WO2021092053A1 - Mcl-1 inhibitor macrocycle compounds for use in clinical management of conditions caused or mediated by senescent cells and for treating cancer - Google Patents

Abstract

This disclosure provides small-molecule compounds with Mcl-l inhibitory activity. Compounds provided in this disclosure promote apoptosis in senescent cells, particularly when combined with inhibitors of other Bcl family proteins. Compounds provided in this disclosure also promote apoptosis in cancer cells. Such compounds can be developed for treating senescent-related conditions, or as chemotherapeutic agents.

Description

Mcl-1 Inhibitor Macrocycle Compounds for Use in Clinical Management of Conditions Caused or Mediated By Senescent Cells and for Treating Cancer CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims benefit of priority to U.S. Provisional Application No.62/932,926, filed November 8, 2019, the disclosure of which is incorporated herein by reference in its entirety. FIELD OF THE INVENTION [0002] The technology disclosed and claimed below relates generally to the field of senescent cells and their role in age-related conditions. This disclosure provides new scaffolds for chemical compounds that inhibit Mcl-1 protein activity. BACKGROUND [0003] Myeloid cell leukemia-1 protein (Mcl-1), a member of antiapoptotic Bcl-2 family proteins, is a key regulator of mitochondrial homeostasis. Alternative splicing occurs at this locus and two transcript variants encoding distinct isoforms have been identified. The longer gene product (isoform 1) enhances cell survival by inhibiting apoptosis while the alternatively spliced shorter gene product (isoform 2) promotes apoptosis and causes removal of the host cell. [0004] Overexpression of Mcl-1 in human primary and drug-resistant cancer cells makes it an attractive cancer therapeutic target. Significant progress has been made in the development of small- molecule Mcl-1 inhibitors in recent years, and three Mcl-1 selective inhibitors have advanced to clinical trials. Xiang et al., Onco Targets Ther.2018; 11: 7301–7314. Omacetaxine mepesuccinate is a drug approved for the treatment for chronic myelogenous leukemia (CML). Seliciclib is under investigation as a potential multiple myeloma treatment. Both drugs act in part by inhibiting synthesis of Mcl-1 protein. MacCallum et al., Cancer Research.65 (12): 5399–5407. [0005] Recent advances in the development of Mcl-1 inhibitors for cancer therapy are discussed by Hird et al., Pharmacol. Therap.2019, 198:59-67. A patent review of Mcl-1 inhibitors has been published by Chen et al., Expert Opin. Ther. Pat.2017 Feb 27(2):163-178. Other related publications include published patent applications WO 2019/143947, WO 2018/178227, WO 2018/236904; Tron et al., Nature Commun (2018) 9:5341, and Followsa et al., Bioorganic & Medicinal Chemistry Letters 29/16, 2019, 2375-2382 and Balazs et al., J. Med. Chem.2019 Aug 19. doi:9b00716. [0006] A previously unrelated area of technology is the treatment of age-related disease by selective elimination of p16 positive senescent cells. U.S. Patents 9,849,128 and 10,213,426 (Laberge et al.) describe treatment of certain age-related conditions using MDM2 inhibitors, Bcl inhibitors, and Akt inhibitors. U.S. Patent 10,426,788 and pre-grant publication US 2018/0000816 A1 (David et al.) describe the use of particular Bcl inhibitors for treatment of age-related conditions. Senescent cells as an emerging target for diseases of ageing has been reviewed by Childs, Marquess, et al., Nat Rev Drug Discov.2017 Oct;16(10):718-735. [0007] Despite the considerable interest in developing selective Mcl-1 inhibitors, verified Mcl-1 inhibitors have been slow to enter the clinic. Tron et al. supra; Soderquist et al., Mol. Cancer Ther.2016;15:2011–2017. The long shallow hydrophobic protein–protein interaction interface has proven challenging to drug with a small molecule and while many inhibitors have been reported in the literature and even in clinical trials, off-target effects have been shown to drive phenotypic activity for many compounds. SUMMARY OF THE INVENTION [0008] This disclosure provides small-molecule compounds with Mcl-l inhibitory activity based on a new chemical scaffold shown in Formula (I):

[0009] The compounds provided in this disclosure promote apoptosis in senescent cells, particularly when combined with inhibitors of other Bcl family proteins. Compounds provided in this disclosure also promote apoptosis in cancer cells. Such compounds can be developed for treating senescent-related conditions, or as chemotherapeutic agents. [0010] The inhibitors can be used for administration to a target tissue in a subject having an age-related condition, thereby selectively eliminating senescent cells in or around the tissue and relieving one or more symptoms or signs of the conditions. Selected compounds from the family can also be formulated and marketed as chemotherapeutic agents. [0011] Preferred Mcl-1 inhibitors have an affinity for Mcl-1 protein of less than 1 µM, 100 nM, 10 nM, or 1 nM. Preferred Mcl-1 inhibitors have an affinity for Mcl-1 protein of less than 1 µM, 100 nM, 10 nM, or 1 nM. Preferred Mcl-1 inhibitors in combination with a Bcl inhibitor has an LD₅₀ for senescent primary pulmonary epithelial cells or cancer cells in culture that is less than 10, 1, or 0.1 µM. [0012] Included as part of this disclosure is a method of enhancing the ability of a Bcl-2, Bcl-xL, or Bcl-w inhibitor to selectively remove senescent cells from a mixed cell population or tissue, by combining the inhibitor with a compound according to any of claims 1 to 20. Also included is a method of enhancing the therapeutic effect of a Bcl-2, Bcl-xL, or Bcl-w inhibitor in a pharmaceutical composition formulated for treatment of a disease caused or mediated by senescent cells, by including in the pharmaceutical composition a compound according to any of claims 1 to 20. [0013] Also included in this disclosure is a combination of an Mcl-1 inhibitor and a Bcl inhibitor for simultaneous or sequential administration to a subject in need thereof. The compounds, compositions, and combinations of this invention can be used in a method of selectively removing senescent cells and/or cancer cells from a mixed cell population or tissue, or for treating a senescence related condition in a tissue in a subject [0014] The disclosure provides unit dose of a pharmaceutical composition comprising an amount of a compound that inhibits Mcl-1 function according to any of claims 1 to 20, optionally in combination with a Bcl inhibitor. The unit dose can be used in the treatment of a senescence associated condition that is caused or mediated at least in part by senescent cells (such as a pulmonary condition), or in the treatment of cancer. The formulation and the amount of the compound in the unit dose configure the unit dose to be effective in selectively removing senescent cells or cancer in or around the tissue in the subject. [0015] Further aspects of the invention are put forth in the description that follows, in the figures, and in the appended claims. DRAWINGS [0016] FIG.1 is taken from a three-dimensional model in which the Mcl-1 inhibitors described in this disclosure are fit into the crystal structure of Bcl family proteins. The annotations can be used as a guide to the reader for developing additional compounds that fall within the chemical formulas that would retain Mcl-1 inhibition activity and senolytic activity. [0017] FIG.2 depicts a genus that covers some of the Mcl-1 inhibitors of this disclosure. [0018] FIG.3 shows particular compounds with demonstrated Mcl-1 inhibitor capacity. [0019] FIGS.4A to 4D depict a synthesis scheme for preparing a representative Mcl-1 inhibitor. [0020] FIG.5 shows the binding affinity (pKi) and senolytic activity (pEC50) of macrocycle compounds for Mcl-1 protein. [0021] FIGS.6A to 6D show senolytic activity (EC₅₀) for combinations of exemplary combinations of Mcl-1 and Bcl inhibitors. [0022] FIGS.7A to 7D show the synergistic coefficient “delta” (δ) for combinations of exemplary combinations of Mcl-1 and Bcl inhibitors. [0023] FIGS.8A, 8B, and 8C show expression of senescent cell markers p16, IL-6, and MMP13 respectively in an osteoarthritis model. The senescence phenotype can be ameliorated by treating with a senolytic agent to remove senescent cells that play a central role in the pathophysiology of the condition. [0024] FIG.9A shows that an effective senolytic agent restores symmetrical weight bearing to treated mice in the osteoarthritis model. FIGS.9B, 9C, and 9D are images showing histopathology of the joints in these mice. Treatment with the agent helps prevent or reverses destruction of the proteoglycan layer. [0025] FIG.10 shows that removing senescent cells helps restore oxygen saturation (SPO2) in a mouse model for cigarette smoke (CS) induced COPD (chronic obstructive pulmonary disease). DETAILED DESCRIPTION [0026] Senescent cells are characterized as cells that no longer have replicative capacity, but remain in the tissue of origin, eliciting a senescence-associated secretory phenotype (SASP). Many age-related conditions are mediated by senescent cells, and that selective removal of the cells from tissues at or around the condition can be used clinically for the treatment of such conditions. [0027] The technology described and claimed below represents the first description of a new class of Mcl-1 inhibitors that can be used to selectively eliminate senescent cells or cancer cells from a target tissue for purposes of treatment. Inhibition of Mcl-1 protein activity [0028] Apoptosis is a highly regulated program of cell death critical for normal development and tissue homeostasis. Impaired apoptosis plays a major role in cancer development and underpins resistance to conventional cytotoxic as well as targeted therapies. [0029] Three subsets of Bcl-2 proteins interact to determine whether cells commit to apoptosis. The signaling cascade is initiated by upregulation of pro-apoptotic BH3-only Bcl-2 family proteins (for example, Bim, Bid, Puma, Noxa) in response to cellular stresses, such as DNA damage or oncogene activation. The BH3-only proteins then associate with anti-apoptotic Bcl-2 relatives (Mcl-1, Bcl-2, Bcl-xL, Bcl-w, Bfl-1/A1, Bcl-b) preventing their binding and inactivation of Bak and Bax (effector Bcl-2 proteins) which can then form oligomeric pores at the outer mitochondrial membrane causing cytochrome c release and caspase activation. Thus, the balance between pro-apoptotic and anti- apoptotic Bcl-2 proteins determines the onset of apoptosis and cell death. Tron et al., Nature Commun (2018) 9:5341. [0030] Although the pro-survival Bcl-2 family members share several functions and structural features, the distinctive regulation of Mcl-1 makes this anti-apoptotic protein unique. In contrast to other anti-apoptotic Bcl-2 proteins, Mcl-1 has a large unstructured amino-terminus core that contains multiple phosphorylation, ubiquitination4 and caspase cleavage sites that tightly control Mcl-1’s short protein half-life (1–4 h), fine-tuning its activity in response to pro-apoptotic and anti-apoptotic stimuli. [0031] The N-terminus of Mcl-1 is unique amongst the Bcl-2 family, in that it is rich in experimentally confirmed and putative regulatory residues and motifs. These include sites for ubiquitination, cleavage and phosphorylation, which influence the protein’s stability, localization, dimerization and function. Modeling Mcl-1 binding of potential small-molecule inhibitors [0032] FIG.1 depicts the binding of a model Mcl-1 inhibitor of this disclosure into the Mcl-1 binding pocket in the Mcl-1 protein. It was produced using a molecular operating environment (MOE) model that depicts three-dimensional docking of certain Mcl-1 inhibitors of this disclosure with the known crystal structure of Mcl-1 protein. Exemplary Mcl-1 inhibitors have a core structure that interacts with a binding region at or near the P2 domain of the Mcl-1, surrounded by alpha helix regions (α3 and α4). These inhibitors block the binding of Mcl-1 to binding partners such as Bim, thereby promoting apoptosis. [0033] Referring to the chemical structures of the Mcl-1 inhibitors, the carboxylic acid or sulfonamide (Position A) interacts with Arg 263 of the Mcl-1 protein. The 3 pyrazole (Position B) is exposed to a solvent accessible region, which means that a range of substituents will generally be tolerated without losing Mcl-1 inhibitor capacity. Accordingly, this position can be derivatized to manipulate physicochemical properties of the compound, such as solubility and detection. The substituent at the 3 position of the indole group (such as methyl) is also in a solvent accessible region and may be derivatized to optimize physicochemical properties. [0034] The annotations in the drawing and the description above can be used as a guide to the reader for developing additional compounds that fall within the structural formulas shown in this disclosure that retain Mcl-1 inhibition activity and senolytic activity. [0035] FIG.2 depicts a structural genus that encompasses some of the Mcl-1 inhibitors of this disclosure. Macrocycle Mcl-1 inhibitor compounds [0036] This section describes Mcl-1 inhibitor macrocyclic compounds having a scaffold based on a core macrocyclic moiety that can provide for a favorable binding conformation in the active site of a Mcl-1 protein and gives compounds that have potent inhibition activity and/or promote apoptosis of target cells. [0037] The compounds can include an indole moiety. In the core macrocycle, the indole moiety can be further connected to an aryl group via the 1-position (e.g., the N atom of the indole) and via the 4-position to a heterocyclic group, and an aryl group, which in turn can be further connected to each other to complete the macrocycle via a second heterocyclic group. Any of the indole moiety, the aryl group and heterocyclic groups can be connected to each other in the macrocycle via linkers (e.g., an alkyl linker, where optionally one of the -CH2- groups has been replaced by a heteroatom, such as O or S) or bonds. Included are macrocyclic compounds including an aryl group, where the aryl group can be a bicyclic fused ring system, such as naphthyl. Included are macrocyclic compounds including 5-membered heterocycles (e.g., a pyrazole, pyrrole or an imidazole). [0038] The compound can include an axis of chirality. Macrocyclic compounds can be present as a stereoisomer (e.g., the Ra isomer or the Sa isomer). [0039] The indole moiety of the macrocyclic compound is further substituted to provide a desirable configuration of substituents that can fit into particular locations of the active site of Mcl-1 protein. The 1-position (e.g., the nitrogen) and the 4-position of the indole include bonds that form part of the backbone of the macrocyclic group. The 2-position of the indole moiety is substituted, for example, with a carboxy group which is optionally further substituted to provide a desirable configuration of substituents that fit into particular locations of the active site of Mcl-1 protein. The carboxy group can be a carboxylic acid moiety, or it can be substituted, for example, with a sulfonamide or a phosphonate. The 3-position of the indole moiety is also substituted, for example, with a straight or branched alkyl group (e.g., C(1-6)alkyl), halogen (e.g., chloro, or fluoro), nitrile, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein any of the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups are optionally further substituted, for example, with an alkoxy group, or a phosphate group. The 5-position of the indole moiety is also substituted, for example, with an alkyl group (e.g., C(1-6)alkyl), halogen (e.g., chloro, or fluoro), or nitrile. [0040] Included are compound described by Formula (I):

wherein: Z¹ is selected from -C(O)OR¹, -C(S)OR¹, -C(O)SR¹, -C(S)SR¹, -C(O)N(R²)SO₂(R³), -OR¹, - SR¹, N(R²)2, C(O)R¹, -OCOR¹, -C(O)N(R²)2, -N(R²)C(O)R¹, -N(R²)C(O)N(R²)2, - N(R²)SO2R³, -SO2R³ and -SO2N(R²)2; R¹ is selected from H, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, substituted heteroaryl, and -(CH2)nOP(O)(OR²)2; R² is selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl; R³ is selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl; X¹ is selected from alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkylalkoxy, substituted alkylalkoxy, halogen, nitrile, cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, -(CR⁴)_mOR^4a, -(CR⁴)_mcycloalkyl-OR^4a, -(CR⁴)_mheterocycloalkyl-OR^4a, - (CR⁴)maryl-OR^4a, and -(CR⁴)mheteroaryl-OR^4a; Y¹ is selected from halogen, nitrile, alkyl, and substituted alkyl; Y²-Y³ are each independently selected from H, alkyl, substituted alkyl, halogen, and nitrile;X²- X⁴ are each independently selected from O, S, NR⁴, SO₂, and CH₂; R⁴ is selected from H, alkyl, and substituted alkyl; R^4a is selected from H, alkyl, substituted alkyl, -P(O)(OR⁴)2, -SO2R³ and -SO2N(R²)2; Z²-Z⁷ are each independently selected from N and CR⁴; R⁵ is selected from alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkylalkoxy, substituted alkylalkoxy, cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, - (CR⁴)mOR^4a, -(CR⁴)mcycloalkyl-OR^4a, -(CR⁴)mcycloalkyl, -(CR⁴)mheterocycloalkyl, - (CR⁴)mheterocycloalkyl-OR^4a, -(CR⁴)maryl-OR^4a, -(CR⁴)maryl, -(CR⁴)mheteroaryl-OR^4a, - (CR⁴)_mheteroaryl, and -(CR⁴)_mN(R⁴)₂; R⁶-R⁷ are each independently selected from H, alkyl and substituted alkyl; R⁸-R¹⁰ are each independently selected from H, alkyl, substituted alkyl, halogen, nitrile, and trifluoromethyl; or R⁸ and R⁹ or R⁹ and R¹⁰ together with the atoms to which they are attached form a 5 or 6 membered ring; n is an integer from 1 to 6; and m is an integer from 0 to 6. [0041] For any of R¹-R¹⁰, Y¹-Y³ and X¹ in a compound of formula (I) that include a substituted alkyl, a substituted alkoxy, substituted cycloalkyl, substituted alkenyl, substituted cycloalkenyl, substituted alkynyl, substituted aryl, substituted heterocycle, substituted heteroaryl, or a substituted alkylakoxy, the substituent can be one to three R^b groups. Each R^b group may be the same or different and optionally chosen from C_(1-6)alkyl (optionally substituted with one to three R^c groups), hydroxyl, C_(1-6)alkoxy (e.g., OCH₃, or OCF₃), -(CR⁴)_mOR^4a, -(CR⁴)_mcycloalkyl-(OR^4a)_p, - (CR⁴)_mheterocycloalkyl-(OR^4a)_p, -(CR⁴)_maryl-(OR^4a)_p, -(CR⁴)_mheteroaryl-(OR^4a)_p, and -(CR⁴)_mN(R^a)₂, halogen, nitrile, acyl, carboxyl, -OP(O)(OR^a)2, and -(CR⁴)mOP(O)(OR^a)2, where each R^a may be the same or different and is chosen from hydrogen, C_(1-6)alkyl, cycloalkyl, C_(1-6)alkenyl, cycloalkenyl, C_{(1- 6)}alkynyl, aryl, heteroaryl and heterocycle, each R^4a is selected from H, C_(1-6)alkyl, -P(O)(OR⁴)₂, - SO₂R³ and -SO₂N(R²)₂, each m is an integer from 0 to 6, each p is 0 or 1, and each R^c may be the same or different and chosen from halogen, nitrile, hydroxyl, C(1-6)alkoxy, amino, or -OP(O)(OR^a)2. Sometimes, for any of R¹-R¹⁰, Y¹-Y³ and X¹ in a compound of formula (I) that include a substituted alkyl, a substituted alkoxy, substituted cycloalkyl, substituted alkenyl, substituted cycloalkenyl, substituted alkynyl, substituted aryl, substituted heterocycle, substituted heteroaryl, or a substituted alkylakoxy, the substituent can be one to three R^b groups selected from C(1-6)alkyl, halogen, nitrile, hydroxyl, C(1-6)alkoxy, amino, acyl, carboxy, -OP(O)(OR^a)2, and - C(1-6)alkyl-OP(O)(OR^a)2, where each R^a may be the same or different and is chosen from H, and C_(1-6)alkyl. [0042] Included are macrocyclic compounds where at least one of Z²-Z⁴ or Z⁵-Z⁷ is N, such that the macrocycle includes at least one 5-membered heterocycle (e.g., a pyrrole, a pyrazole or an imidazole). Sometimes, the macrocycle includes a 5-membered pyrazole groups. Alternatively, the macrocycle includes a 5-membered pyrrole group or an imidazole group. Also included, are macrocyclic compounds where at least one of Z²-Z⁴ is N, and at least one of Z⁵-Z⁷ is N, such that the macrocycle includes two 5-membered heterocycles (e.g., a pyrrole, a pyrazole or an imidazole). Sometimes, two of Z²-Z⁴ are N, and two of Z⁵-Z⁷ are N. Sometimes, the macrocycle includes two 5- membered pyrazole groups. Alternatively, the macrocycle includes two 5-membered imidazole groups. Included are macrocyclic compounds with Z² being CR⁴; and Z³ and Z⁴ being N. Sometimes, Z² is CR⁴, where R⁴ is alkyl, such as C_(1-6)alkyl. Alternatively, Z² and Z³ are N, and Z⁴ is CR⁴. Included are macrocyclic compounds with R⁵ and R⁶ being N and R⁷ being CR⁴. Sometimes, Z⁷ is CR⁴, where R⁴ is H. Alternatively, R⁷ and R⁶ are N and R⁵ is CR⁴. Sometimes, R⁷ and R⁵ are N and R⁶ is CR⁴. [0043] Macrocyclic compounds can be described by Formula (IIa):

