Tetrahydroisoquinoline heterobifunctional BCL-XL degraders

Abstract

This disclosure provides compounds of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, that induce degradation of a BCL-XL protein. These compounds are useful, for example, for treating a cancer in a subject (e.g., a human). This disclosure also provides compositions comprising the compounds of Formula (I), (II), (III), (IV), (V), or (VI), or pharmaceutically acceptable salts thereof, provided herein as well as methods of using and making the same.

Description

[0001] Tetrahydroisoquinoline Heterobifunctional BCL-XL Degraders

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U. S. Provisional Application Serial No. 63 / 717,469, filed November 7, 2024, which is incorporated by reference in its entirety herein.

[0003] TECHNICAL FIELD

[0004] This disclosure provides compounds of Formula (I), (II), (III), (IV), (V), or (VI), or pharmaceutically acceptable salts thereof, that induce degradation of a BCL-XL protein. These compounds are useful, for example, for treating cancer in a subject (e.g., a human). This disclosure also provides compositions comprising the compounds of Formula (I), (II), (III), (IV), (V), or (VI), or pharmaceutically acceptable salts thereof, as well as methods of using and making the same.

[0005] BACKGROUND

[0006] The BCL-2 family of proteins is involved in the regulation of cell apoptosis and includes proteins that are pro-apoptosis, pro-survival, and BH3-only. At a high level, the balance of binding of BH3-only proteins to the pro-apoptosis and pro-survival members of the BCL-2 family can determine whether a cell will undergo apoptosis. The protein BCL-XL, encoded by the BCL2L1 gene, is a pro-survival member of the BCL-2 family. In many cancers, it can be desirable to initiate apoptosis of tumor cells, which may be achieved by decreasing the amount of pro-survival protein (e.g., BCL-XL) available to compete for BH3-only protein binding.

[0007] SUMMARY

[0008] This disclosure provides compounds of Formula (I), (II), (III), (IV), (V), or (VI), or pharmaceutically acceptable salts thereof, that induce degradation of a BCL-XL protein. These compounds are useful, for example, for treating a cancer in a subject (e.g., a human). This disclosure also provides compositions comprising the compounds of Formula (I), (II), (III), (IV), (V), or (VI), or pharmaceutically acceptable salts thereof, as well as methods of using and making the same. Provided herein are compounds of Formula (I) or (II):

[0009]

[0010] Formula (II)

[0011] or pharmaceutically acceptable salts thereof, wherein:

[0012] Z1, R1, Ring A, LA, Ring B, LB, bl, Ring C, Lc, cl, and Ring D are each as defined herein.

[0013] Also provided herein are compounds of Formula (III) or (IV):

[0014]

[0015] Formula (III)

[0016]

[0017] Formula (IV)

[0018] or pharmaceutically acceptable salts thereof, wherein:

[0019] Z1, R1, LA, al, LA2, Ring A, LA3, a3, Ring B, LB, bl, Ring C, Lc, cl, and Ring D are each as defined herein.

[0020] Also provided herein are compounds of Formula (V):

[0021]

[0022] Formula (V)

[0023] or pharmaceutically acceptable salts thereof, wherein:

[0024] Z1, R1, Ring A, LA, al, Ring B, LB, bl, LD, and Ring D are each as defined herein.

[0025] Also provided herein are compounds of Formula (VI):

[0026]

[0027] Formula (VI)

[0028] or pharmaceutically acceptable salts thereof, wherein:

[0029] Z1, R1, Ring A, LA, Ring B, LB, bl, Ring E, LE, el, Ring C, Lc, cl, and Ring D are each as defined herein.

[0030] Also provided herein are pharmaceutical compositions comprising a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0031] Provided herein are methods for treating cancer in a subj ect in need thereof, the methods comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0032] Also provided herein is a BCL-XL protein non-covalently bound with a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof.

[0033] Also provided herein is a ternary complex comprising a BCL-XL protein, a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, and a CRBN protein, or a portion thereof.

[0034] To facilitate understanding of the disclosure set forth herein, a number of additional terms are provided. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Each of the patents, applications, published applications, and other publications that are mentioned throughout the specification and the attached appendices are incorporated herein by reference in their entireties. In the case of conflict between the present disclosure and any content incorporated by reference, the present disclosure controls.

[0035] The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features and advantages of the invention will be apparent from the description and drawings, and from the claims.

[0036] DETAILED DESCRIPTION

[0037] This disclosure provides compounds of Formula (I), (II), (III), (IV), (V), or (VI), or pharmaceutically acceptable salts thereof, that induce degradation of a BCL-XL (also referred to as Bcl-xL herein) protein. These compounds are useful, for example, for treating a cancer. This disclosure also provides compositions comprising the compounds of Formula (I), (II), (III), (IV), (V), or (VI), or pharmaceutically acceptable salts thereof, herein as well as methods of using and making the same.

[0038] Without being bound by any particular theory, it is believed that in healthy cells, pro-apoptotic effectors such as BAX and BAK can move between the cytosol and the mitochondrial outer membrane (MOM), on which Voltage Dependent Anion Channel 2 (VDAC2) can act as a receptor. Pro-survival BCL-2 family members (e.g., BCL-2, BCL-XL, and MCL-1) can retrotranslocate BAX back to the cytosol. A BH3-only protein (e.g., BIM) can engage a rear site on a pro-apoptotic effector (e.g., BAX or BAK) and release the C-terminal transmembrane domain (a9) of the effector, enabling binding to the MOM. Binding of BIM to the canonical BH3 binding groove of BAX or BAK releases the N-terminus and al of BAX or BAK, and subsequent unfolding of the “latch” domain releases BIM from the BH3 binding groove. If a pro-survival BCL-2 family member then binds to BAX or BAK, apoptotic signaling is generally halted. However, if BAX or BAK are allowed to dimerize, then oligomerize, the MOM can be permeabilized, leading to apoptosis.

[0039] An abundance of pro-survival BCL-2 family members is sometimes thought to “prime” cells for death (e.g., via cytotoxic therapies, including BH3 mimetics). It is believed that oncogenic mutations and stresses can cause an upregulation in BH3-only proteins, thus placing a selective pressure on cancer cells for upregulation of the pro-survival BCL-2 family proteins. Thus, with more BH3-only proteins around, the cells are believed to be more sensitive to further manipulations of the BCL-2 family balance. See, e.g., Adams and Cory, Cell Death & Differentiation 25.1 (2018): 27-36, doi: 10.1038 / cdd.2017.161. Compounds that induce degradation of a target protein are sometimes referred to as heterobifunctional compounds, PROTACs, or degraders. Such compounds generally include a moiety that binds to the target protein and a moiety that binds to a ubiquitin E3 ligase (sometimes referred to as an E3 ligase or simply an E3), these two moieties being optionally separated by a linker. To induce degradation, heterobifunctional compounds are believed to induce formation of a ternary complex between the target protein, the compound, and an E3 ligase. Formation of the ternary complex is then followed by ubiquitination of the target protein and degradation of the ubiquitinated target protein by a proteosome. Several E3 ligases have been used as the partner E3 ligase for heterobifunctional degraders. Herein, the cereblon (CRBN) E3 ligase (also referred to herein as a CRBN protein) is used.

[0040] A degradation approach for a target protein can have potential advantages compared to, for example, small molecule inhibition of the target protein. One potential advantage is that the duration of effect of a heterobifunctional compound is generally based on the resynthesis rate of the target protein. Another potential advantage is that many heterobifunctional compounds are believed to be released from the ubiquitinated target protein-E3 ligase complex and made available for formation of further ternary complexes; this is sometimes referred to as “catalytic” turnover of the heterobifunctional compound. Degradation of a target protein can also be advantageous over small molecule inhibition in some cases, as degradation can impair a scaffolding function of a target protein, whereas a small molecule might not. It is also generally believed that for formation of a ternary complex, high affinity to the target protein is not always required.

[0041] Heterobifunctional compounds are further described in, for example, International Publication Nos. WO 2017 / 184995; WO 2019 / 144117; WO 2020 / 163823; WO 2021 / 078301; WO 2021 / 146536; WO 2021 / 007307; WO 2021 / 222114; WO 2022 / 169780; WO 2022 / 103881; WO 2022 / 266491; WO 2023 / 030453; WO 2023 / 044046; WO 2023 / 107606; WO 2023 / 131118; WO 2023 / 185986; WO 2023 / 215449; WO 2023 / 215471; WO 2023 / 215482; WO 2023 / 220425; WO 2024 / 027706; WO 2024 / 179577; WO 2024 / 169976; WO 2024 / 078581; WO 2024 / 077023; WO 2024 / 067818; WO 2024 / 051741; WO 2024 / 012449; WO 2024 / 012557; WO 2024 / 245312; WO 2025 / 036119; WO 2025 / 101571; WO 2025 / 101575; WO 2025 / 101588; WO 2025 / 129024; CN 115141198; CN 117886881; CN 118724894; CN 119301122; Chamberlain and Hamann, Nature Chemical Biology 15.10 (2019): 937-944, doi: 10.1038 / s41589-019-0362-y; Li and Song, Journal of Hematology & Oncology 13 (2020): 1-14, doi: 10.1186 / sl3045-020-00885-3; Wu, et al. Nature Structural & Molecular Biology 27.7 (2020): 605-614, doi: 10.1038 / s41594-020-0438-0; Dong, et al., Journal of Medicinal Chemistry 64.15 (2021): 10606-10620, doi: 10.1021 / acs.jmedchem.lc00895; Yang, et al., Targeted Oncology 16.1 (2021): 1-12, doi: 10.1007 / sl 1523-020-00782-2; Lv, et al., Nature Communications 12.1 (2021): 6896, doi: 10.1038 / s41467-021-27210-x; Zhang et al., RSCMed. Chem., 2025,16, 3495-3506, doi: 10.1039 / D5MD00119F; Zhang et al., European Journal of Medicinal Chemistry 291 (2025): 117624, doi: 10.1016 / j.ejmech.2025.117624; Pal et al., Journal of medicinal chemistry 64.19 (2021): 14230-14246, doi: 10.1021 / acs.jmedchem.lc00517; Poddar et al., Journal of Medicinal Chemistry (2025): 18684, doi: 10.1021 / acs.jmedchem.5c01834; Khan et al., Nature medicine 25.12 (2019): 1938-1947, doi: 10.1038 / s41591-019-0668-z; Zhang et al., European journal of medicinal chemistry 199 (2020): 112397, doi: 10.1016 / j.ejmech.2020.112397; He et al., Nature communications 11.1 (2020): 1996, doi: 10.1038 / s41467-020-15838-0; Zhang et al., Theranostics 12.17 (2022): 7476, doi: doi: 10.7150 / thno.75421; Nayak, et al., Nature communications 15.1 (2024): 2743, doi: 10.1038 / s41467-024-46922-4; Zhang et al., European Journal of Medicinal Chemistry 291 (2025): 117624, doi: 10.1016 / j.ejmech.2025.117624; Zhang et al., Chemical Communications 55.98 (2019): 14765-14768, doi: 10.1039 / C9CC07217A; Zhang et al., European journal of medicinal chemistry 192 (2020): 112186, doi: 10.1016 / j.ejmech.2020.112186.

[0042] Compound Embodiments

[0043] Provided herein are compounds of Formula (I) or (II):

[0044]

[0045] Formula (I)

[0046]

[0047] Formula (II)

[0048] or pharmaceutically acceptable salts thereof, wherein:

[0049] Z1is CH or N;

[0050] R1is selected from the group consisting of:

[0051] (a) -C(O)OH;

[0052] (b) -C(O)OCi-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-3 Rc; and (c) -C(O)-(Co-3 alkylene)-phenyl, wherein the phenyl is optionally substituted with 1-3 Rg;

[0053] Ring A is selected from the group consisting of: (Al) and (A2):

[0054]

[0055] (Al) (A2)

[0056] wherein:

[0057] m2 is 0, 1, or 2,

[0058] each R2is independently selected from the group consisting of: halo, -CN, C1-3 alkoxy, C1-3 haloalkoxy, C2-3 alkynyl, C3-6 cycloalkyl, and C1-3 alkyl optionally substituted with 1-3 Rc, and

[0059] aa represents the point of attachment to -LA-;

[0060] LAis selected from the group consisting of: a bond, -N(Rd)-, and -O-;

[0061] bl is 1, 2, 3, 4, 5, or 6;

[0062] cl is 1, 2, 3, or 4; each LBis independently selected from the group consisting of: LB1and LB3, provided that 0-1 LBis LB3;

[0063] each Lcis independently selected from the group consisting of: LC1and LC3, provided that 0-1 Lcis LC3;

[0064] each LB1and LC1is independently selected from the group consisting of: -CH2-, -CHRL-, and -C(RL)2-, wherein each RLis independently selected from the group consisting of: halo, -CN, -OH, C1-6 alkoxy, C1-6 haloalkoxy, and C1-6 alkyl optionally substituted with 1-6 Rc;

[0065] LB3and LC3are each independently selected from the group consisting of: -N(Rd)- and -O-;

[0066] Ring B is selected from the group consisting of: C3-10 cycloalkylene and 4-8 membered heterocyclylene, each of which is optionally substituted with 1-3 Ra;

[0067] Ring C is selected from the group consisting of: C3-8 cycloalkylene and 4-12 membered nitrogen-containing heterocyclylene, each of which is optionally substituted with 1-3 Ra;

[0068]

[0069] RYais selected from the group consisting of: -H, Rb, and C1-6 alkyl optionally substituted with 1-3 Rc;

[0070] each RYbis independently selected from the group consisting of: halo, C1-3 alkoxy, Ci-3 haloalkoxy, and C1-3 alkyl optionally substituted with 1-3 Rc;

[0071] yl is 0, 1, or 2; and

[0072] yy represents the point of attachment to Ring C or -(Lc)d-; each Rais independently selected from the group consisting of: -F, -CN, -OH, oxo, Ci-3 alkoxy, and C1-3 alkyl optionally substituted with 1-3 Rc;

[0073] each Rbis independently selected from the group consisting of: -(Lb)-Rbland -Rbl, wherein:

[0074] each Lbis an independently selected C1-3 alkylene;

[0075] each Rblis independently selected from the group consisting of: C3-6 cycloalkyl and 4-8 membered heterocyclyl, each of which is optionally substituted with 1-3 Rg;

[0076] each Rcis independently selected from the group consisting of: halo, -CN, -OH, C1-6 alkoxy, C1-6 haloalkoxy, and -NRdRe;

[0077] each Rdand Reis independently selected from the group consisting of: -H, -C(=O)C1-6 alkyl, -C(=O)OC1-6 alkyl, -C(=O)N(Rf)2, and C1-6 alkyl optionally substituted with 1-3 Rh; each Rfis independently selected from the group consisting of: -H and C1-6 alkyl optionally substituted with 1-3 Rh;

[0078] each Rgis independently selected from the group consisting of: Rh, C1-3 alkyl, and C1-3 haloalkyl; and

[0079] each Rhis independently selected from the group consisting of: halo, -CN, C1-6 alkoxy, and C1-6 haloalkoxy.

[0080] In some embodiments, the compounds are compounds of Formula (I), or pharmaceutically acceptable salts thereof.

[0081] In some embodiments, the compounds of Formula (I) are other than:

[0082]

[0083]

[0084] or pharmaceutically acceptable salts thereof.

[0085] In some embodiments of Formula (I), one or more of (l)-(5) applies:

[0086] (1) LAis -N(Rd)- (e.g., -N(Me)-);

[0087] (2) one LBis LB3;

[0088] (3) Ring C is a bicyclic 7-11 membered nitrogen-containing heterocyclylene optionally

[0089] substituted

[0090]

[0091]

[0092] , wherein bb represents the point of attachment to Ring D); and / or

[0093] (4) m2 is 1, and R2is CF3; and / or

[0094] (5) Ring A is (A2). In some embodiments, the compounds are compounds of Formula (II), or pharmaceutically acceptable salts thereof.

[0095] In some embodiments of Formula (I) or (II), LAis -O-.

[0096] In some embodiments of Formula (I) or (II), LAis -N(H)- or -N(CI-3 alkyl)- (e.g., -N(H)- or -N(Me)-).

[0097] In some embodiments of Formula (I) or (II), bl is 1 or 2; and each LBis an independently selected LB1. For example, each LBcan he -CH2-.

[0098] In some embodiments of Formula (I) or (II), bl is 3, 4, or 5; and each LBis an independently selected LB1. For example, each LBcan he -CH2-.

[0099] In some embodiments of Formula (I) or (II), bl is 3, 4, or 5; one LBis LB3; and each remaining LBis an independently selected LB1. In some embodiments, -(LB)bi- is -LB3-(LB1)2-4-cc wherein cc represents the point of attachment to Ring C. In some embodiments, -(LB)bi-is - (LB1)2-4-LB3-CCwherein cc represents the point of attachment to Ring C. In some embodiments, each LB1is CH2. In some embodiments, LB3is -O-, -N(H)-, or -N(CI-3 alkyl)-(e.g., -N(H)- or -N(Me)-).

[0100] In some embodiments of Formula (I) or (II), Ring B is a C3-10 cycloalkylene optionally substituted with 1-3 Ra. In some embodiments, Ring B is a C4-8 (e.g., Ce) cycloalkylene

[0101] optionally substituted with 1-3 Ra. For example, Ring B can be

[0102]

[0103]

[0104] In some embodiments of Formula (I), Ring C is a 4-12 membered nitrogen-containing heterocyclylene optionally substituted with 1-3 Ra, wherein the heterocyclylene contains 1-2 ring nitrogen atoms and no additional ring heteroatoms. In some embodiments, Ring C is piperazinylene optionally substituted with 1-3 Ra. In some embodiments, Ring C is

[0105]

[0106] , wherein bb represents the point of attachment to Ring

[0107] D (e.g., Ring C is

[0108]

[0109] , wherein bb represents the point of attachment to Ring D). In some embodiments, Ring C is

[0110]

[0111] wherein bb represents the point of attachment to Ring D.

[0112] In some embodiments of Formula (I), Ring C is piperidinylene optionally substituted

[0113] with 1-3 Ra(e.g., Ring C i

[0114]

[0115] wherein bb represents the point of attachment to Ring D).

[0116] In some embodiments of Formula (I), Ring C is a bicyclic 7-11 membered nitrogencontaining heterocyclylene optionally substituted with 1-3 Ra, wherein the heterocyclylene contains 1-2 (e.g., 2) ring nitrogen atoms and no additional ring heteroatoms. In some

[0117]

[0118] to Ring D.

[0119] In some embodiments of Formula (II), Ring C is a 6-10 membered nitrogen-containing heterocyclylene optionally substituted with 1-3 Ra. In some embodiments, the heterocyclylene contains one ring nitrogen atom and no additional ring heteroatoms. In some embodiments,

[0120]

[0121] , wherein bb represents the point of attachment to -(L)ci-.

[0122] In some embodiments of Formula (II), -(Lc)ci- is selected from the group consisting of: -(LC1)O-2-LC3-*, -(LC1)I-2-*, and -LC3-(LC1)I-2-*, wherein * represents the point of attachment to Ring D. In some embodiments of Formula (II), each LC1is independently selected from the group consisting of: -CH2-, -CHMe-, and -CMe2-.

[0123] In some embodiments of Formula (II), each LC1is -CH2-.

[0124] In some embodiments of Formula (II), LC3is -N(H)- or -N(CI-3 alkyl)- (e.g., -N(H)- or -N(Me)-). For example, LC3can be -N(H)-.

[0125] In some embodiments of Formula (II), LC3is -O-.

[0126] Also provided herein are compounds of Formula (III) or (IV):

[0127]

[0128] Formula (IV)

[0129] or pharmaceutically acceptable salts thereof, wherein:

[0130] Z1is CH or N;

[0131] R1is selected from the group consisting of:

[0132] (a) -C(O)OH;

[0133] (b) -C(O)OCi-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-3 Rc; and (c) -C(O)-(Co-3 alkylene)-phenyl, wherein the phenyl is optionally substituted with 1-3

[0134] Rg; Ring A is selected from the group consisting of: (Al) and (A2):

[0135]

[0136] (Al) (A2)

[0137] wherein:

[0138] m2 is 0, 1, or 2,

[0139] each R2is independently selected from the group consisting of: halo, -CN, C1-3 alkoxy, Ci-3 haloalkoxy, C2-3 alkynyl, and C1-3 alkyl optionally substituted with 1-3 Rc, and

[0140] aa represents the point of attachment to -(LA3)a3;

[0141] al is 1, 2, 3;

[0142] a3 is 0, 1, or 2;

[0143] each LA1and LA3is independently selected from the group consisting of: -CH2-, -CHRL-, and -C(RL)2-;

[0144] LA2is selected from the group consisting of: a bond, -N(Rd)-, and -O-;

[0145] bl is 1, 2, 3, 4, or 5;

[0146] cl is 1, 2, 3, or 4;

[0147] each LBis independently selected from the group consisting of: LB1and LB3, provided that 0-1 LBis LB3;

[0148] each Lcis independently selected from the group consisting of: LC1and LC3, provided that 0-1 Lcis LC3;

[0149] each LB1and LC1is independently selected from the group consisting of: -CH2-, -CHRL-, and -C(RL)2-;

[0150] LB3and LC3are each independently selected from the group consisting of: -N(Rd)- and -O-;

[0151] each RLis independently selected from the group consisting of: halo, -CN, -OH, C1-6 alkoxy, C1-6 haloalkoxy, and C1-6 alkyl optionally substituted with 1-6 Rc;

[0152] Ring B is selected from the group consisting of: C3-10 cycloalkylene and 4-8 membered heterocyclylene, each of which is optionally substituted with 1-3 Ra; Ring C is selected from the group consisting of: C3-8 cycloalkylene and 4-12 membered nitrogen-containing heterocyclylene, each of which is optionally substituted with 1-3 Ra;

[0153] Ring D is selected from the group consisting of:

[0154]

[0155]

[0156] wherein:

[0157] RYais selected from the group consisting of: -H, Rb, and C1-6 alkyl optionally substituted with 1-3 Rc;

[0158] each RYbis independently selected from the group consisting of: halo, C1-3 alkoxy, Ci- 3 haloalkoxy, and C1-3 alkyl optionally substituted with 1-3 Rc;

[0159] yl is 0, 1, or 2; and

[0160] yy represents the point of attachment to Ring C or -(Lc)d-;

[0161] each Rais independently selected from the group consisting of: -F, -CN, -OH, oxo, Ci-3 alkoxy, and C1-3 alkyl optionally substituted with 1-3 Rc;

[0162] each Rbis independently selected from the group consisting of: -(Lb)-Rbland -Rbl, wherein:

[0163] each Lbis an independently selected C1-3 alkylene;

[0164] each Rblis independently selected from the group consisting of: C3-6 cycloalkyl and 4-8 membered heterocyclyl, each of which is optionally substituted with 1-3 Rg;

[0165] each Rcis independently selected from the group consisting of: halo, -CN, -OH, C1-6 alkoxy, C1-6 haloalkoxy, and -NRdRe;

[0166] each Rdand Reis independently selected from the group consisting of: -H, -C(=O)Ci-6 alkyl, -C(=O)OCi-6 alkyl, -C(=O)N(Rf)2, and C1-6 alkyl optionally substituted with 1-3 Rb; each Rfis independently selected from the group consisting of: -H and C1-6 alkyl optionally substituted with 1-3 Rh; each Rgis independently selected from the group consisting of: Rh, C1-3 alkyl, and Ci-3 haloalkyl; and

[0167] each Rhis independently selected from the group consisting of: halo, -CN, C1-6 alkoxy, and C1-6 haloalkoxy.

[0168] In some embodiments of Formula (III) or (IV), LA2is -O-.

[0169] In some embodiments of Formula (III) or (IV), each LA1is -CH2-.

[0170] In some embodiments of Formula (III) or (IV), a3 is 0 or 1.

[0171] In some embodiments of Formula (III) or (IV), each LA3is -CH2-.

[0172] In some embodiments of Formula (III) or (IV), bl is 2, 3, or 4. In some embodiments, each LBis an independently selected LB1. For example, each can be LBis -CH2-.

[0173] In some embodiments of Formula (III) or (IV), bl is 3, 4, or 5. In some embodiments, one LBis LB3; and each remaining LBis an independently selected LB1. In some embodiments, one LBis -N(H)- or -N(CI-3 alkyl)-; and each remaining LBis -CH2-.

[0174] In some embodiments of Formula (III) or (IV), Ring B is a 4-8 (e.g., 6) membered nitrogen-containing heterocyclylene optionally substituted with 1-3 Ra.

[0175] In some embodiments of Formula (III) or (IV), Ring B is

[0176]

[0177]

[0178] , each of which is optionally substituted with 1-3 Ra, wherein cc represents the

[0179] point of attachment to -(LB)bi- For example, Ring B can be

[0180]

[0181] or

[0182]

[0183] wherein cc represents the point of attachment to -(LB)bi-.

[0184] In some embodiments of Formula (III) or (IV), Ring C is a 4-8 (e.g., 6) membered nitrogen-containing heterocyclylene optionally substituted with 1-3 Ra. For example, Ring C

[0185] is selected from the group consisting of: hCH HD-

[0186]

[0187] each of which is optionally substituted with 1-3 Ra, wherein bb represents the point of attachment to Ring D or -(Lc)ci- In some embodiments of Formula (IV), cl is 1, 2, or 3.

[0188] In some embodiments of Formula (IV), each LC1is -CH2-.

[0189] In some embodiments of Formula (IV), LC3is -N(Rd)-. For example, LC3can be -N(H)-or -N(CI-3 alkyl)- (e.g., -NMe-).

[0190] In some embodiments of Formula (IV), -(Lc)ci- is selected from the group consisting of: -(LC1)O-2-LC3-* and -LC3-(LC1)I-2-*, wherein * represents the point of attachment to Ring D. In some embodiments, each LC1is -CH2-. In some embodiments, LC3is -N(Rd)-. For example, LC3can be -N(H)- or -N(CI-3 alkyl)- (e.g., -NMe-).

[0191] Also provided herein are compounds of Formula (V):

[0192]

[0193] Formula (V)

[0194] or pharmaceutically acceptable salts thereof, wherein:

[0195] Z1is CH or N;

[0196] R1is selected from the group consisting of:

[0197] (a) -C(O)OH;

[0198] (b) -C(O)OCi-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-3 Rc; and (c) -C(O)-(Co-3 alkylene)-phenyl, wherein the phenyl is optionally substituted with 1-3 R-:

[0199] Ring A is selected from the group consisting of: (Al) and (A2):

[0200]

[0201] wherein: m2 is 0, 1, or 2,

[0202] each R2is independently selected from the group consisting of: halo, -CN, C1-3 alkoxy, C1-3 haloalkoxy, C2-3 alkynyl, C3-6 cycloalkyl, and C1-3 alkyl optionally substituted with 1-3 Rc, and

[0203] aa represents the point of attachment to -(LA)ai-;

[0204] al is 1, 2, 3, or 4;

[0205] bl is 1, 2, 3, 4, 5, or 6;

[0206] each LAis independently selected from the group consisting of: LA1and LA3, provided that 0-1 LAis LA3;

[0207] each LBis independently selected from the group consisting of: LB1and LB3, provided that 0-1 LBis LB3;

[0208] each LA1and LB1is independently selected from the group consisting of: -CH2-, -CHRL-, and -C(RL)2-, wherein each RLis independently selected from the group consisting of: halo, -CN, -OH, C1-6 alkoxy, C1-6 haloalkoxy, and C1-6 alkyl optionally substituted with 1-6 Rc;

[0209] LA3and LB3are each independently selected from the group consisting of: -N(Rd)- and -O-;

[0210] LDis selected from the group consisting of:

[0211]

[0212] and -N(Rd)-;

[0213] Ring B is a 4-12 membered nitrogen-containing heterocyclylene optionally substituted with 1-3 Ra;

[0214] Ring D is selected from the group consisting of:

[0215]

[0216]

[0217] RYais selected from the group consisting of: -H, Rb, and C1-6 alkyl optionally substituted with 1-3 Rc; each RYbis independently selected from the group consisting of: halo, C1-3 alkoxy, Ci-3 haloalkoxy, and C1-3 alkyl optionally substituted with 1-3 Rc;

[0218] yl is 0, 1, or 2; and

[0219] yy represents the point of attachment to LD;

[0220] each Rais independently selected from the group consisting of: -F, -CN, -OH, oxo, Ci-3 alkoxy, and C1-3 alkyl optionally substituted with 1-3 Rc;

[0221] each Rbis independently selected from the group consisting of: -(Lb)-Rbland -Rbl, wherein:

[0222] each Lbis an independently selected C1-3 alkylene;

[0223] each Rblis independently selected from the group consisting of: C3-6 cycloalkyl and 4-8 membered heterocyclyl, each of which is optionally substituted with 1-3 Rg;

[0224] each Rcis independently selected from the group consisting of: halo, -CN, -OH, C1-6 alkoxy, C1-6 haloalkoxy, and -NRdRe;

[0225] each Rdand Reis independently selected from the group consisting of: -H, -C(=O)Ci-6 alkyl, -C(=O)OCi-6 alkyl, -C(=O)N(Rf)2, and C1-6 alkyl optionally substituted with 1-3 Rb; each Rfis independently selected from the group consisting of: H and C1-6 alkyl optionally substituted with 1-3 Rb;

[0226] each Rgis independently selected from the group consisting of: Rh, C1-3 alkyl, and C1-3 haloalkyl; and

[0227] each Rhis independently selected from the group consisting of: halo, -CN, C1-6 alkoxy, and C1-6 haloalkoxy.

[0228] In some embodiments of Formula (V), each LA1is -CH2-.

[0229] In some embodiments of Formula (V), LA3is -O-.

[0230] In some embodiments of Formula (V), -(LA)ai- is -LA3-(LA1)o-3-*, wherein * represents the point of attachment to Ring B. In some embodiments, each LA1is -CH2-. In some embodiments, LA3is -O-.

[0231] In some embodiments of Formula (V), each bl is 2, 3, 4, or 5.

[0232] In some embodiments of Formula (V), each LBis an independently selected LB1. For example, each LBcan be -CH2-. In some embodiments of Formula (V), Ring B is a 6-11 membered nitrogen-containing heterocyclylene optionally substituted with 1-3 Ra, wherein the heterocyclylene contains 1-2 (e.g., 2) ring nitrogen atoms and no additional ring heteroatoms.

[0233] In some embodiments of Formula (V), Ring B is

[0234]

[0235]

[0236] , each of which is optionally substituted with 1-3 Ra, wherein cc represents the point of attachment to -(LB)bi-.

[0237] In some embodiments of Formula (V), LDis -N(H)-.

[0238] In some embodiments of Formula (V), LDis

[0239]

[0240] Also provided herein are compounds of Formula (VI):

[0241]

[0242] Formula (VI)

[0243] or pharmaceutically acceptable salts thereof, wherein:

[0244] Z1is CH or N;

[0245] R1is selected from the group consisting of:

[0246] (a) -C(O)OH;

[0247] (b) -C(O)OCi-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with 1-3 Rc; and (c) -C(O)-(Co-3 alkylene)-phenyl, wherein the phenyl is optionally substituted with 1-3 Rg;

[0248] Ring A is selected from the group consisting of: (Al) and (A2):

[0249]

[0250] (Al) (A2)

[0251] wherein:

[0252] m2 is 0, 1, or 2,

[0253] each R2is independently selected from the group consisting of: halo, -CN, C1-3 alkoxy, C1-3 haloalkoxy, C2-3 alkynyl, C3-6 cycloalkyl, and C1-3 alkyl optionally substituted with 1-3 Rc, and

[0254] aa represents the point of attachment to -LA-;

[0255] LAis selected from the group consisting of: a bond, -N(Rd)-, and -O-;

[0256] bl is 0, 1, 2, or 3;

[0257] cl is 0, 1, or 2;

[0258] el is 0, 1, or 2;

[0259] each LBis independently selected from the group consisting of: LB1and LB3, provided that 0-1 LBis LB3;

[0260] each Lcis independently selected from the group consisting of: LC1and LC3, provided that 0-1 Lcis LC3;

[0261] each LEis independently selected from the group consisting of: LE1and LE3, provided that 0-1 LEis LE3;

[0262] each LB1, LC1, and LE1is independently selected from the group consisting of: -CH2-, -CHRL-, and -C(RL)2-, wherein each RLis independently selected from the group consisting of: halo, -CN, -OH, C1-6 alkoxy, C1-6 haloalkoxy, and C1-6 alkyl optionally substituted with 1-6 Rc;

[0263] LB3, LC3, and LE3are each independently selected from the group consisting of: -N(Rd)-and -O-; Ring B is selected from the group consisting of: C3-10 cycloalkylene and 4-8 membered nitrogen-containing heterocyclylene, each of which is optionally substituted with 1-3 Ra;

[0264] Ring C is selected from the group consisting of: C3-8 cycloalkylene and 4-12 membered nitrogen-containing heterocyclylene, each of which is optionally substituted with 1-3 Ra;

[0265] Ring E is selected from the group consisting of: C3-6 cycloalkylene and 4-6 membered nitrogen-containing heterocyclylene, each of which is optionally substituted with 1-3 Ra;

[0266] Ring D is selected from the group consisting of:

[0267]

[0268]

[0269] RYais selected from the group consisting of: -H, Rb, and C1-6 alkyl optionally substituted with 1-3 Rc;

[0270] each RYbis independently selected from the group consisting of: halo, C1-3 alkoxy, Ci-3 haloalkoxy, and C1-3 alkyl optionally substituted with 1-3 Rc;

[0271] yl is 0, 1, or 2; and

[0272] yy represents the point of attachment to -(Lc)ci-;

[0273] each Rais independently selected from the group consisting of: -F, -CN, -OH, oxo, Ci-3 alkoxy, and C1-3 alkyl optionally substituted with 1-3 Rc;

[0274] each Rbis independently selected from the group consisting of: -(Lb)-Rbland -Rbl, wherein:

[0275] each Lbis an independently selected C1-3 alkylene;

[0276] each Rblis independently selected from the group consisting of: C3-6 cycloalkyl and 4-8 membered heterocyclyl, each of which is optionally substituted with 1-3 Rg;

[0277] each Rcis independently selected from the group consisting of: halo, -CN, -OH, C1-6 alkoxy, C1-6 haloalkoxy, and -NRdRe; each Rdand Reis independently selected from the group consisting of: -H, -C(=O)Ci-6 alkyl, -C(=O)OCi-6 alkyl, -C(=O)N(Rf)2, and Ci-6 alkyl optionally substituted with 1-3 Rh;

[0278] each Rfis independently selected from the group consisting of: H and Ci-6 alkyl optionally substituted with 1-3 Rh;

[0279] each Rgis independently selected from the group consisting of: Rh, C1-3 alkyl, and Ci-3 haloalkyl; and

[0280] each Rhis independently selected from the group consisting of: halo, -CN, C1-6 alkoxy, and C1-6 haloalkoxy.

[0281] In some embodiments of Formula (VI), LAis -O-.

[0282] In some embodiments of Formula (VI), Ring B is a C4-8 (e.g., Ce) cycloalkylene

[0283] optionally substituted with 1-3 Ra. In some embodiments, Ring B is

[0284]

[0285] (e.g.,

[0286]

[0287] In some embodiments of Formula (VI), Ring B is a 4-8 membered nitrogen-containing heterocyclylene, each of which is optionally substituted with 1-3 Ra(e.g., Ring B is

[0288]

[0289] , wherein bb represents the point of attachment to -(LB)bi-).

[0290] In some embodiments of Formula (VI), -(LB)bi- is -(LB1)i-3-. In some embodiments, each LB1is -CH2-.

[0291] In some embodiments of Formula (VI), -(LB)bi- is -O-.

[0292] In some embodiments of Formula (VI), Ring E is selected from the group consisting of: C3-6 cycloalkylene and 4-6 membered nitrogen-containing heterocyclylene, each of which is optionally substituted with 1-2 Ra. In some embodiments, Ring E is selected from the group consisting of: C3-6 cycloalkylene and 4-6 membered nitrogen-containing heterocyclylene. In

[0293] I \. / ~i some embodiments, Ring E is selected from the group consisting of:v’ee

[0294] and

[0295]

[0296] , wherein ee represents the point of attachment to ( L' )ei-. In some embodiments of Formula (VI), el is 0 or 1.

[0297] In some embodiments of Formula (VI), each LEis an independently selected LE1(e.g., each LEis -CH2-).

[0298] In some embodiments of Formula (VI), Ring C is a 4-8 (e.g., 6) membered nitrogencontaining heterocyclylene optionally substituted with 1-3 RL4. In some embodiments, Ring C

[0299]

[0300] each of which is optionally substituted with 1-3 Ra, wherein bb represents the point of attachment to -(Lc)ci-.

[0301] In some embodiments of Formula (VI), cl is 0.

[0302] In some embodiments of Formula (VI), cl is 1 or 2.

[0303] In some embodiments of Formula (VI), LC1is -CH2-; and LC3is -N(H)- or -O-.

[0304] In some embodiments of Formula (VI), -(Lc)ci- is -(LC1)0-1-LC3-*, wherein the * represents the point of attachment to Ring D. In some embodiments, LC1is -CH2-; and LC3is -N(H)- or -O-.

[0305] In some embodiments of Formula (I), (II), (III), (IV), (V), or (VI), Ring A is

[0306]

[0307] insome embodiments, m2 is 1. In some embodiments, m2 is 0.

[0308] is

[0309]

[0310] In some embodiments of Formula (I), (II), (III), (IV), (V), or (VI), Ring A is

[0311]

[0312] some embodiments, m2 is 1. In some embodiments, m2 is 0. In some embodiments of Formula (I), (II), (III), (IV), (V), or (VI), Ring A is

[0313]

[0314] In some embodiments of Formula (I), (II), (III), (IV), (V), or (VI), R2is methyl. In some embodiments of Formula (I), (II), (III), (IV), (V), or (VI), R2is -CF3.

