Tetrahydroisoquinoline heterobifunctional BCL-XL degrader

Abstract

The present disclosure provides compounds of formula (I), or pharmaceutically acceptable salts thereof, which induce the degradation of BCL-X L protein. These 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, as well as methods of using and making the same.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 454,486, filed Mar. 24, 2023; No. 63 / 449,728, filed Mar. 3, 2023; No. 63 / 429,834, filed Dec. 2, 2022; No. 63 / 398,752, filed Aug. 17, 2022; and No. 63 / 339,308, 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), 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 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. Broadly 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 ) available to compete for BH3 - only protein binding.

Summary of the Invention

[0004] Summary The present disclosure provides compounds of formula (I) or (II), 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 provided herein, as well as methods of using and making the same.

[0005] As used herein, a compound of formula (I) or (II): TIFF2025516359000001.tif114128 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 3 substituents independently selected from the group consisting of R (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 selected from the group consisting of L T1 is a bond or, independently, C optionally substituted with 1 to 3 substituents selected from the group consisting of oxo and R c alkylene, wherein one CH 1~3 unit of the C 1~3 alkylene may be replaced by -O- or -N(R 2 )-, d )- and A * is (a) C 3~15 cycloalkyl or 3- to 15-membered heterocyclyl, each of which is optionally substituted with R aand R b C, which may be substituted with 1 to 6 substituents independently selected from the group consisting of 3~15 cycloalkyl or 3- to 15-membered heterocyclyl, (b) C 6~15 aryl or 5- to 15-membered heteroaryl, each of which is C and may be substituted with 1 to 6 substituents independently selected from the group consisting of a and R b aryl or 5- to 15-membered heteroaryl, and 6~15 (c) H selected from the group consisting of wherein R is 1 (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 C(O)OC c alkyl which may be substituted with 1 to 3 R 1~6 selected from the group consisting of 2 wherein each R is independently selected from the group consisting of halo, CN, C 3 alkyl, C 4 haloalkyl, C 5 alkoxy, C 1~3 haloalkoxy, OH, and NR 1~3 R 1~3 wherein 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 1~3 ) d - wherein L e and n1 are defined according to (AA) or (BB) as -(L A ) n1 - and wherein A and A are defined according to (AA) or (BB) as -(L n1 ) A - A1 and (AA) n1 is an integer from 3 to 12, 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 selected from the group consisting of provided that L is O-O, N-O, N-N, N-S(O) 0and O—S(O) 0~2 provided that none of the linkages contain wherein 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 optionally substituted with 1 to 6 R 1~6 s, and is selected from the group consisting of VBM is selected from the group consisting of (V1), (V2), (V3), (V4), (V5), (V6), (V7), (V8), and (V1P): TIFF2025516359000002.tif255155, wherein each R 7 and R 8 is independently selected from the group consisting of H, C 1~6 alkyl, C 1~6 haloalkyl, and C 3~6 cycloalkyl, R 7a is selected from the group consisting of halo and CN, mp is 0, 1, or 2, each R p is independently selected from the group consisting of —F, C 1~6 alkyl, C 1~6 haloalkyl, and C 3~6 cycloalkyl, m9 is 0, 1, 2, or 3, m10 is 0, 1, or 2, each R 9 and R 10 is independently halo, CN, C 1~6 alkyl, C 1~6Haloalkyl, C 3~6 Cycloalkyl, C 1~6 Alkoxy, and C 1~6 Selected from the group consisting of haloalkoxy, R 11 is C alkyl which may be substituted with 1 to 6 Rs c and each R 1~10 is independently 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, C alkyl, C alkenyl, or C alkynyl which may be substituted with 1 to 6 Rs c and each R 1~6 is independently -(L 2~6 and each R 2~6 is independently -(L Selected from the group consisting of each R b is independently -(Lb ) b -R b1 and -R b1 selected from the group consisting of, wherein 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 1~3 alkylene selected from the group consisting of, each R b1 is independently C 3~10 cycloalkyl, 4- to 10-membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl selected from the group consisting of, 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 1~6 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 are 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 -substituted C 1~6 alkyl, selected from the group consisting of each R f is independently H and 1 to 3 R h -substituted C 1~6 alkyl, 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 selected from the group consisting of, a compound or a pharmaceutically acceptable salt thereof is provided.

[0006] Also provided herein is a pharmaceutical composition comprising a compound of formula (I) or (II), 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, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or (II), 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), or a pharmaceutically acceptable salt thereof LA protein is provided.

[0009] Also, as used herein, BCL-X L A ternary complex is provided that includes a protein, a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, and a VHL protein or a portion thereof.

[0010] To facilitate understanding of the disclosure described herein, some additional terms are provided. Generally, the nomenclature used herein, as well as laboratory procedures in organic chemistry, pharmaceutical 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 pertains. 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 a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, that induces 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 a composition containing the compounds provided herein, as well as methods of using and making the same.

[0013] While not bound by any particular theory, in healthy cells, apoptosis-promoting effectors such as BAX and BAK can move between the cytosol and the mitochondrial outer membrane (MOM), and it is thought that Voltage Dependent Anion Channel 2 (VDAC2) on the mitochondrial outer membrane (MOM) can act as a receptor. 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 the rear site on apoptosis-promoting effectors (e.g., BAX or BAK) and release the C-terminal transmembrane domain (α9) of the effector 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 survival-promoting BCL-2 family members then bind to BAX or BAK, apoptosis signaling is generally halted. However, when BAX or BAK dimerize and then oligomerize, the MOM can be permeabilized, leading to apoptosis.

[0014] The abundance of survival-promoting BCL-2 family members is often thought to "prime" cells for death (e.g., via cytotoxic therapies including 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 survival-promoting 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 may also be 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 (which may also be referred to as an 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 von Hippel-Lindau (VHL) E3 ligase (also referred to herein as the VHL 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. Degradation can impair the scaffolding function of the target protein, whereas small molecules may not, so in some cases, degradation of the target protein may be more advantageous than small molecule inhibition. 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 International Publication No. WO2017 / 184995, International Publication No. WO2019 / 144117, International Publication No. WO2020 / 163823, International Publication No. WO2021 / 078301, International Publication No. WO2021 / 146536, International Publication No. WO2021 / 007307, International Publication No. WO2021 / 222114, International Publication No. WO2021 / 078301, International Publication No. WO2022 / 169780, International Publication No. WO2023 / 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): TIFF2025516359000003.tif111128 or a pharmaceutically acceptable salt thereof, wherein Ring A is (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 Cycloalkylene or 3- to 15-membered heterocyclylene, and 3~15 (b) Phenylene or 5- to 6-membered heteroarylene, each of which may be substituted with 1 to 6 substituents independently selected from the group consisting of R (b) Phenylene or 5- to 6-membered heteroarylene, each of which may be substituted with 1 to 6 substituents independently selected from the group consisting of R a and R bPhenylene 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, independently, oxo and R c C which may be substituted with 1 to 3 substituents independently selected from the group consisting of 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, and (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 is C(O)OC c which may be substituted with 1 to 3 R 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 -, where L A and n1 are defined according to (AA) or (BB), -(L A ) n1 -, (AA) n1 is an integer from 3 to 12, 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, 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 3~15A cycloalkylene or a 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 A cycloalkylene or a 3- to 15-membered heterocyclylene, and 3~15 (b) An arylene or a 5- to 15-membered heteroarylene, each of which may be substituted with 1 to 6 substituents independently selected from the group consisting of R(b)C 6~15 and R a An arylene or a 5- to 15-membered heteroarylene, b selected from the group consisting of 6~15 provided that L does not contain any of the linkages O—O, N—O, N—N, N—S(O) wherein each R 0 and O—S(O) 0~2 is independently selected from the group consisting of halo, cyano, —OH, —C is independently selected from halo, cyano, —OH, —C L alkoxy, —C 1~6 haloalkoxy, —NR 1~6 R 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 selected from the group consisting of VBM is selected from (V1), (V2), (V3), (V4), (V5), (V6), (V7), (V8), and (V1P): selected from the group consisting of TIFF2025516359000004.tif255156, wherein each R 7 and R 8 is independently H, C 1~6 alkyl, C 1~6Selected from the group consisting of haloalkyl and C 3~6 cycloalkyl, R 7a is selected from the group consisting of halo and CN, mp is 0, 1, or 2, each R p is independently -F, C 1~6 alkyl, C 1~6 haloalkyl, and C 3~6 cycloalkyl, m9 is 0, 1, 2, or 3, m10 is 0, 1, or 2, each R 9 and R 10 is independently selected from the group consisting of halo, CN, C 1~6 alkyl, C 1~6 haloalkyl, C 3~6 cycloalkyl, C 1~6 alkoxy, and C 1~6 haloalkoxy, R 11 is C c alkyl which may be substituted with 1 to 6 R 1~10 s, 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(Rf ) 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, 1 - 6 R's c optionally 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, -(L b ) b -R b1 and -R b1 selected from the group consisting of, wherein 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 1~3 alkylene selected from the group consisting of, each R b1 is independently, C 3~10 cycloalkyl, 4 - 10 membered heterocyclyl, C 6~10 aryl, and 5 - 10 membered heteroaryl selected from the group consisting of, each of which is optionally substituted with 1 - 3 R's g ; 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 1~6Haloalkyl, 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 selected from the group consisting of, A compound or a pharmaceutically acceptable salt thereof is provided.

[0019] In some embodiments, the VBM is selected from the group consisting of (V1), (V2), (V3), and (V4).

[0020] In some embodiments, provided that when the VBM is (V1), (V2), or (V3), (i) in formula (I), L does not contain an adamantylene group, (ii) in formula (II), A * is other than adamantyl.

[0021] In some embodiments, provided that (i) in formula (I), L does not contain an adamantylene group, (ii) in formula (II), A * is other than adamantyl.

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

[0023] In some embodiments, the compound is a compound of formula (II) or a pharmaceutically acceptable salt thereof.

[0024] In some embodiments, ring A is a phenylene optionally substituted with 1 to 3 R a 's.

[0025] In some embodiments, ring A is TIFF2025516359000005.tif24128, wherein aa represents the point of attachment to L or L T1 '.

[0026] In some embodiments, ring A is TIFF2025516359000006.tif19128, wherein aa represents the point of attachment to L or L T1 '. For example, ring A is TIFF2025516359000007.tif can be 19128, where aa represents the bonding point to L or L T1 represents the bonding point to L or L

[0027] In some embodiments, ring A is TIFF2025516359000008.tif is 24128, where aa represents the bonding point to L or L T1 represents the bonding point to L or L. For example, ring A is TIFF2025516359000009.tif can be 23128, where aa represents the bonding point to L or L T1 represents the bonding point to L or L

[0028] In some embodiments, ring A is a 5- to 6-membered heteroarylene which may be substituted with 1 to 3 R a . In some embodiments, ring A is a 5- to 6-membered heteroarylene which may be substituted with 1 to 2 R a . In some embodiments, ring A is a 5-membered heteroarylene which may be substituted with 1 to 2 R a . In some embodiments, ring A is a pyrazolylene which may be substituted with 1 to 2 R a . For example, ring A is selected from the group consisting of TIFF2025516359000010.tif25128, where aa represents the bonding point to L or L T1 represents the bonding point to L or L

[0029] In some embodiments, ring A is a C a cycloalkylene which may be substituted with 1 to 6 R 3~10 . In some embodiments, ring A is a C a cycloalkylene which may be substituted with 1 to 3 R 4~6 . In some embodiments, ring A is a cyclohexylene which may be substituted with 1 to 3 R a . For example, ring A can be 1,4-cyclohexylene

[0030] In some embodiments, one R present on ring A a is C 1~3 alkyl which may be substituted with 1 to 3 Fs. In some embodiments, one R present on ring A 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 TIFF2025516359000011.tif24128, where aa represents the point of attachment to L or L T1 . In some embodiments, ring A is TIFF2025516359000012.tif19128, where aa represents the point of attachment to L or L T1 . For example, ring A can be TIFF2025516359000013.tif19128, where aa represents the point of attachment to L or L T1 . In some embodiments, ring A is TIFF2025516359000014.tif24128, where aa represents the point of attachment to L or L T1 . For example, ring A can be TIFF2025516359000015.tif23128, where aa represents the point of attachment to L or L T1 .

[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 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 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 For example, A * can be phenyl 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, VBM is (V1): TIFF2025516359000016.tif45128.

[0038] In some embodiments, VBM is (V1a): TIFF2025516359000017.tif45128.

[0039] In some embodiments, VBM is (V2): TIFF2025516359000018.tif54128.

[0040] In some embodiments, VBM is (V2a): TIFF2025516359000019.tif54128.

[0041] In some embodiments, the VBM is (V3): TIFF2025516359000020.tif54128.

[0042] In some embodiments, the VBM is (V3a): TIFF2025516359000021.tif54128.

[0043] In some embodiments, the VBM is (V4): TIFF2025516359000022.tif33128.

[0044] In some embodiments, the VBM is (V4a): TIFF2025516359000023.tif33128.

[0045] In some embodiments, one R 7 is H, and the other R 7 is C 1~6 alkyl. In some embodiments, one R 7 is H, and the other R 7 is tert-butyl.

[0046] In some embodiments, the carbon atom to which each R 7 is attached has an (S)-configuration.

[0047] In some embodiments, one R 8 is H, and the other R 8 is C 1~6 alkyl. In some embodiments, one R 8 is H, and the other R 8 is methyl. In some embodiments, each R 8 is H.

[0048] In some embodiments, each R 8The carbon atom to which it is attached has an (S)-configuration.

[0049] In some embodiments, one R 7 is H, and the other R 7 is C 1~6 alkyl, and the carbon atom to which each R 7 is attached has an (S)-configuration, one R 8 is H, and the other R 8 is C 1~6 alkyl, and the carbon atom to which each R 8 is attached has an (S)-configuration.

[0050] In some embodiments, m9 is 0.

[0051] In some embodiments, m10 is 1. In some embodiments, R 10 is C 1~6 alkyl. For example, R 10 can be methyl.

[0052] In some embodiments, mp is 0.

[0053] In some embodiments, m9 is 0, m10 is 1, and mp is 0.

[0054] In some embodiments, VBM is TIFF2025516359000024.tif34128. In some embodiments, VBM is TIFF2025516359000025.tif47128. In some embodiments, VBM is TIFF2025516359000026.tif47128. In some embodiments, VBM is TIFF2025516359000027.tif26128.

[0055] In some embodiments, L is -(L A )n1 - and L A and n1 are defined according to (BB).

[0056] In some embodiments, L A and n1 are defined according to (BB), and n1 is an integer from 3 to 5. In some embodiments, L A and n1 are defined according to (BB), and n1 is an integer from 5 to 9. In some embodiments, L A and n1 are defined according to (BB), and n1 is an integer from 9 to 15.

[0057] In some embodiments, L A and n1 are defined according to (BB), and 1 to 4 occurrences of L A are A3 . In some embodiments, 1 to 3 occurrences of L A are A3 . In some embodiments, 1 to 2 occurrences of L A are A3 .

[0058] In some embodiments, L A and n1 are defined according to (BB), and 0 to 2 occurrences of L A1 are -CHR L - or -C(R L ) 2 -, and each remaining occurrence of L A1 is -CH 2 -. In some embodiments, each occurrence of L A1 is -CH 2 -. In some embodiments, 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, each R L is independently selected from the group consisting of -F and -C 1~3 alkyl optionally substituted with 1 to 3 Fs.

[0059] In some embodiments, L is -(L A3 ) 0~2 -(L A1 ) 1~15 -(L A3 ) 0~1 - bb wherein bb represents the point of attachment to the VBM. In some embodiments, 0 to 2 occurrences of L A1 are -CHR L - or -C(R L ) 2 -, and each remaining occurrence of L A1 is -CH 2 -. In some embodiments, each occurrence of L A1 is -CH 2 -. In some embodiments, 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, 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.

[0060] In some embodiments, L is of formula (L-1): TIFF2025516359000028.tif25128 a divalent group, wherein 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 15, a3b is 0 or 1, L A3b is independently selected from the group consisting of C(=O), -O-, N(H)-, and -N(C 1~3 alkyl)-, bb represents the point of attachment to the VBM.

[0061] In some embodiments of (L-1), a3b is 1. In some embodiments, L A3b is C(=O). In some embodiments, L A3b is -N(H)-. In some embodiments, L A3b is -N(C 1~3 alkyl)-. In some embodiments, L A3b is -O-.

[0062] In some embodiments of (L-1), a3b is 0.

[0063] In some embodiments of (L-1), a3a is 1. In some embodiments, L A3a is O.

[0064] In some embodiments of (L-1), a3a is 0.

[0065] In some embodiments of (L-1), a1 is 1 or 2. In some embodiments of (L-1), a1 is an integer from 3 to 5. In some embodiments of (L-1), a1 is an integer from 5 to 9. In some embodiments of (L-1), a1 is an integer from 9 to 15.

[0066] In some embodiments of (L-1), L A1 of 0 to 2 occurrences is -CHR L - or -C(R L ) 2 -, and each remaining occurrence of L A1 is -CH 2 -. In some embodiments, each occurrence of L A1 is -CH 2 -. In some embodiments, one occurrence of L A1 is -CHR L - or -C(R L ) 2 -, and each remaining occurrence of L A1 is -CH 2 -.

[0067] In some embodiments, each R L is independently selected from the group consisting of -F and -C alkyl optionally substituted with 1 to 3 Fs. 1~3

[0068] In some embodiments, L is -(L A ) n1 - and L A and n1 are defined according to (AA).

[0069] In some embodiments, L A and n1 are defined according to (AA) and n1 is an integer from 3 to 5. In some embodiments, L A and n1 are defined according to (AA) and n1 is an integer from 5 to 9. In some embodiments, L A and n1 are defined according to (AA) and n1 is 6, 7, or 8. In some embodiments, L A and n1 are defined according to (AA) and n1 is an integer from 9 to 12. In some embodiments, L A and n1 are defined according to (AA) and 1 to 2 occurrences of L A are L A4 . In some embodiments, 1 occurrence of L A is L A4 .