wherein: Z¹ is selected from -C(O)OR¹, -C(O)N(R²)SO₂(R³), -OR¹, -C(O)R¹, -C(O)N(R²)₂; R¹ is selected from H, C(1-6) alkyl, substituted C(1-6) alkyl, aryl, substituted aryl, and - (CH2)nOP(O)(OR²)2; R² is selected from H, C_(1-6)alkyl, substituted C_(1-6)alkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl; R³ is selected from C(1-6)alkyl, substituted C(1-6)alkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl; X¹ is selected from C_(1-6)alkyl, substituted C_(1-6)alkyl, halogen, nitrile, -(CR⁴)_mOR^4a, - (CR⁴)_mcycloalkyl-(OR^4a)_p, -(CR⁴)_mheterocycloalkyl-(OR^4a)_p, -(CR⁴)_maryl-(OR^4a)_p, and - (CR⁴)mheteroaryl-(OR^4a)p; Y¹ is selected from halogen, nitrile, C(1-6)alkyl, and substituted C(1-6)alkyl; Y²-Y³ are each independently selected from H, C_(1-6)alkyl, C_(1-6)substituted alkyl, halogen, and nitrile; X² and X⁴ are each independently selected from O, S, NR⁴, SO₂, and CH₂; R⁴ is selected from H, C(1-6)alkyl, and substituted C(1-6)alkyl; R^4a is selected from H, C_(1-6)alkyl, substituted C_(1-6)alkyl, -P(O)(OR⁴)₂, -SO₂R³ and -SO₂N(R²)₂; R⁵ is selected from C_(1-6)alkyl, substituted C_(1-6)alkyl, -(CR⁴)_mOR^4a, -(CR⁴)_mcycloalkyl-OR^4a, - (CR⁴)_mcycloalkyl, -(CR⁴)_mheterocycloalkyl, -(CR⁴)_mheterocycloalkyl-OR^4a, -(CR⁴)_maryl- OR^4a, -(CR⁴)maryl, -(CR⁴)mheteroaryl-OR^4a, -(CR⁴)mheteroaryl, and -(CR⁴)mN(R⁴)2; R⁶-R⁷ and R¹¹ are each independently selected from H, and C(1-6)alkyl; R⁸-R¹⁰ are each independently selected from H, C_(1-6)alkyl, substituted C_(1-6)alkyl, halogen, nitrile, and trifluoromethyl; or R⁸ and R⁹ or R⁹ and R¹⁰ together with the atoms to which they are attached form a 5 or 6 membered carbocyclic, heterocyclic, aryl or heteroaryl ring, optionally substituted with one or more R¹⁶ groups; R¹⁶ is selected from one or more optional substituents, each independently selected from alkyl, substituted alkyl, alkoxy, substituted alkoxy, halogen, nitrile, nitro, carboxy, C(O)NH2, SO2NH2, sulfonate, hydroxyl, alkylsulfonyl, substituted alkylsulfonyl, alkylaminosulfonyl, substituted alkylaminosulfonyl, alkylsulfonylamino, substituted alkylsulfonylamino, alkyloxycarbonyl, substituted alkyloxycarbonyl and –N(R₂)₂; n is an integer from 1 to 6; m is an integer from 0 to 6; and p is 0 or 1. [0044] For any of R¹-R⁵, R⁸-R¹⁰, Y¹-Y³ and X¹ in a compound of formula (IIa) that include a substituted C_(1-6)alkyl, a substituted aryl, substituted heterocycle, or a substituted heteroaryl, the substituent can be one to three R^b groups as described above. [0045] For R¹⁶ in a compound of formula (IIa) that includes a further substituted group (e.g., substituted alkyl, substituted alkoxy, substituted alkylsulfonyl, substituted alkylaminosulfonyl, alkylsulfonylamino, substituted alkylsulfonylamino, or substituted alkyloxycarbonyl), the substituent can be one to three R^b groups as described above. Sometimes, for R¹⁶ in a compound of formula (IIa) that include one to three R^b group, each R^b group can optionally and independently be C(1-6)alkyl, halogen, nitrile, hydroxyl, C_(1-6)alkoxy, amino, -OP(O)(OR^a)₂, and - C_(1-6)alkyl-OP(O)(OR^a)₂, where each R^a may be the same or different and is chosen from H, and C_(1-6)alkyl. [0046] Included are macrocyclic compounds with X⁴ being an oxygen atom. Alternatively, X⁴ is S. Sometimes, X⁴ is CH2. Also included, are macrocyclic compounds where Y² and Y³ are selected from hydrogen, methyl, chloro, fluoro, and nitrile. This disclosure also includes macrocyclic compounds where each of R⁶, R⁷, R¹¹, Y² and Y³ can be hydrogen or methyl. Sometimes, Y² and Y³ are both hydrogen. Sometimes, R⁶, and R¹¹ are both methyl. Sometimes, R⁷, Y² and Y³ are each hydrogen. [0047] Macrocyclic compounds can be described by Formula (IIIa):

wherein: Z¹ is selected from -C(O)OR¹, -C(O)N(R²)SO₂(R³), -OR¹, -C(O)R¹, -C(O)N(R²)₂; R¹ is selected from H, C(1-6)alkyl, substituted C(1-6)alkyl, aryl, substituted aryl, and - (CH2)nOP(O)(OR²)2; R² is selected from H, C_(1-6)alkyl, and substituted C_(1-6)alkyl; R³ is selected from C_(1-6)alkyl, substituted C_(1-6)alkyl, aryl, and substituted aryl; X¹ is selected from C(1-6)alkyl, substituted C(1-6)alkyl, halogen, nitrile, -(CR⁴)mOR^4a, - (CR⁴)mcycloalkyl-(OR^4a)p, -(CR⁴)mheterocycloalkyl-(OR^4a)p, -(CR⁴)maryl-(OR^4a)p, and - (CR⁴)mheteroaryl-(OR^4a)p; Y¹ is selected from halogen, nitrile, C_(1-6)alkyl, and substituted C_(1-6)alkyl; X² is selected from O, S, NR⁴, and SO₂; X³ is selected from S and CH2; R⁴ is selected from H, C(1-6)alkyl, and substituted C(1-6)alkyl; R^4a is selected from H, C_(1-6)alkyl, substituted C_(1-6)alkyl, -P(O)(OR⁴)₂, -SO₂R³ and -SO₂N(R²)₂; R⁵ is selected from C_(1-6)alkyl, substituted C_(1-6)alkyl, -(CR⁴)_mOR^4a, -(CR⁴)_mcycloalkyl-OR^4a, - (CR⁴)mcycloalkyl, -(CR⁴)mheterocycloalkyl, -(CR⁴)mheterocycloalkyl-OR^4a, -(CR⁴)maryl- OR^4a, -(CR⁴)maryl, -(CR⁴)mheteroaryl-OR^4a, -(CR⁴)mheteroaryl, and -(CR⁴)mN(R⁴)2; R⁸-R¹⁰ are each independently selected from H, C_(1-6)alkyl, substituted C_(1-6)alkyl, halogen, nitrile, and trifluoromethyl; or R⁸ and R⁹ or R⁹ and R¹⁰ together with the atoms to which they are attached form a 5 or 6 form a 5 or 6 membered carbocyclic, heterocyclic, aryl or heteroaryl ring, optionally substituted with one or more R¹⁶ groups; each R¹⁶ is independently selected from alkyl, substituted alkyl, alkoxy, substituted alkoxy, halogen, nitrile, nitro, carboxy, C(O)NH₂, SO₂NH₂, sulfonate, hydroxyl, alkylsulfonyl, substituted alkylsulfonyl, alkylaminosulfonyl, substituted alkylaminosulfonyl, alkylsulfonylamino, substituted alkylsulfonylamino, alkyloxycarbonyl, substituted alkyloxycarbonyl and –N(R₂)₂; n is an integer from 1 to 6; m is an integer from 0 to 6; and p is 0 or 1. [0048] For any of R¹-R⁵, R⁸-R¹⁰, Y¹, and X¹ in a compound of formula (IIIa) that include a substituted C_(1-6)alkyl, or a substituted aryl, the substituent can be one to three R^b groups as described above. For R¹⁶ in a compound of formula (IIIa) that includes a further substituted group (e.g., substituted alkyl, substituted alkoxy, substituted alkylsulfonyl, substituted alkylaminosulfonyl, alkylsulfonylamino, substituted alkylsulfonylamino, or substituted alkyloxycarbonyl), the substituent can be one to three R^b groups as described above. [0049] Included are macrocyclic compounds where R⁹ and R¹⁰ or R⁸ and R⁹ together with the atoms through which they are connected form a 5-, or 6-membered carbocyclic, heterocyclic, aryl or heteroaryl ring, optionally substituted with one or more R¹⁶ groups. For example, R⁹ and R¹⁰ can be cyclically linked (-R⁹*R¹⁰-) to provide a second aryl ring, thus providing a naphthyl group. Alternatively, R⁸ and R⁹ can be cyclically linked (-R⁹*R¹⁰-) to provide a second aryl ring, thus providing a naphthyl group. [0050] Included are compounds of any one of formulae (I)-(IIIa), where Z¹ is selected from - C(O)OH, -C(O)OCH2OP(O)(OH)2, -C(O)NHSO2-alkyl, and -C(O)NHSO2-aryl, or a pharmaceutically acceptable salt thereof. Included are compounds where Z¹ is -C(O)OH. Included are compounds where Z¹ is -C(O)OCH₂OP(O)(ONa)₂. Included are compounds were Z¹ is -C(O)NHSO₂-alkyl, or - C(O)NHSO2-aryl. [0051] Included are macrocyclic compounds with Z¹ is of the formula -C(O)Z², where Z² is selected from -OR¹ and -NHSO2R³, and where R¹ is H or -(CH2)nOP(O)(OR²)2, R² is H or C(1-6)alkyl, and R³ is C_(1-6)alkyl, substituted C_(1-6)alkyl, aryl, or substituted aryl, where the substituted C_(1-6)alkyl and the substituted aryl are substituted with one to three R^b groups as described above. This disclosure also includes macrocyclic compounds where R⁸ is hydrogen. [0052] Macrocyclic compounds can be described by Formula (IVa):

wherein: Z² is selected from -OR¹, and -NHSO2R³; R¹ is selected from H, and -(CH₂)_nOP(O)(OR²)₂; R² is selected from H, and C_(1-6)alkyl; R³ is selected from C_(1-6)alkyl, substituted C_(1-6)alkyl, aryl, and substituted aryl; Y¹ is selected from chloro, fluoro, nitrile, and C1-6 alkyl; X² is selected from O, S, NR^4b, and SO2; X³ is selected from S and CH₂; R⁹-R¹⁰ are each independently selected from H, C_(1-6)alkyl, substituted C_(1-6)alkyl, halogen, nitrile, and trifluoromethyl; or R⁹ and R¹⁰ together with the atoms to which they are attached form a 5 or 6 membered aryl, heteroaryl or heterocyclic ring optionally substituted with one or more R^16a groups; each R^16a is independently selected from C(1-6)alkyl, substituted C(1-6)alkyl, C(1-6)alkoxy, substituted C(1-6)alkoxy, halogen, nitrile, and hydroxyl; X¹ is selected from C(1-6)alkyl, halogen, nitrile,

R^4a is selected from H, and -P(O)(OR⁴)2; R⁴ is selected from H, and C_(1-6)alkyl; R^4b is selected from H, and C_1-6 alkyl; and q is an integer from 1 to 6. [0053] For any of R³, and R⁸-R¹⁰ and R^16a in a compound of formula (IVa) that include a substituted C_(1-6)alkyl, a substituted aryl, or a substituted C_(1-6)alkoxy, the substituent can be one to three R^b groups as described above. [0054] Included are macrocyclic compounds with Z² is OH. This disclosure also includes macrocyclic compounds where R⁹ and R¹⁰ are independently selected from H, C(1-6)alkyl, halogen, nitrile, and trifluoromethyl. This disclosure also includes macrocyclic compounds were R⁹ and R¹⁰ together with the atoms to which they are attached from a 5 or 6 membered aryl ring optionally substituted with one or more R^16a groups, where each R^16a group is independently selected from C(1- 6)alkyl, C(1-6)alkoxy, substituted C(1-6)alkoxy, halogen, nitrile and hydroxyl, where the substituted C(1- ₆₎alkoxy is substituted with one to three R^b groups as described above. [0055] Macrocyclic compounds can be described by Formula (Va):

wherein: Y¹ is selected from halogen, nitrile, and C(1-6)alkyl; X² is selected from O, S, NR^4b, and SO2; X³ is selected from S and CH₂; R⁹-R¹⁰ are each independently selected from H, C(1-6)alkyl, substituted C(1-6)alkyl, halogen, nitrile, and trifluoromethyl; or R⁹ and R¹⁰ together with the atoms to which they are attached form a 5 or 6 membered aryl ring optionally substituted with one or more R^16a groups; each R^16a is independently selected from C(1-6)alkyl, substituted C(1-6)alkyl, C(1-6)alkoxy, substituted C(1-6)alkoxy, halogen, nitrile, and hydroxyl; X¹ is selected from C_(1-6)alkyl, halogen, nitrile,

R⁴ is selected from H, and C(1-6)alkyl; R^4a is selected from H, and -P(O)(OR⁴)2; R⁴ and R^4b are each independently selected from H, and C_(1-6) alkyl; and q is an integer from 1 to 6. [0056] For any of R⁹-R¹⁰ or R^16a in a compound of formula (Va) that include a substituted C(1- 6)alkyl, or a substituted C(1-6)alkoxy, the substituent can be one to three R^b groups as described above. Included are macrocyclic compounds where R⁹ and R¹⁰ together with the atoms through which they are connected form a 5-, or 6-membered carbocyclic, heterocyclic, aryl or heteroaryl ring, optionally substituted with one or more R^16a groups. For example, R⁹ and R¹⁰ can be cyclically linked (-R⁹*R¹⁰-) to provide a second aryl ring, thus providing a naphthyl group. [0057] Macrocyclic compounds can be described by Formula (IIb):

wherein: Z¹ is selected from -C(O)OR¹, -C(O)N(R²)SO2(R³), -OR¹, -C(O)R¹, -C(O)N(R²)2; R¹ is selected from H, C(1-6) alkyl, substituted C(1-6)alkyl, aryl, substituted aryl, and - (CH₂)_nOP(O)(OR²)₂; R² is selected from H, C_(1-6)alkyl, substituted C_(1-6)alkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl; R³ is selected from C(1-6)alkyl, substituted C(1-6)alkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl; X¹ is selected from C_(1-6)alkyl, substituted C_(1-6)alkyl, halogen, nitrile, -(CR⁴)_mOR^4a, - (CR⁴)_mcycloalkyl-(OR^4a)_p, -(CR⁴)_mheterocycloalkyl-(OR^4a)_p, -(CR⁴)_maryl-(OR^4a)_p, and - (CR⁴)mheteroaryl-(OR^4a)p; Y¹ is selected from halogen, nitrile, C(1-6)alkyl, and substituted C(1-6)alkyl; Y²-Y³ are each independently selected from H, C_(1-6)alkyl, substituted C_(1-6)alkyl, halogen, and nitrile; X²-X⁴ are each independently selected from O, S, NR⁴, SO2, and CH2; R⁴ is selected from H, C(1-6)alkyl, and C(1-6)substituted alkyl; R^4a is selected from H, C_(1-6)alkyl, substituted C_(1-6)alkyl, -P(O)(OR⁴)₂, -SO₂R³ and -SO₂N(R²)₂; R⁵ is selected from alkyl, substituted alkyl, -(CR⁴)_mOR^4a, -(CR⁴)_mcycloalkyl-OR^4a, - (CR⁴)mcycloalkyl, -(CR⁴)mheterocycloalkyl, -(CR⁴)mheterocycloalkyl-OR^4a, -(CR⁴)maryl- OR^4a, -(CR⁴)maryl, -(CR⁴)mheteroaryl-OR^4a, -(CR⁴)mheteroaryl, and -(CR⁴)mN(R⁴)2; R⁶-R⁷ and R¹¹ are each independently selected from H, and C_1-6 alkyl; R⁸ and R¹²-R¹⁵ are each independently selected from H, C_(1-6)alkyl, substituted C_(1-6)alkyl, halogen, nitrile, and trifluoromethyl; n is an integer from 1 to 6; m is an integer from 0 to 6; and p is 0 or 1. [0058] For any of R¹-R⁵, R⁸, R¹²-R¹⁵, Y¹-Y³ and X¹ in a compound of formula (IIb) that include a substituted C(1-6)alkyl, a substituted aryl, substituted heterocycle, or a substituted heteroaryl, the substituent can be one to three R^b groups as described above. Included are macrocyclic compounds of formula (IIb) with X⁴ being an oxygen atom. Alternatively, X⁴ can be S. Sometimes, X⁴ is CH₂. Also included, are macrocyclic compounds where Y² and Y³ are selected from hydrogen, methyl, chloro, fluoro, and nitrile. This disclosure also includes macrocyclic compounds where each of R⁶-R⁸, R¹¹-R¹⁵, Y² and Y³ can be hydrogen or methyl. Sometimes, Y² and Y³ are both hydrogen. Sometimes, R⁶, and R¹¹ are both methyl. Sometimes, R⁷, R⁸, R¹²-R¹⁵, Y² and Y³ are each hydrogen. [0059] Macrocyclic compounds can be described by Formula (IIIb):

wherein: Z¹ is selected from -C(O)OR¹, -C(O)N(R²)SO2(R³), -OR¹, -C(O)R¹, -C(O)N(R²)2; R¹ is selected from H, C(1-6)alkyl, substituted C(1-6)alkyl, aryl, substituted aryl, and - (CH₂)_nOP(O)(OR²)₂; R² is selected from H, C_(1-6)alkyl, and substituted C_(1-6)alkyl; R³ is selected from C(1-6)alkyl, substituted C(1-6)alkyl, aryl, and substituted aryl; X¹ is selected from C(1-6)alkyl, substituted C(1-6)alkyl, halogen, nitrile, -(CR⁴)mOR^4a, - (CR⁴)mcycloalkyl-(OR^4a)p, -(CR⁴)mheterocycloalkyl-(OR^4a)p, -(CR⁴)maryl-(OR^4a)p, and - (CR⁴)_mheteroaryl-(OR^4a)_p; Y¹ is selected from halogen, nitrile, C_(1-6)alkyl, and substituted C_(1-6)alkyl; X² is selected from O, S, NR⁴, and SO2; X³ is selected from S and CH2; R⁴ is selected from H, C_(1-6)alkyl, and substituted C_(1-6)alkyl; R^4a is selected from H, C_(1-6)alkyl, substituted C_(1-6)alkyl, -P(O)(OR⁴)₂, -SO₂R³ and -SO₂N(R²)₂; R⁵ is selected from C(1-6)alkyl, substituted C(1-6)alkyl, -(CR⁴)mOR^4a, -(CR⁴)mcycloalkyl-OR^4a, - (CR⁴)mcycloalkyl, -(CR⁴)mheterocycloalkyl, -(CR⁴)mheterocycloalkyl-OR^4a, -(CR⁴)maryl- OR^4a, -(CR⁴)_maryl, -(CR⁴)_mheteroaryl-OR^4a, -(CR⁴)_mheteroaryl, and -(CR⁴)_mN(R⁴)₂; n is an integer from 1 to 6; m is an integer from 0 to 6; and p is 0 or 1. [0060] For any of R¹-R⁵, Y¹ and X¹ in a compound of formula (IIIb) that include a substituted C_{(1- 6)}alkyl, or a substituted aryl, the substituent can be one to three R^b groups as described above. Included are compounds of formula (IIb) or (IIIb), where Z¹ is selected from -C(O)OH, - C(O)OCH2OP(O)(OH)2, -C(O)NHSO2-alkyl, and -C(O)NHSO2-aryl, or a pharmaceutically acceptable salt thereof. Included are compounds where Z¹ is -C(O)OH. Included are compounds where Z¹ is - C(O)OCH₂OP(O)(ONa)₂. Included are compounds were Z¹ is -C(O)NHSO₂-alkyl, or -C(O)NHSO₂-aryl. [0061] Included are naphthyl containing macrocyclic compounds where Z¹ is of the formula - C(O)Z², where Z² is selected from -OR¹ and -NHSO2R³, and where R¹ is H or -(CH2)nOP(O)(OR²)2, R² is H or C_(1-6)alkyl, and R³ is C_(1-6)alkyl, C_(1-6) substituted alkyl, aryl, or substituted aryl, where the C_(1-6) substituted alkyl and substituted aryl groups are substituted by one to three R^b groups as described above. [0062] Macrocyclic compounds can be described by Formula (IVb):

wherein: Z² is selected from -OR¹, and -NHSO₂R³; R¹ is selected from H, and -(CH2)nOP(O)(OR²)2; R² is selected from H, and C(1-6)alkyl; R³ is selected from C_(1-6)alkyl, substituted C_(1-6)alkyl, aryl, and substituted aryl; Y¹ is selected from halogen, nitrile, and C_(1-6)alkyl; X² is selected from O, S, NR^4b, and SO2; X³ is selected from S and CH2; X¹ is selected from C_(1-6)alkyl, halogen, nitrile,

