Tetrahydroisoquinoline heterobifunctional BCL-XL degrader

Abstract

The present disclosure relates to BCL-X L compounds of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or pharmaceutically acceptable salts thereof, which induce the degradation of the protein. These compounds are useful, for example, for treating cancer in a subject (e.g., a human). The present disclosure also provides compositions containing the compounds provided herein or pharmaceutically acceptable salts thereof, as well as methods of using and making the same. TIFF2025516358000187.tif96138

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 454,477, filed Mar. 24, 2023; No. 63 / 429,814, filed Dec. 2, 2022; No. 63 / 398,769, filed Aug. 17, 2022; and No. 63 / 339,262, filed May 6, 2022, each of which is hereby incorporated by reference in its entirety.

[0002] Technical Field The present disclosure provides compounds of formula (I) or (II) (e.g., formula (I - A), (I - B), or (I - C)), or pharmaceutically acceptable salts thereof, which induce the degradation of BCL - X L protein. These compounds are useful, for example, for treating cancer in a subject (e.g., a human). The present disclosure also provides compositions containing the compounds or pharmaceutically acceptable salts thereof provided herein, as well as methods of using and making the same.

Background Art

[0003] Background The BCL - 2 family of proteins is involved in the regulation of cell apoptosis and includes apoptosis - promoting, survival - promoting, and BH3 - only proteins. Generally speaking, the balance of binding of BH3 - only proteins to apoptosis - promoting and survival - promoting members of the BCL - 2 family may determine whether a cell undergoes apoptosis. The protein BCL - X L encoded by the BCL2L1 gene is a survival - promoting member of the BCL - 2 family. In many cancers, it may be desirable to initiate apoptosis of tumor cells, which can be achieved by reducing the amount of available survival - promoting proteins (e.g., BCL - X L ) that compete for BH3 - only protein binding.

Summary of the Invention

[0004] Summary The present disclosure provides compounds of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or pharmaceutically acceptable salts thereof, which induce the degradation of the BCL-X L protein. These compounds are useful, for example, for treating cancer in a subject (e.g., a human). The present disclosure also provides compositions containing the compounds provided herein or pharmaceutically acceptable salts thereof, as well as methods of using and making the same.

[0005] As used herein, a compound of formula (I) or (II): TIFF2025516358000002.tif118128 or a pharmaceutically acceptable salt thereof, wherein ring A is (a) C 3-15 cycloalkylene or 3- to 15-membered heterocyclylene, each of which is optionally substituted with 1 to 6 substituents independently selected from the group consisting of R a and R b C 3-15 cycloalkylene or 3- to 15-membered heterocyclylene, and (b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of R a and R b phenylene or 5- to 6-membered heteroarylene, and is selected from the group consisting of L T1 is a bond or C c alkylene optionally substituted with 1 to 3 substituents independently selected from the group consisting of oxo and R 1-3 wherein one CH 1-3 unit of the C 2 alkylene may be replaced by -O- or -N(R d ), and A * is (a) C3-15 A cycloalkyl or 3- to 15-membered heterocyclyl, each of which may be substituted with 1 to 6 substituents independently selected from the group consisting of R a and R b A cycloalkyl or 3- to 15-membered heterocyclyl, and 3-15 Aryl or 5- to 15-membered heteroaryl, each of which may be substituted with 1 to 6 substituents independently selected from the group consisting of R (b) C 6-15 Aryl or 5- to 15-membered heteroaryl, and a and R b Aryl or 5- to 15-membered heteroaryl, and 6-15 (c) H, (c) H, Selected from the group consisting of, R 1 is (a) C(O)OH, (b) C(O)NR d R e and (c) C(O)OC 1-6 Alkyl, wherein C 1-6 Alkyl may be substituted with 1 to 3 R c A C(O)OC 1-6 Alkyl, and Selected from the group consisting of, Each R 2 、R 3 、R 4 、and R 5 is independently selected from the group consisting of halo, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, OH, and NR d R e Selected from the group consisting of, m2 is 0, 1, or 2, m3 and m4 are independently 0, 1, 2, or 3, m5 is 0, 1, 2, 3, or 4, L is -(L A ) n1 -, wherein L Aand n1 is defined according to (AA) or (BB), - (L A ) n1 - and (AA) n1 is an integer from 3 to 15, each L A is independently selected from the group consisting of L A1 , L A3 , and L A4 , provided that 1 to 3 occurrences of L A are L A4 under the condition, (BB) n1 is an integer from 0 to 20, each L A is independently selected from the group consisting of L A1 and L A3 , each L A1 is independently selected from the group consisting of -CH 2 -, -CHR L -, and -C(R L ) 2 -, each L A3 is independently selected from the group consisting of -N(R d )-, -N(R b )-, -O-, -S(O) 0-2 -, and C(=O), each L A4 is independently (a) C 3-15 cycloalkylene or 3- to 15-membered heterocyclylene, each of which may be substituted with 1 to 6 substituents independently selected from the group consisting of R a and R b , C 3-15 cycloalkylene or 3- to 15-membered heterocyclylene, and (b) C 6-15 arylene or 5- to 15-membered heteroarylene, each of which may be substituted with 1 to 6 substituents independently selected from the group consisting of R a and R b , C 6-15 arylene or 5- to 15-membered heteroarylene, and selected from the group consisting of wherein L does not contain any of O - O, N - O, N - N, N - S(O) 0 , and O - S(O) 0-2 bonds, provided that in the formula, each R L is independently halo, cyano, - OH, - C 1-6 alkoxy, - C 1-6 haloalkoxy, - NR d R e , C(=O)N(R f ) 2 , S(O) 0-2 (C 1-6 alkyl), S(O) 0-2 (C 1-6 haloalkyl), S(O) 1-2 N(R f ) 2 , - R b , and C c alkyl which may be substituted with 1 to 6 R 1-6 s, selected from the group consisting of ring C is selected from the group consisting of TIFF2025516358000003.tif21128, each of which may be substituted with 1 to 3 substituents independently selected from the group consisting of R a and R b , where yy is the point of attachment to L, each R a is independently (a) halo, (b) cyano, (c) - OH, (d) oxo, (e) - C 1-6 alkoxy, (f) - C 1-6 haloalkoxy, (g) - NR d R e , (h) C(=O)C 1-6 alkyl, (i) C(=O)C 1-6 haloalkyl, (j) C(=O)OH, (k)C(=O)OC 1-6 alkyl, (l)C(=O)OC 1-6 haloalkyl, (m)C(=O)N(R f ) 2 , (n)S(O) 0-2 (C 1-6 alkyl), (o)S(O) 0-2 (C 1-6 haloalkyl), (p)S(O) 1-2 N(R f ) 2 and (q)each of 1 to 6 R c which may be substituted with, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl selected from the group consisting of, each R b is independently selected from the group consisting of -(L b ) b -R b1 and -R b1 wherein, each b is independently 1, 2, or 3, each -L b is independently selected from the group consisting of -O-, -N(H)-, -N(C 1-3 alkyl)-, -S(O) 0-2 -, C(=O), and C 1-3 alkylene, each R b1 is independently selected from the group consisting of C 3-10 cycloalkyl, 4- to 10-membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, each of which may be substituted with 1 to 3 R g (s), each R c is independently halo, cyano, -OH, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -NR d R e , C(=O)C 1-6Alkyl, C(=O)C 1-6 Haloalkyl, C(=O)OC 1-6 Alkyl, C(=O)OC 1-6 Haloalkyl, C(=O)OH, C(=O)N(R f ) 2 , S(O) 0-2 (C 1-6 Alkyl), S(O) 0-2 (C 1-6 Haloalkyl), and S(O) 1-2 N(R f ) 2 selected from the group consisting of, each R d and R e is, independently, H, C(=O)C 1-6 Alkyl, C(=O)C 1-6 Haloalkyl, C(=O)OC 1-6 Alkyl, C(=O)OC 1-6 Haloalkyl, C(=O)N(R f ) 2 , S(O) 1-2 (C 1-6 Alkyl), S(O) 1-2 (C 1-6 Haloalkyl), S(O) 1-2 N(R f ) 2 , and C h alkyl optionally substituted with 1 to 3 R 1-6 selected from the group consisting of, each R f is, independently, H, and C h alkyl optionally substituted with 1 to 3 R 1-6 selected from the group consisting of, each R g is, independently, R h , C 1-3 Alkyl, and C 1-3 Haloalkyl selected from the group consisting of, each R h is, independently, halo, cyano, -OH, -C 1-6 Alkoxy, -C 1-6 Haloalkoxy, -NH 2 , -N(H)(C 1-3 Alkyl), and -N(C 1-3(alkyl) 2 There is provided a compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

[0006] Also provided herein is a pharmaceutical composition comprising a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0007] Also provided herein is a method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0008] Also provided herein is BCL-X non-covalently bound to a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof L protein.

[0009] Also provided herein is L a ternary complex comprising BCL-X protein, a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, and CRBN protein or a portion thereof.

[0010] To facilitate understanding of the disclosure described herein, some additional terms are provided. In general, the nomenclature used herein, as well as laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described, are well known and commonly used 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 patent, application, published application, and other publication referred to throughout this specification and the accompanying appendix is hereby incorporated by reference in its entirety.

[0011] Details of one or more embodiments of the invention are described in the accompanying drawings and the following description. Other features and advantages of the invention will be apparent from the description and drawings, and from the claims.

DETAILED DESCRIPTION OF THE INVENTION

[0012] Detailed Description The present disclosure provides compounds of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or pharmaceutically acceptable salts thereof, which induce the degradation of the BCL-X L (also referred to herein as Bcl-xL) protein. These compounds are useful, for example, for treating cancer. The present disclosure also provides compositions containing the compounds provided herein or pharmaceutically acceptable salts thereof, as well as methods of using and making the same.

[0013] Without being bound by any particular theory, in healthy cells, apoptosis-promoting effectors such as BAX and BAK can move between the cytosol and the outer mitochondrial membrane (MOM), and it is thought that voltage-dependent anion channel 2 (VDAC2) can act as a receptor on the outer mitochondrial membrane (MOM). Survival-promoting BCL-2 family members (e.g., BCL-2, BCL-X L、and MCL-1) can retrograde transport BAX to the cytosol. BH3-only proteins (e.g., BIM) can engage a posterior site on pro-apoptotic effectors (e.g., BAX or BAK), releasing the effector's C-terminal transmembrane domain (α9) to enable binding to the MOM. Binding of BIM to the canonical BH3-binding groove of BAX or BAK releases the N-terminus and α1 of BAX or BAK, and subsequent unfolding of the "latch" domain releases BIM from the BH3-binding groove. When prosurvival BCL-2 family members bind to BAX or BAK, apoptosis signaling is generally halted. However, if BAX or BAK dimerize and then oligomerize, the MOM can be permeabilized, leading to apoptosis.

[0014] The abundance of prosurvival BCL-2 family members is often thought to "prime" cells for death (e.g., via cytotoxic therapies that include BH3 mimetics). Oncogenic mutations and stress can cause upregulation in BH3-only proteins and thus are thought to exert selective pressure on cancer cells for upregulation of prosurvival BCL-2 family proteins. Thus, cells are thought to be more sensitive to further manipulation of the BCL-2 family balance when more BH3-only proteins are present in the vicinity. See, e.g., Adams and Cory, Cell Death & Differentiation 25.1 (2018):27-36.

[0015] Compounds that induce the 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 E3 ligase or simply E3), and these two moieties are optionally separated by a linker. To induce degradation, heterobifunctional compounds are thought to induce the formation of a ternary complex between the target protein, the compound, and the E3 ligase. Subsequently, following the formation of the ternary complex, ubiquitination of the target protein and degradation of the ubiquitinated target protein by the proteasome occur. Some E3 ligases have been used as partner E3 ligases for heterobifunctional degraders. In this specification, the cereblon (CRBN) E3 ligase (also referred to herein as the CRBN protein) is used.

[0016] The 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 the effect of the heterobifunctional compound generally depends on the rate of resynthesis of the target protein. Another potential advantage is that many heterobifunctional compounds are thought to be released from the ubiquitinated target protein-E3 ligase complex and become available for the formation of further ternary complexes. This is sometimes referred to as the "catalytic" turnover of the heterobifunctional compound. In some cases, degradation of the target protein may be more advantageous than small molecule inhibition because degradation can impair the scaffolding function of the target protein, while small molecules may not. Also, generally, a high affinity for the target protein is not necessarily required for the formation of the ternary complex.

[0017] Heterobifunctional compounds are further described, for example, in WO 2017 / 184995, WO 2019 / 144117, WO 2020 / 163823, WO 2021 / 078301, WO 2021 / 146536, WO 2021 / 007307, WO 2021 / 222114, WO 2021 / 078301, WO 2022 / 169780, WO 2023 / 044046, Chamberlain and Hamann, Nature Chemical Biology 15.10 (2019): 937-944, Li and Song, Journal of Hematology & Oncology 13 (2020): 1-14, Wu, et al. Nature Structural & Molecular Biology 27.7 (2020): 605-614, Dong, et al., Journal of Medicinal Chemistry 64.15 (2021): 10606-10620, Yang, et al., Targeted Oncology 16.1 (2021): 1-12, Lv, et al., Nature Communications 12.1 (2021): 6896.

[0018] Embodiments of the compound As used herein, a compound of formula (I) or (II): TIFF2025516358000004.tif118128 or a pharmaceutically acceptable salt thereof, wherein Ring A is (a) C 3-15 Cycloalkylene or 3- to 15-membered heterocyclylene, each of which is optionally substituted with 1 to 6 substituents independently selected from the group consisting of R a and R b Cycloalkylene or 3- to 15-membered heterocyclylene, and 3-15 (b) Phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted with 1 to 6 substituents independently selected from the group consisting of R a and R b ​Phenylene or 5- to 6-membered heteroarylene, which may be substituted with 1 to 3 substituents independently selected from the group consisting of, selected from the group consisting of, L T1 is a bond, or C c alkyl which may be substituted with 1 to 3 substituents independently selected from the group consisting of oxo and R 1-3 alkylene, and one CH 1-3 unit of the C 2 alkylene may be replaced by -O- or -N(R d )-, A * is (a) C 3-15 cycloalkyl or 3- to 15-membered heterocyclyl, each of which may be substituted with 1 to 6 substituents independently selected from the group consisting of R a and R b C 3-15 cycloalkyl or 3- to 15-membered heterocyclyl, (b) C 6-15 aryl or 5- to 15-membered heteroaryl, each of which may be substituted with 1 to 6 substituents independently selected from the group consisting of R a and R b C 6-15 aryl or 5- to 15-membered heteroaryl, (c) H, selected from the group consisting of, R 1 is (a) C(O)OH, (b) C(O)NR d R e and (c) C(O)OC 1-6 alkyl, wherein the C 1-6 alkyl may be substituted with 1 to 3 R c C(O)OC 1-6 alkyl, selected from the group consisting of, each R 2 R 3 R 4 and R 5is, independently, halo, CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, OH, and NR d R e selected from the group consisting of, m2 is 0, 1, or 2, m3 and m4 are, independently, 0, 1, 2, or 3, m5 is 0, 1, 2, 3, or 4, L is -(L A ) n1 -, wherein L A and n1 are defined according to (AA) or (BB), -(L A ) n1 -, (AA) n1 is an integer from 3 to 15, each L A is, independently, selected from the group consisting of L A1 , L A3 , and L A4 , provided that 1 to 3 occurrences of L A are L A4 , (BB) n1 is an integer from 0 to 20, each L A is, independently, selected from the group consisting of L A1 and L A3 , each L A1 is, independently, -CH 2 -, -CHR L (a)C L ) 2 - selected from the group consisting of, each L A3 is, independently, selected from the group consisting of -N(R d )-, -N(R b )-, -O-, -S(O) 0-2 -, and C(=O), each L A4 is, independently, (a)C 3-15A cycloalkylene or a 3- to 15-membered heterocyclylene, each of which is optionally substituted with 1 to 6 substituents independently selected from the group consisting of R a and R b A cycloalkylene or a 3- to 15-membered heterocyclylene, and 3-15 A cycloalkylene or a 3- to 15-membered heterocyclylene, (b) A C 6-15 An arylene or a 5- to 15-membered heteroarylene, each of which is optionally substituted with 1 to 6 substituents independently selected from the group consisting of R a and R b An arylene or a 5- to 15-membered heteroarylene, and 6-15 An arylene or a 5- to 15-membered heteroarylene, Selected from the group consisting of Provided that L does not contain any of the bonds O—O, N—O, N—N, N—S(O) 0 and O—S(O) 0-2 In the formula, each R L is independently halo, cyano, —OH, —C 1-6 Alkoxy, —C 1-6 Haloalkoxy, —NR d R e , C(═O)N(R f ) 2 , S(O) 0-2 (C 1-6 Alkyl), S(O) 0-2 (C 1-6 Haloalkyl), S(O) 1-2 N(R f ) 2 , —R b and optionally substituted with 1 to 6 R c Selected from the group consisting of C 1-6 Alkyl, Ring C is Selected from the group consisting of TIFF2025516358000005.tif21128, each of which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of R a and R b , where yy is the point of attachment to L, Each R a is independently ​(a) Halo, (b) Cyano, (c) -OH, (d) Oxo, (e) -C 1-6 Alkoxy, (f) -C 1-6 Haloalkoxy, (g) -NR d R e , (h) C(=O)C 1-6 Alkyl, (i) C(=O)C 1-6 Haloalkyl, (j) C(=O)OH, (k) C(=O)OC 1-6 Alkyl, (l) C(=O)OC 1-6 Haloalkyl, (m) C(=O)N(R f ) 2 , (n) S(O) 0-2 (C 1-6 Alkyl), (o) S(O) 0-2 (C 1-6 Haloalkyl), (p) S(O) 1-2 N(R f ) 2 、and (q) Each of which may be substituted with 1 to 6 R c s, and is selected from the group consisting of C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl ; where each R is independently selected from the group consisting of -(L b ) b -R b and -R b1 and -R b1 ; in the formula, each b is independently 1, 2, or 3, each -L b is independently -O-, -N(H)-, -N(C 1-3 Alkyl)-, -S(O) 0-2 -, C(=O), and C 1-3selected from the group consisting of alkylene, each R b1 is independently C 3-10 cycloalkyl, 4- to 10-membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, each of which may be substituted with 1 to 3 R g groups, each R c is independently halo, cyano, -OH, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -NR d R e , C(=O)C 1-6 alkyl, C(=O)C 1-6 haloalkyl, C(=O)OC 1-6 alkyl, C(=O)OC 1-6 haloalkyl, C(=O)OH, C(=O)N(R f ) 2 , S(O) 0-2 (C 1-6 alkyl), S(O) 0-2 (C 1-6 haloalkyl), and S(O) 1-2 N(R f ) 2 selected from the group consisting of each R d and R e is independently H, C(=O)C 1-6 alkyl, C(=O)C 1-6 haloalkyl, C(=O)OC 1-6 alkyl, C(=O)OC 1-6 haloalkyl, C(=O)N(R f ) 2 , S(O) 1-2 (C 1-6 alkyl), S(O) 1-2 (C 1-6 haloalkyl), S(O) 1-2 N(R f ) 2 , and C h alkyl which may be substituted with 1 to 3 R 1-6 selected from the group consisting of each R f is independently H, and 1 to 3 Rh C which may be replaced 1-6 selected from the group consisting of alkyl, each R g is, independently, R h , C 1-3 alkyl, and C 1-3 selected from the group consisting of haloalkyl, each R h is, independently, halo, cyano, -OH, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -NH 2 , -N(H)(C 1-3 alkyl), and -N(C 1-3 alkyl) 2 There are provided compounds or pharmaceutically acceptable salts thereof selected from the group consisting of

[0019] In some embodiments, provided that (i) and (ii): (i) Ring C is substituted with 1 to 3 substituents independently selected from the group consisting of R a and R b (ii) In formula (I), L does not contain an adamantylene group, and in formula (II), A is other than adamantyl, * one or both of are applicable.

[0020] In some embodiments, provided that (i) is applicable. In some embodiments, provided that (ii) is applicable. In some embodiments, provided that both (i) and (ii) are applicable.

[0021] In some embodiments, the compound is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0022] In some embodiments, the compound is a compound of formula (II) or a pharmaceutically acceptable salt thereof.

[0023] In some embodiments, ring A is phenylene or 5- to 6-membered heteroarylene, each of which may be substituted with 1 to 3 substituents independently selected from the group consisting of R a and R b and may be substituted with 1 to 3 substituents independently selected from the group consisting of.

[0024] In some embodiments, ring A is phenylene which may be substituted with 1 to 3 substituents independently selected from the group consisting of R a and R b In some embodiments, ring A is phenylene which may be substituted with 1 to 3 R a 's.

[0025] In some embodiments, ring A is TIFF2025516358000006.tif22128, where aa represents the point of attachment to L or L T1 .

[0026] In some embodiments, ring A is TIFF2025516358000007.tif18128, where aa represents the point of attachment to L or L T1 . For example, ring A can be TIFF2025516358000008.tif19128, where aa represents the point of attachment to L or L T1 .

[0027] In some embodiments, ring A is TIFF2025516358000009.tif22128, where aa represents the point of attachment to L or L T1 . For example, ring A can be TIFF2025516358000010.tif21128, where aa represents the point of attachment to L or L T1 .

[0028] In some embodiments, ring A has 1 to 3 R aIt may be replaced by a 5- to 6-membered heteroarylene. In some embodiments, ring A has 1 to 2 Rs a It may be replaced by a 5- to 6-membered heteroarylene. In some embodiments, ring A has 1 to 2 Rs a It may be replaced by a 5-membered heteroarylene. In some embodiments, ring A has 1 to 2 Rs a It may be replaced by pyrazolylene. For example, ring A is Selected from the group consisting of TIFF2025516358000011.tif21128, where aa represents the point of attachment to L or L T1

[0029] In some embodiments, ring A has 1 to 6 Rs a It may be replaced by C 3-10 Cycloalkylene. In some embodiments, ring A has 1 to 3 Rs a It may be replaced by C 4-6 Cycloalkylene. In some embodiments, ring A has 1 to 3 Rs a It may be replaced by cyclohexylene. For example, ring A can be 1,4-cyclohexylene.

[0030] In some embodiments, one R a Present on ring A is C 1-3 Alkyl which may be replaced by 1 to 3 Fs. In some embodiments, one R a Present on ring A is methyl or CF 3

[0031] In some embodiments, R 1 Is C(O)OH. In some embodiments, R 1 Is C(O)NHR e

[0032] In some embodiments, R 1 Is C(O)OH and ring A is ​​​TIFF2025516358000012.tif is 22128, where aa represents the bonding point to L or L T1 The bonding point to L or L. In some embodiments, ring A is TIFF2025516358000013.tif is 18128, where aa represents the bonding point to L or L T1 The bonding point to L or L. For example, ring A can be TIFF2025516358000014.tif is 19128, where aa represents the bonding point to L or L T1 The bonding point to L or L. In some embodiments, ring A is TIFF2025516358000015.tif is 22128, where aa represents the bonding point to L or L T1 The bonding point to L or L. For example, ring A can be TIFF2025516358000016.tif is 21128, where aa represents the bonding point to L or L T1 The bonding point to L or L.

[0033] In some embodiments, L T1 is C 1-3 alkylene. For example, L T1 can be -CH 2 -.

[0034] In some embodiments, A * is H. In some embodiments, A * is C 3-15 cycloalkyl or a 3- to 15-membered heterocyclyl, each of which may be substituted with 1 to 6 substituents independently selected from the group consisting of R a and R b . In some embodiments, A * is C a cycloalkyl optionally substituted with 1 to 3 R 3-15 . For example, A * can be adamantyl optionally substituted with 1 to 3 R a .

[0035] In some embodiments, m2 is 0. In some embodiments, m3 is 0. In some embodiments, m4 is 0. In some embodiments, m5 is 0.

[0036] In some embodiments, m2 is 0, m3 is 0, m4 is 0, and m5 is 0.

[0037] In some embodiments, ring C is TIFF2025516358000017.tif21128, each of which is selected from the group consisting of 1 to 3 R a where yy is the point of attachment to L.

[0038] In some embodiments, ring C is TIFF2025516358000018.tif24128, each of which is selected from the group consisting of 1 to 3 R a where yy is the point of attachment to L.

[0039] In some embodiments, ring C has 1-2 R a may be further substituted with TIFF2025516358000019.tif22128, where yy is the point of attachment to L. In some embodiments, ring C is TIFF2025516358000020.tif22128, where yy is the point of attachment to L. For example, ring C can be TIFF2025516358000021.tif20128, where yy is the point of attachment to L.

[0040] In some embodiments, L is -(L A ) n1 - and L AAnd n1 is defined according to (AA). In some embodiments, n1 is an integer from 3 to 5. In some embodiments, n1 is an integer from 5 to 9. In some embodiments, n1 is 6, 7, or 8. In some embodiments, n1 is an integer from 9 to 12.

[0041] In some embodiments, L A and n1 are defined according to (AA), and L A one to two occurrences of A4 are L A One occurrence of L A4 is L A Two occurrences of L A4 are L A4 In some embodiments, each L a) C 3-10 Cycloalkylene or 4- to 10-membered heterocyclylene, each of which may be substituted with 1 to 3 R a Cycloalkylene or 4- to 10-membered heterocyclylene, and 3-10 b) Phenylene or 5- to 6-membered heteroarylene, each of which may be substituted with 1 to 3 R Phenylene or 5- to 6-membered heteroarylene, and a is selected from the group consisting of: selected from the group consisting of.

[0042] In some embodiments, L A and n1 are defined according to (AA), and L A one to four occurrences of A3 are L A One to three (e.g., one to two or two to three) occurrences of L A3 are L A3 Zero to one occurrence of L is C(=O), and each remaining occurrence of L A3 is independently selected from the group consisting of -O-, -N(H)-, and -N(C 1-3 alkyl)-.

[0043] In some embodiments, L A and n1 are defined according to (AA), and the 2 to 7 occurrences of L A are as follows. In some embodiments, the 2 to 5 occurrences of L A1 are as follows. In some embodiments, the 0 to 2 (e.g., 0 to 1) occurrences of L A are -CHR A1 - or -C(R A1 ) L -, and each remaining occurrence of L L is -CH 2 -. In some embodiments, each occurrence of L A1 is -CH 2 -. In some embodiments, one occurrence of L A1 is -CHR 2 - or -C(R A1 ) L -, and each remaining occurrence of L L is -CH 2 -. In some embodiments, each R A1 is independently selected from the group consisting of -F and -C 2 alkyl which may be substituted with 1 to 3 Fs (e.g., CH L or CF 1-3 ). 3 3 )

[0044] In some embodiments, L A and n1 are defined according to (AA), and the 8 to 13 occurrences of L A are as follows. In some embodiments, the 0 to 2 occurrences of L A1 are -CHR A1 - or -C(R L ) L -, and each remaining occurrence of L 2 is -CH A1 -. In some embodiments, each occurrence of L 2 is -CH A1 -. In some embodiments, one occurrence of L 2 is -CHR A1 - or -C(R L ) L -​2 - and L A1 each remaining occurrence of is -CH 2 -. In some embodiments, each R L is independently selected from the group consisting of -F and -C 1-3 alkyl which may be substituted with 1 to 3 Fs.

[0045] In some embodiments, L is -(L A ) n1 -, and L A and n1 are defined according to (AA), wherein n1 is an integer from 5 to 9, and the 2 occurrences of L A are L A4 , the 2 to 7 occurrences of L A are L A1 , and the 1 to 3 occurrences of L A are L A3 . In some embodiments, each L A4 is independently C 3-10 cycloalkylene or 4- to 10-membered heterocyclylene, each of which may be substituted with 1 to 3 R a s, C 3-10 cycloalkylene or 4- to 10-membered heterocyclylene, or phenylene or 5- to 6-membered heteroarylene, each of which may be substituted with 1 to 3 R a s, phenylene or 5- to 6-membered heteroarylene, and is selected from the group consisting of. In some embodiments, 0 to 1 occurrence of L A1 is -CHR L - or -C(R L ) 2 -, and each remaining occurrence of L A1 is -CH 2 -. In some embodiments, 0 to 1 occurrence of L A3 is C(=O), and each remaining occurrence of L A3 is independently selected from the group consisting of -O-, -N(H)-, and -N(C 1-3 alkyl)-.