[0070] In some embodiments, L A and n1 are defined according to (AA) and each L A4 is independently selected from the group consisting of C cycloalkylene or 4- to 10-membered heterocyclylene, each optionally substituted with 1 to 3 Rs, C cycloalkylene or 4- to 10-membered heterocyclylene, and phenylene or 5- to 6-membered heteroarylene, each optionally substituted with 1 to 3 Rs. 3~10 a 3~10 a

[0071] In some embodiments, L A and n1 are defined according to (AA), and one to four occurrences of L A are A3 In some embodiments, one to two occurrences of L A are A3 .

[0072] In some embodiments, L A and n1 are defined according to (AA), and two to seven occurrences of L A are A1 In some embodiments, two to five occurrences of L A are A1 In some embodiments, zero to two occurrences of L A1 are -CHR L - or -C(R L ) 2 -, and each remaining occurrence of L A1 is -CH 2 -. In some embodiments, each occurrence of L A1 is -CH 2 -. In some embodiments, one 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, each R L is independently selected from the group consisting of -F and -C 1~3 alkyl which may be substituted with one to three Fs.

[0073] 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 one to two occurrences of L A are A4 , and two to seven occurrences of L A are A1 , and one to three occurrences of L A are A3is. 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 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 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 a 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)-.

[0074] In some embodiments, L is (i)-(L A3 ) 0~2 -(L A1 ) 0~5 -L A4 -(L A1 ) 0~5 -L A3 - bb , (ii)-(L A3 ) 0~2 -(L A1 ) 0~5 -L A4 -(L A1 ) 0~5 - bb selected from the group consisting of, provided that L contains 2 to 7 L A1 wherein bb represents the point of attachment to the VBM. In some embodiments, L A4 is C 3~10A cycloalkylene or a 4- to 10-membered heterocyclylene, each of which may be substituted with 1 to 3 R a and is 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 R a and is selected from the group consisting of a phenylene or a 5- to 6-membered heteroarylene. 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)-.

[0075] In some embodiments, L is -(L A3 ) 0~2 -(L A1 ) 0~5 -L A4 -(L A1 ) 0~5 -L A3 -, provided that L contains 2 to 7 L bb s, where bb represents the point of attachment to the VBM. In some embodiments, L is -(L A1 ) A3 ) 0~1 -(L A1 ) 0~5 -L A4 -(L A1 ) 0~5 -L A3 -, provided that L contains 2 to 5 L bb s, where bb represents the point of attachment to the VBM. In some embodiments, each L A1 is independently C A4 and is 3~10A cycloalkylene or a 4- to 10-membered heterocyclylene, each of which may be substituted with 1 to 3 R a and is 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 R a and is selected from the group consisting of a phenylene or a 5- to 6-membered heteroarylene. 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)-.

[0076] In some embodiments, L is a divalent group of formula (L-2): TIFF2025516359000029.tif30128, wherein a3a is 0 or 1, L A3a and L A3b are independently selected from the group consisting of -O-, -N(H)-, -N(C 1~3 alkyl)-, and C(=O), 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 3~10A cycloalkylene or a 4- to 10-membered heterocyclylene, each of which may be substituted with 1 to 3 R a and is a C 3~10 cycloalkylene or a 4- to 10-membered heterocyclylene, and b) a phenylene or a 5- to 6-membered heteroarylene, each of which may be substituted with 1 to 3 R a and is a phenylene or a 5- to 6-membered heteroarylene selected from the group consisting of bb represents the bonding point to the VBM.

[0077] In some embodiments of (L-2), a3a is 1. In some embodiments, L A3a is -O-.

[0078] In some embodiments of (L-2), a3a is 0.

[0079] In some embodiments of (L-2), L A3b is -N(H)- or -N(C 1~3 alkyl)-.

[0080] In some embodiments of (L-2), L A3b is -O-.

[0081] In some embodiments of (L-2), L A3b is C(=O).

[0082] In some embodiments of (L-2), a3a is 1, L A3a is -O-, and L A3b is C(=O).

[0083] In some embodiments of (L-2), a3a is 1, L A3a is -O-, and L A3b is -O-, -N(H)-, or -N(C 1~3 alkyl)-.

[0084] In some embodiments of (L-2), a3a is 0, and L A3b is C(=O).

[0085] In some embodiments of (L-2), a3a is 0, and L A3b is -O-, -N(H)-, or -N(C 1~3 alkyl)-.

[0086] In some embodiments, L is -(L A3 ) 0~2 -(L A1 ) 0~5 -L A4 -(L A1 ) 0~5 - bb wherein L contains 2 to 7 L A1 's, and bb represents the point of attachment to the VBM. In some embodiments, L is -(L A3 ) 0~1 -(L A1 ) 0~5 -L A4 -(L A1 ) 0~5 -[[]] bb wherein L contains 2 to 5 L A1 's, and bb represents the point of attachment to the VBM. In some embodiments, each L A4 is independently selected from the group consisting of 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 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. 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 -.

[0087] In some embodiments, L is of formula (L-3): TIFF2025516359000030.tif30128 is a divalent group, wherein a3a is 0 or 1, L A3a 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 the VBM.

[0088] In some embodiments of (L-3), a3a is 1. In some embodiments, L A3a is -O-.

[0089] In some embodiments of (L-3), a3a is 0.

[0090] In some embodiments of (L-2) or (L-3), a1a + a1b is 2, 3, or 4. In some embodiments of (L-2) or (L-3), a1a + a1b is 5.

[0091] In some embodiments of (L-2) or (L-3), L A1a and L A1b each occurrence of is -CH 2 -.

[0092] In some embodiments of (L-2) or (L-3), 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 -.

[0093] In some embodiments of (L-2) or (L-3), 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 -.

[0094] In some embodiments of (L-2) or (L-3), 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.

[0095] In some embodiments of (L-2) or (L-3), a1b is 2, 3, or 4, and one occurrence of L A1b is -CHR L - or -C(R L ) 2 -, and each remaining occurrence of L A1b is -CH 2- and L A1a each occurrence of is -CH 2 -. For example, one occurrence of L A1b can be CF 2 , CMe 2 , C(H)F, C(H)Me, or C(H)CF 3 .

[0096] In some embodiments of (L-2) or (L-3), L A4 is a 4- to 10-membered heterocyclylene which may be substituted with 1 to 3 R a s. In some embodiments, L A4 is each optionally substituted with 1 to 3 R a s at one or more ring carbon atoms selected from the group consisting of TIFF2025516359000031.tif46128, wherein cc represents the point of attachment to L A1b . In some embodiments, each R A4 present on L a is independently F or C 1~3 alkyl optionally substituted with 1 to 3 Fs.

[0097] In some embodiments of (L-2) or (L-3), L A4 is a C a cycloalkylene optionally substituted with 1 to 3 R 3~10 s. For example, L A4 can be 1,4-cyclohexylene optionally substituted with 1 to 3 R a s. For example, L A4 can be TIFF2025516359000032.tif16128.

[0098] In some embodiments of (L-2) or (L-3), L A4 is phenylene or 5- to 6-membered heteroarylene, each of which may be optionally substituted with 1 to 3 R a s. In some embodiments, L A4 is optionally substituted with 1 to 3 R aIt may be a phenylene that is replaced. For example, L A4 can be 1,2-phenylene that may be substituted with 1 to 3 Rs. For example, L a can be 1,3-phenylene that may be substituted with 1 to 3 Rs. For example, L A4 can be 1,4-phenylene that may be substituted with 1 to 3 Rs. For example, L a can be 1,3-phenylene that may be substituted with 1 to 3 Rs. For example, L A4 can be 1,4-phenylene that may be substituted with 1 to 3 Rs. a In some embodiments, VBM is (V1), L is (L-1), wherein a3b is 1, and L

[0099] In some embodiments, VBM is (V1a), L is (L-1), wherein a3b is 1, and L A3b is C(=O). In some embodiments, VBM is (V1a), L is (L-1), wherein a3b is 1, and L A3b is C(=O), a3a is 1, and L A3a is -O-, and a1 is 4, 5, or 6. In some embodiments, VBM is TIFF2025516359000033.tif34128, and L is selected from the group consisting of TIFF2025516359000034.tif17148, wherein bb represents the bonding point to VBM.

[0100] In some embodiments, VBM is (V1), L is (L-2), wherein L A3b is C(=O). In some embodiments, VBM is (V1a), L is (L-2), wherein L A3b is C(=O), a3a is 1, and L A3a is -O-, and a1a + a1b is 1, 2, or 3. In some embodiments, VBM is TIFF2025516359000035.tif34128, and L is selected from the group consisting of TIFF2025516359000036.tif43128, wherein bb represents the bonding point to VBM.

[0101] In some embodiments, the compound is selected from the group consisting of the compounds in Table C1 or their pharmaceutically acceptable salts.

[0102]

Table C1

[0103] In some embodiments, the compound is selected from the group consisting of the compounds in Table C2 or their pharmaceutically acceptable salts.

[0104]

Table C2

[0105] Exemplary compounds of formula (I) or (II) also include those shown in Table C1 of U.S. Patent Provisional Application No. 63 / 454,486, filed on March 24, 2023, Table C1 of U.S. Patent Provisional Application No. 63 / 449,728, filed on March 3, 2022, Table C1 of U.S. Patent Provisional Application No. 63 / 429,834, filed on December 2, 2022, Table C1 of U.S. Patent Provisional Application No. 63 / 398,752, filed on August 17, 2022, and Table C1 of U.S. Patent Provisional Application No. 63 / 339,308, filed on May 6, 2022, or pharmaceutically acceptable salts thereof, each Table C1 being incorporated herein by reference in its entirety.

[0106] Certain examples of compounds of formula (I) or (II) were synthesized using methods involving the resolution of stereoisomer mixtures (e.g., SFC separation of stereoisomers). In Table C1, the resolved stereocenters in these compounds are labeled with enhanced stereochemical annotations of "or1" or "or2". In some cases, stereoisomer resolution is performed during the final step of the synthesis, thereby providing the individual stereoisomers of the compounds of formula (I) or (II). Alternatively, in some other cases, the resolution is performed on an intermediate or starting material, where each of the constituent stereoisomers of the intermediate or starting material is separately subjected to subsequent steps of the synthesis to provide the respective compounds of formula (I) or (II) as separate stereoisomers. The methods of resolution and the correlation between the resolved intermediates and the compounds of formula (I) or (II) are disclosed in the Examples and Table P1 herein. One of ordinary skill in the art will understand that under any approach for stereoisomer resolution, stereoisomers having both (R)- and (S)-configurations at the resolved stereocenters are provided. Refer to Table C3, where the compounds of Table C1 that include the or1 annotation for the stereoisomer are provided in the non-stereoisomeric form, followed by the respective stereoisomers having (R)- and (S)-configurations.

[0107]

Table C3

[0108] In some embodiments, the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, has an EC of less than 1 μM (e.g., less than 750 nM, less than 500 nM, or less than 200 nM) 50 and reduces the cell viability in a cell line expressing the BCL-X L protein. In some embodiments, the compound has an EC 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 reduces the cell viability in a cell line expressing the BCL-X L 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 a cell line expressing the BCL-X L protein.

[0109] In some embodiments, the compound of formula (I) or (II), 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 induces the degradation of BCL-X L protein in a cell line expressing the BCL-X L protein. In some embodiments, the compound of formula (I) or (II), 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 induces the degradation of BCL-X L protein in a cell line 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 50and BCL-X L protein in a cell line expressing BCL-X L protein degradation can be induced.

[0110] In some embodiments, the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, has less than 70% (e.g., less than 50%, less than 30%, less than 20%, or less than 10%) of Y min and BCL-X L protein in a cell line expressing BCL-X L protein degradation is induced. In some embodiments, the compound of formula (I) or (II), 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 and BCL-X L protein in a cell line expressing BCL-X L protein degradation is induced. In some embodiments, the compound of formula (I) or (II), 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 and BCL-X L protein in a cell line expressing BCL-X L protein degradation is induced. 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 and BCL-X L protein in a cell line expressing BCL-X L protein degradation can be induced.

[0111] Also provided herein is BCL-X protein non-covalently bound to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof L protein.

[0112] Also provided herein is BCL-X LA ternary complex is provided that includes a protein, a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, and a VHL protein or a portion thereof.

[0113] Chemical Definitions The term "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0114] 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.

[0115] 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 from 1 to 10 (inclusive) carbon atoms therein. An 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 other available valences occupied by hydrogen and / or other substituents defined herein.

[0116] The term "haloalkyl" refers to an alkyl in which one or more hydrogen atoms are independently replaced by a halo selected (e.g., -CF 3 , -CHF 2 , or -CH 2 F).

[0117] The term "alkoxy" refers to an -O-alkyl group (e.g., -OCH 3 ).

[0118] The term "alkylene" refers to a divalent alkyl (e.g., -CH 2-) is meant. Similarly, terms such as "cycloalkylene" and "heterocyclylene" refer to divalent cycloalkyl and heterocyclyl, respectively. To avoid ambiguity, in "cycloalkylene" and "heterocyclylene", can the two groups be on the same ring carbon atom (e.g., TIFF2025516359000058.tif19128 or TIFF2025516359000059.tif19128 such as geminal diradicals), or can they be on different ring atoms (e.g., ring carbon and / or nitrogen atoms (e.g., vicinal ring carbon and / or nitrogen atoms)) (e.g., TIFF2025516359000060.tif20128).

[0119] The term "alkenyl" refers to an acyclic hydrocarbon chain which can be straight-chain or branched-chain 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.

[0120] The term "alkynyl" refers to an acyclic hydrocarbon chain which can be straight-chain or branched-chain 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.

[0121] 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 may be substituted by substituents. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.

[0122] 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 optionally be substituted. The term "saturated" as used in this context means only single bonds exist 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 are 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.

[0123] 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, where at least one ring in the system is independently N, O, S( including oxidized forms such as TIFF2025516359000061.tif15128), and P( It contains one or more heteroatoms selected from the group consisting of (including oxidation forms such as TIFF2025516359000062.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]pyridine, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromanyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, benzod][1,3]dioxolyl, 2,3-dihydrobenzofuranyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[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., TIFF2025516359000063.tif20128), a pyrimidone (e.g., TIFF2025516359000064.tif20128), a pyridazinone (e.g., TIFF2025516359000065.tif20128), pyrazinone (e.g., TIFF2025516359000066.tif20128), and imidazolone (e.g., TIFF2025516359000067.tif16128), etc., which 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") herein is a constituent part of the heteroaryl ring).

[0124] 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 ( TIFF2025516359000068.tif15128, etc., including the oxidized form), and P ( Selected from (including oxidation forms such as TIFF2025516359000069.tif13128) (for example, in the case of monocyclic, bicyclic, or tricyclic, 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.

[0125] 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, e.g., one or more double or triple bonds between constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.

[0126] To avoid ambiguity, unless otherwise specified, for rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, cycloalkyl, etc. as 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., an [x.x.0] ring system, where 0 represents a 0-atom bridge (e.g., TIFF2025516359000070.tif13128)), (ii) a single ring atom (spiro-fused ring system) (e.g., TIFF2025516359000071.tif20128, or TIFF2025516359000072.tif19128), or (iii) an array of contiguous ring atoms (a bridged ring system having all bridge lengths >0) (e.g., TIFF2025516359000073.tif15128, or TIFF2025516359000074.tif14128), and is understood to include those having fused rings.

[0127] In addition, the atoms that make up the compounds of the present embodiment are intended to include all isotopic forms of such atoms. As used herein, isotopes include atoms that have the same atomic number but different mass numbers. General examples, without limitation, of isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 13 C and 14 C.

[0128] In addition, compounds generally or specifically disclosed herein are intended to include all tautomeric forms. Thus, by way of example, a compound containing the moiety: TIFF2025516359000075.tif17128 includes the tautomeric form containing the moiety: TIFF2025516359000076.tif18128. Similarly, a pyridinyl or pyrimidinyl moiety described as optionally substituted with a hydroxyl group includes pyridone or pyrimidone tautomeric forms.

[0129] The compounds provided herein may encompass various stereochemical forms. 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.

[0130] Therapeutic methods Indications Herein, methods are provided for inducing the degradation of the BCL-X L protein. For example, herein, BCL-X useful for treating or preventing cancer LCompounds are provided that can induce the degradation of proteins. 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 The binding of the compound to the protein or BCL-X L Additional methods for assessing the inhibition of the protein are described, for example, in U.S. Patent Application Publication Nos. 2007 / 027135, 2010 / 305122, and 2013 / 096120.

[0131] The effect of protein degradation typically increases over time, but the appearance of degradation (e.g., percentage of degradation 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 degradation after a specific period such as 6 hours, 12 hours, 18 hours, 1 day, 2 days, 3 days, or more. For example, degradation can be expressed as the percentage of degradation after 24 hours.

[0132] Exemplary assays for verifying the mechanism of degradation induction 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.

[0133] The degradation assay can be used to quantify both the on-target degradation-inducing effect and the off-target degradation-inducing effect of compounds such as those provided herein. Exemplary assays include quantitative immunoblotting, other immunoassays (e.g., MesoScale Discovery (MSD) immunoassays), homogeneous time-resolved fluorescence (HTRF), and HiBiT. In some embodiments, cells are contacted with a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, incubated, and then lysates are prepared for gel electrophoresis (e.g., SDS-PAGE), followed by immunoblotting and quantification, and can be compared to a control (e.g., a DMSO-treated control). As another example, a cell line can be engineered to express a HiBiT-tagged BCL-X L protein, and the amount of fluorescence observed upon addition of the complementary LgBiT peptide can be compared between cells treated with a compound of formula (I) or (II), 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. WO 2020 / 163823 and International Publication No. WO 2019 / 144117. In some embodiments, the off-target degradation-inducing effect can be evaluated for protein cysteine dioxygenase 1 (CDO1).