R^4a is selected from H, and -P(O)(OR⁴)₂; R⁴ is selected from H, and C(1-6)alkyl; R^4b is selected from H, and C(1-6) alkyl; and q is an integer from 1 to 6. [0063] For R³ in a compound of formula (IVb) that include a substituted C_(1-6)alkyl, or a substituted aryl, the substituent can be one to three R^b groups as described above. Included are compounds of formula (IVb) wherein Z² is OH, such that the compound of formula (IVb) is represented by the formula (V):

wherein the remaining substituents in formula (V) are as defined form formula (IVb). Included are compounds of any one of formulae (I)-(V), wherein Y¹ is selected from chloro, fluoro, methyl and nitrile. [0064] For example, compounds are includes where Y¹ can be chloro. Included are compounds with X¹ being, halogen (e.g., chloro), C1-6alkyl (e.g., methyl), substituted C1- 6alkyl (e.g., CF3), nitrile, or any of the following structures:

where R^4a is selected from H, and -P(O)(OR⁴)2; R⁴ is selected from H, alkyl, and substituted alkyl, where the substituent can be one to three R^b groups as described above; and q is an integer from 1 to 6; or a pharmaceutically acceptable salt thereof. In Formulae (I)-(V), X¹ can be halogen. Optionally, X¹ can be chloro. In Formulae (I)-(V), X¹ can be methyl. In Formulae (I)-(V), X¹ can be nitrile. In Formulae (I)-(V), X¹ can be X^1a, where R^4a is hydrogen or P(O)(OH)2, and q is 1 to 6. In Formulae (I)- (V), X¹ can be X^1b, where R^4a is hydrogen or P(O)(OH)2. In Formulae (I)-(V), X¹ can be X^1c, where R^4a is hydrogen or P(O)(OH)₂. In Formulae (I)-(V), X¹ can be X^1d, where R^4a is hydrogen or P(O)(OH)₂. In Formulae (I)-(V), X¹ can be X^1e, where R^4a is hydrogen or P(O)(OH)₂. In Formulae (I)-(V), X¹ can be X^1f. In Formulae (I)-(V), X¹ can be X^1g, where R^4a is hydrogen or P(O)(OH)2. [0065] This disclosure includes compounds with X¹ being methyl, chloro, nitrile, X^1a, X^1b, X^1c, X^1d, X^1e; X^1f or X^1g wherein R^4a is selected from H, and -P(O)(OH)2; and q is an integer from 1 to 6. Included are compounds with R⁵ being, C_1-6alkyl (e.g., methyl), substituted C_1-6alkyl, where the substituent can be one to three R^b groups as described above (e.g., CF₃), or any of the following structures:

where R^4a is selected from H, and -P(O)(OR⁴)₂; R⁴ is selected from H, alkyl, and substituted alkyl; and q is an integer from 1 to 6; or a pharmaceutically acceptable salt thereof. [0066] In Formulae (I)-(V), R⁵ can be C1-6 alkyl. Optionally, R⁵ can be methyl. In Formulae (I)- (V), R⁵ can be X^1a, where R^4a is hydrogen or -P(O)(OH)2, and q is 1 to 6. In Formulae (I)-(V), R⁵ can be X^1b, where R^4a is hydrogen or -P(O)(OH)₂. In Formulae (I)-(V), R⁵ can be X^1c, where R^4a is hydrogen or P(O)(OH)₂. In Formulae (I)-(V), R⁵ can be X^1d, where R^4a is hydrogen or P(O)(OH)₂. In Formulae (I)-(VII), R⁵ can be R^5a, where R⁴ is methyl. In Formulae (I)-(V), R⁵ can be X^1f. [0067] Included are compounds with R⁵ being methyl, X^1a, X^1b, X^1c, X^1d, X^1e, R^5a or X^1f, wherein R^4a is selected from H, and -P(O)(OH)₂; R^4b is methyl; and p is an integer from 1 to 6. Included are compounds of any one of formulae (I)-(V), where X² is selected from O, S, NR⁴, and SO₂; R⁴ is selected from H and alkyl (e.g., methyl); and X³ is selected from S and CH₂. Included are compounds of any one of formulae (I)-(V), wherein X² is S. The disclosure also includes compounds of any one of formulae (I)-(V), wherein X³ is S. Included are compounds where both X² and X³ are S. Included are compounds where X² is O and X³ is S. Included are compounds where X² is NR⁴ and X³ is S. Included are compounds where X² is SO₂ and X³ is S. Included are compounds where X² is CH2 and X³ is S. Included are compounds where X² is O and X³ is CH2. Included are compounds where X² is S and X³ is CH2. Included are compounds where X² is NR⁴ and X³ is CH2. Included are compounds where X² is SO₂ and X³ is S. Included are compounds where X² and X³ are both CH₂. [0068] Included are compounds of Formula (V) as defined by compounds 1-32 of Table 1. Table 1: Compounds of Formula (VII)

wherein

[0069] For any of the formulas and structures depicted herein that include a phosphoric acid moiety, such formulas and structures may also include salt forms. For example a phosphoric acid group may be present in an acidic form (e.g., —OP(=O)(OH)₂ —) or salt form (e.g., —OP(=O)(O^–)₂— ). Where applicable, acidic forms of the groups are generally depicted for simplicity, however various salt forms are also meant to be included. A salt of the compound could include a monovalent cation salt, such as sodium or potassium salt. An ordinarily skilled artisan would also recognize that other tautomeric arrangements of the groups depicted in these formulas and structures are possible, and are meant to be included in this disclosure. [0070] Included are any one of the described macrocyclic Mcl-1 inhibitor compounds, stereoisomers thereof (e.g., Ra and Sa isomers), salts thereof (e.g., pharmaceutically acceptable salts), and/or solvate, hydrate and/or prodrug forms thereof. All permutations of stereoisomers, salts, solvates, hydrates, and prodrugs are included in this disclosure. Any Mcl-1 inhibitor compound having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of R-configuration or S-configuration or a mixture thereof. In any of the Mcl-1 inhibitor compounds displaying one or more axis of chirality, if an absolute stereochemistry is not expressly indicated, then each axis may independently be of R_a-configuration or S_a-configuration or a mixture thereof. Exemplary Mcl-1 inhibitor compounds [0071] FIG.3 shows certain Mcl-1 inhibitor compounds of current commercial interest. Other compounds of interest include the following:

(Z)-1⁵-chloro-1³,2¹,2⁵,6¹,9⁵-pentamethyl-1¹H,2¹H,6¹H-10-oxa-4,8-dithia-1(4,1)-indola-2(4,3),6(3,5)- dipyrazola-9(1,3)-benzenacyclotridecaphane-1²-carboxylic acid

(Z)-1⁵-chloro-2¹,2⁵,6¹-trimethyl-1¹H,2¹H,6¹H-10-oxa-4,8-dithia-1(4,1)-indola-2(4,3),6(3,5)-dipyrazola- 9(3,1)-naphthalenacyclotridecaphane-1²-carboxylic acid

(Z)-1⁵-chloro-1³,2¹,2⁵,6¹-tetramethyl-1¹H,2¹H,6¹H-10-oxa-4,8-dithia-1(4,1)-indola-2(4,3),6(3,5)- dipyrazola-9(3,1)-naphthalenacyclotridecaphane-1²-carboxylic acid

(3aR)-1⁵-chloro-1³,2¹,2⁵,6¹-tetramethyl-1¹H,2¹H,6¹H-10-oxa-4,8-dithia-1(4,1)-indola-2(4,3),6(3,5)- dipyrazola-9(3,1)-naphthalenacyclotridecaphane-1²-carboxylic acid

(3aS)-1⁵-chloro-1³,2¹,2⁵,6¹-tetramethyl-1¹H,2¹H,6¹H-10-oxa-4,8-dithia-1(4,1)-indola-2(4,3),6(3,5)- dipyrazola-9(3,1)-naphthalenacyclotridecaphane-1²-carboxylic acid

sodium (Z)-((1⁵-chloro-2¹,2⁵,6¹-trimethyl-1¹H,2¹H,6¹H-10-oxa-4,8-dithia-1(4,1)-indola-2(4,3),6(3,5)- dipyrazola-9(3,1)-naphthalenacyclotridecaphane-1²-carbonyl)oxy)methyl hydrogen phosphate.

(Z)-1⁵,9⁶-dichloro-1³,2¹,2⁵,6¹-tetramethyl-1¹H,2¹H,6¹H-10-oxa-4,8-dithia-1(4,1)-indola-2(4,3),6(3,5)- dipyrazola-9(1,3)-benzenacyclotridecaphane-1²-carboxylic acid

(3aR)-1⁵-chloro-1³,2¹,2⁵,6¹,9⁵-pentamethyl-1¹H,2¹H,6¹H-10-oxa-4,8-dithia-1(4,1)-indola-2(4,3),6(3,5)- dipyrazola-9(1,3)-benzenacyclotridecaphane-1²-carboxylic acid

(3aS)-1⁵-chloro-1³,2¹,2⁵,6¹,9⁵-pentamethyl-1¹H,2¹H,6¹H-10-oxa-4,8-dithia-1(4,1)-indola-2(4,3),6(3,5)- dipyrazola-9(1,3)-benzenacyclotridecaphane-1²-carboxylic acid

sodium (Z)-((1⁵-chloro-1³,2¹,2⁵,6¹-tetramethyl-1¹H,2¹H,6¹H-10-oxa-4,8-dithia-1(4,1)-indola- 2(4,3),6(3,5)-dipyrazola-9(3,1)-naphthalenacyclotridecaphane-1²-carbonyl)oxy)methyl hydrogen phosphate.

(Z)-1⁵,9⁶-dichloro-1³,2¹,2⁵,6¹,9⁵-pentamethyl-1¹H,2¹H,6¹H-10-oxa-4,8-dithia-1(4,1)-indola-2(4,3),6(3,5)- dipyrazola-9(1,3)-benzenacyclotridecaphane-1²-carboxylic acid

(Z)-1³,1⁵-dichloro-2¹,2⁵,6¹-trimethyl-1¹H,2¹H,6¹H-10-oxa-4,8-dithia-1(4,1)-indola-2(4,3),6(3,5)- dipyrazola-9(3,1)-naphthalenacyclotridecaphane-1²-carboxylic acid

(3aR)-1³,1⁵-dichloro-2¹,2⁵,6¹-trimethyl-1¹H,2¹H,6¹H-10-oxa-4,8-dithia-1(4,1)-indola-2(4,3),6(3,5)- dipyrazola-9(3,1)-naphthalenacyclotridecaphane-1²-carboxylic acid

(3aS)-1³,1⁵-dichloro-2¹,2⁵,6¹-trimethyl-1¹H,2¹H,6¹H-10-oxa-4,8-dithia-1(4,1)-indola-2(4,3),6(3,5)- dipyrazola-9(3,1)-naphthalenacyclotridecaphane-1²-carboxylic acid

(Z)-1⁵-chloro-2¹-(2-hydroxyethyl)-1³,2⁵,6¹-trimethyl-1¹H,2¹H,6¹H-10-oxa-4,8-dithia-1(4,1)-indola- 2(4,3),6(3,5)-dipyrazola-9(3,1)-naphthalenacyclotridecaphane-1²-carboxylic acid

(3aR)-1⁵-chloro-2¹-(2-hydroxyethyl)-1³,2⁵,6¹-trimethyl-1¹H,2¹H,6¹H-10-oxa-4,8-dithia-1(4,1)-indola- 2(4,3),6(3,5)-dipyrazola-9(3,1)-naphthalenacyclotridecaphane-1²-carboxylic acid

(3aS)-1⁵-chloro-2¹-(2-hydroxyethyl)-1³,2⁵,6¹-trimethyl-1¹H,2¹H,6¹H-10-oxa-4,8-dithia-1(4,1)-indola- 2(4,3),6(3,5)-dipyrazola-9(3,1)-naphthalenacyclotridecaphane-1²-carboxylic acid

(3aR)-1⁵-chloro-1³,2⁵,6¹-trimethyl-2¹-(2-morpholinoethyl)-1¹H,2¹H,6¹H-10-oxa-4,8-dithia-1(4,1)-indola- 2(4,3),6(3,5)-dipyrazola-9(3,1)-naphthalenacyclotridecaphane-1²-carboxylic acid

(3aS)-1⁵-chloro-1³,2⁵,6¹-trimethyl-2¹-(2-morpholinoethyl)-1¹H,2¹H,6¹H-10-oxa-4,8-dithia-1(4,1)-indola- 2(4,3),6(3,5)-dipyrazola-9(3,1)-naphthalenacyclotridecaphane-1²-carboxylic acid

(3aR)-1⁵-chloro-1³,2¹,2⁵,6¹-tetramethyl-1¹H,2¹H,6¹H-10-oxa-4-thia-1(4,1)-indola-2(4,3),6(3,5)- dipyrazola-9(3,1)-naphthalenacyclotridecaphane-1²-carboxylic acid

(3aS)-1⁵-chloro-1³,2¹,2⁵,6¹-tetramethyl-1¹H,2¹H,6¹H-10-oxa-4-thia-1(4,1)-indola-2(4,3),6(3,5)- dipyrazola-9(3,1)-naphthalenacyclotridecaphane-1²-carboxylic acid

(Z)-1⁵-chloro-1³-cyano-2¹,2⁵,6¹-trimethyl-1¹H,2¹H,6¹H-10-oxa-4,8-dithia-1(4,1)-indola-2(4,3),6(3,5)- dipyrazola-9(3,1)-naphthalenacyclotridecaphane-1²-carboxylic acid

(3aR)-1⁵-chloro-2¹-(2-(dimethylamino)ethyl)-1³,2⁵,6¹-trimethyl-1¹H,2¹H,6¹H-10-oxa-4,8-dithia-1(4,1)- indola-2(4,3),6(3,5)-dipyrazola-9(3,1)-naphthalenacyclotridecaphane-1²-carboxylic acid

(3aS)-1⁵-chloro-2¹-(2-(dimethylamino)ethyl)-1³,2⁵,6¹-trimethyl-1¹H,2¹H,6¹H-10-oxa-4,8-dithia-1(4,1)- indola-2(4,3),6(3,5)-dipyrazola-9(3,1)-naphthalenacyclotridecaphane-1²-carboxylic acid

(Z)-1⁵-chloro-1³,2⁵,6¹-trimethyl-1¹H,6¹H-10-oxa-4,8-dithia-2(4,3)-isoxazola-1(4,1)-indola-6(3,5)- pyrazola-9(3,1)-naphthalenacyclotridecaphane-1²-carboxylic acid

(Z)-1⁵-chloro-2¹-((R)-2-hydroxypropyl)-1³,2⁵,6¹-trimethyl-1¹H,2¹H,6¹H-10-oxa-4,8-dithia-1(4,1)-indola- 2(4,3),6(3,5)-dipyrazola-9(3,1)-naphthalenacyclotridecaphane-1²-carboxylic acid

(Z)-1⁵-chloro-2¹-((S)-2-hydroxypropyl)-1³,2⁵,6¹-trimethyl-1¹H,2¹H,6¹H-10-oxa-4,8-dithia-1(4,1)-indola- 2(4,3),6(3,5)-dipyrazola-9(3,1)-naphthalenacyclotridecaphane-1²-carboxylic acid

(3aS)-1⁵-chloro-1³,2¹,2⁵,6¹-tetramethyl-N-(methylsulfonyl)-1¹H,2¹H,6¹H-10-oxa-4,8-dithia-1(4,1)- indola-2(4,3),6(3,5)-dipyrazola-9(3,1)-naphthalenacyclotridecaphane-1²-carboxamide

(3aR)-1⁵-chloro-1³,2¹,2⁵,6¹-tetramethyl-N-(methylsulfonyl)-1¹H,2¹H,6¹H-10-oxa-4,8-dithia-1(4,1)- indola-2(4,3),6(3,5)-dipyrazola-9(3,1)-naphthalenacyclotridecaphane-1²-carboxamide

(3aR)-1⁵-chloro-2¹,2⁵,6¹-trimethyl-1³-(2-morpholinoethyl)-1¹H,2¹H,6¹H-10-oxa-4,8-dithia-1(4,1)-indola- 2(4,3),6(3,5)-dipyrazola-9(3,1)-naphthalenacyclotridecaphane-1²-carboxylic acid

(3aS)-1⁵-chloro-2¹,2⁵,6¹-trimethyl-1³-(2-morpholinoethyl)-1¹H,2¹H,6¹H-10-oxa-4,8-dithia-1(4,1)-indola- 2(4,3),6(3,5)-dipyrazola-9(3,1)-naphthalenacyclotridecaphane-1²-carboxylic acid

(Z)-1³,1⁵,2¹,2⁵,6¹-pentamethyl-1¹H,2¹H,6¹H-10-oxa-4,8-dithia-1(4,1)-indola-2(4,3),6(3,5)-dipyrazola- 9(3,1)-naphthalenacyclotridecaphane-1²-carboxylic acid

(3aR)-1⁵-chloro-1³,2¹,2⁵,6¹,4-pentamethyl-1¹H,2¹H,6¹H-10-oxa-8-thia-4-aza-1(4,1)-indola- 2(4,3),6(3,5)-dipyrazola-9(3,1)-naphthalenacyclotridecaphane-1²-carboxylic acid

(3aS)-1⁵-chloro-1³,2¹,2⁵,6¹,4-pentamethyl-1¹H,2¹H,6¹H-10-oxa-8-thia-4-aza-1(4,1)-indola- 2(4,3),6(3,5)-dipyrazola-9(3,1)-naphthalenacyclotridecaphane-1²-carboxylic acid

(Z)-1⁵-chloro-1³,2¹,2⁵,6¹-tetramethyl-1¹H,2¹H,6¹H-10-oxa-4,8-dithia-1(4,1)-indola-2(4,3),6(3,5)- dipyrazola-9(3,1)-naphthalenacyclotridecaphane-1²-carboxylic acid 4,4-dioxide

sodium (Z)-1⁵-chloro-1³,2⁵,6¹-trimethyl-2¹-((R)-2-(phosphonatooxy)propyl)-1¹H,2¹H,6¹H-10-oxa-4,8- dithia-1(4,1)-indola-2(4,3),6(3,5)-dipyrazola-9(3,1)-naphthalenacyclotridecaphane-1²-carboxylate

sodium (Z)-1⁵-chloro-1³,2⁵,6¹-trimethyl-2¹-((S)-2-(phosphonatooxy)propyl)-1¹H,2¹H,6¹H-10-oxa-4,8- dithia-1(4,1)-indola-2(4,3),6(3,5)-dipyrazola-9(3,1)-naphthalenacyclotridecaphane-1²-carboxylate

(Z)-1⁵-fluoro-1³,2¹,2⁵,6¹-tetramethyl-1¹H,2¹H,6¹H-10-oxa-4,8-dithia-1(4,1)-indola-2(4,3),6(3,5)- dipyrazola-9(3,1)-naphthalenacyclotridecaphane-1²-carboxylic acid

(3aR)-1⁵-fluoro-1³,2¹,2⁵,6¹-tetramethyl-1¹H,2¹H,6¹H-10-oxa-4,8-dithia-1(4,1)-indola-2(4,3),6(3,5)- dipyrazola-9(3,1)-naphthalenacyclotridecaphane-1²-carboxylic acid

(3aS)-1⁵-fluoro-1³,2¹,2⁵,6¹-tetramethyl-1¹H,2¹H,6¹H-10-oxa-4,8-dithia-1(4,1)-indola-2(4,3),6(3,5)- dipyrazola-9(3,1)-naphthalenacyclotridecaphane-1²-carboxylic acid

(Z)-1⁵-chloro-2¹-(2-hydroxy-2-methylpropyl)-1³,2⁵,6¹-trimethyl-1¹H,2¹H,6¹H-10-oxa-4,8-dithia-1(4,1)- indola-2(4,3),6(3,5)-dipyrazola-9(3,1)-naphthalenacyclotridecaphane-1²-carboxylic acid