[0046] In some embodiments, L is -(L A )n1 - and L A and n1 are defined according to (AA), where n1 is an integer from 5 to 13, and L A one occurrence of is L A4 - and L A two to eleven occurrences of are L A1 - and L A one to three occurrences of are L A3 - is. In some embodiments, each L A4 is independently C 3-10 cycloalkylene or 4- to 10-membered heterocyclylene, each of which may be substituted with one to three R a -, C 3-10 cycloalkylene or 4- to 10-membered heterocyclylene, and phenylene or 5- to 6-membered heteroarylene, each of which may be substituted with one to three R a -, phenylene or 5- to 6-membered heteroarylene, and is selected from the group consisting of. In some embodiments, L A1 zero to one occurrence of is -CHR L - or -C(R L ) 2 -, and L A1 each remaining occurrence of is -CH 2 -. In some embodiments, L A3 zero to one occurrence of is C(=O), and L A3 each remaining occurrence of is independently selected from the group consisting of -O-, -N(H)-, and -N(C 1-3 alkyl)-.

[0047] In some embodiments, L is (i) -(L A3 ) 0-2 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -L A3 -L A4 - bb - and (ii) -(L A3 ) 0-2 -(L A1 ) 0-5 -L A4 -(LA1 ) 0-5 -L A4 - bb selected from the group consisting of, provided that L is 2 to 7 Ls A1 and contains the condition that, in the formula, bb represents the bonding point to ring C. In some embodiments, each L A4 is independently C 3-10 cycloalkylene or 4- to 10-membered heterocyclylene, each of which may be substituted with 1 to 3 Rs a cycloalkylene or 4- to 10-membered heterocyclylene, C 3-10 and phenylene or 5- to 6-membered heteroarylene, each of which may be substituted with 1 to 3 Rs a phenylene or 5- to 6-membered heteroarylene, and is selected from the group consisting of. In some embodiments, 0 to 1 occurrence of L A1 is -CHR L - or -C(R L ) 2 -, and each remaining occurrence of L A1 is -CH 2 -. In some embodiments, 0 to 1 occurrence of L A3 is C(=O), and each remaining occurrence of L A3 is independently selected from the group consisting of -O-, -N(H)-, and -N(C 1-3 alkyl)-.

[0048] In some embodiments, L is -(L A3 ) 0-2 -(L A1 ) 1-11 -(L A3 ) 0-1 -L A4 - bb and in the formula, bb represents the bonding point to ring C. In some embodiments, L A4 is C 3-10 cycloalkylene or 4- to 10-membered heterocyclylene, each of which may be substituted with 1 to 3 Rs a cycloalkylene or 4- to 10-membered heterocyclylene, C 3-10Cycloalkylene or 4- to 10-membered heterocyclylene, and phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted with 1 to 3 R a and phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted with 1 to 3 R, is selected from the group consisting of. In some embodiments, L A1 0 to 1 occurrence of is -CHR L - or -C(R L ) 2 -, and each remaining occurrence of L A1 is -CH 2 -. In some embodiments, 0 to 1 occurrence of L A3 is C(=O), and each remaining occurrence of L A3 is independently selected from the group consisting of -O-, -N(H)-, and -N(C 1-3 alkyl)-.

[0049] In some embodiments, L is -(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -L A4 - bb or -(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -L A3 -L A4 - bb wherein, provided that L contains 2 to 7 L A1 's, and in the formula, bb represents the bonding point to ring C. In some embodiments, each L A4 is independently C 3-10 cycloalkylene or 4- to 10-membered heterocyclylene, each of which is optionally substituted with 1 to 3 R a and is optionally substituted with 1 to 3 R, C 3-10A cycloalkylene or a 4- to 10-membered heterocyclylene, and a phenylene or a 5- to 6-membered heteroarylene, each of which may be substituted with 1 to 3 Rs a and a phenylene or a 5- to 6-membered heteroarylene, each of which may be substituted with 1 to 3 Rs, are selected from the group consisting of. In some embodiments, 0 to 1 occurrence of L A1 is -CHR L - or -C(R L ) 2 -, and each remaining occurrence of L A1 is -CH 2 -. In some embodiments, 0 to 1 occurrence of L A3 is C(=O), and each remaining occurrence of L A3 is independently selected from the group consisting of -O-, -N(H)-, and -N(C 1-3 alkyl)-.

[0050] In some embodiments, L is -(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -(4- to 10-membered heterocyclylene)- bb or -(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -C(=O)-(4- to 10-membered heterocyclylene)- bb wherein, provided that L contains 2 to 7 Ls A1 , and in the formula, bb represents a bonding point to ring C. In some embodiments, L A4 is a C 3-10 cycloalkylene or a 4- to 10-membered heterocyclylene, each of which may be substituted with 1 to 3 Rs a , a C 3-10 cycloalkylene or a 4- to 10-membered heterocyclylene, and a phenylene or a 5- to 6-membered heteroarylene, each of which may be substituted with 1 to 3 Rsa It may be replaced by, and is selected from the group consisting of phenylene or 5- to 6-membered heteroarylene. In some embodiments, L A1 For 0 to 1 occurrences of, -CHR L - or -C(R L ) 2 -, and each remaining occurrence of L A1 is -CH 2 -.

[0051] In some embodiments, L is -(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -(6-membered heterocyclylene)- bb , or -(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -C(=O)-(6-membered heterocyclylene)- bb , provided that L contains 2 to 5 L s, where bb represents the bonding point to ring C. In some embodiments, L A1 is C A4 cycloalkylene or 4- to 10-membered heterocyclylene, each of which may be substituted with 1 to 3 R 3-10 s, C a cycloalkylene or 4- to 10-membered heterocyclylene, and phenylene or 5- to 6-membered heteroarylene, each of which may be substituted with 1 to 3 R 3-10 s, phenylene or 5- to 6-membered heteroarylene, and is selected from the group consisting of. In some embodiments, 0 to 1 occurrences of L a are -CHR A1 - or -C(R L ) L -, and each remaining occurrence of L 2 is -CH A1 -. 2 ​

[0052] In some embodiments, L is of formula (L-1) or (L-2): a divalent group of TIFF2025516358000022.tif62128, wherein Y 1 is N or CH, a3 is 0 or 1, L A3 is selected from the group consisting of -O-, -N(H)-, and -N(C 1-3 alkyl)-, a1a and a1b are independently integers from 0 to 5, provided that a1a + a1b is from 2 to 5, L A1a and L A1b are independently selected from the group consisting of -CH 2 -, -CHR L -, and -C(R L ) 2 -, L A4 is a) C 3-10 cycloalkylene or 4- to 10-membered heterocyclylene, each of which may be substituted with 1 to 3 R a s, C 3-10 cycloalkylene or 4- to 10-membered heterocyclylene, and b) phenylene or 5- to 6-membered heteroarylene, each of which may be substituted with 1 to 3 R a s, phenylene or 5- to 6-membered heteroarylene, selected from the group consisting of bb represents the point of attachment to ring C.

[0053] In some embodiments of (L-1) or (L-2), a3 is 1. In some embodiments, L A3 is -O-. In some embodiments, a3 is 1 and L A3 is -O-.

[0054] In some embodiments of (L-1) or (L-2), a1a + a1b is 3 or 4. For example, a1a + a1b can be 3. For example, a1a + a1b can be 4.

[0055] In some embodiments of (L-1) or (L-2), a1a + a1b is 2.

[0056] In some embodiments of (L-1) or (L-2), L A1a and L A1b each occurrence of 2 is -CH

[0057] In some embodiments of (L-1) or (L-2), L A1a one occurrence of L is -CHR L - or -C(R 2 ) A1a - and each remaining occurrence of L 2 is -CH A1b - and each occurrence of L 2 is CH

[0058] In some embodiments of (L-1) or (L-2), L A1b one occurrence of L is -CHR L ) 2 - and each remaining occurrence of L A1b is -CH 2 - and each occurrence of L A1a is CH 2 -

[0059] In some embodiments of (L-1) or (L-2), L A4 is a 4- to 10-membered heterocyclylene optionally substituted with 1 to 3 R a . In some embodiments of (L-1) or (L-2), L A4 is optionally substituted with 1 to 3 R a at each of one or more ring carbon atoms, Selected from the group consisting of TIFF2025516358000023.tif42140, wherein cc represents the point of attachment to L A1b In some embodiments of (L-1) or (L-2), L A4 Each R present on a May be C substituted with 1 to 3 F 1-3 Is alkyl.

[0060] In some embodiments of (L-1) or (L-2), L A4 May be C substituted with 1 to 3 R a Is cycloalkylene. For example, L 3-10 May be 1,4-cyclohexylene optionally substituted with 1 to 3 R A4 For example, L a May be 1,4-cyclohexylene optionally substituted with 1 to 3 R A4 For example, L May be TIFF2025516358000024.tif11128.

[0061] In some embodiments of (L-1) or (L-2), L A4 Is phenylene or 5- to 6-membered heteroarylene, each of which may be substituted with 1 to 3 R a For example, L A4 May be 1,4-phenylene optionally substituted with 1 to 3 R a For example, L A4 May be 1,2-phenylene optionally substituted with 1 to 3 R a For example, L A4 May be 1,3-phenylene optionally substituted with 1 to 3 R a For example, L

[0062] In some embodiments of (L-1) or (L-2), Y 1 Is N. In some embodiments of (L-1) or (L-2), Y 1 Is CH.

[0063] L is -(L A3 )0-1 -(L A1 ) 1-11 -(L A3 ) 0-1 -L A4 - bb wherein bb represents the bonding point to ring C. In some embodiments, L is -(L A3 ) 0-1 -(L A1 ) 1-11 -(C(=O)) 0-1 -(a 4- to 10-membered heterocyclylene)- bb wherein bb represents the bonding point to ring C. In some embodiments, L is -(L A3 ) 0-1 -(L A1 ) 1-11 -(C(=O)) 0-1 -(a 6-membered heterocyclylene)- bb wherein bb represents the bonding point to ring C. In some embodiments, L is -(L A3 ) 0-1 -(L A1 ) 1-11 -(C(=O)) 0-1 -(piperazinylene or piperidinylene (e.g., piperazinylene))- bb wherein bb represents the bonding point to ring C.

[0064] In some embodiments, L is a divalent group of formula (L-3): TIFF2025516358000025.tif31128, wherein Y 1 is N or CH, a3a is 0 or 1, L A3a is selected from the group consisting of -O-, -N(H)-, and -N(C 1-3 alkyl)-, a1 is an integer from 1 to 11, a3c is 0 or 1, bb represents the bonding point to ring C.

[0065] In some embodiments of (L-3), a3a is 1. In some embodiments, LA3a is -O-. In some embodiments, a3a is 1, and L A3a is -O-.

[0066] In some embodiments of (L-3), a3a is 0.

[0067] In some embodiments of (L-3), a1 is 1 or 2. In some embodiments of (L-3), a1 is an integer from 3 to 5. In some embodiments of (L-3), a1 is an integer from 5 to 9. In some embodiments of (L-3), a1 is an integer from 9 to 11.

[0068] In some embodiments of (L-3), L A1 0 to 1 occurrences of are -CHR L - or -C(R L ) 2 -, and each remaining occurrence of L A1 is -CH 2 -.

[0069] In some embodiments of (L-3), a3c is 0. In some embodiments of (L-3), a3c is 1.

[0070] In some embodiments of (L-3), Y 1 is N. In some embodiments of (L-3), Y 1 is CH.

[0071] In some embodiments (e.g., when L is (L-1) or (L-2)), L is selected from the group consisting of TIFF2025516358000026.tif99131, wherein bb represents the point of attachment to ring C.

[0072] In some embodiments (e.g., when L is (L-1) or (L-2)), L is Selected from the group consisting of TIFF2025516358000027.tif48134, wherein bb represents the point of attachment to ring C.

[0073] In some embodiments (e.g., when L is (L-3)), L is Selected from the group consisting of TIFF2025516358000028.tif129144, wherein bb represents the point of attachment to ring C.

[0074] In some embodiments, L is (L-2), and the compound of formula (I) is a compound of formula (I-A): TIFF2025516358000029.tif56158 or a pharmaceutically acceptable salt thereof, wherein m6 is 0 or 1, a3 is 0 or 1, L A3 is selected from the group consisting of -O-, -N(H)-, and -N(C 1-3 alkyl)-, a1a and a1b are independently integers from 0 to 5, provided that a1a + a1b is 2 to 5, L A1a and L A1b are independently selected from the group consisting of -CH 2 -, -CHR L -, and -C(R L ) 2 -, L A4 is a) C 3-10 cycloalkylene or 4- to 10-membered heterocyclylene, each of which may be substituted with 1 to 3 R a , C 3-10 cycloalkylene or 4- to 10-membered heterocyclylene, and b) phenylene or 5- to 6-membered heteroarylene, each of which may be substituted with 1 to 3 R a , phenylene or 5- to 6-membered heteroarylene, selected from the group consisting of Y1 is a compound or a pharmaceutically acceptable salt thereof, where N or CH.

[0075] In some embodiments, L is (L-1), and the compound of formula (I) is a compound of formula (I-B): TIFF2025516358000030.tif53161 or a pharmaceutically acceptable salt thereof, wherein m6 is 0 or 1, a3 is 0 or 1, L A3 is selected from the group consisting of -O-, -N(H)-, and -N(C 1-3 alkyl)-, a1a and a1b are independently integers from 0 to 5, provided that a1a + a1b is 2 to 5, L A1a and L A1b are independently selected from the group consisting of -CH 2 -, -CHR L -, and -C(R L ) 2 -, L A4 is a) C 3-10 cycloalkylene or 4- to 10-membered heterocyclylene, each of which may be substituted with 1 to 3 R a , C 3-10 cycloalkylene or 4- to 10-membered heterocyclylene, and b) phenylene or 5- to 6-membered heteroarylene, each of which may be substituted with 1 to 3 R a , phenylene or 5- to 6-membered heteroarylene, selected from the group consisting of Y 1 is a compound or a pharmaceutically acceptable salt thereof, where N or CH.

[0076] In some embodiments of formula (I-A) or (I-B), a3 is 1. In some embodiments, L A3 is -O-. In some embodiments, a3 is 1 and LA3 is -O-.

[0077] In some embodiments of formula (I-A) or (I-B), a3 is 0.

[0078] In some embodiments of formula (I-A) or (I-B), a1a + a1b is 3.

[0079] In some embodiments of formula (I-A) or (I-B), a1a + a1b is 2.

[0080] In some embodiments of formula (I-A) or (I-B), L A1a and L A1b each occurrence of is -CH 2 -.

[0081] In some embodiments of formula (I-A) or (I-B), one occurrence of L A1a is -CHR L - or -C(R L ) 2 -, and each remaining occurrence of L A1a is -CH 2 -, and each occurrence of L A1b is CH 2 -.

[0082] In some embodiments of formula (I-A) or (I-B), one occurrence of L A1b is -CHR L - or -C(R L ) 2 -, and each remaining occurrence of L A1b is -CH 2 -, and each occurrence of L A1a is CH 2 -.

[0083] In some embodiments of formula (I-A) or (I-B), L A4 is a 4- to 10-membered heterocyclylene which may be substituted with 1 to 3 R a . In some embodiments of formula (I-A) or (I-B), L A4is optionally substituted at each of one or more ring carbon atoms with one to three Rs a and is selected from the group consisting of TIFF2025516358000031.tif42140, where cc represents the point of attachment to L A1b In some embodiments of formula (I-A) or (I-B), each R present on L A4 is optionally substituted with one to three Fs and is C a alkyl. 1-3

[0084] In some embodiments of formula (I-A) or (I-B), L A4 is optionally substituted with one to three Rs a and is C 3-10 cycloalkylene. For example, L A4 can be 1,4-cyclohexylene optionally substituted with one to three Rs a . For example, L A4 can be TIFF2025516358000032.tif15128.

[0085] In some embodiments of formula (I-A) or (I-B), L A4 is phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted with one to three Rs a . For example, L A4 can be 1,4-phenylene optionally substituted with one to three Rs a . For example, L A4 can be 1,3-phenylene optionally substituted with one to three Rs a . For example, L A4 can be 1,2-phenylene optionally substituted with one to three Rs a .

[0086] In some embodiments, L is (L-3), and the compound of formula (I) is a compound of formula (I-C): TIFF2025516358000033.tif55159 or a pharmaceutically acceptable salt thereof, wherein m6 is 0 or 1, a3a is 0 or 1, L A3a is selected from the group consisting of -O-, -N(H)-, and -N(C 1-3 alkyl)-, a1 is an integer from 1 to 11, a3c is 0 or 1, Y 1 is N or CH, a compound or a pharmaceutically acceptable salt thereof.

[0087] In some embodiments of formula (I-C), a3a is 1. In some embodiments, L A3a is -O-. In some embodiments, a3a is 1 and L A3a is -O-.

[0088] In some embodiments of formula (I-C), a1 is 1 or 2.

[0089] In some embodiments of formula (I-C), a1 is an integer from 3 to 5. In some embodiments of formula (I-C), a1 is an integer from 6 to 8. In some embodiments of formula (I-C), a1 is an integer from 9 to 11.

[0090] In some embodiments of formula (I-C), 0 to 1 occurrence of L A1 is -CHR L - or -C(R L ) 2 -, and each remaining occurrence of L A1 is -CH 2 -.

[0091] In some embodiments of formula (I-C), a3c is 0.

[0092] In some embodiments of formula (I-C), a3c is 1.

[0093] In some embodiments of formula (I-A), (I-B), or (I-C), m6 is 0.

[0094] In some embodiments of formula (I-A), (I-B), or (I-C), R present on ring A a is C alkyl optionally substituted with 1 to 3 -F. 1-3 alkyl.

[0095] In some embodiments of formula (I-A), (I-B), or (I-C), R 1 is C(O)OH.

[0096] In some embodiments of formula (I-A), (I-B), or (I-C), m2 is 0. In some embodiments of formula (I-A), (I-B), or (I-C), m4 is 0.

[0097] In some embodiments of formula (I-A), (I-B), or (I-C), Y 1 is N. In some embodiments of formula (I-A), (I-B), or (I-C), Y 1 is CH.

[0098] In some embodiments, the compound is selected from the group consisting of the compounds in Table C1 or their pharmaceutically acceptable salts.

[0099] [Table C1] TIFF2025516358000035.tif204157TIFF2025516358000036.tif214157TIFF2025516358000037.tif229157TIFF2025516358000038.tif203157TIFF2025516358000039.tif202157TIFF2025516358000040.tif208157TIFF2025516358000041.tif215157TIFF2025516358000042.tif197157TIFF2025516358000043.tif203157TIFF2025516358000044.tif228157TIFF2025516358000045.tif159157

[0100] Exemplary compounds of formula (I) or (II) also include those shown in Table C1 of U.S. Patent Provisional Application No. 63 / 454,477, filed on March 24, 2023, Table C1 of U.S. Patent Provisional Application No. 63 / 429,814, filed on December 2, 2022, Table C1 of U.S. Patent Provisional Application No. 63 / 398,769, filed on August 17, 2022, and Table C1 of U.S. Patent Provisional Application No. 63 / 339,262, filed on May 6, 2022, or pharmaceutically acceptable salts thereof, and each Table C1 is hereby incorporated by reference in its entirety.

[0101] In some embodiments, a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, has an EC 50 less than 1 μM (e.g., less than 750 nM, less than 500 nM, or less than 200 nM) in reducing cell viability in a cell line expressing the BCL-X L protein. In some embodiments, the compound has an EC 50 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) in reducing cell viability in a cell line expressing the BCL-X LReduce the cell viability in cell lines expressing the protein. For example, the compound has an EC of 0.1 nM to 100 nM, 0.1 nM to 50 nM, 1 nM to 50 nM, 1 nM to 20 nM, or 0.1 nM to 1 nM 50 and can reduce the cell viability in cell lines expressing the BCL-X L protein.

[0102] In some embodiments, a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, has a DC of less than 1 μM (e.g., less than 750 nM, less than 500 nM, or less than 200 nM) 50 and can induce the degradation of BCL-X L protein in cell lines expressing the BCL-X L protein. In some embodiments, a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, has a DC 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) 50 and can induce the degradation of BCL-X L protein in cell lines expressing the BCL-X L protein. For example, the compound has a DC of 0.1 nM to 100 nM, 0.1 nM to 50 nM, 1 nM to 50 nM, 1 nM to 20 nM, or 0.1 nM to 1 nM 50 and can induce the degradation of BCL-X L protein in cell lines expressing the BCL-X L protein.

[0103] In some embodiments, a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, has a Y of less than 70% (e.g., less than 50%, less than 30%, less than 20%, or less than 10%) min and can induce the degradation of BCL-X L protein in cell lines expressing the BCL-X LInduces degradation of the protein. In some embodiments, a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, has less than 50% (e.g., less than 40%, less than 30%, less than 20%, less than 10%, or less than 5%) of Y min wherein, BCL-X L in a cell line expressing the BCL-X L Induces degradation of the protein. In some embodiments, a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, has less than 30% (e.g., less than 25%, less than 20%, less than 15%, less than 10%, or less than 5%) of Y min wherein, BCL-X L in a cell line expressing the BCL-X L Induces degradation of the protein. For example, the compound has from about 1% to about 70% (e.g., from about 5% to about 50%, or from about 10% to about 30%) of Y min wherein, BCL-X L in a cell line expressing the BCL-X L can induce degradation of the protein.

[0104] Also provided herein is a BCL-X L protein non-covalently bound to a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof.

[0105] Also provided herein is a ternary complex comprising a BCL-X L protein, a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, and a CRBN protein or a portion thereof.

[0106] Chemical Definitions The term "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0107] The term "oxo" refers to a divalent double-bonded oxygen atom (i.e., "=O"). As used herein, an oxo group is bonded to a carbon atom to form a carbonyl.

[0108] The term "alkyl" refers to a saturated acyclic hydrocarbon group that can be straight-chain or branched-chain and contains the indicated number of carbon atoms. For example, C 1-10 indicates that the group can have 1 to 10 (including 1 and 10) carbon atoms therein. The alkyl group can be either unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, iso-propyl, tert-butyl, n-hexyl. The term "saturated" as used in this context means only single bonds exist between the constituent carbon atoms and the other available valences occupied by hydrogen and / or other substituents defined herein.

[0109] The term "haloalkyl" refers to an alkyl in which one or more hydrogen atoms are independently replaced with a selected halo (e.g., -CF 3 , -CHF 2 , or -CH 2 F).

[0110] The term "alkoxy" refers to an -O-alkyl group (e.g., -OCH 3 ).

[0111] The term "alkylene" refers to a divalent alkyl (e.g., -CH 2 -). Similarly, terms such as "cycloalkylene" and "heterocyclylene" refer to divalent cycloalkyl and heterocyclyl, respectively. To avoid ambiguity, in "cycloalkylene" and "heterocyclylene", the two groups can be on the same ring carbon atom (e.g., TIFF2025516358000046.tif19128 (such as geminal diradicals), or can be on different ring atoms (e.g., ring carbon and / or nitrogen atoms (e.g., vicinal ring carbon and / or nitrogen atoms)) (e.g., TIFF2025516358000047.tif19128).

[0112] The term "alkenyl" refers to an acyclic hydrocarbon chain that can be straight or branched and has one or more carbon-carbon double bonds. The alkenyl moiety contains the indicated number of carbon atoms. For example, C 2-6 indicates that the group can have 2 to 6 (including 2 and 6) carbon atoms therein. The alkenyl group can be either unsubstituted or substituted with one or more substituents.

[0113] The term "alkynyl" refers to an acyclic hydrocarbon chain that can be straight or branched and has one or more carbon-carbon triple bonds. The alkynyl moiety contains the indicated number of carbon atoms. For example, C 2-6 indicates that the group can have 2 to 6 (including 2 and 6) carbon atoms therein. The alkynyl group can be either unsubstituted or substituted with one or more substituents.

[0114] The term "aryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic group of 6 to 20 carbons in which at least one ring in the system is aromatic (e.g., a 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system), where 0, 1, 2, 3, or 4 atoms of each ring can be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, etc.

[0115] As used herein, the term "cycloalkyl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic (e.g., fused, bridged, or spirocyclic, bicyclic, tricyclic, or polycyclic) saturated or partially unsaturated hydrocarbon group having, for example, 3 to 20 ring carbons, preferably 3 to 15 ring carbons, and more preferably 3 to 12 ring carbons or 3 to 10 ring carbons or 3 to 6 ring carbons, where the cycloalkyl group may be substituted. The term "saturated" as used in this context means only single bonds existing between the constituent carbon atoms. Examples of saturated cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Partially unsaturated cycloalkyl has one or more double bonds present in the cycloalkyl, provided that none of the rings in the ring system is aromatic and the partially unsaturated cycloalkyl group is not completely saturated overall, and may have any degree of unsaturation. Examples of partially unsaturated cycloalkyl include, but are not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Non-limiting examples of fused / bridged cycloalkyl include bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[1.1.1]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. Non-limiting examples of spirocyclic cycloalkyl 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.

[0116] As used herein, the term "heteroaryl" means a monocyclic, bicyclic, tricyclic, 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 is independently N, O, S( including oxidized forms such as TIFF2025516358000048.tif14128), and P( Contains one or more heteroatoms selected from the group consisting of (including oxidation forms such as TIFF2025516358000049.tif13128), and at least one ring in the system is aromatic (however, the ring containing heteroatoms, such as tetrahydroisoquinolinyl, such as tetrahydroquinolinyl, is not necessarily required). The heteroaryl group can be either unsubstituted or substituted with one or more substituents. Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiadiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolylbenzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromanyl, 2,3-dihydrobenz[b][1,4]dioxinyl, benz[d][1,3]dioxolyl, 2,3-dihydrobenzofuranyl, tetrahydroquinolinyl, 2,3-dihydrobenz[b][1,4]oxathiinyl, isoindolinyl, and others. In some embodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl. For clarity, heteroaryl also includes aromatic lactams, aromatic cyclic ureas, or their vinylogous analogs, where each ring nitrogen adjacent to the carbonyl is a pyridone (e.g., TIFF2025516358000050.tif19128), pyrimidone (e.g., TIFF2025516358000051.tif19128), pyridazinone (e.g., TIFF2025516358000052.tif19128), pyrazinone (e.g., TIFF2025516358000053.tif19128), and imidazolone (e.g., TIFF2025516358000054.tif15128), etc., are tertiary (i.e., all three valences are occupied by non-hydrogen substituents), and each ring nitrogen adjacent to the carbonyl is tertiary (i.e., the oxo group (i.e., "=O") in this specification is a constituent part of the heteroaryl ring).

[0117] The term "heterocyclyl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic (e.g., fused, bridged, or spirocyclic, bicyclic, tricyclic, or polycyclic) saturated or partially unsaturated ring system having 3 to 15 ring atoms (e.g., 5- to 8-membered monocyclic, 8- to 12-membered bicyclic, or 11- to 15-membered tricyclic ring system) with 1 to 3 heteroatoms if monocyclic, 1 to 6 heteroatoms if bicyclic, or 1 to 9 heteroatoms if tricyclic or polycyclic, and the heteroatoms are O, N, S ( TIFF2025516358000055.tif14128, etc., including the oxidized form), and P ( Selected from (including oxidation forms such as TIFF2025516358000056.tif13128) (for example, in the case of monocyclic, bicyclic, or tricyclic, each having carbon atoms and 1 to 3, 1 to 6, or 1 to 9 heteroatoms of N, O, S, or P, respectively), where 0, 1, 2, or 3 atoms of each ring may be substituted by substituents. The term "saturated" as used in this context means only single bonds existing between the constituent ring atoms and other available valences occupied by hydrogen and / or other substituents defined herein. Examples of saturated heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. A partially unsaturated heterocyclyl group may have any degree of unsaturation, provided that there is one or more double bonds in the heterocyclyl and none of the rings in the ring system is aromatic and the partially unsaturated heterocyclyl group is not completely saturated overall. Examples of partially unsaturated heterocyclyl groups include, but are not limited to, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl.Non-limiting examples of the condensed / bridged heterocyclyl include 2-azabicyclo[1.1.0]butyl, 2-azabicyclo[2.1.0]pentyl, 2-azabicyclo[1.1.1]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-oxabicyclo[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, etc. Non-limiting examples of the spirocyclic heterocyclyl 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, 1,7-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, 1-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, 1-oxaspiro[5.5]undecyl, 3-oxaspiro[5.5]undecyl, 3-oxa-9-azaspiro[5.5]undecyl, etc.

[0118] As used herein, when a ring is described as "partially unsaturated", it means that the ring has one or more additional degrees of unsaturation (in addition to the degrees of unsaturation attributable to the ring itself, for example, one or more double or triple bonds between the 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.

