R 103 and R 104 is independently H, -F, or alkyl, except R 103 and R 104 At least one of them is -F; q is 1 or 2; R 105 is -H, -CO2R 114 , -C(O)R 115 ,-CONR 116 R 117Alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl; each R 106 These are independently -H, -CO2R 118 , -C(O)R 119 ,-CONR 120 R 121 , -OR 122 , -NR 123 R 124 , -NHR 125 R 126 C(O)R 127 -SO2NR 128 R 130 , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, halo, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl;s is 0, 1, or 2;R 109 ~R113 , R 116 ~R 118 , R 120 ~R 126 , and R 128 ~R 130 These are independently -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl;R 107 , R 108 , R 114 , R 115 , and R 127 These are independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl.

[0134] In some embodiments, R 101is a substituted aryl, heteroaryl, or substituted heteroaryl. In other embodiments, R 100 is -H, -CO2R 107 , -C(O)R 108 ,-CONR 109 R 110 These are alkyl, alkenyl, aryl, substituted aryl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, or substituted heteroaryl. In further embodiments, R 102 -H, -CN, -CO2R 111 ,-CONR 112 R 113 These are alkyl, alkenyl, aryl, substituted aryl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, or substituted heteroaryl. In further embodiments, each R 103 and R 104 In other embodiments, each R is independently -H or -F. 103 and R 104 In other embodiments, R is independently -H or -F, provided that at least one of R3 and R4 is -F. 105 is -H, -CO2R 114 , -C(O)R 115 ,-CONR 116 R 117 These are alkyl, alkenyl, aryl, substituted aryl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, or substituted heteroaryl. In further embodiments, each R 106 These are independently -H, -CO2R 118 , -C(O)R 119 ,-CONR 120 R 121 , -OR 122 , -NR 123 R 124These are alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, halo, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl. In further embodiments, R 111 ~R 113 and R 116 ~R 124 In other embodiments, R is independently -H, alkyl, alkenyl, aryl, substituted aryl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, or substituted heteroaryl. 114 and R 115 These are independently alkyl, alkenyl, aryl, substituted aryl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, or substituted heteroaryl.

[0135] In some embodiments, R 100 is -H, -CO2R 107 , -C(O)R 108 ,-CONR 109 R 110 , alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, or substituted heteroaryl; R 101 is -OR 130 , substituted aryl, heteroaryl, substituted heteroaryl, R 102 -H, -CN, -CO2R 111 ,-CONR 112 R 113 , alkyl, alkenyl, aryl, substituted aryl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, or substituted heteroaryl; each R 103 and R 104Independently, is H or -F, except R 103 and R 104 At least one of them is -F; R5 is -H, -CO2R 114 , -C(O)R 115 ,-CONR 116 R 117 , alkyl, alkenyl, aryl, substituted aryl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, or substituted heteroaryl; R 106 These are independently -H, -CO2R 118 , -C(O)R 119 ,-CONR 120 R 121 , -OR 122 , -NR 123 R 124 , alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, halo, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl; R 111 ~R 113 , R 116 ~R 124 , and R 130 R is independently -H, alkyl, alkenyl, aryl, substituted aryl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, or substituted heteroaryl; 114 and R 115 These are independently alkyl, alkenyl, aryl, substituted aryl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, or substituted heteroaryl.

[0136] In some embodiments, R 100 is -H, -CO2R 107These are alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, heteroaryl, or substituted heteroaryl.

[0137] In some embodiments, R 101 R is a substituted aryl or substituted phenyl. In other embodiments, R 101 teeth, [ka] And; R 130 R is alkyl, substituted alkyl, arylalkyl, substituted arylalkyl; 133 is alkyl or substituted alkyl; R 131 is alkyl; R 132 It is an alkyl or substituted alkyl group.

[0138] In some embodiments, R 131 The compounds are -CH3, -CH2CF3, -SO2CF3, and -CH2Ph, where Ph is substituted at the para position with -SO2CF3; R 132 is -CH3; R 133 This is CF3.

[0139] In some embodiments, n is 1 and R3 and R4 are -F.

[0140] In some embodiments, R2 is -H.

[0141] In some embodiments, R5 is -H.

[0142] In some embodiments, R 100 is a substituted alkyl group. In other embodiments, R 100-CH2CF3, -CH2CO2H, -CH2CH2OCH3, -CH2(CH3)2OH, -CH2C(O)N(CH3)2, -CH2CN, -CH2CH2OSi(CH3)3, -CH2CH2OH, -CH2CH2OCH2CH2OH, -CH2CH2OCH2CH2OCH2CH2OCH3, [ka] That is the case.

[0143] In some embodiments, compounds having the following structure are provided. [ka]

[0144] In some embodiments, R 100 is -H, -CO2R 107 It is an alkyl, substituted alkyl, heteroalkyl, heteroaryl, or substituted heteroaryl.

[0145] In some embodiments, R 100 is -H, -CO2R 107 These are alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, or substituted heteroalkyl.

[0146] Some representative compounds are illustrated in Table 1 below.

[0147] Table 1 [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10]

[0148] The compounds described above can be prepared by well-known procedures, some of which are illustrated in the experimental section.

[0149] Method for characterizing and identifying senolytic agents The characterization of senolytic agents can be determined using one or more cell-based assays and one or more animal models described herein or in the art and familiar to those skilled in the art. Senolytic agents can selectively kill one or more types of senescent cells (e.g., presenteric adipocytes, senescent endothelial cells, senescent fibroblasts, senescent neurons, senescent epithelial cells, senescent mesenchymal cells, senescent smooth muscle cells, senescent macrophages, or senescent chondrocytes). In certain embodiments, senolytic agents can selectively kill at least senescent fibroblasts.

[0150] Characterizing an agonist as a senolytic agent can be achieved using one or more cell-based assays and one or more animal models described herein or in the Art. Those skilled in the art will readily understand that characterizing an agonist as a senolytic agent and determining the level of cell death by the agonist can be achieved by comparing the activity of the test agonist with a suitable negative control (e.g., a vehicle or diluent alone, and / or a composition or compound known in the Art not to kill senescent cells) and a suitable positive control. In vitro cell-based assays for characterizing senolytic agents also include controls for determining the effect of the agonist on non-senescent cells (e.g., quiescent or proliferating cells). A senolytic agent reduces (i.e., diminishes) the survival percentage of multiple senescent cells (i.e., reduces the amount of viable senescent cells in an animal or cell-based assay in any way) compared to one or more negative controls. Specific in vitro assay conditions include temperature, buffer (including salts, cations, and culture medium), and other components that maintain the integrity of the test agents and reagents used in the assay, which are familiar to those skilled in the art and / or can be easily determined through routine laboratory work.

[0151] Sources of senescent cells for use in the assay may include, but are not limited to, primary cell cultures or culture-adapted cell lines, including, genetically modified cell lines which may contain recombinant nucleic acid sequences integrated into chromosomes or episomal, immortalized or immortalizable cell lines, somatic cell hybrid cell lines, differentiated or differentiateable cell lines, and transformed cell lines. In some embodiments, senescent cells are isolated from biological samples obtained from a host or subject having a senescent-related disease or disorder. In other embodiments, non-senescent cells may be obtained from a subject or from culture-adapted cell lines, and senescence is induced by methods described herein and in the Art, for example, by irradiation or exposure to a chemotherapeutic agent (e.g., doxorubicin). Biological samples may be, for example, blood samples, biopsy specimens, body fluids (e.g., lung lavage fluid, ascites, mucosal lavage fluid, synovial fluid, etc.), bone marrow, lymph nodes, tissue explants, organ cultures, or any other tissue or cell preparation obtained from a subject. The biological sample may be a tissue or cell preparation whose morphological integrity or physical condition has been destroyed by, for example, dissection, exfoliation, solubilization, fractionation, homogenization, biochemical or chemical extraction, grinding, freeze-drying, sonication, or any other means for processing a sample derived from the subject or biological source. The subject may be human or a non-human animal.

[0152] Transgenic animal models described herein and in the Art can be used to determine the death or removal of senescent cells (see, e.g., Baker et al., Nature, Vol. 479 (2011), pp. 232-236; International Publication No. 2012 / 177927; International Publication No. 2013 / 090645). Exemplary transgenic animal models include a transgene containing a nucleic acid that enables controlled clearance of senescent cells (e.g., p16INK4a-positive senescent cells) as a positive control. The presence and level of senescent cells in the transgenic animal can be determined by measuring the level of one or more detectable labels expressed in the senescent cells of the animal. The transgene nucleotide sequence includes one or more detectable labels, e.g., red fluorescent protein, green fluorescent protein, and one or more luciferases, for detecting the clearance of senescent cells.

[0153] Animal models described herein or in the art include accepted models in the art for determining the efficacy of senolytic agents for treating or preventing (i.e., reducing the likelihood of developing) certain age-related diseases or disorders, such as atherosclerosis models, osteoarthritis models, COPD models, and IPF models. As described herein, lung disease mouse models, such as bleomycin pulmonary fibrosis models, and chronic smoking models are applicable to diseases such as COPD and can be routinely performed by those skilled in the art. Animal models for determining the efficacy of senolytic agents for treating and / or preventing (i.e., reducing the likelihood of developing) chemotherapy and radiotherapy side effects, or for treating or preventing (i.e., reducing the likelihood of developing) metastases are described in International Publication No. 2013 / 090645 and International Publication No. 2014 / 205244. Animal models are also routinely used in this field to determine the efficacy of agents for treating eye diseases, particularly age-related macular degeneration (see, for example, Pennesi et al., Mol. Aspects Med. 33 (2012), pp. 487-509; Zeiss et al., Vet. Pathol. 47 (2010), pp. 396-413; Chavala et al., J. Clin. Invest. 123 (2013), pp. 4170-4181).

[0154] As a non-limiting example, animal models of osteoarthritis have been developed, as described herein. Osteoarthritis in animals can be induced, for example, by inducing damage to the joint, such as by surgically incomplete or complete transection of the anterior cruciate ligament of the knee joint. Animal models of osteoarthritis can be used to evaluate the effectiveness of senolytic agents for treating or preventing osteoarthritis (i.e., reducing the likelihood of its development), causing a reduction in proteoglycan erosion, inducing (i.e., stimulating, enhancing) collagen (such as collagen type 2) production, and reducing pain in animals that have undergone ACL surgery. Immunohistochemical examinations can be performed to investigate the integrity and composition of the joint tissues and cells. Furthermore, immunochemical and / or molecular biological techniques, such as assays for determining the levels of inflammatory molecules (e.g., IL-6) and assays for determining the levels of the aforementioned aging markers, can be performed using the methods and techniques described herein, which are routinely performed by those skilled in the art.

[0155] As another non-limiting example, animal models of atherosclerosis have been developed, as described herein. Animal atherosclerosis can be induced, for example, by feeding animals a high-fat diet or by using transgenic animals that are highly susceptible to developing atherosclerosis. Animal models can be used to determine the effectiveness of senolytic agents to reduce the amount of plaque in atherosclerotic arteries or to inhibit plaque formation, to reduce the lipid content of atherosclerotic plaques (i.e., to reduce or decrease the amount of lipids in the plaques), and to increase or enhance the fibrous cap thickness of the plaques. Lipid levels in atherosclerotic vessels can be detected using Sudan staining. Immunohistological, immunochemical, and molecular biological assays (e.g., to determine the levels of inflammatory molecules (e.g., IL-6) and the levels of the aging markers described above) can all be performed according to the methods routinely performed in the art, as described herein.

[0156] In yet another non-limiting example, a mouse model in which animals are treated with bleomycin is described herein for determining the efficacy of an agonist for treating IPF (e.g., Peng et al., PLoS One vol. 8(4) (2013) e59348.doi:10.1371 / journal.pone.0059348; Mouratis et al., Curr. Opin. Pulm. Med. vol. 17 (2011) pp. 355-361). In animal models of lung disease (e.g., bleomycin animal models or smoke exposure animal models), respiratory measurements can be performed to determine elastance, extensibility, static extensibility, and peripheral capillary oxygen saturation (SpO2). Immunohistological, immunochemical, and molecular biological assays (e.g., for determining the levels of inflammatory molecules (e.g., IL-6) and the levels of the aforementioned aging markers) can all be performed according to the methods routinely performed in the art as described herein.

[0157] In animal models, determining the effectiveness of senolytic agents that selectively kill senescent cells, as described herein, can be carried out using one or more statistical analyses that are familiar to those skilled in the art. For example, statistical analyses such as two-way analysis of variance (ANOVA) can be used to determine the statistical significance of the difference between a group of animals treated with the agent and a group of animals not treated with the agent (i.e., a negative control group which may contain only the vehicle and / or a non-senolytic agent). Statistical packages such as SPSS, MINITAB, SAS, Statistika, Graphpad, GLIM, Genstat, and BMDP are readily available and routinely used by those skilled in the art of animal modeling.

[0158] Those skilled in the art will readily understand that characterizing senolytic agents and determining the level of cell death by senolytic agents can be achieved by comparing the activity of a test agonist with a suitable negative control (e.g., a composition, agonist, or compound known in the art to not kill only vehicles and / or senescent cells) and a suitable positive control. In vitro cell-based assays for characterizing agonists also include controls for determining the effect of the agonist on non-senescent cells (e.g., quiescent or proliferating cells). A useful senolytic agent reduces (i.e., diminishes) the survival percentage of senescent cells (i.e., reduces the amount of viable senescent cells in an animal or cell-based assay in any way) compared to one or more negative controls. Thus, a senolytic agent selectively kills senescent cells compared to the death of non-senescent cells (which may be referred to herein as selectively killing senescent cells more than non-senescent cells).

[0159] In certain embodiments (either in a vitro assay or in vivo (human or non-human animal)), at least one senolytic agent kills at least 20% of senescent cells and less than 5% of non-senescent cells. In other embodiments (either in a vitro assay or in vivo (human or non-human animal)), at least one senolytic agent kills at least about 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, or 65% of senescent cells and less than about 5% or 10% of non-senescent cells. In yet another embodiment (either in a vitro assay or in vivo (human or non-human animal)), at least one senolytic agent kills at least about 30%, 35%, 40%, 45%, 50%, 55%, 60%, or 65% of senescent cells and less than about 5%, 10%, or 15% of non-senescent cells. In further embodiments (either in a vitro assay or in vivo (human or non-human animal)), at least one senolytic agent kills at least about 40%, 45%, 50%, 55%, 60%, or 65% of senescent cells and about 5%, 10%, 15%, 20%, or 25% or less of non-senescent cells. In further embodiments (either in a vitro assay or in vivo (human or non-human animal)), at least one senolytic agent kills at least about 50%, 55%, 60%, or 65% of senescent cells and about 5%, 10%, 15%, 20%, 25%, or 30% or less of non-senescent cells. In other words, the senolytic agent has selectivity to kill at least 5–25, 10–50, 10–100, or 100–1000 times more senescent cells than non-senescent cells.

[0160] With respect to specific embodiments of the methods herein for treating age-related diseases or disorders, the percentage of dead senescent cells may refer to the percentage of dead senescent cells in a tissue or organ that contains senescent cells contributing to the onset, progression, and / or exacerbation of the disease or disorder. In non-limiting examples, brain tissue, eye tissue and parts, lung tissue, heart tissue, arteries, joints, skin, and muscles contain senescent cells that can be reduced by the percentages described above by the senoretic agents herein, thereby providing a therapeutic effect. Furthermore, selective removal of at least 20% or at least 25% of senescent cells from an affected tissue or organ can demonstrate a clinically significant therapeutic effect.

[0161] In particular embodiments of the methods described herein, for example, in relation to treating a cardiovascular disease or disorder associated with arteriosclerosis, such as atherosclerosis, by administering a senolytic agent (i.e., in relation to the vivo method described above), the percentage of dead senescent cells may refer to the percentage of dead senescent cells in the affected artery containing the plaque relative to the dead non-senescent cells in the arterial plaque. In certain embodiments, in the method for treating a cardiovascular disease such as atherosclerosis described herein, at least one senolytic agent kills at least 20% of the senescent cells and less than 5% of the non-senescent cells in the artery. In other embodiments, the senolytic agent selectively kills at least 25% of the senescent cells in the arteriosclerotic artery.

[0162] In some embodiments, with respect to the methods herein for treating osteoarthritis by administering senolytic agents, the percentage of dead senescent cells may refer to the percentage of dead senescent cells in an osteoarthritis joint relative to the percentage of dead non-senescent cells in the osteoarthritis joint. In certain embodiments, in the methods for treating osteoarthritis described herein, at least one senolytic agent kills at least 20% of senescent cells and less than 5% of non-senescent cells in an osteoarthritis joint. In other embodiments, the senolytic agent selectively kills at least 25% of senescent cells in an osteoarthritis joint.

[0163] In some embodiments, with respect to the methods herein for treating age-related lung diseases or disorders (e.g., COPD, IPF) by administering at least one senolytic agent, the percentage of dead senescent cells may refer to the percentage of dead non-senescent cells in the affected lung tissue relative to the percentage of dead non-senescent cells in the affected lung tissue. In certain embodiments, in the methods herein for treating age-related lung diseases and disorders, the senolytic agent kills at least 20% of senescent cells and less than 5% of non-senescent cells in the affected lung tissue. In other embodiments, the senolytic agent selectively kills at least 25% of senescent cells in the affected lung tissue.

[0164] In certain embodiments, a method is provided for identifying (i.e., screening for) activators that are useful senolytic agents for treating or preventing (i.e., reducing the likelihood of developing) age-related diseases or disorders. In some embodiments, a method for identifying senolytic agents for treating such diseases and disorders includes inducing cellular senescence to provide established senescent cells. Methods for inducing cellular senescence are described herein and in the Art and include, for example, exposure to radiation (e.g., typically 10 Gy is sufficient) or chemotherapeutic agents (e.g., doxorubicin or other anthracyclines). After exposure to the activator, the cells are cultured for an appropriate time and under appropriate conditions (e.g., appropriate medium, temperature, and CO2 / O2 levels for a given cell type or cell line) to allow senescence to be established. As discussed herein, cellular senescence can be determined by determining any number of characteristics, such as morphological changes (e.g., by microscopic observation); or the production of senescence-associated galactosidase (SA-gal), p16INK4a, p21, or one or more SASP factors (e.g., IL-6, MMP3). A sample of senescent cells is then brought into contact with a candidate agonist (i.e., mixed, combined, or otherwise allowing interaction between cells and the agonist). Those skilled in the art will understand that the assay will include appropriate negative and positive controls, either historical or performed concurrently. For example, a sample of control non-senescent cells, cultured similarly to senescent cells but not exposed to the senescence-inducing agent, is brought into contact with the candidate agonist. The viability level of the senescent cells is determined and compared to that of the non-senescent cells. If the viability level of the senescent cells is lower than that of the non-senescent cells, the senolistic agent is identified.

[0165] In some embodiments, the method described above for identifying a senolytic agent may further include the step of determining whether the senolytic agent is useful for treating osteoarthritis. This method may further include contacting the identified senolytic agent with cells capable of producing collagen; and determining the level of collagen produced by the cells. In some embodiments, the cells are chondrocytes and the collagen is type II collagen. The method may further include administering a candidate senolytic agent to a non-human animal having arthritis lesions in the joints, and determining one or more of the following: (a) senescent cell levels in the joints, (b) physical function of the animals, (c) levels of one or more markers of inflammation, (d) histological characteristics of the joints, and (e) levels of type II collagen produced, thereby determining the therapeutic efficacy of the senolytic agent, and observing in the treated animals, compared to animals not treated with the senolytic agent, one or more of the following: (i) a decrease in senescent cell levels in the joints of the treated animals, (ii) an improvement in physical function of the treated animals, (iii) a decrease in levels of one or more markers of inflammation in the treated animals, (iv) an increase in histological normality in the joints of the treated animals, and (v) an increase in type II collagen production levels in the treated animals. As described herein and in the art, the physical function of an animal can be determined by techniques for determining the susceptibility of the limb to inducible or innate osteoarthritis conditions, such as the animal's tolerance for bearing weight on the affected limb, or the animal's ability to stay away from unpleasant stimuli such as heat or cold. The determination of the efficacy of the senescent cell-killing agents described herein in animal models can be carried out using one or more statistical analyses that will be familiar to those skilled in the art. Statistical analyses described herein and routinely performed in the art can be applied to data analysis.

[0166] In other embodiments, the method described above for identifying a senolytic agent may further include the step of determining whether the senolytic agent is useful in treating cardiovascular diseases caused by or associated with atherosclerosis. Thus, the method may further include administering candidate senolytic agents to non-human animals or animal models to determine the effectiveness of agents that reduce plaque volume, inhibit plaque formation in atherosclerotic arteries, reduce the lipid content of atherosclerotic plaques (i.e., reduce the amount of lipids in plaques), and / or increase or enhance the fibrous cap thickness of plaques. Lipid levels in atherosclerotic vessels can be detected using Sudan staining. All immunohistochemical assays for determining levels of inflammatory molecules (e.g., IL-6) and / or assays for determining levels of the aging markers described above are described herein and can be carried out according to methods routinely performed in the art.

[0167] In certain embodiments, the method herein for identifying a senolytic agent may include administering a candidate senolytic agent to a non-human animal having atherosclerotic plaques, and determining one or more of the following: (a) arterial senescent cell levels, (b) animal physical function, (c) levels of one or more inflammatory markers, and (d) histological characteristics of affected vessels (e.g., arteries), thereby determining the therapeutic efficacy of the senolytic agent, compared to animals not treated with the senolytic agent, in the treated animals one or more of the following are observed: (i) a decrease in senescent cell levels in the arteries of the treated animals, (ii) an improvement in the physical function of the treated animals, (iii) a decrease in the levels of one or more inflammatory markers in the treated animals, and (iv) an increase in histological normality in the art of the treated animals. As described herein and in the Art, animal physical function can be determined by measuring physical activity. Statistical analyses described herein and routinely performed in the Art can be applied to the analysis of data.