[0134] Also see the assays described in International Publication No. WO 2023 / 044046, International Publication No. WO 2022 / 169780, International Publication No. WO 2021 / 222114, International Publication No. WO 2021 / 146536, International Publication No. WO 2021 / 078301, International Publication No. WO 2021 / 007307, International Publication No. WO 2020 / 163823, International Publication No. WO 2019 / 144117, International Publication No. WO 2017 / 184995, and Khan, et al., Nature Medicine 25.12 (2019): 1938-1947, Balachander, et al., Clinical Cancer Research 26.24 (2020): 6535-6549.

[0135] The binding affinity of the compounds of formula (I) or (II) provided herein, or their pharmaceutically acceptable salts, for BCL-X L can be determined, for example, by the binding IC 50 or K i value (e.g., using a competitive assay), or the K D 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 an FRET pair, and the compounds of formula (I) or (II) provided herein, or their pharmaceutically acceptable salts, can be used as competitors for the BH3-only peptide. See, for example, U.S. Patent Application Publication Nos. 2007 / 0027135, 2010 / 305122, and 2013 / 096120.

[0136] The compounds of formula (I) or (II) provided herein, or their pharmaceutically acceptable salts, bind to BCL-XL The ability to inhibit 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 50 value. One way to measure the inhibition of BCL-X L is to measure the interference with the formation of a complex of BCL-X L 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) 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 the addition of 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 L 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 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) 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.

[0137] The efficacy of degradation by a compound of formula (I) or (II) provided herein, or a pharmaceutically acceptable salt thereof, can be determined by the DC 50 value. As used herein, DC 50 is the concentration of a protein in a cell compared to the concentration of the protein before the cell contacts a compound of formula (I) or (II), or compared to the concentration of the protein in a cell not in contact with a compound of formula (I) or (II) (e.g., BCL-X L protein), and refers to the concentration of a compound of formula (I) or (II) that results in a 50% decrease in the concentration of the 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., using HiBiT detection) in tumor cells that express the BCL-X L protein (e.g., cell lines such as MOLT4, RS4;11, NCI-H146, EJM, HEK293T, HT1080, and / or H929).

[0138] The efficacy of degradation by a compound of formula (I) or (II) provided herein, or a pharmaceutically acceptable salt thereof, can be determined by the EC 50 value. As used herein, EC 50The trough concentration of a protein in a cell, when compared to the concentration of the protein before the cell is contacted with a compound of formula (I) or (II), or when compared to the concentration of the protein in a cell not contacted with a compound of formula (I) or (II), refers to the concentration of a compound of formula (I) or (II) that results in a 50% decrease in the concentration of the protein (e.g., BCL-X L protein). When determined under substantially the same conditions, a compound having a lower EC 50 value is a more potent compound compared to a compound having a higher EC 50 value. In some embodiments, the EC 50 value can be determined in vitro or in vivo (e.g., using HiBiT detection) in tumor cells expressing the BCL-X L protein (e.g., cell lines such as MOLT4, RS4;11, NCI-H146, EJM, HEK293T, HT1080, and / or H929).

[0139] The efficacy of degradation by a compound of formula (I) or (II) provided herein, or a pharmaceutically acceptable salt thereof, can be determined by the Y min value. As used herein, Y min refers to the ratio of the trough concentration of a protein (e.g., BCL-X L protein) in a cell, when compared to the concentration of the protein before the cell is contacted with a compound of formula (I) or (II), or when compared to the concentration of the protein in a cell not contacted with a compound of formula (I) or (II), and is expressed as a percentage. 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 lower Y minCompounds having a value have a higher Y min value and are more potent compounds compared to compounds having a min lower Y value. In some embodiments, the Y L value can be determined in vitro or in vivo (e.g., using HiBiT detection) in tumor cells expressing the BCL-X

[0140] Exemplary assays for determining the efficacy of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, include measuring the effect of a compound of formula (I) or (II), 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 a 3D medium, contacting the cells with a compound of formula (I) or (II), 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), or a pharmaceutically acceptable salt thereof, to the signal from a control experiment (e.g., lacking a compound of formula (I) or (II), 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), or a pharmaceutically acceptable salt thereof, measuring cell proliferation using a suitable reagent (e.g., CELLTITERGLO®), and then comparing the signal from the experiment with a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, to the signal from a control experiment (e.g., lacking a compound of formula (I) or (II), 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, Example B3 and Example B4.

[0141] The cell viability assay can be used to measure the effect of the compounds of formula (I) or (II), or their pharmaceutically acceptable salts, against cell death. For example, cells expressing the BCL-X L protein (e.g., MOLT-4 cells) can be incubated with the compounds of formula (I) or (II), or their pharmaceutically acceptable salts, at various concentrations 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 the compounds of formula (I) or (II), or their pharmaceutically acceptable salts, involves using a competition assay with recombinant BCL-X L protein. For example, purified recombinant affinity-tagged (e.g., His-tagged) BCL-X L protein can be incubated with the compounds of formula (I) or (II), or their pharmaceutically acceptable salts, at various concentrations, 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), or their pharmaceutically acceptable salts. For example, an AlphaLISA competition assay can be performed. See, for example, WO 2019 / 144117.

[0142] An exemplary assay for determining the mechanism of cell death using a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, involves measuring the effect of a compound of formula (I) or (II), 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, 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), or a pharmaceutically acceptable salt thereof, and 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, 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), or a pharmaceutically acceptable salt thereof, and relative caspase activity can be 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 platform for live cell imaging (e.g., the INCUCYTE® SX5 Live-Cell Analysis Instrument). As another example, cells expressing the BCL-X LCells that express a protein (e.g., MOLT-4 cells) can be incubated with compounds of formula (I) or (II) at various concentrations, or their pharmaceutically acceptable salts, and Annexin V positivity can be evaluated using a phosphatidylserine dye (e.g., INCUCYTE® Annexin V Dye), followed by analysis using a live-cell imaging platform (e.g., INCUCYTE® SX5 Live-Cell Analysis Instrument). See, for example, Example B5.

[0143] As another example, the potency and / or efficacy of a compound of formula (I) or (II), or its pharmaceutically acceptable salt, can be evaluated in an animal model, e.g., using a xenograft model (e.g., an established cancer cell line 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 the tumor volume can be 150 - 300 mm 3Once reached, the mice can be randomized into a treatment group and a control group. 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), 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 on a weekly basis. 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 defined as the minimum value of Δ volume for t ≥ 10 days t . The best response between the control arm and the treatment arm can be compared to determine whether the treatment functions better than the control. In some embodiments, tumor samples can also be collected at the end of each study and the levels of relevant proteins (e.g., BCL-X L , BCL-2, MCL-1, BIM, BAX, and / or BAK) can be measured to determine whether the treatment can have a better protein regulation profile compared to the control. In some embodiments, 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 5 days and 6 hours after dosing, relevant proteins can be measured in the tumor samples, and pharmacokinetic studies can be performed on the blood samples or a portion thereof (e.g., plasma).

[0144] 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., BrafA model of 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).

[0145] See, for example, Khan, et al. Nature Medicine 25.12 (2019): 1938-1947, Balachander, et al. Clinical Cancer Research 26.24 (2020): 6535-6549.

[0146] The pharmacokinetic parameters of the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, can be evaluated in an animal model, for example, a mouse model, a rat model, a dog model, or a non-human primate (e.g., cynomolgus monkey) model. 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 compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, 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 compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, 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 before) administering the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. Blood samples can be collected via serial bleeding (e.g., at 8 time points from 0.83 to 24 hours after dosing). At each time point, blood can be collected into a K 2 EDTA tube via a vein (e.g., the saphenous vein) (e.g., approximately 30 μL of blood per time point). The blood samples are placed on wet ice and centrifuged (e.g., at 4600 RPM for 4 minutes) to obtain plasma samples. The plasma samples are diluted (e.g., with an equal volume of pH 3.0 phosphate buffer) and can be 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.

[0147] In some embodiments, %F for a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, is at least 4%. In some embodiments, %F for a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, is at least 10%. In some embodiments, %F for a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, is at least 20%. In some embodiments, %F for a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, is at least 30%. In some embodiments, %F for a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, is at least 40%. In some embodiments, %F for a compound of formula (I) or (II), 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), 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), 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), 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), or a pharmaceutically acceptable salt thereof, is from about 60% to about 80%.

[0148] In some embodiments, the clearance of a compound of formula (I) or (II), 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 of a compound of formula (I) or (II), 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).

[0149] In some embodiments, the AUC of a compound of formula (I) or (II), 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).

[0150] Heterobifunctional degraders can, in some cases, induce the degradation of off-target proteins. For heterobifunctional degraders that utilize VHL, a common off-target protein that can be degraded is CDO1. 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 VHL. CDO1 catalyzes the oxidation of cysteine to cysteine sulfinic acid, and the unwanted degradation can lead to non-specific cytotoxicity.

[0151] In some embodiments, the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, is BCL-X LIt can show effective induction and selective induction of protein degradation. In some embodiments, the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, is 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., CDO1), rather than BCL-X for degradation L The protein can be selectively targeted.

[0152] As used herein, "selective" or "selectively" when referring to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, in a proteolysis assay, refers to at least 5-fold (e.g., at least 10-fold, at least 25-fold, at least 50-fold, or at least 100-fold) superior performance 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 The protein, and the comparator is the BCL-2 protein. For example, when the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, is determined by a degradation assay, it is more BCL-X than the BCL-2 protein L When "selectively" inducing the degradation of the BCL-X 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 the BCL-X protein than for the BCL-2 protein. 50 It has a value.

[0153] 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 proteins), and BCL-X LIt can show potency (e.g., nanomolar potency) against a protein. In some embodiments, the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, is BCL-X L It can show potent degradation of the protein and have minimal potency in the degradation of off-target proteins (e.g., BCL-2 family members (e.g., BCL-2 and / or MCL-1), and / or CDO1) (e.g., when measured by Y min , DC 50 and / or D max values). In some embodiments, the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, can show greater induction of the degradation of BCL-X min , DC 50 and / or D max protein compared to the induction of the degradation of off-target proteins (e.g., BCL-2 family members (e.g., BCL-2 and / or MCL-1), and / or CDO1) (e.g., when measured by Y L values). In some embodiments, the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, can show an induction of the degradation of BCL-X L protein that is at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold greater compared to the induction of the degradation of off-target proteins. In some embodiments, the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, can show an induction of the degradation of BCL-X L protein that is up to 1000-fold greater compared to the induction of the degradation of off-target proteins. In some embodiments, the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, can show an induction of the degradation of BCL-X L protein that is about 2-fold to about 10-fold greater compared to the induction of the degradation of off-target proteins (e.g., CDO1) (e.g., when measured by Y min , DC 50 and / or D maxwhen measured by value). In some embodiments, the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, is about 10-fold to about 100-fold greater in BCL-X L than the induction of off-target protein degradation. In some embodiments, the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, is about 100-fold to about 1000-fold greater in BCL-X L than the induction of off-target protein degradation. In some embodiments, the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, is about 1000-fold to about 10000-fold greater in BCL-X L than the induction of off-target protein degradation.

[0154] BCL-X L Certain agents that inhibit or induce the degradation of BCL-X have demonstrated thrombotoxicity, 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 survival can be monitored using any suitable assay such as those described herein. See, for example, Example B6.

[0155] In some embodiments, when a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, is administered to a subject, it 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, when a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, is administered to a subject, it exhibits about 30% to about 100% platelet survival rate (e.g., about 50% to about 100% platelet survival rate, or about 80% to about 100% platelet survival rate).

[0156] In some embodiments, when a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, is administered to a subject, it 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 about 50% to about 70%. min In some embodiments, when a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, is administered to a subject, it 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, when a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, is administered to a subject, it 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 about 0% to about 50%. min value.

[0157] In some embodiments, when a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, is administered to a subject, it exhibits about 30% to 100% platelet survival rate (e.g., about 50% to about 100% platelet survival rate, or about 80% to about 100% platelet survival rate), and has a Y value of about 50% to about 70%. minhas a value. In some embodiments, a therapeutically effective amount of a compound of formula (I) or (II), 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 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), 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 a Y of about 0% to about 50% min has a value.

[0158] In some embodiments, a therapeutically effective amount of a compound of formula (I) or (II), 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 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), 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 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), 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 a Y of about 0% to about 50% min has a value.

[0159] In some embodiments, a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, when administered to a subject, 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 50% to about 70% minhas a value. In some embodiments, a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, when administered to a subject, 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% min has a value. In some embodiments, a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, when administered to a subject, 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% min has a value.

[0160] In some embodiments, a compound of formula (I) or (II), 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 at least about 30% (e.g., at least about 50% or at least about 80% platelet survival rate). In some embodiments, a compound of formula (I) or (II), 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 30% to about 100% (e.g., about 50% to about 100% or about 80% to about 100% platelet survival rate).

[0161] In some embodiments, a compound of formula (I) or (II), 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 at least about 30% (e.g., at least about 50% or at least about 80% platelet survival rate), and a Y of about 50% to about 70% in the assay described in Example B1 minhas a value. In some embodiments, the compound of formula (I) or (II), 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 less than about 50% of Y in the assay described in Example B1 min has a value. In some embodiments, the compound of formula (I) or (II), 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 from about 0% to about 50% of Y in the assay described in Example B1 min has a value.

[0162] In some embodiments, the compound of formula (I) or (II), 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 from about 30% to 100% platelet viability (e.g., from about 50% to about 100% platelet viability, or from about 80% to about 100% platelet viability), and from about 50% to about 70% of Y in the assay described in Example B1 min has a value. In some embodiments, the compound of formula (I) or (II), 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 from about 30% to 100% platelet viability (e.g., from about 50% to about 100% platelet viability, or from about 80% to about 100% platelet viability), and less than about 50% of Y in the assay described in Example B1 min has a value. In some embodiments, the compound of formula (I) or (II), 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 from about 30% to 100% platelet viability (e.g., from about 50% to about 100% platelet viability, or from about 80% to about 100% platelet viability), and from about 0% to about 50% of Y in the assay described in Example B1min has a value.

[0163] In some embodiments, when the compound of formula (I) or (II), 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 shows at least about 50% platelet viability (e.g., at least about 80% platelet viability), and about 50% to about 70% of Y in the assay described in Example B1 min has a value. In some embodiments, when the compound of formula (I) or (II), 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 shows at least about 50% platelet viability (e.g., at least about 80% platelet viability), and less than about 50% of Y in the assay described in Example B1 min has a value. In some embodiments, when the compound of formula (I) or (II), 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 shows at least about 50% platelet viability (e.g., at least about 80% platelet viability), and about 0% to about 50% of Y in the assay described in Example B1 min has a value.

[0164] In some embodiments, when the compound of formula (I) or (II), 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 shows about 50% to 100% platelet viability (e.g., about 80% to about 100% platelet viability), and about 50% to about 70% of Y in the assay described in Example B1 min has a value. In some embodiments, when the compound of formula (I) or (II), 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 shows about 50% to 100% platelet viability (e.g., about 80% to about 100% platelet viability), and less than about 50% of Y in the assay described in Example B1 minhas a value. In some embodiments, the compound of formula (I) or (II), 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 value of about 0% to about 50% in the assay described in Example B1 min has a value.

[0165] Disclosed herein is a method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is provided. 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.

[0166] Also disclosed herein is a method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as monotherapy is provided. 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.

[0167] Disclosed herein is a method for treating cancer in a subject in need thereof, 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)), and (b) administering to the subject a therapeutically effective amount of a compound of formula (I) or (II), 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

[0168] 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 biomarker associated with cancer (e.g., prior to administration of a compound of formula (I) or (II))), and administering to the subject a therapeutically effective amount of a compound of formula (I) or (II), 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

[0169] Also provided herein is a method of treating cancer in a subject in need thereof, (a) detecting a biomarker associated with cancer (e.g., a mutation, amplification, copy number increase, and / or expression (optionally including expression level) of a biomarker of sensitivity to a particular agent (e.g., HER2 expression, ER expression, PR expression, folate receptor expression)), and (b) administering to the subject a therapeutically effective amount of a compound of formula (I) or (II), 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

[0170] 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 biomarker 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))), A subject is administered a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as a monotherapy or in combination with an additional therapy or therapeutic agent. A method is provided that includes this.

[0171] Provided herein is the use of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment of cancer, for example, any of the cancers provided herein.

[0172] Provided herein is the use of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as a medicament for the treatment of cancer, for example, any of the cancers provided herein.

[0173] Provided herein is the use of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer, for example, any of the cancers provided herein.

[0174] Provided herein are a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use as a medicament. Also provided herein are a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use as a medicament for the treatment of cancer, for example, any of the cancers provided herein.

[0175] Provided herein are a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in the treatment of cancer, for example, any of the cancers provided herein.

[0176] As used herein, "monotherapy" means that when referring to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, the compound of formula (I) or (II), 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., additional targeted chemotherapy agents, anti-cancer agents, chemotherapeutic agents, or checkpoint inhibitors are not administered to the subject during the treatment cycle). As will be understood by those skilled in the art, monotherapy does not exclude the co-administration of pharmaceuticals 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 cutin, fatigue, weight loss, general malaise, shortness of breath, infection, anemia, or gastrointestinal symptoms including nausea, diarrhea, and loss of appetite.

[0177] As used herein, "a subject has previously received one or more therapeutic agents or therapies for cancer" means that the subject has previously been administered 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), or a pharmaceutically acceptable salt thereof, during a previous treatment cycle. In some embodiments, the subject may not be able to tolerate 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 discontinued 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 discontinued response can be determined by the subject's physician.

[0178] As used herein, "the subject is treatment-naive with respect to cancer" means that the subject has not previously been administered one or more therapeutic agents or therapies for cancer.

[0179] 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.