[0315] In some embodiments of Formula (I), (II), (III), (IV), (V), or (VI), yl is 0.

[0316] In some embodiments of Formula (I), (II), (III), (IV), (V), or (VI), yl is 1 or 2.

[0317] In some embodiments of Formula (I), (II), (III), (IV), (V), or (VI), RYais C1-3 alkyl (e.g., methyl).

[0318] In some embodiments of Formula (I), (II), (III), (IV), (V), or (VI), Ring C is

[0319]

[0320] some embodiments, yl is 0. In some embodiments, yl is 1 or 2. In some embodiments, RYais C1-3 alkyl (e.g., methyl).

[0321] In some embodiments of Formula (I), (II), (III), (IV), (V), or (VI), Ring C is

[0322]

[0323] . In some embodiments, yl is 0. In some embodiments, yl is 1 or 2. In some embodiments, RYais C1-3 alkyl (e.g., methyl).

[0324] In some embodiments of Formula (I), (II), (III), (IV), (V), or (VI), Ring C is

[0325]

[0326] methyl).

[0327] In some embodiments of Formula (I), (II), (III), (IV), (V), or (VI), R1is -C(O)OH. In some embodiments of Formula (I), (II), (III), (IV), (V), or (VI), R1is -C(O)OCi-6 alkyl.

[0328] In some embodiments of Formula (I), (II), (III), (IV), (V), or (VI), Z1is CH.

[0329] In some embodiments, the compounds of Formula (I), (II), (III), (IV), (V), or (VI) are

[0330] selected from the group consisting of the compounds depicted in Table Cl, or pharmaceutically acceptable salts thereof.

[0331] Table C1

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398]

[0399]

[0400]

[0401]

[0402]

[0403]

[0404]

[0405]

[0406]

[0407]

[0408]

[0409]

[0410]

[0411] a

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419] Note: for compounds in Table Cl, when a stereogenic center is denoted with “orT in a structural formula, the stereogenic center has been resolved but the configuration at the stereogenic center has not been determined. For example, the structure

[0420]

[0421] represents (A)-2-methyl-3-(l-methylpiperidin-4-yl)propan-l-ol or (5)-2-methyl-3-(l-

[0422] h° J IL J J methylpiperidin-4-yl)propan-l-ol. For example, the structure represents (A)-2-methyl-3-(l-methylpiperidin-4-yl)propan-l-ol or (5)-2-methyl-3-(l-methylpiperidin-4-yl)propan-l-ol.

[0423] In some embodiments, the compounds of Formula (I), (II), (III), (IV), (V), or (VI) are selected from the group consisting of the compounds depicted in Table Cl of U. S. Provisional Application Serial No. 63 / 717,469, filed November 7, 2024; or pharmaceutically acceptable salt thereof, wherein the Table Cl is incorporated herein by reference in its entirety.

[0424] In some embodiments, the compounds of Formula (I), (II), (III), (IV), (V), or (VI), or pharmaceutically acceptable salts thereof, reduce cell viability in a cell line expressing a BCL-XL protein with an EC₅₀ of less than 1 pM (e.g., less than 750 nM, less than 500 nM, or less than 200 nM). In some embodiments, the compounds of Formula (I), (II), (III), (IV), (V), or (VI) reduce cell viability in a cell line expressing the BCL-XL protein with an EC₅₀ of less than 200 nM (e.g., less than 150 nM, less than 200 nM, less than 100 nM, less than 10 nM, less than 1 nM). For example, the compounds can reduce cell viability in a cell line expressing the BCL-XL protein with an EC₅₀ of between 0.1 nM to 100 nM, between 0.1 nM to 50 nM, between 1 nM to 50 nM, between 1 nM to 20 nM, or between 0.1 nM to 1 nM.

[0425] In some embodiments, the compounds of Formula (I), (II), (III), (IV), (V), or (VI), or pharmaceutically acceptable salts thereof, induce degradation of a BCL-XL protein in a cell line expressing the BCL-XL protein with a DC₅₀ of less than 1 pM (e.g., less than 750 nM, less than 500 nM, or less than 200 nM). In some embodiments, the compounds of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, induce degradation of a BCL-XL protein in a cell line expressing the BCL-XL protein with a DC₅₀ of less than 200 nM (e.g., less than 150 nM, less than 200 nM, less than 100 nM, less than 10 nM, less than 1 nM). For example, the compounds can induce degradation of a BCL-XL protein in a cell line expressing the BCL-XL protein with a DC₅₀ of between 0.1 nM to 100 nM, between 0.1 nM to 50 nM, between 1 nM to 50 nM, between 1 nM to 20 nM, or between 0.1 nM to 1 nM.

[0426] In some embodiments, the compounds of Formula (I), (II), (III), (IV), (V), or (VI), or pharmaceutically acceptable salts thereof, induce degradation of a BCL-XL protein in a cell line expressing the BCL-XL protein with an EC₅₀ of less than 1 pM (e.g., less than 750 nM, less than 500 nM, or less than 200 nM). In some embodiments, the compounds of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, induce degradation of a BCL-XL protein in a cell line expressing the BCL-XL protein with an EC₅₀ of less than 200 nM (e.g., less than 150 nM, less than 200 nM, less than 100 nM, less than 10 nM, less than 1 nM). For example, the compounds can induce degradation of a BCL-XL protein in a cell line expressing the BCL-XL protein with an EC₅₀ of between 0.1 nM to 100 nM, between 0.1 nM to 50 nM, between 1 nM to 50 nM, between 1 nM to 20 nM, or between 0.1 nM to 1 nM.

[0427] In some embodiments, the compounds of Formula (I), (II), (III), (IV), (V), or (VI), or pharmaceutically acceptable salts thereof, induce degradation of a BCL-XL protein in a cell line expressing the BCL-XL protein with a Ymin of less than 70% (e.g., less than 50%, less than 30%, less than 20%, or less than 10%). In some embodiments, the compounds of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, induce degradation of a BCL-XL protein in a cell line expressing the BCL-XL protein with a Ymin of less than 50% (e.g., less than 40%, less than 30%, less than 20%, less than 10%, or less than 5%). In some embodiments, the compounds of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, induce degradation of a BCL-XL protein in a cell line expressing the BCL-XL protein with a Ymin of less than 30% (e.g., less than 25%, less than 20%, less than 15%, less than 10%, or less than 5%). For example, the compounds can induce degradation of a BCL-XL protein in a cell line expressing the BCL-XL protein with a Ymin of about 1% to about 70% (e.g., about 5% to about 50% or about 10% to about 30%).

[0428] Also provided herein is a BCL-XL protein non-covalently bound with a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof.

[0429] Also provided herein is a ternary complex comprising a BCL-XL protein, a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, and a CRBN protein, or a portion thereof.

[0430] Chemical definitions

[0431] The term “halo” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0432] The term “oxo” refers to a divalent doubly bonded oxygen atom (i.e., “=O”). As used herein, oxo groups are attached to carbon atoms to form carbonyls.

[0433] The term “alkyl” refers to a saturated acyclic hydrocarbon radical that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, Ci-io indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Alkyl groups can either be unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, Ao-propyl, tert-butyl, w-hexyl. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms and other available valences occupied by hydrogen and / or other substituents as defined herein.

[0434] The term “haloalkyl” refers to an alkyl, in which one or more hydrogen atoms is / are replaced with an independently selected halo (e.g., -CF3, -CHF2, or -CH2F).

[0435] The term “alkoxy” refers to an -O-alkyl radical (e.g., -OCH3).

[0436] The term “alkylene” refers to a divalent alkyl (e.g., -CH2-). Similarly, terms such as “cycloalkylene” and “heterocyclylene” refer to divalent cycloalkyl and heterocyclyl respectively. For avoidance of doubt, in “cycloalkylene” and “heterocyclylene”, the two

[0437] radicals can be on the same ring carbon atom (e.g., a geminal diradical such

[0438]

[0439] ) or on different ring atoms (e.g., ring carbon and / or nitrogen atoms (e.g., vicinal ring carbon and / or nitrogen atoms)

[0440]

[0441] The term “alkenyl” refers to an acyclic hydrocarbon chain that may be a straight chain or branched chain having one or more carbon-carbon double bonds. The alkenyl moiety contains the indicated number of carbon atoms. For example, C2-6 indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it. Alkenyl groups can either be unsubstituted or substituted with one or more substituents.

[0442] The term “alkynyl” refers to an acyclic hydrocarbon chain that may be a straight chain or branched chain having one or more carbon-carbon triple bonds. The alkynyl moiety contains the indicated number of carbon atoms. For example, C2-6 indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it. Alkynyl groups can either be unsubstituted or substituted with one or more substituents.

[0443] The term “aryl” refers to a 6-20 carbon mono-, bi-, tri- or polycyclic group wherein at least one ring in the system is aromatic (e.g., 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system); and wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.

[0444] The term “cycloalkyl” as used herein refers to mono-, bi-, tri-, or polycyclic (e.g., fused, bridged, or spirocyclic bi-, tri-, or polycyclic) saturated or partially unsaturated hydrocarbon groups having, e.g., 3 to 20 ring carbons, preferably 3 to 15 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkyl group may be optionally substituted. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms. Examples of saturated cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Partially unsaturated cycloalkyl may have any degree of unsaturation provided that one or more double bonds is present in the cycloalkyl, none of the rings in the ring system are aromatic, and the partially unsaturated cycloalkyl group is not fully saturated overall. Examples of partially unsaturated cycloalkyl include, without limitation, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Cycloalkyl may include multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyl includes: bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[l.l.l]pentyl, bicyclo[3.1.0]hexyl, bicyclo[2.1.1]hexyl, bicyclo[3.2.0]heptyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[4.2.0]octyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, and the like. Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentyl, spiro[2.5]octyl, spiro[3.5]nonyl, spiro[3.5]nonyl, spiro[3.5]nonyl, spiro[4.4]nonyl, spiro[2.6]nonyl, spiro[4.5]decyl, spiro[3.6]decyl, spiro[5.5]undecyl, and the like.

[0445] The term “heteroaryl”, as used herein, means a mono-, bi-, tri- or polycyclic group having 5 to 20 ring atoms, alternatively 5, 6, 9, 10, or 15 ring atoms; wherein at least one ring in the system contains one or more heteroatoms independently selected from the group

[0446] consisting of N, O, S (inclusive of oxidized forms such as:

[0447]

[0448] and P (inclusive

[0449] of oxidized forms such as:

[0450]

[0451] ) (e.g., N, O, and S (inclusive of oxidized forms such as:

[0452]

[0453] and at least one ring in the system is aromatic (but does not have to be a ring which contains a heteroatom, e.g. tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). In some embodiments, heteroaryl groups contain 1-4 (e.g., 1, 2, or 3) ring heteroatoms each independently selected from the group consisting of N, O, and S (inclusive of oxidized forms

[0454] such as:

[0455]

[0456] Heteroaryl groups can either be unsubstituted or substituted with one or more substituents. Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3- ]pyrimidinyl, pyrrolo[2,3-Z>]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-Z>]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[4,3-Z>]pyridinyl, tetrazolyl, chromanyl, 2,3-dihydrobenzo[Z»][l,4]dioxinyl, benzo[ ][l,3]dioxolyl, 2,3-dihydrobenzofuranyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[Z»][l,4]oxathiinyl, isoindolinyl, and others. In some embodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl. For purposes of clarification, heteroaryl also includes aromatic lactams, aromatic cyclic ureas, or vinylogous analogs thereof, in which each ring nitrogen adjacent to a carbonyl is tertiary (i.e., all three valences are occupied by non-hydrogen substituents), such as one or more of pyridone (e.g.,

[0457]

[0458] imidazolone (e.g.,

[0459]

[0460] wherein each ring nitrogen adjacent to a carbonyl is tertiary (i.e., the oxo group (i.e., “=O”) herein is a constituent part of the heteroaryl ring).

[0461] The term “heterocyclyl” refers to a mono-, bi-, tri-, or polycyclic (e.g., fused, bridged, or spirocyclic bi-, tri-, or polycyclic) saturated or partially unsaturated ring system with 3-15 ring atoms (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-15 membered tricyclic ring system) having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1- 9 heteroatoms if tricyclic or polycyclic, said heteroatoms selected from O, N, S (inclusive of

[0462] oxidized forms such as:

[0463]

[0464] ), and P (inclusive of oxidized forms such as:

[0465]

[0466] (e.g., O, N, and S (inclusive of oxidized forms such as:

[0467]

[0468] carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, S, or P if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. In some embodiments, heterocyclyl groups contain 1-4 (e.g., 1, 2, or 3) ring heteroatoms each independently selected from the group consisting of N, O, and S (inclusive

[0469] of oxidized forms such as:

[0470]

[0471] The term “saturated” as used in this context means only single bonds present between constituent ring atoms and other available valences occupied by hydrogen and / or other substituents as defined herein. Examples of saturated heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. Partially unsaturated heterocyclyl groups may have any degree of unsaturation provided that one or more double bonds is present in the heterocyclyl, none of the rings in the ring system are aromatic, and the partially unsaturated heterocyclyl group is not fully saturated overall. Examples of partially unsaturated heterocyclyl groups include, without limitation, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl. Heterocyclyl may include multiple fused and / or bridged rings. Non-limiting examples of fused / bridged heteorocyclyl includes: 2-azabicyclof 1.1.0]butyl, 2-azabicyclo[2.1.0]pentyl, 2-azabicyclo[l.l.l]pentyl, 3-azabicyclo[3.1.0]hexyl, 5-azabicyclo[2.1.1]hexyl, 3-azabicyclo[3.2.0]heptyl, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptyl, 7-azabicyclo[2.2.1]heptyl, 6-azabicyclo[3.1.1 ]heptyl, 7-azabicyclo[4.2.0]octyl, 2-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2.1]octyl, 2-oxabicyclo[ 1.1,0]butyl, 2-oxabicyclo[2.1.0]pentyl, 2-oxabicyclof 1.1.1 ]pentyl, 3-oxabicyclo[3.1,0]hexyl, 5-oxabicyclo[2.1.1]hexyl, 3-oxabicyclo[3.2.0]heptyl, 3-oxabicyclo[4.1,0]heptyl, 7-oxabicyclo[2.2.1]heptyl, 6-oxabicyclo[3.1.1 ]heptyl, 7-oxabicyclo[4.2.0]octyl, 2-oxabicyclo[2.2.2]octyl, 3-oxabicyclo[3.2.1]octyl,

[0472]

[0473] the like. Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentyl, 4-azaspiro[2.5]octyl, 1-azaspiro[3.5]nonyl, 2-azaspiro[3.5]nonyl, 7-azaspiro[3.5]nonyl, 2-azaspiro[4.4]nonyl, 6-azaspiro[2.6]nonyl, l,7-diazaspiro[4.5]decyl, 7-azaspiro[4.5]decyl 2,5-diazaspiro[3.6]decyl, 3-azaspiro[5.5]undecyl, 2-oxaspiro[2.2]pentyl, 4-oxaspiro[2.5]octyl, l-oxaspiro[3.5]nonyl, 2-oxaspiro[3.5]nonyl, 7-oxaspiro[3.5]nonyl, 2-oxaspiro[4.4]nonyl, 6-oxaspiro[2.6]nonyl, 1,7-dioxaspiro[4.5]decyl, 2,5-dioxaspiro[3.6]decyl, l-oxaspiro[5.5]undecyl, 3-oxaspiro[5.5]undecyl, 3-oxa-9-azaspiro[5.5]undecyl and the like.

[0474] A nitrogen-containing heterocyclyl as used herein refers to a heterocyclyl having 1 -2 ring nitrogen atoms and 0-2 additional ring heteroatoms selected from the group consisting of

[0475] O and S (inclusive of oxidized such as:

[0476]

[0477] The nitrogen-containing heterocyclyl can be monocyclic, bicyclic, or polycyclic as defined elsewhere herein. Examples of monocyclic nitrogen-containing heterocyclyl include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and the like. Examples of bicyclic nitrogen-containing heterocyclyl include 7-azaspiro[3.5]nonyl, l,7-diazaspiro[4.5]decyl, 3-oxa-7,9-diazabicyclo[3.3.1]nonanyl, 2,6-diazaspiro[3.3]heptanyl, and the like.

[0478] As used herein, when a ring is described as being “partially unsaturated”, it means said ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double or triple bonds between constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.

[0479] For the avoidance of doubt, and unless otherwise specified, for rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, cycloalkyl, and the like described herein) containing a sufficient number of ring atoms to form bicyclic or higher order ring systems (e.g., tricyclic, polycyclic ring systems), it is understood that such rings and cyclic groups encompass those having fused rings, including those in which the points of fusion are located (i) on adjacent ring atoms (e.g., [x.x. O] ring systems, in which 0 represents a zero atom

[0480] bridge

[0481]

[0482]

[0483] (iii) a contiguous array of ring atoms (bridged ring systems

[0484] having all bridge lengths > 0) (e.g.,

[0485]

[0486] In addition, atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include13C and14C.

[0487] In addition, the compounds generically or specifically disclosed herein are intended to include all tautomeric forms. Thus, by way of example, a compound containing the moiety:

[0488]

[0489] encompasses the tautomeric form containing the moiety:

[0490]

[0491] Similarly, a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms.

[0492] The compounds provided herein may encompass various stereochemical forms. The compounds also encompass diastereomers as well as optical isomers, e.g., mixtures of enantiomers including racemic mixtures, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds. Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound.

[0493] Methods of Treatment

[0494] Indications

[0495] Provided herein are methods for inducing degradation of a BCL-XL protein. For example, provided herein are compounds capable of inducing degradation of a BCL-XL protein useful for treating or preventing cancers. See, e.g., Guo, et Aging (Albany NY) 13.15 (2021): 19750, doi: 10.18632 / aging.203386; Park, et al. Proceedings of the National Academy of Sciences 112.40 (2015): 12492-12497, doi: 10.1073 / pnas.1507491112; Zhang, etal. Molecular Cancer 14.1 (2015): 1-9, doi: 10.1186 / sl2943-015-0397-y; Beroukhim, et al. Nature 463.7283 (2010): 899-905, doi: 10.1038 / nature08822.

[0496] The term “compound(s) provided herein” refers to compound(s) of Formula (I), (II), (III), (IV), (V), or (VI) as disclosed herein.

[0497] The effect of protein degradation typically increases over time, and the appearance of degradation (e.g., as expressed by the percentage degradation compared to a control, or the parameters Ymin, DC₅₀, EC₅₀, and / or Dmax) is affected by the resynthesis rate of the protein Accordingly, degradation can be examined after a specified period of time, such as 6 hours, 12 hours, 18 hours, 1 day, 2 days, 3 days, or more. For example, degradation can be expressed as the percent degradation after 24 hours.

[0498] Exemplary assays for validating the degradation-inducing mechanism of a compound as provided herein are known in the art and are described, for example, in International Publication No. WO 2019 / 144117 and Wu, et al. Nature Structural & Molecular Biology 27.7 (2020): 605-614, doi: 10.1038 / s41594-020-0438-0.

[0499] Degradation assays can be used to quantify both on- and off-target degradation-inducing effects of compounds, such as those compounds provided herein. Exemplary assays include quantitative immunoblotting, other immunoassays (e.g., MesoScale Discovery (MSD) immunoassays), homogenous time resolved florescence (HTRF), and HiBiT. In some embodiments, cells can be contacted with a compound provided herein, or a pharmaceutically acceptable salt thereof, incubated, and then the lysate can be prepared for gel electrophoresis (e.g., SDS-PAGE), followed by immunoblotting and quantification compared to a control (e.g., a DMSO-treated control). As another example, a cell line can be engineered to express a HiBiT-tagged BCL-XL protein, and the amount of fluorescence observed when the complementary LgBiT peptide is added can be compared between cells treated with a compound provided herein, or a pharmaceutically acceptable salt thereof, and a control (e.g., a DMSO-treated control). See, for instance, Example Bl and Example B2. See also, e.g., International Publication Nos. WO 2020 / 163823 and WO 2019 / 144117. In some embodiments, off-target degradation inducing effects can be assessed for the proteins Eukaryotic peptide chain release factor GTP -binding subunit ERF3A (GSPT1), Ikaros (IKZF1), Helios (IKZF2), Aiolos (IKZF3), and / or casein kinase I isoform alpha (CK1α).

[0500] See also the assays described in International Publication Nos. WO 2023 / 044046; WO 2022 / 169780; WO 2021 / 222114; WO 2021 / 146536; WO 2021 / 078301; WO 2021 / 007307; WO 2020 / 163823; WO 2019 / 144117; WO 2017 / 184995, and Khan, et al. Nature Medicine 25.12 (2019): 1938-1947, doi: 10.1038 / s41591-019-0668-z; Balachander, et al. Clinical Cancer Research 262 (2020): 6535-6549, doi: 10.1158 / 1078-0432. CCR-20-0863.

[0501] Binding affinity of a compound provided herein, or a pharmaceutically acceptable salt thereof to BCL-XL can be determined by, for example, a binding ICso or Ki value (e.g., using a competition assay), or by a KD value (e.g., using a biophysical assay). A compound with a lower binding ICso value, as determined under substantially similar conditions, is a more potent binder relative to a compound with a higher binding ICso value. A compound with a lower binding Ki value, as determined under substantially similar conditions, is a more potent binder relative to a compound with a higher binding Ki value. Similarly, a compound with a lower KD value, as determined under substantially similar conditions, is a more potent binder relative to a compound with a higher KD value. For example, a binding ICso value can be determined in a fluorescence polarization assay using a fluorescently labeled BH3-only peptide (e.g., BAD or BAX) as the competitor. As another example, a binding Ki value can be determined using a time resolved-fluorescence resonance energy transfer (TR-FRET) assay using a fluorescently labeled BH3-only peptide (e.g., BAK) and a fluorescently labeled antibody that binds to BCL-XL, where the fluorophores are a FRET pair, and using a compound provided herein, or a pharmaceutically acceptable salt thereof, as provided herein as a competitor for the BH3-only peptide. See, e.g., U. S. Patent Publication Nos. US 2007 / 0027135, US 2010 / 305122, and US 2013 / 096120.

[0502] Another exemplary assay for evaluating the affinity of a compound provided herein, or a pharmaceutically acceptable salt thereof, includes using a competition assay with recombinant BCL-XL protein. For example, purified recombinant affinity-tagged (e.g., His-tagged) BCL-XL protein can be incubated with various concentrations of a compound provided herein, or a pharmaceutically acceptable salt thereof, and a fixed concentration of affinity- tagged (e.g., biotin-tagged) BAD protein. After a period of incubation, FRET acceptor beads with a complementary affinity tag (e.g., His-acceptor beads) and FRET donor beads (e.g., streptavidin-tagged donor beads) can be added to the mixture, and a FRET reaction can be used to determine an inhibition constant of the compound provided herein, or pharmaceutically acceptable salt thereof. For example, an AlphaLISA competitive assay can be performed. See, e.g., International Publication No. WO 2019 / 144117.

[0503] The ability of a compound provided herein, or a pharmaceutically acceptable salt thereof, to inhibit BCL-XL can be determined using an IC50 value. A compound with a lower IC50 value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher IC50 value. One way that inhibition of BCL-XL can be measured is measuring the interruption of the formation of a complex of BCL-XL with a BH3-only peptide (e.g., BIM). For example, an electrochemiluminescence-based sandwich ELISA assay (e.g., a Meso Scale Discovery (MSD)-ELISA assay) can be used. See, for example, Phillips, D. C., et al. Blood Cancer Journal 5.11 (2015): e368-e368, doi: 10.1038 / bcj.2015.88 and Xiao, Yu, et al. Molecular Cancer Therapeutics 14.8 (2015): 1837-1847, doi: 10.1158 / 1535-7163. MCT-14-0928. In such assays, cells expressing BCL-XL can be incubated with a compound provided herein, or a pharmaceutically acceptable salt thereof for a period of time, lysed, and then evaluated in the assay. A tagged anti-BCL-Xr antibody (e.g., a biotin-tagged anti -BCL-XL antibody) can be immobilized on an assay plate (e.g., a streptavidin assay plate), and then the lysate can be applied to pull down BCL-XL. An anti -BIM antibody (e.g., a rabbit anti -BIM antibody) can be introduced, followed by addition of a detection antibody (e.g., a sulfo-tagged goat anti-rabbit antibody) and measurement of the detection antibody. As another example, interruption of the formation of a complex of BCL-XL with a BH3-only peptide (e.g., BIM) can be measured using a mammalian two-hybrid assay. In such assays, a plasmid encoding the ‘bait’ and ‘prey’ fusion proteins (e.g., the DNA binding domain of GAL4 fused to BCL-XL and the transcriptional activation domain of VP 16 fused to BIM) can be introduced to cells (e.g., HeLa cells) stably expressing a GAL4-luciferase reporter. A compound provided herein, or a pharmaceutically acceptable salt thereof, can be added to the cells in culture, incubated, and the luciferase activity can be measured. See, for example, Souers, Andrew J., et al. Nature Medicine 19.2 (2013): 202-208, doi: 10.1038 / nm.3048.

[0504] Additional methods of evaluating the binding of a compound to BCL-XL protein or the inhibition of a BCL-XL protein are described in, for example, U. S. Patent Publication Nos. US 2007 / 027135; US 2010 / 305122, and US 2013 / 096120. Potency of degradation by a compound provided herein, or a pharmaceutically acceptable salt thereof, as provided herein can be determined by DC₅₀ value. As used herein, DC₅₀ refers to the concentration of the compound provided herein, or a pharmaceutically acceptable salt thereof, that results in a 50% decrease in the concentration of a protein (e.g., BCL-XL protein) in a cell compared to the concentration of the protein before the cell is contacted with the compound provided herein, or a pharmaceutically acceptable salt thereof, or compared to the concentration of the protein in a cell not contacted with the compound provided herein, or a pharmaceutically acceptable salt thereof. A compound with a lower DC₅₀ value, as determined under substantially similar conditions, is a more efficient inducer of degradation relative to a compound with a higher DC₅₀ value. In some embodiments, a DC₅₀ value can be determined (e.g., using HiBiT detection) in vitro or in vivo (e.g., in tumor cells (e.g., cell lines such as MOLT4, RS4;11, NCI-H146, EJM, HEK293T, HT1080, and / or H929) expressing a BCL-XL protein).

[0505] Potency of degradation by a compound provided herein, or a pharmaceutically acceptable salt thereof, as provided herein can be determined by EC₅₀ value. As used herein, EC₅₀ refers to the concentration of the compound provided herein, or a pharmaceutically acceptable salt thereof that results in a 50% decrease in the concentration of a protein (e.g., BCL-XL protein) relative to the trough concentration of the protein in a cell, when compared to the concentration of the protein before the cell is contacted with the compound provided herein, or a pharmaceutically acceptable salt thereof, or compared to the concentration of the protein in a cell not contacted with the compound provided herein, or a pharmaceutically acceptable salt thereof. A compound with a lower EC₅₀ value, as determined under substantially similar conditions, is a more potent compound relative to a compound with a higher EC₅₀ value. In some embodiments, an EC₅₀ value can be determined (e.g., using HiBiT detection) in vitro or in vivo (e.g., in tumor cells (e.g., cell lines such as MOLT4, RS4;11, NCI-H146, EJM, HEK293T, HT1080, and / or H929) expressing a BCL-XL protein).

[0506] Potency of degradation by a compound provided herein, or a pharmaceutically acceptable salt thereof, as provided herein can be determined by Ymin value. As used herein, Ymin refers to the ratio of trough concentration of a protein (e.g., BCL-XL protein) in a cell compared to the concentration of the protein before the cell is contacted with the compound provided herein, or a pharmaceutically acceptable salt thereof, or compared to the concentration of the protein in a cell not contacted with the compound provided herein, or a pharmaceutically acceptable salt thereof, expressed as a percentage. As used herein, Dmax is 1 - Ymin. Ymin can be measured by a HiBiT assay (e.g., as described in Example Bl). A compound with a lower Ymin value, as determined under substantially similar conditions, is a more potent inducer of degradation relative to a compound with a higher Ymin value. In some embodiments, a Ymin value can be determined (e.g., using HiBiT detection) in vitro or in vivo (e.g., in tumor cells (e.g., cell lines such as M0LT4, RS4;11, NCI-H146, EJM, HEK293T, HT1080, and / or H929) expressing a BCL-XL protein).

[0507] An exemplary assay for determining the potency of a compound provided herein, or a pharmaceutically acceptable salt thereof, includes measuring the effect of the compound provided herein, or a pharmaceutically acceptable salt thereof, on cell proliferation and / or viability. Cell proliferation assays can be performed in a number of formats, including 2D and 3D. Similarly, a cell proliferation assay can be performed with any appropriate cell line, including, for example, M0LT4, RS4;11, NCI-H146, EJM, HEK293T, HT1080, and / or H929. As an illustrative example, a 3D cell proliferation assay can include growing cells in a 3D medium, contacting the cells with a compound provided herein, or a pharmaceutically acceptable salt thereof, measuring the cellular proliferation using an appropriate reagent (e.g., CELLTITER-GLO® 3D), and then comparing the signal from an experiment with a compound provided herein, or a pharmaceutically acceptable salt thereof, to the signal from a control experiment (e.g., lacking the compound provided herein, or a pharmaceutically acceptable salt thereof). As another illustrative example, a 2D cell proliferation assay can include plating cells onto a growth surface, optionally letting the cells grow for a period of time, contacting the cells with a compound provided herein, or a pharmaceutically acceptable salt thereof, measuring the cellular proliferation using an appropriate reagent (e.g., CELLTITER-GLO®), and then comparing the signal from an experiment with a compound provided herein, or a pharmaceutically acceptable salt thereof, to the signal from a control experiment (e.g., lacking a compound provided herein, or a pharmaceutically acceptable salt thereof). In some embodiments, assessment degradation-mediated antiproliferation effects from compounds provided herein, CRBN knockout cells can be used in a similar cell viability assay. The CRBN knockout cells can be generated from parental cells (e.g., MOLT-4 cells) using Crispr gene editing technology. CRBN-targeted single guide RNA (sgRNA) and Cas9 protein can be purchased from commercial suppliers, and Cas9-sgRNA ribonucleoproteins (RNPs) can electroporated into parental cells (e.g., MOLT-4 cells) using a kit (e.g., a Neon NxT Electroporation Kit (Invitrogen)). Cell viability can be assessed for the CRBN knockout cells in the same way as for parental cells (e.g., MOLT-4 cells). Additional cell viability assays include MTT assays, which are colorimetric assays based on the reduction of the tetrazolium dye MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) to the insoluble purple formazan, and other similar assays based on related tetrazolium salts. See, for instance, Example B3.

[0508] A cell viability assay can be used to measure the effect of a compound provided herein, or a pharmaceutically acceptable salt thereof, on cell death. For example, cells expressing BCL-XL protein (e.g., MOLT-4 cells) can be incubated with various concentrations of a compound provided herein, or a pharmaceutically acceptable salt thereof, then exposed to a detection reagent (e.g., a CELLTITER-GLO® Cell Viability Assay kit) to determine cell viability.

[0509] An exemplary assay for determining the mechanism of cell death using of a compound provided herein, or a pharmaceutically acceptable salt thereof, includes measuring the effect of the compound provided herein, or a pharmaceutically acceptable salt thereof, on one or more markers of a mechanism of cell death (e.g., apoptosis). Exemplary markers of apoptosis include caspase induction (e.g., caspase 3 / 7 induction) and annexin V staining. Such assays may also be used as determinants of cell viability. For example, cells expressing BCL-XL protein (e.g., MOLT-4 cells) can be incubated with various concentrations of a compound provided herein, or a pharmaceutically acceptable salt thereof, and relative caspase activity can be assessed using a luciferase substrate that is activated by caspase 3 / 7 (e.g., using the CASPASE-GLO® 3 / 7 assay). As another example, cells expressing BCL-XL protein (e.g., MOLT-4 cells) can be incubated with various concentrations of a compound provided herein, or a pharmaceutically acceptable salt thereof, and relative caspase activity can be assessed using a dye that is coupled to an activated caspase motif (e.g., INCUCYTE® Caspase 3 / 7 Green Apoptosis Assay Reagent), followed by analysis using a platform for live cell imaging (e.g., an INCUCYTE® SX5 Live-Cell Analysis Instrument). As another example, cells expressing BCL-XL protein (e.g., MOLT-4 cells) can be incubated with various concentrations of a compound provided herein, or a pharmaceutically acceptable salt thereof, and annexin V positivity can be assessed using phosphatidylserine dye (e.g., an INCUCYTE® Annexin V dye), followed by analysis using a platform for live cell imaging (e.g., an INCUCYTE® SX5 Live-Cell Analysis Instrument).

[0510] As another example, the potency and / or efficacy of a compound provided herein, or a pharmaceutically acceptable salt thereof, can be evaluated in an animal model, for example, a cell line-derived xenograft (CDX) model (e.g., using an established cancer cell line such as M0LT4, HEL, TF1, F36P, 0CI-M1, 0CLM2, SET-2, CMK, M07E, UKE-1, or NCI-H1417), or a patient-derived xenograft (PDX) model. For example, a CDX or PDX model can be run in immunodeficient mice (e.g., athymic nude, outbred homozygous (e.g., Crl: NU(NCr)-Foxnlnu) or Fox Chase SCID (CB17 / Icr-Prkdcscld / IcrIcoCrl), mice). The mice can be female, 6-12 weeks old at tumor implantation and have access to food and water ad libitum. Approximately 70 mg of a tumor can be implanted subcutaneously in the right flank of each mouse. Following implantation, tumors can be measured weekly and once the tumor volumes reach 150-300 mm3, the mice can be randomized into treatment and control groups. In some embodiments, one or more experimental arms can be added to evaluate pharmacokinetics and / or pharmacodynamics. The mice can be treated with a compound provided herein, or a pharmaceutically acceptable salt thereof, (e.g., via IP or PO (oral) administration) and optionally an additional therapy or therapeutic agent (e.g., any of the additional therapies or therapeutic agents described herein). Throughout the study, health condition, body weight and tumor volumes of the mice can be recorded on a weekly basis. The mice can be sacrificed at 28 days or when the tumor reaches 1 cm3, and the tumors can be evaluated (e.g., by tumor weight, by tumor volume). At the end of each study, the Best Response can be calculated for each treatment arm. Best Response is defined as the minimum value of AVolumetfor t > 10 days. Best Responses between the control arm(s) and the treatment arm(s) can be compared to determine if the treatment(s) work better than the control(s). In some embodiments, tumor samples can also be collected at the end of each study and relevant proteins (e.g., BCL-XL, BCL-2, BCL-W, MCL-1, BIM, BAX, and / or BAK) can be measured to determine if the treatment might have a better protein modulation profile compared to a control. In some embodiments, tumor samples can also be collected at the end of each study and analyzed for signaling pathway activity (e.g., via phosphoERK levels). For pharmacokinetic and pharmacodynamic studies, tumor and / or blood samples from the mice can be obtained at the same or different time points than efficacy studies. For example, for pharmacokinetic and pharmacodynamic studies, tumor and / or blood samples from the mice can be obtained at Day 5, 6 hours post dosing, and relevant proteins can be measured in the tumor samples and pharmacokinetic studies can be performed on the blood samples or a portion thereof (e.g., plasma).

[0511] In some embodiments, the PDX is a model of a myeloproliferative neoplasm (MPN) (e.g., CEL, CML, CNL, essential thrombocythemia (e.g., JAK2 mutant (e.g., JAK2 V617F mutant) essential thrombocythemia or JAK2 wild type essential thrombocythemia), polycythemia vera (e.g., JAK2 mutant (e.g., JAK2 V617F mutant) polycythemia vera or JAK2 wild type polycythemia vera), or myelofibrosis (e.g., primary myelofibrosis (e.g., JAK2 mutant (e.g., JAK2 V617F mutant) primary myelofibrosis or JAK2 wild type primary myelofibrosis), post-essential thrombocythemia myelofibrosis (e.g., JAK2 mutant (e.g., JAK2 V617F mutant) post-essential thrombocythemia myelofibrosis or JAK2 wild type post-essential thrombocythemia myelofibrosis), or post-polycythemia vera myelofibrosis (e.g., JAK2 mutant (e.g., JAK2 V617F mutant) post-polycythemia vera myelofibrosis or JAK2 wild type postpolycythemia vera myelofibrosis)))), a CRC (e.g., BRaf mutant CRC (e.g., Braf V600E CRC) or KRas mutant CRC (e.g., KRas G12C mutant CRC or KRas G12D CRC)), a SCLC (e.g., ASCL1 subtype SCLC or NEURODI subtype SCLC), aNSCLC (e.g., BRaf mutant NSCLC (e g., Braf V600E NSCLC), an EGFR mutant NSCLC (e g., EGFR L858R NSCLC or EGFR exon 19 deletion NSCLC), MET mutant NSCLC (e.g., MET exon 14 deletion NSCLC, MET amplified NSCLC), a KRas mutant NSCLC (e.g., KRas G12C NSCLC)), a lung squamous cell carcinoma, a malignant pleural mesothelioma (e.g., a BAP1 mutant malignant pleural mesothelioma), a melanoma (e.g., Braf mutant melanoma (e.g., Braf V600E melanoma)), a breast cancer (e.g., HER2+ breast cancer (e.g., HER2+ breast cancer with ER expression, HER2+ breast cancer without ER expression), HER2 negative breast cancer (e.g., HER2 negative breast cancer with ER expression, HER2 negative breast cancer without ER expression), triple negative breast cancer, or HER2 low breast cancer), a lymphoma (e.g., a T cell lymphoma (e.g., anaplastic large T cell lymphoma, cutaneous T cell lymphoma, or peripheral T cell lymphoma), or a non-Hodgkin lymphoma (e.g., DLBCL, anaplastic large T cell lymphoma, cutaneous T cell lymphoma, or peripheral T cell lymphoma), a leukemia (e.g., T cell leukemia (e.g., a T-ALL (e.g., relap sed / refractory T-ALL)), post-MPN leukemia, M6-AML, M7-AML), a head and neck cancer, a pancreatic cancer, a bladder cancer, an ovarian cancer (e.g., BRCA1 mutant ovarian cancer or BRCA2 mutant ovarian cancer, HGSOC (e.g., BRCA1 mutant HGSOC or BRCA2 mutant HGSOC)), a cervical cancer, an intrahepatic cholangiocarcinoma, or a mesenchymal cancer (e.g., mesenchymal breast cancer or mesenchymal kidney cancer).