(3aR)-1⁵-chloro-2¹-(2-hydroxy-2-methylpropyl)-1³,2⁵,6¹-trimethyl-1¹H,2¹H,6¹H-10-oxa-4,8-dithia-1(4,1)- indola-2(4,3),6(3,5)-dipyrazola-9(3,1)-naphthalenacyclotridecaphane-1²-carboxylic acid

(3aS)-1⁵-chloro-2¹-(2-hydroxy-2-methylpropyl)-1³,2⁵,6¹-trimethyl-1¹H,2¹H,6¹H-10-oxa-4,8-dithia-1(4,1)- indola-2(4,3),6(3,5)-dipyrazola-9(3,1)-naphthalenacyclotridecaphane-1²-carboxylic acid

(Z)-1⁵-chloro-1³-(2-hydroxyethyl)-2¹,2⁵,6¹-trimethyl-1¹H,2¹H,6¹H-10-oxa-4,8-dithia-1(4,1)-indola- 2(4,3),6(3,5)-dipyrazola-9(3,1)-naphthalenacyclotridecaphane-1²-carboxylic acid

(3aR)-1⁵-chloro-1³-(2-hydroxyethyl)-2¹,2⁵,6¹-trimethyl-1¹H,2¹H,6¹H-10-oxa-4,8-dithia-1(4,1)-indola- 2(4,3),6(3,5)-dipyrazola-9(3,1)-naphthalenacyclotridecaphane-1²-carboxylic acid

(3aS)-1⁵-chloro-1³-(2-hydroxyethyl)-2¹,2⁵,6¹-trimethyl-1¹H,2¹H,6¹H-10-oxa-4,8-dithia-1(4,1)-indola- 2(4,3),6(3,5)-dipyrazola-9(3,1)-naphthalenacyclotridecaphane-1²-carboxylic acid

(Z)-1⁵-cyano-1³,2¹,2⁵,6¹-tetramethyl-1¹H,2¹H,6¹H-10-oxa-4,8-dithia-1(4,1)-indola-2(4,3),6(3,5)- dipyrazola-9(3,1)-naphthalenacyclotridecaphane-1²-carboxylic acid

sodium (3aR)-1⁵-chloro-1³,2⁵,6¹-trimethyl-2¹-(2-(phosphonatooxy)ethyl)-1¹H,2¹H,6¹H-10-oxa-4,8- dithia-1(4,1)-indola-2(4,3),6(3,5)-dipyrazola-9(3,1)-naphthalenacyclotridecaphane-1²-carboxylate

sodium (3aS)-1⁵-chloro-1³,2⁵,6¹-trimethyl-2¹-(2-(phosphonatooxy)ethyl)-1¹H,2¹H,6¹H-10-oxa-4,8- dithia-1(4,1)-indola-2(4,3),6(3,5)-dipyrazola-9(3,1)-naphthalenacyclotridecaphane-1²-carboxylate

(Z)-1⁵-chloro-1³,2¹,2⁵,6¹,9⁴,9⁵-hexamethyl-1¹H,2¹H,6¹H-10-oxa-4,8-dithia-1(4,1)-indola-2(4,3),6(3,5)- dipyrazola-9(1,3)-benzenacyclotridecaphane-1²-carboxylic acid

(3aR)-1⁵-chloro-1³,2¹,2⁵,6¹,9⁴,9⁵-hexamethyl-1¹H,2¹H,6¹H-10-oxa-4,8-dithia-1(4,1)-indola- 2(4,3),6(3,5)-dipyrazola-9(1,3)-benzenacyclotridecaphane-1²-carboxylic acid

(3aS)-1⁵-chloro-1³,2¹,2⁵,6¹,9⁴,9⁵-hexamethyl-1¹H,2¹H,6¹H-10-oxa-4,8-dithia-1(4,1)-indola- 2(4,3),6(3,5)-dipyrazola-9(1,3)-benzenacyclotridecaphane-1²-carboxylic acid

(Z)-15-chloro-13-(2-(4-hydroxypiperidin-1-yl)ethyl)-21,25,61-trimethyl-11H,21H,61H-10-oxa-4,8-dithia- 1(4,1)-indola-2(4,3),6(3,5)-dipyrazola-9(3,1)-naphthalenacyclotridecaphane-12-carboxylic acid

(3aR)-15-chloro-13-(2-(4-hydroxypiperidin-1-yl)ethyl)-21,25,61-trimethyl-11H,21H,61H-10-oxa-4,8- dithia-1(4,1)-indola-2(4,3),6(3,5)-dipyrazola-9(3,1)-naphthalenacyclotridecaphane-12-carboxylic acid

(3aS)-15-chloro-13-(2-(4-hydroxypiperidin-1-yl)ethyl)-21,25,61-trimethyl-11H,21H,61H-10-oxa-4,8- dithia-1(4,1)-indola-2(4,3),6(3,5)-dipyrazola-9(3,1)-naphthalenacyclotridecaphane-12-carboxylic acid Combinations of Mcl-1 inhibitors and Bcl inhibitors [0072] The Mcl-1 inhibitors in this disclosure in some contexts are effective as senolytic agents or chemotherapeutic agents as a monotherapy. The Mcl-1 inhibitors can also be paired with one or more Bcl family proteins, particularly Bcl-2, Bcl-xL, Bcl-w, and combinations thereof. The Mcl-1 inhibitor enhances the activity of the Bcl inhibitor, or vice versa, to produce a therapeutic combination for simultaneous or sequential use. [0073] As put forth in US Patents 10,010,546 and 10,258,618 (Laberge et al., Buck Inst. et al.), Bcl inhibitors include, for example, A-107250, A-1155463, A-1331852, AB141523 (2-methoxy- antimycin A3), ABT-737, APG-2575, APG-1252 (BM-1252), APG-2575, AZ-Mcl1, BH3I-1, (-)BI97D6, BM-903, BM-956, BM-957, BM-1074, BM-1197, BXI-61 (NSC354961, 3-[(9-Amino-7-ethoxyacridin-3- yl)diazenyl]pyridine-2,6-diamine) or BXI-72 (NSC334072, bisbenzimide), 2,3-DCPE (2-[[3-(2,3- Dichlorophenoxy)propyl]amino]ethanol), EU5346 (ML311), gossypols, gossypol (BL 193), (-)-gossypol ((-)BL 193), (+)-gossypol ((+)BL 193), R-(-)-gossypol (AT-101), S-(-)-gossypol, apogossypol, gossypolone, HA14-1, JY-1-106, MAIM1, Navitoclax (ABT-263), Obatoclax (GX15-070) pyrogallols, acylpyrogallols, S63845, Sabutoclax (BI-97C1), TM-179, TM-1206, Venetoclax (ABT-199, GDC-0199, RG7601), UM-36, VU661013, WEHl-539, ((R) 4-(4-chlorophenyl)-3-(3-(4-(4-(4-((4-(dimethylamino)-1- (phenylthio)butan-2-yl)amino)-3-nitrophenylsulfonamido)phenyl)piperazin-1-yl)phenyl)-5-ethyl-1- methyl-1H-pyrrole-2-carboxylic acid ("Compound 21”), (R)-5-(4-chlorophenyl)-4-(3-(4-(4-(4-((4- (dimethylamino)-1-(phenylthio)butan-2-yl)amino)-3-nitrophenylsulfonamido)phenyl)piperazin-1- yl)phenyl)-1-ethyl-2-methyl-1H-pyrrole-3-carboxylic acid (“Compound 14”), (R)-5-(4-chlorophenyl)-4- (3-(4-(4-(4-(4-(dimethylamino)-1-(phenylthio)butan-2-ylamino)-3- nitrophenylsulfonamido)phenyl)piperazin-1-yl)phenyl)-1-isopropyl-2-methyl-1H-pyrrole-3-carboxylic acid (“Compound 15”), and pharmaceutically acceptable salts thereof. [0074] As put forth in U.S. Patents 8,691,184 and 9,403,856 (Ascentage), other Bcl inhibitors are aryl sulfonamides that have the following structure:

Formula (I) wherein A is an optionally substituted 2, 3-1H-pyrrolylene; B and E individually are optionally substituted phenyl; C is optionally substituted 1,3-phenylene; D is optionally substituted 1,4- phenylene; and X and Y taken together form the following:

[0075] As put forth in US 2018/0000816 A1 (David et al., Unity Biotechnology) and PCT/US2019/037067 (Beausoleil et al., Unity Biotechnology), other exemplary aryl sulfonamide Bcl inhibitors include compounds that have either of the following structures:

[0076] As put forth in PCT/US2019/030039 (Beausoleil et al., Unity Biotechnology), another class of exemplary Bcl inhibitors are acyl benzylamines that have the following structure:

[0077] As put forth in PCT/US2019/030023 (Beausoleil et al., Unity Biotechnology), another class of Bcl inhibitors are phosphonamidates that have the following structure:

[0078] As put forth in PCT/US2019/030028 (Beausoleil et al., Unity Biotechnology), another class of Bcl inhibitors are phospholidines that have the following structure:

[0079] As put forth in PCT/US2019/030039 (Beausoleil et al., Unity Biotechnology), another class of exemplary Bcl inhibitors are acyl phosphoamidates that have the following structure:

Evaluating compounds for protein binding and senolytic activity [0080] Mcl-1 inhibitors and Bcl inhibitors can be evaluated on the molecular level for their ability to perform in a way that indicates they are suitable senolytic combinations for use according to this invention. For example, where the therapy includes triggering apoptosis of senescent cells by inhibiting Mcl-1, Bcl-2, Bcl-xL, Bcl-w, and combinations thereof, candidate compounds can be tested for their ability to inhibit binding between Mcl-1 and Bcl proteins and their respective cognate ligand. Example 2 provides an illustration of a homogeneous assay (an assay that does not require a separation step) based on oxygen channeling for purposes of determining by direct binding the ability of a candidate Mcl-1 or Bcl inhibitor to disrupt the binding of a cognate ligand to the Mcl-1 family proteins of interest. [0081] Candidate compounds can also be evaluated for an ability to kill senescent cells. Cultured cells are contacted with the compound, and the degree of cytotoxicity or inhibition of the cells is determined. The ability of the compound to kill or inhibit senescent cells can be compared with the effect of the compound on normal cells that are freely dividing at low density, and normal cells that are in a quiescent state at high density. Examples 3 and 5 provide illustrations of selective senescent cell killing using various cell populations that are induced by irradiation to senesce: primary human small airway epithelial cell (SAEC), primary human bronchial epithelial cells (HBEC), human fibroblast IMR90 cell line, or a human endothelial HUVEC cell line. Similar protocols are known and can be developed or optimized for testing the ability of candidate senolytic compounds to kill other senescent cell types. Determining senolytic synergy in combinations of a Mcl-1 inhibitor with a Bcl inhibitor [0082] Many of the effective combinations of Mcl-1 and Bcl inhibitors are attributable at least in part to functional synergy between the two compounds. According to current understanding (and without implying any limitation on the practice of the invention), the proteins Bcl-2, Bcl-xL, and Mcl-1 are all part of a mitochondrial pathway that regulate caspase 3, 6, and 7, leading to apoptosis. Synergy between Mcl-1 inhibitors and Bcl inhibitors may be direct or indirect, leading to enhanced inhibition, decreased regulation of caspase activity, and consequently an increase in apoptosis, leading to elimination of the senescent cell. [0083] To quantify the degree of synergy of a combination of candidate senolytic agents, the combination response can be compared against an expected combination response, under the assumption of non-interaction calculated using a reference model (Tang J. et al. (2015) What is synergy? The saariselkä agreement revisited. Front. Pharmacol.6, 181). Commonly-utilized reference models can include, for example, the highest single agent (HSA) model, where the synergy score quantifies the excess over the highest single drug response (Berenbaum M.C. (1989) What is synergy. Pharmacol. Rev., 41, 93–141); the Loewe additivity model, where the synergy score quantifies the excess over the expected response if the two drugs are the same compound (Loewe S. (1953) The problem of synergism and antagonism of combined drugs. Arzneimiettel Forschung, 3, 286–290); the Bliss independence model, where the expected response is a multiplicative effect as if the two drugs act independently (Bliss C.I. (1939) The toxicity of poisons applied jointly. Ann. Appl. Biol., 26, 585–615); or the Zero interaction potency (ZIP) model, where the expected response corresponds to an additive effect as if the two drugs do not affect the potency of each other (Yadav B. et al. (2015) Searching for drug synergy in complex dose–response landscapes using an interaction potency model. Comput. Struct. Biotechnol. J., 13, 504–505). [0084] To facilitate data processing of the senolytic dose-response matrices performed using different doses of tested combinations of Bcl inhibitors and Mcl-1 inhibitors on senescent cells, the user may employ an algorithm that uses key functions of R-package, called SynergyFinder. This algorithm is described by Ianevski A. et al. (2017) SynergyFinder: a web application for analyzing drug combination dose–response matrix data. Bioinformatics. Aug 1; 33(15): 2413–2415. The algorithm is publicly available from the Netherlands Translational Research Center, and can be accessed via the Internet. User instructions and tutorials of the SynergyFinder package have been published by He, Wennerberg, Aittokallio and Tang in 2016, updated 2018. [0085] Unless explicitly stated or otherwise required, effective combinations of inhibitors according to this invention do not necessarily require measurable synergy at the target engagement level in experiments done in vitro in order to be effective for particular purposes in vivo. However, the user may find it useful to screen for effective combinations by calculating inhibition interactions according to the HAS model, the Loewe additivity model, the Bliss independence model, or the ZIP model. Reference in this disclosure to a delta (“δ”) synergy coefficient or index refers to the δ value calculated according to the ZIP model of Yadav et al., supra. Using this model, the larger the δ value, the stronger the synergistic senolysis. Any δ value larger than 0 shows positive synergy. The δ values given in the experimental sections below were calculated using the ZIP model. [0086] Effective combinations of Mcl-1 inhibitors and inhibitors of other Bcl family members may have a δ value, or synergy coefficient that is greater than 5, 10, 15, 20, 30, 50, 80, or 150. Expressed in ranges, the synergy between such compounds may have δ values in the range of 1-500, 10-100, or 20-100. Formulation of medicaments [0087] Preparation and formulation of pharmaceutical agents for use according to this disclosure can incorporate standard technology, as described, for example, in the current edition of Remington: The Science and Practice of Pharmacy. The formulation will typically be optimized for administration to the target tissue, for example, by local administration, in a manner that enhances access of the active agent to the target senolytic cells and providing the optimal duration of effect, while minimizing side effects or exposure to tissues that are not involved in the condition being treated. [0088] Pharmaceutical preparations for use in treating senescence-related conditions and other diseases can be prepared by mixing an Mcl-1 inhibitor with a pharmaceutically acceptable base or carrier and as needed one or more pharmaceutically acceptable excipients. Depending on the target tissue, it may be appropriate to formulate the pharmaceutical composition for sustained or timed release. Oral timed release formulations may include a mixture of isomeric variants, binding agents, or coatings. Injectable time release formulations may include the active agent in combination with a binding agent, encapsulating agent, or microparticle. For treatment of joint diseases such as osteoarthritis, the pharmaceutical composition is typically formulated for intra-articular administration. For treatment of lung diseases, the composition may be formulated as an aerosol, or for intratracheal administration. [0089] This disclosure provides commercial products that are kits that enclose unit doses of one or more of the agents or compositions described in this disclosure. Such kits typically comprise a pharmaceutical preparation in one or more containers. The preparations may be provided as one or more unit doses (either combined or separate). The kit may contain a device such as a syringe for administration of the agent or composition in or around the target tissue of a subject in need thereof. The product may also contain or be accompanied by an informational package insert describing the use and attendant benefits of the drugs in treating the senescent cell associated condition, and optionally an appliance or device for therapeutic delivery of the composition. Use of Mcl-1 inhibitor compounds and combinations for clinical therapy [0090] Senescent cells accumulate with age, which is why conditions mediated by senescent cells occur more frequently in older adults. In addition, different types of stress on pulmonary tissues may promote the emergence of senescent cells and the phenotype they express. Cell stressors include oxidative stress, metabolic stress, DNA damage (for example, as a result of environmental ultraviolet light exposure or genetic disorder), oncogene activation, and telomere shortening (resulting, for example, from hyperproliferation). Tissues that are subject to such stressors may have a higher prevalence of senescent cells, which in turn may lead to presentation of certain conditions at an earlier age, or in a more severe form. An inheritable susceptibility to certain conditions suggests that the accumulation of disease-mediating senescent cells may directly or indirectly be influenced by genetic components, which can lead to earlier presentation.

[0091] One of the benefits of the senescent cell paradigm is that successful removal of senescent cells may provide the subject with a long-term therapeutic effect. Senescent cells are essentially non-proliferative, which means that subsequent repopulation of a tissue with more senescent cells can only occur by conversion of non-senescent cells in the tissue to senescent cells — a process that takes considerably longer than simple proliferation. As a general principle, a period of therapy with a senolytic agent that is sufficient to remove senescent cells from a target tissue (a single dose, or a plurality of doses given, for example, every day, semi weekly, or weekly, given over a period of a few days, a week, or several months) may provide the subject with a period of efficacy (for example, for two weeks, a month, two months, or more) during which the senolytic agent is not administered, and the subject experiences alleviation, reduction, or reversal of one or more adverse signs or symptoms of the condition being treated.

[0092] To treat a particular senescence-related condition with a senolytic agent according to this disclosure, the therapeutic regimen will depend on the location of the senescent cells, and the pathophysiology of the disease.

Senescence-related conditions suitable for treatment

[0093] The Mcl-1 inhibitors of this disclosure can be used for prevention or treatment of various senescence-related conditions. Such conditions will typically (although not necessarily) characterized by an overabundance of senescent cells (such as cells expressing p16 and other senescence markers) in or around the site of the condition, or an overabundance of expression of p16 and other senescence markers, in comparison with the frequency of such cells or the level of such expression in unaffected tissue. Non-limiting examples of current interest include the treatment of osteoarthritis and lung disease, as illustrated in the following sections.

Treatment of osteoarthritis

[0094] Any of the Mcl-1 inhibitors listed in this disclosure can be developed for treating osteoarthritis in accordance with this disclosure. Similarly, the Mcl-1 inhibitors can be developed for selectively eliminating senescent cells in or around a joint of a subject in need thereof, including but not limited to a joint affected by osteoarthritis.