[0180] 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 cancer, neuroblastoma, pheochromocytoma, paraganglioma), multiple endocrine neoplasia type I and type II tumors, parathyroid cancer, pituitary tumor, thyroid cancer (e.g., papillary thyroid cancer)), eye cancer (e.g., uveal cancer (e.g., uveal melanoma)), gastrointestinal cancer (e.g., anal cancer, bile duct cancer (e.g., cholangiocarcinoma (e.g., intrahepatic cholangiocarcinoma)), colorectal cancer (e.g., colon adenocarcinoma, rectal adenocarcinoma, mucinous adenocarcinoma, mucinous carcinoma), esophageal cancer (e.g., esophageal adenocarcinoma), gallbladder cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), liver cancer (e.g., hepatocellular carcinoma, intrahepatic cholangiocarcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma, pancreatic islet cell cancer), 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, endocervical adenocarcinoma, mucinous carcinoma), ovarian cancer (e.g., serous ovarian cancer, ovarian serous cystadenocarcinoma), uterine cancer (e.g., uterine sarcoma, 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-derived AML, myelodysplasia-derived (MDS-derived) 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-derived myelofibrosis, or polycythemia vera-derived myelofibrosis), myelodysplastic syndrome (MDS) (e.g., M6 MDS or M7 MDS), or myeloma (e.g., 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 a combination thereof.

[0181] 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 bladder cancer) 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, MPN-post AML, MDS-post 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, essential thrombocythemia-post myelofibrosis, or polycythemia vera-post 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), lung squamous cell carcinoma, or malignant pleural mesothelioma (MPM)), neuroblastoma, sarcoma (e.g., bone cancer (e.g., osteosarcoma, chondrosarcoma) or soft tissue sarcoma (Ewing sarcoma, leiomyosarcoma, myxofibrosarcoma, rhabdomyosarcoma)), or skin cancer (e.g., melanoma or Merkel cell carcinoma).

[0182] 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.

[0183] 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.

[0184] In some embodiments, the cancer is MDS. In some embodiments, the cancer is M6 MDS. In some embodiments, the cancer is M7 MDS.

[0185] In some embodiments, the cancer is T-ALL. In some embodiments, the cancer is relapsed / refractory T-ALL.

[0186] 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)).

[0187] In some embodiments, the cancer is SCLC (e.g., ASCL1 subtype SCLC or NEUROD1 subtype SCLC).

[0188] 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 amplification NSCLC), KRas mutant NSCLC (e.g., KRas G12C NSCLC)).

[0189] In some embodiments, the cancer is squamous cell lung cancer.

[0190] 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), or a pharmaceutically acceptable salt thereof, is administered as monotherapy.

[0191] In some embodiments, the cancer is melanoma (e.g., Braf mutant melanoma (e.g., Braf V600E melanoma)).

[0192] 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)).

[0193] 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.

[0194] 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 the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, is administered as a monotherapy.

[0195] 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 the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, is administered as a monotherapy.

[0196] 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 the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, is administered as a monotherapy.

[0197] In some embodiments, the cancer is a head and neck cancer.

[0198] In some embodiments, the cancer is essential thrombocythemia.

[0199] In some embodiments, the cancer is polycythemia vera.

[0200] 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.

[0201] 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 the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, is administered as a monotherapy.

[0202] In some embodiments, the cancer is pancreatic cancer.

[0203] In some embodiments, the cancer is bladder cancer (e.g., bladder urothelial cancer).

[0204] 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).

[0205] In some embodiments, the cancer is cervical cancer.

[0206] In some embodiments, the cancer is colorectal cancer.

[0207] 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 the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, is administered as a monotherapy.

[0208] In some embodiments, the cancer is neuroblastoma.

[0209] In some embodiments, the cancer is intrahepatic bile duct cancer.

[0210] In some embodiments, the cancer is a mesenchymal cancer. In some embodiments, the mesenchymal cancer is mesenchymal breast cancer or mesenchymal kidney cancer.

[0211] In some embodiments, BCL-X L copy number increase or BCL-X L amplification can be detected in a sample from a subject (e.g., detecting three or more copies of the BCL2L1 gene in a sample from a subject). In some embodiments, the subject has been determined to have a cancer that has (e.g., prior to administration of a compound of formula (I) or (II)) a BCL-X L copy number increase or BCL-X L amplification.

[0212] In some embodiments, the cancer has a BCL-X L copy number increase.

[0213] In some embodiments, the cancer has a BCL-X L amplification.

[0214] The involvement of BCL-X in cancer L Non-limiting examples of the 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.

[0215] In some embodiments, the subject has been previously treated with another anti-cancer agent, chemotherapeutic agent, radiation, surgery, multi-kinase inhibitor, or combinations thereof.

[0216] Disclosed herein is a method for treating an eye disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof (e.g., intravitreally or topically). Also provided is a method comprising: 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.

[0217] Disclosed herein is the use of a compound of formula (I) or (II), 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.

[0218] Disclosed herein is the use of a compound of formula (I) or (II), 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.

[0219] Disclosed herein is the use of a compound of formula (I) or (II), 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.

[0220] Also provided herein are compounds of formula (I) or (II), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions 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.

[0221] Provided herein are compounds of formula (I) or (II), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in the treatment of an eye disease or condition, such as any of the eye diseases or conditions provided herein.

[0222] Also provided herein is a method of treating a fibrotic disease or condition and / or a disease or condition associated with senescent cells in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof A method is provided that includes. 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, 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. 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.See 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.

[0223] Provided herein is the use of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment of a fibrotic disease or condition, and / or a disease or condition associated with senescent cells, e.g., any of the fibrotic diseases or conditions provided herein, and / or a disease or condition associated with senescent cells.

[0224] Provided herein is the use of a compound of formula (I) or (II), 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.

[0225] Provided herein is the use of a compound of formula (I) or (II), 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.

[0226] Also provided herein are compounds of formula (I) or (II), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use as a medicament for the treatment of any 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.

[0227] Also provided herein are compounds of formula (I) or (II), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in the treatment of any 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.

[0228] Also provided is a method for modulating (e.g., decreasing) BCL-X L protein activity in a cell, comprising contacting the cell with an effective compound of formula (I) or (II), 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), 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.

[0229] 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 compound provided herein with a cell includes, for example, introducing the 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), which includes in vitro or in vivo administration of the compound provided herein to the cell.

[0230] Also provided are methods of modulating (e.g., decreasing) the level of BCL-X protein in a cell, including contacting the cell with a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. L In some embodiments, the level of BCL-X 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 a cell not contacted with a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. In some embodiments, contacting is in vitro. In some embodiments, contacting is in vivo. In some embodiments, contacting is in vivo and the method includes administering to a subject having a cell expressing BCL-X protein an effective amount of a compound of formula (I) or (II), 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 In some embodiments, the level of BCL-X 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 a cell not contacted with a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. In some embodiments, contacting is in vitro. In some embodiments, contacting is in vivo. In some embodiments, contacting is in vivo and the method includes administering to a subject having a cell expressing BCL-X protein an effective amount of a compound of formula (I) or (II), 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 In some embodiments, the level of BCL-X 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 a cell not contacted with a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. In some embodiments, contacting is in vitro. In some embodiments, contacting is in vivo. In some embodiments, contacting is in vivo and the method includes administering to a subject having a cell expressing BCL-X protein an effective amount of a compound of formula (I) or (II), 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.

[0231] Also provided are methods of modulating (e.g., decreasing) the level of BCL-X protein in a cell, including contacting the cell with a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. LA method for inducing ubiquitination of a protein is provided. 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 expressing BCL-X protein an effective amount of a compound of formula (I) or (II), 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.

[0232] Also provided is a method for forming a ternary complex comprising a BCL-X L protein, a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, and a VHL protein or a fragment thereof in a cell, comprising contacting the cell with the compound of formula (I) or (II), 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 expressing BCL-X protein an effective amount of a compound of formula (I) or (II), 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.

[0233] Also provided herein is a method for inhibiting cell proliferation in vitro or in vivo, comprising contacting a cell with an effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as defined herein is provided.

[0234] Furthermore, provided herein is a method for increasing cell death in vitro or in vivo, comprising contacting a cell with an effective amount of a compound of formula (I) or (II), 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), or a pharmaceutically acceptable salt thereof, for increasing tumor cell death. When used as a medicament, the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, can be administered in the form of a pharmaceutical composition described herein.

[0235] Also provided herein is a method for inducing the degradation of BCL-X protein in mammalian cells, comprising

[0236] contacting a mammalian cell with an effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. L A method is provided. contacting a mammalian cell with an effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. A method is provided.

[0237] Also provided herein is a method for treating a subject having cancer, the method comprising administering to a subject who 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), or a pharmaceutically acceptable salt thereof, as monotherapy or in combination with the first anti-cancer agent.

[0238] 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 a subject a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, as monotherapy or in combination with a first anti-cancer agent.

[0239] 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 over a period of time; (b) After (a), administering to the subject a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, as monotherapy or in combination with a second anti-cancer agent.

[0240] Combination In any of the indications described herein, a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, can be used as monotherapy. In some embodiments, a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, can be used before administering an additional therapeutic agent or additional therapy. For example, one or more doses of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, can be administered to a subject in need thereof over 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), or a pharmaceutically acceptable salt thereof, reduces the size (e.g., tumor burden) of the tumor prior to at least partial resection of the tumor.

[0241] In some embodiments, one or more doses of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, can be administered to a subject in need thereof over 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), 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.

[0242] In some embodiments of any of the methods described herein, a compound of formula (I) or (II), 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 treatment (e.g., chemotherapy) agents.

[0243] Non-limiting examples of additional therapies and treatment agents include RAS pathway targeting therapeutic agents (e.g., Ras / RAF / MEK / PI3K pathway inhibitors (e.g., Ras inhibitors (e.g., KRas inhibitors), KRas targeting therapeutic agents, SOS1 inhibitors, SOS1 / Ras protein-protein interaction inhibitors, SHP2 inhibitors, PI3K-AKT-mTOR pathway inhibitors)), kinase targeting 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, farnesyl transferase inhibitors, Hif2α inhibitors, HSP90 inhibitors, PTEN inhibitors, PARP inhibitors, signaling pathway inhibitors, checkpoint inhibitors, modulators of the apoptosis pathway (e.g., BCL-2 inhibitors), chemotherapy, angiogenesis targeting chemotherapy, immunomodulatory imide drugs (sometimes referred to as "IMiD" or "CELMoD") and immunotherapeutic (anti-PD1 therapy or anti-PD-L1 therapy) immunotargeting agents, and radiation therapy.

[0244] 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).

[0245] In some embodiments, the additional therapy or therapeutic agent is an Abl inhibitor (e.g., a BCR-Abl inhibitor), an ALK inhibitor, an AURKA inhibitor, a BCL-2 inhibitor, a Braf inhibitor, a CDK2 inhibitor, a CDK4 / 6 inhibitor, a CDK7 inhibitor, a CDK9 inhibitor, an EGFR inhibitor, an anti-EGFR antibody or anti-EGFR antibody-drug conjugate, an ERK inhibitor, an EZH2 inhibitor, an FGFR1 inhibitor, an FGFR2 inhibitor, an FGFR3 inhibitor, an FGFR4 inhibitor, a HER2 inhibitor, an anti-HER2 antibody or anti-HER2 antibody-drug conjugate, a JAK inhibitor, a KRas inhibitor, a MEK inhibitor, a MET inhibitor, a 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, an 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.

[0246] 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, an immunotherapy (e.g., anti-PD1 therapy or anti-PD-L1 therapy), chemotherapy, radiation therapy, or a combination thereof.

[0247] 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.

[0248] In some embodiments, the ALK inhibitor is alectinib (e.g., alectinib hydrochloride), brigatinib, ceritinib, crizotinib, ensartinib (e.g., ensartinib hydrochloride), enzotrectinib, 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.

[0249] In some embodiments, the AURKA inhibitor is alisertib, danusertib, ilorasertib, tinengotinib, AT-9283, BI-811283, ENMD-2076, or a combination thereof.

[0250] 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.

[0251] 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.

[0252] 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.

[0253] 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.

[0254] 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 a cancer having the BRaf V600E mutation (e.g., prior to administration of a compound of formula (I) or (II)).

[0255] 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., abtemetinib (RO5126766), dabrafenib (e.g., dabrafenib mesylate, GSK2118436), encorafenib (e.g., BRAFTOVI™, LGX818), naporafenib (LXH254), sorafenib (e.g., sorafenib tosylate), vemurafenib (e.g., ZELBORAF®, RO5185426), ARQ-736, AZ304, BMS-908662 (XL281), C17071479-F, CHIR-265 (RAF265), FORE-8394 (PLX-8394), GDC-0879, GDC-5573 (HM95573), HLX-208, PLX-3603, or PLX-4720).In some embodiments, the cancer is a BRaf mutant CRC (e.g., BRaf V600E mutant CRC), and the additional therapy or therapeutic agent is a BRaf inhibitor (e.g., 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 an anti-EGFR antibody or anti-EGFR antibody-drug conjugate (e.g., amivantamab (e.g., amivantamab-vmjw, or a biosimilar thereof), cetuximab (e.g., ERBITUX® (cetuximab), or a biosimilar thereof (e.g., CMAB-009, CPGJ-602, or KL-140)), cetuximab sarotalocan (AKALUX® (cetuximab sarotalocan), or a biosimilar thereof), depatuxizumab, duligotuzumab, futuximab, imgatuzumab, modotuximab, necitumumab (e.g., PORTRAZZA® (necitumumab), or a biosimilar thereof), nimotuzumab (e.g., BIOMAb EGFR® (nimotuzumab), or a biosimilar thereof), panitumumab (e.g., VECTIBIX® (panitumumab), or a biosimilar thereof), tomuzotuximab, zalutumumab, EMD-55900, EMD-82633, GC-1118, HLX-07, ICR-62, SCT-200, SI-B-001, TAS-0313, or 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., abtiromatinib (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., abtiromatinib (RO5126766), dabrafenib (e.g., dabrafenib mesylate, GSK2118436), encorafenib (e.g., BRAFTOVI™, LGX818), naporafenib (LXH254), sorafenib (e.g., sorafenib tosylate), vemurafenib (e.g., ZELBORAF®, RO5185426), ARQ-736, AZ304, BMS-908662 (XL281), C17071479-F, CHIR-265 (RAF265), FORE-8394 (PLX-8394), GDC-0879, GDC-5573 (HM95573), HLX-208, PLX-3603, or PLX-4720), and panitumumab (e.g., VECTIBIX® (panitumumab), or a biosimilar thereof).In some embodiments, the cancer is a BRaf mutant CRC (e.g., BRaf V600E mutant CRC), and the additional therapy or therapeutic agent is dabrafenib (e.g., dabrafenib mesylate, GSK2118436), encorafenib (e.g., BRAFTOVI™, LGX818), or vemurafenib (e.g., ZELBORAF®, RO5185426), and cetuximab (e.g., ERBITUX® (cetuximab), or a biosimilar thereof (e.g., CMAB-009, CPGJ-602, or KL-140)). In some embodiments, the cancer is a BRaf mutant CRC (e.g., BRaf V600E mutant CRC), and the additional therapy or therapeutic agent is dabrafenib (e.g., dabrafenib mesylate, GSK2118436), encorafenib (e.g., BRAFTOVI™, LGX818), or vemurafenib (e.g., ZELBORAF®, RO5185426), and panitumumab (e.g., VECTIBIX® (panitumumab), or a biosimilar thereof). In some embodiments, the cancer is a BRaf mutant CRC (e.g., BRaf V600E mutant CRC), and the additional therapy or therapeutic agent is dabrafenib (e.g., dabrafenib mesylate, GSK2118436), and cetuximab (e.g., ERBITUX® (cetuximab), or a biosimilar thereof (e.g., CMAB-009, CPGJ-602, or KL-140)). In some embodiments, the cancer is a BRaf mutant CRC (e.g., BRaf V600E mutant CRC), and the additional therapy or therapeutic agent is dabrafenib (e.g., dabrafenib mesylate, GSK2118436), and panitumumab (e.g., VECTIBIX® (panitumumab), or a biosimilar thereof).

[0256] 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., abtormetinib (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., abtormetinib, 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.

[0257] 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., abtmetinib (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., abtmetinib (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., abtmetinib, binimetinib, cobimetinib (e.g., cobimetinib fumarate), milademetinib, 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.

[0258] 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.

[0259] In some embodiments, the CDK4 / 6 inhibitor is abemaciclib, birociclib, dalpiciclib, lerociclib, milciclib, palbociclib, ribociclib (e.g., ribociclib succinate), riviciclib, ronidociclib, trilaciclib (e.g., trilaciclib dihydrochloride), FCN-437, TQB-3616, or a combination thereof.

[0260] In some embodiments, the CDK7 inhibitor is milciclib, roscovitine, samuraciclib, or a combination thereof.

[0261] In some embodiments, the CDK9 inhibitor is fadraciclib, riviciclib, ronidociclib, roscovitine, zotiraciclib, AZD-4573, KB-0742, or a combination thereof.

[0262] 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.

[0263] 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, imuganumab, 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, 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, imugatuzumab, 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.

[0264] 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)).

[0265] 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, valitinib, 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).

[0266] 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.

[0267] 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).

[0268] 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).

[0269] 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.

[0270] 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.

[0271] 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.

[0272] 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.

[0273] 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), sanbozelitinib, tucatinib, bavituximab, anti-HER2 antibody or anti-HER2 antibody-drug conjugate, or a combination thereof.

[0274] 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 amevitamab, 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.

[0275] 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 a cancer having a HER2+ status (e.g., prior to administration of a compound of formula (I) or (II)).

[0276] 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)).

[0277] 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)).

[0278] 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)). 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)).

[0279] 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)). 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)).

[0280] 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, teseptamab, tucatinib, vallecitinib, 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., amevitamab, cinrebafusp alfa, copreloximab, disitamab vedotin, ertumaxomab, gantenerumab, 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, or a biosimilar thereof).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).

[0281] 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).

[0282] 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)). 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)).

[0283] In some embodiments, the cancer is MPN - related 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.

[0284] 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., alobresib, apabetalone, mibebresib, pelabresib, toripalib, 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) at, for example, 24 weeks after the start of treatment. 35 ), 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 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), an 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.

[0285] 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.

[0286] 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., by detecting a KRAS gene having a mutation corresponding to the G12C or G12D mutation in the KRas protein, and / or by detecting a KRas protein having a G12C or G12D mutation). In some embodiments, the subject has been determined to have a cancer having a KRas G12C mutation (e.g., prior to administration of a compound of formula (I) or (II)). In some embodiments, the subject has been determined to have a cancer having a KRas G12D mutation (e.g., prior to administration of a compound of formula (I) or (II)).