[0512] See, e.g., Khan, et al. Nature Medicine 25.12 (2019): 1938-1947, doi: 10.1038 / s41591-019-0668-z; Balachander, et al. Clinical Cancer Research 26.24 (2020): 6535-6549, doi: 10.1158 / 1078-0432. CCR-20-0863.

[0513] The pharmacokinetic parameters of a compound provided herein, or a pharmaceutically acceptable salt thereof, can be evaluated in an animal model, for instance, a mouse model, a rat model, a dog model, or a nonhuman primate (e.g., cynomolgus monkey) model. An exemplary protocol includes the following. For example, pharmacokinetics (PK) studies can be conducted on animals (e.g., male or female CD-I mice, Sprague Dawley rats, beagle dogs, or cynomolgus monkeys) by two delivery routes: intravenous (IV) injection and oral gavage (PO). Animals in both the IV and PO groups (e.g., n = 3) are allowed free access to food and water, or may be fasted. A compound provided herein, or a pharmaceutically acceptable salt thereof, can be formulated in solution for the IV route and solution or suspension for the PO route. On the day of the experiment, the compound provided herein, or a pharmaceutically acceptable salt thereof, can be administered via vein injection (e.g., at 1 mg / kg) for IV route or via oral gavage (e.g., at 0.3 to 100 mg / kg) for PO route. Blood samples can be collected via serial bleeding (e.g., at 8 timepoints from 0.83 to 24 hours post dose). At each timepoint, blood can be collected (e.g., approximately 30 pL of blood / timepoint) in a K2EDTA tube via a vein (e.g., the saphenous vein). Blood samples can be put on wet ice and centrifuged (e.g., at 4600 RPM for 4 minutes) to obtain plasma samples. Plasma samples can be diluted 1:1 (v / v) (e.g., with an equal volume of pH 3.0 phosphate buffer) and submitted to LC-MS / MS for sample analysis. Pharmacokinetic parameters, including clearance (IV), area under the curve (AUC), maximum concentration (Cmax), the time at which maximum concentration is reached (Tmax), mean residence time (MRT) and oral bioavailability (%F) can be calculated using a noncompartmental model.

[0514] In some embodiments, the pharmacokinetic parameters of a compound provided herein, or a pharmaceutically acceptable salt thereof, can be measured in a mouse model (e.g., a CD-1 (ICR) model). An exemplary protocol follows.

[0515] Mice (e.g., male CD-I (ICR) mice, 7-9 weeks of age) are dosed with a compound provided herein, or a pharmaceutically acceptable salt thereof, once, either orally (PO) (e.g., at 3, 10, 30, 100, or 300 mg / kg) or intravenously (IV) (e.g., at 1 mg / kg). The compound provided herein, or a pharmaceutically acceptable salt thereof, is administered to the mice in a solution formulation (e.g., 100% PEG400 for the PO groups or 5% DMSO / 10% Solutol / 85% water for the IV group). The mice have access to food and water ad libitum.

[0516] Blood samples (e.g., 30 pL per sample) from the mice are taken at predetermined intervals, such as 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours, 48 hours, and 72 hours) after the dose is administered (not every mouse will have every time point sampled, also called sparse sampling). The blood is sampled via saphenous vein puncture, then the blood samples (e.g., with K2EDTA as anticoagulant) are temporarily put on ice and then centrifuged (e.g., at 4 °C and 4600 RPM for 5 minutes) within 30 minutes. Plasma samples are acidified via dilution with an equal volume of pH 3.0 phosphate buffer and put on dry ice. After the completion of the last sampling, all samples are stored at -80°C or analyzed in a short time following collection. The concentration of the compound provided herein, or a pharmaceutically acceptable salt thereof, measured in an acidified plasma sample can be determined (e.g., via LC / MS / MS). For example, an acidified plasma sample is prepared for analysis using protein precipitation (e.g., by the addition of methanol), and an internal standard is spiked in at a known concentration. The spiked sample is mixed, centrifuged, and the supernatant is used in an LC / MS / MS method. The LC / MS / MS method uses a KINETEX® C 18 2.6 pm 100 A (50 mm * 2.10 mm) column with a first mobile phase of water (0.1% formic acid) and a second mobile phase of acetonitrile (0.1% formic acid). Multiple reaction monitoring is used to measure the analyte(s) of interest. Using the concentration of the compound provided herein, or a pharmaceutically acceptable salt thereof, in the plasma sample, pharmacokinetic parameters of terminal ti / 2 (hr), tmax (hr), Cmax (ng / mL), AUCiast (hr*ng / mL), AUCinf (hr*ng / mL), AUCrxtr (%), MRTinf (hr), AUCinf / D (hr*kg*ng / mL / mg), and %F, are determined via noncompartmental analysis.

[0517] In some embodiments, the pharmacokinetic parameters of a compound provided herein, or a pharmaceutically acceptable salt thereof, can be measured in a rat model (e.g., a Sprague-Dawley rat model). An exemplary protocol follows.

[0518] Rats (e.g., male Sprague-Dawley rats, 7-9 weeks of age) are dosed with a compound provided herein, or a pharmaceutically acceptable salt thereof, either orally (PO) (e.g., at 10, 30, or 100 mg / kg) or intravenously (IV) (e.g., at 1 mg / kg). The compound provided herein, or a pharmaceutically acceptable salt thereof, is administered to the rats in a solution or suspension formulation (e.g., 10% l-Methyl-2-Pyrrolidinone (NMP) / 15% Solutol / 75% (20% (2-Hydroxypropyl)-P-cyclodextrin (HPBCD) in water) for the PO group or 10% DMSO / 10% Solutol / 80% water solution for the IV group). The rats have access to food and water ad libitum.

[0519] Blood samples (e.g., 150 pL per sample) from the rats are taken at predetermined intervals, such as 5 minutes, 15, minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours, 48 hours, and 72 hours after the dose is administered. The blood is sampled via jugular vein puncture, then the blood samples (e.g., with K2EDTA as anticoagulant) are temporarily put on ice and then centrifuged (e.g., at 4 °C and 6000 RPM for 5 minutes) within 30 minutes. Plasma samples are acidified via dilution with an equal volume of pH 3.0 phosphate buffer and put on dry ice. After the completion of the last sampling, all samples are stored at -80°C or analyzed in a short time following collection. The concentration of the compound provided herein, or a pharmaceutically acceptable salt thereof, can be measured in an acidified plasma sample (e.g., diluted 1:1 v / v with pH 3 phosphate buffer) can be determined (e.g., via LC / MS / MS). For example, an acidified plasma sample is prepared for analysis using protein precipitation (e.g., by the addition of methanol, then methanol / acetonitrile 1:1, v / v containing a known concentration of internal standard). The spiked sample is mixed, centrifuged, and the supernatant is used in an LC / MS / MS method. The LC / MS / MS method uses a KINETEX® C 18 2.6 pm 100 A (50 mm * 2.10 mm) column with a first mobile phase of water (0.1% formic acid (FA)) and a second mobile phase of acetonitrile (0.1% FA). Multiple reaction monitoring is used to measure the analyte(s) of interest. Using the concentration of the compound provided herein, or a pharmaceutically acceptable salt thereof, in the plasma sample, pharmacokinetic parameters of terminal ti / 2 (hr), tmax (hr), Cmax (ng / mL), AUCiast (hr*ng / mL), AUCinf (hr*ng / mL), AUCrxtr (%), MRTinf (hr), AUCinf / D (hr*kg*ng / mL / mg), %F, AUC0-24 (hr*ng / mL), and AUC48-72 (hr*ng / mL) are determined via noncompartmental analysis.

[0520] In some embodiments, the pharmacokinetic parameters of a compound provided herein, or a pharmaceutically acceptable salt thereof, can be measured in a dog model (e.g., a beagle model). An exemplary protocol follows.

[0521] Dogs (e.g., male Beagle dogs) are dosed with a compound provided herein, or a pharmaceutically acceptable salt thereof, orally (PO) (e.g., at 0.3, 1, 3 or 10 mg / kg) or intravenously (IV) (e.g., at 0.1 mg / kg). The compound provided herein, or a pharmaceutically acceptable salt thereof, is administered to the dogs in a solution or suspension formulation (e.g., 10% NMP / 15% Solutol / 75% (20% HPBCD in water)). The dogs are in the fed state.

[0522] Blood samples (e.g., about 0.5 mL) from the dogs are taken at predetermined intervals, such as 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours, 48 hours, and 72 hours after the dose is administered. The blood is sampled via peripheral vein puncture, then the blood samples (e.g., with K2EDTA as anticoagulant) are temporarily put on ice and then centrifuged (e.g., at 2-8 °C and 3200 * gfor 10 minutes) within 30 minutes. Plasma samples are acidified via dilution with an equal volume of pH 3.0 phosphate buffer and put on dry ice. After the completion of the last sampling, all samples are stored at -60 to -80°C or analyzed in a short time following collection. The concentration of the compound provided herein, or a pharmaceutically acceptable salt thereof, can be measured in an acidified plasma sample can be determined (e.g., via LC / MS / MS). For example, an acidified plasma sample is prepared for analysis using protein precipitation (e.g., by the addition of acetonitrile containing internal standard of known concentration). The spiked sample is mixed, centrifuged, and the supernatant is used in an LC / MS / MS method. The LC / MS / MS method uses an ACQUITY UPLC HSS T3 1.8 pm 2.1 x 50 mm column (or an ACQUITY UPLC Protein BEH C4300A 1.7 pm 2.1 x 50 mm column) with a first mobile phase of 0.1% formic acid and 2 mM ammonium formate in water / acetonitrile (v:v, 95:5) and a second mobile phase of 0.1% formic acid and 2 mM ammonium formate in acetonitrile / water (v:v, 95:5). Multiple reaction monitoring is used to measure the analyte(s) of interest. Using the concentration of the compound provided herein, or a pharmaceutically acceptable salt thereof, in the plasma sample, pharmacokinetic parameters of terminal ti / 2 (hr), tmax (hr), Cmax (ng / mL), AUCiast (hr*ng / mL), AUCinf (hr*ng / mL), AUCrxtr (%), MRTinf (hr), %F, and AUC0-24 (hr*ng / mL), are determined via noncompartmental analysis.

[0523] In some embodiments, the pharmacokinetic parameters of a compound provided herein, or a pharmaceutically acceptable salt thereof, can be measured in a non-human primate model (e.g., a cynomolgus monkey model). An exemplary protocol follows.

[0524] Non-human primates (e.g., male cynomolgus monkeys) are dosed with a compound provided herein, or a pharmaceutically acceptable salt thereof, orally (PO) (e.g., at 3 mg / kg) or intravenously (IV) (e.g., at 0.5 mg / kg). The compound provided herein, or a pharmaceutically acceptable salt thereof, is administered to the monkeys in a solution formulation (e.g., 10% NMP / 15% Solutol / 75% (20% HPBCD in water, pH 5)). The monkeys are in the fed state.

[0525] Blood samples (e.g., about 0.5 mL) from the monkeys are taken at predetermined intervals, such as 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours, and 48 hours after the dose is administered. The blood is sampled via peripheral vein puncture, then the blood samples (e.g., with K2EDTA as anticoagulant) are temporarily put on ice and then centrifuged (e.g., at 2-8 °C and 3200 x gfor 10 minutes) within 30 minutes. Plasma samples are acidified via dilution with an equal volume of pH 3.0 phosphate buffer and put on dry ice. After the completion of the last sampling, all samples are stored at -60 to -80°C or analyzed in a short time following collection. The concentration of the compound provided herein, or a pharmaceutically acceptable salt thereof, can be measured in an acidified plasma sample via LC / MS / MS. For example, an acidified plasma sample is prepared for analysis using protein precipitation (e.g., by the addition of acetonitrile containing internal standard of known concentration). The spiked sample is mixed, centrifuged, and the supernatant is used in an LC / MS / MS method. The LC / MS / MS method uses an ACQUITY UPLC BEH C18 1.7 pm 2.1 x 50 mm column with a first mobile phase of 0.1% formic acid and 2 mM ammonium formate in water / acetonitrile (v:v, 95:5) and a second mobile phase of 0.1% formic acid and 2 mM ammonium formate in acetonitrile / water (v:v, 95:5). Multiple reaction monitoring is used to measure the analyte(s) of interest. Using the concentration of the compound provided herein, or a pharmaceutically acceptable salt thereof, in the plasma sample, pharmacokinetic parameters of terminal ti / 2 (hr), tmax (hr), Cmax (ng / mL), AUCiast (hr*ng / mL), AUCinf (hr*ng / mL), AUCrxtr (%), MRTinf (hr), %F, and AUC0-24 (hr*ng / mL), are determined via noncompartmental analysis.

[0526] In some embodiments, the %F for a compound provided herein, or a pharmaceutically acceptable salt thereof, is at least 4%. In some embodiments, the %F for a compound provided herein, or a pharmaceutically acceptable salt thereof, is at least 10%. In some embodiments, the %F for a compound provided herein, or a pharmaceutically acceptable salt thereof, is at least 20%. In some embodiments, the %F for a compound provided herein, or a pharmaceutically acceptable salt thereof, is at least 30%. In some embodiments, the %F for a compound provided herein, or a pharmaceutically acceptable salt thereof, is at least 40%. In some embodiments, the %F for a compound provided herein, or a pharmaceutically acceptable salt thereof, is about 4% to about 80% (e.g., about 4% to about 60%, about 4% to about 40%, about 4% to about 20%, about 4% to about 10%, about 20% to about 40%, or about 20% to about 30%). In some embodiments, the %F for a compound provided herein, or a pharmaceutically acceptable salt thereof, is about 4% to about 20% (e.g., about 4% to about 10%). In some embodiments, the %F for a compound provided herein, or a pharmaceutically acceptable salt thereof, is about 20% to about 40%. In some embodiments, the %F for a compound provided herein, or a pharmaceutically acceptable salt thereof, is about 40% to about 60%. In some embodiments, the %F for a compound provided herein, or a pharmaceutically acceptable salt thereof, is about 60% to about 80%.

[0527] In some embodiments, the oral clearance (CL / F) for a compound provided herein, or a pharmaceutically acceptable salt thereof, dosed PO in rats at 10 mg / kg, is less than 10 mL / min / kg (e.g., less than 5 mL / min / kg, less than 3 mL / min / kg, or less than 1 mL / min / kg). In some embodiments, clearance for a compound provided herein, or a pharmaceutically acceptable salt thereof, dosed PO in rats at 10 mg / kg, is about 0.05 mL / min / kg to about 5 mL / min / kg (e.g., about 0.05 mL / min / kg to about 3 mL / min / kg, about 0.05 mL / min / kg to about 1 mL / min / kg, or about 0.05 mL / min / kg to about 0.5 mL / min / kg).

[0528] In some embodiments, the AUC for a compound provided herein, or a pharmaceutically acceptable salt thereof, dosed PO in rats at 10 mg / kg, is about 10 pM»h to about 350 pM»h (e.g., 10 pM»h to about 150 pM»h, about 50 pM»h to about 350 pM»h, about 100 pM»h to about 350 pM»h, or about 150 pM»h to about 350 pM»h). In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is not a substrate of a human cytochrome P450 enzyme. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is not a substrate of a human cytochrome P450 enzyme where > 25% of clearance is attributed to that enzyme. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is not an inhibitor and / or an inducer of one or more human cytochrome P450 enzymes. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is not an inhibitor and / or an inducer of one or more human cytochrome P450 enzymes, where the IC50 value and / or EC50 value for the one or more human cytochrome P450 enzymes, respectively, is significantly greater than the estimated free fraction concentration of a compound provided herein, or a pharmaceutically acceptable salt thereof, at a clinically relevant dose.

[0529] Exemplary human cytochrome P450 enzymes include those in the CYP1, CYP2, and CYP3 families. Of those, CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2J2, CYP2S1, CYP2E1, CYP3A4, and CYP3 A5 are known drug metabolizing enzymes. In some embodiments, no single cytochrome P450 enzyme is responsible for greater than or equal to 25% of the elimination of a compound provided herein, or a pharmaceutically acceptable salt thereof. Cytochrome P450 inhibition and / or inducing activity can be determined using appropriate in vitro assays, such as those described in the guidance document “In Vitro Drug Interaction Studies — Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions” provided by the U. S. F. D. A. in January 2020, and similarly in the ICH M12 guidance finalized in May 2024. For example, evaluation of cytochrome P450 inhibition can be performed in in vitro studies, in both a reversible and time-dependent manner. In an in vitro inhibition study, the ratio of intrinsic clearance values of a probe substrate for an enzymatic pathway in the absence and in the presence of a compound provided herein, or a pharmaceutically acceptable salt thereof, can be calculated based on these in vitro results; this ratio is referred to as Ri for reversible inhibition, where Ri = 1 + (Imax,u / Ki,u), and Imax,uis the maximal unbound plasma concentration of the compound provided herein, or a pharmaceutically acceptable salt thereof, predicted in human, and Ki,uis the unbound inhibition constant determined in vitro. Specifically, in the case of CYP3 A whereas the enzyme is also expressed at significant levels in the intestine, Ri.gut can be calculated where Ri,gut= 1 + (Igut + Ki,u), and where Igut is predicted human intestinal luminal concentration of the compound provided herein, or a pharmaceutically acceptable salt thereof, calculated as the human oral dose / 250mL. The time-dependent inhibition ratio R2 can similarly be calculated, where R2 = (kobs + kdeg) / kdeg, and kobs is the observed (apparent first order) inactivation rate of the affected cytochrome P450 calculated by kobs = (kinact*Imax,u) / (Ki,u+ *Imax,u), kdeg is the apparent first-order degradation rate constant of the affected cytochrome P450, Ki,uis the unbound concentration of the compound provided herein, or a pharmaceutically acceptable salt thereof, causing half maximal inactivation, and kinact is the maximal inactivation rate constant. Utilizing these equations for Ri, Ri.gut, and R2, the compound provided herein, or a pharmaceutically acceptable salt thereof, can be evaluated for their potential to be an inhibitor of a cytochrome P450, and the drug-drug interaction (DDI) potential can be further investigated using mechanistic or physiological-based pharmacokinetic models of the liver and intestine and / or conducting a clinical DDI study with a sensitive index substrate. Additionally, a compound’s propensity to activate nuclear receptors (e.g., PXR, CAR, or AhR) is evaluated through in vitro cytochrome P450 hepatocyte induction studies and the resulting data can be evaluated via the fold-change method, wherein the fold-change in cytochrome P450 enzyme mRNA levels, when incubated with the compound provided herein, or a pharmaceutically acceptable salt thereof, based on cutoff determined from known positive and negative controls to calibrate the system. For example, a compound provided herein, or a pharmaceutically acceptable salt thereof, is determined to be an inducer if (1) it increases mRNA expression of a cytochrome P450 enzyme in a concentration-dependent manner; and (2) the fold change of cytochrome P450 mRNA expression relative to the vehicle control is > 2-fold at the expected hepatic concentrations of the drug. Additionally, evaluation of cytochrome P450 induction can be performed by a correlation method, wherein correlation methods are used to predict the magnitude of a clinical induction effect (e.g., AUC ratio of an index substrate in the presence and absence of inducers) of a compound provided herein, or a pharmaceutically acceptable salt thereof, according to a calibration curve of relative induction scores (RIS) or Imax.11 / EC50 for a set of known inducers of the same cytochrome P450. If the predicted magnitude is more than a predefined cut-off (e.g., AUC ratio < 0.8), a compound provided herein, or a pharmaceutically acceptable salt thereof, is considered to have induction potential in vivo.

[0530] In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can be tested for its potency in inhibiting hERG potassium channels. The cardiac potassium channel hERG is responsible for a rapid delayed rectifier current (Z&) in human ventricle, and inhibition of Z& is the most common cause of cardiac action potential prolongation by non-cardiac drugs. Increased action potential duration causes prolongation of the QT interval that has been associated with a dangerous ventricular arrhythmia, torsade de pointes. There are several methods of testing hERG inhibition potency, including Fastpatch hERG and manual patch clamp experiments.

[0531] In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is tested for its potency in inhibiting hERG potassium channels using a manual patch clamp assay. For example, in some embodiments, solutions or suspensions of a compound provided herein, or a pharmaceutically acceptable salt thereof, at several concentrations (e.g., 0.3, 1, 3 and 10 pM) can be exposed to single cells. The effect of the compound provided herein, or a pharmaceutically acceptable salt thereof, on the inhibition of hERG potassium channels can be measured in this system using an electrical pulse pattern, the data plotted, and an ICso value calculated for the inhibition of hERG by the compound provided herein, or a pharmaceutically acceptable salt thereof. An exemplary protocol follows.

[0532] In this experiment, hERG potassium channels are expressed in a human embryonic kidney cell line that lacks endogenous / Kr(HEK-293 (ATCC 293T, CRL-3216™)). See, e.g., Brown, Arthur M., and David Rampe. Pharmaceutical News 7.4 (2000): 15-20; Weirich, Jorg, and H. Antoni, Basic Research in Cardiology 93 (1998): sl25-sl32, doi: 10.1007 / s003950050236; and Yap, Yee Guan, and A. J. Camm. Clinical & Experimental Allergy 29 (1999): 174-181, doi: 10.1046 / j.1365-2222.1999.0290s3174.x.

[0533] All chemicals used in solution preparations are purchased from a commercial supplier (e.g., Sigma-Aldrich) and are of ACS reagent grade purity or higher. Stock solutions of the compound provided herein, or a pharmaceutically acceptable salt thereof, positive control compound(s), and reference substance(s) are prepared in dimethyl sulfoxide (DMSO) and stored frozen. Solutions of each compound provided herein, or a pharmaceutically acceptable salt thereof, positive control compound, and reference substance concentrations are prepared fresh daily by diluting stock solutions into HEPES-buffered physiological saline solution (HB-PS; 137 mM NaCl, 4 mM KC1, 1.8 mM CaCl2, 1 mM MgCh, 10 mM HEPES, and 10 mM glucose, pH 7.4). Since previous results have shown that < 0.3% DMSO does not affect channel current, all test and control solutions can contain 0.3% DMSO.

[0534] In some embodiments, a positive control compound can be included in the experiment. In some such embodiments, the positive control compound can be terfenadine (Sigma-Aldrich), for example, in a HB-PS and 0.3% DMSO solution. In some embodiments, a reference compound can be included in the experiment. In some such embodiments, the reference compound can be E-4031 (Sigma- Aldrich), for example, in a HB-PS and 0.3% DMSO solution.

[0535] If necessary, solutions are sonicated to facilitate dissolution. Visible precipitate observed during preparation or exposure of formulations to the test system is noted for reference.

[0536] The effect of a compound provided herein, or a pharmaceutically acceptable salt thereof, are initially evaluated at concentration range of 1 to 10 pM. Subsequent concentrations are evaluated based on the inhibition observed at that concentration.

[0537] HEK-293 cells are transfected with hERG cDNA. Stable transfectants are selected by coexpression of the G418-resistance gene incorporated into the expression plasmid. Selection pressure is maintained by including G418 in the culture medium. Cells are cultured in Dulbecco’s Modified Eagle’s Medium / Ham’s Nutrient Mixture F-12 (DMEM / F-12) supplemented with 10% fetal bovine serum and the appropriate concentrations of penicillin G sodium, streptomycin sulfate, and G418.

[0538] All experiments are performed at near-physiological temperature (33 - 35 °C). Each cell acts as its own control.

[0539] The effect of a compound provided herein, or a pharmaceutically acceptable salt thereof, is evaluated at multiple (e.g., up to four) concentrations. Each concentration will be tested in at least three cells (n > 3). Additional concentration(s) may be tested due to the limits imposed by the physiochemical effects of the compound provided herein, or a pharmaceutically acceptable salt thereof (e.g., solubility or cytotoxicity).

[0540] The positive control compound is tested in at least two (2) cells (n > 2).

[0541] Cells are transferred to the recording chamber and superfused with vehicle control solution. Pipette (intracellular) solution for whole cell recordings is composed of 130 mM potassium aspartate, 5 mM MgCh, 5 mM EGTA, 4 mM ATP, and 10 mM HEPES, pH 7.2. Pipette solution is prepared in batches, aliquoted, stored frozen and a fresh aliquot thawed each day. The recording is performed at a temperature of 33 to 35 °C using a combination of in-line solution pre-heater, chamber heater, and feedback temperature controller. Temperature is measured using a thermistor probe in the recording chamber. Micropipettes for patch clamp recording are made from glass capillary tubing using a P-97 micropipette puller (Sutter Instruments). A commercial patch clamp amplifier (Molecular Devices) is used for whole patch clamp cell recordings. Before digitization, current records are low-pass filtered. Cells stably expressing hERG are held at -80 mV. Onset and steady state inhibition of hERG potassium current due to the compound provided herein, or a pharmaceutically acceptable salt thereof, are measured using a pulse pattern with fixed amplitudes (conditioning prepulse of +20 mV for 1 second; repolarizing test ramp to -80 mV (at -0.5 V / second) repeated at 5 second intervals). Each recording ends with an application of a supramaximal concentration of the reference substance (e.g., E-4031 at 500 nM) to assess the contribution of endogenous currents. The remaining uninhibited current is subtracted off-line digitally from the data to determine the potency of the compound provided herein, or a pharmaceutically acceptable salt thereof, for hERG inhibition. Peak current is measured during the test ramp. A steady state is maintained for at least 20 seconds before applying the compound provided herein, or a pharmaceutically acceptable salt thereof, positive control compound, or reference substance. Peak tail currents are measured until a new steady state is achieved. If a steady state cannot be reached within 12 minutes, the response at 12 minutes is substituted for the steady state value and a notation made.

[0542] Data acquisition and analyses are performed using the commercial suite of pCLAMP programs (Molecular Devices). Steady state is defined by the limiting constant rate of change with time (linear time dependence). The steady state before and after application of each compound provided herein, or a pharmaceutically acceptable salt thereof, is used to calculate the percentage of current inhibited at each concentration.

[0543] In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is tested for its potency in inhibiting hERG potassium channels (e.g., encoded by the KCNH2 gene and expressed in HEK293 cells) using a Fastpatch hERG assay. For example, in some embodiments, solutions or suspensions of a compound provided herein, or a pharmaceutically acceptable salt thereof, at several concentrations (e.g., 0.3, 1, 3 and 10 pM) can be exposed to cells in an automatic parallel patch clamp system. The effect of the compound provided herein, or a pharmaceutically acceptable salt thereof, on the inhibition of hERG potassium channels can be measured in this system using an electrical pulse pattern, the data plotted, and an ICso value calculated for the inhibition of hERG by the compound provided herein, or a pharmaceutically acceptable salt thereof. An exemplary protocol follows.

[0544] The in vitro effects of a compound provided herein, or a pharmaceutically acceptable salt thereof, are evaluated at room temperature using the QPATCH HT® (Sophion Bioscience A / S, Denmark), an automatic parallel patch clamp system. The compound provided herein, or a pharmaceutically acceptable salt thereof, is exposed to hERG at 0.3, 1, 3 and 10 pM in at least five cells (n > 5). The duration of exposure to each compound concentration is at least three minutes.

[0545] Solutions or suspensions of the compound(s) provided herein, or a pharmaceutically acceptable salt thereof, are prepared daily. Various concentrations are prepared by diluting stock solutions into an appropriate HEPES-buffered physiological saline solution (HB-PS).

[0546] Previous results have shown that 0.3% DMSO does not affect channel current. Therefore, all test and control solutions can contain up to 0.3% DMSO.

[0547] Each formulation of a compound provided herein, or a pharmaceutically acceptable salt thereof, can be sonicated (e.g., Model 2510 / 5510, Branson Ultrasonics, Danbury, CT), e.g., at room temperature, to facilitate dissolution.

[0548] In some embodiments, a positive control can be included in the experiment. In some such embodiments, the positive control compound can be cisapride (Tocris Bioscience), for example, in a 0.3% DMSO solution.

[0549] In preparation for the recording session, a glass-lined 96-well compound plate is loaded with the appropriate amounts of solutions of compound(s) provided herein, or a pharmaceutically acceptable salt thereof, and control solutions, and placed in the plate well of the QPATCH® (Sophion Bioscience A / S, Denmark).

[0550] HEK293 (ATCC 293 T, CRL-3216™) cells are stably transfected with the appropriate ion channel cDNA(s). Except for cells that have been stored frozen, stable transfectants are maintained in the culture medium with the appropriate selection pressure and antibiotics.

[0551] All experiments are performed at room temperature. Each cell acts as its own control. Vehicle is applied via the QPATCH® robot pipetting system to naive cells for a 5-10 minute exposure interval. After vehicle application, various concentrations of a compound provided herein, or a pharmaceutically acceptable salt thereof, are applied in at least three (3) minute intervals (n ~ 3, where n = the number of cells / concentration). Each solution exchange on the QPATCH® is performed multiple times, which results in 100% replacement of the compound in the QPlate.

[0552] Positive control(s) are applied in the same manner as the compound provided herein, or a pharmaceutically acceptable salt thereof, to verify sensitivity to ion channel blockade.

[0553] In preparation for a recording session, an intracellular solution (e.g., 137 mM NaCl, 4 mMKCl, ES mMCaCh, 1 mMMgCh, lO mMHEPES, and 10 mM glucose, pH 7.4) is loaded into the intracellular compartments of the QPlate and cell suspension is pipetted into the extracellular compartments. After establishment of a whole-cell configuration, membrane currents are recorded using up to 48 parallel patch clamp amplifiers in the QPATCH® system.

[0554] Valid whole-cell recordings meet the following criteria:

[0555] 1. Membrane resistance > 200 MQ.

[0556] 2. Leak current < 25% channel current or subtracted.

[0557] Onset and block of hERG current is measured using a stimulus voltage pattern consisting of a 500 ms prepulse to -40 mV (leakage subtraction), a 2-second activating pulse to +40 mV followed by a 2-second test pulse to -40 mV. The pulse pattern is repeated continuously at 10 s intervals from a holding potential of -80 mV. Peak tail current is measured during the -40 mV test pulse. Leakage current is calculated from the current amplitude evoked by the -40 mV prepulse and subtracted from the total membrane current record.

[0558] Data acquisition and analyses are performed using conventional software. Steady state is defined by the limiting constant rate of change with time (linear time dependence). The steady state before and after application of a compound provided herein, or a pharmaceutically acceptable salt thereof, will be used to calculate the percentage of current inhibited at each concentration. If current is blocked >50%, estimated ICso values will be calculated using the following formula:

[0559] % Inhibition = { 1 -l / [l+([Test] / IC5o)N] }* 100

[0560] Where [Test] is the concentration of the compound provided herein, or a pharmaceutically acceptable salt thereof, ICso is the concentration of the compound provided herein, or a pharmaceutically acceptable salt thereof, at half-maximal inhibition, N is the Hill coefficient, and % Inhibition is the percentage of current inhibited at each test article concentration. Nonlinear least squares fits are solved with the Solver add-in for Excel (Microsoft, WA). Overestimation of current inhibition, due to rundown, is avoided by a manual adjustment that uses an exponential compensation formula in the QPATCH® analysis software.

[0561] In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is not a hERG inhibitor. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits hERG with an ICso of greater than 60 nM (e.g., greater than 100 nM, 300 nM, 500 nM, 1 pM, 3 pM, 5 pM, 10 pM, 20 pM, or 30 pM). For example, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits hERG with an IC50 of greater than 500 nM (e.g., greater than 1 pM, 3 pM, 5 pM, 10 pM, 20 pM, or 30 gM). In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits hERG with an IC50 of greater than 1 pM (e.g., greater than 3 pM, 5 pM, 10 pM, 20 pM, or 30 pM). In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits hERG with an IC50 of greater than 10 pM (e.g., greater than 20 pM or 30 pM). In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits hERG with an IC50 of greater than 30 pM.

[0562] In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can be evaluated for potential secondary pharmacology. For example, in some embodiments, solutions of a compound provided herein, or a pharmaceutically acceptable salt thereof, at a single or several concentrations can be exposed to a panel of primary cells, cell lines or isolated tissues expressing known pharmacological receptors, enzymes or transporters. The effect of the compound provided herein, or a pharmaceutically acceptable salt thereof, the secondary pharmacological target of interest can be determined, the data is initially plotted as a percent inhibition. For secondary targets exceeding an inhibition threshold (typically > 50%), an IC50 value is generated and calculated following an 8-point concentration curve of the compound provided herein, or a pharmaceutically acceptable salt thereof.

[0563] An exemplary list of assays is included in Table 1 below. One or more of these assays can be used to assess the secondary pharmacological characteristics of a compound provided herein. Exemplary protocols are described in Valentin, Jean-Pierre, and Tim Hammond. Journal of Pharmacological and Toxicological Methods 58.2 (2008): 77-87; doi: 10.1016 / j.vascn.2008.05.007; Wakefield, Ian D., et al. Fundamental & Clinical Pharmacology 16.3 (2002): 209-218, doi: 10.1046 / j.l472-8206.2002.00099.x; Whitebread, Steven, et al. Drag Discovery Today 10.21 (2005): 1421-1433, doi: 10.1016 / S 1359-6446(05)03632-9; and Lounkine, Eugen, et al. Nature 486.7403 (2012): 361-367, doi: 10.1038 / naturel 1159.

[0564] Table 1.

[0565]

[0566]

[0567]

[0568]

[0569]

[0570] Heterobifunctional degraders can, in some cases, induce the degradation of off-target proteins. For heterobifunctional degraders that utilize CRBN, common off-target proteins that can be degraded include GSPT1, IKZF1, IKZF2, IKZF3, and / or CK1α. This degradation is generally believed to be due to the E3 binding moiety of the heterobifunctional degrader facilitating ternary complex formation between the off-target protein and CRBN. GSPT1 is a translation termination factor, and CK1α is a kinase that is involved in many key cellular processes including cell cycle progression and chromosome segregation; these are both commonly essential genes, so undesired degradation of either or both may lead to nonspecific cytotoxicity. The IKZF proteins are zinc finger transcription factors that are involved with cell fate during hematopoiesis, and degradation of these proteins has been associated with hematotoxicity. See, e.g., Moreau, Kevin, et al. British Journal of Pharmacology 177.8 (2020): 1709-1718, doi: 10.1111 / bph.15014.

[0571] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, can exhibit potent and selective induction of degradation of a BCL-XL protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, can selectively target a BCL-XL protein for degradation over an off-target protein, such as another BCL-2 family member (e.g., BCL-2 and / or MCL-1) or non-BCL-2 family member target (e.g., GSPT1, IKZF1, IKZF2, IKZF3, and / or CK1α).

[0572] As used herein, “selective” or “selectively”, when referring to a compound provided herein, or a pharmaceutically acceptable salt thereof in a protein degradation assay, indicates at least a 5-fold (e.g., at least a 10-fold, at least a 25-fold, at least a 50-fold, or at least a 100-fold) superior performance in the protein degradation assay for a specified protein with reference to a comparator protein in the assay. In some embodiments, the specified protein is BCL-XL protein and the comparator is BCL-2 protein. For example, if a compound provided herein, or a pharmaceutically acceptable salt thereof, “selectively” induces degradation of BCL-XL protein over BCL-2 protein as determined by a degradation assay, then the compound has at least a 5-fold (e.g., at least a 10-fold, at least a 25-fold, at least a 50-fold, or at least a 100-fold) smaller DC₅₀ value for BCL-XL protein than for the BCL-2 protein when measured by the degradation assay.

[0573] In some embodiments, the compounds provided herein can exhibit potency (e.g., nanomolar potency) against a BCL-XL protein with minimal activity (e.g., micromolar potency) against BCL-2 family members (e.g., BCL-2 or MCL-1 proteins). In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can exhibit potent degradation of a BCL-XL protein and have minimal potency in degrading (e.g., as measured by Ymin, DC₅₀, EC₅₀, and / or Dmax values) an off-target protein (e.g., a BCL-2 family member (e.g., BCL-2 and / or MCL-1), GSPT1, IKZF1, IKZF2, IKZF3 and / or CK1α). In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can exhibit greater induction of degradation of a BCL-XL protein relative to induction of degradation (e.g., as measured by Ymin, DC₅₀, EC₅₀, and / or Dmax values) of an off-target protein (e.g., a BCL-2 family member (e.g., BCL-2 and / or MCL-1), GSPT1, IKZF1, IKZF2, IKZF3, and / or CK1α). In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold greater induction of degradation of a BCL-XL protein relative to induction of degradation of an off-target protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can exhibit up to 1000-fold greater induction of degradation of a BCL-XL protein relative to induction of degradation of an off-target protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can exhibit from about 2-fold to about 10-fold greater induction of degradation of a BCL-XL protein relative to induction of degradation of an off-target protein (e.g., GSPT1, IKZF1, IKZF2, and / or IKZF3 and / or CK1α) (e.g., as measured by Ymin, DC₅₀, EC₅₀, and / or Dmax values). In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can exhibit from about 10-fold to about 100-fold greater induction of degradation of a BCL-XL protein relative to induction of degradation of an off-target protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can exhibit from about 100-fold to about 1000-fold greater induction of degradation of a BCL-XL protein relative to induction of degradation of an off-target protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can exhibit from about 1000-fold to about 10000-fold greater induction of degradation of a BCL-XL protein relative to induction of degradation of an off-target protein.