[0168] In some embodiments, the methods herein for identifying senolytic agents include administering candidate senolytic agents to non-human animal lung disease models, such as bleomycin models or smoke exposure animal models; and determining one or more of the following characteristics of the senolytic agent: (a) levels of senescent cells in the lungs, (b) lung function of the animals, (c) levels of one or more inflammatory markers, and (d) histological features of the lung tissue, thereby determining the therapeutic efficacy of the senolytic agent, compared to animals not treated with the senolytic agent, in the treated animals one or more of the following characteristics are observed: (i) a decrease in senescent cell levels in the lungs and lung tissue of the treated animals, (ii) an improvement in lung function of the treated animals, (iii) a decrease in levels of one or more inflammatory markers in the treated animals, and (iv) an increase in histological normality of the lung tissue of the treated animals. Respiratory measurements can be performed to determine elastance, extensibility, static extensibility, and peripheral capillary oxygen saturation (SpO2). Lung function can be assessed by determining one of numerous measurements, including expiratory reserve volume (ERV), forced vital capacity (FVC), forced expiratory volume (FEV) (e.g., FEV1 per second), FEV1 / FEV ratio, forced expiratory flow rate 25% to 75%, and maximal spontaneous ventilation (MVV), maximal expiratory flow rate (PEF), and slow vital capacity (SVC). Total lung capacity includes total vital capacity (TLC), vital capacity (VC), residual volume (RV), and functional residual capacity (FRC). Gas exchange across the alveolar capillary membrane can be measured using expanded carbon monoxide volume (DLCO). Peripheral capillary oxygen saturation (SpO2) can also be measured. Statistical analyses described herein and routinely performed in the art can be applied to the analysis of data.

[0169] Methods for treating and preventing age-related diseases and disorders This specification provides methods for treating conditions, diseases, or disorders related to, associated with, or caused by cellular senescence, including age-related diseases and disorders, for subjects requiring such treatment. Age-related diseases or disorders may also be referred to herein as senescent cell-related diseases or disorders. Examples of age-related diseases and disorders include, for example, cardiovascular diseases and disorders, inflammatory diseases and disorders, autoimmune diseases and disorders, lung diseases and disorders, eye diseases and disorders, metabolic diseases and disorders, neurological diseases and disorders (e.g., neurodegenerative diseases and disorders), age-related diseases and disorders induced by aging, skin conditions, age-related diseases, dermatological diseases and disorders, and transplant-related diseases and disorders. A prominent feature of aging is the gradual loss or degeneration of function occurring at the molecular, cellular, tissue, and biological levels. Age-related degeneration causes well-known conditions such as sarcopenia, atherosclerosis and heart failure, osteoporosis, pulmonary dysfunction, renal failure, neurodegeneration (including macular degeneration, Alzheimer's disease, and Parkinson's disease), and numerous others. While different mammalian species have different susceptibility to specific age-related conditions, overall, age-related conditions generally increase at a nearly exponential rate, starting around the midpoint of the species-specific lifespan (e.g., 50-60 years in humans) (see, e.g., Campisi, Annu. Rev. Physiol. 75 (2013), pp. 685-705; Naylor et al., Clin. Pharmacol. Ther. 93 (2013), pp. 105-116).

[0170] Examples of age-related conditions, disorders, or diseases that can be treated by administering any one of the senolytic agents described herein in accordance with the method described herein include: cognitive disorders (e.g., mild cognitive impairment (MCI), Alzheimer's disease, and other dementias, Huntington's disease); cardiovascular diseases (e.g., atherosclerosis, diastolic dysfunction, aortic aneurysm, angina pectoris, arrhythmia, cardiomyopathy, congestive heart failure, coronary artery disease, myocardial infarction, endocarditis, hypertension, carotid artery disease, peripheral vascular disease, cardiac stress tolerance, cardiofibrosis); metabolic diseases and disorders (e.g., obesity, diabetes, metabolic syndrome); motor function disorders and disorders (e.g., Parkinson's disease, motor neuron dysfunction (MND), Huntington's disease); cerebrovascular diseases; emphysema; osteoarthritis; benign prostatic hyperplasia; lung diseases (e.g., idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease) Diseases (COPD, emphysema, bronchiolitis obliterans, asthma); inflammatory / autoimmune diseases and disorders (e.g., osteoarthritis, eczema, psoriasis, osteoporosis, mucositis, transplant-related diseases and disorders); ophthalmic diseases or disorders (e.g., age-related macular degeneration, cataracts, glaucoma, vision loss, presbyopia); diabetic ulcers; metastases; side effects of chemotherapy, side effects of radiotherapy; age-related diseases and disorders (e.g., kyphosis, renal dysfunction, frailty, hair loss, hearing loss, muscle fatigue, skin conditions, sarcopenia, and herniated discs), as well as other age-related diseases induced by aging (e.g., diseases / disorders caused by radiation, chemotherapy, smoking, high-fat / high-sugar diets, and environmental factors); wound healing; skin nevi; fibrous diseases and disorders (e.g., cystic fibrosis, renal fibrosis, hepatic fibrosis, pulmonary fibrosis, oral submucosal fibrosis, cardiac fibrosis, and pancreatic fibrosis). In certain embodiments, one or more of the diseases or disorders described above or herein may be excluded.

[0171] In some embodiments, a method is provided for treating an aging-related disease or disorder by administering a senolytic agent to kill senescent cells (i.e., established senescent cells) associated with the disease or disorder in a subject having the disease or disorder, wherein the disease or disorder is osteoarthritis, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), or atherosclerosis.

[0172] Cardiovascular diseases and disorders In other embodiments, the age-related disease or disorder treated by the methods described herein is a cardiovascular disease. Cardiovascular diseases may include one or more of the following: angina pectoris, arrhythmias, atherosclerosis, cardiomyopathy, congestive heart failure, coronary artery disease (CAD), carotid artery disease, endocarditis, heart attack (coronary thrombosis, myocardial infarction [MI]), high blood pressure / hypertension, aortic aneurysm, cerebral aneurysm, cardiac fibrosis, diastolic dysfunction, hypercholesterolemia / hyperlipidemia, mitral valve prolapse, peripheral vascular disease (e.g., peripheral artery disease (PAD)), cardiac stress tolerance, and stroke.

[0173] In certain embodiments, methods are provided for treating age-related cardiovascular diseases associated with or caused by arteriosclerosis (i.e., hardening of the arteries). The cardiovascular diseases may be one or more of the following: atherosclerosis (e.g., coronary artery disease (CAD) and carotid artery disease), angina pectoris, congestive heart failure, and peripheral vascular diseases (e.g., peripheral artery disease (PAD)). Methods for treating cardiovascular diseases associated with or caused by arteriosclerosis can reduce the likelihood of developing high blood pressure / hypertension, angina pectoris, stroke, and heart attacks (i.e., coronary thrombosis, myocardial infarction (MI)). In certain embodiments, methods are provided for stabilizing atherosclerotic plaques in target vessels (e.g., arteries) to reduce or delay the likelihood of developing thrombotic events such as stroke or myocardial infarction. In certain embodiments, such methods, including the administration of a senolytic agent, reduce (i.e., cause a decrease) the lipid content of atherosclerotic plaques in target blood vessels (e.g., arteries) and / or increase (i.e., cause, enhance, or promote an increase in fibrous cap thickness).

[0174] Atherosclerosis is characterized by patchy intimal plaques (atheromas) that erode the lumen of medium and large arteries, the plaques containing lipids, inflammatory cells, smooth muscle cells, and connective tissue. Atherosclerosis can affect large and medium arteries, including the coronary arteries, carotid arteries, and cerebral arteries, the aorta and its branches, as well as the major arteries of the limbs. In some embodiments, methods are provided for inhibiting the formation of atherosclerotic plaques (or reducing, shrinking, or decreasing the formation of atherosclerotic plaques) by administering senolytic agents. In other embodiments, methods are provided for reducing (reducing, shrinking) the amount (i.e., level) of plaque. Reduction of plaque volume in a blood vessel (e.g., artery) can be determined, for example, by a reduction in the surface area of ​​the plaque, or by a reduction in the extent or degree (e.g., percentage) of occlusion of the blood vessel (e.g., artery), which can be determined by angiography or other visualization methods used in the cardiovascular technology field. Furthermore, this specification provides methods for increasing (or improving, promoting, or enhancing) the stability of atherosclerotic plaques present in one or more target blood vessels (e.g., one or more arteries), such methods comprising administering one of the senolytic agents described herein to the target.

[0175] Subjects suffering from cardiovascular disease can be identified using standard diagnostic methods known in the art for cardiovascular diseases. Generally, the diagnosis of atherosclerosis and other cardiovascular diseases is based on the patient's symptoms (e.g., chest pain or pressure (angina), numbness or weakness in the arms or legs, difficulty or slurred speech, facial drooping, leg pain, high blood pressure, renal failure, and / or erectile dysfunction), medical history, and / or physical examination. The diagnosis can be confirmed by angiography, ultrasonography, or other imaging tests. Subjects at risk of developing cardiovascular disease include those with one or more predisposing factors, such as a family history of cardiovascular disease, and those with other risk factors (i.e., predisposing factors) such as high blood pressure, dyslipidemia, high cholesterol, diabetes, obesity, smoking, sedentary lifestyle, and hypertension. In certain embodiments, a cardiovascular disease that is senescent-related disease / disorder is atherosclerosis.

[0176] The effectiveness of one or more senolytic agents for treating or preventing cardiovascular disease (e.g., atherosclerosis) (i.e., reducing or decreasing the likelihood of developing or occurring) can be readily determined by those skilled in the art in the medical and clinical fields. One or any combination of diagnostic methods, including physical examination, assessment and monitoring of clinical symptoms, and the performance of analytical tests and methods described herein and practiced in the art (e.g., angiography, electrocardiography, stress tests, non-stress tests), can be used to monitor the health status of the subject. The effect of treatment with a senolytic agent or a pharmaceutical composition containing the same can be analyzed using techniques known in the art, such as comparing the symptoms of a treated patient with or at risk of cardiovascular disease with the symptoms of a patient who has not received such treatment or has received a placebo.

[0177] Inflammatory and autoimmune diseases and disorders In certain embodiments, age-related diseases or disorders are inflammatory diseases or disorders that can be treated or prevented (i.e., reduced in likelihood of developing) by following the methods described herein, including the administration of senolytic agents, such as osteoarthritis, in non-limiting examples. Other inflammatory or autoimmune diseases or disorders that can be treated by administering senolytic agents such as the inhibitors and antagonists described herein include osteoporosis, psoriasis, oral mucositis, rheumatoid arthritis, inflammatory bowel disease, eczema, kyphosis, herniated discs, and lung diseases, COPD, and idiopathic pulmonary fibrosis.

[0178] Osteoarthritis is characterized by fibrosis of cartilage, osteosclerosis, and thickening of the synovial membrane and joint capsule in areas of high mechanical stress. Fibrosis is localized surface tissue breakdown accompanied by rupture of the cartilage surface. Initial rupture is tangential to the cartilage surface along the axis of the main collagen bundle. Collagen within the cartilage breaks down, and proteoglycans are lost from the cartilage surface. Without the protective and lubricating effects of proteoglycans in the joint, collagen fibers become more susceptible to deterioration, leading to mechanical failure. Predisposing risk factors for developing osteoarthritis include increased age, obesity, a history of joint injury, joint overuse, weakness of the thigh muscles, and genetics. Symptoms of osteoarthritis include pain or stiffness in the joints, particularly the hip, knee, and lumbar joints, after lack of exercise or overuse; resting stiffness that is relieved after exercise; and pain that worsens after activity or towards the end of the day. Osteoarthritis can affect the neck, little finger joints, base of the thumb, ankles, and even the big toe. Chronic inflammation is considered a major age-related factor contributing to osteoarthritis. Combined with aging, joint overuse and obesity are thought to accelerate the development of osteoarthritis.

[0179] Senolytic agents prevent (i.e., reduce the likelihood of developing), reduce, or inhibit the loss or erosion of the proteoglycan layer of a joint by selectively killing senescent cells, reduce inflammation in the affected joint, and promote (i.e., stimulate, enhance, or induce) the production of collagen (e.g., type II collagen). Removing senescent cells leads to a reduction in the amount (i.e., levels) of inflammatory cytokines such as IL-6 produced in the joint, thereby reducing inflammation. The Specified Methods Provided herein are for treating osteoarthritis, for selectively killing senescent cells in a target osteoarthritis joint, and / or for inducing collagen (such as type II collagen) production in a target joint by administering to the target at least one senolytic agent (which can be combined with at least one pharmaceutically acceptable excipient to form a pharmaceutically acceptable composition) to the target. Senolytic agents can also be used to reduce (inhibit, reduce) the production of metalloproteinase 13 (MMP-13), which breaks down collagen in joints, and to repair the proteoglycan layer or to inhibit the loss and / or breakdown of the proteoglycan layer. Furthermore, treatment with senolytic agents can prevent (i.e., reduce the likelihood of onset), inhibit or reduce bone erosion, or slow bone erosion (i.e., reduce its rate). As described in detail herein, in certain embodiments, senolytic agents are administered directly to osteoarthritis joints (e.g., by intra-articular, topical, perdermal, intradermal, or subcutaneous delivery). Treatment with senolytic agents can also restore, improve, or inhibit the deterioration of joint strength. In addition, methods involving the administration of senolytic agents can reduce joint pain and are therefore useful for pain management in osteoarthritis joints.

[0180] The effectiveness of one or more senolytic agents for treating or preventing osteoarthritis in a subject, and the monitoring of subjects who have received one or more senolytic agents, can be readily determined by those skilled in the art of medicine and clinical practice. To monitor the health status of a subject, one or any combination of diagnostic methods can be used, including physical examination (such as determining tenderness, swelling, or redness of the affected joint), evaluation and monitoring of clinical symptoms (such as pain, stiffness, and mobility), and the performance of analytical tests and methods described herein and practiced in the art (e.g., determining levels of inflammatory cytokines or chemokines, X-ray imaging to determine cartilage loss indicated as narrowing of the space between articular bones, and magnetic resonance imaging (MRI) to provide detailed images of bone and soft tissue, including cartilage). The effectiveness of treatment with one or more senolytic agents can be analyzed by comparing the symptoms of patients who have or are at risk of developing inflammatory diseases or disorders, such as osteoarthritis, with the symptoms of patients who have not received such treatment or who have received placebo treatment.

[0181] In certain embodiments, senolytic agents can be used to treat and / or prevent rheumatoid arthritis (RA) (i.e., reduce or lessen the likelihood of developing it). Rheumatoid arthritis (RA) is an autoimmune disease characterized by dysregulation of the innate and adaptive immune responses, with an increasing incidence with age. Rheumatoid arthritis is typically a chronic inflammatory disease affecting the small joints of the hands and feet. While osteoarthritis is at least partially due to joint wear and tear, rheumatoid arthritis affects the inner layers of the joints, resulting in painful swellings that can lead to bone erosion and joint deformation. RA can also affect other organs of the body, such as the skin, eyes, lungs, and blood vessels. RA can occur in subjects of any age, but it usually begins to develop after the age of 40. The disease is considerably more common in women. In certain embodiments of the methods described herein, RA is excluded.

[0182] Chronic inflammation can also contribute to other age-related or age-related diseases and disorders, such as kyphosis and osteoporosis. Kyphosis is a severe curvature of the spine and is commonly seen in normal and premature aging (see, e.g., Katzman et al., J. Orthop. Sports Phys. Ther. Vol. 40 (2010), pp. 352-360). Age-related kyphosis often develops after osteoporosis weakens the vertebral bones, leading to cracking and compression. A few types of kyphosis target infants or teenagers. Severe kyphosis can affect the lungs, nerves, and other tissues and organs, causing pain and other problems. Kyphosis is associated with cellular senescence. The characterization of the ability of senolytic agents to treat kyphosis can be determined in preclinical animal models used in the art. For example, TTD mice develop kyphosis (see, e.g., de Boer et al., Science vol. 296 (2002), pp. 1276-1279). Other mice that can be used include BubR1, which is known to develop kyphosis. H / H Mice are an example (see, for example, Baker et al., Nature vol. 479 (2011), pp. 232-236). Kyphosis formation is measured visually over time. The level of senescent cells reduced by treatment with senoleptic agents can be determined by detecting the presence of one or more senescent cell-related markers, such as SA-β-Gal staining.

[0183] Osteoporosis is a progressive bone disease characterized by a decrease in bone mass and bone density, which can lead to an increased risk of fracture and can be treated or prevented by the administration of the senolytic agents described herein. Bone mineral density (BMD) decreases, bone microstructure deteriorates, and the amount and type of bone proteins change. Osteoporosis is typically diagnosed and monitored by bone mineral density testing. Postmenopausal women or women showing reduced estrogen levels are at highest risk. Both men and women over 75 years of age are at risk, but women are twice as likely to develop osteoporosis as men. The level of senescent cells reduced by treatment with senolytic agents can be determined by detecting the presence of one or more senescent cell-related markers, such as SA-β-Gal staining.

[0184] In further embodiments, inflammatory / autoimmune diseases that can be treated or prevented (i.e., whose likelihood of developing is reduced) by the senolytic agents described herein include irritable bowel syndrome (IBS) and inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease. Inflammatory bowel disease (IBD) involves chronic inflammation of all or part of the gastrointestinal tract. IBD can be painful and debilitating, in addition to causing life-threatening complications. Ulcerative colitis is an inflammatory bowel disease that causes long-term inflammation in part of the gastrointestinal tract. Symptoms usually appear over time, not suddenly. Ulcerative colitis usually affects only the innermost lining of the intestine (colon) and rectum. Crohn's disease is an inflammatory bowel disease that causes inflammation anywhere along the lining of the gastrointestinal tract, often spreading deep into the affected tissue. This can be associated with abdominal pain, severe diarrhea, and malnutrition. The inflammation caused by Crohn's disease can occur in various areas of the gastrointestinal tract. The diagnosis and monitoring of the disease are carried out according to methods and diagnostic tests routinely performed in the art, such as blood tests, colonoscopy, flexible sigmoidoscopy, barium enema, CT scans, MRI, endoscopy, and small bowel imaging.

[0185] Other inflammatory or autoimmune diseases that can be treated or prevented (i.e., whose likelihood of developing is reduced) by the use of senolytics include eczema, psoriasis, osteoporosis, and lung diseases (e.g., chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), asthma), inflammatory bowel disease, and mucositis (in some cases including radiation-induced oral mucositis). Certain organ-specific fibrosis or fibrotic conditions, such as renal fibrosis, hepatic fibrosis, pancreatic fibrosis, cardiac fibrosis, skin wound healing, and oral submucosal fibrosis, can be treated with the senolytics described herein.

[0186] In certain embodiments, senescent cell-associated disorders are inflammatory skin diseases, such as psoriasis and eczema, which can be treated or prevented (i.e., the likelihood of developing them is reduced) by following the methods herein, including the administration of senolytic agents, as non-limiting examples. Psoriasis is characterized by abnormally excessive and rapid growth of the epidermal layer of the skin. The diagnosis of psoriasis is usually based on the appearance of the skin. Typical skin features of psoriasis are scaly red patches, papules, or patches of skin that may be painful and itchy. In psoriasis, cutaneous and systemic overexpression of various pro-inflammatory cytokines, such as IL-6, the main component of SASP, is observed. Eczema is an inflammation of the skin characterized by redness, skin swelling, itchiness and dryness, crusting, peeling, blistering, cracking, exudation, or bleeding. The effectiveness of senolytic agents for treating psoriasis and eczema, as well as the monitoring of subjects receiving such senolytic agents, can be readily determined by those skilled in the art of the medical or clinical field. One or any combination of diagnostic methods may include physical examination (such as skin appearance), monitoring and evaluation of clinical symptoms (such as itching, swelling, and pain), and the performance of analytical tests and methods described herein and performed in the art (i.e., determination of levels of pro-inflammatory cytokines).

[0187] Other immune disorders or conditions that can be treated or prevented (i.e., whose likelihood of developing is reduced) with the senolytic agents described herein include conditions resulting from a host immune response to an organ graft (e.g., a kidney, bone marrow, liver, lung, or heart graft), such as organ rejection. The senolytic agents described herein can also be used to treat graft-versus-host disease or to reduce its likelihood of developing.

[0188] Lung diseases and disorders In some embodiments, a method is provided for treating or preventing (i.e., reducing the likelihood of developing) age-related lung diseases or disorders by administering the senolistic agents described herein to kill senescent cells associated with the disease or disorder (i.e., established senescent cells) in subjects with the disease or disorder. Examples of age-related lung diseases and disorders include idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis, bronchiectasis, and emphysema.

[0189] COPD is a lung disease characterized by persistent poor airflow due to the destruction of lung tissue (emphysema) and dysfunction of the peripheral airways (obstructive bronchiolitis). The main symptoms of COPD include shortness of breath, wheezing, chest tightness, chronic cough, and excessive sputum production. Elastases derived from smoking-activated neutrophils and macrophages dismantle the extracellular matrix of alveolar structures, leading to air space enlargement and loss of respiratory capacity (see, e.g., Shapiro et al., Am.J.Respir.Cell Mol.Biol. 32 (2005), pp. 367-372). COPD is most commonly caused by tobacco smoke (including cigarette smoke, cigar smoke, sidestream smoke, and pipe smoke), occupational exposure (e.g., exposure to dust, smoke, or haze), and pollution, and develops over decades, suggesting that aging is a risk factor for developing COPD.

[0190] Processes involved in inducing lung damage include, for example, oxidative stress generated by high concentrations of free radicals in cigarette smoke, cytokine release due to inflammatory responses to irritants in the airways, and dysfunction of antiprotease enzymes caused by cigarette smoke and free radicals, leading to protease-mediated lung damage. Genetic susceptibility may also contribute to this disease. In about 1% of people with COPD, the disease is caused by a genetic disorder that leads to low levels of alpha-1-antitrypsin production in the liver. This enzyme is normally secreted into the bloodstream and helps protect the lungs.