[0287] 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-varasib (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-varasib. 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.

[0288] In some embodiments, the MEK inhibitor is abtimetinib, binimetinib, cobimetinib (e.g., cobimetinib fumarate), milademetinib, 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.

[0289] 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)).

[0290] 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)).

[0291] 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).

[0292] 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).

[0293] 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), vebrelitinib, 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.

[0294] In some embodiments, the MET alteration can be detected in a sample from a subject (e.g., detecting the MET gene having an alteration (e.g., gene amplification or exon 14 skipping), and / or detecting the MET protein having a mutation (e.g., exon 14 skipping)). In some embodiments, the subject is determined to have cancer having an MET alteration (e.g., prior to administration of a compound of formula (I) or (II)).

[0295] 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, gumartinib, merestinib, pamreticinib, savolitinib, sitravatinib, tepotinib (e.g., tepotinib hydrochloride hydrate), bevreltinib, zanifrelimab (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).

[0296] In some embodiments, the Hif2α inhibitor is belzutifan, AB-521, DFF-332, NKT-2152, PT-2399, or a combination thereof.

[0297] 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.

[0298] 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.

[0299] 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.

[0300] 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.

[0301] In some embodiments, the LSD1 inhibitor is bomedemstat, iadademstat, pulrodemstat, seclidemstat (HCI-2577), vafidemstat, GSK-2879552, INCB-059872, JBI-802, or a combination thereof.

[0302] 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.

[0303] 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).

[0304] In some embodiments, the STING agonist is ulevostinag, ADU-S100, or a combination thereof.

[0305] In some embodiments, the telomerase inhibitor is imetelstat (e.g., imetelstat sodium).

[0306] 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.

[0307] In some embodiments, the VEGFR inhibitor is apatinib, axitinib, cabozantinib (e.g., cabozantinib S-malate), catequentinib (alontinib), cediranib, dovitinib, famitinib, fruquintinib, glesatinib, ibcasertib, irrotinib, 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, zanazantinib, olinvacimab (or its biosimilar), ramucirumab (or its biosimilar), CEP-11981, ENMD-2076, ODM-203, or a combination thereof.

[0308] 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, milcoplatin, 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, the antibody-drug conjugate comprising a microtubule inhibitor is belantamab mafodotin, brentuximab vedotin, cofetuzumab pelidotin, disitamab vedotin, enfortumab vedotin (e.g., enfortumab vedotin-ejfv, or a biosimilar thereof), mirvetuximab soravtansine (e.g., mirvetuximab soravtansine-gynx, or a biosimilar thereof), polatuzumab vedotin, telisotuzumab vedotin, 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, the antibody-drug conjugate comprising a topoisomerase inhibitor is datopotamab deruxtecan, patritumab deruxtecan, sacituzumab govitecan (e.g., sacituzumab govitecan-hziy, or a biosimilar thereof), trastuzumab deruxtecan (fam-trastuzumab deruxtecan-nxki, or a biosimilar thereof), or a combination thereof.In some embodiments, the 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).

[0309] 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.

[0310] In some embodiments, the cancer is NSCLC (e.g., NSCLC with MET amplification), and the additional therapy or therapeutic agent is teprotumumab vedotin.

[0311] 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 an anti-PD1 therapy.

[0312] 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 an anti-PD-L1 therapy.

[0313] In some embodiments, the cancer is lung cancer (e.g., NSCLC), and the additional therapy or therapeutic agent is pemetrexed and an anti-PD1 therapy.

[0314] In some forms, the cancer is lung cancer (e.g., NSCLC), and the additional therapy or therapeutic agent is pemetrexed and anti-PD-L1 therapy.

[0315] 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.

[0316] 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.

[0317] In some embodiments, the cancer is breast cancer (e.g., HER2+ breast cancer (e.g., HER2+ breast cancer with ER expression, HER2+ breast cancer without ER expression), HER2-negative breast cancer (e.g., HER2-negative breast cancer with ER expression, HER2-negative breast cancer without ER expression), triple-negative breast cancer, or HER2-low breast cancer), and the additional therapy or therapeutic agent is a microtubule inhibitor (e.g., cabazitaxel, docetaxel, nab-paclitaxel, or paclitaxel) and anti-PD1 therapy.

[0318] In some embodiments, the cancer is breast cancer (e.g., HER2+ breast cancer (e.g., HER2+ breast cancer with ER expression, HER2+ breast cancer without ER expression), HER2-negative breast cancer (e.g., HER2-negative breast cancer with ER expression, HER2-negative breast cancer without ER expression), triple-negative breast cancer, or HER2-low breast cancer), and the additional therapy or therapeutic agent is a microtubule inhibitor (e.g., cabazitaxel, docetaxel, nab-paclitaxel, or paclitaxel) and anti-PD-L1 therapy.

[0319] 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.

[0320] 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).

[0321] 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).

[0322] 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)).

[0323] 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).

[0324] 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).

[0325] 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))).

[0326] 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).

[0327] 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.

[0328] 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).

[0329] 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).

[0330] 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).

[0331] 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.

[0332] 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.

[0333] 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).

[0334] 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).

[0335] 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).

[0336] In some embodiments, the folate receptor positive state 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 a cancer that is folate receptor positive (e.g., prior to administration of a compound of formula (I) or (II)).

[0337] 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).

[0338] In some embodiments, the immunomodulatory imide drug is thalidomide, lenalidomide, pomalidomide, iberdomid, avadomide, CC-99282, or a combination thereof.

[0339] In some embodiments, the anti-PD1 therapy is balstilimab, budigalimab, cadonilimab, camrelizumab, semiprimab (e.g., semiprimab-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, tripalizumab, volrustomig, vudalimab, zimberelimab, QL-1604, HX-009, INCB-086550, RG-6139, BAT-1306, SG-001, a biosimilar thereof, or a combination thereof.

[0340] In some embodiments, the PD-L1 inhibitor is INCB-086550.

[0341] 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.

[0342] In some embodiments, the additional therapy is radiation therapy.

[0343] 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.

[0344] 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.

[0345] Exemplary descriptions of agents in combination 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.

[0346] Also provided herein is a method of treating cancer, comprising administering to a subject in need thereof, for use simultaneously, separately, or sequentially for the treatment of cancer, (a) a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, and (b) an additional therapeutic agent wherein the amount of the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent together are effective to treat cancer. In some embodiments, the method comprises (c) administering at least one pharmaceutically acceptable carrier.

[0347] These additional therapeutic agents may be administered, according to standard pharmaceutical practice known to those of skill 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), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of formula (I) or (II), 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), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered sequentially in any order as separate dosages in a therapeutically effective amount, for example, daily or intermittently. In some embodiments, the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered simultaneously as a combined dosage.

[0348] Also, in the present specification, (i) a pharmaceutical combination for treating cancer in a subject in need thereof, for use simultaneously, separately, or sequentially for the treatment of cancer, comprising (a) a compound of formula (I) or (II), 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), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are together effective to treat cancer, a pharmaceutical combination; (ii) a pharmaceutical composition comprising such a combination; (iii) the use of such a combination for the preparation of a medicament for the treatment of cancer; and (iv) a commercial package or product comprising such a combination as a combined preparation for simultaneous, separate, or sequential use and 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.

[0349] 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 all or part of the 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 the disease state, delay or slowing of disease progression, remission or palliation of the disease state (e.g., one or more symptoms of the disease), and amelioration (whether partial or total). “Treatment” can also mean prolonging survival as compared to expected survival in the absence of treatment.

[0350] 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.

[0351] In some embodiments, the subject is a pediatric subject.

[0352] 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 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 to less than 1 year of age, from 1 month to less than 4 months of age, from 3 months to less than 7 months of age, from 6 months 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.

[0353] As used herein, the term "prevent" means to delay, in whole or in part, the onset, recurrence, or spread of a disease or condition described herein, or its symptoms.

[0354] The term "regulatory agency" refers to a national agency for approving the medical use of a pharmaceutical agent in a country. For example, a non-limiting example of a regulatory agency is the US Food and Drug Administration (FDA).

[0355] 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, alleviate, 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), 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., body weight), etc., but can nevertheless be routinely determined by one of ordinary skill in the art.

[0356] The term "effective amount" as used herein with respect to a compound of formula (I) or (II) means an amount of the compound that is sufficient to reduce the growth of or kill cells when administered to the cells in vitro or in vivo. The amount of a compound of formula (I) or (II), 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, etc., but can nevertheless be routinely determined by one of ordinary skill in the art.

[0357] Pharmaceutical Compositions and Administration General In some embodiments, a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, is administered as a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof described herein, one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents.

[0358] 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, buffering substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, protamine sulfate, sodium hydrogen phosphate, potassium hydrogen phosphate, salts or electrolytes such as sodium chloride, 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 including 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 being composed 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 skilled in the art. See, for example, Remington: The Science and Practice of Pharmacy, 22 nd Edition (Pharmaceutical Press, London, UK. 2012).

[0359] Route of Administration and Composition Components In some embodiments, the compounds of formula (I) or (II) described herein, or their pharmaceutically acceptable salts, or their pharmaceutical compositions, 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, intratracheobronchial, intrabursal, intracerebral, intracisternal, intracoronary, intradermal, intraluminal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, 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, ureteral, urethral, and vaginal. In certain embodiments, a preferred route of administration is parenteral (e.g., intratumoral).

[0360] In some embodiments, the compounds of formula (I) or (II) described herein, or their pharmaceutically acceptable salts, or their pharmaceutical compositions, 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.

[0361] The compositions can be formulated for parenteral administration, for example, formulated for injection via intravenous, intramuscular, subcutaneous, or even intraperitoneal routes. Typically, such compositions can be prepared as injectables, either as liquid solutions or suspensions. Solid forms suitable for use in preparing solutions or suspensions upon the addition of a liquid prior to injection can also be prepared, and the preparation can be emulsified. The preparation of such formulations is known to those skilled in the art in light of the present disclosure.

[0362] Suitable pharmaceutical forms for use in injections include sterile aqueous solutions or dispersions, preparations 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.

[0363] The carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyols (such as glycerol, propylene glycol, and liquid polyethylene glycols, etc.), suitable mixtures thereof, and vegetable oils. Appropriate fluidity can be maintained, for example, by the use of coatings such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. In many cases, it is preferable to include isotonic agents, for example, sugars or sodium chloride. Sustained absorption of the injectable composition can be brought about by using in the composition agents that delay absorption, for example, aluminum monostearate and gelatin.

[0364] Sterile injectable solutions are prepared by incorporating the required amount of the active compound, along with the various other ingredients enumerated above, into a suitable solvent and, if necessary, subsequently filtering the solution sterilize. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into 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 that yield a powder of the active ingredient plus any additional desired ingredients from their previously sterile-filtered solutions.

[0365] 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.

[0366] 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, cocooyl caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy - metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grape 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.

[0367] In certain embodiments, the suppository is prepared by mixing a compound described herein with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol, or suppository wax, which 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.

[0368] 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., solid or liquid dosage forms).

[0369] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid formulations, the compound is mixed 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) disintegrating agents 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. Solid compositions of the same type 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.

[0370] 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, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives, etc. In another solid dosage form, powders, marume, solutions, or suspensions (e.g., in propylene carbonate, vegetable oils, 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 (or tablets in capsules) having granules of each drug, bilayer tablets, two-compartment gel capsules, etc. Enteric coatings or extended-release oral dosage forms are also contemplated.

[0371] 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.

[0372] In certain embodiments, the excipients are sterile and free of 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.

[0373] In certain embodiments, the solid oral dosage form can further comprise one or more components that make the composition more chemically and / or structurally amenable to uptake by 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.

[0374] Examples include upper GI targeting techniques such as Accordion Pill (Intec Pharma), floating capsules, and materials that can adhere to the mucosal wall.

[0375] Other examples include lower GI targeting techniques. Several enteric / pH-responsive coatings and excipients are available for targeting various regions within the intestinal tract. These materials are typically polymers designed to dissolve or erode within a specific pH range, which is selected based on the desired GI region of drug release. These materials also function to protect acid-labile drugs from gastric fluid or 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.

[0376] 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.)).

[0377] 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 a 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, generally consists 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.

[0378] 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.

[0379] Dosage The dosage can vary depending on the patient's requirements, the severity of the condition being treated, and the specific 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 that provide continuous delivery.

[0380] 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).

[0381] Regimen The aforementioned 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).

[0382] 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 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, then administration of the therapeutic compound is started during a third period, and then administration is 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.

[0383] As used herein, the term "acceptable" with respect to a formulation, composition, or ingredient means having no continuing adverse effect on the general health of the subject being treated.

[0384] "API (active pharmaceutical ingredient)" refers to the active pharmaceutical ingredient.

[0385] 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.

[0386] 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, pharmaceutically acceptable salts are obtained by reacting the compounds described herein with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. In some cases, pharmaceutically acceptable salts are obtained by reacting a compound having an acidic group described herein with a base to form salts such as ammonium salts, alkali metal salts such as sodium salts or potassium salts, alkaline earth metal salts such as calcium salts or magnesium salts, salts of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine and lysine, 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, and specifically, it is 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.

[0387] The term "pharmaceutical composition" refers to a mixture of a compound described herein and other chemical components such as carriers, stabilizers, diluents, dispersants, suspending agents, and / or thickening agents (collectively referred to herein as "excipients"). Pharmaceutical compositions facilitate 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.

[0388] Preparation of the 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 of skill in the art or in light of the teachings herein.

[0389] 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.

[0390] 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.

[0391] TIFF2025516359000077.tif187132

[0392] Scheme 1 shows the synthesis of Compound IA-3, which is a compound of formula (I), wherein R 1 is C(O)OH and L is (L-1) (wherein a3b is 1 and LA3b is C(=O)), the VBM is (V1) defined by formula (I), and each of the remaining variables is defined according to formula (I). Compound IA-1 is reacted with compound I-L1 under standard conditions for Suzuki coupling to obtain compound IA-2, where X A and X T One of is B(OH) 2 or Bpin, and X A and X T The other of is -Br, each of the remaining variables in IA-1 is defined according to formula (I), and each of the remaining variables in IL-1 is defined according to formulas (I) and (L-1). The C 1~2 in IA-2 is hydrolyzed to obtain the corresponding carboxylic acid, which is then reacted with I-V1 under standard conditions for amide bond formation, where each variable in I-V1 is defined according to formula (I). Then, compound IA-3 is obtained by removing the tert-butyl group under standard conditions for deprotection.

Example

[0393] In some of the examples disclosed herein, the final product of the described chemical reaction sequence is structurally shown using an enhanced stereochemical or1 annotation at one stereocenter. In some such examples, in the chemical name of the same compound, this stereocenter is assigned a provisional configuration (e.g., (R)- or (S)-) based on the wedge / dash representation of the structural formula. However, this stereocenter should be understood to have an arrangement consistent with the or1 annotation. Specifically, this stereocenter is resolved but its specific arrangement is not determined. Thus, unless otherwise specified, the starting materials and intermediates leading to this compound incorporate the or1 annotation at this stereocenter despite the provisional assignments provided in their chemical names.

[0394] For example, compound 134b in Example 38 is a single stereoisomer selected from the following. 6-[8-(1,3-Benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[3-[4-[(2R)-4-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-methyl-4-oxo-butyl]phenoxy]-2-methyl-phenyl]pyridine-2-carboxylic acid, and 6-[8-(1,3-Benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[3-[4-[(2S)-4-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-methyl-4-oxo-butyl]phenoxy]-2-methyl-phenyl]pyridine-2-carboxylic acid.

[0395] The intermediate product provided in step A of the same example incorporates the or1 annotation. Thus, it is a single stereoisomer selected from the following. tert-butyl 6-[8-(1,3-Benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[3-[4-[(2R)-4-ethoxy-2-methyl-4-oxo-butyl]phenoxy]-2-methyl-phenyl]pyridine-2-carboxylate, and tert-butyl 6-[8-(1,3-Benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[3-[4-[(2S)-4-ethoxy-2-methyl-4-oxo-butyl]phenoxy]-2-methyl-phenyl]pyridine-2-carboxylate.

[0396] For further clarification, chemical names taking into account the or1 annotation are provided for the final products having an enhanced stereochemical or1 annotation at one stereocenter. This chemical name takes into account the or1 annotation and is enclosed in parentheses (i.e., “[]”). In these chemical names, the prefix “rel” means that the stereochemical configuration indicated in the chemical name is relative. For example, if a compound contains one stereocenter and its chemical name starts with the prefix “rel”, this stereocenter is resolved, but its absolute configuration is either (R)- or (S)-. Since it is such, it should be labeled with an enhanced stereochemical annotation of or1 in its corresponding structure.

[0397] In the chemical name of a compound having two or more stereocenters, when a stereocenter is labeled with an asterisk (“ * ”), the stereocenter labeled with the asterisk is resolved, but its absolute configuration is either (R)- or (S)-. Since it is such, in a chemical name where one stereocenter is labeled with an asterisk, that stereocenter should be labeled with an enhanced stereochemical annotation of or1 in its corresponding structure.

[0398] For example, the chemical name including an asterisk for compound 134b is as follows. [6-(8-(Benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-(4-((R * )-4-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-methyl-4-oxobutyl)phenoxy)-2-methylphenyl)picolinic acid], included in Example 38.