[0574] Certain agents that inhibit or induce degradation of BCL-XL have demonstrated platelet toxicity, which resulted in dose-limiting toxicity (e.g., thrombocytopenia) in the clinic. See, e.g., Adams and Cory, Cell Death & Differentiation 25.1 (2018): 27-36, doi: 10.1038 / cdd.2017.161; Campbell and Tait. Open Biology 8.5 (2018): 180002, doi: 10.1098 / rsob.180002; Pullarkat et al., Cancer Discovery (2021), doi:10.1158 / 2159-8290. CD-20-1465; Negi and Voisin-Chiret. ChemBioChem (2022), doi: 10.1002 / cbic.202100689. The viability of platelets may be monitored with any appropriate assay, such as those described herein. See, for instance, Example B4.

[0575] In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, results in at least about 30% platelet viability (e.g., at least about 50% platelet viability, or at least about 80% platelet viability) when administered to a subject (e.g., compared to the platelet count of the subject prior to administration of the compound provided herein, or a pharmaceutically acceptable salt thereof). In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, results in about 30% to about 100% platelet viability (e.g., about 50% to about 100% platelet viability, or about 80% to about 100% platelet viability) when administered to a subject (e.g., compared to the platelet count of the subject prior to administration of the compound provided herein, or a pharmaceutically acceptable salt thereof).

[0576] In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, results in at least about 30% platelet viability (e.g., at least about 50% platelet viability, or at least about 80% platelet viability) when administered to a subject (e.g., compared to the platelet count of the subject prior to administration of the compound provided herein, or a pharmaceutically acceptable salt thereof) and has a Ymin value of about 50% to about 70% for a BCL-XL protein. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, results in at least about 30% platelet viability (e.g., at least about 50% platelet viability, or at least about 80% platelet viability) when administered to a subject (e.g., compared to the platelet count of the subject prior to administration of the compound provided herein, or a pharmaceutically acceptable salt thereof) and has a Ymin value of less than about 50% for a BCL-XL protein. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, results in at least about 30% platelet viability (e.g., at least about 50% platelet viability, or at least about 80% platelet viability) when administered to a subject (e.g., compared to the platelet count of the subject prior to administration of the compound provided herein, or a pharmaceutically acceptable salt thereof) and has a Ymin value of about 0% to about 50% for a BCL-XL protein.

[0577] In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, results in between about 30% and 100% platelet viability (e.g., about 50% to about 100% platelet viability, or about 80% to about 100% platelet viability) when administered to a subject (e.g., compared to the platelet count of the subject prior to administration of the compound provided herein, or a pharmaceutically acceptable salt thereof) and has a Ymin value of about 50% to about 70% for a BCL-XL protein. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, results in between about 30% and 100% platelet viability (e.g., about 50% to about 100% platelet viability, or about 80% to about 100% platelet viability) when administered to a subject (e.g., compared to the platelet count of the subject prior to administration of the compound provided herein, or a pharmaceutically acceptable salt thereof) and has a Ymin value of less than about 50% for a BCL-XL protein. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, results in between about 30% and 100% platelet viability (e.g., about 50% to about 100% platelet viability, or about 80% to about 100% platelet viability) when administered to a subject (e.g., compared to the platelet count of the subject prior to administration of the compound provided herein, or a pharmaceutically acceptable salt thereof) and has a Ymin value of about 0% to about 50% for a BCL-XL protein.

[0578] In some embodiments, therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, results in at least about 50% platelet viability (e.g., at least about 80% platelet viability) when administered to a subject (e.g., compared to the platelet count of the subject prior to administration of the compound provided herein, or a pharmaceutically acceptable salt thereof) and has a Ymin value of about 50% to about 70% for a BCL-XL protein. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, results in at least about 50% platelet viability (e.g., at least about 80% platelet viability) when administered to a subject (e.g., compared to the platelet count of the subject prior to administration of the compound provided herein, or a pharmaceutically acceptable salt thereof) and has a Ymin value of less than about 50% for a BCL-XL protein. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, results in at least about 50% platelet viability (e.g., at least about 80% platelet viability) when administered to a subject (e.g., compared to the platelet count of the subject prior to administration of the compound provided herein, or a pharmaceutically acceptable salt thereof) and has a Ymin value of about 0% to about 50% for a BCL-XL protein.

[0579] In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, results in between about 50% and 100% platelet viability (e.g., about 80% to about 100% platelet viability) when administered to a subject (e.g., compared to the platelet count of the subject prior to administration of the compound provided herein, or a pharmaceutically acceptable salt thereof) and has a Ymin value of about 50% to about 70% for a BCL-XL protein. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, results in between about 50% and 100% platelet viability (e.g., about 80% to about 100% platelet viability) when administered to a subject (e.g., compared to the platelet count of the subject prior to administration of the compound provided herein, or a pharmaceutically acceptable salt thereof) and has a Ymin value of less than about 50% for a BCL-XL protein. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, results in between about 50% and 100% platelet viability (e.g., about 80% to about 100% platelet viability) when administered to a subject (e.g., compared to the platelet count of the subject prior to administration of the compound provided herein, or a pharmaceutically acceptable salt thereof) and has a Ymin value of about 0% to about 50% for a BCL-XL protein.

[0580] In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, when tested at a concentration of about 0.25 μM to about 3 μM in the assay in Example B4, shows at least about 30% platelet viability (e.g., at least about 50% platelet viability, or at least about 80% platelet viability). In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, when tested at a concentration of about 0.25 μM to about 3 μM in the assay in Example B4, shows about 30% to about 100% platelet viability (e.g., about 50% to about 100% platelet viability, or about 80% to about 100% platelet viability).

[0581] In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, when tested at a concentration of about 0.25 μM to about 3 μM in the assay in Example B4, shows at least about 30% platelet viability (e.g., at least about 50% platelet viability, or at least about 80% platelet viability) and has a Ymin value of about 50% to about 70% in the assay described in Example Bl. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, when tested at a concentration of about 0.25 μM to about 3 μM in the assay in Example B4, shows at least about 30% platelet viability (e.g., at least about 50% platelet viability, or at least about 80% platelet viability) and has a Ymin value of less than about 50% in the assay described in Example Bl. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, when tested at a concentration of about 0.25 μM to about 3 μM in the assay in Example B4, shows at least about 30% platelet viability (e.g., at least about 50% platelet viability, or at least about 80% platelet viability) and has a Ymin value of about 0% to about 50% in the assay described in Example Bl.

[0582] In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, when tested at a concentration of about 0.25 μM to about 3 μM in the assay in Example B4, shows between about 30% and 100% platelet viability (e.g., about 50% to about 100% platelet viability, or about 80% to about 100% platelet viability) and has a Ymin value of about 50% to about 70% in the assay described in Example Bl. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, when tested at a concentration of about 0.25 μM to about 3 μM in the assay in Example B4, shows between about 30% and 100% platelet viability (e.g., about 50% to about 100% platelet viability, or about 80% to about 100% platelet viability) and has a Ymin value of less than about 50% in the assay described in Example Bl. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, when tested at a concentration of about 0.25 μM to about 3 μM in the assay in Example B4, shows between about 30% and 100% platelet viability (e.g., about 50% to about 100% platelet viability, or about 80% to about 100% platelet viability) and has a Ymin value of about 0% to about 50% in the assay described in Example Bl.

[0583] In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, when tested at a concentration of about 0.25 μM to about 3 μM in the assay in Example B4, shows at least about 50% platelet viability (e.g., at least about 80% platelet viability) and has a Ymin value of about 50% to about 70% in the assay described in Example Bl. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, when tested at a concentration of about 0.25 μM to about 3 μM in the assay in Example B4, shows at least about 50% platelet viability (e.g., at least about 80% platelet viability) and has a Ymin value of less than about 50% in the assay described in Example Bl. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, when tested at a concentration of about 0.25 μM to about 3 μM in the assay in Example B4, shows at least about 50% platelet viability (e.g., at least about 80% platelet viability) and has a Ymin value of about 0% to about 50% in the assay described in Example Bl.

[0584] In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, when tested at a concentration of about 0.25 μM to about 3 μM in the assay in Example B4, shows between about 50% and 100% platelet viability (e.g., about 80% to about 100% platelet viability) and has a Ymin value of about 50% to about 70% in the assay described in Example Bl. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, when tested at a concentration of about 0.25 μM to about 3 μM in the assay in Example B4, shows between about 50% and 100% platelet viability (e.g., about 80% to about 100% platelet viability) and has a Ymin value of less than about 50% in the assay described in Example Bl. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, when tested at a concentration of about 0.25 pM to about 3 pM in the assay in Example B4, shows between about 50% and 100% platelet viability (e.g., about 80% to about 100% platelet viability) and has a Ymin value of about 0% to about 50% in the assay described in Example Bl.

[0585] Provided herein is a method of treating a cancer in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the subject is treatment naive with respect to the cancer. In some embodiments, the subject has received one or more lines of previous therapy for the cancer.

[0586] Also provided herein is a method of treating a cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as a monotherapy. In some embodiments, the subject is treatment naive with respect to the cancer. In some embodiments, the subject has received one or more lines of previous therapy for the cancer.

[0587] Provided herein is a method of treating a cancer in a subject in need of such treatment, the method comprising:

[0588] (a) detecting a biomarker (e.g., a mutation, an amplification, a copy number increase, and / or expression (optionally including level of expression) of the biomarker) associated with the cancer; and

[0589] (b) administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as a monotherapy or in combination with an additional therapy or therapeutic agent.

[0590] Also provided herein is a method of treating a cancer in a subject, wherein the subject has been determined (e.g., prior to administration of a compound provided herein) to have a biomarker (e.g., a mutation, an amplification, a copy number increase, and / or expression (optionally including level of expression) of the biomarker) associated with the cancer, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as a monotherapy or in combination with an additional therapy or therapeutic agent.

[0591] Provided herein is a method of treating a cancer in a subject in need of such treatment, the method comprising:

[0592] (a) detecting a biomarker (e.g., a mutation, an amplification, a copy number increase, and / or expression (optionally including level of expression) of a marker of susceptibility to particular agents (e.g., HER2 expression, ER expression, PR expression, folate receptor expression)) associated with the cancer; and (b) administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as a monotherapy or in combination with an additional therapy or therapeutic agent.

[0593] Also provided herein is a method of treating a cancer in a subject, wherein the subject has been determined (e.g., prior to administration of a compound provided herein) to have a biomarker (e.g., a mutation, an amplification, a copy number increase, and / or expression (optionally including level of expression) of a marker of susceptibility to particular agents (e.g., HER2 expression, ER expression, PR expression, folate receptor expression)) associated with the cancer, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as a monotherapy or in combination with an additional therapy or therapeutic agent.

[0594] Provided herein is use of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment of cancer, for example, any of the cancers provided herein.

[0595] Provided herein is a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment of cancer, for example, any of the cancers provided herein.

[0596] Provided herein is use of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as a medicament for the treatment of cancer, for example, any of the cancers provided herein.

[0597] Provided herein is use of a compound provided herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer, for example, any of the cancers provided herein.

[0598] Provided herein is a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use as a medicament. Also provided herein is a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use as a medicament for the treatment of cancer, for example, any of the cancers provided herein.

[0599] Provided herein is a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating a cancer, for example, any of the cancers provided herein.

[0600] As used herein, “monotherapy”, when referring to a compound provided herein, or a pharmaceutically acceptable salt thereof, means that the compound provided herein, or a pharmaceutically acceptable salt thereof is the only therapeutic agent or therapy (e.g., anticancer agent or therapy) administered to the subject during the treatment cycle (e.g., no additional targeted therapeutics, anticancer agents, chemotherapeutics, or checkpoint inhibitors are administered to the subject during the treatment cycle). Monotherapy does not exclude the co-administration of supportive care agents.

[0601] In some embodiments, the methods provided herein comprise administration of one or more supportive care agents. Such agents (including, for example, over the counter or prescription medications, vitamins, and / or herbal supplements) can be administered for the treatment of side effects (e.g., adverse events), concurrent illnesses, or general symptoms associated with the cancer or treatment, such as pain, rash, edema, photosensitivity, pruritus, skin discoloration, hair brittleness, hair loss, brittle nails, cracked nails, discolored nails, swollen cuticles, fatigue, weight loss, general malaise, shortness of breath, infection, anemia, thrombocytopenia, neutropenia, or gastrointestinal symptoms, including nausea, diarrhea, and lack of appetite. Non-limiting examples of supportive care agents include antiemetic (neurokinin-1 [NK1] antagonists and long-acting serotonin antagonists), a white blood cell growth factor (e.g., filgrastim or pegfilgrastim), biosimilar filgrastim)), a bone-modifying medication (e.g., zoledronic acid, pamidronate, or denosumab), a pain reliever (e.g., opioids, NSAIDS, etc.), a granulocyte colony stimulating factor (G-CSF), and a thrombopoietin receptor agonist (TPO-RA) (e.g., romiplostim (e.g., NPLATE®) and eltrombopag (e.g., PROMACTA®)). In some embodiments, the one or more supportive care agents are selected from the group consisting of a granulocyte colony stimulating factor (G-CSF) and thrombopoietin receptor agonist (TPO-RA). In some embodiments, the supportive care agent is a granulocyte colony stimulating factor (G-CSF). For example, the G-CSF can be filgrastim (e.g., NEUPOGEN®), tpo-filgrastim (e.g., GRANIX®), filgrastim-sndx (e.g., ZARXIO®), filgrastim-aafi (e.g., NIVESTYM®), or pegfilgrastim. In some embodiments, the supportive care agent is a thrombopoietin receptor agonist (TPO-RA). For example, the TPO-RA can be romiplostim (e.g., NPLATE®), eltrombopag (e.g., PROMACTA®), avatrombopag (e.g., DOPTELET®), or lusutrombopag (e.g., MULPLETA®). In some embodiments, the TPO-RA is romiplostim or eltrombopag. In some embodiments the TPO-RA is romiplostim. In some embodiments, the TPO-RA is eltrombopag.

[0602] As used herein, “the subject has previously received one or more therapeutic agents or therapies for the cancer” means that the subject has been previously administered one or more therapeutic agents or therapies (e.g., anticancer agent or therapy) for the cancer other than a compound provided herein or a pharmaceutically acceptable salt thereof, during a prior treatment cycle. In some embodiments, the subject cannot tolerate the one or more therapeutic agents or therapies previously administered for the cancer. In some embodiments, the subject did not respond to the one or more therapeutic agents or therapies previously administered for the cancer. In some embodiments, the subject did not adequately respond to one or more therapeutic agents or therapies previously administered for the cancer. In some embodiments, the subj ect has stopped responding to the one or more therapeutic agents or therapies previously administered for the cancer. In some embodiments, a response, a lack of response, an inadequate response, or a discontinued response can be determined by objective criteria (e.g., tumor volume, or by criteria such as RECIST 1.1, the Lugano 2014 criteria (Cheson, Bruce D., et al. Journal of Clinical Oncology 32.27 (2014): 3059-3067; doi: 10.1200 / JC0.2013.54.8800) or the Global Response Criteria (Olsen, Elise A., et al. Blood, The Journal of the American Society of Hematology 140.5 (2022): 419-437; doi: 10.1182 / blood.2021012057))). In some embodiments, a response, a lack of response, an inadequate response, or a discontinued response can be determined by the subject’s physician.

[0603] In some embodiments, the subject is treatment naive with respect to the cancer. As used herein, “the subject is treatment naive with respect to the cancer”, “the subject is treatment-naive”, or that the subject was “previously untreated” for the cancer means that the subject has not been previously administered one or more therapeutic agents or therapies for the cancer. Treatment of a subject who is treatment naive with respect to the cancer is often referred to as “first-line” therapy.

[0604] In some embodiments, the subject has previously received one or more lines of therapy for the cancer. For example, a subject that has a cancer that is relapsed or refractory has been treated with at least one prior line of therapy (e.g., systemic therapy) (e.g., at least two prior lines of therapy; at least three prior lines of therapy; etc.). In some embodiments, a subject that has a cancer that is relapsed or refractory has failed at least one prior line of therapy (e.g., systemic therapy) (e.g., at least two prior lines of therapy; at least three prior lines of therapy; etc.). Treatment of a subject that has a cancer that is relapsed or refractory is often referred to as “second-line” therapy following failure of one prior line of therapy, “third-line” therapy following failure of two prior lines of therapy, etc.

[0605] For any of the solid tumors described herein, the solid tumor can be primary tumors or metastatic (or secondary) tumors. As used herein, “primary” tumors are those located at the site where the tumor began to grow (i.e., where it originated). As used herein, “metastatic” (or “secondary”) tumors are those that have spread to other parts of body from the original tumor site. In some embodiments, the metastatic or secondary tumors are the same type of cancer as the primary tumor. In some embodiments, the metastatic or secondary tumors are not genetically identical to the primary tumor.

[0606] In some embodiments of the methods described herein, the cancer is relapsed or refractory. As used herein, a cancer that is “relapsed or refractory” (sometimes denoted “r / r”, “R / R”, or “relapsed / refractory”) means that the cancer has returned or progressed after a period of remission or the cancer progressed or did not sufficiently respond to a treatment (e.g., a standard-of-care (SOC) treatment or a treatment that is not a compound provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, a cancer that is relapsed or refractory has no satisfactory alternative treatments. In some embodiments, a cancer that is relapsed or refractory has progressed following one or more prior lines of therapy (e.g., two or more prior lines of therapy; three or more prior lines of therapy). In some embodiments, a subject that has a cancer that is relapsed or refractory has failed at least one prior line of therapy (e.g., systemic therapy) (e.g., at least two prior lines of therapy; at least three prior lines of therapy; etc.).

[0607] In some embodiments of any of the methods or uses described herein, the cancer is breast cancer (e.g., breast invasive carcinoma, breast invasive ductal carcinoma), central or peripheral nervous system tissue cancer (e.g., brain cancer (e.g., astrocytoma, glioblastoma, glioma, oligoastrocytoma)), endocrine or neuroendocrine cancer (e.g., adrenal cancer (e.g., adrenocortical carcinoma, neuroblastoma, pheochromocytoma, paraganglioma), multiple neuroendocrine type I and type II tumors, parathyroid cancer, pituitary tumors, thyroid cancer (e.g., papillary thyroid cancer)), eye cancer (e.g., uveal cancer (e.g., uveal melanoma)), gastrointestinal cancer (e.g., anal cancer, bile duct cancer (e.g., cholangiocarcinoma (e.g., intrahepatic cholangiocarcinoma)), colorectal cancer (e.g., colon adenocarcinoma, rectal adenocarcinoma, mucinous adenocarcinoma, mucinous carcinoma), esophageal cancer (e.g., esophageal adenocarcinoma), gallbladder cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), liver cancer (e.g., hepatocellular carcinoma, intrahepatic bile duct cancer), pancreatic cancer (e.g., pancreatic adenocarcinoma, pancreatic islet cell cancer), small intestine cancer, or stomach cancer (e.g., stomach adenocarcinoma, signet ring cell carcinoma of the stomach)), genitourinary cancer (e.g., bladder cancer (e.g., bladder urothelial carcinoma), kidney cancer (e.g., renal clear cell carcinoma, renal papillary cell carcinoma, kidney chromophobe), prostate cancer (e.g., prostate adenocarcinoma), testicular cancer (e.g., testicular germ cell tumors), or ureter cancer), gynecologic cancer (e.g., cervical cancer (e.g., cervical squamous cell carcinoma, endocervical adenocarcinoma, mucinous carcinoma), ovarian cancer (e.g., serous ovarian cancer, ovarian serous cystadenocarcinoma), uterine cancer (e.g., uterine carcinosarcoma, uterine endometrioid carcinoma, uterine serous carcinoma, uterine papillary serous carcinoma, uterine corpus endometrial carcinoma), or vulvar cancer), head and neck cancer (e.g., ear cancer (e.g., middle ear cancer), head and neck squamous cell carcinoma, nasal cavity cancer, oral cancer, pharynx cancer (e.g., hypopharynx cancer, nasopharynx cancer, oropharyngeal cancer), hematological cancer (e.g., leukemia (e.g., chronic eosinophilic leukemia (CEL), chronic lymphocytic leukemia (CLL), chronic neutrophilic leukemia (CNL), acute lymphocytic leukemia (ALL) (e.g., Philadelphia chromosome positive ALL or T cell ALL (T-ALL)), acute myeloid leukemia (AML) (e.g., acute promyelocytic leukemia (APL), post-MPN AML, post-myelodysplastic syndrome (post-MDS) AML, M6-AML (also known as pure erythroid leukemia (PEL)), or M7-AML (also known as acute megakaryoblastic leukemia (AKML))), chronic myeloid leukemia (CML)), lymphoma (e.g., Hodgkin lymphoma (e.g., nodular lymphocyte predominant Hodgkin lymphoma (NLPHL)), or non-Hodgkin lymphoma (e.g., Burkitt lymphoma (BL), diffuse large B cell lymphoma (DLBCL), diffuse histiocytic lymphoma (DHL), follicular lymphoma (FL), intravascular large B cell lymphoma (IVLBCL), mantle cell lymphoma (MCL), small lymphocytic lymphoma (SLL), a T cell lymphoma (e.g., anaplastic large T cell lymphoma, cutaneous T cell lymphoma, or peripheral T cell lymphoma))), essential thrombocythemia, polycythemia vera, myelofibrosis (e.g., primary myelofibrosis, post-essential thrombocythemia myelofibrosis, or post-polycythemia vera myelofibrosis), a myelodysplastic syndrome (MDS) (e.g., M6 MDS or M7 MDS), or myeloma (e.g., multiple myeloma)), Li-Fraumeni tumors, mesentery cancer (e.g., omentum cancer, peritoneal cancer), pleural cancer, respiratory cancer (e.g., larynx cancer, lung cancer (e.g., lung squamous cell carcinoma, lung adenocarcinoma, malignant pleural mesothelioma, non-small cell lung cancer (NSCLC), small cell lung cancer), tracheal cancer), sarcoma (e.g., bone cancer (e.g., osteosarcoma, chondrosarcoma) or soft tissue sarcoma (Ewing sarcoma, leiomyosarcoma, myxofibrosarcoma, rhabdomyosarcoma)), skin cancer (e.g., melanoma or Merkel cell carcinoma), thymus cancer (e.g., thymoma), or a combination thereof.

[0608] In some embodiments, the cancer is breast cancer, gastrointestinal cancer (e.g., bile duct cancer (e.g., cholangiocarcinoma (e.g., intrahepatic cholangiocarcinoma)), colorectal cancer (CRC), gastrointestinal stromal tumor, or pancreatic cancer), genitourinary cancer (e.g., bladder cancer (e.g., bladder urothelial carcinoma) or kidney cancer), gynecologic cancer (e.g., cervical cancer, ovarian cancer (e.g., high grade serous ovarian cancer (HGSOC), low grade serous ovarian cancer (LGSOC)), or uterine cancer), head and neck cancer (e.g., head and neck squamous cell carcinoma), hematological cancer (e.g., leukemia (e.g., acute lymphocytic leukemia (ALL) (e.g., T-ALL), acute myeloid leukemia (AML) (e.g., APL, post-MPN AML, post-MDS AML, M6-AML, or M7-AML), chronic lymphocytic leukemia (CLL)), lymphoma (e.g., follicular lymphoma (FL), small lymphocytic lymphoma (SLL), a T cell lymphoma (e.g., anaplastic large T cell lymphoma, cutaneous T cell lymphoma, or peripheral T cell lymphoma), or diffuse large B cell lymphoma (DLBCL)), essential thrombocythemia, polycythemia vera, myelofibrosis (e.g., primary myelofibrosis, post-essential thrombocythemia myelofibrosis, or post-polycythemia vera myelofibrosis), or a myelodysplastic syndrome (MDS) (e.g., M6 MDS or M7 MDS)), lung cancer (e.g., non small cell lung cancer (NSCLC), small cell lung cancer (SCLC), lung squamous cell carcinoma, or malignant pleural mesothelioma (MPM)), neuroblastoma, sarcoma (e.g., bone cancer (e.g., osteosarcoma, chondrosarcoma) or soft tissue sarcoma (Ewing sarcoma, leiomyosarcoma, myxofibrosarcoma, rhabdomyosarcoma)), or skin cancer (e.g., melanoma or Merkel cell carcinoma).

[0609] In some embodiments, the cancer is a myeloproliferative neoplasm (MPN). In some embodiments, the myeloproliferative neoplasm is CEL, CML, CNL, essential thrombocythemia, polycythemia vera, or myelofibrosis (e.g., primary myelofibrosis, postessential thrombocythemia myelofibrosis, or post-polycythemia vera myelofibrosis). In some embodiments, the MPN has a JAK2 mutation (e.g., a JAK2 V617F mutation). In some embodiments, the MPN does not have a JAK2 mutation. In some embodiments, the cancer is low-risk myelofibrosis. In some embodiments, the cancer is intermediate (e.g., intermediate- 1 and / or intermediate-2) or high-risk myelofibrosis (e.g., primary myelofibrosis, post-essential thrombocythemia myelofibrosis, or post-polycythemia vera myelofibrosis). In some embodiments, the cancer is intermediate or high-risk myelofibrosis (e.g., primary myelofibrosis, post-essential thrombocythemia myelofibrosis, or post-polycythemia vera myelofibrosis) with a JAK2 mutation (e.g., a JAK2 V617F mutation). In some embodiments, the cancer is intermediate or high-risk myelofibrosis (e.g., primary myelofibrosis, postessential thrombocythemia myelofibrosis, or post-polycythemia vera myelofibrosis) without a JAK2 V617F mutation. In some embodiments, the subject has a platelet count below 50 x 109 / L.

[0610] In some embodiments, the cancer is polycythemia vera. In some embodiments, the cancer is polycythemia vera, and the subject has had an inadequate response to or is intolerant of hydroxyurea.

[0611] In some embodiments, the cancer is a myelodysplastic syndrome (MDS). AMDS, also known as a myelodysplastic neoplasm, is a type of cancer that can occur when the blood-forming cells in the bone marrow become abnormal, resulting in the marrow not making sufficient levels of healthy new blood cells. In some embodiments, the MDS can be classified into one of two subtypes (WHO 2022): MDS with defining genetic abnormalities and a morphologically defined MDS. Non-limiting examples of MDS with defining genetic abnormalities include MDS with low blasts and isolated 5q deletion (MDS-5q), MDS with low blasts and SF3B1 mutation (MDS-5F3B7), and MDS with biallelic TP53 inactivation (MDS-bi7 / <53). Non-limiting examples of morphologically defined MDS include MDS with low blasts (MDS-LB); MDS, hypoplastic (MDS-h); and MDS with increased blasts (MDS-IB) (e.g., MDS-IB 1, MDS-IB2, and MDS with fibrosis (MDS-f)). In other embodiments, the MDS can be classified into one of five subtypes (French-American-British (FAB)): (i) refractory anemia (MDS RA); (ii) refractory anemia with ring sideroblasts (MDS RA with ring sideroblasts); (iii) refractory anemia with excess of blasts (MDS RAEB); (iv) chronic myelomonocytic leukemia (MDS CMML); and (v) refractory anemia with excess of blasts “in transformation” (MDS RAEB “in transformation”). In some embodiments, the MDS is therapy-related MDS (tMDS). In some embodiments, the MDS is MDS RAEB (e.g., M6 MDS). In some embodiments, the MDS can also be classified based on a risk scoring systems such as the International Prognostic Scoring System (IPSS), the Revised International Prognostic Scoring System (IPSS-R), and the Molecular International Prognostic Scoring System (IPSS-M). Such systems can be used to classify subjects into risk categories (e.g., very low, low, intermediate, high, or very high) based on factors such as bone marrow blast percentage, cytogenetics (e.g., specific cytogenetic abnormalities such as normal, del(5q), +8, complex), blood cell counts (e.g., hemoglobin, platelets, and absolute neutrophil count), and genetic mutation data. In some embodiments, the cancer is M6 MDS. In some embodiments, the cancer is M7 MDS.

[0612] In some embodiments, the cancer is T-ALL. In some embodiments, the cancer is relapsed / refractory T-ALL.

[0613] In some embodiments, the cancer is CRC (e.g., Braf mutant CRC (e.g., Braf V600E CRC) or KRas mutant CRC (e.g, KRas G12C CRC or KRas G12D CRC)).

[0614] In some embodiments, the cancer is SCLC (e.g, ASCL1 subtype SCLC or NEUR0D1 subtype SCLC).

[0615] In some embodiments, the cancer is NSCLC (e.g, Braf mutant NSCLC (e.g, Braf V600E NSCLC), EGFR mutant NSCLC (e.g, EGFR L858R NSCLC or EGFR exon 19 deletion NSCLC), MET mutant NSCLC (e.g, MET exon 14 deletion NSCLC, MET amplified NSCLC), KRas mutant NSCLC (e.g, KRas G12C NSCLC)).

[0616] In some embodiments, the cancer is lung squamous cell carcinoma.

[0617] In some embodiments, the cancer is malignant pleural mesothelioma (e.g, BAP1 mutant malignant pleural mesothelioma). In some embodiments, the cancer is malignant pleural mesothelioma, and a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered as a monotherapy.

[0618] In some embodiments, the cancer is melanoma (e.g, Braf mutant melanoma (e.g, Braf V600E melanoma)).

[0619] In some embodiments, the cancer is breast cancer (e.g, HER2+ breast cancer (e.g, HER2+ breast cancer with ER expression, HER2+ breast cancer without ER expression), HER2 negative breast cancer (e.g, HER2 negative breast cancer with ER expression, HER2 negative breast cancer without ER expression), HER2 low breast cancer, triple negative breast cancer, hormone receptor positive breast cancer (ER+ and / or PR+, with or without HER2 positivity)).

[0620] In some embodiments, the cancer is lymphoma. In some embodiments, the lymphoma is a T cell lymphoma (e.g, anaplastic large T cell lymphoma, cutaneous T cell lymphoma, or peripheral T cell lymphoma). In some embodiments, the lymphoma is a non-Hodgkin lymphoma (e.g, DLBCL, anaplastic large T cell lymphoma, cutaneous T cell lymphoma, or peripheral T cell lymphoma). In some embodiments, the lymphoma is peripheral T cell lymphoma.

[0621] In some embodiments, the cancer is leukemia. In some embodiments, the leukemia is a T cell leukemia (e.g, T cell ALL). In some embodiments, the cancer is post-MPN leukemia. In some embodiments, the cancer is a T cell leukemia (e.g., T cell ALL), and a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered as a monotherapy.

[0622] In some embodiments, the cancer is an acute myeloid leukemia (AML). An AML, also known as acute myelocytic leukemia, acute myelogenous leukemia, acute granulocytic leukemia, and acute non-lymphocytic leukemia, is a type of blood cancer that occurs when young abnormal white blood cells referred to as blasts (or leukemia cells), begin to fill up the bone marrow, reducing or preventing normal blood production. In some cases, a MDS or a MPN can evolve over time to become AML; this type of AML is sometimes referred to as secondary AML. In some embodiments, the AML can be classified into one of three subtypes (WHO 2022): AML with defining genetic abnormalities, AML defined by differentiation, and secondary myeloid neoplasms. Non-limiting examples of AML with defining genetic abnormalities is selected from the group consisting of APL (acute promyelocytic leukemia) with PML-RARA fusion, AML with RUNX1:: RUNX1T1 fusion, AML with CBFB:: MYH11 fusion, AML with DEK:: NUP214 fusion, AML with RBM15:: MRTFA fusion, AML with BCR:: ABL1 fusion, AML with KMT2A rearrangement, AML with MECOM rearrangement, AML with NUP98 rearrangement, AML with NPM1 mutation, AML with CEBPA mutation, AML with myelodysplasia-related changes, and AML with other defined genetic alterations. Non-limiting examples of AML defined by differentiation include AML with minimal differentiation, AML without maturation, AML with maturation, acute basophilic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroid leukemia, and acute megakaryoblastic leukemia. In some embodiments, AML can be classified into one of eight subtypes based on cell morphology (FAB): MO (minimal differentiation), Ml (without maturation), M2 (with maturation), M3 (acute promyelocytic leukemia), M4 (myelomonocytic), M5 (monocytic), M6 (erythroleukemia), and M7 (megakaryoblastic). In some embodiments, the AML is M6-AML or M7-AML. In some embodiments, the AML is M6-AML. In some embodiments, the M6-AML is a post-myelodysplastic syndrome (MDS) AML. In some embodiments, the M6-AML is a post- myeloproliferative neoplasm (MPN) AML. In some embodiments, the AML is M7-AML. In some embodiments, the M7-AML is a post-myelodysplastic syndrome (MDS) AML. In some embodiments, the M7-AML is a post-myeloproliferative neoplasm (MPN) AML. In some embodiments, the AML is therapy-related AML (tAML).

[0623] In some embodiments, the cancer is M6-AML. In some embodiments, the M6-AML is a post-MPN AML. In some embodiments, the M6-AML is a post-myelodysplastic syndrome (MDS) AML. In some embodiments, the cancer is M6-AML, and the compound provided herein, or pharmaceutically acceptable salt thereof, is administered as a monotherapy.

[0624] In some embodiments, the cancer is M7-AML. In some embodiments, the M7-AML is a post-MPN AML. In some embodiments, the M7-AML is a post-MDS AML. In some embodiments, the cancer is M7-AML, and the compound provided herein, or pharmaceutically acceptable salt thereof, is administered as a monotherapy.

[0625] In some embodiments, the cancer is head and neck cancer.

[0626] In some embodiments, the cancer is essential thrombocythemia.

[0627] In some embodiments, the cancer is polycythemia vera.

[0628] In some embodiments, the cancer is myelofibrosis. In some embodiments, the cancer is primary myelofibrosis. In some embodiments, the cancer is post-essential thrombocythemia myelofibrosis. In some embodiments, the cancer is post-polycythemia vera myelofibrosis.

[0629] In some embodiments, the cancer is an MDS. In some embodiments, the MDS is M6 MDS. IN some embodiments, the MDS is M7 MDS. In some embodiments, the cancer is an MDS, and a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered as a monotherapy.

[0630] In some embodiments, the cancer is pancreatic cancer.

[0631] In some embodiments, the cancer is bladder cancer (e.g., bladder urothelial carcinoma). In some embodiments, the cancer is ovarian cancer (e.g., BRCA1 mutant ovarian cancer or BRCA2 mutant ovarian cancer). In some embodiments, the cancer is HGSOC (e.g., BRCA1 mutant HGSOC or BRCA2 mutant HGSOC).

[0632] In some embodiments, the cancer is cervical cancer.

[0633] In some embodiments, the cancer is colorectal cancer.

[0634] In some embodiments, the cancer is skin cancer. In some embodiments, the skin cancer is melanoma. In some embodiments, the cancer is Merkel cell carcinoma. In some embodiments, the cancer is Merkel cell carcinoma, and a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered as a monotherapy.

[0635] In some embodiments, the cancer is neuroblastoma.

[0636] In some embodiments, the cancer is intrahepatic cholangiocarcinoma.

[0637] In some embodiments, the cancer is a mesenchymal cancer. In some embodiments, the mesenchymal cancer is mesenchymal breast cancer or mesenchymal kidney cancer.

[0638] In some embodiments, a BCL-XL copy number gain or a BCL-XL amplification can be detected in a sample from the subject (e.g., detecting three or more copies of a BCL2L1 gene in the sample from the subject). In some embodiments, the subject was determined (e.g., prior to administration of a compound provided herein) to have a cancer having a BCL-XL copy number gain or a BCL-XL amplification.

[0639] In some embodiments, the cancer has a BCL-XL copy number gain.

[0640] In some embodiments, the cancer has a BCL-XL amplification.

[0641] Non-limiting examples of BCL-XL involvement in cancers can be found in: Wilson, Wyndham H., et al. The Lancet Oncology 11.12 (2010): 1149-1159, doi: 10.1016 / S1470-2045(10)70261-8; Keitel, Ulrike, et al. Oncotarget 5.23 (2014): 11778, doi: 10.18632 / oncotarget.2634; Chonghaile, Triona Ni, et al. Cancer Discovery 4.9 (2014): 1074- 1087, doi: 10.1158 / 2159-8290. CD-14-0353; Zaanan, Aziz, et al. Journal of Biological Chemistry 290.39 (2015): 23838-23849, doi: 10.1074 / jbc. M115.657833; Zhang, Haichao, et A. Molecular Cancer 14.1 (2015): 1-9, doi: 10.1186 / sl2943-015-0397-y; Soderquist, Ryan S., et al. Nature Communications 9.1 (2018): 1-13, doi: 10.1038 / s41467-018-05815-z; Stover, Elizabeth H., et al. Molecular Cancer Research 17.11 (2019): 2281-2293, doi: 10.1158 / 1541-7786. MCR-18-1243; Concoran, R. B., et al. Annals of Oncology (2019) 30 (suppl_5): vl64, doi: 10.1093 / annonc / mdz244.009; Lakhani, Nehal J., et al. Journal of Clinical Oncology (2020): 3509-3509, doi: 10.1200 / JC0.2020.38; He, Yonghan, et al. Journal of Hematology & Oncology 13.1 (2020): 1-13, doi: 10.1186 / sl3045-020-00928-9; Grubb, Treg, et al. Clinical Cancer Research (2022), doi: 10.1158 / 1078-0432. CCR-22-0669; Joly, Florence, et al. Gynecologic Oncology 165.1 (2022): 30-39, doi: 10.1016 / j.ygyno.2022.01.021; and Nanjo, Shigeki, et al. The Journal of Clinical Investigation (2022), doi: 10.1172 / JCI145099.

[0642] In some embodiments, the subject has previously been treated with another anticancer agent, a chemotherapeutic agent, radiation, surgery, a multi-kinase inhibitor, or a combination thereof.