[0119] To avoid ambiguity, unless otherwise specified, for rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, cycloalkyl, etc. described herein) containing a sufficient number of ring atoms to form a bicyclic or higher order ring system (e.g., tricyclic, polycyclic ring system), such rings and cyclic groups have a condensation point that is (i) on adjacent ring atoms (e.g., [x.x.0] ring system, where 0 represents a 0-atom bridge (e.g., TIFF2025516358000057.tif13128)), (ii) a single ring atom (spiro-fused ring system) (e.g., TIFF2025516358000058.tif19128), or (iii) an array of contiguous ring atoms (bridged ring system with all bridge lengths > 0) (e.g., TIFF2025516358000059.tif14128), and is understood to include those having fused rings.

[0120] In addition, the atoms constituting the compounds of this embodiment are intended to include all isotopic forms of such atoms. Isotopes as used herein include atoms having the same atomic number but different mass numbers. General examples, but not limited to, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 13 C and 14 C.

[0121] In addition, compounds generally or specifically disclosed herein are intended to include all tautomeric forms. Thus, by way of example, a compound containing part: TIFF2025516358000060.tif16128 includes the tautomeric forms containing part: TIFF2025516358000061.tif18128. Similarly, a pyridinyl or pyrimidinyl moiety described as optionally substituted with a hydroxyl group includes pyridone or pyrimidone tautomeric forms.

[0122] The compounds provided herein may include various stereochemical forms. The compounds also include diastereomers and optical isomers, such as mixtures of enantiomers including racemic mixtures, as well as individual enantiomers and diastereomers resulting from structural asymmetry in certain compounds. Unless otherwise indicated, when a disclosed compound is named or depicted by structure without specifying stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound.

[0123] Therapeutic methods Indications As used herein, BCL-X L Methods for inducing the degradation of the protein are provided. For example, as used herein, compounds capable of inducing the degradation of BCL-X L protein useful for treating or preventing cancer are provided. See, for example, Guo, et al. Aging (Albany NY) 13.15 (2021): 19750, Park, et al. Proceedings of the National Academy of Sciences 112.40 (2015): 12492-12497, Zhang, et al. Molecular Cancer 14.1 (2015): 1-9, Beroukhim, et al. Nature 463.7283 (2010): 899-905. BCL-X L Binding of the compound to the protein or BCL-X LAdditional methods for assessing protein inhibition are described, for example, in US Patent Application Publication Nos. 2007 / 027135, 2010 / 305122, and 2013 / 096120.

[0124] The effect of proteolysis typically increases over time, but the appearance of proteolysis (e.g., percentage of proteolysis compared to a control, or parameter Y min , DC 50 , and / or D max represented by) will be understood to be affected by the rate of protein resynthesis. In the art, it is common to examine proteolysis after a specific period such as 6 hours, 12 hours, 18 hours, 1 day, 2 days, 3 days, or more. For example, proteolysis can be expressed as the percentage of proteolysis after 24 hours.

[0125] Exemplary assays for verifying the proteolysis-inducing mechanism of the compounds provided herein are known in the art and are described, for example, in International Publication No. 2019 / 144117 and Wu, et al. Nature Structural & Molecular Biology 27.7 (2020): 605-614.

[0126] The proteolysis assay can be used to quantify both the on-target proteolysis-inducing effect and the off-target proteolysis-inducing effect of compounds such as those provided herein. Exemplary assays include quantitative immunoblotting, other immunoassays (e.g., MesoScale Discovery (MSD) immunoassay), homogeneous time-resolved fluorescence (HTRF), and HiBiT. In some embodiments, cells are contacted with a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, incubated, and then the lysate is prepared for gel electrophoresis (e.g., SDS-PAGE), followed by immunoblotting and quantification and comparison to a control (e.g., DMSO-treated control). As another example, a cell line is transfected with HiBiT-tagged BCL-X LIt can be manipulated to express a protein, and the amount of fluorescence observed when adding a complementary LgBiT peptide can be compared between cells treated with a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, and a control (e.g., a DMSO-treated control). See, for example, Example B1 and Example B2. Also see, for example, International Publication No. 2020 / 163823 and International Publication No. 2019 / 144117. In some embodiments, the off-target cleavage induction effect can be evaluated for the protein eukaryotic peptide chain release factor GTP-binding subunit ERF3A (GSPT1), Ikaros (IKZF1), Helios (IKZF2), Aiolos (IKZF3), and / or casein kinase I isoform alpha (CK1α).

[0127] Also see the assays described in International Publication No. 2023 / 044046, International Publication No. 2022 / 169780, International Publication No. 2021 / 222114, International Publication No. 2021 / 146536, International Publication No. 2021 / 078301, International Publication No. 2021 / 007307, International Publication No. 2020 / 163823, International Publication No. 2019 / 144117, International Publication No. 2017 / 184995, and Khan, et al. Nature Medicine 25.12 (2019): 1938-1947, Balachander, et al. Clinical Cancer Research 26.24 (2020): 6535-6549.

[0128] The binding affinity of the compounds of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)) provided herein, or their pharmaceutically acceptable salts, for BCL-X L can be, for example, the binding IC 50 or K i value (e.g., using a competition assay), or K Dcan be determined by a value (e.g., using a biophysical assay). When determined under substantially the same conditions, a compound having a lower binding IC 50 value is a more potent binder compared to a compound having a higher binding IC 50 value. When determined under substantially the same conditions, a compound having a lower binding K i value is a more potent binder compared to a compound having a higher binding K i value. Similarly, when determined under substantially the same conditions, a compound having a lower K D value is a more potent binder compared to a compound having a higher K D value. For example, the binding IC 50 value can be determined in a fluorescence polarization assay using a BH3-only peptide (e.g., BAD or BAX) labeled with a fluorescent label as a competitor. As another example, the binding K i 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-X L , where the fluorophores are a FRET pair, and a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)) provided herein, or a pharmaceutically acceptable salt thereof is used as a competitor for the BH3-only peptide. See, for example, U.S. Patent Application Publication Nos. 2007 / 0027135, 2010 / 305122, and 2013 / 096120.

[0129] The ability of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)) provided herein, or a pharmaceutically acceptable salt thereof to inhibit BCL-X L can be determined using the IC 50 value. When determined under substantially the same conditions, a compound having a lower IC 50 value is a more potent inhibitor compared to a compound having a higher IC 50It is a more potent inhibitor compared to compounds having the value. BCL-X L One method that can measure the inhibition of BCL-X L is to measure the interference with the formation of a complex of BCL-X with a BH3-only peptide (e.g., BIM). For example, an electrochemiluminescence-based sandwich ELISA assay (e.g., 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, and Xiao, Yu, et al. Molecular Cancer Therapeutics 14.8 (2015): 1837-1847. In such an assay, cells expressing BCL-X L can be incubated with a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)) for a period of time, lysed, and then evaluated in the assay. A tagged anti-BCL-X L antibody (e.g., a biotin-tagged anti-BCL-X L antibody) can be immobilized on an assay plate (e.g., a streptavidin assay plate), and then the lysate can be applied to pull out BCL-X L An anti-BIM antibody (e.g., a rabbit anti-BIM antibody) can be introduced, followed by adding a detection antibody (e.g., a sulfo-tagged goat anti-rabbit antibody), and the detection antibody can be measured. As another example, the interference with the formation of a complex of BCL-X with a BH3-only peptide (e.g., BIM) can be measured using a mammalian two-hybrid assay. In such an assay, "bait" and "prey" fusion proteins (e.g., BCL-X L can be used. In such an assay, "bait" and "prey" fusion proteins (e.g., BCL-X LA plasmid encoding the DNA binding domain of GAL4 fused thereto and the transcriptional activation domain of VP16 fused to BIM can be introduced into cells (e.g., HeLa cells) that stably express the GAL4-luciferase reporter. A compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)) can be added to the cells in culture and incubated, and luciferase activity can be measured. See, for example, Souers, Andrew J., et al. Nature Medicine 19.2 (2013): 202-208.

[0130] The efficacy of degradation by a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)) provided herein, or a pharmaceutically acceptable salt thereof, can be determined by the DC 50 value. As used herein, DC 50 refers to the concentration of a protein in a cell compared to the concentration of the protein before the cell is contacted with a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or compared to the concentration of the protein in a cell that has not been contacted with a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), which results in a 50% decrease in the concentration of the protein (e.g., BCL-X L protein) in the cell. When determined under substantially the same conditions, a compound having a lower DC 50 value is a more efficient inducer of degradation compared to a compound having a higher DC 50 value. In some embodiments, the DC 50 value can be determined in vitro or in vivo (e.g., in tumor cells expressing the BCL-X L protein, such as cell lines such as MOLT4, RS4;11, NCI-H146, EJM, HEK293T, HT1080, and / or H929) (e.g., using HiBiT detection).

[0131] The potency of degradation by the compounds of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)) provided herein, or their pharmaceutically acceptable salts, can be determined by the EC 50 value. As used herein, EC 50 refers to the concentration of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)) that results in a 50% decrease in the concentration of a protein (e.g., BCL-X L 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 of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or when compared to the concentration of the protein in a cell that has not been contacted with the compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)). Compounds having a lower EC 50 value are more potent compounds compared to compounds having a higher EC 50 value when determined under substantially the same conditions. In some embodiments, the EC 50 value can be determined in vitro or in vivo (e.g., in tumor cells expressing the BCL-X L protein, such as cell lines like MOLT4, RS4;11, NCI-H146, EJM, HEK293T, HT1080, and / or H929) (e.g., using HiBiT detection).

[0132] The potency of degradation by the compounds of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)) provided herein, or their pharmaceutically acceptable salts, can be determined by the Y min value. As used herein, Y minrefers to the ratio of the trough concentration of a protein (e.g., BCL-X L protein) in a cell, expressed as a percentage, compared to the concentration of the protein before the cell is contacted with a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or compared to the concentration of the protein in a cell not contacted with a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)). As used herein, D max is 1 - Y min . Y min can be measured by a HiBiT assay as described in Example B1. When determined under substantially the same conditions, a compound having a lower Y min value is a more potent inducer of degradation compared to a compound having a higher Y min value. When determined under substantially the same conditions, a compound having a lower Y min value is a more potent compound compared to a compound having a higher Y min value. In some embodiments, the Y min value can be determined in vitro or in vivo (e.g., using HiBiT detection) in (e.g., tumor cells expressing the BCL-X L protein, such as cell lines like MOLT4, RS4;11, NCI-H146, EJM, HEK293T, HT1080, and / or H929).

[0133] Exemplary assays for determining the potency of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, include measuring the effect of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, on cell proliferation and / or viability. Cell proliferation assays can be performed in several formats including 2D and 3D. Similarly, cell proliferation assays can be performed using any suitable cell line including, for example, MOLT4, RS4;11, NCI-H146, EJM, HEK293T, HT1080, and / or H929. As an exemplary example, a 3D cell proliferation assay can include growing cells in 3D media, contacting the cells with a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, measuring cell proliferation using a suitable reagent (e.g., CELLTITERGLO® 3D), and then comparing the signal from the experiment with a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, to the signal from a control experiment (e.g., lacking a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof)).As another exemplary example, a 2D cell proliferation assay can include plating cells on a growth surface, optionally growing the cells for a period of time, contacting the cells with a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, measuring cell proliferation using an appropriate reagent (e.g., CELLTITERGLO®), and then comparing the signal from an experiment with a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, to the signal from a control experiment (e.g., lacking a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof)). Additional cell viability assays include the MTT assay, a colorimetric assay based on the reduction of the tetrazolium dye MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) to insoluble purple formazan, and other similar assays based on related tetrazolium salts. See, for example, Examples B3 and B4.

[0134] A cell viability assay can be used to measure the effect of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, on cell death. For example, cells expressing the BCL-X L protein (e.g., MOLT-4 cells) can be incubated with various concentrations of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, and then exposed to a detection reagent (e.g., CELLTITER-GLO® Cell Viability Assay kit) to determine cell viability. An exemplary assay for evaluating the affinity of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, is a recombinant BCL-X LIncluding using a competitive assay with a protein. For example, purified recombinant affinity-tagged (e.g., His-tagged) BCL-X L The protein can be incubated with compounds of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)) at various concentrations, or pharmaceutically acceptable salts thereof, and a fixed concentration of affinity-tagged (e.g., biotin-tagged) BAD protein. After a certain period of incubation, FRET acceptor beads with complementary affinity tags (e.g., His-acceptor beads) and FRET donor beads (e.g., streptavidin-tagged donor beads) can be added to the mixture, and the FRET reaction can be used to determine the inhibition constant of the compounds of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or pharmaceutically acceptable salts thereof. For example, an AlphaLISA competitive assay can be performed. See, for example, International Publication No. WO 2019 / 144117.

[0135] An exemplary assay for determining the mechanism of cell death using a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, includes measuring the effect of the compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, on one or more markers of the 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 can also be used as a determinant of cell viability. For example, BCL-X LCells expressing the protein (e.g., MOLT-4 cells) are incubated with compounds of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)) at various concentrations, or their pharmaceutically acceptable salts, and the relative caspase activity can be evaluated using a luciferase substrate activated by caspase 3 / 7 (e.g., using the CASPASE-GLO® 3 / 7 assay). As another example, BCL-X L Cells expressing the protein (e.g., MOLT-4 cells) are incubated with compounds of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)) at various concentrations, or their pharmaceutically acceptable salts, and the relative caspase activity is evaluated using a dye coupled to an activated caspase motif (e.g., the INCUCYTE® Caspase 3 / 7 Green Apoptosis Assay Reagent), followed by analysis using a live-cell imaging platform (e.g., the INCUCYTE® SX5 Live-Cell Analysis Instrument). As another example, BCL-X L Cells expressing the protein (e.g., MOLT-4 cells) are incubated with compounds of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)) at various concentrations, or their pharmaceutically acceptable salts, and annexin V positivity is evaluated using a phosphatidylserine dye (e.g., the INCUCYTE® Annexin V dye), followed by analysis using a live-cell imaging platform (e.g., the INCUCYTE® SX5 Live-Cell Analysis Instrument). See, for example, Example B5.

[0136] As another example, the efficacy and / or effectiveness of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, can be evaluated in an animal model, e.g., a xenograft model (e.g., using established cancer cell lines such as MOLT4, HEL, TF1, F36P, OCI-M1, OCI-M2, SET-2, CMK, M07E, or UKE-1, or a patient-derived xenograft (PDX) model). For example, a PDX model can be performed in immunodeficient mice (e.g., athymic, outbred homozygous (e.g., Crl:NU(NCr)-Foxn1 nu ), or Fox Chase SCID (CB17 / Icr-Prkdc scid / IcrIcoCrl), mice). The mice can be female and 6 - 12 weeks old at the time of tumor implantation and can have free access to food and water. Approximately 70 mg of tumor can be implanted subcutaneously in the right flank of each mouse. After implantation, the tumors can be measured weekly, and when the tumor volume reaches 150 - 300 mm 3 , 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 of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), 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, the health status, body weight, and tumor volume of the mice can be recorded weekly. On day 28, or when the tumor reaches 1 cm 3 , the mice can be sacrificed 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. The best response is Δ volume for t ≥ 10 days tis defined as the minimum value. By comparing the best responses between the control arm and the treatment arm, it can be determined whether the treatment functions better than the control. In some embodiments, the tumor samples can also be collected at the end of each study, and the relevant proteins (e.g., BCL-X L , BCL-2, MCL-1, BIM, BAX, and / or BAK) can be measured to determine whether the treatment may have a better protein regulation profile compared to the control. In some embodiments, the tumor samples can also be collected at the end of each study and analyzed for signal transduction pathway activity (e.g., via phospho-ERK levels). For pharmacokinetic and pharmacodynamic studies, tumor and / or blood samples from the mice can be obtained at the same or different time points as the efficacy study. For example, for pharmacokinetic and pharmacodynamic studies, tumor and / or blood samples from the mice can be obtained at 6 hours on day 5 after dosing, the relevant proteins can be measured in the tumor samples, and the pharmacokinetic study can be performed on the blood samples or a portion thereof (e.g., plasma).

[0137] In some embodiments, the PDX is a myeloproliferative neoplasm (MPN) (e.g., CEL, CML, CNL, essential thrombocythemia (e.g., JAK2 variant (e.g., JAK2 V617F variant) essential thrombocythemia or JAK2 wild-type essential thrombocythemia), polycythemia vera (e.g., JAK2 variant (e.g., JAK2 V617F variant) polycythemia vera or JAK2 wild-type polycythemia vera), or myelofibrosis (e.g., primary myelofibrosis (e.g., JAK2 variant (e.g., JAK2 V617F variant) primary myelofibrosis or JAK2 wild-type primary myelofibrosis), post-essential thrombocythemia myelofibrosis (e.g., JAK2 variant (e.g., JAK2 V617F variant) post-essential thrombocythemia myelofibrosis or JAK2 wild-type post-essential thrombocythemia myelofibrosis), or post-polycythemia vera myelofibrosis (e.g., JAK2 variant (e.g., JAK2 V617F variant) post-polycythemia vera myelofibrosis or JAK2 wild-type post-polycythemia vera myelofibrosis))), CRC (e.g., BRaf variant CRC (e.g., Braf V600E CRC) or KRas variant CRC (e.g., KRas G12C variant CRC or KRas G12D CRC)), SCLC (e.g., ASCL1 subtype SCLC or NEUROD1 subtype SCLC), NSCLC (e.g., BRaf variant NSCLC (e.g., Braf V600E NSCLC), EGFR variant NSCLC (e.g., EGFR L858R NSCLC or EGFR exon 19 deletion NSCLC), MET variant NSCLC (e.g., MET exon 14 deletion NSCLC, MET amplification NSCLC), KRas variant NSCLC (e.g., KRas G12C NSCLC)), squamous cell lung cancer, malignant pleural mesothelioma (e.g., BAP1 variant malignant pleural mesothelioma), melanoma (e.g., Braf variant melanoma (e.g., BrafIt is a model for V600E melanoma, 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), lymphoma (e.g., T-cell lymphoma (e.g., anaplastic large T-cell lymphoma, cutaneous T-cell lymphoma, or peripheral T-cell lymphoma), or non-Hodgkin lymphoma (e.g., DLBCL, anaplastic large T-cell lymphoma, cutaneous T-cell lymphoma, or peripheral T-cell lymphoma)), leukemia (e.g., T-cell leukemia (e.g., T-ALL (e.g., relapsed / refractory T-ALL)), post-MPN leukemia, M6-AML, M7-AML), head and neck cancer, pancreatic cancer, bladder cancer, ovarian cancer (e.g., BRCA1-mutant ovarian cancer or BRCA2-mutant ovarian cancer, HGSOC (e.g., BRCA1-mutant HGSOC or BRCA2-mutant HGSOC)), cervical cancer, intrahepatic cholangiocarcinoma, or mesenchymal cancer (e.g., mesenchymal breast cancer or mesenchymal kidney cancer).

[0138] See, for example, Khan, et al. Nature Medicine 25.12 (2019): 1938-1947, Balachander, et al. Clinical Cancer Research 26.24 (2020): 6535-6549.

[0139] The pharmacokinetic parameters of the compounds of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or their pharmaceutically acceptable salts, can be evaluated in animal models, such as mouse models, rat models, dog models, or non-human primate (e.g., cynomolgus monkey) models. Exemplary assays include the following. For example, pharmacokinetic (PK) studies can be performed on animals (e.g., male or female CD-1 mice, Sprague Dawley rats, beagle dogs, or cynomolgus monkeys) by two delivery routes: intravenous (IV) injection and forced oral administration (PO). Animals in both the IV group and the PO group (e.g., n = 3) are allowed free access to food and water. The compounds of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or their pharmaceutically acceptable salts, can be formulated into a solution for the IV route and a solution or suspension for the PO route. On the day of the experiment, the compounds of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or their pharmaceutically acceptable salts, can be administered via the IV route by intravenous injection (e.g., at 1 mg / kg) or via the PO route by forced oral administration (e.g., at 5 - 10 mg / kg). Optionally, the animals can be pre-dosed orally with a cytochrome P450 inhibitor (e.g., 1-aminobenzotriazole) (e.g., 16 hours prior) before dosing with the compounds of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or their pharmaceutically acceptable salts. Blood samples can be collected via serial bleeding (e.g., at eight time points from 0.83 to 24 hours after dosing). At each time point, blood is taken via a vein (e.g., the saphenous vein) K 2It can be collected in an EDTA tube (e.g., approximately 30 μL of blood / sampling point). The blood sample can be placed on wet ice and centrifuged (e.g., at 4600 RPM for 4 minutes) to obtain a plasma sample. The plasma sample can be diluted (e.g., with an equal volume of pH 3.0 phosphate buffer) and subjected to LC-MS / MS for sample analysis. Pharmacokinetic parameters including clearance (IV or PO depending on the dosing regimen), area under the curve (AUC), and oral bioavailability (%F) can be calculated using a non-compartmental model.

[0140] In some embodiments, %F for a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, is at least 4%. In some embodiments, %F for a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, is at least 10%. In some embodiments, %F for a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, is at least 20%. In some embodiments, %F for a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, is at least 30%. In some embodiments, %F for a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, is at least 40%. In some embodiments, %F for a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, is from about 4% to about 80% (e.g., from about 4% to about 60%, from about 4% to about 40%, from about 4% to about 20%, from about 4% to about 10%, from about 20% to about 40%, or from about 20% to about 30%). In some embodiments, %F for a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, is from about 4% to about 20%. In some embodiments, %F for a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, is from about 20% to about 40%. In some embodiments, %F for a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, is from about 40% to about 60%.In some embodiments, %F for a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, is from about 60% to about 80%.

[0141] In some embodiments, the clearance for a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), 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, the clearance for a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, dosed PO in rats at 10 mg / kg is from about 0.05 mL / min / kg to about 5 mL / min / kg (e.g., from about 0.05 mL / min / kg to about 3 mL / min / kg, from about 0.05 mL / min / kg to about 1 mL / min / kg, or from about 0.05 mL / min / kg to about 0.5 mL / min / kg).

[0142] In some embodiments, the AUC for a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, dosed PO in rats at 10 mg / kg is from about 10 μM·h to about 150 μM·h (e.g., from about 10 μM·h to about 100 μM·h, from about 10 μM·h to about 50 μM·h, or from about 30 μM·h to about 80 μM·h).

[0143] 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 thought to be due to the E3 ligase moiety of the heterobifunctional degrader that facilitates the formation of a ternary complex between the off-target protein and CRBN. GSPT1 is a translation termination factor and CK1α is a kinase involved in many important cellular processes including cell cycle progression and chromosome segregation, and since both are generally essential genes, unwanted degradation of either or both can lead to non-specific cytotoxicity. The IKZF proteins are zinc finger transcription factors involved in cell fate during hematopoiesis, and the degradation of these proteins has been associated with hematotoxicity. See, for example, Moreau, Kevin, et al. British Journal of Pharmacology 177.8 (2020): 1709-1718.

[0144] In some embodiments, a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, is BCL-X L able to show potent induction and selective induction of protein degradation. In some embodiments, a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, is more selective for BCL-X L protein for degradation than an off-target protein, e.g., another BCL-2 family member (e.g., BCL-2 and / or MCL-1), or a non-BCL-2 family member target (e.g., GSPT1, IKZF1, IKZF2, IKZF3, and / or CK1α).

[0145] As used herein, "selective" or "selectively" when referring to a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)) in a proteolysis assay, or a pharmaceutically acceptable salt thereof, exhibits performance that is at least 5-fold (e.g., at least 10-fold, at least 25-fold, at least 50-fold, or at least 100-fold) superior in a proteolysis assay for a particular protein, with reference to a comparator protein in the assay. In some embodiments, the particular protein is BCL-X L protein, and the comparator is BCL-2 protein. For example, a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, when determined by a proteolysis assay, "selectively" induces the proteolysis of BCL-X L protein, the compound has a DC L value that is at least 5-fold (e.g., at least 10-fold, at least 25-fold, at least 50-fold, or at least 100-fold) smaller for BCL-X 50 protein than for BCL-2 protein, as measured by the proteolysis assay.

[0146] In some embodiments, the compounds provided herein have minimal activity (e.g., micromolar potency) against BCL-2 family members (e.g., BCL-2 or MCL-1 protein) and can exhibit potency (e.g., nanomolar potency) against BCL-X L protein. In some embodiments, a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, can exhibit potent proteolysis of BCL-X L protein and have minimal potency in the proteolysis of off-target proteins (e.g., BCL-2 family members (e.g., BCL-2 and / or MCL-1), GSPT1, IKZF1, IKZF2, IKZF3, and / or CK1α) (e.g., Y min 、DC 50, and / or D max (when measured by the value). In some embodiments, a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, is 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) induction of degradation (e.g., Y min , DC 50 , and / or D max value), as compared to, can show a greater induction of degradation of BCL-X L protein. In some embodiments, a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, is at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold greater in the induction of degradation of BCL-X L protein as compared to the induction of degradation of an off-target protein. In some embodiments, a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, is up to 1000-fold greater in the induction of degradation of BCL-X L protein as compared to the induction of degradation of an off-target protein. In some embodiments, a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, is about 2-fold to about 10-fold greater in the induction of degradation of BCL-X L protein as compared to the induction of degradation of an off-target protein (e.g., GSPT1, IKZF1, IKZF2, and / or IKZF3, and / or CK1α) (e.g., Y min , DC 50 , and / or D maxwhen measured by value). In some embodiments, a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, has a BCL-X that is about 10-fold to about 100-fold greater compared to induction of off-target protein degradation L can show induction of protein degradation. In some embodiments, a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, has a BCL-X that is about 100-fold to about 1000-fold greater compared to induction of off-target protein degradation L can show induction of protein degradation. In some embodiments, a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, has a BCL-X that is about 1000-fold to about 10000-fold greater compared to induction of off-target protein degradation L can show induction of protein degradation.

[0147] BCL-X L Certain agents that inhibit or induce the degradation of BCL-X have demonstrated thrombocytotoxicity, which has led to dose-limiting toxicity (e.g., thrombocytopenia) in the clinic. See, for example, Adams and Cory, Cell Death & Differentiation 25.1 (2018):27-36, Campbell and Tait. Open Biology 8.5 (2018):180002, Pullarkat et al., Cancer Discovery (2021) 10.1158 / 2159-8290.CD-20-1465, Negi and Voisin-Chiret. ChemBioChem (2022) (doi:10.1002 / cbic.202100689). Platelet viability can be monitored using any suitable assay such as those described herein. See, for example, Example B6.

[0148] In some embodiments, a therapeutically effective amount of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, when administered to a subject, exhibits at least about 30% platelet survival rate (e.g., at least about 50% platelet survival rate, or at least about 80% platelet survival rate). In some embodiments, a therapeutically effective amount of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, when administered to a subject, exhibits from about 30% to about 100% platelet survival rate (e.g., from about 50% to about 100% platelet survival rate, or from about 80% to about 100% platelet survival rate).

[0149] In some embodiments, a therapeutically effective amount of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, when administered to a subject, exhibits at least about 30% platelet survival rate (e.g., at least about 50% platelet survival rate, or at least about 80% platelet survival rate) and has a Y value of from about 50% to about 70%. min In some embodiments, a therapeutically effective amount of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, when administered to a subject, exhibits at least about 30% platelet survival rate (e.g., at least about 50% platelet survival rate, or at least about 80% platelet survival rate) and has a Y value of less than about 50%. min In some embodiments, a therapeutically effective amount of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, when administered to a subject, exhibits at least about 30% platelet survival rate (e.g., at least about 50% platelet survival rate, or at least about 80% platelet survival rate) and has a Y value of from about 0% to about 50%. min value.

[0150] In some embodiments, a therapeutically effective amount of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, when administered to a subject, exhibits a platelet survival rate of about 30% to 100% (e.g., a platelet survival rate of about 50% to about 100%, or a platelet survival rate of about 80% to about 100%), and has a Y value of about 50% to about 70%. min In some embodiments, a therapeutically effective amount of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, when administered to a subject, exhibits a platelet survival rate of about 30% to 100% (e.g., a platelet survival rate of about 50% to about 100%, or a platelet survival rate of about 80% to about 100%), and has a Y value of less than about 50%. min In some embodiments, a therapeutically effective amount of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, when administered to a subject, exhibits a platelet survival rate of about 30% to 100% (e.g., a platelet survival rate of about 50% to about 100%, or a platelet survival rate of about 80% to about 100%), and has a Y value of about 0% to about 50%. min value.

[0151] In some embodiments, a therapeutically effective amount of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, when administered to a subject, exhibits a platelet survival rate of at least about 50% (e.g., at least about 80% platelet survival rate), and has a Y value of about 50% to about 70%. min In some embodiments, a therapeutically effective amount of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, when administered to a subject, exhibits a platelet survival rate of at least about 50% (e.g., at least about 80% platelet survival rate), and has a Y value of less than about 50%. minhas a value. In some embodiments, a therapeutically effective amount of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, when administered to a subject, exhibits at least about 50% platelet survival rate (e.g., at least about 80% platelet survival rate) and a Y of about 0% to about 50% min has a value.