[0191] Pulmonary fibrosis is a chronic and progressive lung disease characterized by hardening and scarring of the lungs, which can lead to respiratory failure, lung cancer, and heart failure. Fibrosis is associated with epithelial repair. Fibroblasts are activated, increasing the production of extracellular matrix proteins, and their differentiation into contractile myofibroblasts contributes to wound contraction. A temporary matrix seals the injured epithelium, providing a scaffold for epithelial cell migration accompanied by epithelial-mesenchymal transition (EMT). Blood loss associated with epithelial injury induces platelet activation, growth factor production, and an acute inflammatory response. Normally, the epithelial barrier heals and the inflammatory response resolves. However, in fibrotic diseases, the fibroblastic response persists, resulting in unresolved wound healing. The formation of fibroblastic foci is characteristic of this disease, reflecting the location of ongoing fibrosis. As the name suggests, the etiology of IPF is unknown. The involvement of cellular senescence in IPF is suggested by observations that the incidence of the disease increases with age, that lung tissue from IPF patients is rich in SA-β-Gal-positive cells, and that it contains high levels of the aging marker p21 (e.g., Minagawa et al., Am.J.Physiol.Lung Cell.Mol.Physiol. 300 (2011), pp. L391-L401; see also Naylor et al., op. cit.). Short telomeres are a common risk factor for both IPF and cellular senescence (see, for example, Alder et al., Proc.Natl.Acad.Sci.USA 105 (2008), pp. 13051-13056). While we do not wish to be bound by theory, reports (e.g., Minagawa et al., cited above) that SASP components of senescent cells, such as IL-6, IL-8, and IL-1, promote differentiation from fibroblasts to myofibroblasts and epithelial-mesenchymal transition, leading to extensive remodeling of the extracellular matrix in the alveolar and interstitial spaces suggest a contribution of cellular senescence to IPF.

[0192] Individuals at risk of developing pulmonary fibrosis include those exposed to environmental or occupational pollutants such as asbestosis and silicosis; smokers; those with certain typical connective tissue diseases such as rheumatoid arthritis, SLE, and scleroderma; those with other connective tissue-related diseases such as sarcoidosis and Wegener's granulomatosis; those with infections; those taking certain medications (e.g., amiodarone, bleomycin, busulfan, methotrexate, and nitrofurantoin); those receiving radiation therapy to the chest; and those with a family history of pulmonary fibrosis.

[0193] Symptoms of COPD include any one of the following, particularly shortness of breath during physical activity; wheezing; chest tightness; need to clear the throat first thing in the morning due to excessive mucus in the lungs; chronic cough producing sputum that may be clear, white, yellow, or greenish; bluish discoloration of the lips or nail beds (cyanosis); frequent respiratory infections; lack of energy; and unintentional weight loss (observed in later stages of the disease). Subjects with COPD may also experience exacerbations, in which case the symptoms worsen and last for several days or longer. Symptoms of pulmonary fibrosis are well known in the art and include, in particular, shortness of breath during exercise; a dry cough; rapid, shallow breathing; unintentional weight loss; fatigue; arthralgia and muscle pain; and clubbing of the fingers and toes.

[0194] Subjects with COPD or pulmonary fibrosis can be identified using standard diagnostic methods routinely performed in the art. Monitoring the effectiveness of one or more senolytics administered to subjects with or at risk of developing lung disease can be performed using methods typically used for diagnosis. Generally, one or more of the following tests or examinations may be performed: physical examination, patient history, patient family history, chest X-ray, pulmonary function tests (e.g., spirometry), blood tests (e.g., arterial blood gas analysis), bronchoalveolar lavage, lung biopsy, CT scan, and exercise tests.

[0195] Other lung diseases or disorders that can be treated with senolytics include, for example, emphysema, asthma, bronchiectasis, and cystic fibrosis (see, e.g., Fischer et al., Am J Physiol Lung Cell Mol Physiol. 304(6)(2013) pp. 394-400). These diseases can also be exacerbated by tobacco smoke (including cigarette smoke, cigar smoke, sidestream smoke, and pipe smoke), occupational exposure (e.g., exposure to dust, smoke, or haze), infections, and / or pollutants that induce cellular aging and thereby contribute to inflammation. Emphysema is sometimes considered a subgroup of COPD.

[0196] Bronchiectasis is caused by damage to the airways, which widens them, leading to sagging and scarring. Bronchiectasis is usually caused by medical conditions that result in damage to the airway walls or obstruct mucus clearance in the airways. Examples of such conditions include cystic fibrosis and primary ciliary dysfunction (PCD). If only a portion of the lungs is affected, the disorder may be caused by obstruction rather than a medical condition.

[0197] The methods herein for treating or preventing (i.e., reducing the likelihood or onset of) age-related lung disease or impairment may also be used to treat subjects who are elderly and have loss (or degeneration) of lung function (i.e., reduced or impaired lung function compared to younger subjects) and / or degeneration of lung tissue. The respiratory system undergoes various anatomical, physiological, and immunological changes with age. Structural changes include deformation of the chest wall and thoracic vertebrae, which can impair the overall extensibility of the respiratory system and lead to increased effort required for breathing. The respiratory system undergoes structural, physiological, and immunological changes with age. Bronchoalveolar lavage fluid (BAL) from older adults can be found to have an increased percentage of neutrophils and a decreased percentage of macrophages compared to younger adults. Persistent mild inflammation in the lower airways can cause proteolytic and oxidant-mediated damage to the lung matrix, resulting in the loss of alveolar units and impaired gas exchange across the alveolar membranes, which are seen with age. Persistent inflammation of the lower respiratory tract can increase susceptibility to exposure to toxic environments and accelerate lung function decline in older adults (see, e.g., Sharma et al., Clinical Interventions in Aging, Vol. 1 (2006), pp. 253-260). Oxidative stress exacerbates inflammation with age (see, e.g., Brod, Inflamm. Res., Vol. 49 (2000), pp. 561-570; Hendel et al., Cell Death and Differentiation, Vol. 17 (2010), pp. 596-606). As the redox balance changes with aging, increased oxidative stress induces the expression of cytokines, chemokines, adhesion molecules, and enzymes (see, e.g., Chung et al., Ageing Res. Rev., Vol. 8 (2009), pp. 18-30).Constitutive activation and recruitment of macrophages, T cells, and mast cells facilitate protease release, which can lead to extracellular matrix degradation, cell death, remodeling, and other events that can cause tissue and organ damage during chronic inflammation (see, e.g., Demedts et al., Respir. Res. Vol. 7 (2006), pp. 53-63). When senolytics are administered to aging subjects (including asymptomatic middle-aged adults), they can delay and inhibit the decline of lung function by killing and removing senescent cells in the respiratory tract.

[0198] The efficacy of senolytic agents can be readily determined by those skilled in the medical and clinical fields. One or any combination of diagnostic methods, including physical examination, assessment and monitoring of clinical symptoms, and the performance of analytical tests and methods described herein, can be used to monitor the health status of the subject. The effect of treatment with a senolytic agent or a pharmaceutical composition containing an agonist can be analyzed using techniques known in the art, such as comparing the symptoms of a treated patient with or at risk of having a lung disease with the symptoms of a patient who has not received such treatment or who has received a placebo. In addition, methods and techniques for evaluating the mechanical function of the lungs, such as techniques for measuring lung volume, elastance, and airway hyperresponsiveness, can be performed. To determine lung function and to monitor it throughout treatment, numerous measurements can be obtained, including expiratory reserve volume (ERV), forced vital capacity (FVC), forced expiratory volume (FEV) (e.g., FEV1 in one second), FEV1 / FEV ratio, forced expiratory flow rate 25%–75%, and one of the following: maximal spontaneous ventilation (MVV), maximal expiratory flow rate (PEF), or slow vital capacity (SVC). Total lung capacity can be measured using total vital capacity (TLC), vital capacity (VC), residual volume (RV), and functional residual capacity (FRC). Gas exchange across the alveolar capillary membrane can be measured using expanded carbon monoxide volume (DLCO). Peripheral capillary oxygen saturation (SpO2) can also be measured. Normal oxygen levels are typically 95%–100%. If the SpO2 level falls below 90%, it suggests that the subject has hypoxia. A value below 80% is considered a critical condition, requiring intervention to maintain brain and heart function and prevent cardiac or respiratory arrest.

[0199] Neurological diseases and disorders Age-related diseases or disorders that can be treated by administering the senolytic agents described herein include neurological diseases or disorders. Such age-related diseases and disorders include Parkinson's disease, Alzheimer's disease (and other dementias), motor neuron dysfunction (MND), mild cognitive impairment (MCI), Huntington's disease, and eye diseases and disorders such as age-related macular degeneration. Other eye diseases associated with increasing age include glaucoma, vision loss, presbyopia, and cataracts.

[0200] Parkinson's disease (PD) is the second most common neurodegenerative disease. It is a brain disorder characterized by bradykinesia (slowness of movement), tremors, rigidity, and, in later stages, loss of balance. Many of these symptoms are due to the loss of specific neurons in the brain, resulting in a dopamine deficiency. The disease is characterized by neurodegeneration, including the loss of approximately 50-70% of dopaminergic neurons in the substantia nigra pars compacta, a marked loss of dopamine in the striatum, and / or the presence of intracytoplasmic inclusions (Lewy bodies) composed mainly of alpha-synuclein and ubiquitin. Parkinson's disease is also characterized by spontaneous movement deficits such as tremors, muscle rigidity, bradykinesia, and / or postural instability. Individuals at risk of developing Parkinson's disease include those with a family history of Parkinson's disease and those exposed to insecticides (e.g., rotenone or paraquat), herbicides (e.g., Agent Orange), or heavy metals. The aging of dopamine-producing neurons is thought to contribute to the cell death observed in PD through the production of reactive oxygen species (see, for example, Cohen et al., J. Neural Transm. Suppl. Vol. 19 (1983), pp. 89-103), and therefore, the methods described herein and senolytic agents are useful for the treatment and prevention of Parkinson's disease.

[0201] Methods for detecting, monitoring, or quantifying neurodegenerative disorders and / or spontaneous movement deficits associated with Parkinson's disease are publicly known in the art, including histological studies, biochemical studies, and behavioral assessments (see, for example, U.S. Patent Application Publication No. 2012 / 0005765). Symptoms of Parkinson's disease are publicly known in the art, but are not limited to, difficulty initiating or ending spontaneous movements, jerky and rigid movements, muscle atrophy, tremors, and changes in heart rate, but normal reflexes, bradykinesia, and postural instability. There is a growing awareness that people diagnosed with Parkinson's disease may have cognitive impairments, including mild cognitive impairment, in addition to their physical symptoms.

[0202] Alzheimer's disease (AD) is a neurodegenerative disease characterized by a slowly progressing decline in mental function, accompanied by memory impairment, disorientation, and confusion, leading to marked dementia. Age is the single largest precipitating risk factor for developing AD, the leading cause of dementia in older adults (see, e.g., Hebert et al., Arch. Neural. 60 (2003), pp. 1119-1122). Early clinical symptoms show a striking resemblance to mild cognitive impairment (see below). As the disease progresses, impaired judgment, confusion, behavioral changes, disorientation, and difficulty walking and swallowing develop.

[0203] Alzheimer's disease is characterized by the presence of neurofibrillary tangles and amyloid (senile) plaques in histological specimens. The disease primarily affects the limbic and cortical regions of the brain. Silver-affinity plaques containing amyloid-forming A fragments of amyloid precursor protein (APP) are scattered throughout the cerebral cortex and hippocampus. Neurofibrillary tangles are found primarily in pyramidal neurons located in the neocortex, hippocampus, and nucleus basalis of Meynert. Other changes, such as granular vacuolar degeneration in pyramidal cells of the hippocampus, as well as neuronal loss and gliosis in the cortex and hippocampus, are also observed. Individuals at risk of developing Alzheimer's disease include older age, a family history of Alzheimer's disease, the presence of a genetic risk gene (e.g., ApoE4) or a definitive gene mutation (e.g., APP, PS1, or PS2), and a history of head trauma or cardiovascular conditions (e.g., hypertension, heart disease, stroke, diabetes, high cholesterol).

[0204] Numerous behavioral and histopathological assays are known in the art for evaluating Alzheimer's disease phenotypes, characterizing therapeutic agents, and evaluating treatments. Histological analysis is typically performed postmortem. Histological analysis of Aβ levels can be performed by visualizing Aβ deposition in sectioned brain tissue using thioflavin S, Congo red, or anti-A staining (e.g., 4G8, 10D5, or 6E10 antibodies) (see, e.g., Holcomb et al., Nat. Med. 4 (1998), pp. 97-100; Borchelt et al., Neuron Vol. 19 (1997), pp. 939-945; Dickson et al., Am. J. Path. Vol. 132 (1998), pp. 86-101). In vivo methods for visualizing Aβ deposition in transgenic mice have also been described. BSB ((trans,trans)-1-bromo-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene) and PET tracer 1114C-labeled Pittsburgh compound B (PIB) binds to AP plaques (see, for example, Skovronsky et al., Proc. Natl. Acad. Sci. USA, Vol. 97 (2000), pp. 7609-7614; Klunk et al., Ann. Neurol., Vol. 55 (2004), pp. 306-319). 19 The fluorine-containing amyloid-affinity Congo red compound FSB ((E,E)-1-fluoro-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene) enables visualization of Aβ plaques by MRI (see, e.g., Higuchi et al., Nature Neurosci. Vol. 8 (2005), pp. 527-533). Radiolabeled putrescine-modified amyloid-beta peptides label amyloid deposits in vivo in a mouse model of Alzheimer's disease (see, e.g., Wengenack et al., Nat. Biotechnol. Vol. 18 (2000), pp. 868-872).

[0205] Increased glial fibrillary acidic protein (GFAP) by astrocytes is a marker of astrocyte activation and gliosis during neurodegeneration. AP plaques are associated with GFAP-positive activated astrocytes and can be visualized by GFAP staining (see, e.g., Nagele et al., Neurobiol. Aging vol. 25 (2004), pp. 663-674; Mandybur et al., Neurology vol. 40 (1990), pp. 635-639; Liang et al., J. Biol. Chem. vol. 285 (2010), pp. 27737-27744). Neurofibrillary tangles can be identified by immunohistochemistry using thioflavin S fluorescence microscopy and Gallyas silver staining (see, e.g., Gotz et al., J. Biol. Chem. vol. 276 (2001), pp. 529-534; U.S. Patent No. 6,664,443). Neurodegeneration can be visualized using axon staining and axonal transport studies with electron microscopy (see, for example, Ishihara et al., Neuron vol. 24 (1999), pp. 751-762).

[0206] Individuals with Alzheimer's disease can be identified using standard diagnostic methods known in the art for Alzheimer's disease. Generally, the diagnosis of Alzheimer's disease is based on symptoms (e.g., progressive decline in memory function, gradual decline from normal activity and dissatisfaction, apathy, agitation or irritability, aggression, anxiety, sleep disturbances, discomfort, abnormal motor behavior, disinhibition, social withdrawal, loss of appetite, hallucinations, dementia), medical history, neuropsychological examination, and neurological and / or physical examination of the patient. Cerebrospinal fluid can also be evaluated for various proteins associated with Alzheimer's pathology, including tau, amyloid-beta peptide, and AD7C-NTP. Genetic testing for early-onset familial Alzheimer's disease (eFAD), an autosomal dominant genetic disorder, is also available. Clinical genetic testing is available for individuals with AD symptoms or for risk family members of patients with early-onset disease. In the United States, PS2 mutations and APP can be evaluated in clinical laboratories or federally licensed laboratories under the Clinical Laboratory Improvement Amendments. Commercial testing for PS1 mutations is also available (Elan Pharmaceuticals).

[0207] The efficacy of one or more senolytic agents described herein, and the monitoring of subjects who have received one or more senolytic agents, can be readily determined by those skilled in the art in the medical and clinical fields. One or any combination of diagnostic methods, including physical examination, assessment and monitoring of clinical symptoms, and the performance of analytical tests and methods described herein, can be used to monitor the health status of subjects. The effects of administering one or more senolytic agents can be analyzed using techniques known in the art, such as comparing the symptoms of patients with or at risk of Alzheimer's disease who have received treatment with the symptoms of patients who have not received such treatment or who have received a placebo.

[0208] Mild cognitive impairment (MCI) is a brain function syndrome characterized by the onset and progression of cognitive impairment that exceeds what would be expected given an individual's age and educational level, but is not severe enough to interfere with the individual's daily activities. MCI is considered an aspect of cognitive aging, representing a transitional period between normal aging and the potential for dementia (see Pepeu, Dialogues in Clinical Neuroscience, Vol. 6 (2004), pp. 369-377). MCI that primarily affects memory is known as "amnesic MCI." Individuals with amnesic MCI may begin to forget important information that they would have previously recalled easily, such as recent events. Amnesic MCI is often seen as a precursor to Alzheimer's disease. MCI that affects cognitive abilities other than memory is known as "non-amnesic MCI." This type of MCI affects cognitive abilities such as the ability to make sound judgments, the ability to determine the time or sequence of steps required to complete complex tasks, or visual recognition. Individuals with non-amnesic MCI are considered to be more likely to progress to other types of dementia (e.g., Lewy body dementia).

[0209] Among medical professionals, there is a growing awareness that people diagnosed with Parkinson's disease may have MCI (Mild Cognitive Impairment) in addition to their physical symptoms. Recent studies have shown that 20-30% of Parkinson's disease patients have MCI, and that this MCI tends not to be amnesic. Parkinson's disease patients with MCI may sometimes develop full-blown dementia (Parkinson's disease with dementia).

[0210] Methods for detecting, monitoring, quantifying, or evaluating neuropathological defects associated with MCI are known in the art and include astrocyte morphological analysis, acetylcholine release, silver staining to assess neurodegeneration, and PiB PET imaging to detect beta-amyloid deposition (see, for example, U.S. Patent Application Publication 2012 / 0071468; Pepeu, (2004), op. cit.). Methods for detecting, monitoring, quantifying, or evaluating behavioral defects associated with MCI are also known in the art and include the eight-arm radial maze paradigm, non-matching-to-sample task, allocentric place determination task in a water maze, Morris maze test, visuospatial task, delayed response spatial memory task, and olfactory novelty test.

[0211] Motor neuron dysfunction (MND) is a group of progressive neurological disorders that destroy motor neurons, which are cells that control essential voluntary muscle activities such as speech, walking, breathing, and swallowing. Motor neuron dysfunction is classified according to whether the degeneration affects upper motor neurons, lower motor neurons, or both. Examples of MND include, but are not limited to, amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease; progressive bulbar palsy; pseudobulbar palsy; primary lateral sclerosis; progressive muscular atrophy; lower motor neuron disease; and spinal muscular atrophy (SMA) (e.g., SMA1, SMA2, also known as Werdnig-Hoffmann disease; SMA3, also known as Kugelberg-Welander disease; and Kennedy disease), post-polio syndrome, and hereditary spastic paraplegia. In adults, the most common MND is amyotrophic lateral sclerosis (ALS), which affects both upper and lower motor neurons. This can affect the muscles of the arms, legs, or face. Primary lateral sclerosis (ALS) is a disease of the upper motor neurons, while progressive muscular atrophy (MSD) affects only the lower motor neurons of the spinal cord. In progressive bulbar palsy, the lowest motor neurons in the brainstem are most affected, causing slurred speech, chewing, and swallowing difficulties. Mild abnormalities are almost always present in the arms and legs. Patients with MND exhibit the phenotype of Parkinson's disease (e.g., tremor, rigidity, bradykinesia, and / or postural instability). Methods for detecting, monitoring, or quantifying spontaneous movement deficits and / or other deficits associated with Parkinson's disease, such as MND, are known in the art (see, for example, U.S. Patent Application Publication No. 2012 / 0005765).

[0212] Methods for detecting, monitoring, quantifying, or evaluating motor and histopathological impairments associated with MND are known in the art and include histopathological, biochemical, and electrophysiological studies, as well as motor activity analysis (see, e.g., Rich et al., J. Neurophysiol. 88 (2002), pp. 3293-3304; Appel et al., Proc. Natl. Acad. Sci. USA 88 (1991), pp. 647-651). Histopathologically, MND is characterized by motor neuron death, progressive accumulation of surfactant-resistant aggregates containing SOD1 and ubiquitin, and abnormal neurofilament accumulation in motor neuron degeneration. In addition, reactive astroglia and microglia are often detected in diseased tissue. Patients with MND exhibit one or more motor defects, including muscle weakness and wasting, uncontrolled seizures, spasticity, slow, labored movements, and hypersensitive tendon reflexes.

[0213] Ophthalmic diseases and disorders In certain embodiments, age-related disease or disorder is a disease, disorder, or condition of the eye, such as presbyopia, macular degeneration, or cataract. In other certain embodiments, age-related disease or disorder is glaucoma. Macular degeneration is a neurodegenerative disease that causes the loss of photoreceptor cells in the central part of the retina called the macula. Macular degeneration is generally classified into two types: dry and wet. The dry form is more common than the wet form, and about 90% of patients with age-related macular degeneration (ARMD or AMD) are diagnosed with the dry form. Disease in the wet form is usually associated with more severe vision loss. The exact cause of age-related macular degeneration is still unknown, but the number of aging retinal pigment epithelial (RPE) cells increases with age. Age and certain genetic and environmental factors are risk factors for developing ARMD (see, for example, Lyengar et al., Am.J.Hum.Genet. Vol. 74 (2004), pp. 20-39; Kenealy et al., Mol.Vis. Vol. 10 (2004), pp. 57-61; Gorin et al., Mol.Vis. Vol. 5 (1999), Vol. 29). Environmental predisposing factors include omega-3 fatty acid intake (see, e.g., Christen et al., Arch. Ophthalmol. Vol. 129 (2011), pp. 921-929), estrogen exposure (see, e.g., Feshanich et al., Arch. Ophthalmol. Vol. 126 (No. 4) (2008), pp. 519-524), and elevated serum vitamin D levels (see, e.g., Millen et al., Arch. Ophthalmol. Vol. 129 (No. 4) (2011), pp. 481-489). Genetic risk factors include reduced Dicer1 levels (an enzyme involved in microRNA maturation) in the eyes of patients with dry AMD, and this reduction in microRNA contributes to the senescent cell profile.