[0399] Example 1. Preparation of Compound 105a 6-(8-(Benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-((6-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-6-oxohexyl)oxy)-2-methylphenyl)picolinate

[0400] Step A. Methyl 6-(3-bromo-2-methylphenoxy)hexanoate TIFF2025516359000078.tif23128

[0401] To a solution of methyl 6-bromohexanoate (5 g, 23.91 mmol, 1 equiv) in ACN (50 mL) were added potassium carbonate (9.92 g, 71.74 mmol, 3 equiv) and 3-bromo-2-methyl-phenol (4.47 g, 23.91 mmol, 1 equiv). The mixture was stirred at 60 °C for 2 h, then the reaction mixture was concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (heptane / ethyl acetate gradient) to give the title compound (12 g, 19.04 mmol, 79.60% yield). 1 H NMR(400MHz,CDCl 3)δ 7.86 (d, J = 7.6 Hz, 1H), 7.74 (dd, J = 7.6, 16.0 Hz, 2H), 7.51 - 7.45 (m, 1H), 7.42 - 7.33 (m, 4H), 7.09 (t, J = 8.0 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 6.70 (d, J = 7.6 Hz, 1H), 5.06 (s, 2H), 4.11 (s, 2H), 4.00 (t, J = 6.0 Hz, 2H), 3.08 (s, 2H), 2.40 (t, J = 7.6 Hz, 2H), 2.11 (s, 3H), 1.83 (d, J = 7.6 Hz, 2H), 1.77 - 1.71 (m, 2H), 1.58 (d, J = 6.8 Hz, 2H), 1.16 - 1.13 (m, 9H).

[0402] Step B. tert-Butyl 6-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-((6-methoxy-6-oxohexyl)oxy)-2-methylphenyl)picolinate TIFF2025516359000079.tif36128

[0403] A solution of methyl 6-(3-bromo-2-methyl-phenoxy)hexanoate (500 mg, 793.14 μmol, 1 equiv) in 1,4-dioxane (5 mL) was added with cataCXium-A-Pd-G3 (115.52 mg, 158.63 μmol, 0.2 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 (485.84 mg, 793.14 μmol, 1 equiv), and an aqueous solution of potassium carbonate (1.5 M, 1.59 mL, 3 equiv). The mixture was heated at 100 °C for 1 h under microwave irradiation and then concentrated under reduced pressure. The residue was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by silica gel chromatography (heptane / ethyl acetate gradient) to give the title compound (450 mg, 603.64 μmol, yield 76.11%). MS(ESI) m / z: 721.7 [M+H] + 。

[0404] Step C. 6-(3-(6-(8-(Benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-(tert-butoxycarbonyl)pyridin-3-yl)-2-methylphenoxy)hexanoic acid TIFF2025516359000080.tif36128

[0405] A solution of tert-butyl 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[3-(6-methoxy-6-oxo-hexyloxy)-2-methyl-phenyl]pyridine-2-carboxylate (400 mg, 554.88 μmol, 1 equiv) in THF (4 mL) was added with lithium hydroxide monohydrate (69.85 mg, 1.66 mmol, 3 equiv) and water (1.00 g, 55.51 mmol, 1 mL, 100.04 equiv). The mixture was stirred at 25 °C for 12 h, then diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with water (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (350 mg, crude), which was used without further purification. 1 H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 7.6 Hz, 1H), 7.74 (dd, J = 7.6, 16.1 Hz, 2H), 7.51 - 7.45 (m, 1H), 7.42 - 7.33 (m, 4H), 7.09 (t, J = 8.0 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 6.70 (d, J = 7.6 Hz, 1H), 5.06 (s, 2H), 4.11 (s, 2H), 4.00 (t, J = 6.0 Hz, 2H), 3.08 (s, 2H), 2.40 (t, J = 7.6 Hz, 2H), 2.11 (s, 3H), 1.83 (d, J = 7.6 Hz, 2H), 1.77 - 1.71 (m, 2H), 1.58 (d, J = 6.8 Hz, 2H), 1.16 - 1.13 (m, 9H).

[0406] Step D. tert-butyl 6-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-((6-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-6-oxohexyl)oxy)-2-methylphenyl)picolinate TIFF2025516359000081.tif49128

[0407] To a solution of 6-[3-[6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-tert-butoxycarbonyl-3-pyridyl]-2-methyl-phenoxy]hexanoic acid (300 mg, 424.42 μmol, 1 eq) in DMF (5 mL) were added HATU (161.38 mg, 424.42 μmol, 1 eq), DIEA (164.56 mg, 1.27 mmol, 221.78 μL, 3 eq), and (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (377.38 mg, 848.84 μmol, 2 eq). The mixture was stirred at 25 °C for 2 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with water (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (450 mg, crude), which was used without further purification. MS (ESI) m / z: 1133.4 [M+H] + 。

[0408] Step E. 6-(8-(Benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-((6-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-6-oxohexyl)oxy)-2-methylphenyl)picolinic acid TIFF2025516359000082.tif47128

[0409] A solution of tert-butyl 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[3-[6-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-6-oxo-hexoxy]-2-methyl-phenyl]pyridine-2-carboxylate (400 mg, 352.91 μmol, 1 eq) in DCM (1 mL) was treated with TFA (402.4 mg, 3.53 mmol, 270.0 μL, 10 eq). The mixture was stirred at 25 °C for 3 h. The reaction mixture was concentrated under reduced pressure to afford 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 (60 mg, 50.12 μmol, yield 14.20%, purity 90.0%). MS (ESI) m / z: 1077.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.86 - 12.49 (m, 1H), 8.98 (s, 1H), 8.35 (d, J = 7.6 Hz, 1H), 8.03 (d, J = 7.6 Hz, 1H), 8.00 - 7.97 (m, 1H), 7.86 - 7.72 (m, 2H), 7.62 (d, J = 7.2 Hz, 1H), 7.49 - 7.30 (m, 10H), 7.12 - 7.06 (m, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.89 - 6.85 (m, 1H), 6.63 (d, J = 6.8 Hz, 1H), 4.98 (s, 2H), 4.94 - 4.88 (m, 1H), 4.51 (d, J = 9.6 Hz, 1H), 4.45 - 4.35 (m, 1H), 4.24 (s, 1H), 3.99 - 3.88 (m, 4H), 3.66 - 3.50 (m, 2H), 3.03 (t, J = 5.6 Hz, 2H), 2.67 (s, 1H), 2.29 (d, J = 1.2 Hz, 2H), 2.15 (s, 1H), 2.06 - 1.95 (m, 2H), 1.89 (s, 3H), 1.78 - 1.70 (m, 3H), 1.64 - 1.50 (m, 3H), 1.43 (d, J = 8.0 Hz, 2H), 1.37 (d, J = 6.8 Hz, 3H), 0.92 (s, 9H).

[0410] Example 2. Preparation of Compound 10001a 2-(5-(1-((3r,5r,7r)-Adamantan-1-ylmethyl)-5-methyl-1H-pyrazol-4-yl)-6-((10-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-10-oxodecyl)carbamoyl)pyridin-2-yl)-N-(benzo[d]thiazol-2-yl)-1,2,3,4-tetrahydroisoquinoline-8-carboxamide

[0411] Step A. Methyl 10-(3-(1-(adamantan-1-ylmethyl)-5-methyl-1H-pyrazol-4-yl)-6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)picolinamide)decanoate TIFF2025516359000083.tif42128

[0412] To a solution of 3-(1-(adamantan-1-ylmethyl)-5-methyl-1H-pyrazol-4-yl)-6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)picolinic acid (1 g, 1.52 mmol, 1 equiv) in DMF (10 mL) were added methyl 10-aminodecanoate (360.90 mg, 1.52 mmol, 1 equiv, HCl), HATU (577.15 mg, 1.52 mmol, 1 equiv), and DIPEA (588.53 mg, 4.55 mmol, 793.17 μL, 3 equiv) at 25 °C. The reaction mixture was stirred at 25 °C for 1.5 h and diluted with H 2 O (10 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with NaHCO 3It was washed with saturated aqueous solution (10 mL × 3) and brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain a residue, and this was purified by silica gel chromatography (heptane / ethyl acetate gradient) to obtain the title compound (861 mg, 989.73 μmol, yield 65.20%). MS (ESI) m / z: 842.9 [M+H] + 。

[0413] Step B. 10-(3-(1-(Adamantan-1-ylmethyl)-5-methyl-1H-pyrazol-4-yl)-6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)picolinamide)decanoic acid TIFF2025516359000084.tif42128

[0414] A solution of methyl 10-(3-(1-(adamantan-1-ylmethyl)-5-methyl-1H-pyrazol-4-yl)-6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)picolinamide)decanoate (831 mg, 986.82 μmol, 1 equivalent) in THF (10 mL) and H 2 O (1 mL) was added with LiOH·H2O (124.23 mg, 2.96 mmol, 3 equivalents). The reaction mixture was stirred at 40 °C for 20 hours and then concentrated under reduced pressure to obtain a residue. The residue was suspended in water (5 mL), and the pH was adjusted to about 4 with HCl (aqueous solution). The resulting solid was filtered, washed with water, and dried to obtain the title compound (670 mg, 778.60 μmol, yield 78.90%). MS (ESI) m / z: 828.8 [M+H] + 。

[0415] Engineering C.2-(5-(1-((3r,5r,7r)-Adamantan-1-ylmethyl)-5-methyl-1H-pyrazol-4-yl)-6-((10-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-10-oxodecyl)carbamoyl)pyridin-2-yl)-N-(benzo[d]thiazol-2-yl)-1,2,3,4-tetrahydroisoquinoline-8-carboxamide TIFF2025516359000085.tif69128

[0416] To a solution of 10-(3-(1-(adamantan-1-ylmethyl)-5-methyl-1H-pyrazol-4-yl)-6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)picolinamide)decanoic acid (100.00 mg, 120.76 μmol, 1 equiv) in DMF (1 mL) was added (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (53.69 mg, 120.76 μmol, 1 equiv), HATU (45.92 mg, 120.76 μmol, 1 equiv), and DIPEA (46.82 mg, 362.29 μmol, 63.10 μL, 3 equiv). The reaction mixture was stirred at 25 °C for 16 h and then purified by preparative RP-HPLC (water / acetonitrile having 0.1% formic acid each). The fractions containing the pure product were combined and lyophilized to give the title compound (32.33 mg, 29.18 μmol, yield 19.41%, purity 94.60%). MS (ESI) m / z: 1254.4 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6)δ12.96 - 12.73 (m, 1H), 8.98 (s, 1H), 8.36 (d, J = 8.0 Hz, 1H), 8.09 - 7.96 (m, 2H), 7.82 - 7.72 (m, 2H), 7.60 (d, J = 7.2 Hz, 1H), 7.48 - 7.32 (m, 7H), 7.23 (s, 1H), 6.95 (d, J = 8.8 Hz, 1H), 5.09 (d, J = 3.2 Hz, 1H), 5.00 (s, 2H), 4.95 - 4.89 (m, 1H), 4.52 (d, J = 9.2 Hz, 1H), 4.42 (t, J = 8.0 Hz, 1H), 4.28 (s, 1H), 3.88 (t, J = 5.2 Hz, 2H), 3.67 (s, 2H), 3.60 (s, 1H), 3.01 (t, J = 5.6 Hz, 4H), 2.45 (s, 3H), 2.23 (d, J = 7.2 Hz, 1H), 2.13 - 2.08 (m, 1H), 2.05 (s, 3H), 1.99 (d, J = 8.8 Hz, 1H), 1.91 (s, 3H), 1.80 (d, J = 4.4 Hz, 1H), 1.67 - 1.55 (m, 6H), 1.52 (s, 6H), 1.47 - 1.40 (m, 2H), 1.37 (d, J = 6.8 Hz, 3H), 1.30 - 1.23 (m, 3H), 1.20 - 1.06 (m, 10H), 0.93 (s, 9H).

[0417] Example 3. Preparation of Compound 102a 6 - [8 - (1,3 - benzothiazol - 2 - ylcarbamoyl) - 3,4 - dihydro - 1H - isoquinolin - 2 - yl] - 3 - [1 - [16 - [[(1S) - 1 - [(2S,4R) - 4 - hydroxy - 2 - [[(1S) - 1 - [4 - (4 - methylthiazol - 5 - yl)phenyl]ethyl]carbamoyl]pyrrolidine - 1 - carbonyl] - 2,2 - dimethyl - propyl]amino] - 16 - oxo - hexadecyl] - 3,5 - dimethyl - pyrazol - 4 - yl]pyridine - 2 - carboxylic acid

[0418] Step A. Methyl 16 - (4 - bromo - 3,5 - dimethyl - pyrazol - 1 - yl)hexadecanoate TIFF2025516359000086.tif18128

[0419] Methyl 16-bromohexadecanoate (997.98 mg, 2.86 mmol, 1 equiv) in DMF (5 mL), 4-bromo-3,5-dimethyl-1H-pyrazole (500 mg, 2.86 mmol, 1 equiv), K 2 CO 3 (1.18 g, 8.57 mmol, 3 equiv), Cs 2 CO 3 (930.77 mg, 2.86 mmol, 1 equiv), and KI (47.42 mg, 285.67 μmol, 0.1 equiv) were degassed and purged with nitrogen three times. Then the mixture was stirred at 100 °C for 12 h under a nitrogen atmosphere. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (ethyl acetate / petroleum ether gradient) to give the title compound (1 g, 2.24 mmol, 78.57% yield). MS (ESI) m / z: 445.1 [M+H] + .

[0420] Step B. tert-Butyl 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[1-(16-methoxy-16-oxo-hexadecyl)-3,5-dimethyl-pyrazol-4-yl]pyridine-2-carboxylate TIFF2025516359000087.tif42130

[0421] Methyl 16-(4-bromo-3,5-dimethyl-pyrazol-1-yl)hexadecanoate (542.97 mg, 1.22 mmol, 1.5 equiv) in DCE (2 mL) and 1,4-dioxane (5 mL), 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 (500 mg, 816.27 μmol, 1 equiv), K 3 PO 4A mixture of [1.5 M, 2.07 mL, 3.8 eq] and CataCxium Pd G3 [148.62 mg, 204.07 μmol, 0.25 eq] was degassed and purged three times with nitrogen. The mixture was then stirred at 100 °C for 12 h under a nitrogen atmosphere. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with water (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate gradient) to give the title compound (500 mg, 567.64 μmol, 69.54% yield). MS (ESI) m / z: 849.4 [M+H] + 。

[0422] Step C. 16-(4-(6-(8-(Benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-(tert-butoxycarbonyl)pyridin-3-yl)-3,5-dimethyl-1H-pyrazol-1-yl)hexadecanoic acid TIFF2025516359000088.tif57128

[0423] A mixture of tert-butyl 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[1-(16-methoxy-16-oxo-hexadecyl)-3,5-dimethyl-pyrazol-4-yl]pyridine-2-carboxylate (200 mg, 235.53 μmol, 1 eq) and LiOH (16.92 mg, 706.60 μmol, 3 eq) in THF (1.6 mL), H2O (0.8 mL), and MeOH (0.4 mL) was stirred at 50 °C for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound, which was used without further purification (200 mg, 183.45 μmol, 77.89% yield). MS (ESI) m / z: 835.5 [M+H] + 。

[0424] Engineering D.tert-butyl 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[1-[16-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-16-oxo-hexadecyl]-3,5-dimethyl-pyrazol-4-yl]pyridine-2-carboxylate TIFF2025516359000089.tif72150

[0425] A mixture of 16-[4-[6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-tert-butoxycarbonyl-3-pyridyl]-3,5-dimethyl-pyrazol-1-yl]hexadecanoic acid (150 mg, 179.62 μmol, 1 equiv), (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (95.83 mg, 215.54 μmol, 1.2 equiv), HATU (102.44 mg, 269.43 μmol, 1.5 equiv), and triethylamine (54.53 mg, 538.85 μmol, 75.00 μL, 3 equiv) in DMF (1.5 mL) was stirred at 25 °C for 12 h. The reaction mixture was diluted with 50 mL of water and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound, which was used without further purification (200 mg, 118.26 μmol, 65.84% yield). MS(ESI) m / z: 1261.6 [M+H] + 。

[0426] Engineering E.6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[1-[16-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-16-oxo-hexadecyl]-3,5-dimethyl-pyrazol-4-yl]pyridine-2-carboxylic acid TIFF2025516359000090.tif80128

[0427] TFA (3.08 g, 27.01 mmol, 2.00 mL, 340.81 equivalents) and Tf 2 A mixture of tert-butyl 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[1-[16-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-16-oxo-hexadecyl]-3,5-dimethyl-pyrazol-4-yl]pyridine-2-carboxylate (100 mg, 79.26 μmol, 1 equivalent) in Tf + ; 11H NMR (400 MHz, CDCl3) δ = 8.68 (s, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.47 - 7.39 (m, 6H), 7.39 - 7.35 (m, 3H), 7.31 - 7.30 (m, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.38 - 6.29 (m, 1H), 5.15 (s, 2H), 5.09 (t, J = 7.2 Hz, 1H), 4.71 - 4.64 (m, 1H), 4.57 - 4.50 (m, 2H), 4.20 - 4.15 (m, 1H), 3.99 (t, J = 7.2 Hz, 2H), 3.93 (t, J = 6.0 Hz, 2H), 3.61 - 3.56 (m, 1H), 3.49 - 3.41 (m, 1H), 3.13 (t, J = 6.0 Hz, 2H), 2.63 - 2.55 (m, 1H), 2.52 (s, 3H), 2.14 (t, J = 7.6 Hz, 2H), 2.07 (s, 3H), 2.03 (s, 3H), 1.84 - 1.79 (m, 2H), 1.47 (d, J = 6.8 Hz, 4H), 1.31 (s, 4H), 1.22 (s, 20H), 1.06 (s, 9H).