[0152] In some embodiments, a therapeutically effective amount of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, when administered to a subject, exhibits a platelet survival rate of about 50% to 100% (e.g., about 80% to about 100%) and a Y of about 50% to about 70% min has a value. In some embodiments, a therapeutically effective amount of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, when administered to a subject, exhibits a platelet survival rate of about 50% to 100% (e.g., about 80% to about 100%) and a Y of less than about 50% min has a value. In some embodiments, a therapeutically effective amount of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, when administered to a subject, exhibits a platelet survival rate of about 50% to 100% (e.g., about 80% to about 100%) and a Y of about 0% to about 50% min has a value.

[0153] In some embodiments, when a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, is tested at a concentration of about 0.25 μM to about 3 μM in the assay of Example B6, it exhibits at least about 30% platelet viability (e.g., at least about 50% platelet viability, or at least about 80% platelet viability). In some embodiments, when a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, is tested at a concentration of about 0.25 μM to about 3 μM in the assay of Example B6, it exhibits about 30% to about 100% platelet viability (e.g., about 50% to about 100% platelet viability, or about 80% to about 100% platelet viability).

[0154] In some embodiments, when a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, is tested at a concentration of about 0.25 μM to about 3 μM in the assay of Example B6, it exhibits at least about 30% platelet viability (e.g., at least about 50% platelet viability, or at least about 80% platelet viability), and has a Y value of about 50% to about 70% in the assay described in Example B1. min In some embodiments, when a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, is tested at a concentration of about 0.25 μM to about 3 μM in the assay of Example B6, it exhibits at least about 30% platelet viability (e.g., at least about 50% platelet viability, or at least about 80% platelet viability), and has a Y value of less than about 50% in the assay described in Example B1. minhas a value. In some embodiments, a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, when tested at a concentration of about 0.25 μM to about 3 μM in the assay of Example B6, exhibits at least about 30% platelet viability (e.g., at least about 50% platelet viability, or at least about 80% platelet viability), and about 0% to about 50% Y in the assay described in Example B1 min has a value.

[0155] In some embodiments, a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, when tested at a concentration of about 0.25 μM to about 3 μM in the assay of Example B6, exhibits about 30% to 100% platelet viability (e.g., about 50% to about 100% platelet viability, or about 80% to about 100% platelet viability), and about 50% to about 70% Y in the assay described in Example B1 min has a value. In some embodiments, a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, when tested at a concentration of about 0.25 μM to about 3 μM in the assay of Example B6, exhibits about 30% to 100% platelet viability (e.g., about 50% to about 100% platelet viability, or about 80% to about 100% platelet viability), and less than about 50% Y in the assay described in Example B1 min has a value. In some embodiments, a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, when tested at a concentration of about 0.25 μM to about 3 μM in the assay of Example B6, exhibits about 30% to 100% platelet viability (e.g., about 50% to about 100% platelet viability, or about 80% to about 100% platelet viability), and about 0% to about 50% Y in the assay described in Example B1 min has a value.

[0156] In some embodiments, the compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, when tested at a concentration of about 0.25 μM to about 3 μM in the assay of Example B6, exhibits at least about 50% platelet viability (e.g., at least about 80% platelet viability), and has a Y value of about 50% to about 70% in the assay described in Example B1. min In some embodiments, the compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, when tested at a concentration of about 0.25 μM to about 3 μM in the assay of Example B6, exhibits at least about 50% platelet viability (e.g., at least about 80% platelet viability), and has a Y value of less than about 50% in the assay described in Example B1. min In some embodiments, the compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, when tested at a concentration of about 0.25 μM to about 3 μM in the assay of Example B6, exhibits at least about 50% platelet viability (e.g., at least about 80% platelet viability), and has a Y value of about 0% to about 50% in the assay described in Example B1. min In some embodiments, the compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, when tested at a concentration of about 0.25 μM to about 3 μM in the assay of Example B6, exhibits about 50% to 100% platelet viability (e.g., about 80% to about 100% platelet viability), and has a Y value of about 50% to about 70% in the assay described in Example B1.

[0157] In some embodiments, the compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, when tested at a concentration of about 0.25 μM to about 3 μM in the assay of Example B6, exhibits about 50% to 100% platelet viability (e.g., about 80% to about 100% platelet viability), and has a Y value of about 50% to about 70% in the assay described in Example B1. minhas a value. In some embodiments, a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, when tested at a concentration of about 0.25 μM to about 3 μM in the assay of Example B6, exhibits a platelet survival rate of about 50% to 100% (e.g., a platelet survival rate of about 80% to about 100%), and a Y of less than about 50% in the assay described in Example B1 min has a value. In some embodiments, a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, when tested at a concentration of about 0.25 μM to about 3 μM in the assay of Example B6, exhibits a platelet survival rate of about 50% to 100% (e.g., a platelet survival rate of about 80% to about 100%), and a Y of about 0% to about 50% in the assay described in Example B1 min has a value.

[0158] Also provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the subject is treatment-naive with respect to cancer. In some embodiments, the subject has received one or more lines of prior therapy for cancer.

[0159] Also provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as monotherapy. In some embodiments, the subject is treatment-naive with respect to cancer. In some embodiments, the subject has received one or more lines of prior therapy for cancer.

[0160] A method for treating cancer in a subject in need thereof, the method comprising: (a) detecting a biomarker associated with cancer (e.g., a mutation, amplification, copy number increase, and / or expression of a biomarker (optionally including expression level)), (b) administering to the subject a therapeutically effective amount of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as monotherapy or in combination with an additional therapy or therapeutic agent, is provided.

[0161] Also provided is a method for treating cancer in a subject, wherein the subject has been determined to have a biomarker associated with cancer (e.g., a mutation, amplification, copy number increase, and / or expression of a biomarker (optionally including expression level)) (e.g., prior to administration of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C))), and the method comprises administering to the subject a therapeutically effective amount of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as monotherapy or in combination with an additional therapy or therapeutic agent.

[0162] A method for treating cancer in a subject in need thereof, the method comprising: (a) detecting a biomarker associated with cancer (e.g., a mutation, amplification, copy number increase, and / or expression of a biomarker of sensitivity to a particular agent (optionally including expression level) (e.g., HER2 expression, ER expression, PR expression, folate receptor expression)), (b) administering to the subject a therapeutically effective amount of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as monotherapy or in combination with an additional therapy or therapeutic agent, A method is provided that includes

[0163] Also provided herein is a method of treating cancer in a subject, wherein the subject has been determined to have a biomarker associated with cancer (e.g., a mutation, amplification, copy number increase, and / or expression (optionally including expression level) of a marker of sensitivity to a particular agent (e.g., HER2 expression, ER expression, PR expression, folate receptor expression)) (e.g., prior to administration of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C))), and the method comprises administering to the subject a therapeutically effective amount of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as monotherapy or in combination with an additional therapy or therapeutic agent.

[0164] Also provided herein is the use of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment of cancer, such as any of the cancers provided herein.

[0165] Also provided herein is the use of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as a medicament for the treatment of cancer, such as any of the cancers provided herein.

[0166] Also provided herein is the use of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer, such as any of the cancers provided herein.

[0167] As used herein, provided are compounds of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for use as a medicament. Also provided herein are compounds of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for use as a medicament for the treatment of cancer, e.g., any of the cancers provided herein.

[0168] As used herein, provided are compounds of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for use in the treatment of cancer, e.g., any of the cancers provided herein.

[0169] As used herein, "monotherapy" means that when referring to a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, the compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof is the only therapeutic agent or therapy (e.g., anti-cancer agent or therapy) administered to a subject during a treatment cycle (e.g., an additional targeted chemotherapeutic agent, anti-cancer agent, chemotherapeutic agent, or checkpoint inhibitor is not administered to the subject during the treatment cycle). As will be understood by those skilled in the art, monotherapy does not exclude co-administration of a medicament for the treatment of side effects or general symptoms associated with cancer or treatment, such as pain, rash, edema, photosensitivity, itching, skin discoloration, hair fragility, hair loss, brittle nails, cracked nails, discolored nails, thickened cuticles, fatigue, weight loss, general malaise, shortness of breath, infection, anemia, or gastrointestinal symptoms including nausea, diarrhea, and loss of appetite.

[0170] As used herein, "the subject has previously received one or more therapeutic agents or therapies for cancer" means that the subject has previously been administered, during a previous treatment cycle, one or more therapeutic agents or therapies for cancer (e.g., anti-cancer agents or therapies) other than a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is intolerant to one or more therapeutic agents or therapies previously administered for cancer. In some embodiments, the subject did not respond to one or more therapeutic agents or therapies previously administered for cancer. In some embodiments, the subject did not respond adequately to one or more therapeutic agents or therapies previously administered for cancer. In some embodiments, the subject has discontinued responding to one or more therapeutic agents or therapies previously administered for cancer. In some embodiments, the lack of response, inadequate response, or interrupted response can be determined by objective criteria (e.g., by criteria such as tumor volume, or RECIST 1.1). In some embodiments, the lack of response, inadequate response, or interrupted response can be determined by the subject's physician.

[0171] As used herein, "the subject is treatment-naïve with respect to cancer" means that the subject has not previously been administered one or more therapeutic agents or therapies for cancer.

[0172] For any of the solid tumors described herein, the solid tumor can be a primary tumor or a metastatic (or secondary) tumor. As used herein, a "primary" tumor is a tumor located at the site where the tumor began to grow (i.e., where it originated). As used herein, a "metastatic" (or "secondary") tumor is a tumor that has spread from the original tumor site to another part of the body. In some embodiments, the metastatic or secondary tumor is the same type of cancer as the primary tumor. In some embodiments, the metastatic or secondary tumor is not genetically identical to the primary tumor.

[0173] In some embodiments of any of the methods or uses described herein, the cancer is breast cancer (e.g., invasive breast cancer, invasive ductal carcinoma), central or peripheral nervous system tissue cancer (e.g., brain cancer (e.g., astrocytoma, glioblastoma, glioma, oligodendroglioma)), endocrine or neuroendocrine cancer (e.g., adrenal cancer (e.g., adrenocortical carcinoma, neuroblastoma, pheochromocytoma, paraganglioma), multiple endocrine neoplasia type I and type II tumors, parathyroid cancer, pituitary tumor, thyroid cancer (e.g., papillary thyroid carcinoma)), 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 cholangiocarcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma, pancreatic islet cell carcinoma), small intestine cancer, or stomach cancer (e.g., gastric adenocarcinoma, signet ring cell gastric cancer)), genitourinary cancer (e.g., bladder cancer (e.g., bladder urothelial carcinoma), kidney cancer (e.g., clear cell renal cell carcinoma, renal papillary cell carcinoma, kidney chromophobe), prostate cancer (e.g., prostatic adenocarcinoma), testicular cancer (e.g., testicular germ cell tumor), or ureteral cancer), gynecological cancer (e.g., cervical cancer (e.g., cervical squamous cell carcinoma, cervical endometrioid adenocarcinoma, mucinous carcinoma), ovarian cancer (e.g., serous ovarian cancer, ovarian serous cystadenocarcinoma), uterine cancer (e.g., uterine sarcoma, uterine endometrial adenocarcinoma, uterine serous carcinoma, uterine papillary serous carcinoma, uterine corpus endometrialcarcinoma), 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 cavity cancer, pharyngeal cancer (e.g., hypopharyngeal cancer, nasopharyngeal cancer, or oropharyngeal cancer), blood cancer (e.g., leukemia (e.g., chronic eosinophilic leukemia (CEL), chronic lymphocytic leukemia (CLL), chronic neutrophilic leukemia (CNL), acute lymphoblastic leukemia (ALL) (e.g., Philadelphia chromosome-positive ALL or T-cell ALL (T-ALL)), acute myeloid leukemia (AML) (e.g., acute promyelocytic leukemia (APL), MPN-post AML, myelodysplastic syndrome-post (MDS-post) 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 lymphocyte lymphoma (SLL), 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, essential thrombocythemia-post myelofibrosis, or polycythemia vera-post myelofibrosis), myelodysplastic syndrome (MDS) (e.g., M6 MDS or M7 MDS), or multiple myeloma), Li-Fraumeni tumor, mesentery cancer (e.g., omentum cancer, peritoneal cancer), pleural cancer, respiratory cancer (e.g., laryngeal 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 cancer), thymic cancer (e.g., thymoma), or combinations thereof.

[0174] In some embodiments, the cancer is breast cancer, gastrointestinal cancer (e.g., bile duct cancer (e.g., intrahepatic bile duct cancer), colorectal cancer (CRC), gastrointestinal stromal tumor, or pancreatic cancer), genitourinary cancer (e.g., bladder cancer (e.g., urothelial carcinoma of the bladder) or kidney cancer), gynecological 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), blood cancer (e.g., leukemia (e.g., acute lymphoblastic 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), 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 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), squamous cell carcinoma of the lung, 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).

[0175] 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, post-essential thrombocythemia myelofibrosis, or post-polycythemia vera myelofibrosis). In some embodiments, the MPN has a JAK2 mutation (e.g., 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) having a JAK2 mutation (e.g., JAK2 V617F mutation). In some embodiments, the cancer is intermediate or high-risk myelofibrosis (e.g., primary myelofibrosis, post-essential thrombocythemia myelofibrosis, or post-polycythemia vera myelofibrosis) without a JAK2 V617F mutation. In some embodiments, the subject has a platelet count of less than 50×10 9 / L.

[0176] In some embodiments, the cancer is polycythemia vera. In some embodiments, the cancer is polycythemia vera and the subject had an inadequate response to hydroxyurea or was intolerant to hydroxyurea.

[0177] In some embodiments, the cancer is MDS. In some embodiments, the cancer is M6 MDS. In some embodiments, the cancer is M7 MDS.

[0178] In some embodiments, the cancer is T-ALL. In some embodiments, the cancer is relapsed / refractory T-ALL.

[0179] 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)).

[0180] In some embodiments, the cancer is SCLC (e.g., ASCL1 subtype SCLC or NEUROD1 subtype SCLC).

[0181] 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)).

[0182] In some embodiments, the cancer is squamous cell lung cancer.

[0183] 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 the compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, is administered as a monotherapy.

[0184] In some embodiments, the cancer is melanoma (e.g., Braf mutant melanoma (e.g., Braf V600E melanoma)).

[0185] 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)).

[0186] 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 a peripheral T cell lymphoma.

[0187] 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 of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, is administered as a monotherapy.

[0188] In some embodiments, the cancer is M6-AML. In some embodiments, M6-AML is post-MPN AML. In some embodiments, M6-AML is post-myelodysplastic syndrome (MDS) AML. In some embodiments, the cancer is M6-AML, and a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, is administered as a monotherapy.

[0189] In some embodiments, the cancer is M7-AML. In some embodiments, M7-AML is AML following MPN. In some embodiments, M7-AML is AML following MDS. In some embodiments, the cancer is M7-AML, and a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, is administered as a monotherapy.

[0190] In some embodiments, the cancer is a head and neck cancer.

[0191] In some embodiments, the cancer is essential thrombocythemia.

[0192] In some embodiments, the cancer is polycythemia vera.

[0193] In some embodiments, the cancer is myelofibrosis. In some embodiments, the cancer is primary myelofibrosis. In some embodiments, the cancer is myelofibrosis following essential thrombocythemia. In some embodiments, the cancer is myelofibrosis following polycythemia vera.

[0194] In some embodiments, the cancer is MDS. In some embodiments, MDS is M6 MDS. In some embodiments, MDS is M7 MDS. In some embodiments, the cancer is MDS, and a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, is administered as a monotherapy.

[0195] In some embodiments, the cancer is pancreatic cancer.

[0196] In some embodiments, the cancer is bladder cancer (e.g., urothelial bladder cancer).

[0197] 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).

[0198] In some embodiments, the cancer is cervical cancer.

[0199] In some embodiments, the cancer is colorectal cancer.

[0200] 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 of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, is administered as monotherapy.

[0201] In some embodiments, the cancer is neuroblastoma.

[0202] In some embodiments, the cancer is intrahepatic cholangiocarcinoma.

[0203] In some embodiments, the cancer is a mesenchymal cancer. In some embodiments, the mesenchymal cancer is mesenchymal breast cancer or mesenchymal kidney cancer.

[0204] In some embodiments, BCL-X L copy number increase or BCL-X L amplification can be detected in a sample from the subject (e.g., detecting three or more copies of the BCL2L1 gene in a sample from the subject). In some embodiments, the subject has been determined to have a cancer with (e.g., prior to administration of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C))) BCL-X L copy number increase or BCL-X L amplification.

[0205] In some embodiments, the cancer has L an increased copy number.

[0206] In some embodiments, the cancer has L an amplification.

[0207] BCL-X in cancer LNon-limiting examples of involvement can be found in Wilson, Wyndham H., et al. The Lancet Oncology 11.12 (2010): 1149-1159, Keitel, Ulrike, et al. Oncotarget 5.23 (2014): 11778, Chonghaile, Triona Ni, et al. Cancer Discovery 4.9 (2014): 1074-1087, Zaanan, Aziz, et al. Journal of Biological Chemistry 290.39 (2015): 23838-23849, Zhang, Haichao, et al. Molecular Cancer 14.1 (2015): 1-9, Soderquist, Ryan S., et al. Nature Communications 9.1 (2018): 1-13, Stover, Elizabeth H., et al. Molecular Cancer Research 17.11 (2019): 2281-2293, Concoran, R.B., et al. Annals of Oncology (2019) 30 (suppl_5): v159-v193, Lakhani, Nehal J., et al. Journal of Clinical Oncology (2020): 3509-3509 doi:10.1200 / JCO.2020.38, He, Yonghan, et al. Journal of Hematology & Oncology 13.1 (2020): 1-13, 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, and Nanjo, Shigeki, et al. The Journal of Clinical Investigation (2022) doi:10.1172 / JCI145099.

[0208] In some embodiments, the subject has been previously treated with another anti-cancer agent, chemotherapeutic agent, radiation, surgery, multi-kinase inhibitor, or combinations thereof.

[0209] Disclosed herein is a method of treating an eye disease or condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof (intravitreally or topically). In some embodiments, the eye disease or condition is diabetic macular edema. In some embodiments, the eye disease or condition is age-related macular degeneration. In some embodiments, the eye disease or condition is diabetic retinopathy. See, e.g., Crespo-Garcia, Sergio, et al. Cell Metabolism 33.4 (2021): 818-832, Hassan, Jannah Waled, and Ashay D. Bhatwadekar, Frontiers in Pharmacology 13 (2022): 896907.

[0210] Disclosed herein is the use of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment of an eye disease or condition, such as any of the eye diseases or conditions provided herein.

[0211] Disclosed herein is the use of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as a medicament for the treatment of an eye disease or condition, such as any of the eye diseases or conditions provided herein.

[0212] In this specification, there is provided the use of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of an eye disease or condition, such as any of the eye diseases or conditions provided herein.

[0213] Also provided herein is a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use as a medicament for the treatment of an eye disease or condition, such as any of the eye diseases or conditions provided herein.

[0214] Further provided herein is a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment of an eye disease or condition, such as any of the eye diseases or conditions provided herein.

[0215] Also provided herein is a method of treating a subject in need of treatment for a fibrotic disease or condition, and / or a disease or condition associated with senescent cells, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), 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 sclerosis-related lung disease, radiation-related pulmonary fibrosis), radiation-related dermal 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, ulcerative colitis, Crohn's disease, diabetes, aged skin (including photoaging-related pigmentation), survival and function of donor organ transplantation, survival and function of stem cell transplantation, osteoarthritis, recovery from spinal cord injury, Alzheimer's disease, tauopathy, progressive supranuclear palsy, and age-related neurological decline (e.g., associated with impairment of neurovascular coupling). For example, Zhu, Y.I., et al. Aging Cell 14.4 (2015): 644-658, Zhu, Y.I., et al. Aging Cell 15.3 (2016): 428-435, Chang, Jianhui, et al. Nature Medicine 22.1 (2016): 78-83, Zhu, Yi, et al. Aging (Albany NY) 9.3 (2017): 955, Lagares, David, et al. Science Translational Medicine 9.420 (2017): eaal3765, Pan, Jin, et al. International Journal of Radiation Oncology Biology Physics 99.2 (2017): 353-361, Bussian, Tyler J., et al. Nature 562.7728 (2018): 578-582, Moncsek, Anja, et al. Hepatology 67.1(2018):247 - 259, van Willigenburg, Hester, Peter LJ de Keizer, and Ron WF de Bruin. Pharmacological Research 130(2018):322 - 330, Walaszczyk, Anna, et al. Aging Cell 18.3(2019):e12945, Aguayo - Mazzucato, Cristina, et al. Cell Metabolism 30.1(2019):129 - 142, Sessions, Garrett A., et al. The FASEB Journal 33.11(2019):12364, Gerdes, Erin O. Wissler, et al. International Review of Neurobiology 155(2020):203 - 234, Sasaki, Motoko, Yasunori Sato, and Yasuni Nakanuma. Journal of Autoimmunity 107(2020):102377, Yabluchanskiy, Andriy, et al. Geroscience 42(2020):409 - 428, Dookun, Emily, et al. Aging Cell 19.10(2020):e13249, Jia, Kangni, et al. Journal of Cardiovascular Pharmacology 76.4(2020):452 - 460, Sierra - Ramirez, Arantzazu, et al. Aging(Albany NY)12.12(2020):11337, Yang, Hao, et al. Aging(Albany NY)12.13(2020):12750, Lawrie, Allan, and Sheila E. Francis. The Journal of Clinical Investigation 131.11(2021):e149721, Paramos - de - Carvalho, Diogo, et al. Cell Reports 36.1(2021):109334, Tarantini, Stefano, et al. GeroScience 43.5(2021):2427 - 2440, Park, Ji Hee, et al.See The British Journal of Dermatology (2021), Fielder, Edward, et al. ELife 11 (2022): e75492, Suzuki, Keiji, et al. Mutation Research / Genetic Toxicology and Environmental Mutagenesis 876 (2022): 503448, He, An, et al. American Journal of Transplantation 22.11 (2022): 2529-2547, Johnson, Laura A., et al. Inflammatory Bowel Diseases 28.2 (2022): 161-175, Miura, Yugo, et al. Stem Cell Research & Therapy 13.1 (2022): 222, Cooley, Joseph C., et al. JCI Insight 8.3 (2023): e163762. Watanabe, Yusuke, et al. Hepatology Research 53 (2023): 460-472, and Takaya, Kento, et al., Rejuvenation Research 26.1 (2023): 9-20.

[0216] Provided herein is the use of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment of any fibrotic disease or condition, and / or a disease or condition associated with senescent cells, such as any of the fibrotic diseases or conditions provided herein, and / or a disease or condition associated with senescent cells.

[0217] As used herein, provided is the use of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), 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, e.g., any of the fibrotic diseases or conditions provided herein, and / or a disease or condition associated with senescent cells.

[0218] As used herein, provided is the use of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), 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, e.g., any of the fibrotic diseases or conditions provided herein, and / or a disease or condition associated with senescent cells.

[0219] Also provided herein is a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), 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, e.g., any of the fibrotic diseases or conditions provided herein, and / or a disease or condition associated with senescent cells.

[0220] Provided herein is a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment of a fibrotic disease or condition, and / or a disease or condition associated with senescent cells, e.g., any of the fibrotic diseases or conditions provided herein, and / or a disease or condition associated with senescent cells.

[0221] Also provided is a method for modulating (e.g., decreasing) BCL-X protein activity in a cell, which comprises contacting the cell with an effective compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), 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 and the method comprises administering to a subject an effective amount of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof. 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 described herein. L Also provided is a method for modulating (e.g., decreasing) the level of BCL-X protein in a cell, which comprises contacting the cell with a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof. In some embodiments, BCL-X

[0222] As used herein, the term "contacting" refers to bringing the indicated moieties together within an in vitro or in vivo system. For example, "contacting" a cell with a compound provided herein includes in vitro or in vivo administration of a compound provided herein to the cell, including, for example, introducing a compound provided herein into a sample, organoid, or organism (e.g., an animal (e.g., an animal having a tumor) or a human) containing the cell (e.g., grown in culture or derived from a patient).

[0223] Also provided is a method for modulating (e.g., decreasing) BCL-X protein activity in a cell, which comprises contacting the cell with an effective compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof. L Also provided is a method for modulating (e.g., decreasing) the level of BCL-X protein in a cell, which comprises contacting the cell with a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof. In some embodiments, BCL-X LThe level of the protein is reduced 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 cells that have not been contacted with a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), 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, and the method is for BCL-X L administering to a subject having cells having BCL-X L an effective amount of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof. In some embodiments, the cells are cancer cells. In some embodiments, the cells are mammalian cells. In some embodiments, the cells are mammalian cancer cells. In some embodiments, the cancer cells are any cancer described herein.

[0224] Also provided is a method of inducing ubiquitination of BCL-X L protein in cells, comprising contacting the cells with a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), 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, and the method is for BCL-X L administering to a subject having cells having BCL-X L an effective amount of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof. In some embodiments, the cells are cancer cells. In some embodiments, the cells are mammalian cells. In some embodiments, the cells are mammalian cancer cells. In some embodiments, the cancer cells are any cancer described herein. L administering to a subject having cells having BCL-X L an effective amount of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof. In some embodiments, the cells are cancer cells. In some embodiments, the cells are mammalian cells. In some embodiments, the cells are mammalian cancer cells. In some embodiments, the cancer cells are any cancer described herein.

[0225] Also provided is a method of forming a ternary complex comprising contacting a cell with a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, and a BCL-X L protein, with a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, and with a CRBN protein or a fragment thereof in a cell. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo and the method comprises administering to a subject having a cell expressing BCL-X L an effective amount of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof. 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 described herein.

[0226] Also provided herein is a method of inhibiting cell proliferation in vitro or in vivo, the method comprising contacting the cell with an effective amount of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as defined herein.

[0227] Furthermore, provided herein is a method for increasing cell death in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. Also provided herein is a method for increasing tumor cell death in a subject. The method comprises administering to the subject an effective amount of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, to increase tumor cell death.

[0228] When used as a medicament, the compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, can be administered in the form of a pharmaceutical composition described herein.

[0229] Also provided herein is a method for inducing degradation of BCL-X L protein in mammalian cells, the method comprising contacting a mammalian cell with an effective amount of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof.

[0230] Also provided herein is a method for treating a subject having cancer, the method comprising administering, to a subject that has been administered one or more doses of a first anti-cancer agent for a certain period of time, a therapeutically effective amount of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, as monotherapy or in combination with the first anti-cancer agent.

[0231] Also provided herein is a method for treating a subject having cancer, the method comprising (a) administering to the subject one or more doses of a first anti-cancer agent for a certain period of time and (b) After (a), administering to the subject a therapeutically effective amount of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, as monotherapy or in combination with a first anti-cancer agent, comprising.

[0232] Also provided herein is a method of treating a subject having cancer, the method comprising (a) Administering to the subject one or more doses of a first anti-cancer agent for a period of time, (b) After (a), administering to the subject a therapeutically effective amount of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, as monotherapy or in combination with a second anti-cancer agent, comprising.

[0233] Combination In any of the indications described herein, a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, can be used as monotherapy. In some embodiments, a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, can be used before the administration of an additional therapeutic agent or additional therapy. For example, one or more doses of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, can be administered to a subject in need thereof for a period of time, and then at least partial resection of the tumor can be performed. In some embodiments, treatment with one or more doses of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, reduces the size (e.g., tumor mass) of the tumor prior to at least partial resection of the tumor.

[0234] In some embodiments, one or more doses of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, can be administered to a subject in need thereof for a period of time and administered under one or more rounds of radiation therapy. In some embodiments, treatment with one or more doses of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, reduces the size (e.g., tumor burden) of the tumor prior to one or more rounds of radiation therapy.

[0235] In some embodiments of any of the methods described herein, a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), 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 agents (e.g., chemotherapy) agents.

[0236] 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, SOS1 / Ras protein-protein interaction inhibitors, SHP2 inhibitors, PI3K-AKT-mTOR pathway inhibitors)), kinase-targeted therapeutic agents (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 antibody-drug conjugates), 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, mTORC1 inhibitors, YAP inhibitors, proteasome inhibitors, farnesyltransferase inhibitors, Hif2α inhibitors, HSP90 inhibitors, PTEN inhibitors, PARP inhibitors, signal transduction pathway inhibitors, checkpoint inhibitors, modulators of the apoptosis pathway (e.g., BCL-2 inhibitors), chemotherapy, angiogenesis-targeted chemotherapy, immunomodulatory imide drugs (sometimes referred to as "IMiD" or "CELMoD") and immunotherapies (anti-PD1 therapy or anti-PD-L1 therapy) including immune-targeted agents, and radiation therapy.