[0095] Osteoarthritis degenerative joint disease is characterized by fibrillation of the cartilage at sites of high mechanical stress, bone sclerosis, and thickening of the synovium and the joint capsule. Fibrillation is a local surface disorganization involving splitting of the superficial layers of the cartilage. The early splitting is tangential with the cartilage surface, following the axes of the predominant collagen bundles. Collagen within the cartilage becomes disorganized, and proteoglycans are lost from the cartilage surface. In the absence of protective and lubricating effects of proteoglycans in a joint, collagen fibers become susceptible to degradation, and mechanical destruction ensues. Predisposing risk factors for developing osteoarthritis include increasing age, obesity, previous joint injury, overuse of the joint, weak thigh muscles, and genetics. Symptoms of osteoarthritis include sore or stiff joints, particularly the hips, knees, and lower back, after inactivity or overuse; stiffness after resting that goes away after movement; and pain that is worse after activity or toward the end of the day. [0096] Compounds according to this disclosure can be used to reduce or inhibit loss or erosion of proteoglycan layers in a joint, reduces inflammation in the affected joint, and promotes, stimulates, enhances, or induces production of collagen, for example, type 2 collagen. The compound may causes a reduction in the amount, or level, of inflammatory cytokines, such as IL-6, produced in a joint and inflammation is reduced. The compounds can be used for treating osteoarthritis and/or inducing collagen, for example, Type 2 collagen, production in the joint of a subject. A compound also can be used for decreasing, inhibiting, or reducing production of metalloproteinase 13 (MMP-13), which degrades collagen in a joint, and for restoring proteoglycan layer or inhibiting loss and/or degradation of the proteoglycan layer. Treatment with a compound thereby may also reduce the likelihood of, inhibits, or decreases erosion, or slows erosion of the bone. The compound may be administered directly to an osteoarthritic joint, for example, intra-articularly, topically, transdermally, intradermally, or subcutaneously. The compound may also restore, improve, or inhibit deterioration of strength of a join, and reduce joint pain. Treatment of pulmonary conditions [0097] The Mcl-1 inhibitors listed in this disclosure can be developed for treating pulmonary disease in accordance with this disclosure. The Mcl-1 inhibitors can be developed for selectively eliminating senescent cells in or around a lung of a subject in need thereof. Pulmonary conditions that can be treated include idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis, bronchiectasis, and emphysema. [0098] COPD is a lung disease defined by persistently poor airflow resulting from the breakdown of lung tissue, emphysema, and the dysfunction of the small airways, obstructive bronchiolitis. Primary symptoms of COPD include shortness of breath, wheezing, chest tightness, chronic cough, and excess sputum production. Elastase from cigarette smoke-activated neutrophils and macrophages can disintegrate the extracellular matrix of alveolar structures, resulting in enlarged air spaces and loss of respiratory capacity. COPD can be caused by, for example, tobacco smoke, cigarette smoke, cigar smoke, secondhand smoke, pipe smoke, occupational exposure, exposure to dust, smoke, fumes, and pollution, occurring over decades thereby implicating aging as a risk factor for developing COPD. [0099] The processes that cause lung damage include, for example, oxidative stress produced by the high concentrations of free radicals in tobacco smoke, cytokine release due to the inflammatory response to irritants in the airway, and impairment of anti-protease enzymes by tobacco smoke and free radicals, allowing proteases to damage the lungs. Genetic susceptibility can also contribute to the disease. In about 1% percent of people with COPD, the disease results from a genetic disorder that causes low level production of alpha-1-antitrypsin in the liver. Alpha-1-antitrypsin is normally secreted into the bloodstream to help protect the lungs. [0100] Pulmonary fibrosis is a chronic and progressive lung disease characterized by stiffening and scarring of the lung, which can lead to respiratory failure, lung cancer, and heart failure. Fibrosis is associated with repair of epithelium. Fibroblasts are activated, production of extracellular matrix proteins is increased, and transdifferentiation to contractile myofibroblasts contribute to wound contraction. A provisional matrix plugs the injured epithelium and provides a scaffold for epithelial cell migration, involving an epithelial-mesenchymal transition (EMT). Blood loss associated with epithelial injury induces platelet activation, production of growth factors, and an acute inflammatory response. Normally, the epithelial barrier heals and the inflammatory response resolves. However, in fibrotic disease the fibroblast response continues, resulting in unresolved wound healing. Formation of fibroblastic foci is a feature of the disease, reflecting locations of ongoing fibrogenesis. [0101] Subjects at risk of developing pulmonary fibrosis include, for example, those exposed to environmental or occupational pollutants, such as asbestosis and silicosis; those who smoke cigarettes; those who have a connective tissue diseases such as RA, SLE, scleroderma, sarcoidosis, or Wegener’s granulomatosis; those who have infections; those who take certain medications, including, for example, amiodarone, bleomycin, busufan, methotrexate, and nitrofurantoin; those subject to radiation therapy to the chest; and those whose family member have pulmonary fibrosis. [0102] Other pulmonary conditions that can be treated by using a compound according to this condition include emphysema, asthma, bronchiectasis, and cystic fibrosis. Pulmonary diseases can also be exacerbated by tobacco smoke, occupational exposure to dust, smoke, or fumes, infection, or pollutants that contribute to inflammation. [0103] Symptoms of lung disease can include of shortness of breath, wheezing, chest tightness, having to clear one’s throat first thing in the morning because of excess mucus in the lungs, a chronic cough that produces sputum that can be clear, white, yellow or greenish, cyanosis, frequent respiratory infections, lack of energy, and unintended weight loss. Symptoms of pulmonary fibrosis may include shortness of breath, particularly during exercise; dry, hacking cough; fast, shallow breathing; gradual, unintended weight loss; fatigue; aching joints and muscles; and clubbing of the fingers or toes. [0104] Lung function before, during, and after treatment can be determined, for example, by measuring expiratory reserve volume (ERV), forced vital capacity (FVC), forced expiratory volume (FEV), total lung capacity (TLC), vital capacity (VC), residual volume (RV), and functional residual capacity (FRC). Gas exchange across alveolar capillary membrane can be measured using diffusion capacity for carbon monoxide (DLCO). Exercise capacity can be measured as a proxy. Peripheral capillary oxygen saturation (SpO₂) can also be measured: normal oxygen levels are typically between 95% and 100%. An SpO₂ level below 90% suggests the subject has hypoxemia. Values below 80% are considered critical and require intervention to maintain brain and cardiac function and avoid cardiac or respiratory arrest. [0105] Benefits of treatment may include inhibiting progression or reversing of any of these effects. Administration of the senolytic agent may be systemic, or local at a site in or around the lung: for example, by inhalation as an aerosol or powder, or by intubation. Optimally, the agent will improve the SpO2 level and exercise capacity. Definitions [0106] A “senescent cell” is generally thought to be derived from a cell type that typically replicates, but as a result of aging or other event that causes a change in cell state, can no longer replicate. Depending on the context, senescent cells can be identified as expressing p16, or at least one marker selected from p16, senescence-associated β-galactosidase, and lipofuscin; sometimes two or more of these markers, and other markers of the senescence-associated secretory profile (SASP) such as but not limited to interleukin 6, and inflammatory, angiogenic and extracellular matrix modifying proteins. Unless explicity stated otherwise, when senescent cells referred to in the claims, the term does not include cancer cells. [0107] A “senescence associated”, “senescence related” or “age related” disease, disorder, or condition is a physiological condition that presents with one or more symptoms or signs that are adverse to the subject. The condition is “senescence associated” if it is “caused or mediated at least in part by senescent cells.” This means that at least one component of the SASP in or around the affected tissue plays a role in the pathophysiology of the condition such that elimination of at least some of the senescent cells in the affected tissue results in substantial relief or lessening of the adverse symptoms or signs, to the patient’s benefit. Senescence associated disorders that can potentially be treated or managed using the methods and products according to this disclosure include disorders referred to in this disclosure and in previous disclosures referred to in the discussion. Unless explicitly stated otherwise, the term does not include cancer. [0108] An inhibitor of protein function or Mcl-1 function is a compound that to a substantial degree prevents the target protein already expressed in a target cell from performing an enzymatic, binding, or regulatory function that the Mcl-1 protein normally performs in the target cell. This results in elimination of the target cell or rendering the cell more susceptible to the toxicity of another compound or event. A compound qualifies as an “Mcl-1 inhibitor” or a compound that “inhibits Mcl-1 activity” in this disclosure if it has an IC₅₀ when tested in an assay according to Example 2 below that is less than 1,000 nM (1.0 μM). Activity that is less than 100 nM or 10 nM, or between 100 nM and 1 nM is often preferred, depending on the context. [0109] The term “Bcl” or “Bcl protein” refers to the family of Bcl proteins, exemplified by Bcl-2, Bcl-xL, and Bcl-w. [0110] A compound, composition or agent is typically referred to as “senolytic” if it eliminates senescent cells, in preference replicative cells of the same tissue type, or quiescent cells lacking SASP markers. Alternatively or in addition, a compound or combination may effectively be used if it decreases the release of pathological soluble factors or mediators as part of the senescence associated secretory phenotype that play a role in the initial presentation or ongoing pathology of a condition, or inhibit its resolution. In this respect, the term “senolytic” refers to functional inhibition, such that compounds that work primarily by inhibiting rather than eliminating senescent cells (senescent cell inhibitors) can be used in a similar fashion with ensuing benefits. Model senolytic compositions and agents in this disclosure have an EC₅₀ when tested in an assay according to Example 3 or Example 5 below that is less than 1 μM. Activity that is less than 0.1 μM, or between 1 μM and 0.1 μM may be preferred. The selectivity index (SI) (EC50 of senescent cells compared with non-senescent cells of the same tissue type) may be better than 1, 2, 5, or 10, depending on the context. [0111] Selective removal or “elimination” of senescent cells from a mixed cell population or tissue doesn’t require that all cells bearing a senescence phenotype be removed: only that the proportion of senescent cells initially in the tissue that remain after treatment is substantially higher than the proportion of non-senescent cells initially in the tissue that remain after the treatment. [0112] Successful “treatment” of a condition according to this disclosure may have any effect that is beneficial to the subject being treated. This includes decreasing severity, duration, or progression of a condition, or of any adverse signs or symptoms resulting therefrom. Treatment may also be unsuccessful, resulting in no improvement in typical signs and symptoms of the condition. A concurrent objective of therapy is to minimize adverse effects on the target tissue or elsewhere in the treated subject. In some circumstances, senolytic agents can also be used to prevent or inhibit presentation of a condition for which a subject is susceptible, for example, because of an inherited susceptibility of because of medical history. [0113] A “therapeutically effective amount” is an amount of a compound of the present disclosure that (i) treats the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein, (iv) prevents or delays progression of the particular disease, condition or disorder, or (v) at least partially reverses damage caused by the condition prior to treatment. [0114] A “phosphorylated” form of a compound is a compound which bears one or more phosphate groups covalently bound to the core structure through an oxygen atom, which was typically but not necessarily present on the molecule before phosphorylation. For example, one or more –OH or -COOH groups may have been substituted in place of the hydrogen with a phosphate group which is either –OPO₃H₂ or -C_nPO₃H₂ (where n is 1 to 4). In some phosphorylated forms, the phosphate group may be removed in vivo (for example, by enzymolysis), in which case the phosphorylated form may be a pro-drug of the non-phosphorylated form. A non-phosphorylated form has no such phosphate group. A dephosphorylated form is a derivative of a phosphorylated molecule after at least one phosphate group has been removed. [0115] “Small molecule” Mcl-1 inhibitors according to this disclosure have molecular weights less than 20,000 daltons, and are often less than 10,000, 5,000, or 2,000 daltons. Small molecule inhibitors are not antibody molecules or oligonucleotides, and typically have no more than five hydrogen bond donors (the total number of nitrogen–hydrogen and oxygen–hydrogen bonds), and no more than 10 hydrogen bond acceptors (all nitrogen or oxygen atoms). [0116] "Prodrug" refers to a derivative of an active agent that requires a transformation within the body to release the active agent. The transformation can be an enzymatic transformation. Sometimes, the transformation is a cyclization transformation, or a combination of an enzymatic transformation and a cyclization transformation. Prodrugs are frequently, although not necessarily, pharmacologically inactive until converted to the active agent. [0117] "Promoiety" refers to a form of protecting group that when used to mask a functional group within an active agent converts the active agent into a prodrug. Typically, the promoiety will be attached to the drug via bond(s) that are cleaved by enzymatic or non-enzymatic means in vivo. Exemplary promoiety groups include acyl groups capable of forming an ester or thioester group with a hydroxyl or thiol functional group of a compound, and substituted alkyl groups capable of forming an ether or thioether group with a hydroxyl or thiol functional group of a compound, which groups can be cleaved in vivo as described above.

[0118] Unless otherwise stated or required, each of the compound structures referred to in the disclosure include conjugate acids and bases having the same structure, crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and prodrugs. This includes, for example, tautomers, polymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates). [0119] Unless otherwise stated or implied, the term “substituted” when used to modify a specified group or radical means that one or more hydrogen atoms of the specified group or radical are each independently replaced with the same or different substituent groups which is not hydrogen. Unless indicated otherwise, the nomenclature of substituents is arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment. For example, the substituent “arylalkyloxycarbonyl” refers to the group (aryl)-(alkyl)-0-C(0)

[0120] A “linker” is a moiety that covalently connects two or more chemical strucutres, and has a backbone of 100 atoms or less in length between the two strucdtures. The linker may be cleavable or non-cleavable. The linker typically has a backbone of between 1 and 5 or between 1 and 20 atoms in length, in linear or branched form. The bonds between backbone atoms may be saturated or unsaturated. The linker backbone may include a cyclic group, for example, an optionally substituted aryl, heteroaryl, heterocycle or cycloalkyl group.

[0121] For any Mcl-1 inhibitor compound of this disclosure having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each chiral center may independently be of R-configuration or S-configuration or a racemic mixture thereof. The compound may be any stereoisomer of the structure shown, either as an alternative form or as a mixture, unless a particular stereoisomer is explicity referred to.

[0122] Except where otherwise stated or required, other terms used in the specification have their ordinary meaning.

Incorporation by reference

[0123] For all purposes in the United States and in other jurisdictions where effective, each and every publication and patent document cited in this disclosure is hereby incorporated herein by reference in its entirety for all purposes to the same extent as if each such publication or document was specifically and individually indicated to be incorporated herein by reference.