[0214] Dry ARMD involves atrophy of the rPE layer, leading to the loss of photoreceptor cells. Dry ARMD can be caused by aging and thinning of macular tissue, as well as pigmentation in the macula. Aging inhibits both RPE replication and migration, resulting in permanent RPE depletion in the macula of patients with dry ARMD (see, e.g., Iriyama et al., J. Biol. Chem. 283 (2008), pp. 11947-11953). In wet ARMD, new blood vessels grow beneath the retina, leaking blood and fluid. This abnormal, leaking choroidal neovascularization causes retinal cell death, creating blind spots in the central visual field. Various forms of macular degeneration can occur in younger patients as well. Non-age-related etiologies may be associated with genetics, diabetes, malnutrition, head trauma, infection, or other factors.

[0215] A decrease in visual acuity noticed by a patient or ophthalmologist during a routine eye examination may be the first symptom of macular degeneration. The formation of subbruchic exudates or "drusen" in the macula is often the first physical sign that macular degeneration may be progressing. Symptoms include the perception of linear distortion, in some cases the central part of the visual field appearing more distorted than the rest of the visual field, the appearance of a dark, blurred area or "white area" in the center of the visual field, and / or alteration or loss of color perception. Diagnosis and monitoring of patients with macular degeneration can be performed by those skilled in the art in accordance with routine eye examination procedures and patient symptom reporting accepted in the art.

[0216] Presbyopia is an age-related condition in which the ability to focus on near objects gradually disappears as the normal speed and range of eye accommodation decreases with age. The cause is thought to be the loss of elasticity of the lens and the loss of contractile force of the ciliary muscle (see, for example, Heys et al., Mol. Vis. Vol. 10 (2004), pp. 956-963; Petrash, Invest. Ophthalmol. Vis. Sci. Vol. 54 (2013), ORSF 54-ORSF 59). Age-related changes in the mechanical properties of the anterior and posterior lens capsules suggest that the mechanical strength of the posterior lens capsule decreases significantly with age (see, for example, Krag et al., Invest. Ophthalmol. Vis. Sci. Vol. 44 (2003), pp. 691-696; Krag et al., Invest. Ophthalmol. Vis. Sci. Vol. 38 (1997), pp. 357-363).

[0217] The layered structure of the lens capsule also changes, which may be at least partially due to changes in tissue composition (see, e.g., Krag et al., 1997, op. cit., and the literature cited therein). The main structural component of the lens capsule is basement membrane type IV collagen organized into a three-dimensional molecular network (see, e.g., Cummings et al., Connect. Tissue Res. Vol. 55 (2014), pp. 8-12; Veis et al., Coll. Relat. Res. Vol. 1 (1981), pp. 269-286). Type IV collagen is associated with six homologous α chains (α1-6) that form heterotrimeric collagen IV protomers, each containing a specific combination of α112, α345, or α556 chains (see, e.g., Khoshnoodi et al., Microsc. Res. Tech. Vol. 71 (2008), pp. 357-370). The protomer shares structural similarities between the Gly-XY triplet peptide sequence and a triple-helical collagen-like domain (Timpl et al., Eur. J. Biochem. Vol. 95 (1979), pp. 255-263). The N-terminus consists of a helical domain called the 7S domain, which is also involved in protomer interactions (see, for example, Risteli et al., Eur. J. Biochem. Vol. 108 (1980), pp. 239-250).

[0218] Studies suggest that collagen IV influences cellular function inferred from its location in the basement membrane beneath the epithelium, and data support the role of collagen IV in tissue stabilization (see, e.g., Cummings et al., op. cit.). Approximately 20–40% of patients develop posterior capsular opacity (PCO) as a complication within a few years after cataract surgery (see, e.g., Awasthi et al., Arch. Ophthalmol. 127 (2009), pp. 555–562). PCO is caused by the proliferation and activity of residual lens epithelial cells along the posterior capsule in a response similar to wound healing. Growth factors such as fibroblast growth factor, transforming growth factor, epidermal growth factor, hepatocyte growth factor, insulin-like growth factor, and interleukins IL-1 and IL-6 may also promote epithelial cell migration (see, e.g., Awasthi et al., op. cit.; Raj et al., op. cit.). As discussed herein, the production of these factors and cytokines by senescent cells contributes to SASP. In contrast, in vitro studies have shown that collagen IV promotes the adhesion of lens epithelial cells (see, e.g., Olivero et al., Invest. Ophthalmol. Vis. Sci. Vol. 34 (1993), pp. 2825-2834). The adhesion of collagen IV, fibronectin, and laminin to intraocular lenses can inhibit cell migration and reduce the risk of PCOS (see, e.g., Raj et al., Int. J. Biomed. Sci. Vol. 3 (2007), pp. 237-250).

[0219] While we do not wish to be bound by any particular theory, the selective elimination of senescent cells by the senoleptic agents described herein can slow or interfere with (delay, inhibit, or delay) the breakdown of the type IV collagen network. Removing senescent cells, and thereby eliminating the inflammatory effects of SASP, can reduce or inhibit epithelial cell migration, delay (suppress) the onset of presbyopia, or reduce or slow the progression of the condition's severity (e.g., slowing the progression from mild to moderate, or from moderate to severe). Furthermore, the senoleptic agents described herein may be useful after cataract surgery to reduce the likelihood of developing PCO.

[0220] While there is no direct evidence from human studies that cellular senescence is involved in the development of cataracts, BubR1 hypoplasia mice develop bilateral posterior subcapsular cataracts early in life, suggesting that senescence may play a role (e.g., Baker et al., Nat. Cell Biol. Vol. 10 (2008), pp. 825-836). Cataracts are caused by clouding of the lens of the eye, leading to blurred vision and, if left untreated, can result in blindness. Surgery is an effective and routine procedure for removing cataracts. Administration of one or more of the senolytic agents described herein may reduce the likelihood of developing cataracts or slow or inhibit their progression. The presence and severity of cataracts can be monitored by eye examinations using methods routinely performed by those skilled in the field of ophthalmology.

[0221] In certain embodiments, at least one senolytic agent described herein may be administered to subjects at risk of developing presbyopia, cataracts, or macular degeneration. Treatment with a senolytic agent can be initiated in a human subject no later than 40 years of age to delay or inhibit the onset or progression of cataracts, presbyopia, and macular degeneration. Since almost all humans develop presbyopia, in certain embodiments, a senolytic agent can be administered to a human subject as described herein after the subject has reached 40 years of age to delay or inhibit the onset or progression of presbyopia.

[0222] In certain embodiments, age-related diseases or disorders are glaucoma. Glaucoma is a broad term used to describe a group of diseases that cause visual field defects, often without any other significant symptoms. Due to the lack of symptoms, the diagnosis of glaucoma is often delayed until the late stages of the disease. Even if a person with glaucoma does not become blind, their vision is often severely impaired. Normally, a clear fluid flows in and out of the front part of the eye known as the anterior chamber. In individuals with open / wide-angle glaucoma, the drainage of this fluid is too slow, leading to increased intraocular pressure. If left untreated, this high pressure can damage the optic nerve and lead to complete blindness. Loss of peripheral vision is caused by the death of ganglion cells in the retina. Ganglion cells are a specific type of projection neuron that connects the eye to the brain. When the cellular network necessary for fluid outflow was stained with SA-β-Gal, it was observed that aging was increased fourfold in glaucoma patients (e.g., Liton et al., Exp. Gerontol. Vol. 40 (2005), pp. 745-748).

[0223] Standard automated perimetry (visual field testing) is the most widely used technique for monitoring the effectiveness of therapies that inhibit the progression of glaucoma. In addition, several algorithms have been developed to detect progression (e.g., Wesselink et al., Arch. Ophthalmol. 127(3) (2009), pp. 270-274, and its references). Additional methods include gonioscopy (examining the trabecular meshwork and the angle from which fluid drains from the eye); imaging techniques, such as scanning laser tomography (e.g., HRT3), laser polarization (e.g., GDX), and ocular coherence tomography; fundus examination; and pachymetry to determine central corneal thickness.

[0224] Metabolic disorders or conditions Age-related diseases or disorders that can be treated with senoleptic agents include metabolic diseases or disorders. Such senescent cell-related diseases and disorders include diabetes, metabolic syndrome, diabetic ulcers, and obesity.

[0225] Diabetes mellitus is characterized by high blood glucose levels resulting from deficiencies in insulin production, insulin action, or both. The vast majority (90–95%) of all diagnosed cases of diabetes in adults are type 2 diabetes, characterized by a gradual loss of insulin production by the pancreas. Diabetes mellitus is a leading cause of new cases of renal failure, non-traumatic lower limb amputation, and blindness in adults in the United States. Diabetes mellitus is a leading cause of heart disease and stroke and is the seventh leading cause of death in the United States (see, e.g., Centers for Disease Control and Prevention, National Diabetes Fact Sheet: National Estimates and General Information on Diabetes and Pre-diabetes in the United States, 2011 ("Diabetes Fact Sheet")). The senolytic agents described herein can be used to treat type 2 diabetes, particularly age-related, diet-related, and obesity-related type 2 diabetes.

[0226] The involvement of senescent cells in metabolic diseases such as obesity and type 2 diabetes has been suggested to be a response to injury or metabolic dysfunction (see, e.g., Tchkonia et al., Aging Cell, Vol. 9 (2010), pp. 667-684). Adipose tissue from obese mice showed induction of the aging markers SA-β-Gal, p53, and p21 (see, e.g., Tchkonia et al., op. cit.; Minamino et al., Nat. Med., Vol. 15 (2009), pp. 1082-1087). Simultaneous upregulation of tumor necrosis factor and pro-inflammatory cytokines such as Ccl2 / MCP1 was observed in the same adipose tissue (see, e.g., Minamino et al., op. cit.). Since pro-inflammatory SASP components have also been suggested to contribute to type 2 diabetes, the induction of senescent cells in obesity has clinical significance (see, e.g., Tchkonia et al., op. cit.). Similar patterns of upregulation of aging markers and SASP components have been associated with diabetes in both mice and humans (see, e.g., Minamino et al., op. cit.). Therefore, the methods described herein, including the administration of senolytic agents, may be useful in the treatment or prevention of type 2 diabetes, as well as obesity and metabolic syndrome. While we do not wish to be bound by theory, contacting pre-senescent adipocytes with senolytic agents and thereby killing them may provide clinical and health benefits to humans with diabetes, obesity, or metabolic syndrome.

[0227] Subjects with type 2 diabetes can be identified using standard diagnostic methods known in the art for type 2 diabetes. Generally, the diagnosis of type 2 diabetes is based on symptoms (e.g., increased thirst and frequent urination, increased hunger, weight loss, fatigue, blurred vision, slow or frequent wound healing and infection, and / or darkening of the skin), medical history, and / or physical examination of the patient. Subjects at risk of developing type 2 diabetes include those with a family history of type 2 diabetes, overweight, fat distribution, lack of exercise, race, age, prediabetes, and / or gestational diabetes.

[0228] The efficacy of senolytic agents can be readily determined by those skilled in the medical and clinical fields. One or any combination of diagnostic methods, including physical examination, assessment and monitoring of clinical symptoms, and the performance of analytical tests and methods such as those described herein, can be used to monitor the health status of the subject. Subjects receiving one or more senolytic agents described herein for the treatment or prevention of diabetes can be monitored, for example, by assaying glucose and insulin resistance, energy expenditure, body composition, adipose tissue, skeletal muscle, and hepatic inflammation, and / or lipotoxicity (muscle and hepatic lipids by in vivo imaging, and histological lipid accumulation and inflammation in muscle, liver, bone marrow, and pancreatic cells). Other distinctive features or phenotypes of type 2 diabetes are known and can be assayed as described herein and by other methods and techniques that are publicly known and routinely performed in the art.

[0229] Obesity and obesity-related disorders are used to refer to a condition in which a person has a measurably heavier body mass than the ideal body mass for their height and build. Body Mass Index (BMI) is a measurement tool used to determine excess weight and is calculated from a person's height and weight. Humans are considered overweight if their BMI is between 25 and 29, obese if their BMI is between 30 and 39, and severely obese if their BMI is >40. Therefore, the terms obesity and obesity-related refer to human subjects with a body mass index value greater than 30, greater than 35, or greater than 40. A category of obesity not captured by BMI is referred to in this art as “abdominal obesity” and refers to excess fat found around a person’s torso, even if unrelated to BMI, which is a significant factor in health. The simplest and most frequently used indicator of abdominal obesity is waist size. Generally, abdominal obesity is defined as a waist size of 35 inches or more for women and 40 inches or more for men. More complex methods for determining obesity require specialized equipment such as magnetic resonance imaging (MRI) or dual-energy X-ray absorptiometry (DAS).

[0230] A condition or disorder associated with diabetes and aging is diabetic ulcers (i.e., diabetic wounds). Ulcers are lesions of the skin, which may extend to the subcutaneous tissue, or even to the muscle or bone. These lesions occur particularly in the lower extremities. Patients with diabetic venous ulcers exhibit increased levels of cellular senescence at the site of chronic wounds (see, e.g., Stanley et al., J.Vas.Surg., Vol. 33 (2001), pp. 1206-1211). Chronic inflammation is also observed at the site of chronic wounds such as diabetic ulcers (see, e.g., Goren et al., Am.J.Pathol., Vol. 168 (2006), pp. 65-77). This suggests that the pro-inflammatory cytokine phenotype of senescent cells plays a role in the pathology.

[0231] Individuals with type 2 diabetes or at risk of developing type 2 diabetes may have metabolic syndrome. Metabolic syndrome in humans is typically associated with obesity and characterized by one or more of the following: cardiovascular disease, fatty liver, hyperlipidemia, diabetes, and insulin resistance. Patients with metabolic syndrome may present with a range of metabolic disorders or abnormalities, which may include one or more of the following: hypertension, type 2 diabetes, hyperlipidemia, dyslipidemia (e.g., hypertriglyceridemia, hypercholesterolemia), insulin resistance, fatty liver (steatohepatitis), hypertension, atherosclerosis, and other metabolic disorders.

[0232] Renal dysfunction Renal pathologies, such as glomerular diseases, occur in the elderly and can be treated with the administration of the senolytic compounds described herein. Glomerulonephritis is characterized by inflammation of the kidney and the expression of two proteins, IL1α and IL1β (see, e.g., Niemir et al., Kidney Int. Vol. 52 (1997), pp. 393-403). IL1α and IL1β are considered to be major regulators of SASP (see, e.g., Coppe et al., PLoS. Biol. Vol. 6 (2008), pp. 2853-2868). Glomerular diseases are associated with increased abundance of senescent cells, particularly in fibrous kidneys (see, e.g., Sis et al., Kidney Int. Vol. 71 (2007), pp. 218-226).

[0233] Dermatological diseases or disorders Diseases or disorders that can be treated by administering the compounds described herein include dermatological diseases and disorders. Such diseases and disorders include psoriasis and eczema, which are also inflammatory diseases and are discussed in more detail above. Other dermatological diseases and disorders include pleurisy (age-related wrinkles); pruritus (associated with diabetes and aging); paresthesia (as a side effect of chemotherapy associated with diabetes and multiple sclerosis); psoriasis (as described above) and other papular and scaly diseases, such as erythroderma, lichen planus, and lichenoid skin diseases; atopic dermatitis (a form of eczema that is inflammatory); and eczematous rash (often observed in elderly patients and associated with side effects of certain drugs). Other dermatological conditions and disorders associated with aging include eosinophilic dermatosis (associated with certain types of blood cancer); reactive neutrophilic dermatosis (associated with underlying conditions such as inflammatory bowel syndrome); pemphigus (an autoimmune disease in which autoantibodies against desmoglein are formed); bullous pemphigoid and other immunobullous dermatosis (autoimmune cutaneous blister formation); age-related fibrohistocytic proliferation of the skin; and cutaneous lymphomas, which are more common in the elderly population. Another dermatological condition that may be treatable according to the methods described herein is cutaneous lupus, a symptom of lupus erythematosus. Late-onset lupus may be associated with decreased (i.e., reduced) function (i.e., immunosenescence) of T cells, B cells, and cytokines. Other dermatological indications that can be treated with the compounds described herein include, but are not limited to, psoriasis vulgaris, dermatitis, and alopecia, vitiligo, alopecia areata, hidradenitis suppurativa, chronic idiopathic urticaria, actinic keratosis, and seborrheic keratosis induced by cancer therapy (chemotherapy or radiation).

[0234] metastasis In some embodiments, methods are provided for treating or preventing (i.e., reducing the likelihood of developing or experiencing) senescent cell-related diseases (or disorders or conditions) that are metastatic. The senoritics described herein may also be used according to the methods described herein to treat or prevent (i.e., reduce the likelihood of developing) metastasis (i.e., the spread and dissemination of cancer or tumor cells) from one organ or tissue in the body to another.

[0235] Senescent cell-related diseases or disorders include metastasis, and subjects with cancer may benefit from the administration of senolytic agents described herein to inhibit metastasis. Such senolytic agents, when administered to subjects with cancer according to the methods described herein, can inhibit tumor growth. Cancer metastasis occurs when cancer cells (i.e., tumor cells) spread beyond their anatomical developmental and initial colonization sites to other areas of the subject's body. Tumor growth can be determined by tumor size, which can be measured by various methods familiar to those skilled in the art, such as PET scans, MRI, CAT scans, and biopsies. The effect of therapeutic agents on tumor growth can be evaluated by examining the differentiation of tumor cells.

[0236] As used herein and in the art, the terms “cancer” or “tumor” are clinically descriptive terms that typically encompass diseases characterized by abnormal cell proliferation. The term “cancer” is generally used to describe malignant tumors or conditions resulting from tumors. Alternatively, abnormal proliferation may be called neoplasms in the art. The term “tumor” generally refers to any abnormal tissue proliferation characterized, at least in part, by excessive and abnormal cell proliferation, such as when relating to tissue. Tumors may be metastatic and can spread beyond their anatomical origin and initial colonization site to other areas of the body in question. Cancer may include solid tumors or “humoral” tumors (e.g., leukemia and other blood cancers).

[0237] Cells undergo aging due to cancer therapies such as radiation and certain chemotherapy drugs. The presence of senescent cells increases the secretion of inflammatory molecules and promotes tumor progression. This can include increased tumor growth, increased tumor size, increased metastasis, and altered differentiation. When senescent cells are destroyed, tumor progression is significantly inhibited, tumor size decreases, and metastatic growth is little to no (see, for example, International Publication No. 2013 / 090645).

[0238] In some embodiments, a method is provided for preventing (i.e., reducing the likelihood of metastasis occurring), inhibiting, or stabilizing metastasis in a subject with cancer by administering the senolytic agents described herein. In other embodiments, the senolytic agent is administered on one or more days within a treatment window (i.e., a treatment course) not exceeding 7 or 14 days. In yet another embodiment, the treatment course does not exceed 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 days, or not exceeding 21 days. In yet another embodiment, the treatment course is one day. In yet another embodiment, the senolytic agent is administered over two or more days within a treatment window not exceeding 7 or 14 days.

[0239] Because cells may undergo aging due to radiation and certain chemotherapy drugs (e.g., doxorubicin, paclitaxel, gemcitabine, pomalidomide, lenalidomide), the senolytic agents described herein can be administered after chemotherapy or radiation therapy to kill (or accelerate the killing of) these senescent cells. As discussed herein and understood in the art, the establishment of aging, indicated by the presence of a senescence-associated secretory phenotype (SASP), occurs over several days. Therefore, once aging is established, administration of senolytic agents can be initiated to kill senescent cells, thereby reducing the likelihood or extent of metastasis. As discussed herein, the following therapeutic processes for administering senolytic agents can be used in the methods described herein to treat or prevent (i.e., reduce the likelihood or severity of) side effects of chemotherapy or radiation therapy.

[0240] In certain embodiments, if chemotherapy or radiotherapy is administered in a treatment cycle of at least one day of treatment (i.e., chemotherapy or radiotherapy) followed by at least three, four, five, six, seven, eight, nine, ten, eleven, twelfth, thirteenth, and fourteenth days (or about two weeks), fifteen, sixteenth, seventeenth, eighteenth, nineteenth, twenty-twoth days (or about three weeks), or about four weeks (about one month), then the senolytic agent is administered over one or more days during the treatment rest interval (period), starting on or after the second day of the treatment rest interval and ending on or before the last day of the treatment rest interval. As an explanatory example, if n is the number of treatment rest days, the senolytic agent is administered on at least one day and no more than n-1 days of the treatment rest interval. In some embodiments where chemotherapy or radiotherapy is administered in a treatment cycle consisting of at least one day of treatment (i.e., chemotherapy or radiotherapy) followed by at least one week of treatment rest, the senolytic agent is administered over one or more days during the treatment rest interval, beginning on or after the second day of the treatment rest interval and ending on or before the final day of the treatment rest interval.

[0241] Chemotherapy is sometimes called chemotherapy, chemotherapeutic agents, or chemotherapeutic drugs. Many chemotherapeutic agents are compounds called small organic molecules. Chemotherapy is also a term used to describe combinations of chemotherapeutic agents administered to treat specific cancers. As those skilled in the art will understand, chemotherapy can also refer to combinations of two or more chemotherapeutic molecules administered in coordination, which is sometimes called combination chemotherapy. Numerous chemotherapeutic agents are used in the field of oncology, and are not limited to, alkylating agents, antimetabolites, anthracyclines, plant alkaloids, and topoisomerase inhibitors.