[0237] As used herein, a biosimilar antibody refers to an antibody or antigen-binding fragment that has the same primary amino acid sequence as a reference antibody and optionally may have detectable differences in post-translational modifications (e.g., glycosylation and / or phosphorylation) compared to the reference antibody (e.g., different glycoforms).

[0238] 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 a biological agent utilizing an anti-EGFR antibody, an ERK inhibitor, an EZH2 inhibitor, an FGFR1 inhibitor, an FGFR2 inhibitor, an FGFR3 inhibitor, an FGFR4 inhibitor, a HER2 inhibitor, an anti-HER2 antibody or a biological agent utilizing an anti-HER2 antibody, a JAK inhibitor, a KRas inhibitor, a MEK inhibitor, a MET inhibitor, a Hif2α 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-PD1 therapy), a PD-L1 inhibitor (e.g., anti-PD-L1 therapy)), chemotherapy, radiation therapy, or a combination thereof.

[0239] 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, an FGFR1 degrader, an FGFR2 degrader, an FGFR3 degrader, an FGFR4 degrader, a HER2 degrader, a JAK2 degrader, a KRas degrader, a MEK degrader, a MET degrader, a Hif2α 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-PD1 therapy or anti-PD-L1 therapy), chemotherapy, radiation therapy, or a combination thereof.

[0240] In some embodiments, the Abl inhibitor (e.g., BCR-Abl inhibitor) is asimicinib (e.g., asimicinib hydrochloride), bafetinib, bosutinib (e.g., bosutinib monohydrate), danusertib, dasatinib (e.g., dasatinib monohydrate), fulmatinib (e.g., fulmatinib 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.

[0241] 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.

[0242] In some embodiments, the AURKA inhibitor is alisertib, danusertib, ilorasertib, tinengotinib, AT-9283, BI-811283, ENMD-2076, or a combination thereof.

[0243] In some embodiments, the BCL-2 inhibitor is lisaftoclax, navitoclax, obatoclax, venetoclax, oblimersen (e.g., oblimersen sodium), beclanorsen, AZD-0466, BGB-11417, UBX-1325 (or its phosphate prodrug), UBX-1967 (or its phosphate prodrug), ZN-d5, or a combination thereof.

[0244] In some embodiments, the cancer is lung cancer (e.g., SCLC), and the additional therapy or therapeutic agent is a BCL-2 inhibitor (e.g., lisaftoclax, navitoclax, obatoclax, venetoclax, oblimersen (e.g., oblimersen sodium), beclanorsen, AZD-0466, BGB-11417, UBX-1325 (or its phosphate prodrug), UBX-1967 (or its phosphate prodrug), or ZN-d5). In some embodiments, the cancer is lung cancer (e.g., SCLC), and the additional therapy or therapeutic agent is venetoclax.

[0245] In some embodiments, the cancer is non-Hodgkin lymphoma, and the additional therapy or therapeutic agent is a BCL-2 inhibitor (e.g., lisaftoclax, navitoclax, obatoclax, venetoclax, oblimersen (e.g., oblimersen sodium), beclanorsen, AZD-0466, BGB-11417, UBX-1325 (or its phosphate prodrug), UBX-1967 (or its phosphate prodrug), or ZN-d5). In some embodiments, the cancer is non-Hodgkin lymphoma, and the additional therapy or therapeutic agent is venetoclax.

[0246] 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.

[0247] In some embodiments, the BRAF V600E mutation can be detected in a sample from a subject (e.g., by detecting the BRAF gene having a mutation corresponding to the V600E mutation in the BRAF protein and / or by detecting the BRAF protein having the V600E mutation). In some embodiments, the subject has been determined to have cancer having the BRAF V600E mutation (e.g., prior to administration of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C))).

[0248] 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., abtimetinib (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).Some embodiments are such that 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., abtumoracini (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 an 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 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 BRaf inhibitor (e.g., abtumoracitinib (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., abtumoracitinib (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 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 cetuximab (e.g., ERBITUX® (cetuximab), or a biosimilar thereof (e.g., CMAB-009, CPGJ-602, or KL-140)). In some embodiments, the cancer is 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 BRaf mutant CRC (e.g., BRaf V600E mutant CRC), and the additional therapy or therapeutic agent is 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 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).

[0249] In some embodiments, the cancer is BRaf mutant NSCLC (e.g., BRaf V600E mutant NSCLC), and the additional therapy or therapeutic agent is a BRaf inhibitor (e.g., abteminib (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., abteminib, binimetinib, cobimetinib (e.g., cobimetinib fumarate), mirdametinib, pimasertib, refametinib, selumetinib (e.g., selumetinib sulfate), trametinib (e.g., trametinib dimethyl sulfoxide adduct), zapnometinib, FCN-159, GSK-1120212, NFX-179, or TAK-733). In some embodiments, the cancer is 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 adduct).In some embodiments, the cancer is 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 adduct). In some embodiments, the cancer is 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 BRaf mutant NSCLC (e.g., BRaf V600E mutant NSCLC), and the additional therapy or therapeutic agent is encorafenib (e.g., BRAFTOVI™, LGX818), and binimetinib.

[0250] 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., abtimetinib (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., abtimetinib (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., abtimetinib, binimetinib, cobimetinib (e.g., cobimetinib fumarate), mirvetinib, pimasertib, refametinib, selumetinib (e.g., selumetinib sulfate), trametinib (e.g., trametinib dimethyl sulfoxide adduct), 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 adduct). 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 adduct). 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 been previously treated with immunotherapy.

[0251] 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.

[0252] In some embodiments, the CDK4 / 6 inhibitor is abemaciclib, birociclib, dalpiciclib, lerociclib, milciclib, palbociclib, ribociclib (e.g., ribociclib succinate), riviciclib, lonaciclib, trilaciclib (e.g., trilaciclib dihydrochloride), FCN-437, TQB-3616, or a combination thereof.

[0253] In some embodiments, the CDK7 inhibitor is milciclib, roscovitine, samuraciclib, or a combination thereof.

[0254] In some embodiments, the CDK9 inhibitor is fadraciclib, riviciclib, lonaciclib, roscovitine, zotiraciclib, AZD-4573, KB-0742, or a combination thereof.

[0255] In some embodiments, the EGFR inhibitor is abivertinib, afatinib (e.g., afatinib dimaleate), alflutinib (e.g., alflutinib mesylate), almonertinib (e.g., almonertinib mesylate), befotertinib, brigatinib, canertinib, dacomitinib (e.g., dacomitinib monohydrate), dovitinib, erlotinib (e.g., erlotinib hydrochloride), gefitinib, icotinib, lapatinib (e.g., lapatinib ditosylate monohydrate), larotinib, lazertinib, limertinib, mobocertinib (e.g., mobocertinib succinate), nazartinib, neratinib (e.g., neratinib maleate), olmutinib, osimertinib (e.g., osimertinib mesylate), peritinib, poziotinib, pyrotinib (e.g., pyrotinib maleate), lucertinib (SKLB-1028), sapitinib, sunvozertinib, tesevatinib, vandetanib, baricitinib, zorifertinib, BIBW-2948, BPI-7711, HA-121-28, SH-1028, an anti-EGFR antibody or an anti-EGFR antibody-drug conjugate, or a combination thereof.

[0256] Some embodiments are such that 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, or KL-140)), cetuximab sarotalocan (AKALUX® (cetuximab sarotalocan), or a biosimilar thereof), depatuxizumab, durvalumab, futuximab, imiglucerase, 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), tositumomab, zalutumumab, EMD-55900, EMD-82633, GC-1118, HLX-07, ICR-62, SCT-200, SI-B-001, TAS-0313, a biosimilar thereof, or a combination thereof.Some embodiments are such that 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, or KL-140)), cetuximab sarotalocan (AKALUX® (cetuximab sarotalocan), or a biosimilar thereof), depatuxizumab, durvalumab, futuximab, imiglucerase, 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), tomotuzumab, zalutumumab, EMD-55900, EMD-82633, GC-1118, HLX-07, ICR-62, SCT-200, SI-B-001, a biosimilar thereof, or a combination thereof.

[0257] 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 a subject (e.g., by 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 the EGFR protein), and / or by 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 is determined 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)) (e.g., prior to administration of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C))).

[0258] In some embodiments, the cancer is 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., avibiratinib, afatinib (e.g., afatinib dimaleate), alflutinib (e.g., alflutinib mesylate), almonertinib (e.g., almonertinib mesylate), bepotertinib, brigatinib, canertinib, dacomitinib (e.g., dacomitinib monohydrate), dovitinib, erlotinib (e.g., erlotinib hydrochloride), gefitinib, icotinib, lapatinib (e.g., lapatinib ditosylate monohydrate), larotrectinib, lazertinib, limertinib, mobocertinib (e.g., mobocertinib succinate), nazartinib, neratinib (e.g., neratinib maleate), ormutinib, osimertinib (e.g., osimertinib mesylate), pelitinib, poziotinib, pyrotinib (e.g., pyrotinib maleate), lucertinib (SKLB-1028), sapitinib, sanbozelitinib, tesevatinib, vandetanib, baricitinib, zolifertinib, BIBW-2948, BPI-7711, HA-121-28, SH-1028, or an anti-EGFR antibody or anti-EGFR antibody-drug conjugate). In some embodiments, the cancer is 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).

[0259] 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.

[0260] In some embodiments, the EZH2 inhibitor is lirametostat, tazemetostat (e.g., tazemetostat hydrobromide), valemetostat (e.g., valemetostat tosylate), tulmimetostat (CPI-0209), EBI-2511, HH-2853, HM-97662, PF-6821497, 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).

[0261] In some embodiments, the cancer is peripheral T cell lymphoma, and the additional therapy or therapeutic agent is an EZH2 inhibitor (e.g., lirametostat, tazemetostat (e.g., tazemetostat hydrobromide), valemetostat (e.g., valemetostat tosylate), tulmimetostat (CPI-0209), EBI-2511, HH-2853, HM-97662, PF-6821497, SHR-2554, or XNW-5004).

[0262] In some embodiments, the FGFR1 inhibitor is danusertib, dovitinib, erdafitinib, futibatinib, infliximab (e.g., infliximab phosphate), lenvatinib (e.g., lenvatinib mesylate), lucitanib, nintedanib (e.g., nintedanib esylate), pemigatinib, sulfatinib, tasugratinib, tinengotinib, zoligratinib, FH-2001, HMPL-453, LY-2874455, or a combination thereof.

[0263] In some embodiments, the FGFR2 inhibitor is erdafitinib, futibatinib, infigratinib (e.g., infigratinib phosphate), lucitanib, pemigatinib, tasugratinib, zogratinib, bemarituzumab (or its biosimilar), FH-2001, HMPL-453, LY-2874455, or a combination thereof.

[0264] In some embodiments, the FGFR3 inhibitor is dovitinib, erdafitinib, futibatinib, infigratinib (e.g., infigratinib phosphate), lucitanib, masitinib, nintedanib, pemigatinib, tasugratinib, zogratinib, vofatamab (or its biosimilar), EXEL-0999, FH-2001, HMPL-453, LY-2874455, or a combination thereof.

[0265] 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.

[0266] 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, tucatinib, vallecitinib, anti-HER2 antibody or anti-HER2 antibody-drug conjugate, or a combination thereof.

[0267] In some embodiments, the anti-HER2 antibody or anti-HER2 antibody-drug conjugate is anbenitamab, cinrebafusp alpha, 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-pAF1-AS-269, MRG-002, DF-1001, AC-101, MM-111, a biosimilar thereof, or a combination thereof.In some embodiments, the anti-HER2 antibody or anti-HER2 antibody-drug conjugate is amivantamab, cinrebafusp alpha, copreloximab, disitamab vedotin, ertumaxomab, ganitumab, 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-pAF1-AS-269, MRG-002, DF-1001, AC-101, MM-111, a biosimilar thereof, or a combination thereof.

[0268] In some embodiments, the HER2+ status can be detected in a sample from a subject (e.g., via immunohistochemistry (IHC) and / or fluorescence in situ hybridization (FISH)). In some embodiments, the subject has been determined to have cancer with a HER2+ status (e.g., prior to administration of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C))).

[0269] In some embodiments, the HER2 low status can be detected in a sample from a subject (e.g., via IHC and / or FISH). In some embodiments, the subject has been determined to have cancer with a HER2 low status (e.g., prior to administration of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C))).

[0270] In some embodiments, the HER2- status can be detected in a sample from a subject (e.g., via IHC and / or FISH). In some embodiments, the subject has been determined to have cancer with a HER2- status (e.g., prior to administration of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C))).

[0271] In some embodiments, the ER expression status can be detected in a sample from a subject (e.g., via IHC and / or FISH). In some embodiments, the subject has been determined to have cancer with ER expression (e.g., prior to administration of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C))). In some embodiments, the subject has been determined to have cancer without ER expression (e.g., prior to administration of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C))).

[0272] In some embodiments, the PR expression status can be detected in a sample from a subject (e.g., via IHC and / or FISH). In some embodiments, the subject has been determined to have cancer with PR expression (e.g., prior to administration of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C))). In some embodiments, the subject has been determined to have cancer without PR expression (e.g., prior to administration of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C))).

[0273] In some embodiments, the cancer is 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, tescetibinib, tucatinib, balversatib, or an anti-HER2 antibody or anti-HER2 antibody-drug conjugate). In some embodiments, the cancer is 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 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 an anti-HER2 antibody-drug conjugate (e.g., amivantamab, cinrebafusp alfa, copreloximab, disitamab vedotin, ertumaxomab, ganitumab, inetetamab, margetuximab (e.g., margetuximab-cmkb, or its biosimilar), pertuzumab (e.g., PERJETA® (pertuzumab), or its biosimilar (e.g., HLX-11)), trastuzumab (e.g., HERCEPTIN® (trastuzumab), or its biosimilar (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 its biosimilar), trastuzumab duocarmazine, trastuzumab emtansine (e.g., KADCYLA® (trastuzumab emtansine), or its biosimilar (e.g., UJVIRA® (trastuzumab emtansine))), trastuzumab hyaluronidase (e.g., trastuzumab hyaluronidase-oysk, or its biosimilar), zanidatamab, zenocutuzumab, AVX-901, IDM-1, TPIV-100, TAA-013, SHR-A1811, BAT-8001, MDX-210, alpha-Her2-pAF1-AS-269, MRG-002, DF-1001, AC-101, MM-111, or its biosimilar).In some embodiments, the cancer is 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 its biosimilar (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 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 its biosimilar). In some embodiments, the cancer is 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 its biosimilar. In some embodiments, the cancer is HER2-low breast cancer, and the additional therapy is an anti-HER2 antibody or an anti-HER2 antibody-drug conjugate. In some embodiments, the cancer is HER2-low breast cancer, and the additional therapy is trastuzumab deruxtecan (e.g., fam-trastuzumab deruxtecan-nxki, or its biosimilar).

[0274] 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).

[0275] In some embodiments, the JAK V617F mutation can be detected in a sample from a subject (e.g., detecting the JAK2 gene having a mutation corresponding to the V617F mutation in the JAK2 protein, and / or detecting the JAK2 protein having the V617F mutation). In some embodiments, the subject has been determined to have a cancer having the JAK2 V617F mutation (e.g., prior to administration of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C))). In some embodiments, the subject has been determined to have a cancer lacking the JAK2 V617F mutation (e.g., prior to administration of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C))).

[0276] In some embodiments, the cancer is MPN-derived 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 comprising a JAK inhibitor. In some embodiments, the patient has not received a previous line of therapy comprising a JAK inhibitor.

[0277] 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) having a JAK2 mutation (e.g., 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) having a JAK2 mutation (e.g., 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., alobrecib, apabetalone, mibebrecib, pelabrecib, trosalbrecib, 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 with a JAK inhibitor. In some embodiments, the patient has not received a previous line of therapy with a JAK inhibitor. In some embodiments, the treatment effect is, for example, spleen volume reduction (e.g., Spleen Volume Reduction of greater than or equal to 35%, SVR, measured by, for example, MRI or CT), total symptom score reduction (e.g., Total Symptom Score reduction of greater than or equal to 50%, TSS, measured by, for example, Myelofibrosis Symptom Assessment Form (MFSAF) version 4.0), etc., at, for example, 24 weeks after the start of treatment. 35 ), total symptom score (e.g., Total Symptom Score reduction of greater than or equal to 50%, TSS, measured by, for example, Myelofibrosis Symptom Assessment Form (MFSAF) version 4.0 50)) or both. For example, see Harrison, Claire, et al., New England Journal of Medicine 366.9(2012):787-798, and Verstovsek, Srdan, et al. New England Journal of Medicine 366.9(2012):799-807. In some embodiments, the treatment effect is (e.g., SVR 35 and / or TSS 50 In addition to, or instead of) anemia response (e.g., measured according to current International Working Group-Myeloproliferative Neoplasms Research and European LeukemiaNet (IWG-MRT / ELN) criteria), myelofibrosis (e.g., according to the European Consensus Grading System by bone marrow biopsy at 24 or 96 weeks after the start of treatment, etc.), variant allele ratio (e.g., JAK2 V617F variant allele ratio), transfusion independence, overall survival, leukemia-free survival, changes in physical function (e.g., the physical function domain of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30, or measured by death), changes in fatigue (e.g., evaluated using the Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue SF 7a), or combinations thereof.

[0278] In some embodiments, the KRas inhibitor is adagrasib, divarasib (GDC-6036), sotorasib, ARS-1620, ARS-3248, ARS-853, ASP-3082, ATG-012, BI-1701963, BI-1823911, BPI-421286, D-1553, ERAS-3490, GFH-925, JAB-21822, JDQ-443, LY-3537982, MRTX-1133, MRTX-1257, RMC-6236, RMC-6291, RSC-1255, or a combination thereof.

[0279] In some embodiments, a KRas mutation (e.g., a KRas G12C mutation or a KRas G12D mutation) can be detected in a sample from a subject (e.g., detecting a KRAS gene having a mutation corresponding to the G12C or G12D mutation in the KRas protein, and / or detecting a KRas protein having the G12C or G12D mutation). In some embodiments, the subject has been determined to have cancer having a KRas G12C mutation (e.g., prior to administration of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C))). In some embodiments, the subject has been determined to have cancer having a KRas G12D mutation (e.g., prior to administration of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C))).

[0280] In some embodiments, the cancer is KRas mutant lung cancer (e.g., KRas mutant NSCLC), KRas mutant CRC, or KRas mutant pancreatic cancer, and the additional therapy or therapeutic agent is a KRas inhibitor (e.g., adagrasib, d-ubrasib (GDC-6036), sotorasib, ARS-1620, ARS-3248, ARS-853, ASP-3082, ATG-012, BI-1701963, BI-1823911, BPI-421286, D-1553, ERAS-3490, GFH-925, JAB-21822, JDQ-443, LY-3537982, MRTX-1133, MRTX-1257, RMC-6236, RMC-6291, or RSC-1255). In some embodiments, the cancer is KRas mutant lung cancer (e.g., KRas mutant NSCLC (e.g., KRas G12C mutant NSCLC)), KRas mutant CRC (e.g., KRas G12C mutant CRC), or KRas mutant pancreatic cancer (e.g., KRas G12C mutant pancreatic cancer), and the additional therapy or therapeutic agent is adagrasib. In some embodiments, the cancer is KRas mutant lung cancer (e.g., KRas mutant NSCLC (e.g., KRas G12C mutant NSCLC)), KRas mutant CRC (e.g., KRas G12C mutant CRC), or KRas mutant pancreatic cancer (e.g., KRas G12C mutant pancreatic cancer), and the additional therapy or therapeutic agent is d-ubrasib. In some embodiments, the cancer is KRas mutant lung cancer (e.g., KRas mutant NSCLC (e.g., KRas G12C mutant NSCLC)), KRas mutant CRC (e.g., KRas G12C mutant CRC), or KRas mutant pancreatic cancer (e.g., KRas G12C mutant pancreatic cancer), and the additional therapy or therapeutic agent is sotorasib. In some embodiments, the cancer is KRas mutant lung cancer (e.g., KRas mutant NSCLC (e.g., KRas G12D mutant NSCLC)), KRas mutant CRC (e.g., KRas G12D mutant CRC), or KRas mutant pancreatic cancer (e.g., KRas G12D mutant pancreatic cancer), and the additional therapy or therapeutic agent is MRTX1133.

[0281] In some embodiments, the MEK inhibitor is abtimetinib, binimetinib, cobimetinib (e.g., cobimetinib fumarate), mildabemetinib, pimasertib, refametinib, selumetinib (e.g., selumetinib sulfate), trametinib (e.g., trametinib dimethyl sulfoxide adduct), zapnometinib, FCN-159, GSK-1120212, NFX-179, TAK-733, or a combination thereof.

[0282] In some embodiments, the BRCA1 mutation can be detected in a sample from the subject (e.g., detecting the BRCA1 gene having the mutation and / or detecting the BRCA1 protein having the mutation). In some embodiments, the subject has been determined to have a cancer having a BRCA1 mutation (e.g., prior to administration of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C))).

[0283] In some embodiments, the BRCA2 mutation can be detected in a sample from the subject (e.g., detecting the BRCA2 gene having the mutation and / or detecting the BRCA2 protein having the mutation). In some embodiments, the subject has been determined to have a cancer having a BRCA2 mutation (e.g., prior to administration of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C))).

[0284] 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).

[0285] In some embodiments, the cancer is KRas mutant CRC (e.g., KRas G12C mutant NSCLC), and the additional therapy or therapeutic agent is a MEK inhibitor (e.g., binimetinib, cobimetinib, selumetinib, or trametinib).

[0286] In some embodiments, the MET inhibitor is cabozantinib (e.g., cabozantinib S-malate), capmatinib (e.g., capmatinib hydrochloride), crizotinib, foritinib, glesatinib, gumartinib, merestinib, pamufetinib, savolitinib, citravatinib, tepotinib (e.g., tepotinib hydrochloride hydrate), vebreltinib, zanzalintinib (XL-092), amivantamab (e.g., amivantamab-vmjw, or a biosimilar thereof), emibetuzumab (or a biosimilar thereof), RC-108, telisotuzumab vedotin (or a biosimilar thereof), ABBV-400, ABN-401, AL-2846, AMG-337, SAR-125844, TQ-B-3139, or a combination thereof.

[0287] In some embodiments, the MET alteration can be detected in a sample from a subject (e.g., by detecting the MET gene having an alteration (e.g., gene amplification or exon 14 skipping), and / or by detecting the MET protein having a mutation (e.g., exon 14 skipping)). In some embodiments, the subject is determined to have a cancer having an MET alteration (e.g., prior to administration of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C))).

[0288] In some embodiments, the cancer is NCLC with altered MET (e.g., MET-amplified NSCLC or MET exon 14 skipping NSCLC), and the additional therapy or therapeutic agent is a MET inhibitor (e.g., cabozantinib (e.g., cabozantinib S-malate), capmatinib (e.g., capmatinib hydrochloride), crizotinib, foretinib, glesatinib, gumatronicib, merestinib, pamreticinib, savolitinib, sitravatinib, tepotinib (e.g., tepotinib hydrochloride hydrate), bevreltinib, zanazolinib (XL-092), amivantamab (e.g., amivantamab-vmjw, or a biosimilar thereof), emibetuzumab (or a biosimilar thereof), RC-108, telisotuzumab vedotin (or a biosimilar thereof), ABBV-400, ABN-401, AL-2846, AMG-337, SAR-125844, or TQ-B-3139). In some embodiments, the cancer is NCLC with altered MET (e.g., MET-amplified NSCLC or MET exon 14 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 NCLC with altered MET (e.g., MET-amplified NSCLC or MET exon 14 skipping NSCLC), and the additional therapy or therapeutic agent is telisotuzumab vedotin (or a biosimilar thereof).

[0289] In some embodiments, the Hif2α inhibitor is belzutifan, AB-521, DFF-332, NKT-2152, PT-2399, or a combination thereof.

[0290] 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, JPI-289, 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.

[0291] 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.

[0292] In some embodiments, the cancer is triple-negative breast cancer, and the additional therapy or therapeutic agent is a PARP inhibitor (e.g., fuzuloparib (fulzoparib), niraparib (e.g., niraparib tosylate monohydrate), olaparib, pamiparib, rucaparib (e.g., rucaparib camsylate), saraparib (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 saraparib.

[0293] 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 (fulzoparib), niraparib (e.g., niraparib tosylate monohydrate), olaparib, pamiparib, rucaparib (e.g., rucaparib camsylate), saraparib (AZD5305), senaparib, stenoparib, talazoparib (e.g., talazoparib tosylate), veliparib, CEP-9722, JPI-289, or NMS-03305293). Some embodiments are that the cancer is HGSOC (e.g., BRCA1 mutant HGSOC or BRCA2 mutant HGSOC), and the additional therapy or therapeutic agent is saraparib.

[0294] In some embodiments, the LSD1 inhibitor is bomedemstat, iadademstat, pulrodemstat, seclidemstat (HCI-2577), vafidemstat, GSK-2879552, INCB-059872, JBI-802, or a combination thereof.

[0295] In some embodiments, the BET inhibitor is alobrecib, apabetalone, mivebresib, pelabresib, trotabresib, ABBV-744, BI-2536, BMS-986158, INCB-057643, JAB-8263, ODM-207, PLX-2853, ZEN-003694, or a combination thereof.

[0296] In some embodiments, the cancer is myelofibrosis (e.g., primary myelofibrosis, post-essential thrombocythemia myelofibrosis, or post-polycythemia vera myelofibrosis), and the additional therapy or therapeutic agent is a BET inhibitor (e.g., alobrecib, apabetalone, mivebresib, pelabresib, trotabresib, ABBV-744, BI-2536, BMS-986158, INCB-057643, JAB-8263, ODM-207, PLX-2853, or ZEN-003694).

[0297] In some embodiments, the STING agonist is ulevostinag, ADU-S100, or a combination thereof.

[0298] In some embodiments, the telomerase inhibitor is imetelstat (e.g., imetelstat sodium).

[0299] In some embodiments, the TORC1 / 2 inhibitor is apitolisib, bimiralisib, dactolisib, deforolimus, everolimus, fosciclopirox (e.g., fosciclopirox sodium), gedatolisib, onatasertib, paxalisib, sapalisib, sirolimus, sodium 2-hydroxy linoleate, temsirolimus, umirolimus, vistusertib, zandelisib, zotarolimus, BI-860585, CC-115, CLL-442, PF-04691502, or a combination thereof.

[0300] In some embodiments, the VEGFR inhibitor is apatinib, axitinib, cabozantinib (e.g., cabozantinib S-malate), catequentinib (alontinib), cediranib, dovitinib, famitinib, fruquintinib, glesatinib, ibcasertib, irroracetinib, lenvatinib (e.g., lenvatinib mesylate), lucitanib, nintedanib (e.g., nintedanib esylate), pamitinib, 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, zanazolinib, olinvacimab (or its biosimilar), ramucirumab (or its biosimilar), CEP-11981, ENMD-2076, ODM-203, or a combination thereof.

[0301] In some embodiments, the chemotherapy is a platinum complex, a microtubule inhibitor (e.g., a microtubule destabilizing agent or a microtubule stabilizing agent), a topoisomerase inhibitor, a hypomethylating agent, or an antibody-drug conjugate comprising any of them. In some embodiments, the platinum complex is carboplatin, cisplatin, lobaplatin, miliplatine, oxaliplatin, or a combination thereof. In some embodiments, the microtubule inhibitor is cabazitaxel, colchicine, desoxyepothilone B, docetaxel, eribulin, ixabepilone, nab-paclitaxel, paclitaxel, prinabulin, 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, antibody-drug conjugates comprising a microtubule inhibitor are 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, tisotuzumab vedotin, trastuzumab emtansine (e.g., ado-trastuzumab emtansine, or a biosimilar thereof), tusamitamab ravtansine, upifitamab rilsodotin, zilovertamab vedotin, alpha-Her2-pAF1-AS-269, BAT-8001, TAA-013, a biosimilar thereof, or a combination thereof. In some embodiments, the antibody-drug conjugate comprising a microtubule inhibitor is enfortumab vedotin (e.g., enfortumab vedotin-ejfv, or a biosimilar thereof). In some embodiments, the antibody-drug conjugate comprising a microtubule inhibitor is mirvetuximab soravtansine (e.g., mirvetuximab soravtansine-gynx, or a biosimilar thereof). In some embodiments, the antibody-drug conjugate comprising a microtubule inhibitor is trastuzumab emtansine (e.g., ado-trastuzumab emtansine, or a biosimilar thereof). In some embodiments, antibody-drug conjugates comprising a topoisomerase inhibitor are 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 antibody-drug conjugate comprising a topoisomerase inhibitor is sacituzumab govitecan (e.g., sacituzumab govitecan-hziy, or a biosimilar thereof). In some embodiments, the antibody-drug conjugate comprising a topoisomerase inhibitor is trastuzumab deruxtecan (e.g., fam-trastuzumab deruxtecan-nxki, or a biosimilar thereof).