[0643] Provided herein is a method of treating an ocular disease or condition in a subject in need of such treatment, the method comprising administering (e.g., intravitreally or topically) to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the ocular disease or condition is diabetic macular edema. In some embodiments, the ocular disease or condition is age-related macular degeneration. In some embodiments, the ocular disease or condition is diabetic retinopathy. See, e.g., Crespo-Garci, Sergio, et al. Cell Metabolism 33.4 (2021): 818-832, doi: 10.1016 / j.cmet.2021.01.011; Hassan, Jannah Waled, and Ashay D. Bhatwadekar, Frontiers in Pharmacology 13 (2022): 896907, doi: 10.3389 / fphar.2022.896907.

[0644] Provided herein is use of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment of an ocular disease or condition, for example, any of the ocular diseases or conditions provided herein.

[0645] Provided herein is use of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as a medicament for the treatment of an ocular disease or condition, for example, any of the ocular diseases or conditions provided herein.

[0646] Provided herein is use of a compound provided herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of an ocular disease or condition, for example, any of the ocular diseases or conditions provided herein.

[0647] Also provided herein is a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use as a medicament for the treatment of an ocular disease or condition, for example, any of the ocular diseases or conditions provided herein.

[0648] Provided herein is a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating an ocular disease or condition, for example, any of the ocular diseases or conditions provided herein.

[0649] Also provided herein is a method of treating a fibrotic disease or condition and / or a disease or condition associated with senescent cells in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Non-limiting examples of fibrotic diseases or conditions and / or diseases or conditions associated with senescent cells include pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis, systemic fibrosis-associated lung disease, radiation-associated pulmonary fibrosis), radiation-associated skin fibrosis, liver fibrosis, primary sclerosing cholangitis, diabetic macular edema, age-related macular degeneration, diabetic retinopathy, geographic atrophy, ischemia and reperfusion injury, heart failure, recovery from acute myocardial infarction, pulmonary hypertension, inflammatory bowel disease, colitis, Crohn’s disease, diabetes, aging skin (including photoaging-related pigmentation), donor organ transplant survival and function, stem cell transplant survival and function, osteoarthritis, recovery from spinal cord injury, Alzheimer’s disease, tau-opathies, progressive supranuclear palsy, and age- related neurological decline (e.g., related to impaired neurovascular coupling). See, e.g., Zhu, Y. I., et al. Aging Cell 14.4 (2015): 644-658, doi: 10.1111 / acel.12344; Zhu, Y. I., et al. Aging Cell 15.3 (2016): 428-435, doi: 10.1111 / acel.12445; Chang, Jianhui, et al. Nature Medicine 22.1 (2016): 78-83, doi: 10.1038 / nm.4010; Zhu, Yi, et al. Aging (Albany NY) 9,3 (2017): 955, doi: 10.18632 / aging.101202; Lagares, David, et al. Science Translational Medicine 9.420 (2017): eaal3765, doi: 10.1126 / scitranslmed.aal3765; Pan, Jin, et al. International Journal of Radiation Oncology Biology Physics 99.2 (2017): 353-361, doi: 10.1016 / j.ijrobp.2017.02.216; Bussian, Tyler J., et al. Nature 562.7728 (2018): 578-582, doi: 10.1038 / s41586-018-0543-y; Moncsek, Anja, et al. Hepatology 67.1 (2018): 247-259, doi: 10.1002 / hep.29464; van Willigenburg, Hester, Peter LJ de Keizer, and Ron WF de Bruin. Pharmacological Research 130 (2018): 322-330, doi: 10.1016 / j.phrs.2018.02.015; Walaszczyk, Anna, et al. Aging Cell 18.3 (2019): el2945, doi: 10. I l l 1 / acel.12945; Aguayo-Mazzucato, Cristina, et al. Cell Metabolism 30.1 (2019): 129-142, doi: 10.1016 / j.cmet.2019.05.006; Sessions, Garrett A., et al. The FASEB Journal 33 l (2019): 12364, doi: 10.1096 / fj.201900815RR; Gerdes, Erin O, Wissler, et al. International Review of Neurobiology’ 155 (2020): 203-234, doi: 10.1016 / bs.im.2020.03.019; Sasaki, Motoko, Yasunori Sato, and Yasuni Nakanuma. Journal of Autoimmunity 107 (2020): 102377, doi: 10.1016 / j.jaut.2019.102377; Yabluchanskiy, Andriy, et al. Geroscience 42 (2020): 409-428, doi: 10.1007 / sl l357-020-00154-8; Dookun, Emily, et al. Aging Cell 19.10 (2020): e!3249, doi: 10.1111 / acel.13249; Jia, Kangni, et al. Journal of Cardiovascular Pharmacology 76.4 (2020): 452-460, doi: 10.1097 / FJC.0000000000000878; Sierra-Ramirez, Arantzazu, et al. Aging (Albany NY) 12.12 (2020): 11337, doi: 10.18632 / aging.103607; Yang, Hao, et al. Aging (Albany NY) 12.13 (2020): 12750, doi: 10.18632 / aging.103177; Lawrie, Allan, and Sheila E. Francis, The Journal of Clinical Investigation 131.11 (2021): e!49721, doi: 10.1172 / JCI149721; Paramos-de-Carvalho, Diogo, et al. Cell Reports 36.1 (2021): 109334, doi: 10.1016 / j.celrep.2021.109334; Tarantini, Stefano, et al. GeroScience 43.5 (2021): 2427-2440, doi: 10.1007 / sll357-021-00440-z; Park, Ji Hee, et al. The British Journal of Dermatolog).’ (2022) 186(4): 740-742, doi: 10.1111 / bjd.20893; Fielder, Edward, et al. ELife 11 (2022): e75492, doi: 10.7554 / eLife.75492; Suzuki, Keiji, et al. Mutation Research / enetic Toxicology and Environmental Mutagenesis 876 (2022): 503448, doi: 10.1016 / j. mrgentox, 2022, 503448; He, An, et al. American Journal of Transplantation 22 A l (2022): 2529-2547, doi: 10.1111 / ajt.17154; Johnson, Laura A., et al. Inflammatory Bowel Diseases 2.2 (2022): 161-175, doi: 10.1093 / ibd / izab 166; Miura, Yugo, et al. Stem Cell Research & Therapy 13.1 (2022): 222, doi: 10.1186 / sl3287-022-02901-4; Cooley, Joseph C., et al. JCI Insight 8.3 (2023): e!63762, doi: 10.1172 / jci. insight.163762; Watanabe, Yusuke, et al. Hepatology Research 53 (2023): 460-472, doi: 10.1111 / hepr.13879; and Takaya, Kento, et al., Rejuvenation Research 26.1 (2023): 9-20, doi: 10,1089 / rej.2022.0048.

[0650] Provided herein is use of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment of a fibrotic disease or condition and / or a disease or condition associated with senescent cells, for example, any of the fibrotic diseases or conditions and / or diseases or conditions associated with senescent cells provided herein.

[0651] Provided herein is use of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as a medicament for the treatment of a fibrotic disease or condition and / or a disease or condition associated with senescent cells, for example, any of the fibrotic diseases or conditions and / or diseases or conditions associated with senescent cells provided herein.

[0652] Provided herein is use of a compound provided herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a fibrotic disease or condition and / or a disease or condition associated with senescent cells, for example, any of the fibrotic diseases or conditions and / or diseases or conditions associated with senescent cells provided herein.

[0653] Also provided herein is a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use as a medicament for the treatment of a fibrotic disease or condition and / or a disease or condition associated with senescent cells, for example, any of the fibrotic diseases or conditions and / or diseases or conditions associated with senescent cells provided herein.

[0654] Provided herein is a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating a fibrotic disease or condition and / or a disease or condition associated with senescent cells, for example, any of the fibrotic diseases or conditions and / or diseases or conditions associated with senescent cells provided herein.

[0655] Also provided is a method for modulating (e.g., decreasing) BCL-XL protein activity in a cell, comprising contacting the cell with an effective compound provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method comprises administering an effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, to a subject. In some embodiments, the cell is a cancer cell. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a mammalian cancer cell. In some embodiments, the cancer cell is any cancer as described herein.

[0656] As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, “contacting” a cell with a compound provided herein includes the administration of a compound provided herein to the cell, in vitro or in vivo, including, for example, introducing a compound provided herein into a sample containing cells (e.g., grown in culture or derived from a patient), an organoid, or an organism (e.g., an animal (e.g., an animal bearing a tumor), or a human).

[0657] Also provided is a method of modulating (e.g., decreasing) the level of BCL-XL protein in a cell, comprising contacting the cell with a compound provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the level of BCL-XL protein is decreased by at least 30% (e.g., at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, or at least 99%) compared to a cell not contacted with the compound provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method comprises administering an effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, to a subject having a cell having a BCL-XL protein. In some embodiments, the cell is a cancer cell. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a mammalian cancer cell. In some embodiments, the cancer cell is any cancer as described herein.

[0658] Also provided is a method of inducing ubiquitination of a BCL-XL protein in a cell, comprising contacting the cell with a compound provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method comprises administering an effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, to a subject having a cell having a BCL-XL protein. In some embodiments, the cell is a cancer cell. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a mammalian cancer cell. In some embodiments, the cancer cell is any cancer as described herein. Also provided is a method of forming a ternary complex comprising a BCL-XL protein, a compound provided herein, or a pharmaceutically acceptable salt thereof, and a CRBN protein or fragment thereof in a cell, comprising contacting the cell with a compound provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method comprises administering an effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, to a subject having a cell having a BCL-XL protein. In some embodiments, the cell is a cancer cell. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a mammalian cancer cell. In some embodiments, the cancer cell is any cancer as described herein.

[0659] Also provided herein is a method of inhibiting cell proliferation, in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.

[0660] Further provided herein is a method of increasing cell death, in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. Also provided herein is a method of increasing tumor cell death in a subject. The method comprises administering to the subject a compound provided herein, or a pharmaceutically acceptable salt thereof, in an amount effective to increase tumor cell death.

[0661] When employed as pharmaceuticals, the compounds provided herein, or pharmaceutically acceptable salts thereof, can be administered in the form of pharmaceutical compositions as described herein.

[0662] Also provided herein is a method for inducing degradation of a BCL-XL protein in a mammalian cell, the method comprising contacting the mammalian cell with an effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof.

[0663] Also provided herein is a method of treating a subject having a cancer, wherein the method comprises:

[0664] administering a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, as a monotherapy or in conjunction with a first anticancer agent to the subject who has been administered one or more doses of the first anticancer agent to the subject.

[0665] Also provided herein is a method of treating a subject having a cancer, wherein the method comprises:

[0666] (a) administering one or more doses of a first anticancer agent to the subject; and (b) after (a), administering a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, as a monotherapy or in conjunction with the first anticancer agent to the subject.

[0667] Also provided herein is a method of treating a subject having a cancer, wherein the method comprises:

[0668] (a) administering one or more doses of a first anticancer agent to the subject; and (b) after (a), administering a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, as a monotherapy or in conjunction with a second anticancer agent to the subject.

[0669] Combinations

[0670] In any of the indications described herein, a compound provided herein, or a pharmaceutically acceptable salt thereof, can be used as a monotherapy. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can be used prior to administration of an additional therapeutic agent or additional therapy. For example, a subject in need thereof can be administered one or more doses of a compound provided herein, or a pharmaceutically acceptable salt thereof, for a period of time and then undergo at least partial resection of the tumor. In some embodiments, the treatment with one or more doses of a compound provided herein, or a pharmaceutically acceptable salt thereof, reduces the size of the tumor (e.g., the tumor burden) prior to the at least partial resection of the tumor.

[0671] In some embodiments, a subject in need thereof can be administered one or more doses of a compound provided herein, or a pharmaceutically acceptable salt thereof, for a period of time and after one or more rounds of radiation therapy. In some embodiments, the treatment with one or more doses of a compound provided herein, or a pharmaceutically acceptable salt thereof, reduces the size of the tumor (e.g., the tumor burden) prior to the one or more rounds of radiation therapy.

[0672] In some embodiments of any the methods described herein, the compound provided herein, or a pharmaceutically acceptable salt thereof, is administered in combination with a therapeutically effective amount of at least one additional therapeutic agent selected from one or more additional therapies or therapeutic (e.g., chemotherapeutic) agents.

[0673] Non-limiting examples of additional therapies and therapeutic agents include: RAS pathway targeted therapeutic agents (e.g., Ras / RAF / MEK / PI3K pathway inhibitors, (e.g., Ras inhibitors (e.g., KRas inhibitors), KRas-targeted therapeutic agents, SOS1 inhibitors, SOSl / Ras protein-protein interaction inhibitors, SHP2 inhibitors, PI3K-AKT-mT0R pathway inhibitors)), kinase-targeted therapeutics (e.g., MEK inhibitors, ERK inhibitors, Raf inhibitors (e.g., BRaf inhibitors), PI3K inhibitors, Abl inhibitors (e.g., BCR-Abl inhibitors), ALK inhibitors, AKT inhibitors, AURKA inhibitors, mTOR inhibitors, CDK2 inhibitors, CDK4 / 5 inhibitors, CDK4 / 6 inhibitors, CDK7 inhibitors, CDK9 inhibitors, MET (also known as cMET) inhibitors, FAK inhibitors, FGFR1 inhibitors, FGFR2 inhibitors, FGFR3 inhibitors, FGFR4 inhibitors, ErbB family inhibitors (e.g., EGFR inhibitors, anti-EGFR antibodies or anti-EGFR antibody-drug conjugates, HER2 inhibitors, anti-HER2 antibodies or anti-HER2 antibodyutilizing biologies), JAK inhibitors (e.g., JAK inhibitors having activity against JAK1, JAK2, and / or JAK1 / 2), Src inhibitors, VEGFR inhibitors), LSD1 inhibitors, EZH2 inhibitors, BET inhibitors, STING agonists, telomerase inhibitors, mTORCl inhibitors, YAP inhibitors, proteasome inhibitors, farnesyl transferase inhibitors, Hif2a inhibitors, HSP90 inhibitors, PTEN inhibitors, PARP inhibitors, signal transduction pathway inhibitors, checkpoint inhibitors, modulators of the apoptosis pathway (e.g., BCL-2 inhibitors), chemotherapeutics, angiogenesis-targeted therapies, immune-targeted agents, including immunomodulatory imide drugs (sometimes called “IMiDs” or “CELMoDs”) and immunotherapy (e.g., anti-PDl therapy or anti-PD-Ll therapy), and radiotherapy.

[0674] As used herein, a biosimilar antibody refers to an antibody or antigen-binding fragment that has the same primary amino acid sequence as compared to a reference antibody and optionally, may have detectable differences in post-translation modifications (e.g., glycosylation and / or phosphorylation) as compared to the reference antibody (e.g., a different glycoform).

[0675] In some embodiments, the additional therapy or therapeutic agent is an Abl inhibitor (e.g., a BCR-Abl inhibitor), an ALK inhibitor, an AURKA inhibitor, a BCL-2 inhibitor, a Braf inhibitor, a CDK2 inhibitor, a CDK4 / 6 inhibitor, a CDK7 inhibitor, a CDK9 inhibitor, an EGFR inhibitor, an anti-EGFR antibody or anti-EGFR antibody-drug conjugate, an ERK inhibitor, an EZH2 inhibitor, a FGFR1 inhibitor, a FGFR2 inhibitor, a FGFR3 inhibitor, a FGFR4 inhibitor, a HER2 inhibitor, an anti-HER2 antibody or anti-HER2 antibody-drug conjugate, a JAK inhibitor, a KRas inhibitor, a MEK inhibitor, a MET inhibitor, a Hif2a inhibitor, a PARP inhibitor, a VEGFR inhibitor, an LSD1 inhibitor, a BET inhibitor, a STING agonist, a telomerase inhibitor, a TORC1 / 2 inhibitor, an immunomodulatory imide drug, immunotherapy (e.g., a PD-1 inhibitor (e.g., anti-PDl therapy), a PD-L1 inhibitor (e.g., anti-PD-Ll therapy)), L-asparaginase, chemotherapy, radiotherapy, or a combination thereof.

[0676] In some embodiments, the additional therapy or therapeutic agent is an Abl degrader (e.g., a BCR- Abl degrader), an ALK degrader, an AURKA degrader, a BCL-2 degrader, a BRaf degrader, a CDK2 degrader, a CDK4 / 6 degrader, a CDK7 degrader, a CDK9 degrader, an EGFR degrader, an ERK degrader, an EZH2 degrader, a FGFR1 degrader, a FGFR2 degrader, a FGFR3 degrader, a FGFR4 degrader, a HER2 degrader, a JAK2 degrader, a KRas degrader, a MEK degrader, a MET degrader, a Hif2a degrader, a PARP degrader, a VEGFR degrader, an LSD1 degrader, a BET degrader, a telomerase degrader, a TORC1 / 2 degrader, an immunomodulatory imide drug, immunotherapy (e.g., anti-PDl therapy or anti-PD-Ll therapy), chemotherapy, radiotherapy, or a combination thereof.

[0677] In some embodiments, the Abl inhibitor (e.g., BCR-Abl inhibitor) is asciminib (e.g., asciminib hydrochloride), bafetinib, bosutinib (e.g., bosutinib monohydrate), danusertib, dasatinib (e.g., dasatinib monohydrate), flumatinib (e.g., flumatinib mesylate), imatinib (e.g., imatinib mesylate), nilotinib (e.g., nilotinib monochloride monohydrate), olverembatinib (e.g., olverembatinib mesylate), ponatinib (e.g., ponatinib hydrochloride), radotinib (e.g., radotinib dihydrochloride), ruserontinib, vandetanib, AN-019, AT-9283, IkT-148009, NPB-001-056, or a combination thereof.

[0678] In some embodiments, the ALK inhibitor is alectinib (e.g., alectinib hydrochloride), brigatinib, ceritinib, crizotinib, ensartinib (e.g., ensartinib hydrochloride), entrectinib, fidrisertib, lorlatinib, TQ-B-3101, TQ-B-3139, or a combination thereof. In some embodiments, the ALK inhibitor is alectinib (e.g., alectinib hydrochloride), brigatinib, ceritinib, crizotinib, ensartinib (e.g., ensartinib hydrochloride), fidrisertib, lorlatinib, TQ-B-3101, TQ-B-3139, or a combination thereof.

[0679] In some embodiments, the AURKA inhibitor is alisertib, danusertib, ilorasertib, tinengotinib, AT-9283, BI-811283, ENMD-2076, or a combination thereof.

[0680] In some embodiments, the BCL-2 inhibitor is asaretoclax (ZN-d5), dalvotoclax (TQB-3909), eiletoclax (lonitoclax), foselutoclax (UBX-1325), lisaftoclax, mesutoclax, obatoclax, pelcitoclax (dual BCL-2 / BCL-xL inhibitor), sonrotoclax, surzetoclax, venetoclax, oblimersen (e.g., oblimersen sodium), beclanorsen, AZD-0466, and UBX-1967 (or a phosphate prodrug thereof), or a combination thereof.

[0681] In some embodiments, the cancer is a lung cancer (e.g., SCLC), and the additional therapy or therapeutic agent is a BCL-2 inhibitor (e.g., asaretoclax (ZN-d5), dalvotoclax (TQB- 3909), eiletoclax (lonitoclax), foselutoclax (UBX-1325), lisaftoclax, mesutoclax, obatoclax, pelcitoclax (dual BCL-2 / BCL-xL inhibitor), sonrotoclax, surzetoclax, venetoclax, oblimersen (e.g., oblimersen sodium), beclanorsen, AZD-0466, and UBX-1967 (or a phosphate prodrug thereof)). In some embodiments, the cancer is a lung cancer (e.g., SCLC), and the additional therapy or therapeutic agent is venetoclax.

[0682] In some embodiments, the cancer is a non-Hodgkin lymphoma, and the additional therapy or therapeutic agent is a BCL-2 inhibitor (e.g., asaretoclax (ZN-d5), dalvotoclax (TQB-3909), eiletoclax (lonitoclax), foselutoclax (UBX-1325), lisaftoclax, mesutoclax, obatoclax, pelcitoclax (dual BCL-2 / BCL-xL inhibitor), sonrotoclax, surzetoclax, venetoclax, oblimersen (e.g., oblimersen sodium), beclanorsen, AZD-0466, and UBX-1967 (or a phosphate prodrug thereof)). In some embodiments, the cancer is a non-Hodgkin lymphoma, and the additional therapy or therapeutic agent is venetoclax.

[0683] In some embodiments, the BRaf inhibitor is avutometinib (RO5126766), dabrafenib (e.g., dabrafenib mesylate, GSK2118436), encorafenib (e.g., BRAFTOVI™, LGX818), naporafenib (LXH254), sorafenib (e.g., sorafenib tosylate), vemurafenib (e.g., ZELBORAF®, RO5185426), ARQ-736, AZ304, BMS-908662 (XL281), C17071479-F, CHIR-265 (RAF265), FORE-8394 (PLX-8394), GDC-0879, GDC-5573 (HM95573), HLX-208, PLX-3603, PLX-4720, or a combination thereof.

[0684] In some embodiments, a BRaf V600E mutation can be detected in a sample from the subject (e.g., detecting a BRAF gene having a mutation corresponding to a V600E mutation in BRaf protein and / or detecting a BRaf protein having a V600E mutation). In some embodiments, the subject was determined (e.g., prior to administration of a compound provided herein) to have a cancer having a BRaf V600E mutation.

[0685] In some embodiments, the cancer is a BRaf mutant CRC (e.g., BRaf V600E mutant CRC), and the additional therapy or therapeutic agent is a BRaf inhibitor (e.g., avutometinib (RO5126766), dabrafenib (e.g., dabrafenib mesylate, GSK2118436), encorafenib (e.g., BRAFTOVI™, LGX818), naporafenib (LXH254), sorafenib (e.g., sorafenib tosylate), vemurafenib (e.g., ZELBORAF®, RO5185426), ARQ-736, AZ304, BMS-908662 (XL281), C17071479-F, CHIR-265 (RAF265), FORE-8394 (PLX-8394), GDC-0879, GDC-5573 (HM95573), HLX-208, PLX-3603, or PLX-4720). In some embodiments, the cancer is a BRaf mutant CRC (e.g., BRaf V600E mutant CRC), and the additional therapy or therapeutic agent is a BRaf inhibitor (e.g., avutometinib (RO5126766), dabrafenib (e.g., dabrafenib mesylate, GSK2118436), encorafenib (e.g., BRAFTOVI™, LGX818), naporafenib (LXH254), sorafenib (e.g., sorafenib tosylate), vemurafenib (e.g., ZELBORAF®, RO5185426), ARQ-736, AZ304, BMS-908662 (XL281), C17071479-F, CHIR-265 (RAF265), FORE-8394 (PLX-8394), GDC-0879, GDC-5573 (HM95573), HLX-208, PLX-3603, or PLX-4720) and an anti-EGFR antibody or anti-EGFR antibody-drug conjugate (e.g., amivantamab (e.g., amivantamab-vmjw, or a biosimilar thereof), cetuximab (e.g., ERBITUX® (cetuximab), or a biosimilar thereof (e.g., CMAB-009, CPGJ-602, or KL-140)), cetuximab sarotalocan (AKALUX® (cetuximab sarotalocan), or a biosimilar thereof), depatuxizumab, duligotuzumab, futuximab, imgatuzumab, modotuximab, necitumumab (e.g., PORTRAZZA® (necitumumab), or a biosimilar thereof), nimotuzumab (e.g., BIOMAb EGFR® (nimotuzumab), or a biosimilar thereof), panitumumab (e.g., VECTIBIX® (panitumumab), or a biosimilar thereof), tomuzotuximab, zalutumumab, EMD-55900, EMD-82633, GC-1118, HLX-07, ICR-62, SCT-200, SI-B-001, TAS-0313, or biosimilars thereof). In some embodiments, the cancer is a BRaf mutant CRC (e.g., BRaf V600E mutant CRC), and the additional therapy or therapeutic agent is a BRaf inhibitor (e.g., avutometinib (RO5126766), dabrafenib (e.g., dabrafenib mesylate, GSK2118436), encorafenib (e.g., BRAFTOVI™, LGX818), naporafenib (LXH254), sorafenib (e.g., sorafenib tosylate), vemurafenib (e.g., ZELBORAF®, RO5185426), ARQ-736, AZ304, BMS-908662 (XL281), C17071479-F, CHIR-265 (RAF265), FORE-8394 (PLX-8394), GDC-0879, GDC-5573 (HM95573), HLX-208, PLX-3603, or PLX-4720) and cetuximab (e.g., ERBITUX® (cetuximab), or a biosimilar thereof (e.g., CMAB-009, CPGJ-602, or KL-140)). In some embodiments, the cancer is a BRaf mutant CRC (e.g., BRaf V600E mutant CRC), and the additional therapy or therapeutic agent is a BRaf inhibitor (e.g., avutometinib (RO5126766), dabrafenib (e.g., dabrafenib mesylate, GSK2118436), encorafenib (e.g., BRAFTOVI™, LGX818), naporafenib (LXH254), sorafenib (e.g., sorafenib tosylate), vemurafenib (e.g., ZELBORAF®, RO5185426), ARQ-736, AZ304, BMS-908662 (XL281), C17071479-F, CHIR-265 (RAF265), FORE-8394 (PLX-8394), GDC-0879, GDC-5573 (HM95573), HLX-208, PLX-3603, or PLX-4720) and panitumumab (e.g., VECTIBIX® (panitumumab), or a biosimilar thereof). In some embodiments, the cancer is a BRaf mutant CRC (e.g., BRaf V600E mutant CRC), and the additional therapy or therapeutic agent is a dabrafenib (e.g., dabrafenib mesylate, GSK2118436), encorafenib (e.g., BRAFTOVI™, LGX818), or vemurafenib (e.g., ZELBORAF®, RO5185426) and cetuximab (e.g., ERBITUX® (cetuximab), or a biosimilar thereof (e.g., CMAB-009, CPGJ-602, or KL-140)). In some embodiments, the cancer is a BRaf mutant CRC (e.g., BRaf V600E mutant CRC), and the additional therapy or therapeutic agent is dabrafenib (e.g., dabrafenib mesylate, GSK2118436), encorafenib (e.g., BRAFTOVI™, LGX818), or vemurafenib (e.g., ZELBORAF®, RO5185426) and panitumumab (e.g., VECTIBIX® (panitumumab), or a biosimilar thereof). In some embodiments, the cancer is a BRaf mutant CRC (e.g., BRaf V600E mutant CRC), and the additional therapy or therapeutic agent is a dabrafenib (e.g., dabrafenib mesylate, GSK2118436) and cetuximab (e.g., ERBITUX® (cetuximab), or a biosimilar thereof (e.g., CMAB-009, CPGJ-602, or KL-140)). In some embodiments, the cancer is a BRaf mutant CRC (e.g., BRaf V600E mutant CRC), and the additional therapy or therapeutic agent is dabrafenib (e.g., dabrafenib mesylate, GSK2118436) and panitumumab (e.g., VECTIBIX® (panitumumab), or a biosimilar thereof).

[0686] In some embodiments, the cancer is a BRaf mutant NSCLC (e.g., BRaf V600E mutant NSCLC), and the additional therapy or therapeutic agent is a BRaf inhibitor (e.g., avutometinib (RO5126766), dabrafenib (e.g., dabrafenib mesylate, GSK2118436), encorafenib (e.g., BRAFTOVI™, LGX818), naporafenib (LXH254), sorafenib (e.g., sorafenib tosylate), vemurafenib (e.g., ZELBORAF®, RO5185426), ARQ-736, AZ304, BMS-908662 (XL281), C17071479-F, CHIR-265 (RAF265), FORE-8394 (PLX-8394), GDC-0879, GDC-5573 (HM95573), HLX-208, PLX-3603, or PLX-4720) and a MEK inhibitor (e.g., avutometinib, binimetinib, cobimetinib (e.g., cobimetinib fumarate), mirdametinib, pimasertib, refam etinib, selumetinib (e.g., selumetinib sulfate), trametinib (e.g., trametinib dimethyl sulfoxide), zapnometinib, FCN-159, GSK-1120212, NFX-179, or TAK-733). In some embodiments, the cancer is a BRaf mutant NSCLC (e.g., BRaf V600E mutant NSCLC), and the additional therapy or therapeutic agent is dabrafenib (e.g., dabrafenib mesylate, GSK2118436), encorafenib (e.g., BRAFTOVI™, LGX818), or vemurafenib (e.g., ZELBORAF®, RO5185426), and binimetinib, cobimetinib (e.g., cobimetinib fumarate), selumetinib (e.g., selumetinib sulfate), or trametinib (e.g., trametinib dimethyl sulfoxide). In some embodiments, the cancer is a BRaf mutant NSCLC (e.g., BRaf V600E mutant NSCLC), and the additional therapy or therapeutic agent is dabrafenib (e.g., dabrafenib mesylate, GSK2118436) and trametinib (e.g., trametinib dimethyl sulfoxide). In some embodiments, the cancer is a BRaf mutant NSCLC (e.g., BRaf V600E mutant NSCLC), and the additional therapy or therapeutic agent is vemurafenib (e.g., ZELBORAF®, RO5185426), and cobimetinib (e.g., cobimetinib fumarate). In some embodiments, the cancer is a BRaf mutant NSCLC (e.g., BRaf V600E mutant NSCLC), and the additional therapy or therapeutic agent is encorafenib (e.g., BRAFTOVI™, LGX818) and binimetinib.

[0687] In some embodiments, the cancer is a BRaf mutant melanoma (e.g., BRaf V600E mutant melanoma), and the additional therapy or therapeutic agent is a BRaf inhibitor (e.g., avutometinib (RO5126766), dabrafenib (e.g., dabrafenib mesylate, GSK2118436), encorafenib (e.g., BRAFTOVI™, LGX818), naporafenib (LXH254), sorafenib (e.g., sorafenib tosylate), vemurafenib (e.g., ZELBORAF®, RO5185426), ARQ-736, AZ304, BMS-908662 (XL281), C17071479-F, CHIR-265 (RAF265), FORE-8394 (PLX-8394), GDC-0879, GDC-5573 (HM95573), HLX-208, PLX-3603, or PLX-4720). In some embodiments, the cancer is a BRaf mutant melanoma (e.g., BRaf V600E mutant melanoma), and the additional therapy or therapeutic agent is a BRaf inhibitor (e.g., avutometinib (RO5126766), dabrafenib (e.g., dabrafenib mesylate, GSK2118436), encorafenib (e.g., BRAFTOVI™, LGX818), naporafenib (LXH254), sorafenib (e.g., sorafenib tosylate), vemurafenib (e.g., ZELBORAF®, RO5185426), ARQ-736, AZ304, BMS-908662 (XL281), C17071479-F, CHIR-265 (RAF265), FORE-8394 (PLX-8394), GDC-0879, GDC-5573 (HM95573), HLX-208, PLX-3603, or PLX-4720) and a MEK inhibitor (e.g., avutometinib, binimetinib, cobimetinib (e.g., cobimetinib fumarate), mirdametinib, pimasertib, refametinib, selumetinib (e.g., selumetinib sulfate), trametinib (e.g., trametinib dimethyl sulfoxide), zapnometinib, FCN-159, GSK-1120212, NFX-179, or TAK-733). In some embodiments, the cancer is a BRaf mutant melanoma (e.g., BRaf V600E mutant melanoma), and the additional therapy or therapeutic agent is dabrafenib (e.g., dabrafenib mesylate, GSK2118436), encorafenib (e.g., BRAFTOVI™, LGX818), or vemurafenib (e.g., ZELBORAF®, RO5185426), and binimetinib, cobimetinib (e.g., cobimetinib fumarate), selumetinib (e.g., selumetinib sulfate), or trametinib (e.g., trametinib dimethyl sulfoxide). In some embodiments, the cancer is a BRaf mutant melanoma (e.g., BRaf V600E mutant melanoma), and the additional therapy or therapeutic agent is dabrafenib (e.g., dabrafenib mesylate, GSK2118436) and trametinib (e.g., trametinib dimethyl sulfoxide). In some embodiments, the cancer is a BRaf mutant melanoma (e.g., BRaf V600E mutant melanoma), and the additional therapy or therapeutic agent is vemurafenib (e.g., ZELBORAF®, RO5185426), and cobimetinib (e.g., cobimetinib fumarate). In some embodiments, the cancer is a BRaf mutant melanoma (e.g., BRaf V600E mutant melanoma), and the additional therapy or therapeutic agent is encorafenib (e.g., BRAFTOVI™, LGX818) and binimetinib. In some such embodiments, the subject has previously been treated with an immunotherapy.

[0688] In some embodiments, the CDK2 inhibitor is ebvaciclib, fadraciclib, milciclib, pacritinib (e.g., pacritinib citrate), roniciclib, roscovitine, BLU-222, NUV-422, PF-07104091, TQB-3616, or a combination thereof. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib, birociclib, dalpiciclib, lerociclib, milciclib, palbociclib, ribociclib (e.g., ribociclib succinate), riviciclib, roniciclib, trilaciclib (e.g., trilaciclib dihydrochloride), FCN-437, TQB-3616, or a combination thereof.

[0689] In some embodiments, the CDK7 inhibitor is milciclib, roscovitine, samuraciclib, or a combination thereof.

[0690] In some embodiments, the CDK9 inhibitor is fadraciclib, riviciclib, roniciclib, roscovitine, zotiraciclib, AZD-4573, KB-0742, or a combination thereof.

[0691] In some embodiments, the EGFR inhibitor is abivertinib, afatinib (e.g., afatinib dimaleate), alflutinib (e.g., alflutinib mesylate), almonertinib (e.g., almonertinib mesylate), asandeutertinib, befotertinib, brigatinib, canertinib, dacomitinib (e.g., dacomitinib monohydrate), dovitinib, erlotinib (e.g., erlotinib hydrochloride), gefitinib, icotinib (e.g., icotinib hydrochloride), lapatinib (e.g., lapatinib ditosylate monohydrate), larotinib, lazertinib (e.g., lazertinib mesylate), limertinib, mobocertinib (e.g., mobocertinib succinate), nazartinib, neratinib (e.g., neratinib maleate), olmutinib, osimertinib (e.g., osimertinib mesylate), pelitinib, pirotinib, poziotinib, pyrotinib (e.g., pyrotinib maleate), rezivertinib (e.g., rezivertinib mesylate), ruserontinib (SKLB-1028), sacibertinib, sapitinib, sevabertinib, sunvozertinib, sutetinib, tarloxotinib, tesevatinib, vandetanib, varlitinib, zipalertinib, zorifertinib, BEBT-109, BIBW-2948, FHND-9041, HA- 121-28, PLB-1004, SH-1028, or a combination thereof.

[0692] In some embodiments, the anti-EGFR antibody or anti-EGFR antibody-drug conjugate is ametumumab, amivantamab (e.g., amivantamab-vmjw, or a biosimilar thereof), becotatug, cetuximab (e.g., ERBITUX® (cetuximab), or a biosimilar thereof (e.g., CMAB-009, CPGJ-602, orKL-140)), cetuximab sarotalocan (AKALUX® (cetuximab sarotalocan), or a biosimilar thereof), dalmitamig, depatuxizumab, duligotuzumab, ficerafusp alfa, futuximab, imgatuzumab, izalontamab (SI-B-001), matuzumab, modotuximab, necitumumab (e.g., PORTRAZZA® (necitumumab), or a biosimilar thereof), nimotuzumab (e.g., BIOMAb EGFR® (nimotuzumab), or a biosimilar thereof), panitumumab (e.g., VECTIBIX® (panitumumab), or a biosimilar thereof (e.g., QL-1203)), petosemtamab, tomuzotuximab, zalutumumab, EMD-55900, EMD-82633, GC-1118, HLX-07, ICR-62, SCT-200, biosimilars thereof, or a combination thereof. In some embodiments, the anti-EGFR antibody or anti-EGFR antibody-drug conjugate is amivantamab (e.g., amivantamab-vmjw, or a biosimilar thereof), cetuximab (e.g., ERBITUX® (cetuximab), or a biosimilar thereof (e.g., CMAB-009, CPGJ-602, orKL-140)), cetuximab sarotalocan (AKALUX® (cetuximab sarotalocan), or a biosimilar thereof), depatuxizumab, duligotuzumab, futuximab, imgatuzumab, modotuximab, necitumumab (e.g., PORTRAZZA® (necitumumab), or a biosimilar thereof), nimotuzumab (e.g., BIOMAb EGFR® (nimotuzumab), or a biosimilar thereof), panitumumab (e.g., VECTIBIX® (panitumumab), or a biosimilar thereof), tomuzotuximab, zalutumumab, EMD-55900, EMD-82633, GC-1118, HLX-07, ICR-62, SCT-200, SLB-001, biosimilars thereof, or a combination thereof.

[0693] In some embodiments, an EGFR mutation (e.g., an EGFR exon 19 deletion or an EGFR L858R mutation (with or without an EGFR T790M mutation)) can be detected in a sample from the subject (e.g., detecting an EGFR gene having a mutation (e.g., a mutation corresponding to an EGFR exon 19 deletion or an EGFR L858R mutation (with or without an EGFR T790M mutation) in an EGFR protein) and / or detecting an EGFR protein having a mutation (e.g., an EGFR exon 19 deletion or an EGFR L858R mutation (with or without an EGFR T790M mutation))). In some embodiments, the subject was determined (e.g., prior to administration of a compound provided herein) to have a cancer having an EGFR mutation (e.g., an EGFR exon 19 deletion or an EGFR L858R mutation (with or without an EGFR T790M mutation)).