[0124] U.S. Patents 9,849,128 and 10,213,426 (Laberge et al„ Unity Biotechnology et al.) are hereby incorporated herein by reference in their entirety for all purposes, including treatment of certain age-related conditions (including osteoarthritis and pulmonary conditions) by removing senescent cells from affected tissue with a senolytic agent. U.S. Patent s10,426,788 and 10,195,213 and pre- grant publication US 2018/0000816 A1 (David et al, Unity Biotechnology.) are hereby incorporated herein by reference in their entirety for all purposes, including the use of particular Bcl inhibitors for treatment of age-related conditions, including lung disease. U.S. Patents 8,691,184 and 9,403,856 (Ascentage), and international applications PCT/US2019/030039, PCT/US2019/030023, and PCT/US2019/030028 (Beausoleil et al., Unity Biotechnology) are hereby incorporated herein by reference in their entirety for all purposes, including the preparation of other Bcl inhibitor compounds suitable for combining with Mcl-1 inhibitors disclosed herein. U.S. provisional patent application 62/752,938 is hereby incorporated herein by reference in its entirety for all purposes, including the use of combinations of Mcl-1 inhibitors and Bcl inhibitors for removing senescent cells and treating senescence-associated conditions. EXAMPLES Example 1: Synthesis of a model Mcl-1 inhibitor [0125] FIGS.4A to 4D depict a synthesis scheme for preparing (Z)-15-chloro-13,21,25,61,95 - pentamethyl-11H,21H,61H-10-oxa-4,8-ditha-1(4,1)-indola-2(4,3),6(3,5)-dipyrazola-9(1,3)- benzenacyclotridecaphane-12-carboxylic acid. [0126] Referring to FIG.4A: Synthesis of (3-bromo-4-chlorophenyl) hydrazine was done as follows: To a solution of 3-bromo-4-chloroaniline (250 g, 1.10 mol) in HCl (8000 mL, 12 M) was added NaNO2 (251g, 3.63 mol) slowly, the mixture was stirred at 0 °C for 1 hour. SnCl2.2H2O (1.36 kg, 6.05 mol) was dissolved in HCl (4.50 L, 12 M) and added to the reaction mixture very slowly. The mixture was stirred at 0 °C for 12 hours. LCMS showed 3-bromo-4-chloroaniline was consumed completely and desired MS was detected. The mixture was filtered, and the cake was concentrated under vacuum to give (3-bromo-4-chlorophenyl) hydrazine (600 g, crude product, HCl salt) as white solid. LCMS obsd. (ESI+) [(M+H)+]: 222.9. The crude product contained with SnCl₂ and SnCl₄. [0127] Synthesis of ethyl (E)-2-(2-(3-bromo-4-chlorophenyl) hydrazineylidene) butanoate: To a mixture of (3-bromo-4-chlorophenyl) hydrazine (100 g, crude product, HCl salt) and ethyl 2- oxobutanoate (42.4 g, 326 mmol) in Ethyl acetate (800 mL) was added T3P (173 g, 50% purity in EA, 271 mmol) at 25 °C, then heated to 100 °C and stirred for 12 hours. LCMS showed (3-bromo-4- chlorophenyl) hydrazine was consumed and desired product MS was detected. The reaction mixture was added to water (1 L), then the aqueous phase was extracted with ethyl acetate (1 L × 3). The combined organic phase was washed with brine (1000 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give a residue to give ethyl (E)-2-(2-(3-bromo-4-chlorophenyl) hydrazineylidene) butanoate (60.0 g, 66.3% yield) as red oil, which was used directly for next step without further purification. LCMS obsd. (ESI+) [(M+H)+]: 335.0. [0128] Synthesis of ethyl 4-bromo-5-chloro-3-methyl-1H-indole-2-carboxylate. To a solution of ethyl (E)-2-(2-(3-bromo-4-chlorophenyl) hydrazineylidene) butanoate (60.0 g, 180 mmol) in toluene (800 mL) was added to BF₃-Et₂O (purity ^48%, 400 mL) at 25 °C. The mixture was then stirred at 100 °C for 3 hours. TLC (PE/EA=10:1) showed that the starting material was consumed completely, and new spots were formed. The reaction mixture was poured into water (600 mL) and extracted with EA (500 mL). The organic layer was washed with water (300 mL × 3) and brine (500 mL). The resulting organic layer was combined and dried over Na2SO4, concentrated in vacuo. The residue was purified by flash chromatography (PE/EA = 10:1) to give ethyl 4-bromo-5-chloro-3-methyl-1H-indole-2- carboxylate (10 g, crude) as brown solid. [0129] Synthesis of ethyl 1-(3-acetoxypropyl)-4-bromo-5-chloro-3-methyl-1H-indole-2- carboxylate. To a solution of ethyl 4-bromo-5-chloro-3-methyl-1H-indole-2-carboxylate (7.00 g, crude) and 3-chloropropyl acetate (15.1 g, 111 mmol) in DMF (100 mL) was added Cs2CO3 (7.20 g, 22.1 mmol) and KI (11.0 g, 66.3 mmol) and K₂CO₃ (9.15 g, 66.3 mmol). Then the mixture was stirred at 100 °C for 4 hours. LCMS showed starting material was consumed completely and the desired product MS was detected. TLC (PE/EA = 1:1) showed that the starting material was consumed completely, and new spots were formed. The reaction mixture was filtered, and the solution was poured into water (200 mL) and extracted with EA (100 mL × 3). The organic layer was combined and washed with brine (200 mL), dried over Na₂SO₄, and concentrated in vacuo. The residue was purified by silica gel chromatography with PE/EA = 70:1 to 60:1 to give ethyl 1-(3-acetoxypropyl)-4-bromo-5- chloro-3-methyl-1H-indole-2-carboxylate (5.00 g, 54.3% yield) as yellow oil. LCMS obsd. (ESI+) [(M+H)+]: 418.0 [0130] Referring to FIG.4B: 2.1. Synthesis of (1,5-dimethyl-1H-pyrazol-3yl) methanol was done as follows. To a solution of ethyl 1,5-dimethyl-1H-pyrazole-3-carboxylate (33.0 g, 196 mmol) in THF (600 mL) was added LiAlH4 (14.9 g, 392 mmol) in portions at 25 °C under N2. The mixture was stirred at 75 °C for 12 hours.1H NMR showed that the reactant was about 10% remained and desired product was detected. The reaction was quenched with NaOH (15 mL, 15% in water) and then water (15 mL). The crude reaction mixture was filtered and then filtrate was dried over Na₂SO₄, concentrated in vacuo to give (1,5-dimethyl-1H-pyrazol-3yl) methanol (29.4 g, 90.0% yield) as yellow oil. [0131] Synthesis of (4-bromo-1,5-dimethyl-1H-pyrazol-3yl) methanol. To a solution of (1,5- dimethyl-1H-pyrazol-3yl) methanol (38.0 g, 301 mmol) in DCM (400 mL) was added NBS (48.3 g, 271 mmol) at 25 °C under N2. The mixture was stirred at 25 °C for 1 hour. LCMS showed that the starting material was consumed completely, and desired product MS was detected. The reaction was poured into water (200 mL) and extracted with DCM (100 mL × 2). The organic layer was combined and washed with brine (300 mL), dried over Na₂SO₄, concentrated in vacuo. The residue was purified by flash silica gel chromatography with PE/EA = 3:1 to give (4-bromo-1,5-dimethyl-1H-pyrazol-3yl) methanol (60.0 g, 97.1% yield) as white solid. LCMS obsd. (ESI+) [(M+H)+]: 205.1 [0132] Synthesis of 4-bromo-3-(((4-methoxybenzyl) oxy) methyl)-1,5-dimethyl-1H-pyrazole. To a solution of (4-bromo-1,5-dimethyl-1H-pyrazol-3yl) methanol (35.0 g, 171 mmol) in DMF (500 mL) was added NaH (8.23 g, 60% purity, 206 mmol) at 0 °C under N2. The mixture was stirred at 25 °C for 60 minutes. Then 4-methoxybenzyl chloride (29.9 g, 191 mmol) was added to the mixture and then the mixture was stirred at 25 °C for 2 hours. LCMS and TLC (PE/EA = 3:1) of the reaction mixture showed that the starting material was consumed completely, and new spot was formed. The reaction was quenched with water (1 L) and then extracted with EA (1.5 L × 2). The organic layer was combined and washed with brine (2 L), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography with PE/EA = 3:1 to give 4-bromo-3-(((4-methoxybenzyl) oxy) methyl)-1,5-dimethyl-1H-pyrazole (54.0 g, 97.3% yield) as yellow solid. LCMS obsd. (ESI+) [(M+H)+]: 327.0. [0133] Synthesis of 3-(((4-methoxybenzyl) oxy) methyl)-1,5-dimethyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2yl)-1H-pyrazole. To a solution of 4-bromo-3-(((4-methoxybenzyl) oxy) methyl)- 1,5-dimethyl-1H-pyrazole (100 g, 307 mmol) in THF (400 mL) was added n-BuLi (148 mL, 2.5 M, 369 mmol) at -78 °C. The mixture was stirred at -78 °C for 1 hour.2-isopropoxy-4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (57.2 g, 307 mmol) was added into the reaction and the mixture was stirred at 25 °C for 2 hours. TLC (PE/EA = 1/1) showed 4-bromo-3-[(4-methoxyphenyl)-methoxymethyl]-1, 5-dimethyl- pyrazole was consumed and a new spot was observed. The reaction solution was concentrated. The residue was purified by silica gel (PE/EA = 4/1) to give 3-(((4-methoxybenzyl) oxy) methyl)-1,5- dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-1H-pyrazole (80 g, 69.9% yield) as a white solid which was detected by LCMS. LCMS obsd. (ESI+) [(M+H)+]: 373.0 [0134] Referring to FIG.4C: Synthesis of ethyl 1-(3-acetoxypropyl)-5-chloro-4-(3-(((4- methoxybenzyl) oxy) methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-methyl-1H-indole-2-carboxylate was accomplished as follows. To a solution of ethyl 1-(3-acetoxypropyl)-4-bromo-5-chloro-3-methyl-1H- indole-2-carboxylate (10.0 g, 24.0 mmol) and 3-(((4-methoxybenzyl) oxy) methyl)-1,5-dimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-1H-pyrazole (9.83 g, 26.4 mmol) in 1,4-Dioxane (100 mL) and Water (5 mL) was added Pd(dppf)Cl2. DCM (1.96 g, 2.40 mmol) and Cs2CO3 (19.5 g, 59.9 mmol) at 25 °C under N₂. The mixture was stirred at 95 °C under N₂ for 3 hours. LCMS showed that the starting material was consumed completely, and desired product mass was detected. The reaction was concentrated in vacuo. The residue was purified by silica gel chromatography with PE/EA = 1:1 to 1:2 to get a crude product. Then the crude was purified by reversed-flash to give ethyl 1-(3- acetoxypropyl)-5-chloro-4-(3-(((4-methoxybenzyl) oxy) methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3- methyl-1H-indole-2-carboxylate (6.50 g, 46.5% yield) as yellow oil. LCMS obsd. (ESI+) [(M+H)+]: 582.1 [0135] Synthesis of ethyl 1-(3-acetoxypropyl)-5-chloro-4-(3-(hydroxymethyl)-1,5-dimethyl-1H- pyrazol-4-yl)-3-methyl-1H-indole-2-carboxylate. To a solution of ethyl 1-(3-acetoxypropyl)-5-chloro-4- (3-(((4-methoxybenzyl) oxy) methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-methyl-1H-indole-2-carboxylate (2.40 g, 4.12 mmol) in DCM (28 mL) was added TFA (4 mL) slowly at 20 °C. Then the mixture was stirred at 20 °C for 15 minutes. LCMS of the reaction mixture showed that the starting material was consumed completely and 70% of desired product MS was detected. TLC (PE/EA = 1:1) showed that the starting material was consumed completely, and new spots were formed. The reaction was added to water (30 mL) and basified by NaHCO3 (sat.,) to pH = 7-8. Then the mixture was extracted with DCM (30 mL × 3). The organic layer was washed with brine (50 mL) then dried over Na2SO4, concentrated in vacuo. The residue was purified by silica gel chromatography with PE/EA = 1:2 to 0:1 to give ethyl 1-(3-acetoxypropyl)-5-chloro-4-(3-(hydroxymethyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3- methyl-1H-indole-2-carboxylate (1.80 g, 94.5% yield) as colorless oil. LCMS obsd. (ESI+) [(M+H)+]: 462.2 [0136] Synthesis of ethyl 1-(3-acetoxypropyl)-4-(3-(bromomethyl)-1,5-dimethyl-1H-pyrazol-4-yl)- 5-chloro-3-methyl-1H-indole-2-carboxylate. To a solution of ethyl 1-(3-acetoxypropyl)-5-chloro-4-(3- (hydroxymethyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-methyl-1H-indole-2-carboxylate (2.00 g, 4.33 mmol) in DCM (40 mL) and were added PPh3 (3.41 g, 12.9 mmol) and CBr4 (4.30 g, 12.9 mmol). The mixture was stirred at 20 °C for 2 hours. LCMS showed the starting material was consumed completely and desired MS was detected. TLC (PE/EA = 1:1) showed the starting material was consumed completely and new spots were formed. The mixture was purified by silica gel chromatography with PE/EA = 1:1 to give ethyl 1-(3-acetoxypropyl)-4-(3-(bromomethyl)-1,5-dimethyl- 1H-pyrazol-4-yl)-5-chloro-3-methyl-1H-indole-2-carboxylate (1.90 g, 83.6% yield) as colorless oil. LCMS obsd. (ESI+) [(M+H)+]: 526.1 [0137] Referring to FIG.4D: ethyl 5-((acetylthio)methyl)-1-methyl-1H-pyrazole-3-carboxylate was synthesized as follows. To a mixture of ethyl 5-(bromomethyl)-1-methyl-1H-pyrazole-3- carboxylate (7.50 g, 30.3 mmol) in MeCN (120 mL) was added AcSK (5.20 g, 45.5 mmol) and KI (504 mg, 3.03 mmol) at 25°C. The mixture was stirred at 25^oC for 2 hours. TLC (PE/EA = 1/1) showed ethyl 5-(bromomethyl)-1-methyl-1H-pyrazole-3-carboxylate was consumed and a new spot was observed. The solution was concentrated, and the residue was purified by silica column (PE/EA = 1/1) to give ethyl 5-((acetylthio)methyl)-1-methyl-1H-pyrazole-3-carboxylate (7.00 g, 95.2% yield) as a yellow oil, confirmed by LCMS. LCMS obsd. (ESI+) [(M+H)+]: 242.9 [0138] Synthesis of ethyl 5-(((3-hydroxy-5-methylphenyl) thio) methyl)-1-methyl-1H-pyrazole-3- carboxylate. To a solution of compound ethyl 5-((acetylthio)methyl)-1-methyl-1H-pyrazole-3- carboxylate (1.55 g, 6.42 mmol) and compound 3-bromo-5-methylphenol (1.00 g, 5.35 mmol) in 1,4- dioxane (30 mL) was added Pd₂(dba)₃ (245 mg, 0.267 mmol), X-phos (255 mg, 0.535 mmol) and K2CO3 (2.95 g, 21.4 mmol) at 20^oC The mixture was stirred at 130 ^oC for 12 hours under N2. TLC (PE/EA = 1/1) showed ethyl 5-((acetylthio)methyl)-1-methyl-1H-pyrazole-3-carboxylate was consumed and new spots were detected. The reaction solution was poured into water (50 mL), then extracted with EA (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to give a crude residue. The residue was purified by silica column (PE/EA = 1/0, 1/1) to give ethyl 5-(((3-hydroxy-5-methylphenyl) thio) methyl)-1-methyl-1H-pyrazole-3- carboxylate (1.22 g, 74.8 % yield) as a white solid. [0139] Synthesis of ethyl 5-(((3-((tert-butyldiphenylsilyl) oxy)-5-methylphenyl) thio) methyl)-1- methyl-1H-pyrazole-3-carboxylate. To a solution of ethyl 5-(((3-hydroxy-5-methylphenyl) thio) methyl)-1-methyl-1H-pyrazole-3-carboxylate (2.50 g, 8.16 mmol) in THF (30 mL) was added NaH (979 mg, 60% purity, 24.5 mmol) at 0 °C. The mixture was stirred at 0 ^oC for 15 minutes, TBDPS-Cl (3.36 g, 12.2 mmol) was added. The mixture was stirred at for 1 hour. LCMS showed ethyl 5-(((3-hydroxy-5- methylphenyl) thio) methyl)-1-methyl-1H-pyrazole-3-carboxylate was consumed and the desired MS was detected. The reaction solution was quenched by water (60 mL) at 0 °C, extracted by EA (50 mL × 3). Then the organic layers were combined and washed by brine (50 mL), dried over Na₂SO₄, filtered and concentrated to give a residue. The residue was purified by silica column (PE/EA = 10/1, 1/1) to give ethyl 5-(((3-((tert-butyldiphenylsilyl) oxy)-5-methylphenyl) thio) methyl)-1-methyl-1H- pyrazole-3-carboxylate (3.10 g, 74.5% yield) as a light-yellow oil. LCMS obsd. (ESI+) [(M+H)+]: 545.2 [0140] Synthesis of (5-(((3-((tert-butyldiphenylsilyl) oxy)-5-methylphenyl) thio) methyl)-1-methyl- 1H-pyrazol-3-yl) methanol. To a solution of ethyl 5-(((3-((tert-butyldiphenylsilyl) oxy)-5-methylphenyl) thio) methyl)-1-methyl-1H-pyrazole-3-carboxylate (3.00 g, 5.51 mmol) in THF (20 mL) was added LiAlH₄ (628 mg, 16.5 mmol) at 0 ^oC, the mixture was stirred at 0 ^oC for 1 hour. LCMS showed starting material was consumed and the desired product MS was detected. The reaction solution was quenched by NaOH (15% in water, 0.63 mL) and water (0.63 mL) at 0 ^oC, then filtered and concentrated to give (5-(((3-((tert-butyldiphenylsilyl) oxy)-5-methylphenyl) thio) methyl)-1-methyl-1H- pyrazol-3-yl) methanol (2g, 72.2 % yield) as a light-yellow oil. LCMS obsd. (ESI+) [(M+H)+]: 503.2. [0141] Synthesis of 3-(bromomethyl)-5-(((3-((tert-butyldiphenylsilyl) oxy)-5-methylphenyl) thio) methyl)-1-methyl-1H-pyrazole. To a solution of (5-(((3-((tert-butyldiphenylsilyl) oxy)-5-methylphenyl) thio) methyl)-1-methyl-1H-pyrazol-3-yl) methanol (1.9 g, 3.78 mmol) and PPh3 (2.97 g, 11.3 mmol) in DCM (40 mL) was added CBr₄ (1.29 g, 11.3 mmol). The mixture was stirred at 20 ^oC for 1 hour. LCMS showed (5-(((3-((tert-butyldiphenylsilyl) oxy)-5-methylphenyl) thio) methyl)-1-methyl-1H-pyrazol-3-yl) methanol was consumed and the desired MS was detected. The reaction was concentrated to give a residue. The residue was triturated by EA (10 mL) and the filtrate was concentrated to give 3- (bromomethyl)-5-(((3-((tert-butyldiphenylsilyl) oxy)-5-methylphenyl) thio) methyl)-1-methyl-1H-pyrazole (2.80 g) (crude) as a light-yellow oil. LCMS obsd. (ESI+) [(M+H)+]: 567.0. [0142] Synthesis of S-((5-(((3-((tert-butyldiphenylsilyl)oxy)-5-methylphenyl) thio)methyl)-1- methyl-1H-pyrazol-3-yl)methyl) ethanethioate. To a solution of 3-(bromomethyl)-5-(((3-((tert- butyldiphenylsilyl) oxy)-5-methylphenyl) thio) methyl)-1-methyl-1H-pyrazole (2.80 g, crude) in MeCN (30 mL) was added AcSK (1.69 g, 14.8 mmol) at 20 oC, the mixture was stirred at 20 ^oC for 2 hours. LCMS showed 3-(bromomethyl)-5-(((3-((tert-butyldiphenylsilyl) oxy)-5-methylphenyl) thio) methyl)-1- methyl-1H-pyrazole was consumed and the desired product MS was detected. The reaction was filtered and concentrated to give a residue. The residue was purified by silica column (PE/EA = 10/1, 1/1) to give S-((5-(((3-((tert-butyldiphenylsilyl)oxy)-5-methylphenyl) thio) methyl)-1-methyl-1H-pyrazol- 3-yl)methyl) ethanethioate (650 mg, 23.4 % yield) as light-yellow oil. LCMS obsd. (ESI+) [(M+H)+]: 561.5 [0143] Synthesis of ethyl 4-(3-((((5-(((3-((tert-butyl diphenylsilyl) oxy)-5-methylphenyl) thio) methyl)-1-methyl-1H-pyrazol-3-yl) methyl) thio) methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-5-chloro-1-(3- hydroxypropyl)-3-methyl-1H-indole-2-carboxylate. To a solution of compound S-((5-(((3-((tert- butyldiphenylsilyl)oxy)-5-methylphenyl) thio) methyl)-1-methyl-1H-pyrazol-3-yl) methyl) ethanethioate (561 mg, 1.07 mmol) and K2CO3 (1.48 g, 10.7 mmol), PPh3 (280 mg, 1.0698mmol), KI (178 mg, 1.07 mmol) in EtOH (10 mL) was added ethyl 1-(3-acetoxypropyl)-4-(3-(bromomethyl)-1,5-dimethyl-1H- pyrazol-4-yl)-5-chloro-3-methyl-1H-indole-2-carboxylate (600 mg, 1.07 mmol) in THF (10 mL) over 5 minutes, the mixture was stirred at 20 ^oC for 12 hours. LCMS showed compound starting material was consumed and the desired product MS was detected. The reaction solution was concentrated to give a residue. The residue was purified by silica column (PE/EA = 1/0, 2/1) to give compound ethyl 4-(3- ((((5-(((3-((tert-butyldiphenylsilyl)oxy)-5-methylphenyl)thio)methyl)-1-methyl-1H-pyrazol-3- yl)methyl)thio)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-5-chloro-1-(3-hydroxypropyl)-3-methyl-1H-indole- 2-carboxylate (800 mg, 81.2 % yield) as a light-yellow oil. LCMS obsd. (ESI+) [(M+H)+]: 920.4 [0144] Synthesis of ethyl 5-chloro-4-(3-((((5-(((3-hydroxy-5-methylphenyl) thio) methyl)-1- methyl-1H-pyrazol-3-yl) methyl) thio) methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-1-(3-hydroxypropyl)-3- methyl-1H-indole-2-carboxylate. To a solution of ethyl 4-(3-((((5-(((3-((tert-butyldiphenylsilyl)oxy)-5- methylphenyl)thio)methyl)-1-methyl-1H-pyrazol-3-yl)methyl)thio)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)- 5-chloro-1-(3-hydroxypropyl)-3-methyl-1H-indole-2-carboxylate (800 mg, 0.869 mmol) in THF (10 mL) was added TBAF (1 M, 0.869 mL, 0.869 mol) at 20 ^oC, and the mixture was stirred at 20 ^oC for 1 hour. LCMS showed ethyl 4-(3-((((5-(((3-((tert-butyldiphenylsilyl)oxy)-5-methylphenyl)thio)methyl)-1-methyl- 1H-pyrazol-3-yl)methyl)thio)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-5-chloro-1-(3-hydroxypropyl)-3- methyl-1H-indole-2-carboxylate was consumed and the desired product MS was detected. The reaction solution was poured into water (20 mL), extracted with EA (20 mL × 3). The organic layers were combined and washed by brine (30 mL), dried over Na2SO4, filtered and concentrated under vacuum to give a residue. The residue was purified by silica column (PE/EA = 10/1, 1/3) to give ethyl 5-chloro-4-(3-((((5-(((3-hydroxy-5-methylphenyl)thio)methyl)-1-methyl-1H-pyrazol-3- yl)methyl)thio)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-1-(3-hydroxypropyl)-3-methyl-1H-indole-2- carboxylate (440 mg, 74.2 % yield) as a light-yellow solid. LCMS obsd. (ESI+) [(M+H)+]: 682.3. [0145] Synthesis of ethyl (Z)-15-chloro-13,21,25,61,95-pentamethyl-11H,21H,61H-10-oxa-4,8- dithia-1(4,1)-indola-2(4,3),6(3,5)-dipyrazola-9(1,3)-benzenacyclotridecaphane-12-carboxylate. To a solution of ethyl (Z) 5-chloro-4-(3-((((5-(((3-hydroxy-5-methylphenyl)thio)methyl)-1-methyl-1H-pyrazol- 3-yl)methyl)thio)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-1-(3-hydroxypropyl)-3-methyl-1H-indole-2- carboxylate (150 mg, 0.220 mmol) and PPh₃ (173 mg, 0.660 mmol) in toluene (8 mL) and THF (8 mL) was added DBAD (152 mg, 0.660 mmol) at 20 ^oC, the mixture was stirred at 60 °C for 2 hours. LCMS showed starting material was consumed and the desired MS was detected. The reaction solution was concentrated to give a residue. The residue was purification by silica column (PE/EA = 1/1, 1/2) to give ethyl (Z)-15-chloro-13,21,25,61,95-pentamethyl-11H,21H,61H-10-oxa-4,8-dithia-1(4,1)-indola- 2(4,3),6(3,5)-dipyrazola-9(1,3)-benzenacyclotridecaphane-12-carboxylate (100 mg, 68.5% yield) as a light-yellow solid. LCMS obsd. (ESI+) [(M+H)+]: 664.4 [0146] Synthesis of (Z)-15-chloro-13,21,25,61,95-pentamethyl-11H,21H,61H-10-oxa-4,8-dithia- 1(4,1)-indola-2(4,3),6(3,5)-dipyrazola-9(1,3)-benzenacyclotridecaphane-12-carboxylic acid. To a solution of compound ethyl (Z)-15-chloro-13,21,25,61,95-pentamethyl-11H,21H,61H-10-oxa-4,8- dithia-1(4,1)-indola-2(4,3),6(3,5)-dipyrazola-9(1,3)-benzenacyclotridecaphane-12-carboxylate (100 mg, 0.151 mmol) in THF (2 mL) and water (2 mL) and MeOH (1 mL) was added NaOH (602 mg, 15.1mmol), the mixture was stirred at 50 ^oC for 5 hours. LCMS showed starting material was consumed and the desired product MS was detected. The reaction solution was diluted by water (10 mL), then extracted by EA (10 mL × 3). The organic layers were combined and concentrated under vacuum at 20 ^oC to give a residue. The residue was purified by Prep-HPLC (TFA) to give (Z)-15- chloro-13,21,25,61,95-pentamethyl-11H,21H,61H-10-oxa-4,8-dithia-1(4,1)-indola-2(4,3),6(3,5)- dipyrazola-9(1,3)-benzenacyclotridecaphane-12-carboxylic acid (15.3 mg, 15.8% yield) as a white solid. LCMS obsd. (ESI+) [(M+H)+]: 636.2. Example 2: Measuring inhibition of Mcl-1 and Bcl protein [0147] The ability of candidate compounds to inhibit Mcl-1 and Bcl activity can be measured on the molecular level by direct binding. This assay uses a homogenous assay technology based on oxygen channeling that is marketed by PerkinElmer Inc., Waltham, Massachusetts: see Eglin et al., Current Chemical Genomics, 2008, 1, 2-10. The test compound is combined with the target Mcl-1 or Bcl protein, and a peptide representing the corresponding cognate ligand, labeled with biotin. The mixture is then combined with streptavidin bearing luminescent donor beads and luminescent acceptor beads, which proportionally reduces luminescence if the compound has inhibited the peptide from binding to the Bcl protein. [0148] Mcl-1, Bcl-2, Bcl-xL and Bcl-w are available from Sigma-Aldrich Co., St. Louis, Missouri. Biotinylated BIM peptide (ligand for Bcl-2) and BAD peptide (ligand for Bcl-xL) are described in US 2016/0038503 A1. AlphaScreen® Streptavidin donor beads and Anti-6XHis AlphaLISA® acceptor beads are available from PerkinElmer. [0149] To conduct the assay, a 1:4 dilution series of the compound is prepared in DMSO, and then diluted 1:100 in assay buffer. In a 96-well PCR plate, the following are combined in order: 10 µL peptide (120 nM BIM or 60 nM BIM), 10 µL test compound, and 10 µL Bcl protein (0.8 nM Bcl-2/W or 0.4 nM Bcl-xL). The assay plate is incubated in the dark at room temperature for 24 h. The next day, donor beads and acceptor beads are combined, and 5 μL is added to each well. After incubating in the dark for 30 minute, luminescence is measured using a plate reader, and the affinity or degree of inhibition by each test compound is determined. [0150] FIG.5 shows the binding affinity (pKi) for Mcl-1 protein of representative macrocycle compounds designed to inhibit Mcl-1 activity. Example 3: Measuring senolytic activity in cultured cell lines [0151] Human fibroblast IMR90 cells can be obtained from the American Type Culture Collection (ATCC®) with the designation CCL-186. The cells are maintained at <75% confluency in DMEM containing FBS and Pen/Strep in an atmosphere of 3% O2, 10% CO2, and ~95% humidity. The cells are divided into groups: irradiated cells (cultured for 14 days after irradiation prior to use) and quiescent cells (cultured at high density for four day prior to use). [0152] On day 0, the irradiated cells are prepared as follows. IMR90 cells are washed, placed in T175 flasks at a density of 50,000 cells per mL, and irradiated at 10-15 Gy. Following irradiation, the cells are plated at 100 μL in 96-well plates. On days 1, 3, 6, 10, and 13, the medium in each well is aspirated and replaced with fresh medium. [0153] On day 10, the quiescent healthy cells are prepared as follows. IMR90 cells are washed, combined with 3 mL of TrypLE™ trypsin-containing reagent (Thermofisher Scientific, Waltham, Massachusetts) and cultured for 5 min until the cells have rounded up and begin to detach from the plate. Cells are dispersed, counted, and prepared in medium at a concentration of 50,000 cells per mL. 100 μL of the cells is plated in each well of a 96-well plate. Medium is changed on day 13. On day 14, test inhibitor compounds are combined with the cells as follows. A DMSO dilution series of each test compound is prepared at 200 times the final desired concentration in a 96-well PCR plate. Immediately before use, the DMSO stocks are diluted 1:200 into prewarmed complete medium. Medium is aspirated from the cells in each well, and 100 μL/well of the compound containing medium is added. [0154] Candidate senolytic agents for testing are cultured with the cells for 6 days, replacing the culture medium with fresh medium and the same compound concentration on day 17. Bcl 2 inhibitors are cultured with the cells for 3 days. The assay system uses the properties of a thermostable luciferase to enable reaction conditions that generate a stable luminescent signal while simultaneously inhibiting endogenous ATPase released during cell lysis. At the end of the culture period, 100 μL of CellTiter-Glo® reagent (Promega Corp., Madison, Wisconsin) is added to each of the wells. The cell plates are placed for 30 seconds on an orbital shaker, and luminescence is measured. [0155] Other cell lines and primary cell cultures may be used as an alternative to IMR90 fibroblasts are human umbilical vein (HUVEC) cells, human retinal microvascular endothelial cells (HRMEC), and other lines matched to the intended cell target for therapy. [0156] FIG.5 shows the senolytic activity (EC50) of representative macrocycle compounds designed to inhibit Mcl-1 activity. Example 4: Inducing senescence in primary cultures of lung epithelial cells [0157] The ability to induce senescence in human primary cells in culture was performed to set up for in vitro experiments testing candidate senolytic combinations for the treatment of lung disease. Primary human small airway epithelial cells (SAEC) and human bronchial epithelial cells (HBEC) were obtained from Lonza^®, ATCC^®, and Promocell^®. Cells were maintained and propagated at <75% confluency in Airway Epithelial Cell Growth Medium or Small Airway Epithelial Cell Growth Medium (Promocell^®; Heidelberg, Germany) at 20% O2, 5% CO2, and ~95% humidity. To make these primary cells senescent, x-ray irradiation was employed. [0158] On Day 0, SAEC or HBEC cells were covered with TrypLE trypsin-containing reagent (Thermofisher Scientific^®, Waltham, Massachusetts) and incubated for 8 min until the cells rounded up and began to detach from the plate. Cells were dispersed, counted, and prepared in medium at a concentration of 94,400 cells per mL. This cell suspension was plated in 384-well plates at a volume of 25 µL per well (2360 cells/well). Within 24-hours after cell plating, the 384-well plates were irradiated at 12 Gy to generate senescent cells (SnC). Control 384-well plates were processed in parallel that were not irradiated and served as controls and represent normal, non-senescent cells (NsC). [0159] On Day 3, the medium in each well was aspirated and replaced with 25 μL fresh medium. On Day 7, senescence of cells was determined through senescence β-galactosidase staining (Biovision^®, Cat. K320-250). To determine induction of the senescence biomarker p16 in irradiated cells, qPCR was performed using Cells-to-CT to measure relative gene expression by real-time RT- PCR and TaqMan detection chemistry (ThermoFisher Scientific^®, Cat. A35374) using primers specific for p16 or a housekeeping control gene Tbp (ThermoFisher Scientific^®, Cat.4331182). Example 5: Synergistic efficacy of senolytic combinations on senescent epithelial cells [0160] Combinations of Mcl-1 inhibitor and Bcl inhibitor compounds were tested for their senolytic potential by performing dose-response matrices on senescent cells. [0161] Primary human SAECs were made senescent as described in Example 4. Fresh media was added on Day 7 and candidate senolytic combinations were added in a dose-response matrix on a 384-well plate in a 11 x 7 well format. On the x-axis, Bcl inhibitors were tested at the following final concentrations: 0, 0.010, 0.022, 0.046, 0.1, 0.22, 0.46, 1.00, 2.15, 4.64, 10 μM (left to right), whereas on the y-axis an Mcl-1 inhibitor was added at 2.50, 1.16, 0.54, 0.25, 0.12, 0.05 μM (top to bottom). Candidate senolytics in dimethyl sulfoxide (DMSO) were added using a Tecan^® D300e Digital Dispenser (Tecan Life Sciences^®). Each plate also included a similar matrix in which the candidate senolytic was substituted with DMSO to serve as a viability normalization control. [0162] The candidate senolytics were cultured with the senescent SAECs for 3 days. On Day 10, the end of the assay period, the plates were removed from the incubator and allowed to equilibrate at room temperature for 15 minutes. Then, 25 μL of CellTiter-Glo^® reagent (Promega^® Corp., Madison, Wisconsin) was added to each of the wells. The assay system used the properties of a thermostable luciferase to enable reaction conditions that generate a stable luminescent signal while simultaneously inhibiting endogenous ATPase released during cell lysis. The cell plates were placed for 30 seconds on an orbital shaker and then allowed to stand at room temperature for 30 minutes before measuring luminescence. The luminescence readings were normalized to the DMSO controls to determine % cell survival/growth and plotted against candidate senolytic concentrations. [0163] Synergistic senolysis was calculated using the Zero Interaction Potency Delta (δ) methodology as described in Yadav et al., Comput Struct Biotechnol J. 2015; 13: 504–513, which is incorporated by reference. The “delta” (δ) factor indicates the degree of synergy achieved and was calculated using equation (19) as described in Yadav et al 2015 and herein. For example, a δ = 0.2 corresponds to 20% of response beyond expectation). Thus, the larger the δ value, the stronger the synergistic senolysis. The delta scoring requires the parameters for the dose–response curves both in monotherapy and in combination and at least three dose–response data points. A delta score can be calculated for each senolytic dose combination in the matrix, which allows for a surface plot of delta scores. Such a surface plot enables one to characterize drug interaction effects over the full dose matrix, which is more informative than what a single summary score can provide. [0164] FIGS.6A to 6D show EC₅₀ results obtained for various senolytic combinations. FIGS .7A to 7D show the corresponding synergistic coefficient “delta” (δ). The data demonstrate synergistic senolysis with the Bcl-2/Bcl-xL inhibitor navitoclax in combination with four different Mcl-1 inhibitors tested: AMG-176 (FIGS.6A and 7A), S-63845 (FIGS.6B and 7B), AZD-5991 (FIGS 6C and 7C), and A-1210477 (FIGS 7D and 8D). [0165] This assay can be used or adapted to screen combinations of an Mcl-1 inhibitor with a Bcl inhibitor to determine whether they work to remove senescent cells from any target tissue type, or remove cancer cell. Example 6: Efficacy of senolytic agents in an osteoarthritis model [0166] This example illustrates the testing of an MDM2 inhibitor in a mouse model for treatment of osteoarthritis. It can be adapted mutatis mutandis to test and develop Mcl-1 inhibitors and inhibitor combinations for use in clinical therapy of osteoarthritis. [0167] The model was implemented as follows. C57BL/6J mice underwent surgery to cut the anterior cruciate ligament of one rear limb to induce osteoarthritis in the joint of that limb. During week 3 and week 4 post-surgery, the mice were treated with 5.8 μg of Nutlin-3A (n=7) per operated knee by intra-articular injection, q.o.d. for 2 weeks. At the end of 4 weeks post-surgery, joints of the mice were monitored for presence of senescent cells, assessed for function, monitored for markers of inflammation, and underwent histological assessment. [0168] Two control groups of mice were included in the studies performed: one group comprising C57BL/6J or 3MR mice that had undergone a sham surgery (n = 3) (i.e., surgical procedures followed except for cutting the ACL) and intra-articular injections of vehicle parallel to the GCV (ganciclovir) treated group; and one group comprising C57BL/6J or 3MR mice that had undergone an ACL surgery and received intra-articular injections of vehicle (n=5) parallel to the GCV- treated group. RNA from the operated joints of mice from the Nutlin-3A treated mice was analyzed for expression of SASP factors (mmp3, IL-6) and senescence markers (p16). qRT-PCR was performed to detect mRNA levels. [0169] FIGS.8A, 8B, and 8C show expression of p16, IL-6, and MMP13 in the tissue, respectively. The OA inducing surgery was associated with increased expression of these markers. Treatment with Nutlin-3A reduced the expression back to below the level of the controls. Treatment with Nutlin-3A cleared senescent cells from the joint. [0170] Function of the limbs was assessed 4 weeks post-surgery by a weight bearing test to determine which leg the mice favored. The mice were allowed to acclimate to the chamber on at least three occasions prior to taking measurements. Mice were maneuvered inside the chamber to stand with one hind paw on each scale. The weight that was placed on each hind limb was measured over a three second period. At least three separate measurements were made for each animal at each time point. The results were expressed as the percentage of the weight placed on the operated limb versus the contralateral unoperated limb. [0171] FIG.9A shows the results of the functional study. Untreated mice that underwent osteoarthritis inducing surgery favored the unoperated hind limb over the operated hind limb (Δ). However, clearing senescent cells with Nutlin-3A abrogated this effect in mice that have undergone surgery