[0302] In some embodiments, the cancer is 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 lung cancer (e.g., NSCLC (e.g., squamous cell carcinoma)), and the additional therapy or therapeutic agent is docetaxel.

[0303] In some embodiments, the cancer is NSCLC (e.g., NSCLC with MET amplification), and the additional therapy or therapeutic agent is tezspirevedotin.

[0304] In some embodiments, the cancer is lung cancer (e.g., NSCLC), and the additional therapy or therapeutic agent is a platinum complex (e.g., carboplatin, cisplatin, lobaplatin, miliplatine, or oxaliplatin) and anti-PD1 therapy.

[0305] In some embodiments, the cancer is lung cancer (e.g., NSCLC), and the additional therapy or therapeutic agent is a platinum complex (e.g., carboplatin, cisplatin, lobaplatin, miliplatine, or oxaliplatin) and anti-PD-L1 therapy.

[0306] In some embodiments, the cancer is lung cancer (e.g., NSCLC), and the additional therapy or therapeutic agent is pemetrexed and anti-PD1 therapy.

[0307] In some embodiments, the cancer is lung cancer (e.g., NSCLC), and the additional therapy or therapeutic agent is pemetrexed and anti-PD-L1 therapy.

[0308] In some embodiments, the cancer is lung cancer (e.g., SCLC), and the additional therapy or therapeutic agent is a platinum complex (e.g., carboplatin, cisplatin, lobaplatin, miliplatine, 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 lung cancer (e.g., SCLC), and the additional therapy or therapeutic agent is carboplatin and etoposide. In some embodiments, the cancer is lung cancer (e.g., SCLC), and the additional therapy or therapeutic agent is cisplatin and etoposide.

[0309] 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.

[0310] 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 an anti-PD1 therapy.

[0311] 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 an anti-PD-L1 therapy.

[0312] 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.

[0313] 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).

[0314] 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).

[0315] 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)).

[0316] 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).

[0317] 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).

[0318] In some embodiments, the cancer is 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))).

[0319] In some embodiments, the cancer is HER2-low breast cancer, and the additional therapy or therapeutic agent is trastuzumab deruxtecan (e.g., fam-trastuzumab deruxtecan-nxki, or a biosimilar thereof).

[0320] In some embodiments, the cancer is head and neck cancer, and the additional therapy or therapeutic agent is a microtubule inhibitor (e.g., cabazitaxel, docetaxel, nab-paclitaxel, or paclitaxel). Some embodiments are that the cancer is head and neck cancer, and the additional therapy or therapeutic agent is docetaxel.

[0321] In some embodiments, the cancer is cervical cancer, and the additional therapy or therapeutic agent is a microtubule inhibitor (e.g., cabazitaxel, docetaxel, nab-paclitaxel, or paclitaxel).

[0322] In some embodiments, the cancer is endometrial cancer, and the additional therapy or therapeutic agent is a microtubule inhibitor (e.g., cabazitaxel, docetaxel, nab-paclitaxel, or paclitaxel).

[0323] In some embodiments, the cancer is prostate cancer and the additional therapy or therapeutic agent is a microtubule inhibitor (e.g., cabazitaxel, docetaxel, nab-paclitaxel, or paclitaxel).

[0324] In some embodiments, the cancer is 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 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, miliplatine, or oxaliplatin). In some embodiments, the cancer is ovarian cancer (e.g., HGSOC) and the additional therapy or therapeutic agent is nab-paclitaxel or paclitaxel and carboplatin.

[0325] In some embodiments, the cancer is 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 pancreatic cancer and the additional therapy or therapeutic agent is a microtubule inhibitor (e.g., cabazitaxel, docetaxel, nab-paclitaxel, or paclitaxel) and gemcitabine.

[0326] In some embodiments, the cancer is 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).

[0327] In some embodiments, the cancer is 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).

[0328] 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).

[0329] In some embodiments, the folate receptor positive status can be detected in a sample from the subject (e.g., via immunohistochemistry (IHC) and / or fluorescence in situ hybridization (FISH)). In some embodiments, the subject has been determined to have a folate receptor positive cancer (e.g., prior to administration of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C))).

[0330] 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).

[0331] In some embodiments, the immunomodulatory imide drug is thalidomide, lenalidomide, pomalidomide, iberdomide, avadomide, CC-99282, or a combination thereof.

[0332] In some embodiments, the anti-PD1 therapy is balstilimab, budigalimab, cadonilimab, camrelizumab, semaprilimab (e.g., semaprilimab-rwlc, or a biosimilar thereof), cetrelimab, dostarlimab (e.g., dostarlimab-gxly, or a biosimilar thereof), ezabenlimab, geptanolimab, ivonescimab, nivolumab (e.g., OPDIVO® (nivolumab), or a biosimilar thereof), nofazinlimab, pembrolizumab (e.g., KEYTRUDA® (pembrolizumab), or a biosimilar thereof), 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, tripalimab, volrustomig, vudalimab, zimberelimab, QL-1604, HX-009, INCB-086550, RG-6139, BAT-1306, SG-001, a biosimilar thereof, or a combination thereof.

[0333] In some embodiments, the PD-L1 inhibitor is INCB-086550.

[0334] In some embodiments, the anti-PD-L1 therapy is adebrelumab, atezolizumab (e.g., TECENTRIQ® (atezolizumab), or a biosimilar thereof), avelumab (e.g., BAVENCIO® (avelumab), or a biosimilar thereof), bintrafusp alpha, cosibelimab, danburstotug, durvalumab (e.g., IMFINZI® (durvalumab), or a biosimilar thereof), envafolimab (e.g., ENWEIDA® (envafolimab), or a biosimilar thereof), erfonrilimab, pacmilimab, socazolimab, sugemalimab (e.g., CEJEMLY® (sugemalimab), or a biosimilar thereof), A-167, APL-502, AUPM-170, BNT-311, SHR-1701, a biosimilar thereof, or a combination thereof.

[0335] In some embodiments, the additional therapy is radiation therapy.

[0336] In some embodiments, the cancer is head and neck cancer (e.g., head and neck squamous cell carcinoma), and the additional therapy is radiation therapy.

[0337] 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.

[0338] Exemplary descriptions of drugs combined with BCL-2 family inhibitors are provided in Hikita, Hayato, et al. Hepatology 52.4 (2010): 1310-1321, Chen, Jun, et al. Molecular Cancer Therapeutics 10.12 (2011): 2340-2349, Inuzuka, Hiroyuki, et al. Nature 471.7336 (2011): 104-109, Wertz, Ingrid E., et al. Nature 471.7336 (2011): 110-114, Tan, Nguyen, et al. Clinical Cancer Research 17.6 (2011): 1394-1404, Wong, Maureen, et al. Molecular Cancer Therapeutics 11.4 (2012): 1026-1035, Corcoran, Ryan B., et al. Cancer Cell 23.1 (2013): 121-128, Waibel, Michaela, et al. Cell Reports 5.4 (2013): 1047-1059, Frederick, Dennie T., et al. PloS One 9.7 (2014): e101286, Vlahovic, Gordana, et al. Investigational New Drugs 32.5 (2014): 976-984, Faber, Anthony C., et al. Cancer Discovery 4.1 (2014): 42-52, Leverson, Joel D., et al. Science Translational Medicine 7.279 (2015): 279ra40-279ra40, Guo, Jun, et al. PLoS One 10.3 (2015): e0114363, Lheureux, Stephanie, et al. International Journal of Cancer 136.5 (2015): E340-E350, Zoeller, Jason J., et al. Cancer Research 76.14_Supplement (2016): 4358-4358, Weeden, Clare E., et al. Oncogene 37.It can be found in 32(2018):4475-4488, Lucantoni, Federico, et al., Cell Death & Disease 9.2(2018):1-13, Iavarone, Claudia, et al., Molecular Cancer Therapeutics 18.3(2019):642-655, Fleury, Hubert, et al., Nature Communications 10.1(2019):1-15, Lohard, Steven, et al., Nature Communications 11.1(2020):1-16, Bertino, Erin M., et al., Clinical Cancer Research 27.6(2021):1604-1611, Guo, Ting, et al., Aging 13.15(2021):19750, Puglisi, Martina, et al., Future Oncology 17.21(2021):2747-2758, Harrison, Claire N., et al., Journal of Clinical Oncology 40.15(2022):1671, Kohler, Jens, et al., Molecular Cancer Therapeutics 20.4(2021):641-654, Jaaks, Patricia, et al., Nature 603.7899(2022):166-173, Sobol, Benjamin, et al., International Journal of Molecular Sciences 23.14(2022):7850, Passamonti, J Clin Oncol 40,(2022)(suppl 16;abstr 7015), Qin, J Clin Oncol 40,(2022)(suppl 16;abstr e20612), Potter, Danielle S., et al., Cancer Research 82.12_Supplement(2022):3691-3691, and Shebl, Bassem, et al., Cancer Research 82.12_Supplement(2022):3888-3888.

[0339] Also provided herein is a method of treating cancer, which comprises administering to a subject in need thereof, for the treatment of cancer, (a) a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, and (b) an additional therapeutic agent, either simultaneously, separately, or sequentially, wherein the amounts of the compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are together effective to treat cancer. In some embodiments, the method comprises (c) administering at least one pharmaceutically acceptable carrier.

[0340] These additional therapeutic agents may be administered, according to standard pharmaceutical practice known to those skilled in the art, via the same or different routes of administration and / or at the same or different dosing schedules, as part of the same or separate dosage forms, together with one or more doses of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered simultaneously as separate dosages. In some embodiments, the compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered sequentially in any order as separate dosages in therapeutically effective amounts, e.g., daily or intermittent dosages. In some embodiments, the compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered simultaneously as a combined dosage.

[0341] Also, in this specification, (i) a pharmaceutical combination for treating cancer in a subject in need thereof, for use simultaneously, separately, or sequentially for treating cancer, comprising (a) a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), 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), wherein the amounts of the compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are together effective to treat cancer, (ii) a pharmaceutical composition comprising such a combination, (iii) the use of such a combination for the preparation of a medicament for treating cancer, and (iv) a commercial package or product comprising such a combination as a combined preparation for simultaneous, separate, or sequential use and for a method of treating cancer in a subject in need thereof, are provided. In some embodiments, the pharmaceutical combination comprises (c) at least one pharmaceutically acceptable carrier.

[0342] As used herein, the terms “treating” or “treatment” refer to therapeutic or palliative means. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms associated with a disease, disorder or condition, whether detectable or undetectable, diminishment of the extent of the disease, stabilization (i.e., not worsening) of a disease state, delay or slowing of disease progression, remission or palliation of a disease state (e.g., one or more symptoms of a disease), and amelioration (whether partial or total), whether or not measurable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0343] As used herein, the terms "subject", "individual", or "patient" are used interchangeably and refer to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and humans. In some embodiments, the subject is a human. In some embodiments, the subject is experiencing and / or exhibiting at least one symptom of a disease, disorder, or condition to be treated and / or prevented.

[0344] In some embodiments, the subject is a pediatric subject.

[0345] As used herein, the term "pediatric subject" refers to a subject less than 21 years of age at the time of diagnosis or treatment. The term "pediatric" can be further divided into various subpopulations including: neonates (from birth to 1 month of age), infants (from 1 month to 2 years of age), children (from 2 years to 12 years of age), and adolescents (from 12 years to 21 years (up to but not including the 22nd birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: W.B. Saunders Company, 1996, Rudolph AM, et al. Rudolph’s Pediatrics, 21st Ed. New York: McGraw-Hill, 2002, and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994. In some embodiments, the pediatric subject is from birth to 28 days of age, from 29 days of age to less than 2 years of age, from 2 years to less than 12 years of age, or from 12 years to 21 years (up to but not including the 22nd birthday). In some embodiments, the pediatric subject is from birth to 28 days of age, from 29 days of age to less than 1 year of age, from 1 month of age to less than 4 months of age, from 3 months of age to less than 7 months of age, from 6 months of age to less than 1 year of age, from 1 year to less than 2 years of age, from 2 years to less than 3 years of age, from 2 years to less than 7 years of age, from 3 years to less than 5 years of age, from 5 years to less than 10 years of age, from 6 years to less than 13 years of age, from 10 years to less than 15 years of age, or from 15 years to less than 22 years of age.

[0346] As used herein, the term "prevent" means to delay the onset, recurrence, or spread of a disease or condition described herein, or symptoms thereof, in whole or in part.

[0347] The term "regulatory agency" refers to a national agency for approving the medical use of pharmaceutical agents in a country. For example, a non-limiting example of a regulatory agency is the US Food and Drug Administration (FDA).

[0348] The term "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 a particular disease, disorder, or condition, or (iii) delay the onset of one or more symptoms of a particular disease, disorder, or condition described herein. The amount of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, corresponding to such an amount will vary depending on factors such as the particular compound, disease state and its severity, the identity of the subject in need of treatment (e.g., weight), etc., but can nevertheless be routinely determined by one of ordinary skill in the art.

[0349] The term "effective amount" as used herein with respect to a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)) means an amount of the compound that is sufficient to reduce cell proliferation or kill cells when administered to the cells in vitro or in vivo. The amount of a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, corresponding to such an amount will vary depending on factors such as the particular compound and the genetics of the cells being treated, but can nevertheless be routinely determined by one of ordinary skill in the art.

[0350] Pharmaceutical Compositions and Administration General In some embodiments, a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)), or a pharmaceutically acceptable salt thereof, is administered as a pharmaceutical composition comprising the compound described herein or a pharmaceutically acceptable salt thereof, one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents.

[0351] In some embodiments, the compounds can be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tween, poloxamer, 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, protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, salts or electrolytes such as zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene-polyoxypropylene block polymer, and lanolin, but are not limited thereto. Cyclodextrins such as α-, β-, and γ-cyclodextrins, or chemically modified derivatives such as hydroxyalkyl cyclodextrins containing 2- and 3-hydroxypropyl-β-cyclodextrin, or other solubilizing derivatives can also be used to enhance the delivery of the compounds described herein. Dosage forms or compositions can be prepared that contain the compounds described herein in the range of 0.005% to 100%, with the remainder consisting of non-toxic excipients. The contemplated compositions can contain from 0.001% to 100%, in one embodiment from 0.1 to 95%, in another embodiment from 75 to 85%, and in a further embodiment from 20 to 80% of the compounds provided herein. The actual methods for preparing such dosage forms are known or apparent to those of ordinary skill in the art. See, for example, Remington: The Science and Practice of Pharmacy, 22 nd nd Edition (Pharmaceutical Press, London, UK. 2012).

[0352] Route of Administration and Composition Components In some embodiments, a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)) described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, can be administered to a subject in need thereof by any acceptable route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, endocervical, endosinusial, intratracheal, enteral, epidural, interstitial, intraperitoneal, intraarterial, intrapulmonary, intrabursal, intracerebral, intracisternal, intracoronary, intradermal, intraluminal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intramuscular, intramesenteric, intramyeloid, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intrathecal, intrasynovial, intratesticular, intrasubarachnoid, intratubular, intratumoral, intrauterine, intravascular, intravenous, intravitreal, nasal, nasogastric, oral, parenteral, percutaneous, epidural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, urethral, urethral, and vaginal. In certain embodiments, a preferred route of administration is parenteral (e.g., intratumoral).

[0353] In some embodiments, a compound of formula (I) or (II) (e.g., formula (I-A), (I-B), or (I-C)) described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, can be administered orally to a subject in need thereof. Without being bound by any particular theory, oral dosing (e.g., as compared to IV dosing) is thought to be preferred by patients for reasons of convenience, perceived efficacy, and / or past experience.

[0354] The composition can be formulated for parenteral administration, for example, formulated for injection via intravenous, intramuscular, subcutaneous, or even intraperitoneal routes. Typically, such a composition can be prepared as an injectable as either a liquid solution or a suspension. Prior to injection, it is also possible to prepare a solid form suitable for use in preparing a solution or suspension upon addition of a liquid, or to emulsify the preparation. The preparation of such formulations is known to those skilled in the art in light of the present disclosure.

[0355] Pharmaceutical forms suitable for use as injectables include sterile aqueous solutions or dispersions, formulations containing sesame oil, peanut oil, or aqueous propylene glycol, and sterile powders for the immediate preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and fluid to the extent that easy injection is possible. It should also be stable under the conditions of manufacture and storage and must be protected against the contaminating action of microorganisms such as bacteria and fungi.

[0356] The carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyols (such as glycerol, propylene glycol, and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. Appropriate fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of a dispersion, and by the use of surfactants. Prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. In many cases, it is preferable to include isotonic agents, such as sugars or sodium chloride. Sustained absorption of the injectable composition can be brought about by using agents that delay absorption, such as aluminum monostearate and gelatin, in the composition.

[0357] The sterile injectable solutions are prepared by incorporating the required amount of the active compound in a suitable solvent along with the various other ingredients enumerated above and, if necessary, subsequently filtering sterilizing. Generally, dispersions are prepared by incorporating the various sterilized active ingredients in a sterile vehicle containing a 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 ingredients from their previously sterile-filtered solutions.

[0358] Intratumoral injection is discussed, for example, in Lammers, et al., “Effect of Intratumoral Injection on the Biodistribution and the Therapeutic Potential of HPMA Copolymer-Based Drug Delivery Systems” Neoplasia. 2006, 10, 788 - 795.

[0359] Pharmacologically acceptable excipients that can be used in rectal compositions as gels, creams, enemas, or rectal suppositories include, but are not limited to, cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (such as PEG ointments), glycerin, glycerinated gelatin, hardened vegetable oils, poloxamer, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharin, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxyd SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p - hydroxybenzoate, sodium propyl p - hydroxybenzoate, diethylamine, carbomer, carbopol, methyl hydroxybenzoate, macrogol cetostearyl ether, cocoil caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy - metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins such as vitamin A and E, and potassium acetate, any one or more of which may be mentioned.

[0360] In certain embodiments, the suppository can be prepared by mixing the compounds described herein with a suitable non - irritating excipient or carrier such as cocoa butter, polyethylene glycol, or suppository wax that is solid at ambient temperature but liquid at body temperature and thus melts in the rectum to release the active compound. In other embodiments, the composition for rectal administration is in the form of an enema.

[0361] In other embodiments, the compounds described herein or their pharmaceutical compositions are suitable for topical delivery to the gastrointestinal or GI tract by oral administration (e.g., in solid or liquid dosage forms).

[0362] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid formulations, the compound is admixed with one or more pharmaceutically acceptable excipients such as sodium citrate or dicalcium phosphate, and / or: a) fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, etc., c) humectants such as glycerol, d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicic acids, and sodium carbonate, e) dissolution retardants such as paraffin, f) absorption promoters such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, etc., h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may contain buffering agents. Similar types of solid compositions may also be used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0363] In one embodiment, the composition is in the form of a unit dosage form such as a pill or tablet, and thus the composition, together with the compounds provided herein or pharmaceutically acceptable salts thereof, may contain, for example, diluents such as lactose, sucrose, dicalcium phosphate, lubricants such as magnesium stearate, and binders such as starch, acacia gum, polyvinylpyrrolidin, gelatin, cellulose, cellulose derivatives, etc. In another solid dosage form, powders, marume, solutions, or suspensions (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglycerides) are encapsulated in capsules (gelatin or cellulose-based capsules). Unit dosage forms in which one or more of the compounds provided herein or additional active agents are physically separated include, for example, capsules having granules of each drug (or tablets in capsules), bilayer tablets, two-compartment gel capsules, etc. Enteric coatings or extended-release oral dosage forms are also contemplated.

[0364] 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, for example, phenol and ascorbic acid.

[0365] In certain embodiments, the excipients are sterile and do not contain generally undesirable substances. 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. Usually, USP / NF standards are sufficient.

[0366] In certain embodiments, the solid oral dosage form can further include one or more components that make the composition more chemically and / or structurally amenable to uptake of the compound into the stomach or lower GI, such as the ascending colon and / or transverse colon and / or distal colon and / or small intestine. Exemplary formulation techniques are described, for example, in Filipski, K.J., et al., Current Topics in Medicinal Chemistry, 2013, 13, 776-802.

[0367] Examples include upper GI targeting techniques such as the Accordion Pill (Intec Pharma), floating capsules, and materials that can adhere to the mucosal wall.

[0368] Other examples include lower GI targeting techniques. To target various regions within the intestinal tract, several enteric / pH-responsive coatings and excipients are available. These materials are typically polymers designed to dissolve or erode at specific pH ranges, which are selected based on the desired GI region of drug release. These materials also function to protect acid-labile drugs from gastric fluid or to limit exposure when the active ingredient can cause irritation in the upper GI (e.g., hydroxypropyl methylcellulose phthalate-based, Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit-based (methacrylic acid-methyl methacrylate copolymer), and Marcoat). Other techniques include dosage forms that respond to the local flora within the GI tract, pressure-controlled colon delivery capsules, and Pulsincap.

[0369] The ophthalmic composition can include, but is not limited to, one or more of the following: viscogens (e.g., carboxymethylcellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol), stabilizers (e.g., Pluronic (triblock copolymer), cyclodextrin), and preservatives (e.g., benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.)).

[0370] The topical composition can include ointments and creams. An ointment is typically a semisolid preparation based on petrolatum or other petroleum derivatives. A cream containing the selected active agent is typically a viscous liquid or semisolid emulsion, often either oil-in-water or water-in-oil. The cream base is typically washable and contains an oil phase, an emulsifier, and an aqueous phase. The oil phase, sometimes referred to as the "internal" phase, is generally composed of petrolatum and fatty alcohols such as cetyl alcohol or stearyl alcohol. The aqueous phase usually, but not always, 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. Like other carriers or vehicles, the ointment base should be inert, stable, non-irritating, and non-sensitizing.

[0371] In any of the foregoing embodiments, the pharmaceutical compositions described herein can include one or more of lipids, internal bilayer crosslinkable multilamellar vesicles, biodegradable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or polyanhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.

[0372] Dosage The dosage can vary depending on the patient's requirements, the severity of the condition being treated, and the particular compound used. The determination of the appropriate dosage for a particular situation can be made by those skilled in the medical arts. The total daily dosage can be divided and administered in portions throughout the day or by means providing continuous delivery.

[0373] In some embodiments, the compounds described herein are administered at dosages of about 0.001 mg / kg to about 500 mg / kg (e.g., about 0.001 mg / kg to about 200 mg / kg, about 0.01 mg / kg to about 200 mg / kg, about 0.01 mg / kg to about 150 mg / kg, about 0.01 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 50 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 5 mg / kg, about 0.01 mg / kg to about 1 mg / kg, about 0.01 mg / kg to about 0.5 mg / kg, about 0.01 mg / kg to about 0.1 mg / kg, about 0.1 mg / kg to about 200 mg / kg, about 0.1 mg / kg to about 150 mg / kg, about 0.1 mg / kg to about 100 mg / kg, about 0.1 mg / kg to about 50 mg / kg, about 0.1 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 5 mg / kg, about 0.1 mg / kg to about 1 mg / kg, about 0.1 mg / kg to about 0.5 mg / kg).

[0374] Regimen The foregoing dosages can be administered on a daily basis (e.g., as a single dose or as multiple divided doses) or on a non-daily basis (e.g., every other day, every two days, every three days, once a week, twice a week, once every two weeks, once a month).

[0375] In some embodiments, the administration period of the compounds described herein is 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 further embodiments, the period during which administration is stopped is 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 certain embodiments, the therapeutic compound is administered to the individual for a period of time and then administered again for another period of time. In another embodiment, the therapeutic compound is administered during a first period and a second period after the first period, administration is stopped during the second period, and then administration of the therapeutic compound is started during a third period and then stopped during a fourth period after the third period. In one aspect of this embodiment, the administration period of the therapeutic compound and the subsequent period during which administration is stopped are repeated over a determined or undetermined period of time. In further embodiments, the administration period is 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 further embodiments, the period during which administration is stopped is 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.

[0376] As used herein, the term "acceptable" with respect to a formulation, composition, or ingredient means that it has no persistent adverse effects on the general health of the subject being treated.

[0377] "API" refers to the active pharmaceutical ingredient.

[0378] 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 compatible with the other components of the pharmaceutical formulation and is suitable for use in contact with human and animal tissues or organs without undue toxicity, irritation, allergic response, immunogenicity, or other problems or complications, and is "pharmaceutically acceptable" in the sense that it has a reasonable benefit / risk ratio. See, for example, Remington: The Science and Practice of Pharmacy, 21st ed; Lippincott Williams & Wilkins: Philadelphia, PA, 2005, Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et 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.

[0379] The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to the organism to which it is administered and does not inactivate the biological activity and properties of the compound. In certain examples, a pharmaceutically acceptable salt is obtained by reacting a compound described herein with an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. In some cases, a pharmaceutically acceptable salt is obtained by reacting a compound having an acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt such as a sodium salt or a potassium salt, an alkaline earth metal salt such as a calcium salt or a magnesium salt, a salt of an organic base such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and a salt with an amino acid such as arginine, lysine, etc., or by other previously determined methods. The term "pharmacologically acceptable salt" is not particularly limited as long as it can be used in pharmaceuticals. Examples of salts formed by the compounds described herein with bases include the following. Its salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum, its salts with organic bases such as methylamine, ethylamine, and ethanolamine, its salts with basic amino acids such as lysine and ornithine, and ammonium salts. The salt may be an acid addition salt, 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, and acidic amino acids such as aspartic acid and glutamic acid.

[0380] The term "pharmaceutical composition" refers to a mixture of the compounds described herein and other chemical constituents such as carriers, stabilizers, diluents, dispersants, suspending agents, and / or thickening agents (collectively referred to herein as "excipients"). The pharmaceutical composition facilitates the administration of the compound to a subject. There are a plurality of techniques for administering the compound, including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration, which are known in the art.

[0381] Preparation of Compounds The compounds disclosed herein can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or intermediates that are readily prepared, by using any standard synthetic methods and procedures known to those skilled in the art or in light of the teachings herein.

[0382] The preparation of organic molecules, as well as standard synthetic methods and procedures for functional group transformation and manipulation, can be obtained from the relevant scientific literature or from standard textbooks in the field. Without being limited to any one or several sources, classical 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 for organic synthesis known to those skilled in the art. The following description of the synthetic methods is designed to illustrate, without limitation, general procedures for the preparation of the compounds of the present disclosure.

[0383] The synthetic processes disclosed herein can tolerate a wide variety of functional groups and, thus, can use various substituted starting materials. The processes generally provide the desired final compound at or near the end of the overall process, although in certain instances it may be desirable to further convert the compound to its pharmaceutically acceptable salt.

[0384] TIFF2025516358000062.tif148150

[0385] Scheme 1 shows the synthesis of compound IB-3, which is a compound of formula (I-B), wherein R 1is C(O)OH, and each of the remaining variables is defined according to formula (I-B). Compound IB-1 is reacted with compound I-L1 under standard conditions for Suzuki coupling to obtain compound IB-2, wherein X A and X T one of which is B(OH) 2 or Bpin, and X A and X T the other of which is -Br, and each of the remaining variables in IB-1 and I-L1 is defined according to formula (I-B). Hydrolysis of the C 1-2 alkyl ester in IB-2 gives the corresponding carboxylic acid, which is then reacted with I-C1 under standard conditions for amide bond formation, wherein each variable in I-C1 is defined according to formula (I-B). Then, removal of the tert-butyl group under standard conditions for deprotection gives compound IB-3.

[0386] TIFF2025516358000063.tif105128

[0387] Compound IC-3 is a compound of formula (I-C), wherein R 1 is C(O)OH, a3c is 1, and each of the remaining variables is defined according to formula (I-C), and is prepared from IA-1 and I-L2 using the method shown for compound IB-3 in Scheme 1 above. One of X A and X T is B(OH) 2 or Bpin, and the other of X A and X T is -Br, and each of the remaining variables in IA-1 and I-L2 is defined according to formula (I-C).