[0242] Cancers that may metastasize may be solid tumors or humoral tumors (e.g., blood cancers, e.g., leukemia). Humoral tumors are classified in the art as those occurring in the blood, bone marrow, and lymph nodes, and generally include leukemia (myeloid and lymphoid), lymphoma (e.g., Hodgkin lymphoma), and melanoma (including multiple myeloma). Examples of leukemias include acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), and hairy cell leukemia. Solid tumors that occur more frequently in humans include, for example, prostate cancer, testicular cancer, breast cancer, brain cancer, pancreatic cancer, colon cancer, thyroid cancer, stomach cancer, lung cancer, ovarian cancer, Kaposi's sarcoma, skin cancer (including squamous cell carcinoma), kidney cancer, head and neck cancer, throat cancer, squamous cell carcinoma that forms in the moist mucosal lining of the nose, mouth, and throat, bladder cancer, osteosarcoma (bone cancer), cervical cancer, endometrial cancer, esophageal cancer, liver cancer, and kidney cancer. In certain detailed embodiments, the senescent cell-related diseases or disorders that are treated or prevented (i.e., whose likelihood of developing or manifesting is reduced) by the methods described herein are melanoma cells, prostate cancer cells, testicular cancer cells, breast cancer cells, brain cancer cells, pancreatic cancer cells, colon cancer cells, thyroid cancer cells, gastric cancer cells, lung cancer cells, ovarian cancer cells, Kaposi's sarcoma cells, skin cancer cells, kidney cancer cells, head and neck cancer cells, throat cancer cells, squamous cell carcinoma cells, bladder cancer cells, osteosarcoma cells, cervical cancer cells, endometrial cancer cells, esophageal cancer cells, liver cancer cells, or metastases of kidney cancer cells.

[0243] The methods described herein are also useful for inhibiting, stabilizing, or slowing the progression of metastatic cancer of any one of the tumor types described in the medical field. These cancer (tumor) types include: adrenocortical carcinoma, pediatric adrenocortical carcinoma, AIDS-related cancer, anal cancer, appendiceal cancer, basal cell carcinoma, pediatric basal cell carcinoma, bladder cancer, pediatric bladder cancer, bone cancer, brain tumor, pediatric astrocytoma, pediatric brainstem glioma, pediatric atypical teratoma / rhabdoid tumor of the central nervous system, pediatric embryonic tumor of the central nervous system, pediatric germ cell tumor of the central nervous system, pediatric craniopharyngiomas, pediatric ependymoma, breast cancer, pediatric bronchial tumor, carcinoid tumor, pediatric carcinoid tumor, gastrointestinal carcinoid tumor, cancer of unknown primary origin, pediatric primary Unknown cancer, pediatric cardiac tumor, cervical cancer, pediatric cervical cancer, pediatric chordoma, chronic myeloproliferative disorder, colon cancer, colorectal cancer, pediatric colorectal cancer, extrahepatic bile duct cancer, intraductal carcinoma in situ (DCIS), endometrial cancer, esophageal cancer, pediatric esophageal cancer, pediatric sensory neuroblastoma, eye cancer, malignant fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, pediatric gastric cancer, gastrointestinal stromal tumor (GIST), pediatric gastrointestinal stromal tumor (GIST), pediatric extracranial germ cell tumor, extragonadal germ cell tumor, gestational trophoblastic neoplasm, glioma, head and neck cancer, pediatric head and neck cancer, hepatocyte (Liver) cancer, hypopharyngeal cancer, kidney cancer, renal cell carcinoma, Wilms' tumor, pediatric kidney tumor, Langerhans cell histiocytosis, laryngeal cancer, pediatric laryngeal cancer, leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), hairy cell leukemia, lip cancer, primary liver cancer, primary pediatric liver cancer, carcinoma in situ (LCIS), lung cancer, non-small cell lung cancer, small cell lung cancer, lymphoma, AIDS-related lymphoma, Burkitt lymphoma, cutaneous T-cell lymphoma, Dikin lymphoma, non-Hodgkin lymphoma, primary central nervous system lymphoma (CNS), melanoma, pediatric melanoma, intraocular melanoma, Merkel cell carcinoma, malignant mesothelioma, pediatric malignant mesothelioma, occult primary metastatic squamous cell carcinoma of the neck, midline tract cancer associated with the NUT gene, oral cancer, multiple endocrine neoplasia syndrome in children, mycosis fungoides, myelodysplastic syndrome, myelodysplastic neoplasm, myeloproliferative neoplasm, multiple myeloma, nasal cavity cancer, nasopharyngeal cancer, pediatric nasopharyngeal cancer, neuroblastoma, oral cancer, pediatric oral cancer, oropharyngeal cancer, ovarian cancer, pediatric ovarian cancer, epithelial ovarian cancer,Low-grade tumors: ovarian cancer, pancreatic cancer, pediatric pancreatic cancer, pancreatic neuroendocrine tumors (islet cell tumors), pediatric papillomatosis, paraganglioma, paranasal sinus cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary tumor, plasma cell neoplasm, pediatric pleuropulmonary blastoma, prostate cancer, rectal cancer, renal pelvis transitional cell carcinoma, retinoblastoma, salivary gland cancer, pediatric salivary gland cancer, Ewing's sarcoma family tumors, Kaposi's sarcoma, osteosarcoma, rhabdomyoblastoma. Sarcoma, pediatric rhabdomyosarcoma, soft tissue sarcoma, uterine sarcoma, Sézary syndrome, pediatric skin cancer, non-melanoma skin cancer, small intestine cancer, squamous cell carcinoma, pediatric squamous cell carcinoma, testicular cancer, pediatric testicular cancer, throat cancer, thymoma and thymic carcinoma, pediatric thymoma and thymic carcinoma, thyroid cancer, pediatric thyroid cancer, ureteral transitional cell carcinoma, urethral cancer, endometrial cancer, vaginal cancer, vulvar cancer, and Waldenström macroglobulinemia.

[0244] Side effects of chemotherapy and radiotherapy In other embodiments, senescence-related disorders or conditions are chemotherapy or radiotherapy side effects. Examples of chemotherapeutic agents that induce senescence in non-cancer cells include anthracyclines (such as doxorubicin and daunorubicin), taxols (such as paclitaxel), gemcitabine, pomalidomide, and lenalidomide. One or more senolytic agents administered as described herein may be used to treat and / or prevent (i.e., reduce the likelihood or occurrence of) chemotherapy or radiotherapy side effects. Removal or destruction of senescent cells can improve the acute toxicity of chemotherapy or radiotherapy, including acute toxicity involving energy imbalance. Acute toxic side effects include, but are not limited to, gastrointestinal toxicity (e.g., nausea, vomiting, constipation, loss of appetite, diarrhea), peripheral neuropathy, fatigue, malaise, decreased physical activity, hematological toxicity (e.g., anemia), hepatotoxicity, alopecia (hair loss), pain, infection, mucositis, fluid retention, skin toxicity (e.g., rash, dermatitis, hyperpigmentation, urticaria, photosensitivity, nail changes), oral (e.g., oral mucositis), gingival or pharyngeal problems, or any toxic side effects caused by chemotherapy or radiotherapy. For example, toxic side effects caused by radiotherapy or chemotherapy can be mitigated by the methods described herein. Accordingly, in certain embodiments, methods are provided herein for improving (reducing, inhibiting, or preventing (i.e., reducing the likelihood of occurrence)) acute toxicity of chemotherapy or radiotherapy or both, or for reducing the severity of toxic side effects (i.e., adverse side effects), by administering an agent to a subject that selectively kills, removes, or destroys senescent cells, or promotes selective destruction. Administration of the senolytic agents described herein for treating, reducing the likelihood of occurrence of, or reducing the severity of side effects of chemotherapy or radiotherapy can be achieved by the same therapeutic process as described above for the treatment / prevention of metastasis.As described for the treatment or prevention of metastasis (i.e., reducing the likelihood of its occurrence), senolytics should be administered during the chemotherapy rest interval or radiotherapy rest interval, or after the completion of the chemotherapy treatment regimen or radiotherapy treatment regimen.

[0245] In more detailed embodiments, acute toxicity is acute toxicity involving energy imbalance and may include one or more of the following: weight loss, endocrine changes (e.g., hormonal imbalance, changes in hormone signaling), and changes in body composition. In certain embodiments, acute toxicity involving energy imbalance relates to a decrease or reduction in the subject's physical activity capacity, such as being indicated by a decrease or reduction in energy expenditure compared to what would be observed in a subject that did not receive medical treatment. In non-limiting examples, such acute toxic effects involving energy imbalance include low physical activity. In other embodiments, energy imbalance includes fatigue or malaise.

[0246] In some embodiments, the chemotherapy side effect that is to be treated or prevented (i.e., reduced in likelihood of occurring) by the senolytic agents described herein is cardiotoxicity. Subjects with cancer being treated with anthracyclines (such as doxorubicin and daunorubicin) can be treated with one or more senolytic agents described herein that reduce, improve, or decrease the cardiotoxicity of anthracyclines. As is well understood in the medical field, anthracyclines are cardiotoxic, and therefore, even if the cancer responds to the drug, there are limits to the maximum lifetime dose that a subject can receive. By administering one or more senolytic agents, cardiotoxicity can be reduced, so that additional doses of anthracyclines can be administered to the subject, resulting in an improved prognosis for cancer. In some embodiments, cardiotoxicity is caused by the administration of anthracyclines such as doxorubicin. Doxorubicin is an anthracycline poisomerase inhibitor approved for the treatment of multiple myeloma in combination with bortezomib in patients with ovarian cancer after platinum-based therapy failure; patients with Kaposi's sarcoma after first-line systemic chemotherapy failure or intolerance to therapy; or patients who have not previously received bortezomib or have received at least one prior therapy. The total lifetime dose of doxorubicin to patients is 550 mg / m². 2 If the dose exceeds this level, it may cause myocardial damage that can lead to congestive heart failure. Cardiotoxicity may occur even at lower doses if the patient is also receiving mediastinal radiation or another cardiotoxic drug.

[0247] In other embodiments, the senolytic agents described herein can be used in the methods herein for improving chronic or long-term adverse events. Chronic toxic adverse events typically result from multiple exposures to or administration of chemotherapy or radiotherapy over longer periods. Certain toxic effects appear considerably later after treatment (also known as delayed toxic effects) and are due to damage to organs or systems caused by the therapy. Organ dysfunction (e.g., neurological, pulmonary, cardiovascular, and endocrine dysfunction) has been observed in patients treated for cancer in childhood (see, e.g., Hudson et al., JAMA 309 92013) 2371-2381). While we do not wish to be bound by any particular theory, it may be possible to reduce the likelihood of chronic adverse events occurring, reduce or decrease the severity of chronic adverse events, or delay the timing of their onset by destroying senescent cells, which are certain normal cells whose aging is induced by chemotherapy or radiotherapy. Chronic and / or delayed toxic side effects that may occur in patients receiving chemotherapy or radiotherapy include, but are not limited to, cardiomyopathy, congestive heart disease, inflammation, premature menopause, osteoporosis, infertility, cognitive impairment, peripheral neuropathy, secondary cancer, cataracts and other vision problems, hearing loss, chronic fatigue, reduced lung capacity, and lung disease.

[0248] In addition, administering senolytics can clinically or statistically significantly enhance sensitivity to chemotherapy or radiotherapy by killing or removing senescent cells in cancer patients compared to cases without senolytics. In other words, administering senolytics to subjects treated with the corresponding chemotherapy or radiotherapy can inhibit the development of resistance to chemotherapy or radiotherapy.

[0249] Age-related diseases and disorders The senoretic agents described herein selectively kill senescent cells. Thus, targeting senescent cells during the aging process can be a preventive strategy. Therefore, administering the senoretic agents described herein to a target can prevent complications and delay death in elderly subjects. Furthermore, by selectively killing senescent cells, the immune system can be strengthened, healthy life expectancy can be extended, and the quality of life of the subject can be improved.

[0250] Senolytic agents may also be useful in treating or preventing (i.e., reducing the likelihood of developing) age-related diseases or disorders that occur as part of the natural aging process or when a subject is exposed to aging-inducing agents or factors (e.g., radiation, chemotherapy, smoking, high-fat / high-sugar diets, other environmental factors). Age-related disorders or diseases or age-sensitive traits may be associated with aging-inducing stimuli. The effectiveness of the therapeutic methods described herein can be manifested by reducing the number of symptoms of age-related disorders or age-sensitive traits associated with aging-inducing stimuli, by reducing the severity of one or more symptoms, or by delaying the progression of age-related disorders or age-sensitive traits associated with aging-inducing stimuli. In other embodiments, preventing age-related disorders or aging-sensitive traits associated with age-related stimuli means preventing (i.e., reducing the likelihood of onset) or delaying the onset of or recurrence of one or more age-related disorders or aging-sensitive traits associated with age-related stimuli. Examples of age-related disorders or symptoms include renal dysfunction, kyphosis, herniated discs, frailty, hair loss, hearing loss, vision loss (blindness or visual impairment), muscle fatigue, skin conditions, skin nevi, diabetes, metabolic syndrome, and sarcopenia. Vision loss refers to a condition in which a person who previously had vision has lost it. Various scales have been developed to describe the degree of vision loss and visual impairment based on visual acuity tests. Age-related diseases and conditions may also include dermatological conditions, such as, but are not limited to, the following: wrinkles including fine lines on the surface, hyperpigmentation, scars, keloids, dermatitis, psoriasis, eczema (including seborrheic dermatitis), rosacea, vitiligo, ichthyosis vulgaris, dermatomyositis, and actinic keratosis. Frailty is defined as a clinically recognizable condition of increased vulnerability resulting from an age-related decline in reserve and function across multiple physiological systems that impairs the ability of the subject to cope with everyday or acute stressors.Frailty can be characterized by impaired energetic characteristics, such as reduced grip strength, decreased energy, slow gait, reduced physical activity, and / or unintentional weight loss. Studies suggest that a patient can be diagnosed as frail if three of the five characteristics described above are observed (e.g., Fried et al., J.Gerontol.A Biol.Sci.Med, Sci. Vol. 56 (No. 3) (2001) pp. M146-M156; Xue, Clin.Geriatr.Med. Vol. 27 (No. 1) (2001) pp. 1-15). In certain embodiments, aging, as well as age-related diseases and disorders, can be treated or prevented (i.e., the likelihood of developing) by administering senolytics. Senolytics can inhibit the aging of adult stem cells, or inhibit, kill, or promote the removal of senescent adult stem cells. The importance of preventing stem cell aging to maintain the regenerative capacity of tissues has been discussed, for example, in Park et al., J. Clin. Invest. 113 (2004), pp. 175-179; and Sousa-Victor, Nature 506 (2014), pp. 316-321.

[0251] Methods for measuring aging are well known in the art. For example, bone aging can be measured by the incidence of non-vertebral fractures, hip fractures, total fractures, vertebral fractures, recurrent fractures, post-fracture functional recovery, decreased bone mineral density in the lumbar spine and hip, knee deformity, NSAID use, number of painful joints, and osteoarthritis. Aging can also be measured in muscles by decreased function, fall rate, reaction time, and grip strength, decreased muscle mass in the upper and lower limbs, and dual-task 10-meter walking speed. Furthermore, cardiovascular aging can be measured by changes in systolic and diastolic blood pressure, incidence of hypertension, major cardiovascular events such as myocardial infarction, stroke, and congestive heart disease, and cardiovascular mortality. In addition, brain aging can be measured by cognitive decline, incidence of depression, and incidence of dementia. Furthermore, immune system aging can be measured by infection rates, upper respiratory tract infection rates, influenza-like illness rates, incidence of severe infections leading to hospitalization, cancer incidence, transplant infection rates, and gastrointestinal infection rates. Other signs of aging, though not limited to these, include, but are not limited to, a decline in oral health, tooth loss, GI symptom rate, changes in fasting blood glucose and / or insulin levels, changes in body composition, decline in renal function, quality of life, onset of impairment in activities of daily living, and admission to a nursing home. Methods for measuring skin aging are known in the art and include transepidermal water loss (TEWL), skin hydration, skin elasticity, area ratio analysis of crow's feet wrinkles, sensitivity, radiance, roughness, blemishes, sagging, skin tone homogeneity, softness, and undulation (changes in depth).

[0252] Administration of the senolytic agents described herein can extend survival compared to the expected survival time if the subject does not receive treatment. Subjects requiring treatment include not only those who already have a disease or disorder, but also those who are prone to or at risk of developing a disease or disorder, and those seeking preventive treatment for a disease, condition, or disorder. Subjects may have a genetic predisposition to develop a disease or disorder that would benefit from the clearance of senescent cells, or they may be at a certain age at which administration of the senolytic agent would provide a clinical benefit of delaying the onset or reducing the severity of a disease, including age-related diseases or disorders.

[0253] In other embodiments, methods are provided for treating age-related diseases or disorders, further comprising identifying subjects who would benefit from treatment with the senolistic agents described herein (i.e., phenotyping, personalized treatment). These methods first include detecting the level of senescent cells in a specific organ or tissue of the subject. Biological samples may be obtained from the subject and may include, for example, blood samples, serum or plasma samples, biopsy specimens, body fluids (e.g., lung lavage fluid, ascites, mucosal lavage fluid, synovial fluid, vitreous fluid, cerebrospinal fluid), bone marrow, lymph nodes, tissue explants, organ cultures, or any other tissue or cell preparation derived from the subject. The level of senescent cells may be determined according to any of the in vitro assays or techniques described herein. For example, senescent cells can be detected by morphological features (e.g., observed under a microscope) or by the production of senescence-related markers such as galactosidase (SA-β-gal), p16INK4a, p21, PAI-1, or one or more SASP factors (e.g., IL-6, MMP3). Senescent and non-senescent cells in a biological sample can also be used in in vitro cell assays to determine the ability of a senoritic agent to kill target senescent cells without causing undesirable toxicity to non-senescent cells by exposing the cells to any of the senoritic agents described herein. In addition, these methods can be used to monitor the levels of target senescent cells before, during, and after treatment with a senoritic agent. In certain embodiments, the presence of senescent cells can be detected (e.g., by determining the mRNA expression levels of senescent cell markers), and the treatment course and / or non-treatment intervals can be adjusted accordingly.

[0254] Methods for treating and preventing GPX4 disease and disorder A method is provided for treating, preventing, or improving symptoms of a target glutathione peroxidase 4 (GPX4)-related disorder, comprising administering an effective amount of one or more compounds or compositions disclosed herein. In some embodiments, the GPX4-related disorder is cancer, neurotic disorder, neurodegenerative disorder, spondylometritis, mixed cerebral palsy, pontocerebellar hypoplasia, or male infertility.

[0255] In some embodiments, the GPX4-related disease is cancer. Non-limiting examples of cancer include hepatocellular carcinoma, sarcoma, glioma, renal cell carcinoma, ovarian cancer, prostate cancer, breast cancer, pancreatic cancer, melanoma, colon cancer, diffuse large B-cell lymphoma, leukemia, lung cancer, clear cell carcinoma, or non-small cell lung cancer. In some embodiments, the cancer is hepatocellular carcinoma. In other embodiments, the cancer is metastatic. In yet another embodiment, the cancer is hypersensitive to ferroptosis. In yet another embodiment, the cancer is refractory to standard cancer treatment. In yet another embodiment, the cancer has mesenchymal characteristics. In yet another embodiment, the cancer is resistant to multiple therapies.

[0256] Furthermore, this specification also provides a method for modulating the activity of GPX4 in a subject, comprising administering an effective amount of one or more compounds or compositions disclosed herein. In some embodiments, the modulation includes inhibiting GPX4 activity.

[0257] Furthermore, this specification also provides a method for increasing the level of peroxides in a subject, comprising administering an effective amount of one or more compounds or compositions disclosed herein. Non-limiting examples of peroxides include hydrogen peroxide, organic hydroperoxides, lipid peroxides, and combinations thereof.

[0258] Furthermore, this specification also provides a method for inducing ferroptosis in cells, comprising contacting the cells with an effective amount of one or more compounds or compositions disclosed herein. The cells may have abnormal lipid accumulation. In some embodiments, the cells are cancer cells, and cancer cells include, but are not limited to, hepatocellular carcinoma, sarcoma, glioma, renal cell carcinoma, ovarian cancer, prostate cancer, breast cancer, pancreatic cancer, melanoma, colon cancer, diffuse large B-cell lymphoma, leukemia, lung cancer, clear cell carcinoma, or non-small cell lung cancer cells. In other embodiments, the cancer cells are hepatocellular carcinoma cells.

[0259] In some embodiments, the cancer cells are metastatic. In other embodiments, the cancer cells are hypersensitive to ferroptosis. In yet another embodiment, the cancer has mesenchymal characteristics. In yet another embodiment, the cancer is resistant to multiple therapies.

[0260] Hypersensitivity to ferropotosis can be identified by NADPH levels, GCH1 expression, NF2-YAP activity, EMT signature, and GPX4 expression. In some embodiments, cancer cells are selected from the group consisting of hepatocellular carcinoma, sarcoma, glioma, renal cell carcinoma, ovarian cancer, prostate cancer, breast cancer, pancreatic cancer, melanoma, colon cancer, diffuse large B-cell lymphoma, leukemia, lung cancer, clear cell carcinoma, or non-small cell lung cancer cells. In some embodiments, the cancer is hepatocellular carcinoma cells.

[0261] Pharmaceutical composition and method of administration Furthermore, this specification provides pharmaceutical compositions comprising the senolytic agents described herein and at least one pharmaceutically acceptable excipient, which may also be called a pharmaceutically suitable excipient or carrier (i.e., a non-toxic substance that does not interfere with the activity of the active ingredient). The pharmaceutical compositions may be sterile aqueous or non-aqueous solutions, suspensions, or emulsions (e.g., microemulsions). The excipients described herein are examples and are not limiting. An effective dose or therapeutically effective dose refers to the amount of one or more senolytic agents that, when administered to a subject, either as a single dose or as part of a series of doses, is effective in producing the desired therapeutic effect.

[0262] When administering two or more senolytic agents to treat a disease or disorder described herein, each senolytic agent may be formulated into a separate pharmaceutical composition. Pharmaceutical preparations can be prepared that each of the separate pharmaceutical compositions (for example, which may be referred to as a first pharmaceutical composition and a second pharmaceutical composition, each containing a first and a second senolytic agent) is included. Each of the pharmaceutical compositions in the preparation may be administered simultaneously (i.e., concurrently) and via the same route of administration, or at different times and via the same or different routes of administration. Alternatively, two or more senolytic agents may be formulated together in a single pharmaceutical composition.