[0694] In some embodiments, the cancer is an EGFR mutant NSCLC (e.g., EGFR exon 19 deletion NSCLC or EGFR L858R (with or without T790M) mutant NCLC), and the additional therapy or therapeutic agent is an EGFR inhibitor (e.g., abivertinib, afatinib (e.g., afatinib dimaleate), alflutinib (e.g., alflutinib mesylate), almonertinib (e.g., almonertinib mesylate), asandeutertinib, befotertinib, brigatinib, canertinib, dacomitinib (e.g., dacomitinib monohydrate), dovitinib, erlotinib (e.g., erlotinib hydrochloride), gefitinib, icotinib (e.g., icotinib hydrochloride), lapatinib (e.g., lapatinib ditosylate monohydrate), larotinib, lazertinib (e.g., lazertinib mesylate), limertinib, mobocertinib (e.g., mobocertinib succinate), nazartinib, neratinib (e.g., neratinib maleate), olmutinib, osimertinib (e.g., osimertinib mesylate), pelitinib, pirotinib, poziotinib, pyrotinib (e.g., pyrotinib maleate), rezivertinib (e.g., rezivertinib mesylate), ruserontinib (SKLB-1028), sacibertinib, sapitinib, sevabertinib, sunvozertinib, sutetinib, tarloxotinib, tesevatinib, vandetanib, varlitinib, zipalertinib, zorifertinib, BEBT-109, BIBW-2948, FHND-9041, HA-121-28, PLB-1004, SH-1028, or an anti-EGFR antibody or anti-EGFR antibody-drug conjugate). In some embodiments, the cancer is an EGFR mutant NSCLC (e.g., EGFR exon 19 deletion NSCLC or EGFR L858R (with or without T790M) mutant NCLC), and the additional therapy or therapeutic agent is osimertinib (e.g., osimertinib mesylate).

[0695] In some embodiments, the ERK inhibitor is rineterkib, temuterkib, ulixertinib, ASN- 0007, ASTX-029, ATG-017, BPI-27336, HH-2710, JSI-1187, MK-8353, or a combination thereof.

[0696] In some embodiments, the EZH2 inhibitor is lirametostat, mevrometostat (PF-6821497), tazemetostat (e.g., tazemetostat hydrobromide), valemetostat (e.g., valemetostat tosylate), tulmimetostat (CPI-0209), EBI-2511, HH-2853, HM-97662, SHR-2554, XNW-5004, or a combination thereof. In some embodiments, the EZH2 inhibitor also inhibits EZH1 (also referred to as an EZH1 / 2 inhibitor).

[0697] In some embodiments, the cancer is peripheral T cell lymphoma, and the additional therapy or therapeutic agent is an EZH2 inhibitor (e.g., lirametostat, mevrometostat (PF-6821497), tazemetostat (e.g., tazemetostat hydrobromide), valemetostat (e.g., valemetostat tosylate), tulmimetostat (CPI-0209), EBI-2511, HH-2853, HM-97662, SHR-2554, XNW-5004).

[0698] In some embodiments, the FGFR1 inhibitor is danusertib, dovitinib, erdafitinib, futibatinib, infigratinib (e.g., infigratinib phosphate), lenvatinib (e.g., lenvatinib mesylate), lucitanib, nintedanib (e.g., nintedanib esylate), pemigatinib, surufatinib, tasurgratinib, tinengotinib, zoligratinib, FH-2001, HMPL-453, LY-2874455, or a combination thereof.

[0699] In some embodiments, the FGFR2 inhibitor is erdafitinib, futibatinib, infigratinib (e.g., infigratinib phosphate), lucitanib, pemigatinib, tasurgratinib, zoligratinib, bemarituzumab (or biosimilars thereof), FH-2001, HMPL-453, LY-2874455, or a combination thereof.

[0700] In some embodiments, the FGFR3 inhibitor is dovitinib, erdafitinib, futibatinib, infigratinib (e.g., infigratinib phosphate), lucitanib, masitinib, nintedanib, pemigatinib, tasurgratinib, zoligratinib, vofatamab (or biosimilars thereof), EXEL-0999, FH-2001, HMPL-453, LY-2874455, or a combination thereof.

[0701] In some embodiments, the FGFR4 inhibitor is axitinib, erdafitinib, futibatinib, infigratinib (e.g., infigratinib phosphate), irpagratinib, nintedanib, pemigatinib, FH-2001, H3B-6527, LY-2874455, or a combination thereof.

[0702] In some embodiments, the HER2 inhibitor is afatinib (e.g., afatinib dimaleate), dacomitinib (e.g., dacomitinib monohydrate), lapatinib (e.g., lapatinib ditosylate monohydrate), mobocertinib (e.g., mobocertinib succinate), neratinib (e.g., neratinib maleate), poziotinib, pyrotinib (e.g., pyrotinib maleate), sunvozertinib, tesevatinib, tucatinib, varlitinib, an anti-HER2 antibody or anti-HER2 antibody-drug conjugate, or a combination thereof.

[0703] In some embodiments, the anti-HER2 antibody or anti-HER2 antibody-drug conjugate is anbenitamab, cinrebafusp alfa, coprelotamab, disitamab vedotin, ertumaxomab, gancotamab, inetetamab, margetuximab (e.g., margetuximab-cmkb, or a biosimilar thereof), pertuzumab (e.g., PERJETA® (pertuzumab), or a biosimilar thereof (e.g., HLX-11)), trastuzumab (e.g., HERCEPTIN® (trastuzumab), or a biosimilar thereof (e.g., FACEPTOR® (trastuzumab), HERTICAD® (trastuzumab), TUZNUE® (trastuzumab), ZERCEPAC® (trastuzumab), trastuzumab-anns, trastuzumab-dkst, trastuzumab-dttb, trastuzumab-pkrb, trastuzumab-qyyp, EG-12014, or TX-05)), trastuzumab deruxtecan (e.g., fam-trastuzumab deruxtecan-nxki, or a biosimilar thereof), trastuzumab duocarmazine, trastuzumab emtansine (e.g., KADCYLA® (trastuzumab emtansine), or a biosimilar thereof (e.g., UJVIRA® (trastuzumab emtansine))), trastuzumab hyaluronidase (e.g., trastuzumab hyaluronidase-oysk, or a biosimilar thereof), zanidatamab, zenocutuzumab, AVX-901, IDM-1, TPIV-100, TAA-013, SHR-A1811, BAT-8001, MDX-210, Alpha-Her2-pAFl-AS-269, MRG-002, DF-1001, AC-101, MM-111, biosimilars thereof, or a combination thereof. In some embodiments, the anti-HER2 antibody or anti-HER2 antibody-drug conjugate is anbenitamab, cinrebafusp alfa, coprelotamab, disitamab vedotin, ertumaxomab, gancotamab, inetetamab, margetuximab (e.g., margetuximab-cmkb, or a biosimilar thereof), pertuzumab (e.g., PERJETA® (pertuzumab), or a biosimilar thereof (e.g., HLX-11)), trastuzumab (e.g., HERCEPTIN® (trastuzumab), or a biosimilar thereof (e.g., FACEPTOR® (trastuzumab), HERTICAD® (trastuzumab), TUZNUE® (trastuzumab), ZERCEPAC® (trastuzumab), trastuzumab-anns, trastuzumab-dkst, trastuzumab-dttb, trastuzumab-pkrb, trastuzumab-qyyp, EG-12014, or TX-05)), trastuzumab deruxtecan (e.g., fam-trastuzumab deruxtecan-nxki, or a biosimilar thereof), trastuzumab duocarmazine, trastuzumab emtansine (e.g., KADCYLA® (trastuzumab emtansine), or a biosimilar thereof (e.g., UJVIRA® (trastuzumab emtansine))), trastuzumab hyaluronidase (e.g., trastuzumab hyaluronidase-oysk, or a biosimilar thereof), zanidatamab, zenocutuzumab, TAA-013, SHR-A1811, BAT-8001, MDX-210, Alpha-Her2-pAFl-AS-269, MRG-002, DF-1001, AC-101, MM-111, biosimilars thereof, or a combination thereof.

[0704] In some embodiments, HER2+ status can be detected in a sample from the subject (e.g., via immunohistochemistry (IHC) and / or fluorescent in situ hybridization (FISH)). In some embodiments, the subject was determined (e.g., prior to administration of a compound provided herein) to have a cancer with HER2+ status.

[0705] In some embodiments, HER2 low status can be detected in a sample from the subject (e.g., via IHC and / or FISH). In some embodiments, the subject was determined (e.g., prior to administration of a compound provided herein) to have a cancer with HER2 low status. In some embodiments, HER2- status can be detected in a sample from the subject (e.g., via IHC and / or FISH). In some embodiments, the subject was determined (e.g., prior to administration of a compound provided herein) to have a cancer with HER2- status.

[0706] In some embodiments, ER expression status can be detected in a sample from the subject (e.g., via IHC and / or FISH). In some embodiments, the subject was determined (e.g., prior to administration of a compound provided herein) to have a cancer with ER expression. In some embodiments, the subject was determined (e.g., prior to administration of a compound provided herein) to have a cancer without ER expression.

[0707] In some embodiments, PR expression status can be detected in a sample from the subject (e.g., via IHC, and / or FISH). In some embodiments, the subject was determined (e.g., prior to administration of a compound provided herein) to have a cancer with PR expression. In some embodiments, the subject was determined (e.g., prior to administration of a compound provided herein) to have a cancer without PR expression.

[0708] In some embodiments, the cancer is a HER2+ breast cancer (e.g., HER2+ breast cancer with ER expression, HER2+ breast cancer without ER expression), and the additional therapy is a HER2 inhibitor (e.g., afatinib (e.g., afatinib dimaleate), dacomitinib (e.g., dacomitinib monohydrate), lapatinib (e.g., lapatinib ditosylate monohydrate), mobocertinib (e.g., mobocertinib succinate), neratinib (e.g., neratinib maleate), poziotinib, pyrotinib (e.g., pyrotinib maleate), sunvozertinib, tesevatinib, tucatinib, varlitinib, or an anti-HER2 antibody or anti-HER2 antibody-drug conjugate). In some embodiments, the cancer is a HER2+ breast cancer (e.g., HER2+ breast cancer with ER expression, HER2+ breast cancer without ER expression), and the additional therapy is tucatinib. In some embodiments, the cancer is a HER2+ breast cancer (e.g., HER2+ breast cancer with ER expression, HER2+ breast cancer without ER expression), and the additional therapy is an anti-HER2 antibody or anti-HER2 antibody-drug conjugate (e.g., anbenitamab, cinrebafusp alfa, coprelotamab, disitamab vedotin, ertumaxomab, gancotamab, inetetamab, margetuximab (e.g., margetuximab-cmkb, or a biosimilar thereof), pertuzumab (e.g., PERJETA® (pertuzumab), or a biosimilar thereof (e.g., HLX-11)), trastuzumab (e.g., HERCEPTIN® (trastuzumab), or a biosimilar thereof (e.g., FACEPTOR® (trastuzumab), HERTICAD® (trastuzumab), TUZNUE® (trastuzumab), ZERCEPAC® (trastuzumab), trastuzumab -anns, trastuzumab-dkst, trastuzumab-dttb, trastuzumab-pkrb, trastuzumab-qyyp, EG-12014, or TX-05)), trastuzumab deruxtecan (e.g., fam-trastuzumab deruxtecan-nxki, or a biosimilar thereof), trastuzumab duocarmazine, trastuzumab emtansine (e.g., KADCYLA® (trastuzumab emtansine), or a biosimilar thereof (e.g., UJVIRA® (trastuzumab emtansine))), trastuzumab hyaluronidase (e.g., trastuzumab hyaluronidase-oysk, or a biosimilar thereof), zanidatamab, zenocutuzumab, AVX-901, IDM-1, TPIV-100, TAA-013, SHR-A1811, BAT-8001, MDX-210, Alpha-Her2-pAFl-AS-269, MRG-002, DF-1001, AC-101, MM-111, or biosimilars thereof). In some embodiments, the cancer is a HER2+ breast cancer (e.g., HER2+ breast cancer with ER expression, HER2+ breast cancer without ER expression), and the additional therapy is trastuzumab (e.g., HERCEPTIN® (trastuzumab), or a biosimilar thereof (e.g., FACEPTOR® (trastuzumab), HERTICAD® (trastuzumab), TUZNUE® (trastuzumab), ZERCEPAC® (trastuzumab), trastuzumab -anns, trastuzumab-dkst, trastuzumab-dttb, trastuzumab -pkrb, trastuzumab -qyyp, EG-12014, or TX-05)). In some embodiments, the cancer is a HER2+ breast cancer (e.g., HER2+ breast cancer with ER expression, HER2+ breast cancer without ER expression), and the additional therapy is trastuzumab deruxtecan (e.g., fam-trastuzumab deruxtecan-nxki, or a biosimilar thereof). In some embodiments, the cancer is a HER2+ breast cancer (e.g., HER2+ breast cancer with ER expression, HER2+ breast cancer without ER expression), and the additional therapy is trastuzumab emtansine, or a biosimilar thereof. In some embodiments, the cancer is a HER2 low breast cancer, and the additional therapy is an anti-HER2 antibody or anti-HER2 antibodydrug conjugate. In some embodiments, the cancer is a HER2 low breast cancer, and the additional therapy is trastuzumab deruxtecan (e.g., fam-trastuzumab deruxtecan-nxki, or a biosimilar thereof).

[0709] In some embodiments, the JAK inhibitor is adelatinib, baricitinib, brepocitinib, deuruxolitinib, fedratinib (e.g., fedratinib dihydrochloride monohydrate), filgotinib (e.g., filgotinib maleate), gandotinib, gusacitinib, ilginatinib, izencitinib, jaktinib, momelotinib (e.g., momelotinib dihydrochloride), nezulcitinib, pacritinib (e.g., pacritinib citrate), peficitinib (e.g., peficitinib hydrobromide), ropsacitinib, ruxolitinib (e.g., ruxolitinib phosphate), tasocitinib (e.g., tofacitinib citrate), AT-9283, TQ-05105, or a combination thereof. In some embodiments, the JAK inhibitor is fedratinib (e.g., fedratinib dihydrochloride monohydrate), momelotinib (e.g., momelotinib dihydrochloride), pacritinib (e.g., pacritinib citrate), ruxolitinib (e.g., ruxolitinib phosphate), or a combination thereof. In some embodiments, the JAK inhibitor is fedratinib (e.g., fedratinib dihydrochloride monohydrate). In some embodiments, the JAK inhibitor is momelotinib (e.g., momelotinib dihydrochloride). In some embodiments, the JAK inhibitor is pacritinib (e.g., pacritinib citrate). In some embodiments, the JAK inhibitor is ruxolitinib (e.g., ruxolitinib phosphate).

[0710] In some embodiments, a JAK V617F mutation can be detected in a sample from the subject (e.g., detecting a JAK2 gene having a mutation corresponding to a V617F mutation in JAK2 protein and / or detecting a JAK2 protein having a V617F mutation). In some embodiments, the subject was determined (e.g., prior to administration of a compound provided herein) to have a cancer having a JAK2 V617F mutation. In some embodiments, the subject was determined (e.g., prior to administration of a compound provided herein) to have a cancer lacking a JAK2 V617F mutation.

[0711] In some embodiments, the cancer is post-MPN AML, M6-AML, or M7-AML, and the additional therapy or therapeutic agent is a JAK inhibitor (e.g., ruxolitinib (e.g., ruxolitinib phosphate), fedratinib (e.g., fedratinib dihydrochloride monohydrate), momelotinib (e.g., momelotinib dihydrochloride), or pacritinib (e.g., pacritinib citrate)). In some embodiments, the patient has received a previous line of therapy including a JAK inhibitor. In some embodiments, the patient has not received a previous line of therapy including a JAK inhibitor.

[0712] In some embodiments, the cancer is intermediate (e.g., intermediate- 1 and / or intermediate-2) or high-risk myelofibrosis (e.g., primary myelofibrosis, post-essential thrombocythemia myelofibrosis, or post-polycythemia vera myelofibrosis), and the additional therapy or therapeutic agent is a JAK inhibitor (e.g., ruxolitinib (e.g., ruxolitinib phosphate), fedratinib (e.g., fedratinib dihydrochloride monohydrate), momelotinib (e.g., momelotinib dihydrochloride), or pacritinib (e.g., pacritinib citrate)). In some embodiments, the cancer is intermediate (e.g., intermediate- 1 and / or intermediate-2) or high-risk myelofibrosis (e.g., primary myelofibrosis, post-essential thrombocythemia myelofibrosis, or post-polycythemia vera myelofibrosis), and the additional therapy or therapeutic agent is a JAK inhibitor (e.g., ruxolitinib (e.g., ruxolitinib phosphate), fedratinib (e.g., fedratinib dihydrochloride monohydrate), momelotinib (e.g., momelotinib dihydrochloride), or pacritinib (e.g., pacritinib citrate)) and a BET inhibitor (e.g., alobresib, apabetalone, mivebresib, pelabresib, trotabresib, ABBV-744, BI-2536, BMS-986158, INCB-057643, JAB-8263, ODM-207, PLX-2853, or ZEN-003694). In some embodiments, the cancer is intermediate (e.g., intermediate- 1 and / or intermediate-2) or high-risk myelofibrosis (e.g., primary myelofibrosis, post-essential thrombocythemia myelofibrosis, or post-polycythemia vera myelofibrosis) with a JAK2 mutation (e.g., a JAK2 V617F mutation), and the additional therapy or therapeutic agent is a JAK inhibitor (e.g., ruxolitinib (e.g., ruxolitinib phosphate), fedratinib (e.g., fedratinib dihydrochloride monohydrate), momelotinib (e.g., momelotinib dihydrochloride), or pacritinib (e.g., pacritinib citrate)). In some embodiments, the cancer is intermediate (e.g., intermediate-1 and / or intermediate-2) or high-risk myelofibrosis (e.g., primary myelofibrosis, post-essential thrombocythemia myelofibrosis, or post-polycythemia vera myelofibrosis) with a JAK2 mutation (e.g., a JAK2 V617F mutation), and the additional therapy or therapeutic agent is a JAK inhibitor (e.g., ruxolitinib (e.g., ruxolitinib phosphate), fedratinib (e.g., fedratinib dihydrochloride monohydrate), momelotinib (e.g., momelotinib dihydrochloride), or pacritinib (e.g., pacritinib citrate)) and a BET inhibitor (e.g., alobresib, apabetalone, mivebresib, pelabresib, trotabresib, ABBV-744, BI-2536, BMS-986158, INCB-057643, JAB-8263, ODM-207, PLX-2853, or ZEN-003694). In some embodiments, the JAK inhibitor is fedratinib (e.g., fedratinib dihydrochloride monohydrate). In some embodiments, the JAK inhibitor is momelotinib (e.g., momelotinib dihydrochloride). In some embodiments, the JAK inhibitor is pacritinib (e.g., pacritinib citrate). In some embodiments, the JAK inhibitor is ruxolitinib (e.g., ruxolitinib phosphate). In some embodiments, the patient has received a previous line of therapy including a JAK inhibitor. In some embodiments, the patient has not received a previous line of therapy including a JAK inhibitor. In some embodiments, treatment effect can be measured by Spleen Volume Reduction (e.g., Spleen Volume Reduction of greater than or equal to 35% (SVR35), for example, measured by MRI or CT), Total Symptom Score (e.g., Total Symptom Score reduction of greater than or equal to 50% (TSSso), for example, measured by the Myelofibrosis Symptom Assessment Form (MFSAF) version 4.0), or both, such as at 24 weeks after beginning of treatment; see, e.g., Harrison, Claire, et al., New England Journal of Medicine 366.9 (2012): 787-798, doi: 10.1056 / NEJMoal 110556; and Verstovsek, Srdan, et al. New England Journal of Medicine 366.9 (2012): 799-807, doi: 10.1056 / NEJMoal 110557. In some embodiments, treatment effect can be measured (e.g., in addition to or instead of SVR35 and / or TSSso) by anemia response (e.g., measured by current International Working Group-Myeloproliferative Neoplasms Research and European LeukemiaNet (IWG-MRT / ELN) criteria), bone marrow fibrosis (e.g., according to the European Consensus Grading System through bone marrow biopsy, such as at 24 or 96 weeks after beginning of treatment), variant allele fraction (e.g., JAK2 V617F variant allele fraction), transfusion independence, overall survival, leukemia-free survival, change in physical functioning (e.g., measured by the physical functioning domain of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 or death), change in fatigue (e.g., assessed using the Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue SF 7a), or a combination thereof.

[0713] In some embodiments, the KRas inhibitor or degrader is adagrasib (MRTX-849), ALTA3263, AMG410, AN9025, ARS-1620, ARS-3248, ARS-853, ARV-806, ASP-4396, ATG-012, AZD-0022, BBO-11818, BBO-8520, BGB-53038, BI 3706674, BI-1701963, BI-1823911, BPI-421286, BPI-572270, BPI-585725, BRSD-143, CGT9109, daraxonrasib (RMC-6236), divarasib (GDC-6036), elisrasib (D-3S-001), ERAS-0015, ERAS-3490, ERAS-4001, FMC-376, fulzerasib (GFH-925), garsorasib (D-1553), GDC-7035, GEC-255, GFH276, GFH375, GFH547, GFS784, GH-35, glecirasib (JAB-21822), HBW-012336, HBW-016-K, HEC211909, HRS-4642, HS-10370, HS-10529, INCB-161734, INCB186748, JAB-23E73, JDQ-443, LY3962673, LY4066434, MK-1084, MRTX1133, MRTX-1257, olomorasib (LY-3537982), PF-07934040, PF-07985045, PT0253, QLC-1101, QTX3034, QTX3046, QTX3544, RCZY-680, RCZY-690, RMC-5127, RMC-6291, RMC-7977, RNK-08954, RO7673396, RP-03707, RP04340, RSC-1255, setidegrasib (ASP-3082), SHR-1127, sotorasib (AMG-510), TSN-1611, YL-15293, YL-17231, ZG-19018, zoldonrasib (RMC-9805), or a combination thereof. In some embodiments, the KRas inhibitor or degrader is a pan-Ras inhibitor or degrader. In some embodiments, the pan-Ras inhibitor or degrader is daraxonrasib (RMC-6236), RMC-7977, ERAS-0015, GFH276, GFH547, AN9025, RO7673396, BPI-572270, RCZY-690, RCZY-680, GFS784, or a combination thereof. In some embodiments, the KRas inhibitor or degrader is a pan-KRas inhibitor or degrader. In some embodiments, the pan-KRas inhibitor or degrader is BI 3706674, YL-17231, PF-07934040, PF-07985045, BGB-53038, LY4066434, JAB-23E73, ALTA3263, BBO-11818, QTX3544, QTX3034, ERAS-4001, AMG410, BRSD-143, CGT9109, HBW-016-K, HEC211909, RP04340, BPI-585725, or a combination thereof. In some embodiments, the KRas inhibitor or degrader is a Ras G12V inhibitor or degrader. In some embodiments, the Ras G12V inhibitor or degrader is RMC-5127. In some embodiments, the KRas inhibitor or degrader is a KRas G12D inhibitor or degrader. In some embodiments, the KRas G12D inhibitor or degrader is MRTX1133, HRS-4642, GDC-7035, LY3962673, GFH375, RNK-08954, AZD-0022, QTX3046, INCB-161734, INCB 186748, ASP-4396, setidegrasib (ASP-3082), ARV-806, PT0253, RP-03707, TSN-1611, QLC-1101, HS-10529, HBW-012336, zoldonrasib (RMC-9805), or a combination thereof. In some embodiments, the KRas inhibitor or degrader is a KRas G12C inhibitor or degrader. In some embodiments, the KRas G12C inhibitor or degrader is sotorasib (AMG-510), adagrasib (MRTX-849), garsorasib (D-1553), fulzerasib (GFH-925), olomorasib (LY-3537982), divarasib (GDC-6036), MK-1084, glecirasib (JAB-21822), GH-35, elisrasib (D-3S-001), ZG-19018, FMC-376, YL-15293, HS-10370, BBO-8520, GEC-255, BI-1823911, ERAS-3490, or a combination thereof.

[0714] In some embodiments, a KRas mutation (e.g., a KRas G12C mutation or a KRas G12D mutation) can be detected in a sample from the subject (e.g., detecting a KRAS gene having a mutation corresponding to a G12C mutation or a G12D mutation in KRas protein and / or detecting a KRas protein having a G12C mutation or a G12D mutation). In some embodiments, the subject was determined (e.g., prior to administration of a compound provided herein) to have a cancer having a KRas G12C mutation. In some embodiments, the subject was determined (e.g., prior to administration of a compound provided herein) to have a cancer having a KRas G12D mutation.

[0715] In some embodiments, the cancer is a KRas mutant lung cancer (e.g., a KRas mutant NSCLC), a KRas mutant CRC, or a KRas mutant pancreatic cancer, and the additional therapy or therapeutic agent is a KRas inhibitor or degrader (e.g., adagrasib (MRTX-849), ALTA3263, AMG410, AN9025, ARS-1620, ARS-3248, ARS-853, ARV-806, ASP-4396, ATG-012, AZD-0022, BBO-11818, BBO-8520, BGB-53038, BI 3706674, BI-1701963, BI-1823911, BPI-421286, BPI-572270, BPI-585725, BRSD-143, CGT9109, daraxonrasib (RMC-6236), divarasib (GDC-6036), elisrasib (D-3S-001), ERAS-0015, ERAS-3490, ERAS-4001, FMC-376, fulzerasib (GFH-925), garsorasib (D-1553), GDC-7035, GEC-255, GFH276, GFH375, GFH547, GFS784, GH-35, glecirasib (JAB-21822), HBW-012336, HBW-016-K, HEC211909, HRS-4642, HS-10370, HS-10529, INCB-161734, INCB186748, JAB-23E73, JDQ-443, LY3962673, LY4066434, MK-1084, MRTX1133, MRTX-1257, olomorasib (LY-3537982), PF-07934040, PF-07985045, PT0253, QLC-1101, QTX3034, QTX3046, QTX3544, RCZY-680, RCZY-690, RMC-5127, RMC-6291, RMC-7977, RNK-08954, RO7673396, RP-03707, RP04340, RSC-1255, setidegrasib (ASP-3082), SHR-1127, sotorasib (AMG-510), TSN-1611, YL-15293, YL-17231, ZG-19018, zoldonrasib (RMC-9805), or a combination thereof). In some embodiments, the cancer is a KRas mutant lung cancer (e.g., a KRas mutant NSCLC (e.g., a KRas G12C mutant NSCLC)), a KRas mutant CRC (e.g., a KRas G12C mutant CRC), or a KRas mutant pancreatic cancer (e.g., a KRas G12C mutant pancreatic cancer), and the additional therapy or therapeutic agent is adagrasib. In some embodiments, the cancer is a KRas mutant lung cancer (e.g., a KRas mutant NSCLC (e.g., a KRas G12C mutant NSCLC)), a KRas mutant CRC (e.g., a KRas G12C mutant CRC), or a KRas mutant pancreatic cancer (e.g., a KRas G12C mutant pancreatic cancer), and the additional therapy or therapeutic agent is divarasib. In some embodiments, the cancer is a KRas mutant lung cancer (e.g., a KRas mutant NSCLC (e.g., a KRas G12C mutant NSCLC)), a KRas mutant CRC (e.g., a KRas G12C mutant CRC), or a KRas mutant pancreatic cancer (e.g., a KRas G12C mutant pancreatic cancer), and the additional therapy or therapeutic agent is sotorasib. In some embodiments, the cancer is a KRas mutant lung cancer (e.g., a KRas mutant NSCLC (e.g., a KRas G12D mutant NSCLC)), a KRas mutant CRC (e.g., a KRas G12D mutant CRC), or a KRas mutant pancreatic cancer (e.g., a KRas G12D mutant pancreatic cancer), and the additional therapy or therapeutic agent is MRTX1133.

[0716] In some embodiments, the MEK inhibitor is avutometinib, binimetinib, cobimetinib (e.g., cobimetinib fumarate), mirdametinib, pimasertib, refametinib, selumetinib (e.g., selumetinib sulfate), trametinib (e.g., trametinib dimethyl sulfoxide), zapnometinib, FCN-159, GSK-1120212, NFX-179, TAK-733, or a combination thereof.

[0717] In some embodiments, a BRCA1 mutation can be detected in a sample from the subject (e.g., detecting a BRCA1 gene having a mutation and / or detecting a BRCA1 protein having a mutation). In some embodiments, the subject was determined (e.g., prior to administration of a compound provided herein) to have a cancer having a BRCA1 mutation.

[0718] In some embodiments, a BRCA2 mutation can be detected in a sample from the subject (e.g., detecting a BRCA2 gene having a mutation and / or detecting a BRCA2 protein having a mutation). In some embodiments, the subject was determined (e.g., prior to administration of a compound provided herein) to have a cancer having a BRCA2 mutation.

[0719] In some embodiments, the cancer is ovarian cancer (e.g., BRCA1 mutant ovarian cancer or BRCA2 mutant ovarian cancer, HGSOC (e.g., BRCA1 mutant HGSOC or BRCA2 mutant HGSOC), or LGSOC), and the additional therapy or therapeutic agent is a MEK inhibitor (e.g., binimetinib, cobimetinib, selumetinib, or trametinib). In some embodiments, the cancer is BRCA1 mutant ovarian cancer, and the additional therapy or therapeutic agent is a MEK inhibitor (e.g., binimetinib, cobimetinib, selumetinib, or trametinib). In some embodiments, the cancer is BRCA2 mutant ovarian cancer, and the additional therapy or therapeutic agent is a MEK inhibitor (e.g., binimetinib, cobimetinib, selumetinib, or trametinib). In some embodiments, the cancer is HGSOC (e.g., BRCA1 mutant HGSOC or BRCA2 mutant HGSOC), and the additional therapy or therapeutic agent is a MEK inhibitor (e.g., binimetinib, cobimetinib, selumetinib, or trametinib). In some embodiments, the cancer is LGSOC (e.g., BRCA1 mutant HGSOC or BRCA2 mutant HGSOC), and the additional therapy or therapeutic agent is a MEK inhibitor (e.g., binimetinib, cobimetinib, selumetinib, or trametinib).

[0720] In some embodiments, the cancer is a KRas mutant CRC (e.g., a KRas G12C mutant NSCLC), and the additional therapy or therapeutic agent is a MEK inhibitor (e.g., binimetinib, cobimetinib, selumetinib, or trametinib).

[0721] In some embodiments, the MET inhibitor is cabozantinib (e.g., cabozantinib 5-malate), capmatinib (e.g., capmatinib hydrochloride), crizotinib, foritinib, glesatinib, gumarontinib, merestinib, pamufetinib, savolitinib, sitravatinib, tepotinib (e.g., tepotinib hydrochloride hydrate), vebreltinib, zanzalintinib (XL-092), amivantamab (e.g., amivantamab-vmjw, or a biosimilar thereof), emibetuzumab (or biosimilars thereof), RC-108, telisotuzumab vedotin (or biosimilars thereof), ABBV-400, ABN-401, AL-2846, AMG-337, SAR-125844, TQ-B-3139, or a combination thereof.

[0722] In some embodiments, a MET alteration can be detected in a sample from the subject (e.g., detecting a MET gene having an alteration (e.g., gene amplification or exonl4 skipping) and / or detecting a MET protein having a mutation (e.g., exonl4 skipping)). In some embodiments, the subject was determined (e.g., prior to administration of a compound provided herein) to have a cancer having a MET alteration.

[0723] In some embodiments, the cancer is a MET-altered NCLC (e.g., MET amplified NSCLC or MET exonl4 skipping NSCLC), and the additional therapy or therapeutic agent is a MET inhibitor (e.g., cabozantinib (e.g., cabozantinib 5-malate), capmatinib (e.g., capmatinib hydrochloride), crizotinib, foritinib, glesatinib, gumarontinib, merestinib, pamufetinib, savolitinib, sitravatinib, tepotinib (e.g., tepotinib hydrochloride hydrate), vebreltinib, zanzalintinib (XL-092), amivantamab (e.g., amivantamab-vmjw, or a biosimilar thereof), emibetuzumab (or biosimilars thereof), RC-108, telisotuzumab vedotin (or biosimilars thereof), ABBV-400, ABN-401, AL-2846, AMG-337, SAR-125844, or TQ-B-3139). In some embodiments, the cancer is a MET-altered NCLC (e.g., MET amplified NSCLC or MET exonl4 skipping NSCLC), and the additional therapy or therapeutic agent is capmatinib (e.g., capmatinib hydrochloride) or tepotinib (e.g., tepotinib hydrochloride hydrate). In some embodiments, the cancer is a MET-altered NCLC (e.g., MET amplified NSCLC or MET exonl4 skipping NSCLC), and the additional therapy or therapeutic agent is telisotuzumab vedotin (or biosimilars thereof).

[0724] In some embodiments, the Hif2a inhibitor is belzutifan, AB-521, DFF-332, NKT-2152, PT-2399, or a combination thereof.

[0725] In some embodiments, the PARP inhibitor is fuzuloparib (fluzoparib), niraparib (e.g., niraparib tosylate monohydrate), olaparib, pamiparib, rucaparib (e.g., rucaparib camsylate), saruparib (AZD5305), senaparib, stenoparib, talazoparib (e.g., talazoparib tosylate), veliparib, CEP-9722, JPL289, NMS-03305293, or a combination thereof. In some embodiments, the PARP inhibitor is a PARP1 inhibitor. In some embodiments, the PARP1 inhibitor is saruparib (AZD5305), NMS-03305293, or a combination thereof. In some embodiments, the cancer is BRCA1 mutant breast cancer or BRCA2 mutant breast cancer, and the additional therapy or therapeutic agent is a PARP inhibitor (e.g., fuzuloparib (fluzoparib), niraparib (e.g., niraparib tosylate monohydrate), olaparib, pamiparib, rucaparib (e.g., rucaparib camsylate), saruparib (AZD5305), senaparib, stenoparib, talazoparib (e.g., talazoparib tosylate), veliparib, CEP-9722, JPI-289, or NMS-03305293). In some embodiments, the cancer is BRCA1 mutant breast cancer or BRCA2 mutant breast cancer, and the additional therapy or therapeutic agent is saruparib.

[0726] In some embodiments, the cancer is triple negative breast cancer, and the additional therapy or therapeutic agent is a PARP inhibitor (e.g., fuzuloparib (fluzoparib), niraparib (e.g., niraparib tosylate monohydrate), olaparib, pamiparib, rucaparib (e.g., rucaparib camsylate), saruparib (AZD5305), senaparib, stenoparib, talazoparib (e.g., talazoparib tosylate), veliparib, CEP-9722, JPI-289, or NMS-03305293). In some embodiments, the cancer is triple negative breast cancer, and the additional therapy or therapeutic agent is saruparib.

[0727] In some embodiments, the cancer is HGSOC (e.g., BRCA1 mutant HGSOC or BRCA2 mutant HGSOC), and the additional therapy or therapeutic agent is a PARP inhibitor (e.g., fuzuloparib (fluzoparib), niraparib (e.g., niraparib tosylate monohydrate), olaparib, pamiparib, rucaparib (e.g., rucaparib camsylate), saruparib (AZD5305), senaparib, stenoparib, talazoparib (e.g., talazoparib tosylate), veliparib, CEP-9722, JPI-289, or NMS-03305293). In some embodiments, the cancer is HGSOC (e.g., BRCA1 mutant HGSOC or BRCA2 mutant HGSOC), and the additional therapy or therapeutic agent is saruparib.

[0728] In some embodiments, the LSD1 inhibitor is bomedemstat, iadademstat, pulrodemstat, seclidemstat (HCI-2577), vafidemstat, GSK-2879552, INCB-059872, JBI-802, or a combination thereof.

[0729] In some embodiments, the BET inhibitor is alobresib, apabetalone, mivebresib, pelabresib, trotabresib, ABBV-744, BI-2536, BMS-986158, INCB-057643, JAB-8263, ODM-207, PLX-2853, ZEN-003694, or a combination thereof.

[0730] In some embodiments, the cancer is myelofibrosis (e.g., primary myelofibrosis, postessential thrombocythemia myelofibrosis, or post-polycythemia vera myelofibrosis), and the additional therapy or therapeutic agent is a BET inhibitor (e.g., alobresib, apabetalone, mivebresib, pelabresib, trotabresib, ABBV-744, BI-2536, BMS-986158, INCB-057643, JAB-8263, ODM-207, PLX-2853, or ZEN-003694).

[0731] In some embodiments, the STING agonist is ulevostinag, ADU-S100, or a combination thereof. In some embodiments, the telomerase inhibitor is imetelstat (e.g., imetelstat sodium). In some embodiments, the TORC1 / 2 inhibitor is apitolisib, bimiralisib, dactolisib, deforolimus, everolimus, fosciclopirox (e.g., fosciclopirox sodium), gedatolisib, onatasertib, paxalisib, sapanisertib, sirolimus, sodium 2-hydroxylinoleate, temsirolimus, umirolimus, vistusertib, zandelisib, zotarolimus, BI-860585, CC-115, CLL-442, PF-04691502, or a combination thereof.

[0732] In some embodiments, the VEGFR inhibitor is apatinib, axitinib, cabozantinib (e.g., cabozantinib 5-malate), catequentinib (alontinib), cediranib, dovitinib, famitinib, fruquintinib, glesatinib, ibcasertib, ilorasertib, lenvatinib (e.g., lenvatinib mesylate), lucitanib, nintedanib (e.g., nintedanib esylate), pamufetinib, pazopanib (e.g., pazopanib hydrochloride), regorafenib (e.g., regorafenib monohydrate), sitravatinib, sorafenib (e.g., sorafenib tosylate), sunitinib (e.g., sunitinib malate), surufatinib (sulfatinib), telatinib, tinengotinib, tivozanib (e.g., tivozanib hydrochloride monohydrate), vandetanib, vorolanib, zanzalintinib, olinvacimab (or biosimilars thereof), ramucirumab (or biosimilars thereof), CEP-11981, ENMD-2076, ODM-203, or a combination thereof.