Example

[0388] Example 1. Preparation of Compound 111a 6-(8-(Benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-(((1r,4r)-4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)-3-oxopropyl)cyclohexyl)oxy)-2-methylphenyl)picolinic acid

[0389] Step A. Ethyl (1r,4r)-4-(3-bromo-2-methylphenoxy)cyclohexane-1-carboxylate

[0390] TIFF2025516358000064.tif22128

[0391] To a solution of ethyl 4-hydroxycyclohexanecarboxylate (10 g, 58.06 mmol, 1 equiv) and 3-bromo-2-methyl-phenol (11.95 g, 63.87 mmol, 1.1 equiv) in THF (100 mL) was added DIAD (18.79 g, 92.90 mmol, 18.06 mL, 1.6 equiv) at 0 °C. The mixture was then stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (ethyl acetate / petroleum ether gradient) to give the title compound (3.6 g, 10.55 mmol, yield 18.17%). 3 H NMR (400 MHz, CDCl 1 ) δ 7.14 (d, J = 8.0 Hz, 1H), 6.97 (t, J = 8.0 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 4.20 - 4.11 (m, 3H), 2.39 - 2.35 (m, 2H), 2.30 (s, 3H), 2.19 - 2.14 (m, 2H), 2.09 - 2.04 (m, 2H), 1.62 - 1.52 (m, 5H), 1.26 (t, J = 6.8 Hz, 3H). 3

[0392] Step B. ((1r,4r)-4-(3-bromo-2-methylphenoxy)cyclohexyl)methanol

[0393] TIFF2025516358000065.tif18128

[0394] To a solution of ethyl 4-(3-bromo-2-methyl-phenoxy)cyclohexanecarboxylate (3.6 g, 10.55 mmol, 1 equiv) in THF (15 mL) was added LAH (480.49 mg, 12.66 mmol, 1.2 equiv) at 0 °C. The resulting mixture was then stirred at 25 °C for 1.5 h. The reaction was quenched by adding a saturated aqueous solution of sodium sulfate (10 mL), and then extracted with ethyl acetate (10 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (2.96 g, crude), which was used without further purification. 1 H NMR(400MHz,CDCl 3 )δ7.13(d,J=8.0Hz,1H),6.97(t,J=8.0Hz,1H),6.81(d,J=8.4Hz,1H),4.13-4.08(m,1H),3.50(d,J=6.4Hz,2H),2.30(s,3H),2.20-2.14(m,2H),1.95-1.86(m,2H),1.53-1.45(m,3H),1.14-1.04(m,2H).

[0395] Step C. (1r,4r)-4-(3-Bromo-2-methylphenoxy)cyclohexane-1-carbaldehyde

[0396] TIFF2025516358000066.tif20128

[0397] A solution of DMSO (3.09 g, 39.57 mmol, 3.09 mL, 4 eq) in DCM (10 mL) was added dropwise with a solution of oxalyl chloride (2.51 g, 19.79 mmol, 1.73 mL, 2 eq) in DCM (2 mL) at -70 °C under a nitrogen atmosphere. The mixture was stirred at -70 °C for 1 hour. Then, [4-(3-bromo-2-methyl-phenoxy)cyclohexyl]methanol (2.96 g, 9.89 mmol, 1 eq) in DCM (10 mL) was added dropwise at -70 °C. The solution was stirred at -70 °C for 1 hour. TEA (6.01 g, 59.36 mmol, 8.26 mL, 6 eq) was added and the mixture was stirred at -70 °C for 0.5 hour under a nitrogen atmosphere. The reaction mixture was quenched by the addition of water (10 mL), then diluted with 10 mL of DCM and extracted with DCM (10 mL × 3). The combined organic layers were washed with water (5 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (3 g, crude), which was used without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 9.62 - 9.59 (m, 1H), 7.16 - 7.01 (m, 3H), 4.36 - 4.23 (m, 1H), 2.39 - 2.31 (m, 1H), 2.25 - 2.18 (m, 3H), 2.03 - 1.92 (m, 4H), 1.50 - 1.38 (m, 4H).

[0398] Step D. Ethyl (E)-3-((1r,4r)-4-(3-bromo-2-methylphenoxy)cyclohexyl)acrylate

[0399] TIFF2025516358000067.tif22128

[0400] A solution of NaH (56.52 mg, 1.41 mmol, purity 60%, 2.1 equiv) in THF (3 mL) at 0 °C was added with ethyl 2 - diethoxyphosphorylacetate (301.75 mg, 1.35 mmol, 267.04 mL, 2 equiv). Subsequently, 4-(3 - bromo - 2 - methyl - phenoxy)cyclohexanecarbaldehyde (200 mg, 672.98 mmol, 1 equiv) was added, and the mixture was stirred at 25 °C for 6 h. The reaction mixture was quenched by adding a saturated aqueous solution of ammonium chloride (5 mL) at 0 °C, and then extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with water (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by silica gel chromatography (ethyl acetate / petroleum ether gradient) to give the title compound (140 mg, 362.12 mmol, yield 53.81%). 1 H NMR (400 MHz, CDCl3) δ 7.14 (d, J = 8.0 Hz, 1H), 7.01 - 6.87 (m, 2H), 6.80 (d, J = 8.4 Hz, 1H), 5.82 (dd, J = 1.2, 15.6 Hz, 1H), 4.21 - 4.15 (m, 2H), 4.16 - 4.07 (m, 1H), 2.30 (s, 3H), 2.26 - 2.16 (m, 3H), 1.97 - 1.89 (m, 2H), 1.58 - 1.48 (m, 2H), 1.33 - 1.26 (m, 5H).

[0401] Step E. Ethyl 3 - ((1r,4r)-4-(3 - bromo - 2 - methylphenoxy)cyclohexyl)propanoate

[0402] TIFF2025516358000068.tif22128

[0403] Ethyl (E)-3-[4-(3 - bromo - 2 - methyl - phenoxy)cyclohexyl]prop - 2 - enoate (1.6 g, 4.36 mmol, 1 equiv) in EtOH (15 mL), PtO 2A mixture of (98.92 mg, 435.64 mmol, 0.1 eq) was degassed and purged three times with hydrogen. The mixture was stirred at 25 °C for 3 h under a hydrogen atmosphere (balloon, ~15 psi). The reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by preparative RP-HPLC (water / acetonitrile each having 0.1% formic acid). The fractions containing the pure product were combined and lyophilized to give the title compound (1.4 g, 3.79 mmol, 87.02% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.17 - 7.10 (m, 1H), 7.06 (t, J = 8.0 Hz, 1H), 7.03 - 6.99 (m, 1H), 4.27 - 4.17 (m, 1H), 4.11 - 4.04 (m, 2H), 2.33 - 2.26 (m, 2H), 2.20 (s, 3H), 2.03 (d, J = 10.0 Hz, 2H), 1.75 (d, J = 12.0 Hz, 2H), 1.55 - 1.42 (m, 2H), 1.39 - 1.21 (m, 3H), 1.17 (t, J = 7.2 Hz, 3H), 1.11 - 0.97 (m, 2H).

[0404] Step F. tert-Butyl 6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-(((1r,4r)-4-(3-ethoxy-3-oxopropyl)cyclohexyl)oxy)-2-methylphenyl)picolinate

[0405] TIFF2025516358000069.tif39128

[0406] Ethyl 3-[4-(3-bromo-2-methyl-phenoxy)cyclohexyl]propanoate (200 mg, 541.58 mmol, 1 equiv), tert-butyl 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxylate (546.40 mg, 758.21 mmol, 1.4 equiv), [2-(2-aminophenyl)phenyl]palladium(1+); bis(1-adamantyl)-butyl-phosphane; methanesulfonate (78.88 mg, 108.32 mmol, 0.2 equiv), and an aqueous solution of potassium carbonate (1.5 M, 541.58 mL, 1.5 equiv) in dioxane (2.5 mL) were degassed and purged three times with nitrogen. The mixture was stirred at 100 °C for 1 h under microwave heating. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (ethyl acetate / petroleum ether gradient) to afford the title compound (440 mg, crude). 1 H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J = 7.6 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.50 - 7.40 (m, 3H), 7.40 - 7.30 (m, 2H), 7.12 - 7.03 (m, 1H), 6.99 - 6.89 (m, 2H), 6.59 - 6.49 (m, 1H), 5.03 - 4.90 (m, 2H), 4.27 - 4.14 (m, 1H), 4.03 (d, J = 6.8 Hz, 2H), 3.87 (t, J = 5.6 Hz, 2H), 3.29 (s, 2H), 3.03 (t, J = 5.6 Hz, 2H), 2.29 (t, J = 7.6 Hz, 2H), 2.05 (d, J = 11.2 Hz, 1H), 1.84 (s, 3H), 1.79 - 1.70 (m, 2H), 1.50 - 1.42 (m, 2H), 1.23 (d, J = 8.4 Hz, 2H), 1.19 - 1.17 (m, 3H), 1.07 (s, 2H), 1.00 (s, 9H).

[0407] Engineering G. 3 - ((1r,4r)-4-(3-(6-(8-(Benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-(tert-butoxycarbonyl)pyridin-3-yl)-2-methylphenoxy)cyclohexyl)propanoic acid

[0408] TIFF2025516358000070.tif51128

[0409] A mixture of tert-butyl 6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-(((1r,4r)-4-(3-ethoxy-3-oxopropyl)cyclohexyl)oxy)-2-methylphenyl)picolinate (440 mg, 567.77 mmol, 1 equiv), LiOH monohydrate (71.47 mg, 1.70 mmol, 3 equiv) in THF (1.2 mL) and water (0.4 mL) was stirred at 25 °C for 1.5 h. The mixture was concentrated, redissolved in water (20 mL), and the pH was adjusted to 2 by adding an aqueous solution of 1 M HCl. The resulting solid was filtered and dried under reduced pressure to give the title compound (380 mg, 508.76 mmol, yield 89.61%).

[0410] Engineering H. tert-butyl 6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-(((1r,4r)-4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)-3-oxopropyl)cyclohexyl)oxy)-2-methylphenyl)picolinate

[0411] TIFF2025516358000071.tif51128

[0412] A mixture of 3-[4-[3-[6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-tert-butoxycarbonyl-3-pyridyl]-2-methyl-phenoxy]cyclohexyl]propanoic acid (150 mg, 200.83 mmol, 1 equiv), 2-(2,6-dioxo-3-piperidyl)-5-fluoro-6-piperazin-1-yl-isoindoline-1,3-dione (72.37 mg, 200.83 mmol, 1 equiv), HATU (114.54 mg, 301.24 mmol, 1.5 equiv), and DIPEA (77.86 mg, 602.48 mmol, 104.94 mL, 3 equiv) in DMF (1.5 mL) was stirred at 25 °C for 12 h. The mixture was concentrated under reduced pressure to give the title compound (120 mg, crude).

[0413] Step I. 6-(8-(Benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-(((1r,4r)-4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)-3-oxopropyl)cyclohexyl)oxy)-2-methylphenyl)picolinate

[0414] TIFF2025516358000072.tif47128

[0415] tert-Butyl 6-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-(((1r,4r)-4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)-3-oxopropyl)cyclohexyl)oxy)-2-methylphenyl)picolinic acid (120 mg, 110.17 mmol, 1 equiv) in TFA (0.8 mL) and DCM (0.8 mL) was stirred at 40 °C for 1.5 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by preparative RP-HPLC (water / acetonitrile each having 0.1% formic acid). The fractions containing the pure product were combined and lyophilized to give the title compound (54.27 mg, 50.87 mmol, 46.17% yield, 96.84% purity). MS (ESI) m / z: 1033.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ = 13.00 - 12.72 (m, 1H), 11.11 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 8.00 - 8.00 (m, 1H), 7.82 - 7.73 (m, 2H), 7.62 (d, J = 7.6 Hz, 1H), 7.57 - 7.12 (m, 7H), 7.11 - 7.04 (m, 1H), 6.94 (dd, J = 8.4, 17.6 Hz, 2H), 6.61 (d, J = 7.6 Hz, 1H), 5.11 (dd, J = 5.2, 12.8 Hz, 1H), 4.98 (s, 2H), 4.25 - 4.14 (m, 1H), 3.91 (t, J = 5.6 Hz, 2H), 3.76 (s, 3H), 3.28 - 3.19 (m, 4H), 3.02 (t, J = 5.6 Hz, 2H), 2.93 - 2.84 (m, 1H), 2.64 - 2.53 (m, 2H), 2.38 (t, J = 7.6 Hz, 2H), 2.13 - 1.99 (m, 3H), 1.87 (s, 3H), 1.81 (d, J = 11.2 Hz, 2H), 1.52 - 1.24 (m, 6H), 1.15 - 1.02 (m, 2H).

[0416] Example 2. Preparation of Compound 104 6-(8-(Benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-((7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)heptyl)oxy)-2-methylphenyl)picolinate

[0417] Step A. tert-Butyl 8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0418] TIFF2025516358000073.tif39128

[0419] 2-(tert-Butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid (6.5 g, 1 equivalent, 23 mmol) was dissolved in dimethylformamide (30 mL). To the mixture were added HATU (11 g, 1.2 equivalents, 28 mmol), followed by benzothiazol-2-amine (4.2 g, 1.2 equivalents, 28 mmol) and N,N-diisopropylethylamine (4.5 g, 6.1 mL, 1.5 equivalents, 35 mmol). The mixture was stirred at room temperature overnight. The mixture was concentrated. The crude product was extracted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was then purified by silica gel chromatography (ethyl acetate / hexane) to give the title compound (8.1 g, 20 mmol, 84% yield). MS (ESI) m / z: 410.2 [M+H] +

[0420] Step B. N-(Benzothiazol-2-yl)-1,2,3,4-tetrahydroisoquinoline-8-carboxamide hydrochloride

[0421] TIFF2025516358000074.tif39128

[0422] tert-Butyl 8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (8 g, 0.02 mol) was suspended in 4 M HCl in 1,4-dioxane (80 mL). The mixture was then stirred at room temperature overnight. The precipitate was collected by filtration. The solid was washed three times with ethyl acetate and then dried under vacuum to give the title compound (8 g, 0.02 mol, yield 100%). MS (ESI) m / z: 310.1 [M+H] +

[0423] Step C. tert-Butyl 6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-bromopicolinate

[0424] TIFF2025516358000075.tif40128

[0425] N-(Benzo[d]thiazol-2-yl)-1,2,3,4-tetrahydroisoquinoline-8-carboxamide, HCl (6.0 g, 1 equivalent, 17 mmol) was suspended in dimethylacetamide (60 mL). To the mixture was added tert-butyl 3-bromo-6-chloropicolinate (6.6 g, 1.3 equivalents, 23 mmol), followed by cesium carbonate (28 g, 5 equivalents, 87 mmol). The mixture was then heated at 120 °C for 20 h. The mixture was cooled to room temperature. Then 180 mL of water was added to the mixture. The mixture was then stirred at room temperature for 10 min, after which the mixture was filtered and washed with water. The product was then recrystallized from 40 mL of ethanol. The precipitate was collected by filtration and washed twice with ethanol. The solid was then dried under vacuum overnight to give the title compound (5.2 g, 9.2 mmol, yield 53%). MS (ESI) m / z: 565.1 [M+H] +

[0426] Step D. Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

[0427] TIFF2025516358000076.tif23128

[0428] 3-Bromo-2-methylphenol (2.0 g, 1 equivalent, 11 mmol) was dissolved in 1,4-dioxane (20 mL). To the mixture were added 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi(1,3,2-dioxaborolane) (4.1 g, 1.5 equivalents, 16 mmol), followed by potassium acetate (3.1 g, 3 equivalents, 32 mmol) and PdCl 2 (dppf)-CH 2 Cl 2 adduct (0.44 g, 0.05 equivalent, 0.53 mmol). The mixture was then heated at 85 °C. After overnight, the mixture was cooled to room temperature. The mixture was then filtered through celite, and the filtrate was extracted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over Na 2 SO 4 and filtered, and evaporated to dryness. The crude product was then purified by silica gel chromatography (ethyl acetate / hexane gradient). The combined fractions were evaporated to dryness. The product was then recrystallized from cold ether to give the title compound (2.1 g, 9.0 mmol, 84% yield). MS (ESI) m / z: 235.2 [M+H] +

[0429] Step E. 7-(2-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)heptan-1-ol

[0430] TIFF2025516358000077.tif23128

[0431] 2-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (100 mg, 1 equivalent, 427 μmol), 7-bromoheptan-1-ol (91.7 mg, 1.1 equivalents, 470 μmol), and K 2 CO 3(177 mg, 3 eq, 1.28 mmol) was suspended in acetonitrile (4 mL). The mixture was then heated at 70 °C overnight. After completion, the mixture was evaporated. The crude product was then purified by silica gel chromatography (ethyl acetate / hexane gradient) to give the title product 7-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)heptan-1-ol (108 mg, 310 μmol, 72.6% yield). MS(ESI) m / z: 349.3 [M+H] +

[0432] Step F. tert-Butyl 6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-((7-hydroxyheptyl)oxy)-2-methylphenyl)picolinate

[0433] TIFF2025516358000078.tif40128

[0434] tert-Butyl 6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-bromopicolinate (150 mg, 1 eq, 265 μmol), 7-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)heptan-1-ol (111 mg, 1.2 eq, 318 μmol), and mesylate [(di(1-adamantyl)-n-butylphosphine)-2-(2’-amino-1,1’-biphenyl)]palladium(II) (9.66 mg, 0.05 eq, 13.3 μmol) were suspended in 1,4-dioxane (2.4 mL) and 0.6 mL of 1.5 M K 3 PO 4 (aqueous solution). The mixture was heated at 100 °C for 30 minutes using microwave. After completion, the mixture was concentrated and then purified by preparative RP-HPLC (water / acetonitrile each having 0.1% formic acid). The fractions containing the pure product were combined and lyophilized to give the title compound (67 mg, 95 μmol, 36%). MS(ESI) m / z: 707.3 [M+H]+

[0435] Step G. tert-Butyl 6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(2-methyl-3-((7-oxoheptyl)oxy)phenyl)picolinate

[0436] TIFF2025516358000079.tif39128

[0437] tert-Butyl 6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-((7-hydroxyheptyl)oxy)-2-methylphenyl)picolinate (50 mg, 1 equiv, 71 μmol) was dissolved in dichloromethane (4 mL). Dess-Martin periodinane (36 mg, 26 μL, 1.2 equiv, 85 μmol) was added to the mixture. The mixture was then stirred at room temperature for 2 h. A few drops of methanol were added. The mixture was then concentrated under reduced pressure to afford the title compound, which was used without further purification. MS(ESI) m / z: 705.3 [M+H] +

[0438] Step H. tert-Butyl 6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-((7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)heptyl)oxy)-2-methylphenyl)picolinate

[0439] TIFF2025516358000080.tif44135

[0440] tert-Butyl 6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(2-methyl-3-((7-oxoheptyl)oxy)phenyl)picolinate (crude, 50 mg, 1 eq, 71 μmol) was resuspended in ethanol (5 mL). To the mixture was added 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(piperazin-1-yl)isoindoline-1,3-dione (38 mg, 1.5 eq, 0.11 mmol), followed by sodium cyanoborohydride (22 mg, 5 eq, 0.35 mmol) and acetic acid (4.3 mg, 4.1 μL, 1 eq, 71 μmol). The mixture was then stirred at room temperature overnight. After completion, the solvent was removed. The crude product was then purified by preparative RP-HPLC (water / acetonitrile each having 0.1% formic acid). The fractions containing the pure product were combined and lyophilized to give the title compound (30 mg, 29 μmol, 40%). MS (ESI) m / z: 1049.3 [M+H] +

[0441] Step I. 6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-((7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)heptyl)oxy)-2-methylphenyl)picolinate

[0442] TIFF2025516358000081.tif44135

[0443] tert-Butyl 6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-((7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)heptyl)oxy)-2-methylphenyl)picolinate (30 mg, 1 equivalent, 29 μmol) was dissolved in dichloromethane (2.4 mL). 0.6 mL of TFA was added to the mixture. The mixture was then stirred at room temperature for 24 hours. The solvent was removed. The residue was then purified by preparative RP-HPLC (water / acetonitrile each having 0.1% formic acid). The fractions containing the pure product were combined and lyophilized to give the title compound (15 mg, 15 μmol, 53%) as a yellow solid. MS (ESI) m / z: 993.2 [M+H] +

[0444] Example 3. Preparation of Compound 106 6-[8-(1,3-Benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[3-[2-[1-[2-[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]piperazin-1-yl]-2-oxo-ethyl]-4-piperidyl]ethoxy]-2-methyl-phenyl]pyridine-2-carboxylic acid

[0445] Step A. tert-Butyl 4-[2-(3-bromo-2-methyl-phenoxy)ethyl]piperidine-1-carboxylate

[0446] TIFF2025516358000082.tif22128

[0447] tert-Butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (5 g, 21.80 mmol, 1 equivalent), 3-bromo-2-methyl-phenol (4.08 g, 21.80 mmol, 1 equivalent), PPh 3A mixture of (7.43 g, 28.35 mmol, 1.3 eq) was degassed and purged three times with nitrogen, then DIAD (5.29 g, 26.16 mmol, 5.09 mL, 1.2 eq) was added dropwise at 0 °C, and the mixture was stirred at 25 °C for 12 h. The reaction was diluted with H 2 O (100 mL) and extracted with EtOAC (60 mL × 3). The combined organic layers were washed with H 2 O (60 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a residue, which was then purified by silica gel chromatography (ethyl acetate / hexane) to give the title compound (8.2 g, 18.53 mmol, 84.97% yield). MS (ESI) m / z: 344.0 [M-tBu] + .

[0448] Step B. 4-[2-(3-Bromo-2-methyl-phenoxy)ethyl]piperidine

[0449] TIFF2025516358000083.tif18128

[0450] To a solution of tert-butyl 4-[2-(3-bromo-2-methyl-phenoxy)ethyl]piperidine-1-carboxylate (8.2 g, 20.59 mmol, 1 eq) in dioxane (100 mL) was added 4.0 N HCl in dioxane. The mixture was stirred at 25 °C for 2 h and then concentrated under reduced pressure to give the title compound, which was used without further purification (6 g, crude).

[0451] Step C. Ethyl 2-[4-[2-(3-bromo-2-methyl-phenoxy)ethyl]-1-piperidyl]acetate

[0452] TIFF2025516358000084.tif18128

[0453] A solution of 4-[2-(3-bromo-2-methyl-phenoxy)ethyl]piperidine (3 g, 10.06 mmol, 1 equiv) in ACN (30 mL) was added with ethyl 2-bromoacetate (2.02 g, 12.07 mmol, 1.34 mL, 1.2 equiv) and TEA (3.05 g, 30.18 mmol, 4.20 mL, 3 equiv). The mixture was stirred at 20 °C for 12 h. Then, it was diluted with H 2 O (30 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic layers were washed with H 2 O (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was then purified by silica gel chromatography (ethyl acetate / hexane) to give the title compound (3 g, 7.73 mmol, yield 76.82%). MS (ESI) m / z: 385.8 [M+H] + .

[0454] Step D. tert-Butyl 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[3-[2-[1-(2-ethoxy-2-oxo-ethyl)-4-piperidyl]ethoxy]-2-methyl-phenyl]pyridine-2-carboxylate

[0455] TIFF2025516358000085.tif54128

[0456] A solution of ethyl 2-[4-[2-(3-bromo-2-methyl-phenoxy)ethyl]-1-piperidyl]acetate (700 mg, 1.82 mmol, 1 equiv) in 1,4-dioxane (8 mL) was added to di-tert-butyl(cyclopentyl)phosphane; dichloropalladium; iron (237.43 mg, 364.29 mmol, 0.2 equiv), KF (1.5 M, 1.82 mL, 1.5 equiv), and tert-butyl 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxylate (1.23 g, 2.00 mmol, 1.1 equiv). The mixture was stirred at 90 °C for 2 h, then diluted with 30 mL of H 2 O and extracted with ethyl acetate (60 mL × 3). The combined organic layers were washed with H 2 O (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was then purified by silica gel chromatography (ethyl acetate / hexane) to give the title compound (600 mg, 721.54 mmol, 39.61% yield). MS (ESI) m / z: 790.5 [M+H] + .

[0457] Step E. 2-[4-[2-[3-[6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-tert-butoxycarbonyl-3-pyridyl]-2-methyl-phenoxy]ethyl]-1-piperidyl]acetic acid

[0458] TIFF2025516358000086.tif54128

[0459] A solution of tert-butyl 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[3-[2-[1-(2-ethoxy-2-oxo-ethyl)-4-piperidyl]ethoxy]-2-methyl-phenyl]pyridine-2-carboxylate (600 mg, 759.51 mmol, 1 equiv) in THF (3 mL) was added with LiOH·H2O (95.62 mg, 2.28 mmol, 3 equiv) and H2O (1 mL). The mixture was stirred at 20 °C for 1 h. The pH of the reaction mixture was adjusted to 5 with citric acid, diluted with H 2 O (10 mL), and extracted with DCM (10 mL × 3). The combined organic layers were washed with H 2 O (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound, which was used without further purification (410 mg, crude). MS (ESI) m / z: 762.3 [M+H] + .

[0460] Step F. tert-butyl 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[3-[2-[1-[2-[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]piperazin-1-yl]-2-oxo-ethyl]-4-piperidyl]ethoxy]-2-methyl-phenyl]pyridine-2-carboxylate

[0461] TIFF2025516358000087.tif73128

[0462] A solution of 2-[4-[2-[3-[6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-tert-butoxycarbonyl-3-pyridyl]-2-methyl-phenoxy]ethyl]-1-piperidyl]acetic acid (70 mg, 91.87 mmol, 1 equiv) in DMF (1 mL) was added with 2-(2,6-dioxo-3-piperidyl)-5-fluoro-6-piperazin-1-yl-isoindoline-1,3-dione (36.42 mg, 101.06 mmol, 1.1 equiv), HATU (38.43 mg, 101.06 mmol, 1.1 equiv), and DIPEA (35.62 mg, 275.62 mmol, 48.01 mL, 3 equiv) at 25 °C. The reaction mixture was stirred at 25 °C for 2 h, then the reaction mixture was diluted with 5 mL of water and filtered to obtain the title compound, which was used without further purification (166 mg, crude). MS(ESI) m / z: 553.1 [M+2H] + / 2。

[0463] Step G. 6-[8-(1,3-Benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[3-[2-[1-[2-[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]piperazin-1-yl]-2-oxo-ethyl]-4-piperidyl]ethoxy]-2-methyl-phenyl]pyridine-2-carboxylic acid

[0464] TIFF2025516358000088.tif68128

[0465] A solution of tert-butyl 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[3-[2-[1-[2-[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxoisoindolin-5-yl]piperazin-1-yl]-2-oxo-ethyl]-4-piperidyl]ethoxy]-2-methyl-phenyl]pyridine-2-carboxylate (166 mg, 150.33 mmol, 1 eq) in DCM (1 mL) and TFA (1 mL) was stirred at 40 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by preparative RP-HPLC (water / acetonitrile each having 0.1% formic acid). The fractions containing the pure product were combined and lyophilized to give the title compound (32.33 mg, 29.18 mmol, yield 19.41%, purity 94.60%). MS (ESI) m / z: 1048.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.11 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.81 - 7.73 (m, 2H), 7.62 (d, J = 7.6 Hz, 1H), 7.55 - 7.28 (m, 7H), 7.09 (t, J = 8.0 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.62 (d, J = 7.6 Hz, 1H), 5.11 (dd, J = 5.4, 12.8 Hz, 1H), 4.98 (s, 2H), 4.04 - 3.96 (m, 2H), 3.92 (t, J = 5.6 Hz, 2H), 3.77 - 3.70 (m, 2H), 3.62 (s, 2H), 3.21 (s, 4H), 3.03 (t, J = 5.6 Hz, 2H), 2.91 - 2.81 (m, 3H), 2.63 - 2.57 (m, 2H), 2.11 - 1.98 (m, 3H), 1.88 (s, 3H), 1.79 - 1.64 (m, 5H), 1.50 (d, J = 3.2 Hz, 1H), 1.25 (d, J = 11.6 Hz, 3H).