[0428] Example 4. Preparation of Compound 101a TIFF2025516359000091.tif271286 - [8 - (1,3 - benzothiazol - 2 - ylcarbamoyl) - 3,4 - dihydro - 1H - isoquinolin - 2 - yl] - 3 - [1 - [6 - [[(1S) - 1 - [(2S,4R) - 4 - hydroxy - 2 - [[(1S) - 1 - [4 - (4 - methylthiazol - 5 - yl)phenyl]ethyl]carbamoyl]pyrrolidine - 1 - carbonyl] - 2,2 - dimethyl - propyl]amino] - 6 - oxo - hexyl] - 3,5 - dimethyl - pyrazol - 4 - yl]pyridine - 2 - carboxylic acid

[0429] Procedure for the preparation of methyl 6 - (4 - bromo - 3,5 - dimethyl - pyrazol - 1 - yl)hexanoate 4 - Bromo - 3,5 - dimethyl - 1H - pyrazole (1 g, 5.71 mmol, 1 equiv), methyl 6 - bromohexanoate (2.39 g, 11.43 mmol, 2 equiv), K 2 CO 3(789.63 mg, 5.71 mmol, 1 equiv), and KI (47.42 mg, 285.67 μmol, 0.05 equiv) was degassed and purged three times with N 2 and then the mixture was stirred at 100 °C for 12 h under a N 2 atmosphere. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL × 3). Then the combined organic layers were washed with brine (100 mL × 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether:ethyl acetate = 1:0~0:1). Compound methyl 6-(4-bromo-3,5-dimethyl-pyrazol-1-yl)hexanoate (700 mg, 2.1 mmol, 40.4% yield) was obtained as a yellow oil. MS (ESI) m / z: 303.0 [M+H] + 1 H NMR (400 MHz, CDCl 3 ) δ = 4.05 - 3.95 (m, 2H), 3.68 (s, 3H), 2.32 (t, J = 7.6 Hz, 2H), 2.27 - 2.15 (m, 6H), 1.80 (q, J = 7.6 Hz, 2H), 1.71 - 1.64 (m, 2H), 1.39 - 1.30 (m, 2H).

[0430] Procedure for the preparation of tert-butyl 6-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(6-methoxy-6-oxohexyl)-3,5-dimethyl-1H-pyrazol-4-yl)picolinate Methyl 6-(4-bromo-3,5-dimethyl-pyrazol-1-yl)hexanoate (371.23 mg, 1.22 mmol, 1.5 eq), 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 (500 mg, 816.27 μmol, 1 eq), K 3 PO 4 (1.5 M, 2.07 mL, 3.8 eq), and a mixture of [2-(2-aminophenyl)phenyl]palladium(1+); bis(1-adamantyl)-butyl-phosphane; methanesulfonate (148.62 mg, 204.07 μmol, 0.25 eq) was degassed and purged with N 2 three times, and then the mixture was stirred at 100 °C for 12 h under an N 2 atmosphere. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL × 3), then the combined organic layers were washed with brine (100 mL × 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1 / 0 to 3 / 2). tert-Butyl 6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(6-methoxy-6-oxohexyl)-3,5-dimethyl-1H-pyrazol-4-yl)picolinate (250 mg, 336.1 μmol, yield 41.1%, purity 95.3%) was obtained as a yellow solid. MS(ESI) m / z: 709.4 [M+H] + 1 H NMR(400 MHz, CDCl 3)δ=7.83 - 7.72 (m, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.34 - 7.32 (m, 1H), 7.29 - 7.21 (m, 4H), 7.18 - 7.12 (m, 1H), 6.79 (d, J = 8.8 Hz, 1H), 4.95 (s, 2H), 4.03 - 3.95 (m, 2H), 3.89 (t, J = 7.6 Hz, 2H), 3.59 (s, 3H), 2.98 (t, J = 5.6 Hz, 2H), 2.25 (t, J = 7.6 Hz, 2H), 1.95 (d, J = 10.8 Hz, 6H), 1.79 - 1.71 (m, 2H), 1.59 (d, J = 7.6 Hz, 2H), 1.37 - 1.30 (m, 2H), 1.21 - 1.18 (m, 9H).

[0431] Procedure for the Preparation of C. 6-[4-[6-[8-(1,3-Benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-tert-butoxycarbonyl-3-pyridyl]-3,5-dimethyl-pyrazol-1-yl]hexanoic Acid To a solution of tert-butyl 6-(8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(6-methoxy-6-oxohexyl)-3,5-dimethyl-1H-pyrazol-4-yl)picolinate (200 mg, 282.14 μmol, 1 equiv) in THF (1.5 mL) and water (0.7 mL) was added LiOH (20.27 mg, 846.42 μmol, 3 equiv). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL × 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO 2 , DCM:MeOH = 10:1). Compound 6-[4-[6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-tert-butoxycarbonyl-3-pyridyl]-3,5-dimethyl-pyrazol-1-yl]hexanoic acid (200 mg, 261.6 μmol, yield 92.7%, purity 90.9%) was obtained as a yellow solid. MS(ESI) m / z: 695.2 [M+H] +

[0432] Procedure for the preparation of tert-butyl 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[1-[6-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-6-oxo-hexyl]-3,5-dimethyl-pyrazol-4-yl]pyridine-2-carboxylate A mixture of 6-[4-[6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-tert-butoxycarbonyl-3-pyridyl]-3,5-dimethyl-pyrazol-1-yl]hexanoic acid (100 mg, 143.92 μmol, 1 equiv), (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (76.78 mg, 172.70 μmol, 1.2 equiv), HATU (82.08 mg, 215.88 μmol, 1.5 equiv), and Et 3 N (43.69 mg, 431.75 μmol, 60.09 μL, 3 equiv) was degassed and purged with N 2 three times, and then the mixture was stirred at 25 °C for 12 h under an N 2 atmosphere. Then, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with water (30 mL × 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (SiO 2, and purified by DCM:MeOH = 10:1). tert-Butyl 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[1-[6-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-6-oxo-hexyl]-3,5-dimethyl-pyrazol-4-yl]pyridine-2-carboxylate (100 mg, 62.0 μmol, yield 43.1%, purity 69.6%) was obtained as a white solid. MS(ESI) m / z: 1121.7 [M+H] + 1 H NMR(400 MHz, CDCl 3 ) δ = 8.60 (s, 1H), 7.81 - 7.73 (m, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.34 - 7.14 (m, 9H), 6.81 - 6.74 (m, 1H), 6.42 - 6.27 (m, 1H), 4.99 - 4.91 (m, 2H), 4.69 - 4.61 (m, 1H), 4.50 - 4.38 (m, 6H), 4.03 - 3.94 (m, 2H), 3.91 - 3.82 (m, 2H), 3.56 - 3.45 (m, 1H), 3.03 - 2.92 (m, 2H), 2.34 - 2.26 (m, 1H), 2.28 - 2.22 (m, 3H), 1.95 - 1.88 (m, 6H), 1.75 - 1.52 (m, 6H), 1.42 - 1.34 (m, 3H), 1.18 (s, 9H), 0.96 (s, 9H).

[0433] Procedure for the preparation of step E. 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[1-[6-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-6-oxo-hexyl]-3,5-dimethyl-pyrazol-4-yl]pyridine-2-carboxylic acid CH2 Cl 2 (800 μL) of a mixture of tert-butyl 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[1-[6-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-6-oxo-hexyl]-3,5-dimethyl-pyrazol-4-yl]pyridine-2-carboxylate (80 mg, 71.34 μmol, 1 equivalent) and TFA (1.23 g, 10.81 mmol, 800.00 μL, 151.46 equivalents) was degassed and purged with N 2 and purged with N 2 The mixture was stirred at 25 °C for 2 hours under a N atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC. 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[1-[6-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-6-oxo-hexyl]-3,5-dimethyl-pyrazol-4-yl]pyridine-2-carboxylic acid (4.2 mg, 3.8 μmol, yield 5.3%, purity 95.7%) was obtained as a white solid MS(ESI) m / z: 1065.6 [M+H] + 1 H NMR(400 MHz, CD 3OD) δ = 8.86 (s, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.59 (d, J = 7.2 Hz, 1H), 7.49 - 7.25 (m, 9H), 7.01 (d, J = 9.2 Hz, 1H), 5.06 (s, 3H), 5.01 - 4.96 (m, 2H), 4.62 - 4.53 (m, 2H), 4.41 (s, 1H), 3.99 (d, J = 5.6 Hz, 4H), 3.87 (d, J = 11.2 Hz, 1H), 3.76 - 3.70 (m, 1H), 3.09 (s, 2H), 2.49 - 2.41 (m, 3H), 2.32 - 2.24 (m, 2H), 2.21 - 2.15 (m, 1H), 2.04 (d, J = 18.0 Hz, 6H), 1.84 - 1.75 (m, 2H), 1.67 - 1.53 (m, 3H), 1.49 (br d, J = 6.8 Hz, 3H), 1.36 - 1.28 (m, 3H), 1.07 - 0.93 (m, 9H)

[0434] Example 5. Preparation of Compound 103a TIFF2025516359000092.tif 281286 - [8 - (1,3 - benzothiazol - 2 - ylcarbamoyl) - 3,4 - dihydro - 1H - isoquinolin - 2 - yl] - 3 - [1 - [8 - [[(1S) - 1 - [(2S,4R) - 4 - hydroxy - 2 - [[(1S) - 1 - [4 - (4 - methylthiazol - 5 - yl)phenyl]ethyl]carbamoyl]pyrrolidine - 1 - carbonyl] - 2,2 - dimethyl - propyl]amino] - 8 - oxo - octyl] - 3,5 - dimethyl - pyrazol - 4 - yl]pyridine - 2 - carboxylic acid

[0435] Procedure for the Preparation of Methyl 8 - Bromooctanoate in Step A To a solution of 8 - bromooctanoic acid (10 g, 44.82 mmol, 1 equiv) in MeOH (50 mL), SOCl 2 (6.40 g, 53.79 mmol, 3.90 mL, 1.2 equiv) was added at 0 °C. The mixture was stirred at 65 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was used in the next reaction. Methyl 8 - bromooctanoate (13 g, crude) was obtained as a brown liquid. 11H NMR (400 MHz, CD 3 OD) δ = 3.58 (s, 3H), 3.50 - 3.46 (m, 1H), 3.38 - 3.31 (m, 1H), 2.27 - 2.23 (m, 2H), 1.79 - 1.67 (m, 2H), 1.54 (s, 2H), 1.38 (s, 2H), 1.27 (s, 4H).

[0436] Procedure for the Preparation of Methyl 8-(4-Bromo-3,5-dimethyl-pyrazol-1-yl) octanoate To a solution of 8-bromooctanoate (5 g, 21.09 mmol, 1 equiv) and 4-bromo-3,5-dimethyl-1H-pyrazole (3.69 g, 21.09 mmol, 1 equiv) in DMF (30 mL), K 2 CO 3 (8.74 g, 63.26 mmol, 3 equiv) and KI (175.01 mg, 1.05 mmol, 0.05 equiv) were added. The mixture was stirred at 90 °C for 9 h. The residue was washed with brine (90 mL), extracted with 90 mL of DCM (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0 - 25% ethyl acetate / petroleum ether). Methyl 8-(4-bromo-3,5-dimethyl-pyrazol-1-yl) octanoate (2.2 g, 6.8 mmol, yield 32.3%) was obtained as a yellow oil. MS (ESI) m / z: 332.8 [M + H] + . 1 1H NMR (400 MHz, CDCl 3 ) δ = 3.95 - 3.91 (m, 2H), 3.63 (s, 3H), 2.28 - 2.24 (m, 2H), 2.19 - 2.16 (m, 6H), 1.74 - 1.70 (m, 2H), 1.59 - 1.56 (m, 2H), 1.29 (s, 6H).

[0437] Procedure for the Preparation of tert-Butyl 6-[8-(1,3-Benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[1-(8-methoxy-8-oxooctyl)-3,5-dimethyl-pyrazol-4-yl]pyridine-2-carboxylate Methyl 8-(4-bromo-3,5-dimethyl-pyrazol-1-yl)octanoate (494.81 mg, 1.49 mmol, 1.5 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 (610 mg, 995.84 μmol, 1 equiv), and K 3 PO 4 (1.5 M, 2.52 mL, 3.8 equiv) in a mixture of [2-(2-aminophenyl)phenyl]palladium(1+); bis(1-adamantyl)-butyl-phosphane; methanesulfonate (181.31 mg, 248.96 μmol, 0.25 equiv), and DCE (2 mL) were added. The reaction mixture was degassed and purged 3 times with N 2 and then the mixture was stirred at 100 °C for 9 h under N 2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1 / 0 to 2 / 1). tert-Butyl 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[1-(8-methoxy-8-oxooctyl)-3,5-dimethyl-pyrazol-4-yl]pyridine-2-carboxylate (355 mg, 481.7 μmol, 48.3% yield) was obtained as a yellow solid. MS(ESI) m / z: 738.5 [M+H] + . 1 H NMR (400 MHz, CDCl 3)δ 7.83 - 7.72 (m, 1H), 7.51 - 7.44 (m, 1H), 7.40 - 7.32 (m, 1H), 7.30 - 7.21 (m, 4H), 7.17 - 7.09 (m, 1H), 6.79 (d, J = 8.8 Hz, 1H), 5.03 - 4.88 (m, 2H), 4.03 - 3.96 (m, 2H), 3.87 (t, J = 7.6 Hz, 2H), 3.58 (s, 3H), 3.01 - 2.97 (m, 2H), 2.23 (t, J = 7.6 Hz, 2H), 1.98 - 1.90 (m, 6H), 1.70 (d, J = 7.2 Hz, 2H), 1.56 (s, 5H), 1.27 (s, 4H), 1.23 - 1.17 (m, 9H)

[0438] Procedure for the Preparation of D.8-[4-[6-[8-(1,3-Benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-tert-butoxycarbonyl-3-pyridyl]-3,5-dimethyl-pyrazol-1-yl]octanoic Acid To a solution of tert-butyl 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[1-(8-methoxy-8-oxo-octyl)-3,5-dimethyl-pyrazol-4-yl]pyridine-2-carboxylate (200 mg, 271.40 μmol, 1 eq) in THF (10 mL) was added LiOH·H 2 O (19.50 mg, 814.20 μmol, 3 eq), water (1 mL), and MeOH (1 mL). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO 2 , ethyl acetate / petroleum ether = 2:1). 8-[4-[6-[8-(1,3-Benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-tert-butoxycarbonyl-3-pyridyl]-3,5-dimethyl-pyrazol-1-yl]octanoic acid (136 mg, 188.1 μmol, 69.3% yield) was obtained as a yellow solid. MS(ESI) m / z: 723.4 [M + H] + . 11H NMR (400 MHz, CDCl 3 ) δ = 7.75 - 7.72 (m, 1H), 7.46 (d, J = 7.2 Hz, 1H), 7.24 - 7.21 (m, 3H), 7.19 (s, 2H), 7.16 - 7.13 (m, 1H), 6.72 (d, J = 8.8 Hz, 1H), 5.23 (s, 1H), 4.81 - 4.77 (m, 1H), 4.08 - 4.03 (m, 1H), 3.93 - 3.82 (m, 4H), 2.97 (t, J = 5.2 Hz, 2H), 1.96 (d, J = 12.8 Hz, 6H), 1.88 (s, 3H), 1.66 (s, 3H), 1.40 - 1.36 (m, 2H), 1.19 - 1.15 (m, 8H), 1.11 (s, 9H).

[0439] Procedure for the preparation of tert-butyl 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[1-[8-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-8-oxo-octyl]-3,5-dimethyl-pyrazol-4-yl]pyridine-2-carboxylate To a solution of 8-[4-[6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-tert-butoxycarbonyl-3-pyridyl]-3,5-dimethyl-pyrazol-1-yl]octanoic acid (100 mg, 138.33 μmol, 1 equiv) in DMF (1 mL) were added HATU (78.90 mg, 207.50 μmol, 1.5 equiv) and TEA (41.99 mg, 415.00 μmol, 57.76 μL, 3 equiv). The mixture was stirred at 25 °C for 0.5 h, then (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (73.80 mg, 166.00 μmol, 1.2 equiv) was added to the mixture. The mixture was stirred at 25 °C for 8.5 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC. tert-Butyl 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[1-[8-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-8-oxo-octyl]-3,5-dimethyl-pyrazol-4-yl]pyridine-2-carboxylate (77 mg, 66.9 μmol, yield 48.4%) was obtained as a yellow solid. MS(ESI) m / z: 575.7 [M+2H / 2] + 。 1 H NMR(400MHz, CDCl 3)δ=8.68(s,1H),7.86(d,J=7.6Hz,1H),7.69-7.67(m,1H),7.58(d,J=7.6Hz,1H),7.40-7.31(m,10H),6.86(d,J=8.8Hz,1H),6.19-6.15(m,1H),5.09(t,J=7.2Hz,1H),5.04(s,2H),4.77-4.73(m,1H),4.59-4.52(m,2H),4.16-4.04(m,5H),3.95(t,J=7.6Hz,2H),3.60-3.56(m,1H),3.07(t,J=5.6Hz,2H),2.52(s,3H),2.30-2.15(m,3H),2.05-2.02(m,9H),1.77-1.61(m,11H),1.47(d,J=6.8Hz,3H),1.27(s,9H),1.04(s,9H).

[0440] Procedure for the preparation of F.6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[1-[8-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-8-oxo-octyl]-3,5-dimethyl-pyrazol-4-yl]pyridine-2-carboxylic acid CH 2 Cl 2A solution of tert-butyl 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[1-[8-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-8-oxo-octyl]-3,5-dimethyl-pyrazol-4-yl]pyridine-2-carboxylate (50 mg, 43.50 μmol, 1 eq) in (0.5 mL) was added with TFA (770.00 mg, 6.75 mmol, 0.5 mL, 155.25 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC. 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[1-[8-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-8-oxo-octyl]-3,5-dimethyl-pyrazol-4-yl]pyridine-2-carboxylic acid (23.4 mg, 21.1 μmol, yield 48.6%, purity 98.8%) was obtained as a white solid. MS(ESI) m / z: 1094.4 [M+H] + 。 1 H NMR(400 MHz, CDCl 3)δ=8.66(d, J = 4.0Hz, 1H), 7.87 - 7.84(m, 1H), 7.65 - 7.58(m, 2H), 7.50 - 7.32(m, 9H), 7.01(d, J = 8.8Hz, 1H), 6.30 - 6.27(m, 1H), 5.15(s, 2H), 5.11 - 5.08(m, 1H), 4.72 - 4.68(m, 1H), 4.64 - 4.60(m, 1H), 4.52 - 4.51(m, 1H), 4.16 - 4.08(m, 1H), 4.03 - 3.91(m, 4H), 3.60 - 3.56(m, 1H), 3.11(t, J = 6.0Hz, 2H), 2.51 - 2.44(m, 4H), 2.25 - 2.02(m, 10H), 1.90 - 1.76(m, 4H), 1.49(d, J = 6.8Hz, 4H), 1.29(s, 7H), 1.03(s, 9H).