[0263] In other embodiments, a combination of at least one senolytic agent and at least one inhibitor of the mTOR, NF-B, or PI3K pathway can be administered to a subject requiring it. When both at least one senolytic agent and one or more inhibitors of the mTOR, NF-B, or PI3K pathway are used together in the methods herein for selectively killing senescent cells, each of the agonists may be formulated in the same pharmaceutical composition or in separate pharmaceutical compositions. For example, a pharmaceutical preparation can be prepared containing each of two separate pharmaceutical compositions, each containing each of the senolytic agents and one or more inhibitors of the mTOR, NF-B, or PI3K pathway, which may conveniently be referred to as, for example, a first pharmaceutical composition and a second pharmaceutical composition. Each of the pharmaceutical compositions in the preparation may be administered simultaneously and via the same route of administration, or at different times via the same or different routes of administration.

[0264] The pharmacokinetics of a senolytic agent (or one or more of its metabolites) administered to a subject can be monitored by determining the levels of the senolytic agent in biological fluids, e.g., blood, blood fractions (e.g., serum), and / or urine, and / or in other biological samples or biological tissues derived from the subject. The levels of the senolytic agent during the course of treatment can be measured using any method for detecting the agonist that has been practiced in the Art and described herein.

[0265] The dosage of the senolytic agents described herein for the treatment of senescent-related diseases or disorders may depend on the condition of the subject, i.e., the stage of the disease, the severity of the symptoms caused by the disease, the general health status, as well as age, sex, and weight, and other factors that would be obvious to a person skilled in the art of medicine. The pharmaceutical composition may be administered in a manner appropriate to the disease to be treated, as determined by a person skilled in the art of medicine. In addition to the factors described herein and above with respect to the use of senolytic agents for the treatment of senescent-related diseases or disorders, the appropriate duration and frequency of administration of the senolytic agent may also be determined or adjusted by factors such as the patient's condition, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. The optimal dose of the agonist can generally be determined using experimental models and / or clinical trials. The optimal dose may depend on the subject's body mass, weight, or blood volume. Usually, it is preferable to use the minimum dose sufficient to provide effective therapy. The design and execution of preclinical and clinical studies of the senolytic agents described herein (including when administered for preventive benefit) are well within the technical scope of a person skilled in the art of the relevant field. When administering two or more senolytics to treat age-related diseases or disorders, the optimal dose of each senolytic may vary, such as being less than when either agonist is administered alone as monotherapy. In certain embodiments, the combination of two senolytics may act synergistically or additively, allowing each agonist to be used in a lower dose than when administered alone. The amount of senolytics that can be administered per day may be, for example, about 0.01 mg / kg to 100 mg / kg (e.g., about 0.1 to 1 mg / kg, about 1 to 10 mg / kg, about 10 to 50 mg / kg, or about 50 to 100 mg / kg body weight). In other embodiments, the amount of senolytics that can be administered per day may be about 0.01 mg to 1000 mg / kg, about 100 to 500 mg / kg, or about 500 to 1000 mg / kg body weight.The optimal dose (per day or per treatment cycle) may vary depending on the age-related disease or disorder being treated, and may also depend on the route of administration and the treatment regimen.

[0266] Pharmaceutical compositions containing senolytic agents can be formulated in a manner appropriate to the method of delivery by using techniques routinely practiced in the art. The composition may be in the form of a solid (e.g., tablet, capsule), a semi-solid (e.g., gel), a liquid, or a gas (aerosol). In other particular embodiments, the senolytic agent (or a pharmaceutical composition containing it) is administered as a bolus injection. In particular embodiments, when the senolytic agent is delivered by injection, the senolytic agent is delivered via blood vessels to an organ or tissue containing senescent cells to be killed, according to techniques routinely practiced by those skilled in the medical field.

[0267] Pharmaceutically acceptable excipients are well known in the pharmaceutical field and are described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5th edition, 2006, and Remington: The Science and Practice of Pharmacy (Gennaro, 21st edition, Mack Pub. Co., Easton, Pennsylvania (2005)). Exemplary pharmaceutically acceptable excipients include sterile saline and phosphate-buffered saline at physiological pH. Preservatives, stabilizers, dyes, and buffers may also be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents may be used. Generally, the type of excipient is selected based on the mode of administration and the chemical composition of the active ingredient. Alternatively, the compositions described herein may be formulated as lyophilized products. The compositions described herein may be lyophilized using one or more suitable excipient solutions to solubilize and / or dilute the activators of the composition at administration, or otherwise formulated as lyophilized products. In other embodiments, the activator can be encapsulated in liposomes using techniques known and practiced in the art. The pharmaceutical composition can be formulated to suit any suitable mode of administration described herein and in the art.

[0268] Pharmaceutical compositions can be delivered to the target requiring them by any one of several routes known to those skilled in the art. In non-limiting examples, compositions can be delivered orally, intravenously, intraperitoneally, by infusion (e.g., bolus infusion), subcutaneously, enterally, rectally, intranasally, by inhalation, buccally, sublingually, intramuscularly, percutaneously, intradermally, topically, intraocularly, vaginally, rectally, or intracranially by injection, or any combination thereof. In certain embodiments, the administration of the above-described doses is intravenously, intraperitoneally, directly to the target tissue or organ, or via a subcutaneous route. In certain embodiments, delivery methods include drug coatings or permeable stents in which the agonist is a senolytic agent. Formulations suitable for such delivery methods are described in more detail herein.

[0269] In certain embodiments, a senolytic agent (which may be combined with at least one pharmaceutically acceptable excipient to form a pharmaceutical composition) is administered directly to a target tissue or organ containing senescent cells that contribute to the manifestation of the disease or disorder. In certain embodiments, when treating osteoarthritis, at least one senolytic agent is administered directly (i.e., intraarticularly) to the osteoarthritis joint of the target that requires it. In other specific embodiments, the senolytic agent may be administered to the joint via a topical, transdermal, intradermal, or subcutaneous route. In other specific embodiments, a method is provided for treating cardiovascular diseases or disorders associated with arteriosclerosis, such as atherosclerosis, by direct administration to the artery. In other embodiments, a senolytic agent (which may be combined with at least one pharmaceutically acceptable excipient to form a pharmaceutical composition) for treating age-related lung disease or disorder may be administered, for example, by inhalation, intranasal, intubation, or intrathecal delivery to deliver the senolytic agent more directly to the affected lung tissue. In another non-limiting example, a senolytic agent (or a pharmaceutical composition containing a senolytic agent) may be delivered directly to the eye by injection (e.g., intraocular or intravitreal) or by application to the conjunctiva under the eyelid as a cream, ointment, gel, or eye drops. In a more detailed embodiment, a senolytic agent or a pharmaceutical composition containing a senolytic agent may be formulated as a sustained-release (also called controlled-release) composition or administered as a bolus injection.

[0270] Pharmaceutical compositions (for example, for oral administration, or for injection, infusion, subcutaneous delivery, intramuscular delivery, intraperitoneal delivery, or other methods) may be in liquid form. A liquid pharmaceutical composition may contain, for example, one or more of the following: a sterile diluent, such as water, a saline solution, preferably physiological saline, Ringer's solution, isotonic sodium chloride, a fixing oil that can act as a solvent or suspension medium, polyethylene glycol, glycerin, propylene glycol, or other solvent, an antibacterial agent, an antioxidant, a chelating agent, a buffering agent, and an agent for adjusting tonicity, such as sodium chloride or dextrose. Parenteral compositions may be sealed in glass or plastic ampoules, disposable syringes, or multi-dose vials. The use of physiological saline is preferred, and pharmaceutical compositions for injection are preferably sterile. In other embodiments, a liquid pharmaceutical composition may be applied to the eye in the form of eye drops to treat an ophthalmic condition or disease. A liquid pharmaceutical composition may be administered orally.

[0271] For oral formulations, at least one of the senolytic agents described herein may be used alone or in combination with appropriate additives to prepare tablets, powders, granules, or capsules, along with diluents, buffers, wetting agents, preservatives, colorants, and flavoring agents as needed. The compounds may also be formulated with buffers and / or enteric coatings provided to protect the compounds from the low pH of the gastric environment. Senolytic agents contained in pharmaceutical compositions may also be formulated for oral delivery, for example, with flavoring agents and / or enteric coatings in liquid, solid, or semi-solid formulations.

[0272] A pharmaceutical composition comprising any one of the senolytic agents described herein may be formulated for sustained release or slow release (also known as sustained release or controlled release). Such compositions can generally be prepared using well-known techniques and can be administered, for example, by oral, rectal, intradermal, or subcutaneous implantation, or by implantation into a desired target site. Sustained-release formulations may contain compounds dispersed in a carrier matrix and / or contained in a reservoir surrounded by a rate-controlled membrane. Excipients for use in such formulations may be biocompatible and biodegradable, and preferably the formulation results in a relatively constant level of active ingredient release. The amount of active ingredient contained in a sustained-release formulation depends on the implantation site, release rate and expected release duration, and the nature of the condition, disease, or disorder to be treated or prevented.

[0273] In certain embodiments, pharmaceutical compositions containing senolytic agents are formulated for transdermal, intradermal, or topical administration. The compositions may be administered as powder / talc, or as other solids, liquids, sprays, aerosols, ointments, foams, creams, gels, or pastes, using syringes, bandages, transdermal patches, inserts, or syringe-like applicators. The compositions are preferably in the form of controlled-release or sustained-release formulations, administered topically or injected directly (intradermally or subcutaneously) into the skin adjacent to or within the area to be treated. The active composition may also be delivered by iontophoresis. Preservatives may be used to prevent the growth of fungi and other microorganisms. Suitable preservatives, but not limited to, include benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, thimerosal, and combinations thereof.

[0274] Pharmaceutical compositions containing senolytic agents can be formulated in the form of emulsions for topical application. The emulsion comprises one liquid dispersed in a second liquid body. The emulsion may be an oil-in-water emulsion or a water-in-oil emulsion. Either or both of the oil phase and the aqueous phase may contain one or more surfactants, emulsifiers, emulsifying stabilizers, buffers, and other excipients. The oil phase may contain other oily, pharmaceutically approved excipients. Suitable surfactants include, but are not limited to, anionic surfactants, nonionic surfactants, cationic surfactants, and amphoteric surfactants. The topical application composition may also contain at least one suitable suspending agent, antioxidant, chelating agent, emollient, or humectant.

[0275] Ointments and creams can be formulated using, for example, an aqueous or oily base with suitable thickeners and / or gelling agents added. Lotions can be formulated using an aqueous or oily base and generally further contain one or more emulsifiers, stabilizers, dispersants, suspenders, thickeners, or colorants. Liquid sprays can be delivered from a pressurized pack, for example, through a specially shaped closure. Oil-in-water emulsions can also be used in compositions, patches, bandages, and articles. These systems are semi-solid emulsions, microemulsions, or foamy emulsion systems.

[0276] Controlled-release or sustained-release transdermal or topical formulations can be achieved by adding sustained-release additives, such as polymer structures or matrices, available in the art. For example, compositions can be administered using hot-melt extruded articles, such as bioadhesive hot-melt extruded films. The formulation may contain a crosslinked polycarboxylic acid polymer formulation. The crosslinking agent may be present in an amount that provides adequate adhesion and allows the system to remain attached to the surface of target epithelial or endothelial cells for a sufficient time to enable the desired release of the compound.

[0277] The insert, transdermal patch, bandage, or article may contain a mixture or coating of polymers that provide a constant rate of release of an active ingredient over a long period of time. In some embodiments, the article, transdermal patch, or insert may contain a water-soluble pore-forming agent, such as polyethylene glycol (PEG), which can be mixed with a water-insoluble polymer to increase the durability of the insert and extend the release of the active ingredient.

[0278] Polymer formulations can also be used to provide controlled or sustained release. Bioadhesive polymers described in the Art can be used. For example, sustained-release gels and compounds may be incorporated into a polymer matrix, such as a hydrophobic polymer matrix. Examples of polymer matrices include microparticles. The microparticles may be microspheres, and the core may be made of a different material than the polymer shell. Alternatively, the polymer may be molded as a thin slab or film, a powder produced by grinding or other standard techniques, or a gel such as a hydrogel. The polymer may also be in the form of a coating to facilitate the delivery of the senolytic agent, or as part of a bandage, stent, catheter, vascular graft, or other device. The matrix can be formed by solvent evaporation, spray drying, solvent extraction, and other methods known to those skilled in the art.

[0279] This specification provides kits containing one or more unit doses, usually oral or injectable, of the agents described herein. Such kits may include a container containing the unit dose, an informational leaflet describing the use of the drug and its associated benefits in the treatment of senescent cell-related diseases, and optionally an instrument or device for delivering the composition.

[0280] Combination therapy The compounds and compositions disclosed herein may also be used in combination with one or more other active ingredients. In certain embodiments, the compounds may be administered in combination with or in succession with other therapeutic agents. Such other therapeutic agents include those known to treat, prevent, or improve one or more of the conditions disclosed herein. Many such therapeutic agents are known in the art.

[0281] It should be understood that any suitable combination of the compounds and compositions provided herein with one or more of the therapeutic agents and optionally one or more further pharmacologically active substances is considered to be within the scope of this disclosure. In some embodiments, the compounds and compositions provided herein are administered before or after one or more additional active ingredients.

[0282] Examples of compounds that can be administered together with the compounds disclosed herein include, but are not limited to, dasatinib, quercetin, fisetin, leeutolin, curcumin, curcumin analog EF24, Navioclax (ABT253), A1331852, A1155463, geldamycin, tanespimycin, albespimycin, piperlongumeine, FOXO-4 peptide, Nutlin3a, cardiac glycosides (e.g., ouabain, prosillaris A, digol Examples include xyn (and others), HSP-90 inhibitors, triptolide, EF-24, procyanidin C1, azithromycin, roxithromycin, 25-hydroxycholesterol, SSK1, BIRC5 knockout, BCL-2 inhibitors, Src inhibitors, PD-1, CTLA-4 ipilimumab, pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, semiprimab, ofatumumab, blinatumomab, daratumumab, elotuzumab, obinutuzumab, tarimozine, laharpalepbec, necitumumab, lenalidomide, dinutuximab, and combinations thereof.

[0283] Finally, it should be noted that alternative methods exist for carrying out the present invention. Therefore, these embodiments should be considered illustrative rather than restrictive, and the present invention should not be limited to the details given herein, but may be modified within the scope of the appended claims and their equivalents.

[0284] All publications and patents cited herein are incorporated by reference in their entirety.

[0285] The following examples are for illustrative purposes only and are not intended to limit the scope of the present invention. [Examples]

[0286] Scheme 1 shows the preparation of compounds 1, 2, and 3. [ka]

[0287] Example 1: (8S,11R,13S,14S,17S)-11-(4-cyclopropylphenyl)-17-(1,1-difluoropropane-2-in-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3-one O-(2-methoxyethyl)oxime(1) [ka] (11S, 13S, 17S)-11-(4-cyclopropylphenyl)-17-(1,1-difluoropropane-2-in-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene-3-one (100) (35 mg, 0.08 mmol, 1.0 equivalent) was stirred in methanol (1 mL, 0.1 M), to which O-(2-methoxyethyl)hydroxylamine (101) (0.15 mmol, 2.0 equivalents) was added, followed by D-(+)-camphor-10-sulfonic acid (4 mg, 0.015 mmol, 0.2 equivalents) at ambient temperature. The reaction mixture was stirred at room temperature for 2 hours, and LC-MS analysis indicated that the reaction was complete by then. The mixture was concentrated by rotary evaporation to obtain compound 1 as a mixture of E and Z isomers.

[0288] Example 2: (8S,11R,13S,14S,17S,Z)-11-(4-cyclopropylphenyl)-17-(1,1-difluoropropane-2-in-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3-one O-(2-methoxyethyl)oxime(2 ) and (8S,11R,13S,14S,17S,E)-11-(4-cyclopropylphenyl)-17-(1,1-difluoropropane-2-in-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3-one O-(2-methoxyethyl)oxime(3) [ka] Compound 1 was purified by reverse-phase HPLC (Higgins Analytical Inc.) 20×250 mm; ELSD and 254 UV detection; mobile phase A: 10 mmol ammonium bicarbonate in water; mobile phase B: 5% acetonitrile aqueous solution to 90% acetonitrile aqueous solution over 40 minutes to obtain pure geometric isomers 2 (5 mg, yield 12%) and 3 (14.6 mg, yield 36%).

[0289] Compound 2: 1 H NMR (500MHz, DMSO-d6): δ7.02 (d, J=8.3Hz, 2H), 6.97~6.92 (m, 2H), 6.28 (s, 1H), 5.42 (s, 1H), 4. 29(d, J=6.8Hz, 1H), 4.24(t, J=5.2, 5.2Hz, 1H), 4.04~3.99(m, 2H), 3.51~3.47(m, 2H), 3.23(s, 3H ), 2.59~2.53 (m, 1H), 2.39 (d, J=13.3Hz, 2H), 2.26~2.04 (m, 4H), 1.96~1.89 (m, 1H), 1.82 (m, 2H), 1.76~1.57 (m, 3H), 1.34 (m, 1H), 1.23 (m, 1H), 0.92~0.83 (m, 2H), 0.62~0.56 (m, 2H), 0.45 (s, 3H). Theoretical mass: 535.29, Mass (ESI+) measured value: 536.5 [M+H]

[0290] Compound 3: 1 H NMR (500MHz, DMSO-d6): δ7.02 (d, J=8.2Hz, 2H), 6.94 (d, J=8.4Hz, 2H), 5.77 (s, 1H), 4.28 (d, J =6.8Hz, 1H), 4.26~4.21(m, 1H), 4.07~4.01(m, 2H), 3.51~3.45(m, 2H), 3.43(s, 2H), 3.20(s, 3 2.65 (dd, J=11.5, 5.5Hz, 2H), 2.40 (s, 3H), 2.18~2.03 (m, 3H), 1.96~1.89 (m, 1H), 1.82 (m, 2H), 1.76~1.56 (m, 4H), 1.35~1.20 (m, 2H), 0.92~0.85 (m, 2H), 0.62~0.55 (m, 2H), 0.43 (s, 3H). Theoretical mass: 535.29, Mass (ESI+) determination value: 536.5 [M+H].

[0291]

change

[0292] Preparation of 1,2,3,4-tetra-O-acetyl-L-fucose (102) [ka] L-fucose(101) (50 g, 0.3 mol) was dissolved in a solution of acetic anhydride (400 mL, 4.23 mol) and pyridine (800 mL, 9.9 mol). The reaction mixture was stirred overnight at room temperature, concentrated under reduced pressure, diluted with HCl (2000 mL), washed with water (1000 mL), 10% citric acid aqueous solution (3 × 700 mL), water (1000 mL), and brine (1000 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was azeotropically mixed with toluene (200 mL) and dried under high vacuum to obtain the crude product 1,2,3,4-tetra-O-acetyl-L-fucose(102) (100 g, quantitative), which was used in the next step without any further purification.

[0293] Preparation of (2S,3R,4R,5S)-4,5-bis(acetyloxy)-6-bromo-2-methyloxane-3-ylacetate (103) [ka] 1,2,3,4-tetra-O-acetyl-L-fucose (102) (101 g, 0.3 mol) was dissolved in anhydrous dichloromethane (500 mL) and cooled to 0°C. Then, HBr (33% in AcOH, 135 mL) was added, and the reaction mixture was heated to room temperature with stirring for 2 hours, poured into an ice / water mixture, and the organic layer was separated. The aqueous phase was extracted with CH2Cl2 (200 mL). The organic layer was washed with saturated NaHCO3 (100 mL) and brine (150 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain (2S,3R,4R,5S)-4,5-bis(acetyloxy)-6-bromo-2-methyloxan-3-ylacetate (103) (115 g, quantitatively) as a yellow oil. The crude substance was used in the next step without further purification.

[0294] Preparation of (2S,3R,4S)-4-(acetyloxy)-2-methyl-3,4-dihydro-2H-pyran-3-ylacetate (104) [ka] To a refluxed, stirred solution of Zn (111 g, 1.7 mol) and 1-methylimidazole (25 mL, 0.31 mol) in anhydrous ethyl acetate (1200 mL), a solution of (2S,3R,4R,5S)-4,5-bis(acetyloxy)-6-bromo-2-methyloxan-3-ylacetate (103) (100 g, 0.28 mol) in anhydrous ethyl acetate (200 mL) was added dropwise over 40 minutes. The reaction mixture was heated under reflux for 3 hours until TLC analysis indicated completion of the reaction. The reaction mixture was cooled to room temperature, stirred for a further 30 minutes, and then filtered through a Celite pad. The crude product was concentrated under reduced pressure and purified by silica gel flash chromatography (0-10% ELISA in hexane) to obtain the desired product (2S,3R,4S)-4-(acetyloxy)-2-methyl-3,4-dihydro-2H-pyran-3-ylacetate (104) (38 g, yield 63%).

[0295] Preparation of (2S,3R,4S)-4,6-bis(acetyloxy)-2-methyloxane-3-ylacetate (105) [ka] (2S,3R,4S)-4-(acetyloxy)-2-methyl-3,4-dihydro-2H-pyran-3-yl acetate (104) (75 g, 0.35 mol) was added to a chilled solution of anhydrous dichloromethane (500 mL) (ice / water bath) with acetic acid (190 mL, 3.3 mol) and anhydrous acetic acid (290 mL, 3 mol). The reaction mixture was stirred for 15 minutes, then 19 mL of 33% HBr solution in AcOH was added, and stirring was continued for another 30 minutes until the solution turned pale yellow. TLC analysis showed that the starting material had been completely consumed (lower spot, 25% HCl / hexane). The reaction was quenched by adding an ice / water mixture. The organic layer was thoroughly washed with water (2 × 1 L), followed by chilled saturated NaHCO3 aqueous solution (1 L), water (1 L), and brine (1 L). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum to obtain the crude product, which was purified by silica gel flash chromatography (0-20% siRNA in hexane) to obtain the desired product (2S,3R,4S)-4,6-bis(acetyloxy)-2-methyloxane-3-ylacetate (105) as a white solid (83 g, yield 86.2%).