[0466] Example 4. Preparation of Compound 110 6-[8-(1,3-Benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[3-[4-[3-[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxoisoindolin-5-yl]piperazin-1-yl]propyl]phenoxy]-2-methyl-phenyl]pyridine-2-carboxylic acid

[0467] Step A. Ethyl 3-[4-(3-bromo-2-methyl-phenoxy)phenyl]propanoate

[0468] TIFF2025516358000089.tif23128

[0469] A mixture of ethyl 3-(4-hydroxyphenyl)propanoate (5 g, 25.74 mmol, 1 equiv), 1,3-dibromo-2-methyl-benzene (12.87 g, 51.49 mmol, 2 equiv), Cs 2 CO 3 (10.07 g, 30.89 mmol, 1.2 equiv), and 2,2,6,6-tetramethylheptane-3,5-dione (1.19 g, 6.44 mmol, 1.33 mL, 0.25 equiv) in NMP (50 mL) was degassed and purged three times with nitrogen. Then CuI (2.45 g, 12.87 mmol, 0.5 equiv) was added and the mixture was stirred at 120 °C for 12 h under a nitrogen atmosphere. The reaction mixture was filtered, the filtrate was diluted with 30 mL of water and extracted with ethyl acetate (40 mL × 2). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was then purified by silica gel chromatography (ethyl acetate / hexane) to give the title compound (7.6 g, 20.92 mmol, 81.27% yield). 1 H NMR(400MHz,CDCl 3)δ 7.35 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 8.4 Hz, 2H), 7.01 (t, J = 8.0 Hz, 1H), 6.86 - 6.80 (m, 3H), 4.14 (q, J = 7.2 Hz, 2H), 2.93 (t, J = 8.0 Hz, 2H), 2.61 (t, J = 8.0 Hz, 2H), 2.34 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H).

[0470] Process B. 3-[4-(3-Bromo-2-methyl-phenoxy)phenyl]propan-1-ol

[0471] TIFF2025516358000090.tif18128

[0472] To a mixture of ethyl 3-[4-(3-bromo-2-methyl-phenoxy)phenyl]propanoate (7.6 g, 20.92 mmol, 1 equiv) in THF (70 mL), LiAlH 4 (794.01 mg, 20.92 mmol, 1 equiv) was added slowly at 0 °C, then the mixture was stirred at 25 °C for 2 h under a nitrogen atmosphere. The mixture was slowly poured into ice water (150 mL). The pH was adjusted to pH 4 - 5, extracted with EtOAc (60 mL × 3), washed with brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound, which was used without further purification (6 g, 18.68 mmol, 89.28% yield). 1 H NMR (400 MHz, CDCl 3 ) δ = 7.32 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 8.4 Hz, 2H), 6.98 (t, J = 8.0 Hz, 1H), 6.85 - 6.79 (m, 3H), 3.67 (t, J = 6.4 Hz, 2H), 2.70 - 2.66 (m, 2H), 2.33 (s, 3H), 1.91 - 1.83 (m, 2H).

[0473] Process C. 3-[4-(3-Bromo-2-methyl-phenoxy)phenyl]propanal

[0474] TIFF2025516358000091.tif18128

[0475] A solution of oxalyl dichloride (2.37 g, 18.68 mmol, 1.64 mL, 2 eq) in DCM (5 mL) was added a mixture of DMSO (2.92 g, 37.36 mmol, 2.92 mL, 4 eq) in DCM (5 mL) at -70 °C and stirred for 0.5 h. 3-[4-(3-Bromo-2-methyl-phenoxy)phenyl]propan-1-ol (3 g, 9.34 mmol, 1 eq) in DCM (5 mL) was added to the mixture over 20 min. TEA (5.67 g, 56.04 mmol, 7.80 mL, 6 eq) was added to the mixture and then the reaction was stirred at -70 °C for 2 h. The reaction mixture was quenched by the addition of water (60 mL) at 0 °C and then extracted with DCM (30 mL×2). The combined organic layers were washed with brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (ethyl acetate / hexane) to give the title compound (2.6 g, 8.15 mmol, yield 87.21%). 1 H NMR(400MHz,CDCl 3 )δ9.84(s,1H),7.35(d,J=8.0Hz,1H),7.15(d,J=8.4Hz,2H),7.02(t,J=8.0Hz,1H),6.86-6.81(m,3H),2.97-2.91(m,2H),2.82-2.76(m,2H),2.34(s,3H).

[0476] Step D. tert-Butyl 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[2-methyl-3-[4-(3-oxopropyl)phenoxy]phenyl]pyridine-2-carboxylate

[0477] TIFF2025516358000092.tif47128

[0478] 3-[4-(3-Bromo-2-methyl-phenoxy)phenyl]propanal (100 mg, 313.29 mmol, 1 equiv), tert-butyl 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxylate (153.52 mg, 250.63 mmol, 0.8 equiv), Ad2nBuP Pd G3 (cataCXium® A Pd G3, 45.63 mg, 62.66 mmol, 0.2 equiv), K 2 CO 3 (1.5 M aqueous solution, 313.29 mL, 1.5 equiv) solution was degassed and purged with nitrogen three times, then the mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (methanol / DCM) to give the title compound (100 mg, 107.30 mmol, yield 11.42%). MS (ESI) m / z: 725.2 [M+H] + 。

[0479] Step E. tert-butyl 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[3-[4-[3-[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]piperazin-1-yl]propyl]phenoxy]-2-methyl-phenyl]pyridine-2-carboxylate

[0480] TIFF2025516358000093.tif46128

[0481] tert-Butyl 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[2-methyl-3-[4-(3-oxopropyl)phenoxy]phenyl]pyridine-2-carboxylate (100 mg, 137.96 mmol, 1 eq), 2-(2,6-dioxo-3-piperidyl)-5-fluoro-6-piperazin-1-yl-isoindoline-1,3-dione (49.71 mg, 137.96 mmol, 1 eq), acetic acid (8.28 mg, 137.96 mmol, 7.89 mL, 1 eq), NaBH(OAc) 3 (43.86 mg, 206.94 mmol, 1.5 eq) in DCM (1 mL) was degassed and purged three times with nitrogen. The mixture was stirred at 25 °C for 20 h under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (ethyl acetate / hexane) to give the title compound (150 mg, 104.10 mmol, 75.46% yield). MS (ESI) m / z: 1071.3 [M+H] + .

[0482] Step F. 6-[8-(1,3-Benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[3-[4-[3-[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]piperazin-1-yl]propyl]phenoxy]-2-methyl-phenyl]pyridine-2-carboxylic acid

[0483] TIFF2025516358000094.tif42128

[0484] A mixture of tert-butyl 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[3-[4-[3-[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxoisoindolin-5-yl]piperazin-1-yl]propyl]phenoxy]-2-methylphenyl]pyridine-2-carboxylate (120 mg, 112.23 mmol, 1 equiv), TFA (12.80 mg, 112.23 mmol, 8.31 mL, 1 equiv) in DCM (1 mL) was stirred at 25 °C for 3 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by preparative RP-HPLC (water / acetonitrile each having 0.1% formic acid). The fractions containing the pure product were combined and lyophilized to give the title compound (38.86 mg, 36.59 mmol, yield 32.60%, purity 95.4%). MS (ESI) m / z: 1070.3 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.40 (d, J = 7.6 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 7.2 Hz, 1H), 7.56 - 7.45 (m, 4H), 7.43 - 7.38 (m, 3H), 7.23 (s, 1H), 7.11 - 7.06 (m, 3H), 6.96 (d, J = 9.2 Hz, 1H), 6.91 (d, J = 8.0 Hz, 2H), 5.24 (s, 2H), 5.00 - 4.91 (m, 1H), 3.94 (t, J = 6.4 Hz, 2H), 3.60 (s, 4H), 3.17 (t, J = 6.0 Hz, 2H), 3.07 - 2.96 (m, 4H), 2.92 - 2.79 (m, 3H), 2.76 - 2.68 (m, 3H), 2.20 - 2.12 (m, 4H), 1.92 (s, 3H).

[0485] Example 5. Preparation of Compound 118 TIFF2025516358000095.tif321286-(8-(Benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-(3-(1-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-4-yl)propoxy)-2-methylphenyl)picolinate

[0486] Step A. tert-Butyl 4-[3-(3-bromo-2-methyl-phenoxy)propyl]piperidine-1-carboxylate To a solution of 3-bromo-2-methyl-phenol (1 g, 5.35 mmol, 1 equiv) and tert-butyl 4-(3-bromopropyl)piperidine-1-carboxylate (1.64 g, 5.35 mmol, 1 equiv) in MeCN (4 mL) was added K 2 CO 3 (2.22 g, 16.04 mmol, 3 equiv), and the mixture was stirred at 60 °C. After 2 h, the reaction solution was concentrated under reduced pressure and purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give tert-butyl 4-[3-(3-bromo-2-methyl-phenoxy)propyl]piperidine-1-carboxylate (2.2 g, 5.34 mmol, 99.8% yield) as a colorless oil. MS (ESI) m / z: 312.4 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ = 7.14 (d, J = 8.0 Hz, 1H), 6.99 (t, J = 8.0 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 4.14 - 4.06 (m, 2H), 3.94 (t, J = 6.4 Hz, 2H), 2.69 (t, J = 2.4, 12.8 Hz, 2H), 2.32 (s, 3H), 1.88 - 1.79 (m, 2H), 1.70 (d, J = 12.8 Hz, 2H), 1.48 - 1.43 (m, 12H), 1.18 - 1.08 (m, 2H)

[0487] Process B. 4-[3-(3-Bromo-2-methyl-phenoxy)propyl]piperidine A solution of tert-butyl 4-[3-(3-bromo-2-methyl-phenoxy)propyl]piperidine-1-carboxylate (2.2 g, 5.34 mmol, 1 eq) in 4 M HCl in EtOAc (10 mL) was stirred at 25 °C. After 1 hour, the reaction mixture was filtered and concentrated under reduced pressure to give 4-[3-(3-bromo-2-methyl-phenoxy)propyl]piperidine (1.6 g, 5.12 mmol, 96.05% yield) as a white solid, which was carried on to the next step without further purification. MS (ESI) m / z: 314.4 [M+H] + ; 1 HNMR (400 MHz, CDCl 3 ) δ = 7.14 (d, J = 8.0 Hz, 1H), 6.99 (t, J = 8.0 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 4.14 - 4.06 (m, 2H), 3.94 (t, J = 6.4 Hz, 2H), 2.69 (t, J = 2.4, 12.8 Hz, 2H), 2.32 (s, 3H), 1.88 - 1.79 (m, 2H), 1.70 (d, J = 12.8 Hz, 2H), 1.48 - 1.43 (m, 12H), 1.18 - 1.08 (m, 2H).

[0488] Process C. 4-[3-(3-Bromo-2-methyl-phenoxy)propyl]-1-(2,2-diethoxyethyl)piperidine To a solution of 4-[3-(3-bromo-2-methyl-phenoxy)propyl]piperidine (1.5 g, 4.80 mmol, 1 eq) and 2-bromo-1,1-diethoxy-ethane (946.71 mg, 4.80 mmol, 722.68 uL, 1 eq) in MeCN (5 mL) was added K 2 CO 3 (1.99 g, 14.41 mmol, 3 eq) and potassium iodide (797.46 mg, 4.80 mmol, 1 eq). The mixture was stirred at 80 °C for 8 hours. The reaction mixture was concentrated under reduced pressure and subjected to column chromatography (SiO 2, purified by ethyl acetate / MeOH = 1 / 0 to 20 / 1), to obtain 4-[3-(3-bromo-2-methyl-phenoxy)propyl]-1-(2,2-diethoxyethyl)piperidine (1.7 g, 3.97 mmol, 82.6% yield) as a yellow oil. MS(ESI) m / z: 430.5 [M+H] + 。

[0489] Step D. tert-Butyl 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[3-[3-[1-(2,2-diethoxyethyl)-4-piperidyl]propoxy]-2-methyl-phenyl]pyridine-2-carboxylate A mixture of 4-[3-(3-bromo-2-methyl-phenoxy)propyl]-1-(2,2-diethoxyethyl)piperidine (800 mg, 1.87 mmol, 1 equivalent), tert-butyl 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxylate (1.14 g, 1.87 mmol, 1 equivalent), and [2-(2-aminophenyl)phenyl]palladium(1+); bis(1-adamantyl)-butyl-phosphane; methanesulfonate (136.00 mg, 186.74 μmol, 0.1 equivalent), KF (1.5 M, 3.73 mL, 3 equivalents) in dioxane (5 mL) and H 2 O (1 mL) was degassed and purged 3 times with N 2 and then stirred at 100 °C in a microwave reactor. After 1 hour, the reaction solution was concentrated under reduced pressure and purified by column chromatography (SiO 2, purified by ethyl acetate / MeOH = 1 / 0 to 10 / 1), to obtain compound tert-butyl 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[3-[3-[1-(2,2-diethoxyethyl)-4-piperidyl]propoxy]-2-methyl-phenyl]pyridine-2-carboxylate (1.5 g, 1.72 mmol, yield 91.99%, purity 95.52%) as a yellow oil, which was carried forward without further purification. MS(ESI) m / z: 834.8 [M+H] + ; 1 H NMR(400MHz,CDCl 3 ) δ = 7.85 (d, J = 8.0Hz, 1H), 7.59 (dd, J = 7.2, 15.6Hz, 2H), 7.40 - 7.30 (m, 5H), 7.14 - 7.06 (m, 1H), 6.90 (d, J = 8.8Hz, 1H), 6.80 (d, J = 8.4Hz, 1H), 6.69 (d, J = 7.6Hz, 1H), 5.12 - 4.95 (m, 2H), 4.81 - 4.60 (m, 1H), 4.12 - 4.08 (m, 2H), 3.97 (t, J = 6.4Hz, 2H), 3.72 - 3.68 (m, 2H), 3.61 - 3.54 (m, 2H), 3.07 (t, J = 5.2Hz, 4H), 2.64 - 2.52 (m, 2H), 2.05 (s, 3H), 1.84 - 1.80 (m, 2H), 1.69 - 1.55 (m, 9H), 1.24 - 1.20 (m, 6H), 1.15 (s, 9H).

[0490] Step E. 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[2-methyl-3-[3-[1-(2-oxoethyl)-4-piperidyl]propoxy]phenyl]pyridine-2-carboxylic acid To a solution of tert-butyl 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[3-[3-[1-(2,2-diethoxyethyl)-4-piperidyl]propoxy]-2-methyl-phenyl]pyridine-2-carboxylate (100 mg, 119.89 μmol, 1 equiv) in formic acid (2 mL). The mixture was stirred at 90 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[2-methyl-3-[3-[1-(2-oxoethyl)-4-piperidyl]propoxy]phenyl]pyridine-2-carboxylic acid hydrochloride (70 mg, 99.5 μmol, 83% yield) as a dark green oil, which was carried on without further purification. MS(ESI) m / z: 722.5 [M+H] + .

[0491] Step F. 6-[8-(1,3-Benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[3-[3-[1-[2-[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxo-isoindolin-5-yl]piperazin-1-yl]ethyl]-4-piperidyl]propoxy]-2-methyl-phenyl]pyridine-2-carboxylic acid To a solution of 2-(2,6-dioxo-3-piperidyl)-5-fluoro-6-piperazin-1-yl-isoindoline-1,3-dione hydrochloride (47.36 mg, 119.34 μmol, 1.2 equiv) in dichloromethane (2 mL) at 0 °C was added a solution of 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[2-methyl-3-[3-[1-(2-oxoethyl)-4-piperidyl]propoxy]phenyl]pyridine-2-carboxylic acid (70 mg, 99.45 μmol, 1 equiv). The mixture was warmed to room temperature with stirring. After 15 min, NaBH(OAc) 3(63.23 mg, 298.36 μmol, 3 eq) was added, and the mixture was stirred at 25 °C for 15 minutes. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (column: Phenomenex luna C18 150×25 mm×10 μm; mobile phase: [water (1% formic acid)-MeCN]; B%: 28% - 58%, 8 min) to give 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[3-[3-[1-[2-[4-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1,3-dioxoisoindolin-5-yl]piperazin-1-yl]ethyl]-4-piperidyl]propoxy]-2-methyl-phenyl]pyridine-2-carboxylic acid (11.8 mg, 10.8 μmol, yield 10.8%, purity 95.9%) as a yellow solid. MS (ESI) m / z: 1048.5 [M+H] + ; 1 1H NMR (400 MHz, DMSO-d 6 ) δ = 11.10 (s, 1H), 8.18 (s, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 11.2 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.48 - 7.40 (m, 3H), 7.39 - 7.31 (m, 3H), 7.07 (t, J = 7.6 Hz, 1H), 6.87 (dd, J = 6.0, 7.8 Hz, 2H), 6.65 (d, J = 7.6 Hz, 1H), 5.10 (dd, J = 5.6, 12.8 Hz, 1H), 4.96 (s, 2H), 3.98 (dd, J = 2.0, 6.0 Hz, 2H), 3.89 (t, J = 5.6 Hz, 2H), 3.23 (s, 6H), 3.01 - 2.97 (m, 4H), 2.61 (d, J = 1.6 Hz, 2H), 2.56 (s, 4H), 2.21 (s, 1H), 2.13 - 1.99 (m, 4H), 1.90 (s, 3H), 1.80 - 1.55 (m, 6H), 1.41 - 1.18 (m, 6H).

[0492] Example 6. Preparation of Compound 112a TIFF2025516358000096.tif231286-(8-(Benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-(((1s,4r)-4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propyl)cyclohexyl)oxy)-2-methylphenyl)picolinate

[0493] Step A. Procedure for the preparation of 3-((1r,4s)-4-(3-bromo-2-methylphenoxy)cyclohexyl)propan-1-ol To a solution of ethyl 3-((1r,4r)-4-(3-bromo-2-methylphenoxy)cyclohexyl)propanoate (300 mg, 812.36 μmol, 1 equiv) in THF (5 mL) was added LiAlH 4 (37.00 mg, 974.84 μmol, 1.2 equiv) at 0 °C under N 2 2. The mixture was then stirred at 25 °C for 1.5 h. The reaction mixture was quenched by the addition of 0.5 mL of H 2 2O, 0.5 mL of 15% NaOH, and 1.5 mL of H 2 2O, and then extracted with 3 mL of EtOAc (1 mL × 3). The combined organic layers were dried over Na 2 2SO 4 4, filtered, and concentrated under reduced pressure to give 3-((1r,4s)-4-(3-bromo-2-methylphenoxy)cyclohexyl)propano-1-ol (277 mg, crude) as a white solid.

[0494] Step B. Procedure for the preparation of 3-((1r,4r)-4-(3-bromo-2-methylphenoxy)cyclohexyl)propanal To a solution of DMSO (264.53 mg, 3.39 mmol, 264.53 μL, 4 equiv) in DCM (2 mL) was added a solution of (COCl) 2 (214.88 mg, 1.69 mmol, 148.19 μL, 2 equiv) in DCM (2 mL) at N 2It was added dropwise at -70 °C under an atmosphere. The mixture was stirred at -70 °C for 1 hour. Then, 3-((1r,4s)-4-(3-bromo-2-methylphenoxy)cyclohexyl)propan-1-ol (277 mg, 846.43 μmol, 1 equivalent) in DCM (2 mL) was added dropwise at -70 °C. The solution was stirred at -70 °C for 1 hour. Then, TEA (513.90 mg, 5.08 mmol, 706.88 μL, 6 equivalents) was added to the solution. The solution was stirred at N 2 under an atmosphere at -70 °C for 0.5 hour. The reaction mixture was quenched by the addition of 10 mL of H 2 O, then diluted with 10 mL of DCM, and extracted with 30 mL of DCM (10 mL×3). The combined organic layers were washed with 15 mL of H 2 O (5 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a yellow residue. The residue was purified by flash silica gel chromatography (eluent: 0 - 10% ethyl acetate / petroleum ether) to obtain 3-((1r,4r)-4-(3-bromo-2-methylphenoxy)cyclohexyl)propanal (220 mg, 676.4 μmol, yield 79.9%) as a yellow solid.

[0495] Procedure for the preparation of tert-butyl 6-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(2-methyl-3-(((1r,4r)-4-(3-oxopropyl)cyclohexyl)oxy)phenyl)picolinate 3-((1r,4r)-4-(3-bromo-2-methylphenoxy)cyclohexyl)propanal (220 mg, 676.42 μmol, 1 equivalent), tert-butyl 6-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate (497.21 mg, 811.71...

Claims

1. Compound of formula (I): or a pharmaceutically acceptable salt thereof, in the formula, Ring A is or In the formula, aa represents the connection point to L. R １ However, it is C(O)OH, Each R ２ 、R ３ 、R ４ 、and R ５ is independently selected from the group consisting of halo, CN, C １－３ alkyl, C １－３ haloalkyl, C １－３ alkoxy, C １－３ haloalkoxy, OH, and NR ｄ R ｅ and is selected from the group consisting of: m2 is 0, m3 is 0, m4 is 0, m5 is 0, L, -(LA3) 0-1 -(LA1) 0-5 -LA4 -(LA1) 0-5 -(6-membered heterocyclylene)-bb, and -(L A3) 0-1 -(L A1) 0-5 -L A4 -(L A1) 0-5 -C(=O)-(6-membered heterocyclylene)- bb Selected from the group consisting of, However, L must contain 2 to 5 L A1 molecules. bb represents the bond point to ring C, Each L Ａ１ However, independently, -CH ２ -----CHR Ｌ -, and -C(R Ｌ ) ２ - Selected from the group consisting of, Each L Ａ３ However, independently, -N(R ｄ )-,-N(R ｂ )-, -O-, -S(O) ０－２ -, and C (=O) are selected from the group, Each L Ａ４ However, they became independent, (a) C ３－１５ Cycloalkylene or 3- to 15-membered heterocyclene, each of which is R ａ and R ｂ It may be substituted with 1 to 6 substituents independently selected from the group consisting of C ３－１５ Cycloalkylene or 3-15 member heterocyclylene, (b) C ６－１５ Arylene or 5- to 15-membered heteroarylene, each of which is R ａ and R ｂ It may be substituted with 1 to 6 substituents independently selected from the group consisting of C ６－１５ Arirene or 5-15 member heteroarirene, Selected from the group consisting of, However, L is O-O, N-O, N-N, N-S(O) ０ , and O-S(O) ０－２ Provided that it does not contain any of the bonds, In the formula, each R Ｌ However, independently, halo, cyano, -OH, -C １－６ Alkoxy, -C １－６ Haloalkoxy, -NR ｄ R ｅ , C(=O)N(R ｆ ) ２ , S(O) ０－２ (C １－６ Alkyl), S(O) ０－２ (C １－６ Haloalkyl), S(O) １－２ N(R) ｆ ) ２ , -R ｂ , and 1 to 6 R ｃ C may be replaced with １－６ Selected from the group consisting of alkyl groups, Ring C is In the equation, yy is the connection point to L, Each R ａ However, they became independent, (a) Hello, (b) Cyano, (c)-OH, (d) Oxo, (e)-C １－６ Alkoxy, (f) - C １－６ Haloalkoxy, (g)-NR ｄ R ｅ 、 (h)C(=O)C １－６ Alkyl, (i) C(=O)C １－６ Haloalkyl, (j)C(=O)OH, (k)C(=O)OC １－６ Alkyl, (l)C(=O)OC １－６ Haloalkyl, (m)C(=O)N(R ｆ ) ２ 、 (n) S(O) ０－２ (C １－６ Alkyl), (o)S(O) ０－２ (C １－６ Haloalkyl), (p)S(O) １－２ N(R) ｆ ) ２ , and (q) 1 to 6 R each ｃ It may be replaced with C １－６ Alkyl, C ２－６ Alkenyl, or C ２－６ Alkinyl Selected from the group consisting of, Each R ｂ However, independently, -(L ｂ ) ｂ -R ｂ１ and -R ｂ１ Selected from the group consisting of, in the formula, Each b is independently 1, 2, or 3. Each -L ｂ However, independently, -O-, -N(H)-, -N(C) １－３ Alkyl)-,-S(O) ０－２ -, C (=O), and C １－３ Selected from the group consisting of alkylenes, Each R ｂ１ However, independently, C ３－１０ Cycloalkyl, 4-10 membered heterocyclyl, C ６－１０ Selected from the group consisting of aryls and 5- to 10-membered heteroaryls, each of which has 1 to 3 R ｇ It may also be replaced with Each R ｃ is independently halo, cyano, -OH, -C １－６ alkoxy, -C １－６ haloalkoxy, -NR ｄ R ｅ , C(=O)C １－６ alkyl, C(=O)C １－６ haloalkyl, C(=O)OC １－６ alkyl, C(=O)OC １－６ haloalkyl, C(=O)OH, C(=O)N(R ｆ ) ２ , S(O) ０－２ (C １－６ alkyl), S(O) ０－２ (C １－６ haloalkyl), and S(O) １－２ N(R ｆ ) ２ is selected from the group consisting of Each R ｄ and R ｅ However, independently, H, C(=O)C １－６ Alkyl, C(=O)C １－６ Haloalkyl, C(=O)OC １－６ Alkyl, C(=O)OC １－６ Haloalkyl, C(=O)N(R) ｆ ) ２ , S(O) １－２ (C １－６ Alkyl), S(O) １－２ (C １－６ Haloalkyl), S(O) １－２ N(R) ｆ ) ２ , and 1 to 3 R ｈ C may be replaced with １－６ Selected from the group consisting of alkyl groups, Each R ｆ However, independently, H and 1 to 3 R ｈ C may be replaced with １－６ Selected from the group consisting of alkyl groups, Each R ｇ However, R ｈ , C １－３ Alkyl and C １－３ Selected from the group consisting of haloalkyls, Each R ｈ However, independently, halo, cyano, -OH, -C １－６ Alkoxy, -C １－６ Haloalkoxy, -NH ２ , -N(H)(C １－３ Alkyl), and -N(C １－３ Alkyl) ２ Selected from the group consisting of, A compound or a pharmaceutically acceptable salt thereof.

2. One R exists on ring A. ａ However, C may be substituted with 1 to 3 Fs. １－３ The compound according to claim 1, wherein it is alkyl.

3. One R exists on ring A. ａ However, methyl or CF ３ The compound according to claim 1.

4. Each L Ａ４ However, they became independent, a) C ３－１０ Cycloalkylene or 4- to 10-membered heterocyclene, each of which contains 1 to 3 R ａ It may be replaced with C ３－１０ Cycloalkylene or 4-10 membered heterocyclylene, b) Phenylene or 5-6 member heteroarylene, each of which has 1-3 R ａ Phenylene or 5-6 member heteroarylene, which may be substituted with A compound according to claim 1, selected from the group consisting of the following.

5. L Ａ１ The occurrence of 0 to 2 of -CHR Ｌ - or -C (R Ｌ ) ２ - and L Ａ１ Each remaining occurrence is -CH ２ - The compound according to claim 1.

6. L Ａ１ Each occurrence is -CH ２ - The compound according to claim 5.

7. L Ａ１ The appearance of one instance of -CHR Ｌ - or -C (R Ｌ ) ２ - and L Ａ１ Each remaining occurrence is -CH ２ - The compound according to claim 5.

8. Each R Ｌ However, independently, -F and -C may be substituted with 1 to 3 Fs. １－３ A compound according to claim 5, selected from the group consisting of alkyl groups.

9. The compound is as follows: The compound according to claim 1, which is selected from the group consisting of or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

11. A pharmaceutical composition according to claim 10 for use in the treatment of cancer.

12. The pharmaceutical composition according to claim 11, wherein the treatment of cancer comprises administering an additional therapy or therapeutic agent.

13. The pharmaceutical composition according to claim 12, wherein the additional therapy or therapeutic agent is an ALK inhibitor, a BCL-2 inhibitor, a BCR-Abl 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 an anti-EGFR antibody-drug conjugate, an ERK inhibitor, a FGFR1 inhibitor, a FGFR2 inhibitor, a FGFR3 inhibitor, a FGFR4 inhibitor, a HER2 inhibitor, an anti-HER2 antibody or an anti-HER2 antibody-drug conjugate, a JAK inhibitor, a KRas inhibitor, a MEK inhibitor, a MET inhibitor, a PARP inhibitor, a LSD1 inhibitor, a BET inhibitor, a telomerase inhibitor, a TORC1 / 2 inhibitor, chemotherapy, radiotherapy, or a combination thereof.

14. The pharmaceutical composition according to claim 13, wherein the additional therapy or therapeutic agent is a JAK inhibitor.

15. The pharmaceutical composition according to claim 11, wherein the cancer is breast cancer, colorectal cancer, bile duct 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.

16. The pharmaceutical composition according to claim 15, wherein the blood cancer is acute lymphoblastic 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.

17. The pharmaceutical composition according to claim 16, wherein the blood cancer is essential thrombocythemia, polycythemia vera, myelofibrosis, or a combination thereof.

18. The pharmaceutical composition according to claim 17, wherein the blood cancer has a JAK2 mutation.

19. The pharmaceutical composition according to claim 18, wherein the JAK2 mutation is JAK2 V617F.

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