[0441] Example 6. Preparation of Compound 104a TIFF2025516359000093.tif731286 - [8-(1,3-Benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[1-[14-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-14-oxo-tetradecyl]-3,5-dimethyl-pyrazol-4-yl]pyridine-2-carboxylic acid

[0442] Procedure for the Preparation of Methyl 14-Hydroxytetradecanoate in Step A To a solution of 14-hydroxytetradecanoic acid (4 g, 16.37 mmol, 1 equiv) in DMF (40 mL), K 2 CO 3 (6.79 g, 49.11 mmol, 3 equiv) was added, then MeI (3.49 g, 24.55 mmol, 1.53 mL, 1.5 equiv) was added, and the mixture was stirred at 80 °C for 4 h under N 2 atmosphere. The reaction mixture was saturated with NH 4It was quenched with Cl (6 mL), and then extracted with 45 mL (15 mL × 3) of ethyl acetate. The combined organic layers were washed with 18 mL (6 mL × 3) of brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain methyl 14-hydroxytetradecanoate (4.6 g, crude product) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ = 3.67 - 3.53 (m, 3H), 3.05 - 2.76 (m, 2H), 2.45 - 2.05 (m, 2H), 1.63 - 1.41 (m, 4H), 1.20 (d, J = 7.6 Hz, 10H), 0.80 - 0.42 (m, 8H)

[0443] Step B. Procedure for the preparation of methyl 14-(p-toluenesulfonyloxy)tetradecanoate A mixture of methyl 14-hydroxytetradecanoate (2.62 g, 10.14 mmol, 1 equivalent), DMAP (619.36 mg, 5.07 mmol, 0.5 equivalent), and TEA (3.08 g, 30.42 mmol, 4.23 mL, 3 equivalents) in DCM (26.2 mL) was degassed and purged with N 2 three times, and then 4-methylbenzenesulfonyl chloride (3.87 g, 20.28 mmol, 2 equivalents) was added at 0 °C. The mixture was stirred at 25 °C for 4 hours under an N 2 atmosphere. The residue was diluted with water (25 mL) and extracted with 75 mL of DCM (25 mL × 3). The combined organic layers were washed with 60 mL (20 mL × 3) of brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 30 / 1 to 20 / 1) to obtain methyl 14-(p-toluenesulfonyloxy)tetradecanoate (3.3 g, 8.0 mmol, yield 79.8%) as a yellow oil. 1 H NMR (400 MHz, CDCl 3) δ = 7.72 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 3.95 (t, J = 6.4 Hz, 2H), 3.59 (s, 3H), 2.38 (s, 3H), 2.24 - 2.22 (s, 2H), 1.57 - 1.51 (m, 6H), 1.22 - 1.21 (m, 16H).

[0444] Procedure for the preparation of methyl 14 - bromotetradecanoate To a solution of methyl 14 - (p - tolylsulfonyloxy)tetradecanoate (2.7 g, 6.54 mmol, 1 eq) in acetone (50 mL) was added LiBr (5.68 g, 65.44 mmol, 1.64 mL, 10 eq). The mixture was stirred at 70 °C for 12 h. The reaction mixture was filtered, concentrated under reduced pressure to remove acetone, and then extracted with ethyl acetate (60 mL, 20 mL × 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 14 - bromotetradecanoate (2 g, crude) as a brown oil. 1 H NMR (400 MHz, CDCl 3 ) δ = 3.60 (s, 3H), 3.34 (t, J = 6.8 Hz, 2H), 2.25 - 2.21 (m, 2H), 1.82 - 1.73 (m, 2H), 1.54 (d, J = 7.2 Hz, 2H), 1.34 (d, J = 7.6 Hz, 2H), 1.22 - 1.19 (m, 16H).

[0445] Procedure for the preparation of methyl 14 - (4 - bromo - 3,5 - dimethyl - pyrazol - 1 - yl)tetradecanoate To a solution of methyl 14 - bromotetradecanoate (2 g, 6.22 mmol, 1 eq) and 4 - bromo - 3,5 - dimethyl - 1H - pyrazole (1.09 g, 6.22 mmol, 1 eq) in DMF (20 mL) was added K 2 CO 3(2.58 g, 18.67 mmol, 3 equiv) and KI (51.67 mg, 311.24 μmol, 0.05 equiv) were added. The mixture was stirred at 90 °C for 6 h. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (60 mL, 20 mL×3). The combined organic layers were washed with brine (45 mL, 15 mL×3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1 / 0 - 0 / 1) to give methyl 14-(4-bromo-3,5-dimethyl-pyrazol-1-yl)tetradecanoate (1.35 g, 3.1 mmol, 50.9% yield, 97.5% purity) as a brown oil. MS (ESI) m / z: 416.5 [M+H] + .

[0446] Procedure for the preparation of tert-butyl 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[1-(14-methoxy-14-oxo-tetradecyl)-3,5-dimethyl-pyrazol-4-yl]pyridine-2-carboxylate To a solution of methyl 14-(4-bromo-3,5-dimethyl-pyrazol-1-yl)tetradecanoate (0.5 g, 1.20 mmol, 1 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 (884.74 mg, 1.44 mmol, 1.2 equiv) in 1,4-dioxane (8 mL) and water (2 mL), K 3 PO 4(766.49 mg, 3.61 mmol, 3 eq) and [2-(2-aminophenyl)phenyl]palladium(1+); bis(1-adamantyl)-butyl-phosphane; methanesulfonate (87.66 mg, 120.36 μmol, 0.1 eq) were added. The mixture was stirred at 100 °C for 9 h to obtain a brown solution. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC to give tert-butyl 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[1-(14-methoxy-14-oxo-tetradecyl)-3,5-dimethyl-pyrazol-4-yl]pyridine-2-carboxylate (0.2 g, 238.7 μmol, yield 19.8%, purity 98%) as a brown oil. MS(ESI) m / z: 821.3 [M+H] + 。 1 H NMR(400 MHz, CDCl 3 ) δ = 7.84 (d, J = 7.6 Hz, 1H), 7.57 - 7.54 (m, 1H), 7.39 - 7.37 (m, 1H), 7.35 - 7.21 (m, 4H), 7.18 - 7.10 (m, 1H), 6.87 (d, J = 8.8 Hz, 1H), 5.00 (s, 2H), 4.09 - 4.05 (m, 2H), 3.99 - 3.94 (m, 2H), 3.67 (s, 3H), 3.07 - 3.04 (m, 2H), 2.33 - 2.28 (m, 2H), 2.05 - 2.02 (d, J = 12.0 Hz, 6H), 1.78 (d, J = 6.8 Hz, 2H), 1.64 - 1.61 (m, 2H), 1.36 - 1.25 (m, 27H).

[0447] Step F. Procedure for the preparation of 14-[4-[6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-tert-butoxycarbonyl-3-pyridyl]-3,5-dimethyl-pyrazol-1-yl]tetradecanoic acid A solution of tert-butyl 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[1-(14-methoxy-14-oxo-tetradecyl)-3,5-dimethyl-pyrazol-4-yl]pyridine-2-carboxylate (0.2 g, 243.58 μmol, 1 equiv) in THF (2 mL) and water (0.5 mL) was added with LiOH·H 2 O (204.41 mg, 4.87 mmol, 20 equiv). The mixture was stirred at 25 °C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give 14-[4-[6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-tert-butoxycarbonyl-3-pyridyl]-3,5-dimethyl-pyrazol-1-yl]tetradecanoic acid (0.2 g, crude) as a brown gum. MS (ESI) m / z: 807.4 [M+H] + .

[0448] Procedure for the preparation of tert-butyl 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[1-[14-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-14-oxo-tetradecyl]-3,5-dimethyl-pyrazol-4-yl]pyridine-2-carboxylate A solution of 14-[4-[6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-tert-butoxycarbonyl-3-pyridyl]-3,5-dimethyl-pyrazol-1-yl]tetradecanoic acid (0.2 g, 247.82 μmol, 1 equiv) and (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (110.18 mg, 247.82 μmol, 1 equiv) in DMF (2 mL) was added with HATU (141.34 mg, 371.72 μmol, 1.5 equiv) and DIPEA (96.08 mg, 743.45 μmol, 129.49 μL, 3 equiv). The mixture was stirred at 25 °C for 2 h to obtain a brown solution. The reaction mixture was quenched with water (3 mL) and extracted with ethyl acetate 9 mL (3 mL × 3). The combined organic layers were washed with brine 9 mL (3 mL × 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (eluent: 0 - 20% MeOH / DCM) to obtain tert-butyl 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[1-[14-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-14-oxo-tetradecyl]-3,5-dimethyl-pyrazol-4-yl]pyridine-2-carboxylate (70 mg, 52.4 μmol, yield 21.1%, purity 92.4%) as a brown oil. MS(ESI) m / z: 1234.5 [M+H] + 。 1 H NMR(400MHz,CDCl 3)δ = 8.69 (s, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.43 - 7.41 (m, 4H), 7.40 - 7.34 (m, 4H), 6.86 (d, J = 8.8 Hz, 1H), 6.34 - 6.22 (m, 1H), 5.32 (s, 1H), 5.13 - 4.99 (m, 3H), 4.70 (s, 1H), 4.60 - 4.52 (m, 2H), 4.22 - 4.14 (m, 1H), 4.08 (s, 2H), 4.03 - 3.94 (m, 2H), 3.60 (dd, J = 3.2, 10.8 Hz, 1H), 3.08 (t, J = 5.2 Hz, 2H), 2.63 - 2.57 (m, 1H), 2.56 - 2.53 (m, 3H), 2.19 (s, 2H), 2.07 (s, 3H), 2.04 (s, 3H), 1.80 (dd, J = 1.6, 3.2 Hz, 2H), 1.49 (d, J = 6.8 Hz, 5H), 1.31 - 1.23 (m, 27H), 1.07 (s, 9H).

[0449] Procedure for the preparation of Project H. 6 - [8 - (1,3 - benzothiazol - 2 - ylcarbamoyl) - 3,4 - dihydro - 1H - isoquinolin - 2 - yl] - 3 - [1 - [14 - [[(1S) - 1 - [(2S,4R) - 4 - hydroxy - 2 - [[(1S) - 1 - [4 - (4 - methylthiazol - 5 - yl)phenyl]ethyl]carbamoyl]pyrrolidine - 1 - carbonyl] - 2,2 - dimethyl - propyl]amino] - 14 - oxo - tetradecyl] - 3,5 - dimethyl - pyrazol - 4 - yl]pyridine - 2 - carboxylic acid A solution of tert-butyl 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[1-[14-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-14-oxo-tetradecyl]-3,5-dimethyl-pyrazol-4-yl]pyridine-2-carboxylate (50 mg, 40.53 μmol, 1 equiv) in TFA (0.5 mL) and DCM (1 mL) was stirred at 25 °C for 3 h to obtain a brown solution. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC to give 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[1-[14-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-14-oxo-tetradecyl]-3,5-dimethyl-pyrazol-4-yl]pyridine-2-carboxylic acid (18.6 mg, 15.6 μmol, yield 38.7%, purity 98.9%) as a yellow solid. MS(ESI) m / z: 1178.1 [M+H] + 。 1 H NMR(400 MHz, CD 3OD) δ = 8.87 (s, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.64 - 7.58 (m, 1H), 7.49 - 7.33 (m, 9H), 7.08 (d, J = 8.8 Hz, 1H), 5.09 (s, 2H), 5.04 - 4.97 (m, 1H), 4.64 - 4.59 (m, 1H), 4.56 (t, J = 8.4 Hz, 1H), 4.42 (s, 1H), 4.06 - 3.97 (m, 4H), 3.87 (d, J = 11.2 Hz, 1H), 3.74 (dd, J = 4.0, 11.2 Hz, 1H), 3.16 - 3.05 (m, 2H), 2.50 - 2.42 (m, 3H), 2.31 - 2.21 (m, 2H), 2.20 - 2.14 (m, 1H), 2.05 (d, J = 16.4 Hz, 6H), 2.00 - 1.91 (m, 1H), 1.82 - 1.74 (m, 2H), 1.62 - 1.56 (m, 2H), 1.50 (d, J = 7.2 Hz, 3H), 1.29 (s, 18H), 1.06 - 0.99 (m, 9H).

[0450] Example 7. Preparation of Compound 106a TIFF2025516359000094.tif281296-(8-(Benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-((7-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptyl)oxy)-2-methylphenyl)picolinate

[0451] Procedure for the preparation of methyl 7-(3-bromo-2-methyl-phenoxy)heptanoate in Step A To a solution of methyl 7-bromoheptanoate (1.79 g, 8.02 mmol, 1.5 eq) in MeCN (10 mL), K 2 CO 3(2.22 g, 16.04 mmol, 3 eq) and 3-bromo-2-methyl-phenol (1 g, 5.35 mmol, 1 eq) were added. The mixture was stirred at 60 °C for 2 h. The reaction mixture was concentrated under reduced pressure to remove MeCN, and a residue was obtained. The residue was diluted with water (20 mL) and extracted with ethyl acetate 30 mL (10 mL × 3). The combined organic layers were washed with water 15 mL (5 mL × 3) to obtain a residue. The residue was purified by flash silica gel chromatography (eluent of 0 - 38% ethyl acetate / petroleum ether) to obtain methyl 7-(3-bromo-2-methyl-phenoxy)heptanoate (1.8 g, 3.8 mmol, yield 71.5%, purity 70%) as a brown solid.

[0452] Procedure for the preparation of tert-butyl 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[3-(7-methoxy-7-oxo-heptyloxy)-2-methyl-phenyl]pyridine-2-carboxylate Methyl 7-(3-bromo-2-methyl-phenoxy)heptanoate (350 mg, 701.64 μmol, purity 66%, 1 eq), 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 (382.03 mg, 561.31 μmol, purity 90%, 1.2 eq) in 1,4-dioxane (7 mL), Ad 2 nBuP Pd G3 (cataCXium® A Pd G3) (102.20 mg, 140.33 μmol, 0.2 eq), and K 2 CO 3 (1.5 M, 701.64 μL, 1.5 eq) of the mixture was degassed, N 2It was purged three times and then the mixture was stirred at 80 °C for 3 hours. The reaction mixture was concentrated under reduced pressure to remove 1,4-dioxane and a residue was obtained. The residue was diluted with water (3 mL) and extracted with ethyl acetate (20 mL, 10 mL×2). The combined organic layers were washed with water (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product tert-butyl 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[3-(7-methoxy-7-oxo-heptyloxy)-2-methyl-phenyl]pyridine-2-carboxylate (480 mg, crude), which was used in the next step without further purification as a white solid. MS(ESI) m / z: 735.7 [M+H] + 。

[0453] Step C. Procedure for the preparation of 7-[3-[6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-tert-butoxycarbonyl-3-pyridyl]-2-methyl-phenoxy]heptanoic acid tert-Butyl 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[3-(7-methoxy-7-oxo-heptyloxy)-2-methyl-phenyl]pyridine-2-carboxylate (300 mg, 408.22 μmol, 1 equivalent) in THF (2.5 m...

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 ; m2 is 0, m3 is 0, m4 is 0, m5 is 0, L is given by equation (L-2): It is a divalent base, and in the formula, L A3b is C (=O), a3a is 1, L A3a is -O-, a1a and a1b are independent integers between 0 and 5. Here, a1a + a1b is 1, 2, or 3. L A1a and L A1b are independently selected from the group consisting of -CH 2-, -CHR L-, and -C(R L) 2-. L A4, a) C3-10 cycloalkylene or 4-10 member heterocyclene, each of which may be substituted with 1-3 Ra, and b) Phenylene or 5-6 member heteroarylene, each of which may be substituted with 1-3 Ra units. Selected from the group consisting of, bb represents the connection point to VBM, 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, VBM, And, 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) Each of 1 to 6 R 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 However, 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 are each, 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 are selected from the group consisting of: 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, However, L is a compound or a pharmaceutically acceptable salt thereof, provided that it does not contain an adamantylene group.

2. L Ａ１ａ and L Ａ１ｂ Each occurrence is -CH ２ - The compound according to claim 1.

3. L Ａ１ｂ The appearance of one instance of -CHR Ｌ - or -C (R Ｌ ) ２ - and L Ａ１ｂ Each remaining occurrence is -CH ２ - and L Ａ１ａ Each occurrence is -CH ２ - is, The compound according to claim 1.

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

5. L Ａ４ but, 1 to 3 R ａ A 4- to 10-membered heterocyclene which may be substituted with 1 to 3 R ａ 1,4-cyclohexylene which may be substituted with, and 1 to 3 R ａ 1,4-phenylene may be substituted with A compound according to claim 1, selected from the group consisting of the following.

6. L is A compound according to claim 1, selected from the group consisting of, where bb represents a bond site to VBM.

7. 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.

8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

9. A pharmaceutical composition according to claim 8 for use in the treatment of cancer.

10. The pharmaceutical composition according to claim 9, wherein the treatment of cancer comprises administering an additional therapy or therapeutic agent.

11. The pharmaceutical composition according to claim 10, 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 FFFR1 inhibitor, a FFFR2 inhibitor, a FFFR3 inhibitor, a FFFR4 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.

12. The pharmaceutical composition according to claim 11, wherein the additional therapy or therapeutic agent is a JAK inhibitor.

13. The pharmaceutical composition according to claim 9, 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.

14. The pharmaceutical composition according to claim 13, 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.

15. The pharmaceutical composition according to claim 14, wherein the blood cancer is essential thrombocythemia, polycythemia vera, myelofibrosis, or a combination thereof.

16. The pharmaceutical composition according to claim 15, wherein the blood cancer has a JAK2 mutation.

17. The pharmaceutical composition according to claim 16, wherein the JAK2 mutation is JAK2 V617F.

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