[0733] In some embodiments, the chemotherapy is a platinum complex, a microtubule inhibitor (e.g., a microtubule destabilizer or a microtubule stabilizer), a topoisomerase inhibitor, a hypomethylating agent, or an antibody-drug conjugate including any thereof. In some embodiments, the platinum complex is carboplatin, cisplatin, lobaplatin, miriplatin, oxaliplatin, or a combination thereof. In some embodiments, the microtubule inhibitor is cabazitaxel, colchicine, desoxyepothilone B, docetaxel, eribulin, ixabepilone, nab-paclitaxel, paclitaxel, plinabulin, sabizabulin, tirbanibulin, vinblastine, vinflunine, vinorelbine, or a combination thereof. In some embodiments, the microtubule inhibitor is cabazitaxel, docetaxel, nab-paclitaxel, paclitaxel, or a combination thereof. In some embodiments, the topoisomerase inhibitor is aclarubicin, amsacrine, belotecan, camptothecin, daunorubicin, dexrazoxane, elliptinium, epirubicin, etoposide, gepotidacin, idarubicin, mitoxantrone, nemonoxacin, pirarubicin, pixantrone, razoxane, rubitecan, sobuzoxane, temozolomide, teniposide, topotecan, SN-38, or a combination thereof. In some embodiments, the hypomethylating agent is azacitidine, decitabine, or a combination thereof. In some embodiments, the chemotherapy is a platinum complex and a topoisomerase inhibitor (e.g., cisplatin and etoposide). In some embodiments, the antibody-drug conjugate including the microtubule inhibitor is belantamab mafodotin, brentuximab vedotin, cofetuzumab pelidotin, disitamab vedotin, enfortumab vedotin (e.g., enfortumab vedotin-ejfv, or a biosimilar thereof), mirvetuximab soravtansine (e.g., mirvetuximab soravtansine-gynx, or a biosimilar thereof), polatuzumab vedotin, telisotuzumab vedotin, tisotumab vedotin, trastuzumab emtansine (e.g., ado-trastuzumab emtansine, or a biosimilar thereof), tusamitamab ravtansine, upifitamab rilsodotin, zilovertamab vedotin, Alpha-Her2-pAFl-AS-269, BAT-8001, TAA-013, biosimilars thereof, or a combination thereof. In some embodiments, the antibody-drug conjugate including the microtubule inhibitor is enfortumab vedotin (e.g., enfortumab vedotin-ejfv, or a biosimilar thereof). In some embodiments, the antibody-drug conjugate including the microtubule inhibitor is mirvetuximab soravtansine (e.g., mirvetuximab soravtansine-gynx, or a biosimilar thereof). In some embodiments, the antibody-drug conjugate including the microtubule inhibitor is trastuzumab emtansine (e.g., ado-trastuzumab emtansine, or a biosimilar thereof). In some embodiments, the antibody-drug conjugate including the topoisomerase inhibitor is datopotamab deruxtecan, patritumab deruxtecan, sacituzumab govitecan (e.g., sacituzumab govitecan-hziy, or a biosimilar thereof), trastuzumab deruxtecan (fam-trastuzumab deruxtecan-nxki, or a biosimilar thereof), or a combination thereof. In some embodiments, the antibodydrug conjugate including the topoisomerase inhibitor is sacituzumab govitecan (e.g., sacituzumab govitecan-hziy, or a biosimilar thereof). In some embodiments, the antibody-drug conjugate including the topoisomerase inhibitor is trastuzumab deruxtecan (e.g., famtrastuzumab deruxtecan-nxki, or a biosimilar thereof).

[0734] In some embodiments, the cancer is a lung cancer (e.g., NSCLC (e.g., squamous cell carcinoma)), and the additional therapy or therapeutic agent is a microtubule inhibitor (e.g., cabazitaxel, docetaxel, nab -paclitaxel, or paclitaxel). In some embodiments, the cancer is a lung cancer (e.g., NSCLC (e.g., squamous cell carcinoma)), and the additional therapy or therapeutic agent is docetaxel.

[0735] In some embodiments, the cancer is NSCLC (e.g., NSCLC with a MET amplification), and the additional therapy or therapeutic agent is telisotuzumab vedotin.

[0736] In some embodiments, the cancer is a lung cancer (e.g., NSCLC), and the additional therapy or therapeutic agent is a platinum complex (e.g., carboplatin, cisplatin, lobaplatin, miriplatin, or oxaliplatin) and anti-PDl therapy.

[0737] In some embodiments, the cancer is a lung cancer (e.g., NSCLC), and the additional therapy or therapeutic agent is a platinum complex (e.g., carboplatin, cisplatin, lobaplatin, miriplatin, or oxaliplatin) and anti-PD-Ll therapy.

[0738] In some embodiments, the cancer is a lung cancer (e.g., NSCLC), and the additional therapy or therapeutic agent is a pemetrexed and anti-PDl therapy. In some embodiments, the cancer is a lung cancer (e.g., NSCLC), and the additional therapy or therapeutic agent is a pemetrexed and anti-PD-Ll therapy.

[0739] In some embodiments, the cancer is a lung cancer (e.g., SCLC), and the additional therapy or therapeutic agent is a platinum complex (e.g., carboplatin, cisplatin, lobaplatin, miriplatin, or oxaliplatin) and a topoisomerase inhibitor (e.g., aclarubicin, amsacrine, belotecan, camptothecin, daunorubicin, dexrazoxane, elliptinium, epirubicin, etoposide, gepotidacin, idarubicin, mitoxantrone, nemonoxacin, pirarubicin, pixantrone, razoxane, rubitecan, sobuzoxane, temozolomide, teniposide, topotecan, or SN-38). In some embodiments, the cancer is a lung cancer (e.g., SCLC), and the additional therapy or therapeutic agent is carboplatin and etoposide. In some embodiments, the cancer is a lung cancer (e.g., SCLC), and the additional therapy or therapeutic agent is cisplatin and etoposide.

[0740] In some embodiments, the cancer is breast cancer (e.g., HER2+ breast cancer (e.g., HER2+ breast cancer with ER expression, HER2+ breast cancer without ER expression), HER2 negative breast cancer (e.g., HER2 negative breast cancer with ER expression, HER2 negative breast cancer without ER expression), triple negative breast cancer, or HER2 low breast cancer), and the additional therapy or therapeutic agent is a microtubule inhibitor (e.g., cabazitaxel, docetaxel, nab-paclitaxel, or paclitaxel). In some embodiments, the cancer is triple negative breast cancer, and the additional therapy or therapeutic agent is a microtubule inhibitor (e.g., cabazitaxel, docetaxel, nab-paclitaxel, or paclitaxel). In some embodiments, the cancer is triple negative breast cancer, and the additional therapy or therapeutic agent is nab-paclitaxel or paclitaxel.

[0741] In some embodiments, the cancer is breast cancer (e.g., HER2+ breast cancer (e.g., HER2+ breast cancer with ER expression, HER2+ breast cancer without ER expression), HER2 negative breast cancer (e.g., HER2 negative breast cancer with ER expression, HER2 negative breast cancer without ER expression), triple negative breast cancer, or HER2 low breast cancer), and the additional therapy or therapeutic agent is a microtubule inhibitor (e.g., cabazitaxel, docetaxel, nab-paclitaxel, or paclitaxel) and anti-PDl therapy.

[0742] In some embodiments, the cancer is breast cancer (e.g., HER2+ breast cancer (e.g., HER2+ breast cancer with ER expression, HER2+ breast cancer without ER expression), HER2 negative breast cancer (e.g., HER2 negative breast cancer with ER expression, HER2 negative breast cancer without ER expression), triple negative breast cancer, or HER2 low breast cancer), and the additional therapy or therapeutic agent is a microtubule inhibitor (e.g., cabazitaxel, docetaxel, nab-paclitaxel, or paclitaxel) and anti-PD-Ll therapy. In some embodiments, the cancer is breast cancer (e.g., HER2+ breast cancer (e.g., HER2+ breast cancer with ER expression, HER2+ breast cancer without ER expression), HER2 negative breast cancer (e.g., HER2 negative breast cancer with ER expression, HER2 negative breast cancer without ER expression), triple negative breast cancer, or HER2 low breast cancer), and the additional therapy or therapeutic agent is capecitabine.

[0743] In some embodiments, the cancer is breast cancer (e.g., HER2+ breast cancer (e.g., HER2+ breast cancer with ER expression, HER2+ breast cancer without ER expression), HER2 negative breast cancer (e.g., HER2 negative breast cancer with ER expression, HER2 negative breast cancer without ER expression), triple negative breast cancer, or HER2 low breast cancer), and the additional therapy or therapeutic agent is sacituzumab govitecan (e.g., sacituzumab govitecan-hziy, or a biosimilar thereof).

[0744] In some embodiments, the cancer is breast cancer (e.g., HER2+ breast cancer (e.g., HER2+ breast cancer with ER expression, HER2+ breast cancer without ER expression), HER2 negative breast cancer (e.g., HER2 negative breast cancer with ER expression, HER2 negative breast cancer without ER expression), triple negative breast cancer, or HER2 low breast cancer), and the additional therapy or therapeutic agent is trastuzumab deruxtecan (e.g., fam-trastuzumab deruxtecan-nxki, or a biosimilar thereof).

[0745] In some embodiments, the cancer is breast cancer (e.g., HER2+ breast cancer (e.g., HER2+ breast cancer with ER expression, HER2+ breast cancer without ER expression), HER2 negative breast cancer (e.g., HER2 negative breast cancer with ER expression, HER2 negative breast cancer without ER expression), triple negative breast cancer, or HER2 low breast cancer), and the additional therapy or therapeutic agent is trastuzumab (e.g., HERCEPTIN® (trastuzumab), or a biosimilar thereof (e.g., FACEPTOR® (trastuzumab), HERTICAD® (trastuzumab), TUZNUE® (trastuzumab), ZERCEPAC® (trastuzumab), trastuzumab-anns, trastuzumab-dkst, trastuzumab-dttb, trastuzumab-pkrb, trastuzumab-qyyp, EG-12014, or TX-05)).

[0746] In some embodiments, the cancer is hormone receptor positive breast cancer, and the additional therapy or therapeutic agent is hormone therapy (e.g., tamoxifen, toremifene, or a combination thereof).

[0747] In some embodiments, the cancer is hormone receptor positive breast cancer, and the additional therapy or therapeutic agent is a selective estrogen receptor degrader (SERD) (e.g., fulvestrant, elacestrant, or a combination thereof).

[0748] In some embodiments, the cancer is a HER2+ breast cancer (e.g., HER2+ breast cancer with ER expression, HER2+ breast cancer without ER expression), and the additional therapy or therapeutic agent is trastuzumab deruxtecan (e.g., fam-trastuzumab deruxtecan-nxki, or a biosimilar thereof) or trastuzumab emtansine (e.g., KADCYLA® (trastuzumab emtansine), or a biosimilar thereof (e.g., UJVIRA® (trastuzumab emtansine))).

[0749] In some embodiments, the cancer is a HER2 low breast cancer, and the additional therapy or therapeutic agent is trastuzumab deruxtecan (e.g., fam-trastuzumab deruxtecan-nxki, or a biosimilar thereof).

[0750] In some embodiments, the cancer is a head and neck cancer, and the additional therapy or therapeutic agent is a microtubule inhibitor (e.g., cabazitaxel, docetaxel, nab-paclitaxel, or paclitaxel). In some embodiments, the cancer is a head and neck cancer, and the additional therapy or therapeutic agent is docetaxel.

[0751] In some embodiments, the cancer is a cervical cancer, and the additional therapy or therapeutic agent is a microtubule inhibitor (e.g., cabazitaxel, docetaxel, nab-paclitaxel, or paclitaxel).

[0752] In some embodiments, the cancer is an endometrial cancer, and the additional therapy or therapeutic agent is a microtubule inhibitor (e.g., cabazitaxel, docetaxel, nab-paclitaxel, or paclitaxel).

[0753] In some embodiments, the cancer is a prostate cancer, and the additional therapy or therapeutic agent is a microtubule inhibitor (e.g., cabazitaxel, docetaxel, nab-paclitaxel, or paclitaxel).

[0754] In some embodiments, the cancer is an ovarian cancer (e.g., HGSOC) and the additional therapy or therapeutic agent is a microtubule inhibitor (e.g., cabazitaxel, docetaxel, nab-paclitaxel, or paclitaxel). In some embodiments, the cancer is an ovarian cancer (e.g., HGSOC) and the additional therapy or therapeutic agent is a microtubule inhibitor (e.g., cabazitaxel, docetaxel, nab-paclitaxel, or paclitaxel) and a platinum complex (e.g., carboplatin, cisplatin, lobaplatin, miriplatin, or oxaliplatin). In some embodiments, the cancer is an ovarian cancer (e.g., HGSOC) and the additional therapy or therapeutic agent is nab-paclitaxel or paclitaxel and carboplatin.

[0755] In some embodiments, the cancer is a pancreatic cancer, and the additional therapy or therapeutic agent is a microtubule inhibitor (e.g., cabazitaxel, docetaxel, nab-paclitaxel, or paclitaxel). In some embodiments, the cancer is a pancreatic cancer, and the additional therapy or therapeutic agent is a microtubule inhibitor (e.g., cabazitaxel, docetaxel, nab-paclitaxel, or paclitaxel) and gemcitabine. In some embodiments, the cancer is a bladder cancer (e.g., bladder urothelial carcinoma), and the additional therapy or therapeutic agent is enfortumab vedotin (e.g., enfortumab vedotin-ejfv, or a biosimilar thereof).

[0756] In some embodiments, the cancer is a bladder cancer (e.g., bladder urothelial carcinoma), and the additional therapy or therapeutic agent is sacituzumab govitecan (e.g., sacituzumab govitecan-hziy, or a biosimilar thereof).

[0757] In some embodiments, the cancer is triple negative breast cancer, and the additional therapy or therapeutic agent is sacituzumab govitecan (e.g., sacituzumab govitecan-hziy, or a biosimilar thereof).

[0758] In some embodiments, folate receptor positivity status can be detected in a sample from the subject (e.g., via immunohistochemistry (IHC) and / or fluorescent in situ hybridization (FISH)). In some embodiments, the subject was determined (e.g., prior to administration of a compound provided herein) to have a cancer that is folate receptor positive.

[0759] In some embodiments, the cancer is folate receptor positive ovarian cancer (e.g., folate receptor positive HGSOC), and the additional therapy or therapeutic agent is mirvetuximab soravtansine (e.g., mirvetuximab soravtansine-gynx, or a biosimilar thereof).

[0760] In some embodiments the immunomodulatory imide drug is avadomide, lenalidomide, golcadomide, iberdomide, mezigdomide, pomalidomide, thalidomide, or a combination thereof.

[0761] In some embodiments, the anti-PDl therapy is balstilimab, budigalimab, cadonilimab, camrelizumab, cemiplimab (e.g., cemiplimab-rwlc, or a biosimilar thereof), cetrelimab, danvilostomig, dostarlimab (e.g., dostarlimab-gxly, or a biosimilar thereof), enlonstobart (SG-001), ezabenlimab, geptanolimab, iparomlimab (QL-1604), ivonescimab, lorigerlimab, nivolumab (e.g., OPDIVO® (nivolumab), or a biosimilar thereof (e.g., ABP-206, BCD-263, or JPB-898)), nofazinlimab, pembrolizumab (e.g., KEYTRUDA® (pembrolizumab), or a biosimilar thereof (e.g., ABP-234, BAT-3306, BCD-201, CT-P51, FYB-206, GME-751, MB-12, QL-2107, RPH-075, or SB-27)), penpulimab, pidilizumab, pimivalimab, prolgolimab, pucotenlimab, retifanlimab (e.g., retifanlimab-dlwr, or a biosimilar thereof), rilvegostomig, rosnilimab, rulonilimab, sasanlimab, serplulimab, sintilimab (e.g., TYVYT® (sintilimab), or a biosimilar thereof), spartalizumab, tebotelimab, tislelizumab, toripalimab, treprilimab, volrustomig, vudalimab, zimberelimab, 609-A, BAT-1306, BAT-1308, HX-009, IBI-363, INCB-086550, JS-207, LZM-009, MHB-039A, RC-148, RG-6139, SSGJ-707, ZG-005, biosimilars thereof, or a combination thereof. In some embodiments, the anti-PDl therapy is a bispecific antibody or antigen-binding fragment thereof (e.g., cadonilimab, danvilostomig, ivonescimab, lorigerlimab, rilvegostomig, tebotelimab, volrustomig, vudalimab, AZD7709, HX-009, JS-207, MHB-039A, RC-148, RG-6139, SSGJ-707, ZG-005, biosimilars thereof, or a combination thereof). In some embodiments, the anti-PDl therapy is an anti-PDl and anti-CD47 bispecific antibody or antigen-binding fragment thereof (e.g., HX-009, or a biosimilar thereof).

[0762] In some embodiments, the PD-L1 inhibitor is INCB-086550 or INCB-099280.

[0763] In some embodiments, the anti-PD-Ll therapy is adebrelimab, atezolizumab (e.g., TECENTRIQ® (atezolizumab), or a biosimilar thereof), avelumab (e.g., BAVENCIO® (avelumab), or a biosimilar thereof), benmelstobart (APL-502), bintrafusp alfa, cosibelimab, danburstotug, durvalumab (e.g., IMFINZI® (durvalumab), or a biosimilar thereof), envafolimab (e.g., ENWEIDA® (envafolimab), or a biosimilar thereof), erfonrilimab, lesabelimab, pacmilimab, socazolimab, sugemalimab (e.g., CEJEMLY® (sugemalimab), or a biosimilar thereof), tagitanlimab (A-167), AUPM-170, BNT-311, SHR-1701, biosimilars thereof, or a combination thereof. In some embodiments, the anti-PD-Ll therapy is a bispecific antibody or antigen-binding fragment thereof (e.g., erfonrilimab, BNT-311, biosimilars thereof, or a combination thereof).

[0764] In some embodiments, the additional therapy is radiotherapy.

[0765] In some embodiments, the cancer is head and neck cancer (e.g., head and neck squamous cell carcinoma), and the additional therapy is radiotherapy.

[0766] In some embodiments, the additional therapy includes a BRaf inhibitor and a MEK inhibitor. For example, the additional therapy can include dabrafenib and trametinib, vemurafenib and cobimetinib, or encorafenib and binimetinib.

[0767] Exemplary descriptions of agents in combination with BCL-2 family inhibitors can be found in: Hikita, Hayato, et al. Hepatology 52.4 (2010): 1310-1321, doi: 10.1002 / hep.23836; Chen, Jun, et al. Molecular Cancer Therapeutics 10.12 (2011): 2340-2349, doi: 10.1158 / 1535-7163 MCT-11-0415; Inuzuka, Hiroyuki, et al. Nature 471.7336 (2011): 104-109, doi: 10.1038 / nature09732; Wertz, Ingrid E., et al. Nature 471.7336 (2011): 110-114, doi: 10.1038 / nature09779; Tan, Nguyen, et al. Clinical Cancer Research 17.6 (2011): 1394-1404, doi: 10.1158 / 1078-0432. CCR-10-2353; Wong, Maureen, et al. Molecular Cancer Therapeutics 11.4 (2012): 1026-1035, doi: 10.1158 / 1535-7163. MCT-11-0693; Corcoran, Ryan B., et al. Cancer Cell 23.1 (2013): 121-128, doi: 10.1016 / j.ccr.2012.11.007; Waibel, Michaela, et al. Cell Reports 5.4 (2013): 1047-1059, doi: 10.1016 / j.celrep.2013.10.038; Frederick, Dennie T., et al. PloSOne 9.7 (2014): el01286, doi: 10.1371 / journal. pone.0101286; Vlahovic, Gordana, et al. Investigational New Drugs 32.5 (2014): 976-984, doi: 10.1007 / sl0637-014-0116-3; Faber, Anthony C., et al. Cancer Discovery 4.1 (2014): 42-52, doi: 10.1158 / 2159-8290. CD- 13-0315; Leverson, Joel D., et al. Science Translational Medicine 7.279 (2015): 279ra40-279ra40, doi: 10.1126 / scitranslmed.aaa4642; Guo, Jun, et al. PLoS One 10.3 (2015): eOl 14363, doi: 10.1371 / journal. pone.0114363; Lheureux, Stephanie, et al. International Journal of Cancer 136.5 (2015): E340-E350, doi: 10.1002 / ij c.29104; Zoeller, Jason J., et al. Cancer Research 76.14_Supplement (2016): 4358-4358, doi: 10.1158 / 1538-7445. AM2016-4358; Weeden, Clare E., et al. Oncogene 37.32 (2018): 4475-4488, doi: 10.1038 / s41388-018-0268-2; Lucantoni, Federico, et al. Cell Death & Disease 9.2 (2018): 1- 13, doi: 10.1038 / s41419-017-0039-y; lavarone, Claudia, et al. Molecular Cancer Therapeutics 18.3 (2019): 642-655, doi: 10.1158 / 1535-7163. MCT-18-0413; Fleury, Hubert, et al. Nature Communications 10.1 (2019): 2556, doi: 10.1038 / s41467-019-10460-l; Lohard, Steven, et al. Nature Communications 11.1 (2020): 259, doi: 10.1038 / s41467-019-13689-y; Bertino, Erin M., et al. Clinical Cancer Research 27.6 (2021): 1604-1611, doi: 10.1158 / 1078-0432. CCR-20-4084; Guo, Ting, et al. Aging 13.15 (2021): 19750, doi: 10.18632 / aging.203386; Puglisi, Martina, et al. Future Oncology 17.21 (2021): 2747-2758, doi: 10.2217 / fon-2021-0140; Harrison, Claire N., et al. Journal of Clinical Oncology 40.15 (2022): 1671, doi: 10.1200 / JC0.21.02188; Kohler, Jens, et al. Molecular Cancer Therapeutics 20.4 (2021): 641-654, doi: 10.1158 / 1535-7163. MCT-20-0531; Jaaks, Patricia, et al. Nature 603.7899 (2022): 166-173, doi: 10.1038 / s41586-022-04437-2; Sobol, Benjamin, et al. International Journal of Molecular Sciences 23.14 (2022): 7850, doi: 10.3390 / ijms23147850; Passamonti, J Clin Oncol 40, (2022) (suppl 16; abstr 7015), doi: 10.1200 / JC0.2022.40.16_suppl.7015; Qin, J Clin Oncol 40, (2022) (suppl 16; abstr e20612), doi: 10.1200 / JC0.2022.40.16_suppl.e20612; Potter, Danielle S., etal. Cancer Research 82.12_Supplement (2022): 3691-3691, doi: 10.1158 / 1538-7445. AM2022-3691; and Shebl, Bassem, et al. Cancer Research 82.12_Supplement (2022): 3888-3888, doi: 10.1158 / 1538-7445. AM2022-3888.

[0768] Also provided herein is a method of treating cancer, comprising administering to a subject in need thereof (a) a compound provided herein, or a pharmaceutically acceptable salt thereof, and (b) an additional therapeutic agent, for simultaneous, separate or sequential use for the treatment of cancer, wherein the amounts of the compound provided herein, or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are together effective in treating the cancer. In some embodiments, the method comprises administering (c) at least one pharmaceutically acceptable carrier.

[0769] These additional therapeutic agents may be administered with one or more doses of the compound provided herein, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, as part of the same or separate dosage forms, via the same or different routes of administration, and / or on the same or different administration schedules according to standard pharmaceutical practice known to one skilled in the art. In some embodiments, the compound provided herein, or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered simultaneously as separate dosages. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered as separate dosages sequentially in any order, in jointly therapeutically effective amounts, e.g., in daily or intermittently dosages. In some embodiments, the compound provided herein, or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered simultaneously as a combined dosage.

[0770] Also provided herein is (i) a pharmaceutical combination for treating a cancer in a subject in need thereof, which comprises (a) a compound provided herein, or a pharmaceutically acceptable salt thereof, and (b) at least one additional therapeutic agent (e.g., any of the exemplary additional therapeutic agents described herein or known in the art), for simultaneous, separate or sequential use for the treatment of cancer, wherein the amounts of the compound provided herein, or a pharmaceutically acceptable salt thereof, and of the additional therapeutic agent are together effective in treating the cancer; (ii) a pharmaceutical composition comprising such a combination; (iii) the use of such a combination for the preparation of a medicament for the treatment of cancer; and (iv) a commercial package or product comprising such a combination as a combined preparation for simultaneous, separate or sequential use; and to a method of treatment of cancer in a subject in need thereof. In some embodiments, the pharmaceutical combination comprises (c) at least one pharmaceutically acceptable carrier.

[0771] As used herein, the terms “treat” or “treatment” refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease or disorder or condition, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0772] As used herein “remission” refers to the absence of or a significant reduction of disease signs or symptoms. In some embodiments, remission may be determined by the subject’s physician. In some embodiments, remission can be determined by objective criteria, such as by criteria such as RECIST 1.1, the Lugano 2014 criteria (Cheson, Bruce D., et al. Journal of Clinical Oncology 32.27 (2014): 3059-3067; doi: 10.1200 / JC0.2013.54.8800) or the Global Response Criteria (Olsen, Elise A., et al. Blood, The Journal of the American Society of Hematology 140.5 (2022): 419-437; doi: 10.1182 / blood.2021012057).

[0773] As used herein, the terms “prevent” or “prevention” refer to prophylactic measures. Beneficial or desired clinical results include, but are not limited to, the delay, arrest, or preclusion of the onset, recurrence or spread, in whole or in part, of a disease or condition, or a symptom thereof, such as any of those provided herein.

[0774] As used herein, the terms “subject,” “individual,” or “patient,” are used interchangeably, refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and / or exhibited at least one symptom of the disease, disorder, or condition to be treated and / or prevented.

[0775] In some embodiments, the subject is a pediatric subject.

[0776] The term “pediatric subject” as used herein refers to a subject under the age of 17 years at the time of diagnosis or treatment. The term “pediatric” can be further be divided into various subpopulations including: neonates (from birth through the first 27 days of life); infants (28 days up to 23 months); children (two years of age to 11 years of age); and adolescents (12 years of age to younger than 17 years (up to, but not including, the seventeenth birthday)). See 21 CFR 201.57(c)(9)(iv)(A); Regulatory Considerations Guidance at FN 1; and Guidance -Pediatric Drug Development: Regulatory Considerations — Complying With the Pediatric Research Equity Act and Qualifying for Pediatric Exclusivity Under the Best Pharmaceuticals for Children Act, U. S. Food & Drug Administration (May 17, 2023). In some embodiments, a pediatric subject is from birth through the first 28 days of life, from 29 days of age to less than two years of age, from two years of age to less than 12 years of age, or 12 years of age through 16 years of age (up to, but not including, the seventeenth birthday). In some embodiments, a pediatric subject is from birth through the first 28 days of life, from 29 days of age to less than 1 year of age, from one month of age to less than four months of age, from three months of age to less than seven months of age, from six months of age to less than 1 year of age, from 1 year of age to less than 2 years of age, from 2 years of age to less than 3 years of age, from 2 years of age to less than seven years of age, from 3 years of age to less than 5 years of age, from 5 years of age to less than 10 years of age, from 6 years of age to less than 13 years of age, from 10 years of age to less than 15 years of age, or from 15 years of age to less than 17 years of age.

[0777] The term “regulatory agency” refers to a country's agency for the approval of the medical use of pharmaceutical agents with the country. For example, a non-limiting example of a regulatory agency is the U. S. Food and Drug Administration (FDA).

[0778] The phrase “therapeutically effective amount” means an amount of a compound that, when administered to a subject in need thereof is sufficient to (i) treat a disease, disorder, or condition, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, disorder, or condition, or (iii) delay the onset of one or more symptoms of the particular disease, disorder, or condition as described herein. The amount of the compound that will correspond to such an amount may vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the subject in need of treatment, the use or identity of prior treatments, as well as whether the compound is administered in combination with another agent (e.g., another therapeutic agent or a supportive care agent).

[0779] The phrase “effective amount” means an amount of a compound that, when administered to a cell, in vitro or in vivo, is sufficient to reduce proliferation of the cell or to kill the cell. The amount of the compound that will correspond to such an amount will vary depending upon factors such as the particular compound and genetics of the cell to be treated, as well as whether the compound is administered in combination with another agent (e.g., another therapeutic agent or a supportive care agent).

[0780] Pharmaceutical Compositions and Administration

[0781] General

[0782] In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered as a pharmaceutical composition that includes the compound, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents as described herein.

[0783] In some embodiments, the compounds can be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-a-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and wool fat. Cyclodextrins such as a-, 0-, and y-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-P-cyclodextrins, or other solubilized derivatives can also be used to enhance delivery of compounds described herein. Dosage forms or compositions containing a compound as described herein in the range of 0.005% to 100% with the balance made up from non-toxic excipient may be prepared. The contemplated compositions may contain 0.001%-100% of a compound provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 22ndEdition (Pharmaceutical Press, London, UK. 2012).

[0784] Routes of Administration and Composition Components

[0785] In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition thereof, can be administered to a subject in need thereof by any accepted route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intrabursal, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, intravitreal, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral and vaginal. In certain embodiments, a preferred route of administration is parenteral (e.g., intratumoral).

[0786] In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition thereof, can be administered orally to a subject in need thereof. Without being bound by any particular theory, it is believed that oral dosing (e.g., versus IV dosing) can be preferred by patients for convenience, perception of efficacy, and / or past experience.

[0787] Compositions can be formulated for parenteral administration, e.g., formulated for injection via the intravenous, intramuscular, sub-cutaneous, or even intraperitoneal routes. Typically, such compositions can be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for use to prepare solutions or suspensions upon the addition of a liquid prior to injection can also be prepared; and the preparations can also be emulsified. The preparation of such formulations will be known to those of skill in the art in light of the present disclosure.

[0788] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that it may be easily injected. It also should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.

[0789] The carrier also can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0790] Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques, which yield a powder of the active ingredient, plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0791] Intratumoral injections are discussed, e.g., in Lammers, et al., “Effect of Intratumoral Injection on the Biodistribution and the Therapeutic Potential of HPMA Copolymer-Based Drug Delivery Systems” Neoplasia. 2006, 70, 788-795, doi: 10.1593 / neo.06436.

[0792] Pharmacologically acceptable excipients usable in the rectal composition as a gel, cream, enema, or rectal suppository, include, without limitation, any one or more of cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (like PEG ointments), glycerine, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol Vaseline, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-oxybenzoate, sodium propyl p-oxybenzoate, diethylamine, carbomers, carbopol, methyloxybenzoate, macrogol cetostearyl ether, cocoyl capryl ocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methyl sulfonyl methane (MSM), lactic acid, glycine, vitamins, such as vitamin A and E and potassium acetate.

[0793] In certain embodiments, suppositories can be prepared by mixing the compound described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum and release the active compound. In other embodiments, compositions for rectal administration are in the form of an enema.

[0794] In other embodiments, the compounds described herein, or a pharmaceutical composition thereof, are suitable for local delivery to the digestive or GI tract by way of oral administration (e.g., solid or liquid dosage forms.).

[0795] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compound is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate and / or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0796] In one embodiment, the compositions will take the form of a unit dosage form such as a pill or tablet and thus the composition may contain, along with a compound, or pharmaceutically acceptable salt thereof, as provided herein, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives, or the like. In another solid dosage form, a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils, PEGs, poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin or cellulose base capsule). Unit dosage forms in which one or more compounds provided herein or additional active agents are physically separated are also contemplated; e.g., capsules with granules (or tablets in a capsule) of each drug; two-layer tablets; two-compartment gel caps, etc. Enteric coated or delayed release oral dosage forms are also contemplated.

[0797] Other physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents or preservatives that are particularly useful for preventing the growth or action of microorganisms. Various preservatives are well known and include, for example, phenol and ascorbic acid.

[0798] In certain embodiments the excipients are sterile and generally free of undesirable matter. These compositions can be sterilized by conventional, well-known sterilization techniques. For various oral dosage form excipients such as tablets and capsules sterility is not required. The USP / NF standard is usually sufficient.

[0799] In certain embodiments, solid oral dosage forms can further include one or more components that chemically and / or structurally predispose the composition for delivery of the compounds to the stomach or the lower GI; e.g., the ascending colon and / or transverse colon and / or distal colon and / or small bowel. Exemplary formulation techniques are described in, e.g., Filipski, K. J., et al., Current Topics in Medicinal Chemistry, 2013, 13, 776-802, doi: 10.2174 / 1568026611313070002.

[0800] Examples include upper-GI targeting techniques, e.g., Accordion Pill (Intec Pharma), floating capsules, and materials capable of adhering to mucosal walls.

[0801] Other examples include lower-GI targeting techniques. For targeting various regions in the intestinal tract, several enteric / pH-responsive coatings and excipients are available. These materials are typically polymers that are designed to dissolve or erode at specific pH ranges, selected based upon the GI region of desired drug release. These materials also function to protect acid labile drugs from gastric fluid or limit exposure in cases where the active ingredient may be irritating to the upper GI (e.g., hydroxypropyl methylcellulose phthalate series, Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit series (methacrylic acid-methyl methacrylate copolymers), and Marcoat). Other techniques include dosage forms that respond to local flora in the GI tract, Pressure-controlled colon delivery capsule, and Pulsincap.

[0802] Ocular compositions can include, without limitation, one or more of any of the following: viscogens (e.g., Carboxymethylcellulose, Glycerin, Polyvinylpyrrolidone, Polyethylene glycol); Stabilizers (e.g., Pluronic (triblock copolymers), Cyclodextrins); Preservatives (e.g., Benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.)).

[0803] Topical compositions can include ointments and creams. Ointments are semisolid preparations that are typically based on petrolatum or other petroleum derivatives. Creams containing the selected active agent are typically viscous liquid or semisolid emulsions, often either oil-in-water or water-in-oil. Cream bases are typically water-washable, and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase, also sometimes called the “internal” phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic, or amphoteric surfactant. As with other carriers or vehicles, an ointment base should be inert, stable, nonirritating, and non-sensitizing.

[0804] In any of the foregoing embodiments, pharmaceutical compositions described herein can include one or more one or more of the following: lipids, interbilayer crosslinked multilamellar vesicles, biodegradable poly(D, L-lactic-co-glycolic acid) [PLGA]-based or poly anhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.

[0805] Dosages

[0806] The dosages may be varied depending on the requirement of the patient, the severity of the condition being treated, and the particular compound being employed. Determination of the proper dosage for a particular situation can be determined by one skilled in the medical arts. The total daily dosage may be divided and administered in portions throughout the day or by means providing continuous delivery.

[0807] In some embodiments, the compounds described herein are administered at a dosage of from about 0.001 mg / kg to about 500 mg / kg (e.g., from about 0.001 mg / kg to about 200 mg / kg; from about 0.01 mg / kg to about 200 mg / kg; from about 0.01 mg / kg to about 150 mg / kg; from about 0.01 mg / kg to about 100 mg / kg; from about 0.01 mg / kg to about 50 mg / kg; from about 0.01 mg / kg to about 10 mg / kg; from about 0.01 mg / kg to about 5 mg / kg; from about 0.01 mg / kg to about 1 mg / kg; from about 0.01 mg / kg to about 0.5 mg / kg; from about 0.01 mg / kg to about 0.1 mg / kg; from about 0. 1 mg / kg to about 200 mg / kg; from about 0.1 mg / kg to about 150 mg / kg; from about 0.1 mg / kg to about 100 mg / kg; from about 0.1 mg / kg to about 50 mg / kg; from about 0.1 mg / kg to about 10 mg / kg; from about 0.1 mg / kg to about 5 mg / kg; from about 0.1 mg / kg to about 1 mg / kg; from about 0.1 mg / kg to about 0.5 mg / kg).

[0808] Regimens

[0809] The foregoing dosages can be administered on a daily basis (e.g., as a single dose or as two or more divided doses) or non-daily basis (e.g., every other day, every two days, every three days, once weekly, twice weeks, once every two weeks, once a month).

[0810] In some embodiments, the period of administration of a compound described herein is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In an embodiment, a compound provided herein is administered to an individual for a period of time followed by a separate period of time (e.g., a dosing holiday). In another embodiment, a compound provided herein is administered for a first period and a second period following the first period, with administration stopped during the second period (e.g., a dosing holiday), followed by a third period where administration of the compound provided herein is started and then a fourth period following the third period where administration is stopped (e.g., a dosing holiday). In an aspect of this embodiment, the period of administration of a compound provided herein followed by a period where administration is stopped (e.g., a dosing holiday) is repeated for a determined or undetermined period of time. In a further embodiment, a period of administration is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped (e.g., a dosing holiday) is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.

[0811] The term “acceptable” with respect to a formulation, composition, or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[0812] “API” refers to an active pharmaceutical ingredient.

[0813] The term “excipient” or “pharmaceutically acceptable excipient” means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed. Rowe el al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed, Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed., ' Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0814] The term “pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain instances, pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. In some instances, pharmaceutically acceptable salts are obtained by reacting a compound having acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, A-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined. The term “pharmacologically acceptable salts” is not specifically limited as far as it can be used in medicaments. Examples of a salt that the compounds described herein form with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine, and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt. The salts can be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid:organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.

[0815] In some embodiments, a pharmaceutically acceptable salt is an anion salt selected from the group consisting of: a mesylate salt, a besylate salt, an acetate salt, a benzenesulfonate salt, a benzoate salt, a bicarbonate salt, a bitartrate salt, a bromide salt, a calcium edetate salt, a camsylate salt, a carbonate salt, a chloride salt, a citrate salt, a dihydrochloride salt, an edetate salt, an edisylate salt, an estolate salt, an esylate salt, a fumarate salt, a gluceptate salt, a gluconate salt, a glucuronate salt, a glutamate salt, a glycollylarsanilate salt, a hexylresorcinol salt, a hydramine salt, a hydrobromide salt, a hydrochloride salt, a hydroxynaphthoate salt, an iodide salt, an isethionate salt, a lactate salt, a lactobionate salt, a malate salt, a maleate salt, a mandelate salt, a mesylate salt, a methylbromide salt, a methylnitrate salt, a methylsulfate salt, a mucate salt, a napsylate salt, a nitrate salt, a pamoate (embonate) salt, a pantothenate salt, a phosphate / diphosphate salt, a polygalacturonate salt, a salicylate salt, a stearate salt, a subacetate salt, a succinate salt, a sulfate salt, an oleate salt, a tannate salt, a tartrate salt, a teoclate salt, and a triethiodide salt.