[0172] FIGS.9B, 9C, and 9D show histopathology of joint tissue from these experiments. Osteoarthritis induced by ACL surgery caused the proteoglycan layer was destroyed. Clearing of senescent cells using Nutlin-3A completely abrogated this effect. Example 7: Efficacy of senolytic agents in a pulmonary disease model [0173] This example illustrates the testing of inhibitors in a mouse model for treatment of lung disease: specifically, a model for idiopathic pulmonary fibrosis (IPF). It can be adapted mutatis mutandis to test and develop Mcl-1 inhibitors and inhibitor combinations for use in clinical therapy of pulmonary disease. [0174] The effect of a senolytic agent or combination in mice exposed to smoke is assessed by senescent cell clearance, lung function, and histopathology. The mice suitable for this study include the 3MR strain, described in US 2017/0027139 A1 and in Demaria et al., Dev Cell.2014 December 22; 31(6): 722–733. The 3MR mouse has a transgene encoding thymidine kinase that converts the prodrug ganciclovir (GCV) to a compound that is lethal to cells. The enzyme in the transgene is placed under control of the p16 promoter, which causes it to be specifically expressed in senescent cells. Treatment of the mice with GCV eliminates senescent cells. [0175] Other mice used in this study include the INK-ATTAC strain, described in US 2015/0296755 A1 and in Baker et al., Nature 2011 Nov 2;479(7372):232-236. The INK-ATTAC mouse has a transgene encoding switchable caspase 8 under control of the p16 promoter. The caspase 8 can be activated by treating the mice with the switch compound AP20187, whereupon the caspase 8 directly induces apoptosis in senescent cells, eliminating them from the mouse. [0176] To conduct the experiment, six-week-old 3MR (n=35) or INK-ATTAC (n=35) mice were chronically exposed to cigarette smoke generated from a Teague TE-10 system, an automatically- controlled cigarette smoking machine that produces a combination of side-stream and mainstream cigarette smoke in a chamber, which is transported to a collecting and mixing chamber where varying amounts of air is mixed with the smoke mixture. The COPD protocol was adapted from the COPD core facility at Johns Hopkins University (Rangasamy et al., 2004, J. Clin. Invest. 114:1248-1259; Yao et al., 2012, J. Clin. Invest. 122:2032-2045). [0177] Mice received a total of 6 hours of cigarette smoke exposure per day, 5 days a week for 6 months. Each lighted cigarette (3R4F research cigarettes containing 10.9 mg of total particulate matter (TPM), 9.4 mg of tar, and 0.726 mg of nicotine, and 11.9 mg carbon monoxide per cigarette [University of Kentucky, Lexington, KY]) was puffed for 2 seconds and once every minute for a total of 8 puffs, with the flow rate of 1.05 L/min, to provide a standard puff of 35 cm³. The smoke machine was adjusted to produce a mixture of side stream smoke (89%) and mainstream smoke (11%) by smoldering 2 cigarettes at one time. The smoke chamber atmosphere was monitored for total suspended particulates (80-120 mg/m³) and carbon monoxide (350 ppm). [0178] Beginning at day 7, (10) INK-ATTAC and (10) 3MR mice were treated with AP20187 (3x per week) or ganciclovir (5 consecutive days of treatment followed by 16 days off drug, repeated until the end of the experiment), respectively. An equal number of mice received the corresponding vehicle. The remaining 30 mice (15 INK-ATTAC and 153MR) were evenly split with 5 of each genetically modified strain placed into three different treatment groups. One group (n=10) received Nutlin-3A (25 mg/kg dissolved in 10% DMSO/3% Tween-20™ in PBS, treated 14 days consecutively followed by 14 days off drug, repeated until the end of the experiment). One group (n=10) received ABT-263 (Navitoclax) (100 mg/kg dissolved in 15% DMSO/5% Tween-20, treated 7 days consecutively followed by 14 days off drug, repeated until the end of the experiment), and the last group (n=10) received only the vehicle used for ABT-263 (15% DMSO/5% Tween-20), following the same treatment regimen as ABT-263. An additional 70 animals that did not receive exposure to cigarette smoke were used as controls for the experiment. [0179] After two months of cigarette smoke (CS) exposure, lung function was assessed by monitoring oxygen saturation using the MouseSTAT PhysioSuite™ pulse oximeter (Kent Scientific). Animals were anesthetized with isoflurane (1.5%) and the toe clip was applied. Mice were monitored for 30 seconds and the average peripheral capillary oxygen saturation (SpO₂) measurement over this duration was calculated. [0180] FIG.10 shows the results. Clearance of senescent cells via AP2018, ganciclovir, ABT- 263 (Navitoclax), or Nutlin-3A resulted in statistically significant increases in SpO2 levels in mice after two months of cigarette smoke exposure, compared with untreated controls. Example 8: Measuring cytotoxicity for cancer cells in vitro and in vivo [0181] The cellular activity of compounds can be evaluated in the interleukin-3 (IL-3)–dependent prolymphocytic FL5.12 murine cell line. Withdrawal of IL-3 induces FL5.12 apoptosis, by up- regulation of the proapoptotic factors Bim and Puma. Overexpression of Bcl-2 (FL5.12-Bcl-2) or Bcl-xL (FL5.12-Bcl-xL) protects against the effects of IL-3 withdrawal by sequestration of Bim and Puma. Compounds reverse the protection afforded by overexpression of Bcl-2 or Bcl-xL. Compounds are ineffective in eliciting cell death in the presence of IL-3 where FL5.12 cells are not subject to proapoptotic stimuli. The ability of compounds to kill FL5.12-Bcl-2 or FL5.12-Bcl-xL cells under IL-3 withdrawal can be attenuated in the presence of the caspase inhibitor ZVAD, indicating that cell killing is caspase dependent. [0182] Co-immunoprecipitation studies can be done to determine if BH3 mimetic induced cytotoxicity can be attributed to the disruption of intracellular Bcl-2 family protein-protein interactions. Compounds induce a dose-dependent decrease in Bim:Bcl-xL interactions in FL5.12-Bcl-xL cells. Similar results are also observed for the disruption of Bim:Bcl-2 complexes in FL5.12-Bcl-2 cells indicating that compounds restore IL-3–dependent cell death by attenuating the ability of Bcl-xL and Bcl-2 to sequester proapoptotic factors such as Bim. [0183] Testing of the ability of compounds and combinations listed in this disclosure to specifically kill cancer cells can be tested in similar assays using other established cell lines. These include HeLa cells, OVCAR-3, LNCaP, and any of the Authenticated Cancer Cell Lines available from Millipore Sigma, Burlington MA, U.S.A. Compounds specifically kill cancer cells if they are lethal to the cells at a concentration that is at least 5-fold lower, and preferably 25- or 100-fold lower than a non-cancerous cell of the same tissue type. The control cell has morphologic features and cell surface markers similar to the cancer cell line being tested, but without signs of cancer. [0184] In vivo, Mcl-1 inhibitors and Mcl-1/Bcl inhibitor combinations are evaluated in flank xenograft models established from sensitive SCLC (H889) and hematologic (RS4;11) cell lines, or using other tumor-forming cancer cell lines, according to what type of cancer is of particular interest to the user. When dosed orally or intravenously, compounds induce rapid and complete tumor responses (CR) that are durable for several weeks after the end of treatment in all animals bearing H889 (SCLC) or RS4;11 (ALL) tumors. Similar treatment of mice bearing H146 SCLC tumors can induce rapid regressions in the animals.

* * * * *

[0185] The several hypotheses presented in this disclosure provide a premise by way of which the reader may understand various aspects of the invention. This premise is provided for the intellectual enrichment of the reader. Practice of the invention does not require detailed understanding or application of the hypothesis. Except where stated otherwise, features of the hypothesis presented in this disclosure do not limit application or practice of the claimed invention.

[0186] For example, except where the elimination of senescent cells is explicitly required, the compounds may be used for treating the conditions described regardless of their effect on senescent cells. Although many of the senescence-related conditions referred to in this disclosure occur predominantly in older patients, the occurrence of senescent cells and the pathophysiology they mediate can result from other events, such as irradiation, other types of tissue damage, other types of disease, and genetic abnormalities. The invention may be practiced on patients of any age having the condition indicated, unless otherwise explicitly indicated or otherwise required.

[0187] Although the compounds and compositions referred to in this disclosure are illustrated in the context of eliminating senescent cells and cancer cells, and the treatment of senescence- associated conditions and cancer, the compounds and combinations described herein and derivatives thereof that are novel can be prepared and used for any purpose, including but not limited to laboratory use, the treatment of senescence-related conditions, creation of a library for screening of new pharmaceuticals, the decoration of pastry, and for diagnostic purposes.

[0188] While the invention has been described with reference to the specific examples and illustrations, changes can be made and equivalents can be substituted to adapt to a particular context or intended use as a matter of routine development and optimization and within the purview of one of ordinary skill in the art, thereby achieving benefits of the invention without departing from the scope of what is claimed and their equivalents.