[0296] Preparation of (2S,3R,4S,6S)-4-(acetyloxy)-6-bromo-2-methyloxan-3-yl acetate (106) [ka] (2S,3R,4S)-4,6-bis(acetyloxy)-2-methyloxane-3-ylacetate (105) (82 g, 0.3 mol) was dissolved in anhydrous dichloromethane (700 mL) and 33% HBr in acetic acid (80 mL) was added at 0°C. The reaction mixture was stirred for 15 minutes, and then the reaction was quenched by adding ice-cold water (300 mL). The aqueous phase was extracted with dichloromethane (3 × 700 mL), and the combined organic layer was washed with brine (2 × 500 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain (2S,3R,4S,6S)-4-(acetyloxy)-6-bromo-2-methyloxane-3-ylacetate (106) as a sticky oil. The crude product was proceeded to the next step as quickly as possible without any further purification.

[0297] Preparation of (2S,3R,4S,6S)-4-(acetyloxy)-6-[(1,3-dioxo-2,3-dihydro-1H-isoindole-2-yl)oxy]-2-methyloxan-3-yl acetate (107) [ka] To a solution of crude (2S,3R,4S,6S)-4-(acetyloxy)-6-bromo-2-methyloxan-3-yl acetate (106) and N-hydroxyphthalimide (54 g, 0.33 mol) in anhydrous dichloromethane (600 mL), triethylamine (55 mL, 0.33 mol), followed by BF3·OEt2 (92 mL, 0.75 mol), was added at 0°C. The reaction mixture was allowed to return to room temperature and stirred for 1 hour until it turned greenish-gray. A cooled saturated aqueous solution of NaHCO3 (500 mL) was added, and the organic layer was separated. The aqueous layer was extracted with dichloromethane (3 × 500 mL), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude substance. (2S,3R,4S,6S)-4-(acetyloxy)-6-[(1,3-dioxo-2,3-dihydro-1H-isoindole-2-yl)oxy]-2-methyloxan-3-yl acetate (107) was obtained as a white foamy solid (75 g, 66% yield in two steps) by silica gel flash chromatography (10% to 60% ethyl hexane).

[0298] LC / MS (Method B): RT=4.32 min; m / z=377.1, measured value=378.2[M + H] + Total time = 12 minutes. 1H NMR (500MHz, chloroform d3) δ7.85 (ddd, J=5.5, 3.3, 0.6Hz, 2H), 7.76 (ddd, J=5.9, 2.9, 0.8Hz, 2H), 5.62~5.52 (m, 1H), 5.43 (ddd, J=12.5, 5.3, 3.0H) z, 1H), 5.38~5.23(m, 1H), 4.97(td, J=6.7, 6.7, 5.6Hz, 1H), 2.35~2.18( m, 2H), 2.17(s, 3H), 2.03(d, J=0.6Hz, 3H), 1.14(dd, J=6.5, 0.6Hz, 3H).

[0299] Preparation of (2S,3R,4S,6S)-4-(acetyloxy)-6-(aminooxy)-2-methyloxane-3-yl acetate (108) [ka] A methanol (500 mL) solution of (2S,3R,4S,6S)-4-(acetyloxy)-6-[(1,3-dioxo-2,3-dihydro-1H-isoindole-2-yl)oxy]-2-methyloxan-3-yl acetate (107) (25 g, 0.066 mol) was cooled to 0°C in an ice / water bath. Hydrazine hydrate (5.5 mL, 0.066 mol) was slowly added, and the resulting reaction mixture was stirred at 0°C for a further 30 minutes. The precipitate was filtered, the filtrate was diluted with dichloromethane (500 mL), washed with chilled NaHCO3 aqueous solution (2 × 350 mL), water (350 mL), and brine (350 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain crude (2S,3R,4S,6S)-4-(acetyloxy)-6-(aminooxy)-2-methyloxan-3-yl acetate (108) (12 g, yield 78%) as an off-white foamy solid. LC / MS: m / z = 247.2, measured value = 248.3 [M + H] + Total time = 6 minutes.

[0300] Scheme 3 shows the preparation of compounds 4, 5, 6, and 22. [ka]

[0301] Example 3: (2S,3R,4S,6S)-6-((((11S,13S,17S,E:Z)-11-(4-cyclopropylphenyl)-17-(1,1-difluoropropane-2-in-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3-ylidene)amino)oxy)-2-methyltetrahydro-2H-pyran-3,4-diyldiacetate(22) [ka] (8S,11R,13S,14S,17S)-11-(4-cyclopropylphenyl)-17-(1,1-difluoropropane-2-in-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3-one (100) (52 mg, 0.11 mmol) To a 1.1 mL, 0.1 M (1 / 1) pyridine solution, (2S,3R,4S,6S)-6-(aminooxy)-2-methyltetrahydro-2H-pyran-3,4-diyldiaacetate (31.0 mg, 0.12 mmol, 1.1 equivalents), followed by p-toluenesulfonic acid monohydrate (11.0 mg, 0.05 mmol, 0.5 equivalents), was added at ambient temperature. The reaction mixture was stirred at room temperature for 3 hours, and LC-MS analysis indicated that the reaction was complete at that point. The reaction mixture was concentrated and dried to obtain (2S,3R,4S,6S)-6-((((11S,13S,17S,E:Z)-11-(4-cyclopropylphenyl)-17-(1,1-difluoropropane-2-in-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3-ylidene)amino)oxy)-2-methyltetrahydro-2H-pyran-3,4-diyldiaacetate (22) (78 mg, yield 100%).

[0302] Example 4: (8S,11S,13S,14S,17S)-11-(4-cyclopropylphenyl)-17-(1,1-difluoropropane-2-in-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3-one O-((2S,4S,5S,6S)-4,5-dihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxime (4) [ka] (2S,3R,4S,6S)-6-((((11S,13S,17S,E:Z)-11-(4-cyclopropylphenyl)-17-(1,1-difluoropropane-2-in-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3-ylidene)amino)oxy)-2-methyltetrahydro-2H-pyran-3,4-diyldiaacetate (22) (78 mg, 0.11 mmol, 1.0 equivalent) was stirred in methanol (1.6 mL) and water (0.4 mL), to which trimethylamine (73 μL, 0.56 mmol, 5.0 equivalents) was added at ambient temperature. The reaction mixture was stirred at room temperature for 16 hours, and LC-MS analysis confirmed that the reaction was complete, yielding (8S,11S,13S,14S,17S)-11-(4-cyclopropylphenyl)-17-(1,1-difluoropropane-2-in-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3-one O-((2S,4S,5S,6S)-4,5-dihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxime (4).

[0303] Example 5: (8S,11S,13S,14S,17S,E)-11-(4-cyclopropylphenyl)-17-(1,1-difluoropropane-2-in-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3-one O-((2S,4S,5S,6S)-4,5-dihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxime(5 ) and (8S,11S,13S,14S,17S,Z)-11-(4-cyclopropylphenyl)-17-(1,1-difluoropropane-2-in-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3-one O-((2S,4S,5S,6S)-4,5-dihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxime(6) [ka] Compound 4 was purified by reverse-phase HPLC (CLIPEUS C-18 10um (Higgins Analytical Inc.) 20×250mm; ELSD and 254UV detection; mobile phase A: 10 mmol ammonium bicarbonate in water; mobile phase B: 5% acetonitrile aqueous solution to 90% acetonitrile aqueous solution over 40 minutes) to obtain pure geometric isomers 5 (22.7 mg, yield 33%) and 6 (5.9 mg, yield 8.6%).

[0304] Compound 5: 1H NMR(500 MHz, DMSO-d6): δ7.03(d, J=8.4Hz, 2H), 6.95(d, J=8.5Hz, 2H), 5.81(s, 1H), 5.41(s, 1H), 5.30~5.26(m, 1H), 4.55(d , J=6.2Hz, 1H), 4.31~4.26(m, 2H), 4.23(t, J=5.3, 5.3Hz, 1H), 3.72~3.63(m, 2H), 2.67(dt, J=16.8, 5.7, 5.7Hz, 1H) 2.42 (d, J=13.3Hz, 4H), 2.23~2.04 (m, 3H), 1.97~1.90 (m, 1H), 1.86~1.78 (m, 2H), 1.78~1.65 (m, 3H), 1.62 (dt, J=11.6, 5.7, 5.7Hz, 2H), 1.36~1.19 (m, 2H), 1.02 (d, J=6.5Hz, 3H), 0.93~0.83 (m, 2H), 0.62~0.56 (m, 2H), 0.44 (s, 3H). Theoretical mass: 607.3, Measured mass (ESI+): 608.5 [M+H].

[0305] Compound 6: 1 H NMR(500 MHz, DMSO-d6): δ7.03 (d, J=8.2Hz, 2H), 6.95 (d, J=8.5Hz, 2H), 6.31 (s, 1H), 5.41 (s, 1H), 5.30~5.24 (m, 1H), 4.56 (d, J=6.1Hz, 1H), 4.29 (t, J=5.2, 5.2Hz, 2H), 4.24 (t, J=5.2, 5.2Hz, 1H), 3.80 (dt, J=12.0, 8.1, 8.1Hz, 1H), 3.69 (q, J=7.0, 6.5, 6.5Hz, 1H), 2.39 (d, J = 12.6 Hz, 2H), 2.25~2.04 (m, 4H), 1.96~1.89 (m, 1H), 1.88~1.78 (m, 3H), 1.72 (dd, J = 25.7, 9.0 Hz, 2H), 1.62 (dd, J = 12.4, 4.9 Hz, 2H), 1.34 (q, J = 11.5, 11.5, 11.5 Hz, 1H), 1.28~1.18 (m, 1H), 1.03 (d, J = 6.6 Hz, 3H), 0.91~0.86 (m, 2H), 0.62~0.56 (m, 2H), 0.45 (s, 3H). Theoretical mass: 607.3, Measured mass (ESI+): 608.5 [M+H].

[0306] Scheme 4 shows the preparation of intermediate 114. [ka]

[0307] Preparation of tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (111) [ka] Di-tert-butyl dicarbonate (1.84 g, 8.44 mmol, 1.1 equivalents) was added at 0°C to a stirred solution of 2-(piperazine-1-yl)ethane-1-ol (110) (1.0 g, 7.68 mmol, 1.0 equivalent) in THF (76 mL). The reaction mixture was stirred at 0°C for 10 minutes, then heated to room temperature for 6 hours, at which point the reaction was complete according to LC-MS analysis. The reaction mixture was quenched with water (76 mL) and extracted with ethyl acetate (2 × 200 mL). The combined organic layers were dried over Na₂SO₄, filtered, concentrated, and dried to obtain tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (111) (1.76 g, 100% yield).

[0308] Preparation of tert-butyl 4-(2-((1,3-dioxoisoindoline-2-yl)oxy)ethyl)piperazine-1-carboxylate (113) [ka] To a stirred solution of tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (111) (1.7 g, 7.39 mmol, 1.0 equivalent) in THF (74 mL), N-hydroxypthalamide (112) (1.2 g, 7.39 mmol, 1.0 equivalent), triphenylphosphine (2.13 g, 8.13 mmol, 1.1 equivalent), and then diisopropyl azodicarboxylate were added at room temperature. The reaction mixture was stirred at room temperature for 16 hours, at which point the reaction was complete according to LCMS analysis. The reaction mixture was quenched with water (76 mL) and extracted with ethyl acetate (2 × 200 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated. The crude material was diluted with diethyl ether (30 mL) and hexane (70 mL) and stirred at room temperature for 1 hour. The mixture was filtered through a sintered funnel to remove most of the triphenylphosphine oxide. The filtrate was purified with normal-phase silica gel (0-60% ethyl hexane) to obtain tert-butyl 4-(2-((1,3-dioxoisoindorin-2-yl)oxy)ethyl)piperazine-1-carboxylate (113) as a white solid (2.16 g, 78%).

[0309] Preparation of tert-butyl 4-(2-(aminooxy)ethyl)piperazine-1-carboxylate (114) [ka] To a stirred solution of tert-butyl 4-(2-((1,3-dioxoisoindolin-2-yl)oxy)ethyl)piperazine-1-carboxylate (113) (0.2 g, 0.52 mmol, 1.0 equivalent) in THF (74 mL), hydrazine monohydrate (0.12 mL, 1.6 mmol, 3.0 equivalent) was added at room temperature. The reaction mixture was stirred at room temperature for 1 hour, at which point the reaction was complete according to LC-MS analysis. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated to obtain tert-butyl 4-(2-(aminooxy)ethyl)piperazine-1-carboxylate (114) (0.13 g, 100%).

[0310] Scheme 5 shows the preparation of compounds 7 and 23. [ka]

[0311] Example 6: tert-butyl4-(2-((((8S,11R,13S,14S,17S,E)-11-(4-cyclopropylphenyl)-17-(1,1-difluoropropane-2-in-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3-ylidene)amino)oxy)ethyl)piperazine-1-carboxylate(23) [ka] (8S,11R,13S,14S,17S)-11-(4-cyclopropylphenyl)-17-(1,1-difluoropropane-2-in-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3-one (100) (0.1 g, 0.216 mmol, 1.0 equivalent) was stirred in methanol (3 mL), to which tert-butyl 4-(2-(aminooxy)ethyl)piperazine-1-carboxylate (114) (0.16 g, 0.43 mmol, 2.0 equivalents), followed by D-(+)-camphor-10-sulfonic acid (10 mg, 0.08 mmol, 0.4 equivalents) was added at ambient temperature. The reaction mixture was stirred at room temperature for 16 hours, at which point the reaction was complete according to LC-MS analysis. The mixture was concentrated by rotary evaporation. The residue was analyzed using reverse-phase HPLC (CLIPEUS C-18 10um (Higgins Analytical HPLC)). (Inc.) 20×250mm; ELSD and 254UV detection; Mobile phase A: 10 mmol ammonium bicarbonate in water; Mobile phase B: Purified over 40 minutes with 5% acetonitrile aqueous solution to 90% acetonitrile aqueous solution to obtain tert-butyl 4-(2-((((8S,11R,13S,14S,17S,E)-11-(4-cyclopropylphenyl)-17-(1,1-difluoropropane-2-in-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3-ylidene)amino)oxy)ethyl)piperazine-1-carboxylate (23) (59 mg, yield 50%).

[0312] Example 7: (8S,11R,13S,14S,17S,E)-11-(4-cyclopropylphenyl)-17-(1,1-difluoropropane-2-in-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3-one O-(2-(piperazine-1-yl)ethyl)oxime (7) [ka] tert-butyl 4-(2-((((8S,11R,13S,14S,17S,E)-11-(4-cyclopropylphenyl)-17-(1,1-difluoropropane-2-in-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3-ylidene)amino)oxy)ethyl)piperazine-1-carboxylate (23) (10 mg, 0.014 mmol) was mixed with 4M HCl (in dioxane) (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours, and LC-MS analysis indicated that the reaction was complete at that point. The reaction mixture was concentrated to obtain (8S,11R,13S,14S,17S,E)-11-(4-cyclopropylphenyl)-17-(1,1-difluoropropane-2-in-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3-one O-(2-(piperazine-1-yl)ethyl)oxime (7) (13 mg, 100%).

[0313] 1H NMR (500MHz, DMSO-d6): δ7.03(dd, J=8.3, 3.9Hz, 2H), 6.95(d, J=7.4Hz, 2H), 6.36(s, 1H), 4.31(d, J=6.8Hz, 3H), 4.24(t, J=5.6, 5.6Hz, 1H), 3.73~3.63(m, 2H), 3.50~3.44(m, 3H), 2.45(s, 2H), 2.43~2.37(m, 2H), 2.29~2.21(m, 1H), 2.18(s, 1H) , 2.15(dd, J=9.0, 5.7Hz, 1H), 2.13~2.04(m, 1H), 1.94(dt, J=12.6, 4.3, 4.3Hz, 1H), 1.83(ddd, J=10.4, 8.4, 5.1Hz, 2H), 1 .76~1.57(m, 3H), 1.39~1.17(m, 3H), 0.93~0.86(m, 2H), 0.59(tq, J=4.5, 4.5, 2.7, 2.1, 2.1Hz, 2H), 0.45(d, J=5.0Hz, 3H). Theoretical mass: 589.35, measured mass (ESI+): 590.5 [M+H].

[0314] Scheme 6 shows the synthesis of intermediate 118. [ka]

[0315] Preparation of 2-(2-(4-methylpiperazin-1-yl)ethoxy)isoindoline-1,3-dione (117) [ka] 2-(4-methylpiperazin-1-yl)ethanol (116) (1.0 g, 6.9 mmol, 1.01 equivalent) was added dropwise to a stirred solution of 2-hydroxyisoindoline-1,3-dione (112) (1.12 g, 6.9 mmol, 1 equivalent) and triphenylphosphine (2.0 g, 7.6 mmol, 1.1 equivalent) in THF (25 ml) at 0°C. The mixture was then stirred at 0°C for 30 minutes, after which DIAD (1.5 mL, 7.6 mmol, 1.1 equivalent) was added dropwise. The reaction mixture was stirred at 0°C for a further 30 minutes, then warmed to room temperature and stirred for 16 hours. The solvent was removed under reduced pressure, and the residue was redissolved in SiO (35 mL). The organic layer was washed with saturated NaHCO3 (2 × 25 mL), dried over Na2SO4, filtered, and concentrated to approximately 15 mL under reduced pressure. The organic layer was cooled to 0°C, and 15 mL of cooled 1 M aqueous HCl solution was added. After the addition was complete, the mixture was warmed to room temperature and stirred for 20 minutes. The layers were separated, and the aqueous layer was washed with Et2O (2 × 15 mL). After cooling to 0°C, the aqueous layer was basicized by slowly adding saturated NaHCO3 solution, and then extracted with CHCl3 (3 × 25 mL). The organic extracts were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 2-(2(4-methylpiperazine-1-yl)ethoxy)isoindoline-1,3-dione (117) as a beige solid (1.1 g, 55%). Theoretical mass: 289.14, measured mass (ESI+): 290.1 ​​[M+H].

[0316] Preparation of O-(2-(4-methylpiperazine-1-yl)ethyl)hydroxylamine (118) [ka] To a stirred solution of 2-(2-(4-methylpiperazin-1-yl)ethoxy)isoindoline-1,3-dione (117) (200 mg, 0.69 mmol) in MeOH:DCM (2:1, 3 mL), hydrazine monohydrate (0.1 mL, 2.1 mmol, 3 equivalents) was added, and stirring was continued at 0°C for 1 hour. After the reaction was complete, the solvent was removed under vacuum, the residue was redissolved in ethyl acetate, washed twice with water (2 × 3 mL), dried over Na₂SO₄, and concentrated to obtain O-(2-(4-methylpiperazin-1-yl)ethyl)hydroxylamine (118), which was used in the next step without further purification (110 mg, crude). Theoretical mass: 159.13, measured mass (ESI+): 160.0 [M+H].

[0317] Scheme 7 shows the preparation of compound 8. [ka]

[0318] Example 8: (8S,11R,13S,14S,17S,E)-11-(4-cyclopropylphenyl)-17-(1,1-difluoropropane-2-in-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3-one O-(2-(4-methylpiperazine-1-yl)ethyl)oxime(8) [ka] To a stirred solution of (8S,11R,13S,14S,17S)-11-(4-cyclopropylphenyl)-17-(1,1-difluoropropane-2-in-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3-one (100) (35 mg, 0.07 mmol, 1.0 equivalent) in methanol (0.7 mL, 0.1 M), O-(2-(4-methylpiperazine-1-yl)ethyl)hydroxylamine (118) (36 mg, 0.22 mmol, 3.0 equivalents), followed by D-(+)-camphor-10-sulfonic acid (3.5 mg, 0.01 mmol, 0.2 equivalents), was added at ambient temperature. The reaction mixture was stirred at room temperature for 2 hours, and LC-MS analysis indicated that the reaction was complete at that point. The volatile substances were concentrated by rotary evaporation. The residue was purified by reverse-phase HPLC (CLIPEUS C-18 10um (Higgins Analytical Inc.) 20×250mm; ELSD and 254UV detection; mobile phase A: 10 mmol ammonium bicarbonate in water; mobile phase B: 5% acetonitrile aqueous solution to 90% acetonitrile aqueous solution over 40 minutes) to obtain (8S,11R,13S,14S,17S,E)-11-(4-cyclopropylphenyl)-17-(1,1-difluoropropane-2-in-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3-one O-(2-(4-methylpiperazine-1-yl)ethyl)oxime (8) (3.9 mg, yield 8.5%).

[0319] 1H NMR (500MHz, DMSO-d6): δ7.07~7.00(m, 2H), 6.97~6.91(m, 2H), 5.96(s, 1H), 5.71(s , 1H), 5.40(d, J=6.0Hz, 1H), 4.31~4.20(m, 2H), 2.87(s, 1H), 2.71(s, 1H), 2.42~2.32 (m, 5H), 2.20~2.01(m, 3H), 1.93(ddt, J=17.1, 11.8, 5.5, 5.5Hz, 2H), 1.86~1.55(m, 5H), 1.38~1.17(m, 2H), 0.92~0.83(m, 2H), 0.62~0.56(m, 2H), 0.44(d, J=5.5Hz, 3H). Theoretical mass: 603.364, measured mass (ESI+): 605.5[M+H] + .