[0816] In some embodiments, a pharmaceutically acceptable salt is a cation salt selected from the group consisting of: a benzathine salt, a chloroprocaine salt, a choline salt, a tromethamine salt, a diethanolamine salt, an ethylenediamine salt, a meglumine salt, a procaine salt, an aluminum salt, a calcium salt, a lithium salt, a magnesium salt, a potassium salt, a sodium salt, and a zinc salt.

[0817] Examples of pharmaceutically acceptable salts also include those disclosed in e.g., Berge, Stephen M., Lyle D. Bighley, and Donald C. Monkhouse. "Pharmaceutical salts." Journal of pharmaceutical sciences 66.1 (1977): 1-19 doi: 10.1002 / jps.2600660104, Bharate, Sonali S. "Recent developments in pharmaceutical salts: FDA approvals from 2015 to 2019." Drug Discovery Today 26.2 (2021): 384-398 doi: 10.1016 / j.drudis.2020.11.016, and Bharate, Sonali S. "Modulation of biopharmaceutical properties of drugs using sulfonate counterions: A critical analysis of FDA-approved pharmaceutical salts." Journal of Drug Delivery Science and Technology 66 (2021): 102913 doi: 10.1016 / j.jddst.2021.102913.

[0818] The term “pharmaceutical composition” refers to a mixture of a compound described herein with other chemical components (referred to collectively herein as “excipients”), such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and / or thickening agents. The pharmaceutical composition facilitates administration of the compound to a subject. Multiple techniques of administering a compound exist in the art including, but not limited to: rectal, oral, intravenous, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

[0819] As used herein, “reacting” refers to bringing a chemical entity into physical contact with one or more additional chemical entities (reactants, reagents, catalysts, etc.) under appropriate conditions (e.g., appropriate temperature, appropriate solvent, appropriate reaction atmosphere, etc.) to facilitate one or more chemical transformations that lead to the product(s) as described herein.

[0820] Compound Preparation

[0821] The compounds disclosed herein can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or in light of the teachings herein.

[0822] Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); Smith, M. B., March, J., March' s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001; and Greene, T. W., Wuts, P. G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999, are useful and recognized reference textbooks of organic synthesis known to those in the art. The following descriptions of synthetic methods are designed to illustrate, but not to limit, general procedures for the preparation of compounds of the present disclosure.

[0823] The synthetic processes disclosed herein can tolerate a wide variety of functional groups; therefore, various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof.

[0824] EXAMPLES

[0825] In some of the examples disclosed herein, the final product of a described chemical reaction sequence is structurally depicted with an enhanced stereochemical rel notation at one stereogenic center. In some such examples, in the chemical name of the same compound, this stereogenic center is assigned a tentative configuration (e.g., (A)- or (5)-) based on the wedge / dash representation of the structural formula. However, this stereogenic center should be understood to have a configuration consistent with the rel notation. Specifically, this stereogenic center has been resolved, but its specific configuration has not been determined. Accordingly, unless otherwise specified, starting materials and intermediates leading to this compound incorporate the rel notation at this stereogenic center following stereochemical resolution(s), notwithstanding the tentative assignments provided in their chemical names.

[0826] Example 1: 6-(8-(benzo [d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl)-3-(3-(4-((l-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6-yl)piperazin-l-yl)ethyl)piperidin-4-yl)methyl)phenoxy)propyl)picolinic acid (Compound 118)

[0827]

[0828] Step 1: 6-bromo-3-iodo-l-methyl-lH-indazole

[0829] To a solution of 6-bromo-3-iodo-lH-indazole (7 g, 21.68 mmol, 1 equiv. and potassium carbonate (8.99 g, 65.03 mmol, 3 equiv.) in DMF (70 mL) was added Mel (6.15 g, 43.35 mmol, 2.70 mL, 2 equiv)). The mixture was stirred at 25 °C for 12 hours. The reaction mixture was quenched by the addition of water (100 mL), diluted with ethyl acetate (100 mL), and extracted with ethyl acetate (300 mL). The combined organic layers were washed with brine (300 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (0~2% ethyl acetate / petroleum ether) to give 6-bromo-3-iodo-l-methyl-lH-indazole (5.1 g) as a red solid.

[0830] 'H NMR (400 MHz, DMSO-d6) 3 = 8.04 (s, 1H), 7.43 - 7.26 (m, 2H), 4.05 (s, 3H)

[0831] Step 2: l-(6-bromo-l-methyl-lH-indazol-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(lH,3H)-dione

[0832] A mixture of 6-bromo-3-iodo-l-methyl-lH-indazole (7.3 g, 21.66 mmol, 1 equiv.). 3-(4-methoxybenzyl)dihydropyrimidine-2,4(lH,3H)-dione (6.09 g, 26.00 mmol, 1.2 equiv.). (lR,2R)-cyclohexane-l,2-diamine (247.39 mg, 2.17 mmol, 0.1 equiv., Cui (825.21 mg, 4.33 mmol, 0.2 equiv)), and cesium carbonate (14.12 g, 43.33 mmol, 2 equiv)) in dioxane (150 mL) was degassed and purged with N2 three times. The mixture was stirred at 60 °C for 16 hours under a N2 atmosphere. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (300 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (0-30% ethyl acetate / petroleum ether) to give l-(6-bromo-l -methyl- lH-indazol-3-yl)-3-(4-methoxybenzyl)dihy dropyrimidine-2,4(lH,3H)-dione (5.3 g) as a yellow solid.

[0833] LC-MS (ESI): m / z = 445.1 [M+H]+

[0834] 'H NMR (400 MHz, DMSO-d6) 3 = 7.98 (s, 1H), 7.57 (d, J= 8.4 Hz, 1H), 7.29 - 7.20 (m, 3H), 6.87 (d, J= 8.4 Hz, 2H), 4.85 (s, 2H), 3.99 - 3.91 (m, 5H), 3.72 (s, 3H), 2.95 (t, J = 6.8 Hz, 2H).

[0835] Step 3: tert-butyl 4-(3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6-yl)piperazine-l-carboxylate

[0836] A mixture of tert-butyl piperazine- 1 -carboxylate (2.52 g, 13.54 mmol, 3 equiv.). l-(6-bromo-l-methyl-lH-indazol-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(lH,3H)-dione (2 g, 4.51 mmol, 1 equiv.)., and cesium carbonate (4.41 g, 13.54 mmol, 3 equiv.) in dioxane (40 mL) was degassed and purged with N2 three times. RuPhos (421.06 mg, 902.34 pmol, 0.2 equiv.) and Pd2(dba)s (413.14 mg, 451.17 pmol, 0.1 equiv.) were then added to the mixture. The mixture was stirred at 100 °C for 12 hours under a N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (0-63% ethyl acetate / petroleum ether) to give tert-butyl 4-(3-(3 -(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidin- 1 (2H)-yl)- 1 -methyl- lH-indazol-6-yl)piperazine-l -carboxylate (2.2 g) as a yellow solid.

[0837] LC-MS (ESI): m / z = 549.3 [M+H]+

[0838] 'H NMR (400 MHz, DMSO-d6) 3 = 7.42 (d, J= 8.8 Hz, 1H), 7.24 (d, J= 8.4 Hz, 2H), 6.95 - 6.84 (m, 4H), 4.84 (s, 2H), 3.94 - 3.85 (m, 5H), 3.72 (s, 3H), 3.50 (s, 4H), 3.23 - 3.15 (m, 4H), 2.92 (t, J= 6.8 Hz, 2H), 1.43 (s, 9H)

[0839] Step 4: l-(l-methyl-6-(piperazin-l-yl)-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione

[0840] To a solution of tert-butyl 4-(3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6-yl)piperazine-l-carboxylate (1 g, 1.82 mmol, 1 equivi) in TFA (10 mL) was added trifluoromethanesulfonic acid (1 mL). The mixture was stirred at 70 °C for 2 hours. The crude reaction mixture was poured into water (500 mL) and extracted with DCM / methanol (10:1) (500 mL). The combined aqueous phase was concentrated in vacuo to give l-(l-methyl-6-(piperazin-l-yl)-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione as a yellow oil. The crude product was purified by re-crystallization from ethyl acetate (40 mL) to give l-(l-methyl-6-(piperazin-l-yl)-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (500.44 mg) as a white solid.

[0841] LC-MS (ESI): m / z = 329.1 [M+H]+

[0842] 'H NMR (400 MHz, DMSO -de) 6 = 10.51 (s, 1H), 8.67 (s, 2H), 7.51 (d, J= 9.6 Hz, 1H), 7.03 - 6.86 (m, 2H), 3.94 - 3.84 (m, 5H), 3.43 (d, J= 4.8 Hz, 4H), 3.28 (s, 4H), 2.74 (t, J = 6.8 Hz, 2H)

[0843] Step 5: (E)-4-(4-((3-bromoallyl)oxy)benzyl)-l-(2,2-diethoxyethyl)piperidine To a solution of (E)-4-(4-((3-bromoallyl)oxy)benzyl)piperidine (720 mg, 2.32 mmol, 1 equiv.) in MeCN (10 mL) was added potassium carbonate (962.30 mg, 6.96 mmol, 3 equiv.)., KI (385.26 mg, 2.32 mmol, 1 equiv.)., and 2-bromo- 1,1 -di ethoxy ethane (457.37 mg, 2.32 mmol, 349.14 pL, 1 equiv ^). The mixture was stirred at 60 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (0-20% ethyl acetate / petroleum ether) to give (E)-4-(4-((3-bromoallyl)oxy)benzyl)-l -(2, 2-di ethoxy ethyl)piperi dine (800 mg) as a colorless oil.

[0844] LC-MS (ESI): m / z = 428.0 [M+H]+

[0845] 'H NMR (400 MHz, DMSO-d6) 8 = 7.10 - 7.02 (m, 2H), 6.84 (dd, J= 2.0, 8.4 Hz, 2H), 6.80 - 6.67 (m, 1H), 6.57 - 6.42 (m, 1H), 4.64 (dd, J= 1.6, 6.0 Hz, 1H), 4.55 - 4.47 (m, 2H), 3.57 - 3.50 (m, 2H), 3.46 - 3.41 (m, 2H), 2.83 (d, J= 11.2 Hz, 2H), 2.41 (d, J= 6.4 Hz, 2H), 2.34 (d, J= 5.2 Hz, 2H), 1.90 (t, J= 10.8 Hz, 2H), 1.47 (d, J= 12.4 Hz, 2H), 1.37 (m, 1H), 1.14 (m, 2H), 1.09 (t, J= 7.2 Hz, 6H)

[0846] Step 6: tert-butyl (E)-6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl)-3-(3-(4-((l-(2,2-diethoxyethyl)piperidin-4-yl)methyl)phenoxy)prop-l-en-l-yl)picolinate

[0847] A mixture of (E)-4-(4-((3-bromoallyl)oxy)benzyl)-l -(2, 2-di ethoxy ethyl)piperi dine (800 mg, 1.88 mmol, 1 equiv.). tert-butyl 6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)picolinate (1.38 g, 2.25 mmol, 1.2 equiv. KF (1.5 M, 3.75 mL, 3 equiv.), and cataCXium A Pd G3 (273.28 mg, 375.25 pmol, 0.2 equiv.) in dioxane (20 mL) was degassed and purged with N2 three times. The mixture was stirred at 100 °C for 2 hours under a N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (0-60% ethyl acetate / petroleum ether) to give tert-butyl (E)-6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl)-3-(3-(4-((l-(2,2-diethoxyethyl)piperidin-4-yl)methyl)phenoxy)prop-l-en-l-yl)picolinate (670 mg) as a yellow oil.

[0848] LC-MS (ESI): m / z = 832.3 [M+H]+

[0849] Step 7: tert-butyl 6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl)-3-(3-(4-((l-(2,2-diethoxyethyl)piperidin-4-yl)methyl)phenoxy)propyl)picolinate

[0850] To a solution of tert-butyl (E)-6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl)-3-(3-(4-((l-(2,2-diethoxyethyl)piperidin-4-yl)methyl)phenoxy)prop-l-en-l-yl)picolinate (670 mg, 805.23 pmol, 1 equiv. in EtOH (10 mL) was added Rh / AhCh (662.93 mg, 322.09 pmol, 5% purity, 0.4 equiv^). The mixture was stirred at 25 °C for 24 hours under a H2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (0-60% ethyl acetate / petroleum ether) to give tert-butyl 6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl)-3-(3-(4-((l-(2,2-diethoxyethyl)piperidin-4-yl)methyl)phenoxy)propyl)picolinate (470 mg) as a yellow oil.

[0851] LC-MS (ESI): m / z = 834.4 [M+H]+

[0852] Step 8: 6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl)-3-(3-(4-((l-(2-oxoethyl)piperidin-4-yl)methyl)phenoxy)propyl)picolinic acid

[0853] A solution of tert-butyl 6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl)-3-(3-(4-((l-(2,2-diethoxyethyl)piperidin-4-yl)methyl)phenoxy)propyl)picolinate (80 mg, 95.91 pmol, 1 equiv. in HCOOH (1 mL) was stirred at 90 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give 6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihy...

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (I) or (II):Formula (II)or a pharmaceutically acceptable salt thereof, wherein:Z1is CH or N;R1is selected from the group consisting of:(a) -C(O)OH;(b) -C(O)OCi-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with 1-3 Rc; and (c) -C(O)-(Co-3 alkylene)-phenyl, wherein the phenyl is optionally substituted with 1-3 Rg;Ring A is selected from the group consisting of: (Al) and (A2):(Al) (A2)wherein:m2 is 0, 1, or 2,each R2is independently selected from the group consisting of: halo, -CN, C1-3 alkoxy, C1-3 haloalkoxy, C2-3 alkynyl, C3-6 cycloalkyl, and C1-3 alkyl optionally substituted with 1-3 Rc, andaa represents the point of attachment to -LA-;LAis selected from the group consisting of: a bond, -N(Rd)-, and -O-;bl is 1, 2, 3, 4, 5, or 6;cl is 1, 2, 3, or 4;each LBis independently selected from the group consisting of: LB1and LB3, provided that 0-1 LBis LB3;each Lcis independently selected from the group consisting of: LC1and LC3, provided that 0-1 Lcis LC3;each LB1and LC1is independently selected from the group consisting of: -CH2-, -CHRL-, and -C(RL)2-, wherein each RLis independently selected from the group consisting of: halo, -CN, -OH, C1-6 alkoxy, C1-6 haloalkoxy, and C1-6 alkyl optionally substituted with 1-6 Rc;LB3and LC3are each independently selected from the group consisting of: -N(Rd)- and -O-;Ring B is selected from the group consisting of: C3-10 cycloalkylene and 4-8 membered heterocyclylene, each of which is optionally substituted with 1-3 Ra;Ring C is selected from the group consisting of: C3-8 cycloalkylene and 4-12 membered nitrogen-containing heterocyclylene, each of which is optionally substituted with 1-3 Ra;D s eRing i s lected from the group consisting of:RYais selected from the group consisting of: -H, Rb, and Ci-6 alkyl optionally substituted with 1-3 Rc;each RYbis independently selected from the group consisting of: halo, C1-3 alkoxy, Ci-3 haloalkoxy, and C1-3 alkyl optionally substituted with 1-3 Rc;yl is 0, 1, or 2; andyy represents the point of attachment to Ring C or -(Lc)ci-;each Rais independently selected from the group consisting of: -F, -CN, -OH, oxo, Ci-3 alkoxy, and C1-3 alkyl optionally substituted with 1-3 Rc;each Rbis independently selected from the group consisting of: -(Lb)-Rbland -Rbl, wherein:each Lbis an independently selected C1-3 alkylene;each Rblis independently selected from the group consisting of: C3-6 cycloalkyl and 4-8 membered heterocyclyl, each of which is optionally substituted with 1-3 Rg;each Rcis independently selected from the group consisting of: halo, -CN, -OH, C1-6 alkoxy, C1-6 haloalkoxy, and -NRdRe;each Rdand Reis independently selected from the group consisting of: -H, -C(=O)Ci-6 alkyl, -C(=O)OCi-6 alkyl, -C(=O)N(Rf)2, and C1-6 alkyl optionally substituted with 1-3 Rb; each Rfis independently selected from the group consisting of: -H and C1-6 alkyl optionally substituted with 1-3 Rh;each Rgis independently selected from the group consisting of: Rh, C1-3 alkyl, and C1-3 haloalkyl; andeach Rhis independently selected from the group consisting of: halo, -CN, C1-6 alkoxy, and C1-6 haloalkoxy.

2. The compound of claim 1, wherein the compound is a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2, wherein the compound of Formula (I) is other than:or a pharmaceutically acceptable salt thereof.

4. The compound of claim 2 or 3, wherein one or more of (l)-(5) applies:(1) LAis -N(Rd)- (e.g., -N(Me)-);(2) one LBis LB3;(3) Ring C is a bicyclic 7-11 membered nitrogen-containing heterocyclylene optionallysubstitutedwherein bb represents the point of attachment to Ring D);(4) m2 is 1, and R2is CF3; and / or(5) Ring A is (A2).

5. The compound of claim 1, wherein the compound is a compound of Formula (II), or a pharmaceutically acceptable salt thereof.

6. The compound of any one of claims 1-5, wherein LAis -O-; orLAis -N(H)- or -N(CI-3 alkyl)-; orLAis -N(H)- or -N(Me)-).

7. The compound of any one of claims 1-6, wherein bl is 1 or 2; and each LBis an independently selected LB1; orbl is 3, 4, or 5; and each LBis an independently selected LB1; orbl is 3, 4, or 5; one LBis LB3; and each remaining LBis an independently selected LB1.

8. The compound of claim 7, wherein -(LB)bi- is -LB3-(LB1)2-4-ccwherein cc represents the point of attachment to Ring C; or-(LB)bi- is - (LB1)2-4-LB3-CCwherein cc represents the point of attachment to Ring C.

9. The compound of claim 7 or 8, wherein each LB1is CH2.

10. The compound of claim 7 or 9, wherein LB3is -O-, -N(H)-, or -N(CI-3 alkyl)-; orLB3is -N(H)- or -N(Me)-.

11. The compound of any one of claims 1-10, wherein Ring B is a C3-10 cycloalkylene optionally substituted with 1-3 Ra; orRing B is a C4-8 (e.g., Ce) cycloalkylene optionally substituted with 1-3 Ra; orRing12. The compound of any one of claims 2-4 or 6-11, wherein Ring C is a 4-12 membered nitrogen-containing heterocyclylene optionally substituted with 1-3 Ra, wherein the heterocyclylene contains 1-2 ring nitrogen atoms and no additional ring heteroatoms; or Ring C is piperazinylene optionally substituted with 1-3 Ra; orRing C iswherein bb represents the point of attachment to Ring D; orRing C is, wherein bb represents the point of attachment to Ring D; orRing C is piperidinylene optionally substituted with 1-3 Ra; orattachment to Ring D.

13. The compound of any one of claims 2-4 or 6-11, wherein Ring C is a bicyclic 7-11 membered nitrogen-containing heterocyclylene optionally substituted with 1-3 Ra, wherein the heterocyclylene contains 1-2 (e.g., 2) ring nitrogen atoms and no additional ring heteroatoms; orto Ring D.

14. The compound of any one of claims 5-11, wherein Ring C is a 6-10 membered nitrogen-containing heterocyclylene optionally substituted with 1-3 Ra; orRing C is a 6-10 membered nitrogen-containing heterocyclylene optionally substituted with 1-3 Ra, wherein the heterocyclylene contains one ring nitrogen atom and no additional ring heteroatoms; or, wherein bb represents the point of attachment to -(Lc)ci-.

15. The compound of any one of claims 1, 5-11, or 14, wherein -(Lc)ci- is selected from the group consisting of: -(Lcl)o-2-LC3-*, -(LC1)I-2-*, and -LC3-(LC1)I-2-*, wherein * represents the point of attachment to Ring D.

16. The compound of any one of claims 1, 5-11, or 14-15, wherein each LC1is independently selected from the group consisting of: -CH2-, -CHMe-, and -CMe2-; or each LC1is -CH2-.

17. The compound of any one of claims 1, 5-11, or 14-16, wherein LC3is -N(H)- or -N(CI-3 alkyl)- (e.g., -N(H)- or -N(Me)-); orLC3is -N(H)-; orLC3is -O-.

18. A compound of Formula (III) or (IV):Formula (IV)or a pharmaceutically acceptable salt thereof, wherein:Z1is CH or N;R1is selected from the group consisting of:(a) -C(O)OH;(b) -C(O)OCi-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with 1-3 Rc; and (c) -C(O)-(Co-3 alkylene)-phenyl, wherein the phenyl is optionally substituted with 1-3 Rg;Ring A is selected from the group consisting of: (Al) and (A2):wherein:m2 is 0, 1, or 2,each R2is independently selected from the group consisting of: halo, -CN, C1-3 alkoxy, C1-3 haloalkoxy, C2-3 alkynyl, and C1-3 alkyl optionally substituted with 1-3 Rc, andaa represents the point of attachment to -(LA3)a3;al is 1, 2, 3;a3 is 0, 1, or 2;each LA1and LA3is independently selected from the group consisting of: -CH2-, -CHRL-, and -C(RL)2-;LA2is selected from the group consisting of: a bond, -N(Rd)-, and -O-;bl is 1, 2, 3, 4, or 5;cl is 1, 2, 3, or 4;each LBis independently selected from the group consisting of: LB1and LB3, provided that 0-1 LBis LB3;each Lcis independently selected from the group consisting of: LC1and LC3, provided that 0-1 Lcis LC3;each LB1and LC1is independently selected from the group consisting of: -CH2-, -CHRL-, and -C(RL)2-;LB3and LC3are each independently selected from the group consisting of: -N(Rd)- and -O-;each RLis independently selected from the group consisting of: halo, -CN, -OH, C1-6 alkoxy, C1-6 haloalkoxy, and C1-6 alkyl optionally substituted with 1-6 Rc;Ring B is selected from the group consisting of: C3-10 cycloalkylene and 4-8 membered heterocyclylene, each of which is optionally substituted with 1-3 Ra;Ring C is selected from the group consisting of: C3-8 cycloalkylene and 4-12 membered nitrogen-containing heterocyclylene, each of which is optionally substituted with 1-3 Ra;D s eRing i s lected from the group consisting of:RYais selected from the group consisting of: -H, Rb, and Ci-6 alkyl optionally substituted with 1-3 Rc;each RYbis independently selected from the group consisting of: halo, C1-3 alkoxy, Ci-3 haloalkoxy, and C1-3 alkyl optionally substituted with 1-3 Rc;yl is 0, 1, or 2; andyy represents the point of attachment to Ring C or -(Lc)ci-;each Rais independently selected from the group consisting of: -F, -CN, -OH, oxo, Ci-3 alkoxy, and C1-3 alkyl optionally substituted with 1-3 Rc;each Rbis independently selected from the group consisting of: -(Lb)-Rbland -Rbl, wherein:each Lbis an independently selected C1-3 alkylene;each Rblis independently selected from the group consisting of: C3-6 cycloalkyl and 4-8 membered heterocyclyl, each of which is optionally substituted with 1-3 Rg;each Rcis independently selected from the group consisting of: halo, -CN, -OH, C1-6 alkoxy, C1-6 haloalkoxy, and -NRdRe;each Rdand Reis independently selected from the group consisting of: -H, -C(=O)Ci-6 alkyl, -C(=O)OCi-6 alkyl, -C(=O)N(Rf)2, and C1-6 alkyl optionally substituted with 1-3 Rb; each Rfis independently selected from the group consisting of: -H and C1-6 alkyl optionally substituted with 1-3 Rh;each Rgis independently selected from the group consisting of: Rh, C1-3 alkyl, and C1-3 haloalkyl; andeach Rhis independently selected from the group consisting of: halo, -CN, C1-6 alkoxy, and C1-6 haloalkoxy.

19. The compound of claim 18, wherein LA2is -O-.

20. The compound of claim 18 or 19, wherein each LA1is -CH2-.

21. The compound of any one of claims 18-20, wherein a3 is 0 or 1.

22. The compound of any one of claims 18-21, wherein each LA3is -CH2-.

23. The compound of any one of claims 18-22, wherein bl is 2, 3, or 4.

24. The compound of any one of claims 18-23, wherein each LBis an independently selected LB1; optionally wherein each LBis -CH2-.

25. The compound of any one of claims 18-22, wherein bl is 3, 4, or 5.

26. The compound of claim 25, wherein one LBis LB3; and each remaining LBis an independently selected LB1; orone LBis -N(H)- or -N(CI-3 alkyl)-; and each remaining LBis -CH2-.

27. The compound of any one of claims 18-26, wherein Ring B is a 4-8 (e.g., 6) membered nitrogen-containing heterocyclylene optionally substituted with 1-3 Ra; orRing B iseach of which is optionally substituted with 1-3 Ra, wherein cc represents the point of attachment to -(LB)bi-; orwherein cc represents the point of attachment to -(LB)bi-.

28. The compound of any one of claims 18-27, wherein Ring C is a 4-8 (e.g., 6) membered nitrogen-containing heterocyclylene optionally substituted with 1-3 Ra; orRing C is selected from the group consisting of:andbb, each of which is optionally substituted with 1-3 Ra, wherein bb represents the point of attachment to Ring D or -(Lc)ci-.

29. The compound of any one of claims 18-28, wherein cl is 1, 2, or 3.

30. The compound of any one of claims 18-29, wherein -(Lc)ci- is selected from the group consisting of: -(Lcl)o-2-LC3-* and -LC3-(LC1)I-2-*, wherein * represents the point of attachment to Ring D.

31. The compound of any one of claims 18-30, wherein each LC1is -CH2-.

32. The compound of any one of claims 18-31, wherein LC3is -N(Rd)-; or LC3is -N(H)- or -N(CI-3 alkyl)-; orLC3is -NMe-.

33. A compound of Formula (V):Formula (V)or a pharmaceutically acceptable salt thereof, wherein:Z1is CH or N;R1is selected from the group consisting of:(a) -C(O)OH;(b) -C(O)OCi-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with 1-3 Rc; and (c) -C(O)-(Co-3 alkylene)-phenyl, wherein the phenyl is optionally substituted with 1-3 Rg;Ring A is selected from the group consisting of: (Al) and (A2):(Al) (A2)wherein:m2 is 0, 1, or 2,each R2is independently selected from the group consisting of: halo, -CN, C1-3 alkoxy, C1-3 haloalkoxy, C2-3 alkynyl, C3-6 cycloalkyl, and C1-3 alkyl optionally substituted with 1-3 Rc, andaa represents the point of attachment to -(LA)ai-;al is 1, 2, 3, or 4;bl is 1, 2, 3, 4, 5, or 6;each LAis independently selected from the group consisting of: LA1and LA3, provided that 0-1 LAis LA3;each LBis independently selected from the group consisting of: LB1and LB3, provided that 0-1 LBis LB3;each LA1and LB1is independently selected from the group consisting of: -CH2-, -CHRL-, and -C(RL)2-, wherein each RLis independently selected from the group consisting of: halo, -CN, -OH, C1-6 alkoxy, C1-6 haloalkoxy, and C1-6 alkyl optionally substituted with 1-6 Rc;LA3and LB3are each independently selected from the group consisting of: -N(Rd)- and -O-;LDis selected from the group consisting of:and -N(Rd)-;Ring B is a 4-12 membered nitrogen-containing heterocyclylene optionally substituted with 1-3 Ra;Ring D is selected from the group consisting of:RYais selected from the group consisting of: -H, Rb, and C1-6 alkyl optionally substituted with 1-3 Rc;each RYbis independently selected from the group consisting of: halo, C1-3 alkoxy, Ci-3 haloalkoxy, and C1-3 alkyl optionally substituted with 1-3 Rc;yl is 0, 1, or 2; andyy represents the point of attachment to LD;each Rais independently selected from the group consisting of: -F, -CN, -OH, oxo, Ci-3 alkoxy, and C1-3 alkyl optionally substituted with 1-3 Rc;each Rbis independently selected from the group consisting of: -(Lb)-Rbland -Rbl, wherein:each Lbis an independently selected C1-3 alkylene;each Rblis independently selected from the group consisting of: C3-6 cycloalkyl and 4-8 membered heterocyclyl, each of which is optionally substituted with 1-3 Rg;each Rcis independently selected from the group consisting of: halo, -CN, -OH, C1-6 alkoxy, C1-6 haloalkoxy, and -NRdRe;each Rdand Reis independently selected from the group consisting of: -H, -C(=O)C1-6 alkyl, -C(=O)OC1-6 alkyl, -C(=O)N(Rf)2, and C1-6 alkyl optionally substituted with 1-3 Rh; each Rfis independently selected from the group consisting of: H and C1-6 alkyl optionally substituted with 1-3 Rb;each Rgis independently selected from the group consisting of: Rh, C1-3 alkyl, and Ci-3 haloalkyl; andeach Rhis independently selected from the group consisting of: halo, -CN, C1-6 alkoxy, and C1-6 haloalkoxy.

34. The compound of claim 33, wherein -(LA)ai- is -LA3-(LA1)o-3-*, wherein * represents the point of attachment to Ring B.

35. The compound of claim 33 or 34, wherein each LA1is -CH2-.

36. The compound of any one of claims 33-35, wherein LA3is -O-.

37. The compound of any one of claims 33-36, wherein each bl is 2, 3, 4, or 5.

38. The compound of any one of claims 33-37, wherein each LBis an independently selected LB1; oreach LBis -CH2-.

39. The compound of any one of claims 33-38, wherein Ring B is a 6-11 membered nitrogen-containing heterocyclylene optionally substituted with 1-3 Ra, wherein the heterocyclylene contains 1-2 (e.g., 2) ring nitrogen atoms and no additional ring heteroatoms; orRing B is, each of which is optionally substituted with 1-3 Ra, wherein cc represents the point of attachment to -(LB)bi-.

40. The compound of any one of claims 33-39, wherein LDis -N(H)-; or41. A compound of Formula (VI):Formula (VI)or a pharmaceutically acceptable salt thereof, wherein:Z1is CH or N;R1is selected from the group consisting of:(a) -C(O)OH;(b) -C(O)OCi-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-3 Rc; and (c) -C(O)-(Co-3 alkylene)-phenyl, wherein the phenyl is optionally substituted with 1-3 Rg;Ring A is selected from the group consisting of: (Al) and (A2):wherein:m2 is 0, 1, or 2,each R2is independently selected from the group consisting of: halo, -CN, C1-3 alkoxy, C1-3 haloalkoxy, C2-3 alkynyl, C3-6 cycloalkyl, and C1-3 alkyl optionally substituted with 1-3 Rc, andaa represents the point of attachment to -LA-;LAis selected from the group consisting of: a bond, -N(Rd)-, and -O-;bl is 0, 1, 2, or 3;cl is 0, 1, or 2;el is 0, 1, or 2;each LBis independently selected from the group consisting of: LB1and LB3, provided that 0-1 LBis LB3;each Lcis independently selected from the group consisting of: LC1and LC3, provided that 0-1 Lcis LC3;each LEis independently selected from the group consisting of: LE1and LE3, provided that 0-1 LEis LE3;each LB1, LC1, and LE1is independently selected from the group consisting of: -CH2-, -CHRL-, and -C(RL)2-, wherein each RLis independently selected from the group consisting of: halo, -CN, -OH, C1-6 alkoxy, C1-6 haloalkoxy, and C1-6 alkyl optionally substituted with 1-6 Rc;LB3, LC3, and LE3are each independently selected from the group consisting of: -N(Rd)-and -O-;Ring B is selected from the group consisting of: C3-10 cycloalkylene and 4-8 membered nitrogen-containing heterocyclylene, each of which is optionally substituted with 1-3 Ra;Ring C is selected from the group consisting of: C3-8 cycloalkylene and 4-12 membered nitrogen-containing heterocyclylene, each of which is optionally substituted with 1-3 Ra;Ring E is selected from the group consisting of: C3-6 cycloalkylene and 4-6 membered nitrogen-containing heterocyclylene, each of which is optionally substituted with 1-3 Ra;RYais selected from the group consisting of: -H, Rb, and Ci-6 alkyl optionally substituted with 1-3 Rc;each RYbis independently selected from the group consisting of: halo, C1-3 alkoxy, Ci-3 haloalkoxy, and C1-3 alkyl optionally substituted with 1-3 Rc;yl is 0, 1, or 2; andyy represents the point of attachment to -(Lc)ci-;each Rais independently selected from the group consisting of: -F, -CN, -OH, oxo, Ci-3 alkoxy, and C1-3 alkyl optionally substituted with 1-3 Rc;each Rbis independently selected from the group consisting of: -(Lb)-Rbland -Rbl, wherein:each Lbis an independently selected C1-3 alkylene;each Rblis independently selected from the group consisting of: C3-6 cycloalkyl and 4-8 membered heterocyclyl, each of which is optionally substituted with 1-3 Rg;each Rcis independently selected from the group consisting of: halo, -CN, -OH, C1-6 alkoxy, C1-6 haloalkoxy, and -NRdRe;each Rdand Reis independently selected from the group consisting of: -H, -C(=O)Ci-6 alkyl, -C(=O)OCi-6 alkyl, -C(=O)N(Rf)2, and C1-6 alkyl optionally substituted with 1-3 Rb; each Rfis independently selected from the group consisting of: H and C1-6 alkyl optionally substituted with 1-3 Rb;each Rgis independently selected from the group consisting of: Rh, C1-3 alkyl, and C1-3 haloalkyl; andeach Rhis independently selected from the group consisting of: halo, -CN, C1-6 alkoxy, and C1-6 haloalkoxy.

42. The compound of claim 41, wherein LAis -O-.

43. The compound of claim 41 or 42, wherein Ring B is a C4-8 (e.g., Ce) cycloalkylene optionally substituted with 1-3 Ra; orRingRing B is a 4-8 membered nitrogen-containing heterocyclylene, each of which is optionally substituted with 1-3 Ra; orRing, wherein bb represents the point of attachment to -(LB)bi-.

44. The compound of any one of claims 41-43, wherein -(LB)bi- is -(LB1)i-3-, optionally wherein each LB1is -CH2-; or-(LB)bi- is -O-.

45. The compound of any one of claims 41-44, wherein Ring E is selected from thegroup consisting of:, wherein ee represents the point of attachment to -(LE)ei-.

46. The compound of any one of claims 41-45, wherein el is 0 or 1.

47. The compound of any one of claims 41-46, wherein each LEis an independently selected LE1, optionally wherein each LEis -CH2-.

48. The compound of any one of claims 41-47, wherein Ring C is a 4-8 (e.g., 6) membered nitrogen-containing heterocyclylene optionally substituted with 1-3 RL4; orRing C is selected from the group consisting of: hQ-H l-O-L andbb, each of which is optionally substituted with 1-3 Ra, wherein bb represents the point of attachment to -(Lc)ci-.

49. The compound of any one of claims 41-48, wherein cl is 0.

50. The compound of any one of claims 41-48, wherein cl is 1 or 2.

51. The compound of any one of claims 41-48 or 50, wherein -(Lc)ci- is -(LC1)0-1-LC3-*, wherein the * represents the point of attachment to Ring D; optionally wherein LC1is -CH2-, and LC3is -N(H)- or -O-.

52. The compound of any one of claims 1-51, wherein Ringoptionally wherein m2 is 1; or53. The compound of any one of claims 1-51, wherein Ringoptionally wherein m2 is 1; or54. The compound of any one of claims 1-53, wherein R2is methyl.

55. The compound of any one of claims 1-54, wherein Ring; orRing56. The compound of any one of claims 1-55, wherein yl is 0.

57. The compound of any one of claims 1-56, wherein RYais C1-3 alkyl (e.g., methyl).

58. The compound of any one of claims 1-54, wherein Ring; yl is 0; and RYais C1-3 alkyl (e.g., methyl).

59. The compound of any one of claims 1-58, wherein R1is -C(O)OH.

60. The compound of any one of claims 1-59, wherein Z1is CH.

61. A compound selected from the group consisting of the compounds depicted in Table Cl, or a pharmaceutically acceptable salt thereof.

62. A pharmaceutical composition comprising a compound of any one of claims 1-61, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

63. A method for treating a cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-61, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 62.

64. The method of claim 63, comprising administering an additional therapy or therapeutic agent; optionallywherein the additional therapy or therapeutic agent is an ALK inhibitor, a BCL-2 inhibitor, a BCR-Abl inhibitor, a BRaf inhibitor, a CDK2 inhibitor, CDK 4 / 6 inhibitor, a CDK7 inhibitor, a CDK9 inhibitor, an EGFR inhibitor, an anti-EGFR antibody, an ERK inhibitor, a FGFR1 inhibitor, a FGFR2 inhibitor, a FGFR3 inhibitor, a FGFR4 inhibitor, a HER2 inhibitor, a JAK2 inhibitor, a KRas inhibitor, a MEK inhibitor, a MET inhibitor, a PARP inhibitor, an LSD1 inhibitor, a BET inhibitor, a telomerase inhibitor, a TORC1 / 2 inhibitor, L-asparaginase, chemotherapy, radiotherapy, or a combination thereof.

65. The method of claim 63 or 64, wherein the cancer is breast cancer, colorectal cancer, bile duct cancer, colorectal cancer, gastrointestinal stromal tumor, pancreatic cancer, bladder cancer, kidney cancer, cervical cancer, ovarian cancer, uterine cancer, head and neck cancer, hematological cancer, lung cancer, skin cancer, or a combination thereof.

66. The method of claim 65, wherein the hematological cancer is acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), small lymphocytic lymphoma (SLL), essential thrombocythemia, polycythemia vera, myelofibrosis, or a combination thereof.

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