Claims

CLAIMS The invention claimed is: 1. A compound of formula (I):

wherein: Z¹ is selected from -C(O)OR¹, -C(S)OR¹, -C(O)SR¹, -C(S)SR¹, -C(O)N(R²)SO2(R³), - OR¹, -SR¹, N(R²)₂, C(O)R¹, -OCOR¹, -C(O)N(R²)₂, -N(R²)C(O)R¹, -N(R²)C(O)N(R²)₂, - N(R²)SO₂R³, -SO₂R³ and -SO₂N(R²)₂; R¹ is selected from H, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, substituted heteroaryl, and -(CH₂)_nOP(O)(OR²)₂; R² is selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl; R³ is selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl; X¹ is selected from alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkylalkoxy, substituted alkylalkoxy, halogen, nitrile, cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, -(CR⁴)mOR^4a, -(CR⁴)mcycloalkyl-OR^4a, -(CR⁴)mheterocycloalkyl-OR^4a, -(CR⁴)maryl-OR^4a, and -(CR⁴)mheteroaryl-OR^4a; Y¹ is selected from halogen, nitrile, alkyl, and substituted alkyl; Y²-Y³ are each independently selected from H, alkyl, substituted alkyl, halogen, and nitrile; X²-X⁴ are each independently selected from O, S, NR⁴, SO2, and CH2; R⁴ is selected from H, alkyl, and substituted alkyl; R^4a is selected from H, alkyl, substituted alkyl, -P(O)(OR⁴)₂, -SO₂R³ and -SO₂N(R²)₂; Z²-Z⁷ are each independently selected from N and CR⁴; R⁵ is selected from alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkylalkoxy, substituted alkylalkoxy, cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, -(CR⁴)_mOR^4a, -(CR⁴)_mcycloalkyl-OR^4a, -(CR⁴)_mcycloalkyl, -(CR⁴)_mheterocycloalkyl, - (CR⁴)_mheterocycloalkyl-OR^4a, -(CR⁴)_maryl-OR^4a, -(CR⁴)_maryl, -(CR⁴)_mheteroaryl-OR^4a, - (CR⁴)mheteroaryl, and -(CR⁴)mN(R⁴)2; R⁶-R⁷ are each independently selected from H, alkyl and substituted alkyl; R⁸-R¹⁰ are each independently selected from H, alkyl, substituted alkyl, halogen, nitrile, and trifluoromethyl; or R⁸ and R⁹ or R⁹ and R¹⁰ together with the atoms to which they are attached form a 5 or 6 membered ring; n is an integer from 1 to 6; and m is an integer from 0 to 6. 2. The compound of claim 1, wherein the compound is of the formula (IIa):

wherein: Z¹ is selected from -C(O)OR¹, -C(O)N(R²)SO2(R³), -OR¹, -C(O)R¹, -C(O)N(R²)2; R¹ is selected from H, C_(1-6) alkyl, substituted C_(1-6) alkyl, aryl, substituted aryl, and - (CH₂)_nOP(O)(OR²)₂; R² is selected from H, C(1-6)alkyl, substituted C(1-6)alkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl; R³ is selected from C_(1-6)alkyl, substituted C_(1-6)alkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl; X¹ is selected from C_(1-6)alkyl, substituted C_(1-6)alkyl, halogen, nitrile, -(CR⁴)_mOR^4a, - (CR⁴)mcycloalkyl-(OR^4a)p, -(CR⁴)mheterocycloalkyl-(OR^4a)p, -(CR⁴)maryl-(OR^4a)p, and - (CR⁴)_mheteroaryl-(OR^4a)_p; Y¹ is selected from halogen, nitrile, C_(1-6)alkyl, and substituted C_(1-6)alkyl; Y²-Y³ are each independently selected from H, C_(1-6)alkyl, C_(1-6)substituted alkyl, halogen, and nitrile; X² and X⁴ are each independently selected from O, S, NR⁴, SO2, and CH2; R⁴ is selected from H, C_(1-6)alkyl, and substituted C_(1-6)alkyl; R^4a is selected from H, C(1-6)alkyl, substituted C(1-6)alkyl, -P(O)(OR⁴)2, -SO2R³ and - SO2N(R²)2; R⁵ is selected from C_(1-6)alkyl, substituted C_(1-6)alkyl, -(CR⁴)_mOR^4a, -(CR⁴)_mcycloalkyl- OR^4a, -(CR⁴)_mcycloalkyl, -(CR⁴)_mheterocycloalkyl, -(CR⁴)_mheterocycloalkyl-OR^4a, -(CR⁴)_maryl- OR^4a, -(CR⁴)maryl, -(CR⁴)mheteroaryl-OR^4a, -(CR⁴)mheteroaryl, and -(CR⁴)mN(R⁴)2; R⁶-R⁷ and R¹¹ are each independently selected from H, and C(1-6)alkyl; R⁸-R¹⁰ are each independently selected from H, C(1-6)alkyl, substituted C(1-6)alkyl, halogen, nitrile, and trifluoromethyl; or R⁸ and R⁹ or R⁹ and R¹⁰ together with the atoms to which they are attached form a 5 or 6 membered carbocyclic, heterocyclic, aryl or heteroaryl ring, optionally substituted with one or more R¹⁶ groups; R¹⁶ is selected from one or more optional substituents, each independently selected from alkyl, substituted alkyl, alkoxy, substituted alkoxy, halogen, nitrile, nitro, carboxy, C(O)NH2, SO2NH2, sulfonate, hydroxyl, alkylsulfonyl, substituted alkylsulfonyl, alkylaminosulfonyl, substituted alkylaminosulfonyl, alkylsulfonylamino, substituted alkylsulfonylamino, alkyloxycarbonyl, substituted alkyloxycarbonyl and –N(R₂)₂; n is an integer from 1 to 6; m is an integer from 0 to 6, and p is 0 or 1. 3. The compound of claim 2, wherein the compound is of the formula (IIIa):

wherein: Z¹ is selected from -C(O)OR¹, -C(O)N(R²)SO₂(R³), -OR¹, -C(O)R¹, -C(O)N(R²)₂; R¹ is selected from H, C(1-6)alkyl, substituted C(1-6)alkyl, aryl, substituted aryl, and - (CH₂)_nOP(O)(OR²)₂; R² is selected from H, C_(1-6)alkyl, and substituted C_(1-6)alkyl; R³ is selected from C_(1-6)alkyl, substituted C_(1-6)alkyl, aryl, and substituted aryl; X¹ is selected from C(1-6)alkyl, substituted C(1-6)alkyl, halogen, nitrile, -(CR⁴)mOR^4a, - (CR⁴)mcycloalkyl-(OR^4a)p, -(CR⁴)mheterocycloalkyl-(OR^4a)p, -(CR⁴)maryl-(OR^4a)p, and - (CR⁴)_mheteroaryl-(OR^4a)_p; Y¹ is selected from halogen, nitrile, C_(1-6)alkyl, and substituted C_(1-6)alkyl; X² is selected from O, S, NR⁴, and SO2; X³ is selected from S and CH2; R⁴ is selected from H, C_(1-6)alkyl, and substituted C_(1-6)alkyl; R^4a is selected from H, C_(1-6)alkyl, substituted C_(1-6)alkyl, -P(O)(OR⁴)₂, -SO₂R³ and - SO2N(R²)2; R⁵ is selected from C(1-6)alkyl, substituted C(1-6)alkyl, -(CR⁴)mOR^4a, -(CR⁴)mcycloalkyl- OR^4a, -(CR⁴)mcycloalkyl, -(CR⁴)mheterocycloalkyl, -(CR⁴)mheterocycloalkyl-OR^4a, -(CR⁴)maryl- OR^4a, -(CR⁴)_maryl, -(CR⁴)_mheteroaryl-OR^4a, -(CR⁴)_mheteroaryl, and -(CR⁴)_mN(R⁴)₂; R⁸-R¹⁰ are each independently selected from H, C_(1-6)alkyl, substituted C_(1-6)alkyl, halogen, nitrile, and trifluoromethyl; or R⁸ and R⁹ or R⁹ and R¹⁰ together with the atoms to which they are attached form a 5 or 6 form a 5 or 6 membered carbocyclic, heterocyclic, aryl or heteroaryl ring, optionally substituted with one or more R¹⁶ groups; each R¹⁶ is independently selected from alkyl, substituted alkyl, alkoxy, substituted alkoxy, halogen, nitrile, nitro, carboxy, C(O)NH2, SO2NH2, sulfonate, hydroxyl, alkylsulfonyl, substituted alkylsulfonyl, alkylaminosulfonyl, substituted alkylaminosulfonyl, alkylsulfonylamino, substituted alkylsulfonylamino, alkyloxycarbonyl, substituted alkyloxycarbonyl and –N(R2)2; n is an integer from 1 to 6; m is an integer from 0 to 6, and p is 0 or 1. 5. The compound of claim 4, wherein the compound is of the formula (IVa):

wherein: Z² is selected from -OR¹, and -NHSO₂R³; R¹ is selected from H, and -(CH2)nOP(O)(OR²)2; R² is selected from H, and C(1-6)alkyl; R³ is selected from C_(1-6)alkyl, substituted C_(1-6)alkyl, aryl, and substituted aryl; Y¹ is selected from chloro, fluoro, nitrile, and C_1-6 alkyl; X² is selected from O, S, NR^4b, and SO2; X³ is selected from S and CH2; R⁹-R¹⁰ are each independently selected from H, C(1-6)alkyl, substituted C(1-6)alkyl, halogen, nitrile, and trifluoromethyl; or R⁹ and R¹⁰ together with the atoms to which they are attached form a 5 or 6 membered aryl, heteroaryl or heterocyclic ring optionally substituted with one or more R^16a groups; each R^16a is independently selected from C(1-6)alkyl, substituted C(1-6)alkyl, C(1-6)alkoxy, substituted C(1-6)alkoxy, halogen, nitrile, and hydroxyl; X¹ is selected from C_(1-6)alkyl, halogen, nitrile,

, , ,

R^4a is selected from H, and -P(O)(OR⁴)2; R⁴ is selected from H, and C(1-6)alkyl; R^4b is selected from H, and C_1-6 alkyl; and q is an integer from 1 to 6. 6. The compound of claim 5, wherein the compound is of the formula (Va):

wherein: Y¹ is selected from halogen, nitrile, and C_(1-6)alkyl; X² is selected from O, S, NR^4b, and SO₂; X³ is selected from S and CH₂; R⁹-R¹⁰ are each independently selected from H, C(1-6)alkyl, substituted C(1-6)alkyl, halogen, nitrile, and trifluoromethyl; or R⁹ and R¹⁰ together with the atoms to which they are attached form a 5 or 6 membered aryl ring optionally substituted with one or more R^16a groups; each R¹⁶ is independently selected from C_(1-6)alkyl, substituted C_(1-6)alkyl, C_(1-6)alkoxy, substituted C_(1-6)alkoxy, halogen, nitrile, and hydroxyl; X¹ is selected from C_(1-6)alkyl, halogen, nitrile,

, ,

R⁴ is selected from H, and C(1-6)alkyl; R^4a is selected from H, and -P(O)(OR⁴)₂; R⁴ and R^4b are each independently selected from H, and C_(1-6) alkyl; and q is an integer from 1 to 6. 7. The compound of claim 2, wherein the compound is of formula (IIb):

wherein: Z¹ is selected from -C(O)OR¹, -C(O)N(R²)SO₂(R³), -OR¹, -C(O)R¹, -C(O)N(R²)₂; R¹ is selected from H, C_(1-6) alkyl, substituted C_(1-6)alkyl, aryl, substituted aryl, and - (CH2)nOP(O)(OR²)2; R² is selected from H, C(1-6)alkyl, substituted C(1-6)alkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl; R³ is selected from C_(1-6)alkyl, substituted C_(1-6)alkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl; X¹ is selected from C(1-6)alkyl, substituted C(1-6)alkyl, halogen, nitrile, -(CR⁴)mOR^4a, - (CR⁴)mcycloalkyl-(OR^4a)p, -(CR⁴)mheterocycloalkyl-(OR^4a)p, -(CR⁴)maryl-(OR^4a)p, and - (CR⁴)_mheteroaryl-(OR^4a)_p; Y¹ is selected from halogen, nitrile, C_(1-6)alkyl, and substituted C_(1-6)alkyl; Y²-Y³ are each independently selected from H, C(1-6)alkyl, substituted C(1-6)alkyl, halogen, and nitrile; X²-X⁴ are each independently selected from O, S, NR⁴, SO2, and CH2; R⁴ is selected from H, C_(1-6)alkyl, and C_(1-6)substituted alkyl; R^4a is selected from H, C(1-6)alkyl, substituted C(1-6)alkyl, -P(O)(OR⁴)2, -SO2R³ and - SO2N(R²)2; R⁵ is selected from alkyl, substituted alkyl, -(CR⁴)_mOR^4a, -(CR⁴)_mcycloalkyl-OR^4a, - (CR⁴)_mcycloalkyl, -(CR⁴)_mheterocycloalkyl, -(CR⁴)_mheterocycloalkyl-OR^4a, -(CR⁴)_maryl-OR^4a, - (CR⁴)maryl, -(CR⁴)mheteroaryl-OR^4a, -(CR⁴)mheteroaryl, and -(CR⁴)mN(R⁴)2; R⁶-R⁷ and R¹¹ are each independently selected from H, and C1-6 alkyl; R⁸ and R¹²-R¹⁵ are each independently selected from H, C_(1-6)alkyl, substituted C_(1-6)alkyl, halogen, nitrile, and trifluoromethyl; n is an integer from 1 to 6; m is an integer from 0 to 6; and p is 0 or 1. 8. The compound of claim 7, wherein the compound is of formula (IIIb):

wherein: Z¹ is selected from -C(O)OR¹, -C(O)N(R²)SO2(R³), -OR¹, -C(O)R¹, -C(O)N(R²)2; R¹ is selected from H, C_(1-6)alkyl, substituted C_(1-6)alkyl, aryl, substituted aryl, and - (CH₂)_nOP(O)(OR²)₂; R² is selected from H, C_(1-6)alkyl, and substituted C_(1-6)alkyl; R³ is selected from C(1-6)alkyl, substituted C(1-6)alkyl, aryl, and substituted aryl; X¹ is selected from C(1-6)alkyl, substituted C(1-6)alkyl, halogen, nitrile, -(CR⁴)mOR^4a, - (CR⁴)_mcycloalkyl-(OR^4a)_p, -(CR⁴)_mheterocycloalkyl-(OR^4a)_p, -(CR⁴)_maryl-(OR^4a)_p, and - (CR⁴)_mheteroaryl-(OR^4a)_p; Y¹ is selected from halogen, nitrile, C(1-6)alkyl, and substituted C(1-6)alkyl; X² is selected from O, S, NR⁴, and SO2; X³ is selected from S and CH₂; R⁴ is selected from H, C_(1-6)alkyl, and substituted C_(1-6)alkyl; R^4a is selected from H, C(1-6)alkyl, substituted C(1-6)alkyl, -P(O)(OR⁴)2, -SO2R³ and - SO2N(R²)2; R⁵ is selected from C(1-6)alkyl, substituted C(1-6)alkyl, -(CR⁴)mOR^4a, -(CR⁴)mcycloalkyl- OR^4a, -(CR⁴)_mcycloalkyl, -(CR⁴)_mheterocycloalkyl, -(CR⁴)_mheterocycloalkyl-OR^4a, -(CR⁴)_maryl- OR^4a, -(CR⁴)_maryl, -(CR⁴)_mheteroaryl-OR^4a, -(CR⁴)_mheteroaryl, and -(CR⁴)_mN(R⁴)₂; n is an integer from 1 to 6; m is an integer from 0 to 6; and p is 0 or 1. 9. The compound of claim 8, wherein the compound is of the formula (IVb):

wherein: Z² is selected from -OR¹, and -NHSO2R³; R¹ is selected from H, and -(CH₂)_nOP(O)(OR²)₂; R² is selected from H, and C_(1-6)alkyl; R³ is selected from C_(1-6)alkyl, substituted C_(1-6)alkyl, aryl, and substituted aryl; Y¹ is selected from halogen, nitrile, and C(1-6)alkyl; X² is selected from O, S, NR^4b, and SO₂; X³ is selected from S and CH₂; X¹ is selected from C_(1-6)alkyl, halogen, nitrile,

, , ,

R^4a is selected from H, and -P(O)(OR⁴)₂; R⁴ is selected from H, and C_(1-6)alkyl; R^4b is selected from H, and C(1-6) alkyl; and q is an integer from 1 to 6. 10. The compound of claim 9, wherein Z² is OH. 11. The compound of any one of claims 1 to 10, wherein Y¹ is selected from chloro, fluoro, methyl, and nitrile. 12. The compound of any one of claims 1 to 11, wherein X¹ is selected from methyl, chloro,

R^4a is selected from H, and -P(O)(OH)2; and q is an integer from 1 to 6. 13. The compound of any one of claims 1 to 12, wherein R⁵ is selected from methyl,

R^4a is selected from H, and -P(O)(OH)₂; R^4b is methyl; and q is an integer from 1 to 6.

14. The compound of claim 10, selected from the following table:

wherein

. 15. The compound of any preceding claim, wherein X² is S. 16. The compound of any preceding claim, wherein X³ is S. 17. The compound of any preceding claim, wherein Y¹ is Cl. 18. A compound selected from the following:

(3aR)-15-chloro-13-(2-(4-hydroxypiperidin-1-yl)ethyl)-21,25,61-trimethyl-11H,21H,61H-10-oxa-4,8- dithia-1(4,1)-indola-2(4,3),6(3,5)-dipyrazola-9(3,1)-naphthalenacyclotridecaphane-12-carboxylic acid. 19. The compound of any preceding claim, which has an IC50 for Mcl-1 of less than 100 nM. 20. The compound of any preceding claim, which in combination with a Bcl inhibitor has an LD₅₀ for senescent primary pulmonary epithelial cells in culture that is less than 1 µM. 21. A method of enhancing the ability of a Bcl-2, Bcl-xL, or Bcl-w inhibitor to selectively remove senescent cells from a mixed cell population or tissue, comprising combining the inhibitor with a compound according to any of claims 1 to 20. 22. A method of enhancing the therapeutic efficacy of a Bcl-2, Bcl-xL, or Bcl-w inhibitor in a pharmaceutical composition formulated for treatment of a disease caused or mediated by senescent cells, comprising including in the pharmaceutical composition a compound according to any of claims 1 to 20. 23. A pharmaceutical composition comprising a compound according to any of claims 1 to 20 in a pharmaceutically compatible excipient. 24. The composition of claim 23, which further comprises a Bcl-2, Bcl-xL, or Bcl-w inhibitor or a means for inhibiting Bcl-2, Bcl-xL, or Bcl-w. 25. A combination of an Mcl-1 inhibitor and a Bcl inhibitor for simultaneous or sequential administration in therapy. 26. A method of selectively removing senescent cells and/or cancer cells from a mixed cell population or tissue, comprising contacting a cell, a cell population or a tissue with a compound according to any of claims 1 to 20, a composition according to claim 23 or 24, or a combination according to claim 25.

27. A method of treating a senescence related condition in a tissue in a subject (wherein the senescence related condition is characterized as being caused or mediated at least in part by senescent cells, or is characterized as having an overabundance of senescent cells in or around the tissue, in comparison with unaffected tissue), the method comprising: administering to a tissue of a subject in need thereof, an amount of a compound according to any of claims 1 to 20, a composition according to claim 23 or 24, or a combination according to claim 25 that is effective to selectively remove senescent cells from the tissue, thereby relieving or ameliorating one or more signs or symptoms of a senescence related condition in the subject.

28. A unit dose of a pharmaceutical composition comprising: an amount of a compound that inhibits Mcl-1 function according to any of claims 1 to 20 for use as a monotherapy in the treatment of a senescence associated condition that is caused or mediated at least in part by senescent cells, wherein the composition contains a formulation of the compound configured for administration to a target tissue in a subject that manifests the senescence associated condition, wherein the formulation and the amount of the compound in the unit dose configure the unit dose to be effective in selectively removing senescent cells in or around the tissue in the subject, thereby decreasing the severity of one or more signs or symptoms of the condition without causing adverse effects in the subject when administered to the tissue as a single dose.

29. A unit dose of a pharmaceutical composition comprising: an amount of a compound that inhibits Mcl-1 function according to any of claims 1 to 20 in combination with a compound that inhibits a Bel protein for use in the treatment of a senescence associated condition that is caused or mediated at least in part by senescent cells, wherein the composition contains a formulation of the compound configured for administration to a target tissue in a subject that manifests the senescence associated condition, wherein the formulation and the amount of the compound in the unit dose configure the unit dose to be effective in selectively removing senescent cells in or around the tissue in the subject, thereby decreasing the severity of one or more signs or symptoms of the condition without causing adverse effects in the subject when administered to the tissue as a single dose.

30. The unit dose of claim 28 or claim 29, packaged with or accompanied by informatoin describing the use and attendant benefits of the drugs in treating the senescent cell associated condition.

31. Use of a compound according to any of claims 1 to 20, a composition according to claim 23 or 24, or a combination according to claim 25 in the manufacture of a medicament for treating a senescence-related condition.

32. A method of treating cancer, comprising administering to a tissue of a subject in need thereof an amount of a compound according to any of claims 1 to 20, a composition according to claim 23 or 24, or a combination according to claim 25 that is effective to selectively remove cancer cells from the tissue.

33. A compound according to any of claims 1 to 20, a composition according to claim 23 or 24, or a combination according to claim 25 for use in selectively eliminating cancer cells from a tissue or mixed cell population or for use in treating cancer.

34. Use of a compound according to any of claims 1 to 20, a composition according to claim 23 or 24, or a combination according to claim 25 in the manufacture of a medicament for treating a cancer.

Other technical aspects of the invention put forth in the specification can optionally be incorporated into the claims to provide additional distinguishing characteristics.