[0320] Scheme 8 shows the preparation of compound 9. [ka]

[0321] Example 9: (8S,11R,13S,14S,17S,E)-11-(4-cyclopropylphenyl)-17-(1,1-difluoropropane-2-in-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3-one O-(2-morpholinoethyl)oxime (9) [ka] (11S,13S,17S)-11-(4-cyclopropylphenyl)-17-(1,1-difluoropropane-2-in-1-yl)-17-hydroxy-13-methyl-6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene-3(2H)-one (100) (35 mg, 0.08 mmol, 1.0 equivalent) was mixed with pyridine (0.7 mL, 0.1 M) and then O-(2-morpholinoethyl)hydroxylamine (122) (42 mg, 0.23 mmol, 3.0 equivalents), followed by p-toluenesulfonic acid monohydrate (7.3 mg, 0.04 mmol, 0.5 equivalents) was added at ambient temperature. The reaction mixture was stirred at room temperature for 16 hours, and LC-MS analysis indicated that the reaction was complete at that point. The reaction mixture was purified by reverse-phase HPLC (CLIPEUS C-18 10um (Higgins Analytical Inc.) 20×250mm; ELSD and 254UV detection; mobile phase A: 10 mmol ammonium bicarbonate in water, mobile phase B: 5% acetonitrile aqueous solution to 90% acetonitrile aqueous solution over 40 minutes) to obtain (8S,11R,13S,14S,17S,E)-11-(4-cyclopropylphenyl)-17-(1,1-difluoropropane-2-in-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3-one O-(2-morpholinoethyl)oxime (9) (8.5 mg, yield 19%).

[0322] 1H NMR (500MHz, DMSO-d6): δ7.02(d, J=8.3Hz, 2H), 6.94(d, J=8.5Hz, 2H), 5.77(s, 1H), 5.41(s, 1H) ), 4.28(d, J=6.8Hz, 1H), 4.23(t, J=5.2, 5.2Hz, 1H), 4.05(t, J=5.9, 5.9Hz, 2H), 3.50(t, J=4.7, 4.7Hz, 4H), 2.67~2.59(m, 2H), 2.43~2.31(m, 9H), 2.19~2.03(m, 3H), 2.02~1.88(m, 1H), 1.82(m , 1H), 1.77~1.56(m, 4H), 1.36~1.19(m, 2H), 0.92~0.85(m, 2H), 0.62~0.55(m, 2H), 0.43(s, 3H). Theoretical mass: 590.33, measured mass (ESI+): 591.7[M+H].

[0323] Scheme 9 shows the preparation of compounds 10, 11, and 12. [ka]

[0324] Example 10: (8S,11R,13S,14S,17S)-11-(4-cyclopropylphenyl)-17-(1,1-difluoropropane-2-in-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3-one O-(2-(2-hydroxyethoxy)ethyl)oxime(10) [ka] (8S,11R,13S,14S,17S)-11-(4-cyclopropylphenyl)-17-(1,1-difluoropropane-2-in-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3-one (100) (35 mg, 0.08 mmol, 1.0 equivalent) was mixed with pyridine (0.7 mL, 0.1 M), to which 2-(2-(aminooxy)ethoxy)ethanol (123) (27 mg, 0.23 mmol, 3.0 equivalents) was added, followed by p-toluenesulfonic acid monohydrate (7.3 mg, 0.04 mmol, 0.5 equivalents) at ambient temperature. The reaction mixture was stirred at room temperature for 16 hours. LC-MS analysis indicated that the reaction was complete at that point, yielding compound 10.

[0325] Example 11: (8S,11R,13S,14S,17S,Z)-11-(4-cyclopropylphenyl)-17-(1,1-difluoropropane-2-in-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3-one O-(2-(2-hydroxyethoxy)ethyl)oxime(1 1) and (8S,11R,13S,14S,17S,E)-11-(4-cyclopropylphenyl)-17-(1,1-difluoropropane-2-in-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3-one O-(2-(2-hydroxyethoxy)ethyl)oxime(12) [ka] Compound 10 was purified by reverse-phase HPLC (CLIPEUS C-18 10um (Higgins Analytical Inc.) 20×250 mm, ELSD and 254 UV detection; mobile phase A: 10 mmol ammonium bicarbonate in water, mobile phase B: 5% acetonitrile aqueous solution to 90% acetonitrile aqueous solution over 40 minutes) to obtain pure geometric isomers 11 (4 mg, yield 10%) and 12 (18 mg, yield 42%).

[0326] Compound 11: 1 H NMR (500MHz, chloroform-d3): δ7.05(d, J=7.9Hz, 2H), 7.02~6.92(m, 2H), 6.45(s, 1H), 4.32(d, J=7.4Hz, 1H), 4.23~4.18(m, 2H), 3.80~3.75(m, 2H), 3.73(m, 2H), 3.65~3.58(m, 2H), 2.89(t , J=5.4, 5.4Hz, 1H), 2.60~2.25(m, 10H), 2.13~2.06(m, 1H), 2.05(s, 1H), 1.99(m, 1H), 1.85 (m, 2H), 1.79~1.70(m, 2H), 1.49~1.33(m, 2H), 0.93(m, 2H), 0.69~0.62(m, 2H), 0.59(s, 3H). Theoretical mass: 565.3, measured mass (ESI+): 566.2 [M+H].

[0327] Compound 12: 1H NMR (500MHz, DMSO-d6): δ7.03(d, J=8.3Hz, 2H), 6.96(d, J=8.5Hz, 2H), 5.79(s, 1H), 5.42(s, 1H), 4.53(t, J=5 .5, 5.5Hz, 1H), 4.30(d, J=7.3Hz, 1H), 4.24(t, J=5.4, 5.4Hz, 1H), 4.05(dd, J=5.9, 4.0Hz, 2H), 3.60~3.55(m, 2 H), 3.45(m, 2H), 3.41~3.37(m, 2H), 2.69~2.62(m, 1H), 2.42(d, J=13.4Hz, 3H), 2.19~2.06(m, 6H), 1.97~1.90( m, 1H), 1.83(m, 1H), 1.76~1.57(m, 4H), 1.37~1.19(m, 2H), 0.94~0.84(m, 2H), 0.66~0.54(m, 2H), 0.45(s, 3H). Theoretical mass: 565.3, measured mass (ESI+): 566.5[M+H].

[0328] Scheme 10 shows the preparation of compounds 13, 14, and 15. [ka]

[0329] Example 12: (8S,11R,13S,14S,17S)-11-(4-cyclopropylphenyl)-17-(1,1-difluoropropane-2-in-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3-one O-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)oxime(13) [ka] To a stirred solution of (8S,11R,13S,14S,17S)-11-(4-cyclopropylphenyl)-17-(1,1-difluoropropane-2-in-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3-one (100) (35 mg, 0.07 mmol, 1.0 equivalent) in pyridine (0.7 mL, 0.1 M), O-(2-(2-methoxyethoxy)ethyl)hydroxylamine (124) (20.0 mg, 0.15 mmol, 2.0 equivalent), followed by p-toluenesulfonic acid monohydrate (7.2 mg, 0.03 mmol, 0.5 equivalent), was added at ambient temperature. The reaction mixture was stirred at room temperature for 16 hours, and the reaction was analyzed by LC-MS at that point to obtain compound 13.

[0330] Example 13: (8S,11R,13S,14S,17S,Z)-11-(4-cyclopropylphenyl)-17-(1,1-difluoropropane-2-in-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3-one O-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)oxime(1 4) and (8S,11R,13S,14S,17S,E)-11-(4-cyclopropylphenyl)-17-(1,1-difluoropropane-2-in-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3-one O-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)oxime(15) [ka] Compound 13 was purified by reverse-phase HPLC (CLIPEUS C-18 10um (Higgins Analytical Inc.) 20×250 mm; ELSD and 254 UV detection; mobile phase A: 10 mmol ammonium bicarbonate in water, mobile phase B: 5% acetonitrile aqueous solution to 90% acetonitrile aqueous solution over 40 minutes) to obtain pure geometric isomers 14 (5.4 mg, yield 13%) and 15 (13.3 mg, yield 33%).

[0331] Compound 14: 1 H NMR (500MHz, DMSO-d6): δ7.03(d, J=8.3Hz, 2H), 6.95(d, J=8.4Hz, 2H), 6.29(s, 1H), 5.42(s, 1H), 4.30(d, J=7.2Hz, 1H), 4.25(t, J=5 .5, 5.5Hz, 1H), 4.02(dd, J=5.7, 4.2Hz, 2H), 3.58(t, J=5.0, 5.0Hz, 2H), 3.53~3.49(m, 2H), 3.44~3.40(m, 2H), 3.23(s, 3H), 2.58(d, J=5.4Hz, 1H), 2.40(d, J=13.3Hz, 2H), 2.27~2.05(m, 4H), 1.97~1.90(m, 1H), 1.83(tt, J=8.4, 8.4, 5.1, 5.1Hz, 2H), 1.77~1.58(m, 3H) ), 1.35(q, J=11.5, 11.5, 11.5Hz, 1H), 1.24(qd, J=12.4, 12.2, 12.2, 5.4Hz, 1H), 0.93~0.84(m, 2H), 0.63~0.57(m, 2H), 0.46(s, 3H). Theoretical mass: 579.3, measured mass (ESI+): 580.3 [M+H].

[0332] Compound 15: 1H NMR (500MHz, DMSO-d6): δ7.03(d, J=8.3Hz, 2H), 6.95(d, J=8.4Hz, 2H), 5.79(s, 1H), 5.42(s, 1H), 4.30(d, J=7.3Hz, 1H), 4.2 4(t, J=5.4, 5.4Hz, 1H), 4.05(dd, J=5.9, 4.0Hz, 2H), 3.57(t, J=4.9, 4.9Hz, 2H), 3.51~3.46(m, 2H), 3.39(dd, J=5.7, 3.8Hz, 2H), 3.20(s, 3H), 2.70~2.62(m, 1H), 2.58~2.53(m, 1H), 2.42(d, J=13.7Hz, 3H), 2.19~2.06(m, 3H), 1.97~1.90(m, 1H), 1.83 (tt, J=8.3, 8.3, 5.1, 5.1Hz, 1H), 1.78~1.58(m, 4H), 1.37~1.19(m, 2H), 0.93~0.86(m, 2H), 0.62~0.57(m, 2H), 0.45(s, 3H). Theoretical mass: 579.3, measured mass (ESI+): 580.6 [M+H].

[0333] Scheme 11 shows the preparation of compound 16. [ka]

[0334] Example 14: (8S,11R,13S,14S,17S)-11-(4-cyclopropylphenyl)-17-(1,1-difluoropropane-2-in-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3-one O-ethyloxime (16) To a stirred solution of (8S,11R,13S,14S,17S)-11-(4-cyclopropylphenyl)-17-(1,1-difluoropropane-2-in-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3-one (100) (35 mg, 0.07 mmol, 1.0 equivalent) in pyridine (0.7 mL, 0.1 M), O-ethylhydroxylamine hydrochloride (125) (22 mg, 0.22 mmol, 3.0 equivalents) was added, followed by p-toluenesulfonic acid monohydrate (7.2 mg, 0.04 mmol, 0.5 equivalents) at ambient temperature. The reaction mixture was stirred at room temperature for 16 hours, at which point the reaction was complete according to LC-MS analysis. The reaction mixture was purified by reverse-phase HPLC (CLIPEUS C-18 10um (Higgins Analytical Inc.) 20×250mm; ELSD and 254UV detection; mobile phase A: 10 mmol ammonium bicarbonate in water, mobile phase B: 5% acetonitrile aqueous solution to 90% acetonitrile aqueous solution over 40 minutes) to obtain (8S,11R,13S,14S,17S)-11-(4-cyclopropylphenyl)-17-(1,1-difluoropropane-2-in-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3-one O-ethyloxime (16) (6.7 mg, yield 17%).

[0335] 1H NMR (500MHz, DMSO-d6): δ7.02(dd, J=8.3, 2.4Hz, 2H), 6.97~6.92(m, 2H), 5.41(s, 1H), 4.28(s, 1H), 4.24(d, J=5) .0Hz, 1H), 3.96(dq, J=12.1, 7.0, 7.0, 7.0Hz, 2H), 2.68~2.59(m, 1H), 2.44~2.35(m, 3H), 2.25~2.04(m, 3H), 1.9 2(dt, J=12.4, 4.3, 4.3Hz, 1H), 1.82(tt, J=8.5, 8.5, 5.1, 5.1Hz, 1H), 1.76~1.57(m, 3H), 1.38~1.18(m, 2H), 1.1 4(td, J=7.1, 7.0, 4.9Hz, 3H), 0.92~0.85(m, 2H), 0.59(dddd, J=6.3, 5.4, 4.1, 1.2Hz, 2H), 0.44(d, J=6.7Hz, 3H). Theoretical mass: 505.2792, measured mass (ESI+): 506.5[M+H].

[0336] Scheme 12 shows the preparation of compound 17. [ka]

[0337] Example 15: 2-((((8S,11R,13S,14S,17S)-11-(4-cyclopropylphenyl)-17-(1,1-difluoropropane-2-in-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3-ylidene)amino)oxy)acetic acid(17) [ka] (8S, 11R, 13S, 14S, 17S)-11-(4-cyclopropylphenyl)-17-(1,1-difluoropropane-2-in-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3-one (100) (35 mg, 0.08 mmol, 1.0 equivalent) was mixed with pyridine (0.7 mL, 0.1 M) and then 2...

Claims

1. Compound of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the formula, R １ is, -OR ３６ , substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl; R ２ -H, -CN, -CO ２ R ７ , -CONR ８ R ９ , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl; Each R ３ and R ４ is independently H, -F, or alkyl n is either 1 or 2; R ５ is -H, -CO ２ R １０ , -C(O)R １１ , -CONR １２ R １３ , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl; R ６ X is -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl, or X is = O or = NR １４ In that case, it does not exist; R ２７ This includes hydrogen, halo, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, and -NR. ２８ R ２９ ,-NCONR ３０ R ３１ , -CONR ３２ R ３３ , -CO ２ R ３４ , -NCO ２ R ３５ And; X is = O, = NR １４ , or -OR １５ And; R １４ is, -OR １６ , -NR １７ R １８ , or -N ＋ R ４０ R ４１ R ４２ And; R ７ ~R １０ , R １２ , R １３ , R １５ , and R ２８ ~R ３６ Independently, -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl or R ８ and R ９ , R １２ and R １３ , R ２８ and R ２９ , R ３０ and R ３１ , R ３２ and R ３３ These may, together with the atoms to which they are attached, form a cycloheteralkyl ring or a substituted cycloheteralkyl ring; R １１ is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl; R １６ is -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, substituted heteroarylalkynyl, or a carbohydrate derivative; R １７ and R １８ These are independently -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, substituted heteroarylalkynyl, carbohydrate derivative, R １９ CO-, R ２０ R ２１ NCO-, R ２２ OCO-, or R ２３ SO ２ - and however, each substituent may be substituted with a carbohydrate derivative, R １７ and R １８ Both are R １９ CO-, R ２１ R ２０ NCO-, R ２２ OCO-, R ２３ SO ２ -Neither either of those, nor any combination thereof; R １９ is an alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, substituted heteroarylalkynyl, or a carbohydrate derivative or R １９ and R １７ These may, together with the atoms to which they are attached, form a cycloheteralkyl ring or a substituted cycloheteralkyl ring, provided that all substituents are substituted with carbohydrate derivatives; R ２０ and R ２１ Independently, -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl, or a carbohydrate derivative, or R ２０ and R １７ These may, together with the atoms to which they are attached, form a cycloheteralkyl ring or a substituted cycloheteralkyl ring which may be substituted with =O, or R ２０ and R ２１ These may, together with the atoms to which they are attached, form a cycloheteralkyl ring or a substituted cycloheteralkyl ring, provided that all substituents are substituted with carbohydrate derivatives; R ２２ is an alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, substituted heteroarylalkynyl, or a carbohydrate derivative or R ２２ and R １７ These may, together with the atoms to which they are attached, form a cycloheteralkyl ring or a substituted cycloheteralkyl ring, provided that all substituents are substituted with carbohydrate derivatives; R ２３ is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl, provided that any substituents may be substituted with carbohydrate derivatives, or R ２３ and R １７ may together with the atoms to which they are attached form a cycloheteroalkyl ring or a substituted cycloheteroalkyl ring, provided that any substituents may be substituted with carbohydrate derivatives; R ４０ R ４１ and R ４２ are alkyl; provided that when X is =O, n is 1, R ３ and R ４ are -F, and R ２７ is -H, R １ is not phenyl or substituted phenyl, except that R １ may be phenyl substituted at the para position with -OR ２５ , and R ２５ is cycloalkyl, substituted cycloalkyl, or alkyl, cycloalkyl, substituted cycloalkyl substituted with -CF ３ , or R ４３ SO ２ -, where R ４３ is alkyl or CF ３ in the formula, compound.

2. R １ These are substituted aryl, heteroaryl, and substituted heteroaryl, and R ２ -H, -CN, -CO ２ R ７ , -CONR ８ R ９ , alkyl, alkenyl, aryl, substituted aryl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, or substituted heteroaryl; each R ３ and R ４ Independently, is H or -F, where R ３ and R ４ At least one of them is -F; R ５ is -H, -CO ２ R １０ , -C(O)R １１ , -CONR １２ R １３ , alkyl, alkenyl, aryl, substituted aryl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, or substituted heteroaryl; R ６ R is -H, alkyl, alkenyl, aryl, substituted aryl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, or substituted heteroaryl; ２７ is hydrogen, halo, -NR ２８ R ２９ , -CONR ３２ R ３３ , or -CO ２ R ３４ And; R ７ ~R １０ , R １２ , R １３ , R １５ , and R ２８ ~R ３６ R is independently -H, alkyl, alkenyl, aryl, substituted aryl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, or substituted heteroaryl; １１ R is independently an alkyl, alkenyl, aryl, substituted aryl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, or substituted heteroaryl; １６ R is -H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, substituted heteroaryl, or a carbohydrate derivative; R １７ and R １８ These are independently -H, alkyl, alkenyl, aryl, substituted aryl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, substituted heteroaryl, carbohydrate derivatives, R １９ CO-, R ２０ R ２１ NCO-, R ２２ OCO-, or R ２３ SO ２ - and; R １９ is an alkyl, alkenyl, aryl, substituted aryl, arylalkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, substituted heteroalkenyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or a carbohydrate derivative, or R １９ and R １７ These may form a cycloheteralkyl ring or a substituted cycloheteralkyl ring together with the atoms to which they are attached, provided that the substituents are all substituted with carbohydrate derivatives; R ２０ and R ２１ Independently, is an alkyl, alkenyl, aryl, substituted aryl, arylalkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, substituted heteroalkenyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or carbohydrate derivative, or R ２０ and R ２１ These may, together with the atoms to which they are attached, form a cycloheteralkyl ring or a substituted cycloheteralkyl ring, provided that all substituents are substituted with carbohydrate derivatives; R ２２ is an alkyl, alkenyl, aryl, substituted aryl, arylalkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, substituted heteroalkenyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or a carbohydrate derivative, or R ２２ and R １７ These may, together with the atoms to which they are attached, form a cycloheteralkyl ring or a substituted cycloheteralkyl ring, provided that all substituents are substituted with carbohydrate derivatives; R ２３ is an alkyl, alkenyl, aryl, substituted aryl, arylalkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, substituted heteroalkenyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or carbohydrate derivative, wherein any substituent may be substituted with a carbohydrate derivative, or R ２３ and R １７ The compound according to claim 1, wherein the substituents may, together with the atoms to which they are attached, form a cycloheteralkyl ring or a substituted cycloheteralkyl ring, provided that all substituents are substituted with carbohydrate derivatives.

3. R １ The compound according to claim 1, wherein is a substituted aryl or substituted phenyl.

4. n is 1, R ３ and R ４ The compound according to claim 1, wherein is -F.

5. R ２ The compound according to claim 1, wherein is -H.

6. R ５ The compound according to claim 1, wherein is -H.

7. The compound according to claim 1, wherein X = O.

8. X is -OR １５ And R ６ The compound according to claim 1, wherein is -H or methyl.

9. X is = NR １４ The compound according to claim 1.

10. R １４ ha-OR １６ The compound according to claim 9.

11. R １４ Ha-NR １７ R １８ The compound according to claim 9.

12. R １８ is R ２０ R ２１ The compound according to claim 11, wherein it is NCO-.

13. R １８ is R ２２ The compound according to claim 11, wherein it is OCO-.

14. R １８ is R ２０ R ２１ The compound according to claim 11, wherein it is NCO-.

15. R １８ is R ２３ SO ２ - The compound according to claim 11.

16. A pharmaceutical composition comprising the compound described in claim 1 and a pharmaceutically acceptable vehicle.

17. A method for treating age-related diseases or disorders, comprising administering a therapeutically effective amount of the compound described in claim 1 to a subject in need thereof.

18. Compound of formula (III): 【Chemistry 2】 or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the formula, R １００ is -H, -CO ２ R １０７ , -C(O)R １０８ , -CONR １０９ R １１０ , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl; R １０１ is, -OR １３０ aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl; R １０２ -H, -CN, -CO ２ R １１１ , -CONR １１２ R １１３ , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl; Each R １０３ and R １０４ These are independently H, -F, or alkyl; q is either 1 or 2; R １０５ is -H, -CO ２ R １１４ , -C(O)R １１５ , -CONR １１６ R １１７ , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl; Each R １０６ These are independently -H and -CO ２ R １１８ , -C(O)R １１９ , -CONR １２０ R １２１ , -OR １２２ , -NR １２３ R １２４ , - NHR １２５ R １２６ C(O)R １２７ , -SO ２ NR １２８ R １３０ , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, halo, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl; s is 0, 1, or 2; R １０９ ~R １１３ , R １１６ ~R １１８ , R １２０ ~R １２６ , and R １２８ ~R １３０ These are independently -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl; R １０７ , R １０８ , R １１４ , R １１５ , and R １２７ These are independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl. compound.

19. A pharmaceutical composition comprising the compound described in claim 18 and a pharmaceutically acceptable vehicle.

20. A method for treating age-related diseases or disorders, comprising administering a therapeutically effective amount of the compound described in claim 18 to a subject in need thereof.

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